COVID-19 Trials Designs and Tools

for Promising Results

4272020 Cytel Inc 1

1 2 3 4 5

The webinar will begin shortly

Panel and presentation order

4272020 Cytel Inc 2

Edward Mills - (Moderator) SVP Cytel

Srinivas Murthy - Critical Care Physician University of British Columbia

amp Co-Chair SOLIDARITY trial from WHO

Craig Rayner - President Integrated Drug Development Certara

Louis Dron - Director Cytel

Kristian Thorlund - SVP Cytel

Randomized Embedded Multifactorial Adaptive

Platform trial for Community-Acquired Pneumonia

Srinivas Murthy

University of British Columbia

Outcomes

Int A1

Int A2

Int A3hellip5

Antibiotic trial

Outcomes

Int B1

Int B2

Macrolide trial

Traditional RCTs ndash serial testing of single hypotheses

REMAP ndash a self-learning system

Randomized Embedded Multifactorial Adaptive Platform

Int C1

Int C2

Steroid usetrial

Outcomes

Empiric antibiotic

Macrolide duration

Steroid use plan

OutcomesEligibility

Adaptive Randomisation

Over 50 sites in 13 countries

wwwremapcaporg

Panel and presentation order

4272020 Cytel Inc 2

Edward Mills - (Moderator) SVP Cytel

Srinivas Murthy - Critical Care Physician University of British Columbia

amp Co-Chair SOLIDARITY trial from WHO

Craig Rayner - President Integrated Drug Development Certara

Louis Dron - Director Cytel

Kristian Thorlund - SVP Cytel

Randomized Embedded Multifactorial Adaptive

Platform trial for Community-Acquired Pneumonia

Srinivas Murthy

University of British Columbia

Outcomes

Int A1

Int A2

Int A3hellip5

Antibiotic trial

Outcomes

Int B1

Int B2

Macrolide trial

Traditional RCTs ndash serial testing of single hypotheses

REMAP ndash a self-learning system

Randomized Embedded Multifactorial Adaptive Platform

Int C1

Int C2

Steroid usetrial

Outcomes

Empiric antibiotic

Macrolide duration

Steroid use plan

OutcomesEligibility

Adaptive Randomisation

Over 50 sites in 13 countries

wwwremapcaporg

Randomized Embedded Multifactorial Adaptive

Platform trial for Community-Acquired Pneumonia

Srinivas Murthy

University of British Columbia

Outcomes

Int A1

Int A2

Int A3hellip5

Antibiotic trial

Outcomes

Int B1

Int B2

Macrolide trial

Traditional RCTs ndash serial testing of single hypotheses

REMAP ndash a self-learning system

Randomized Embedded Multifactorial Adaptive Platform

Int C1

Int C2

Steroid usetrial

Outcomes

Empiric antibiotic

Macrolide duration

Steroid use plan

OutcomesEligibility

Adaptive Randomisation

Over 50 sites in 13 countries

wwwremapcaporg

Outcomes

Int A1

Int A2

Int A3hellip5

Antibiotic trial

Outcomes

Int B1

Int B2

Macrolide trial

Traditional RCTs ndash serial testing of single hypotheses

REMAP ndash a self-learning system

Randomized Embedded Multifactorial Adaptive Platform

Int C1

Int C2

Steroid usetrial

Outcomes

Empiric antibiotic

Macrolide duration

Steroid use plan

OutcomesEligibility

Adaptive Randomisation

Over 50 sites in 13 countries

wwwremapcaporg

Over 50 sites in 13 countries

wwwremapcaporg

REMAP-CAP

bull Randomisedbull Rather than random clinician choice

bull Embeddedbull Recruitment by clinical staff (and or research coordinators)bull Deliver intervention using usual clinical processes

bull Multifactorialbull Simultaneously assess different aspects of treatment

bull Adaptivebull Frequent Bayesian adaptive analysesbull Response adaptive randomizationbull Add subtract domains and intervention

bull Platform Trialbull All ICU patients with CAP included

Pandemic Appendix to Core Protocol

bullPandemic strata designed as a sleeping stratabull Activated by the REMAP-CAP trial steering committee

13 March 2020

bullActivation of Pandemic Strata results in a number of changes to

bull Eligibility criteria

bull Primary end-point

bull Statistical model

bull Frequency of RAR

bull New pandemic-specific domains

Changes to eligibility

Does the patient have clinically suspected or proven pandemic infection

bull Clinically suspected = treating clinician believes that pandemic infection is a likely diagnosis

bull That testing is being done is not sufficient must think pandemic infection is likely

bull Response to this question drives a number of changes to eligibility CRF randomization and primary end-point

bull Suspected or proven hospital-acquired pandemic infection are eligible

Changed definitions

ICU

bull During a pandemic an ICU is defined as an area that is capable of providing ICU-level carebull [NIV with a sealed mask] invasive mechanical ventilation or

vasopressors via continuous infusion

bull Existing wards which provide sealed mask NIV which do not have expanded capabilities do not qualify

bull May be a physical ICU or an area not usually designated as an ICU which has been re-purposed

Primary end-point

Days alive and out of ICU at Day 21

bull Censored at hospital discharge (no need to follow-up after hospital discharge until usual D90)

Statistical Model

bull Domains considered relevant to the pandemic are analyzed using a separate statistical model

bull RAR occurs separately for patients with and without pandemic infection

PISOP patients = Pandemic Infection Suspected or ProvenPINSNP patients = Pandemic Infection Neither Suspected Nor Proven

Analysis and RAR during pandemic

bull Statistical model evaluates all pandemic domainsbull Evaluates patients who are confirmed COVID-19

and not confirmed COVID-19 separately with borrowing between stratum as appropriate

bull Reduction in statistical trigger from 099 to 095 probability of superiority

bull RAR driven off confirmed COVID-19 for future suspected and confirmed patients

bull Assesses safety in suspected patients who turn out to be non-COVID patients

Current Domains in pandemic model

bull Corticosteroid strategybull Sites can choose different set of interventions for

pandemic and non-pandemic patients

bull Macrolide durationbull Important given French uncontrolled case-seriesbull Only accessible if allocated to a beta-lactam + macrolide

combination in antibiotic domain

bull Can still get assignment for antibiotics and antiviral analyzed in non-pandemic statistical model

COVID-19 Specific Domains

bull COVID-19 Antiviral Domainbull No antiviral for COVID-19 (no placebo)

bull Lopinavirritonavir (ldquoKaletrardquo)

bull Hydroxychloroquine

bull COVID-19 Immune Modulation Domainbull No immune modulation for COVID-19 (no placebo)

bull Interferon-β-1a

bull Anakinra (Interleukin-1 receptor antagonist - not available at launch in all regions)

bull Tocilizumab + sarulumab in UK

bull COVID19 Anticoagulationbull Therapeutic Heparin

bull Routine thromboprophylaxis

bull Vitamin C

bull Convalescent Plasma

Consent processes during pandemic

bull Have requested permission to use phone electronic confirmation of agreement to participate from person responsible

bull Verbal consent from participant if competent to consent

Role of DSMB

bull Granted more flexibility

bull Can ask for additional analyses that might be relevant

bull Permitted to contact public health authorities direct with any information that they believe is important to public health response to COVID-19

REMAP-COVID

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

Pandemic Appendix to Core Protocol

bullPandemic strata designed as a sleeping stratabull Activated by the REMAP-CAP trial steering committee

13 March 2020

bullActivation of Pandemic Strata results in a number of changes to

bull Eligibility criteria

bull Primary end-point

bull Statistical model

bull Frequency of RAR

bull New pandemic-specific domains

Changes to eligibility

Does the patient have clinically suspected or proven pandemic infection

bull Clinically suspected = treating clinician believes that pandemic infection is a likely diagnosis

bull That testing is being done is not sufficient must think pandemic infection is likely

bull Response to this question drives a number of changes to eligibility CRF randomization and primary end-point

bull Suspected or proven hospital-acquired pandemic infection are eligible

Changed definitions

ICU

bull During a pandemic an ICU is defined as an area that is capable of providing ICU-level carebull [NIV with a sealed mask] invasive mechanical ventilation or

vasopressors via continuous infusion

bull Existing wards which provide sealed mask NIV which do not have expanded capabilities do not qualify

bull May be a physical ICU or an area not usually designated as an ICU which has been re-purposed

Primary end-point

Days alive and out of ICU at Day 21

bull Censored at hospital discharge (no need to follow-up after hospital discharge until usual D90)

Statistical Model

bull Domains considered relevant to the pandemic are analyzed using a separate statistical model

bull RAR occurs separately for patients with and without pandemic infection

PISOP patients = Pandemic Infection Suspected or ProvenPINSNP patients = Pandemic Infection Neither Suspected Nor Proven

Analysis and RAR during pandemic

bull Statistical model evaluates all pandemic domainsbull Evaluates patients who are confirmed COVID-19

and not confirmed COVID-19 separately with borrowing between stratum as appropriate

bull Reduction in statistical trigger from 099 to 095 probability of superiority

bull RAR driven off confirmed COVID-19 for future suspected and confirmed patients

bull Assesses safety in suspected patients who turn out to be non-COVID patients

Current Domains in pandemic model

bull Corticosteroid strategybull Sites can choose different set of interventions for

pandemic and non-pandemic patients

bull Macrolide durationbull Important given French uncontrolled case-seriesbull Only accessible if allocated to a beta-lactam + macrolide

combination in antibiotic domain

bull Can still get assignment for antibiotics and antiviral analyzed in non-pandemic statistical model

COVID-19 Specific Domains

bull COVID-19 Antiviral Domainbull No antiviral for COVID-19 (no placebo)

bull Lopinavirritonavir (ldquoKaletrardquo)

bull Hydroxychloroquine

bull COVID-19 Immune Modulation Domainbull No immune modulation for COVID-19 (no placebo)

bull Interferon-β-1a

bull Anakinra (Interleukin-1 receptor antagonist - not available at launch in all regions)

bull Tocilizumab + sarulumab in UK

bull COVID19 Anticoagulationbull Therapeutic Heparin

bull Routine thromboprophylaxis

bull Vitamin C

bull Convalescent Plasma

Consent processes during pandemic

bull Have requested permission to use phone electronic confirmation of agreement to participate from person responsible

bull Verbal consent from participant if competent to consent

Role of DSMB

bull Granted more flexibility

bull Can ask for additional analyses that might be relevant

bull Permitted to contact public health authorities direct with any information that they believe is important to public health response to COVID-19

REMAP-COVID

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

Changes to eligibility

Does the patient have clinically suspected or proven pandemic infection

bull Clinically suspected = treating clinician believes that pandemic infection is a likely diagnosis

bull That testing is being done is not sufficient must think pandemic infection is likely

bull Response to this question drives a number of changes to eligibility CRF randomization and primary end-point

bull Suspected or proven hospital-acquired pandemic infection are eligible

Changed definitions

ICU

bull During a pandemic an ICU is defined as an area that is capable of providing ICU-level carebull [NIV with a sealed mask] invasive mechanical ventilation or

vasopressors via continuous infusion

bull Existing wards which provide sealed mask NIV which do not have expanded capabilities do not qualify

bull May be a physical ICU or an area not usually designated as an ICU which has been re-purposed

Primary end-point

Days alive and out of ICU at Day 21

bull Censored at hospital discharge (no need to follow-up after hospital discharge until usual D90)

Statistical Model

bull Domains considered relevant to the pandemic are analyzed using a separate statistical model

bull RAR occurs separately for patients with and without pandemic infection

PISOP patients = Pandemic Infection Suspected or ProvenPINSNP patients = Pandemic Infection Neither Suspected Nor Proven

Analysis and RAR during pandemic

bull Statistical model evaluates all pandemic domainsbull Evaluates patients who are confirmed COVID-19

and not confirmed COVID-19 separately with borrowing between stratum as appropriate

bull Reduction in statistical trigger from 099 to 095 probability of superiority

bull RAR driven off confirmed COVID-19 for future suspected and confirmed patients

bull Assesses safety in suspected patients who turn out to be non-COVID patients

Current Domains in pandemic model

bull Corticosteroid strategybull Sites can choose different set of interventions for

pandemic and non-pandemic patients

bull Macrolide durationbull Important given French uncontrolled case-seriesbull Only accessible if allocated to a beta-lactam + macrolide

combination in antibiotic domain

bull Can still get assignment for antibiotics and antiviral analyzed in non-pandemic statistical model

COVID-19 Specific Domains

bull COVID-19 Antiviral Domainbull No antiviral for COVID-19 (no placebo)

bull Lopinavirritonavir (ldquoKaletrardquo)

bull Hydroxychloroquine

bull COVID-19 Immune Modulation Domainbull No immune modulation for COVID-19 (no placebo)

bull Interferon-β-1a

bull Anakinra (Interleukin-1 receptor antagonist - not available at launch in all regions)

bull Tocilizumab + sarulumab in UK

bull COVID19 Anticoagulationbull Therapeutic Heparin

bull Routine thromboprophylaxis

bull Vitamin C

bull Convalescent Plasma

Consent processes during pandemic

bull Have requested permission to use phone electronic confirmation of agreement to participate from person responsible

bull Verbal consent from participant if competent to consent

Role of DSMB

bull Granted more flexibility

bull Can ask for additional analyses that might be relevant

bull Permitted to contact public health authorities direct with any information that they believe is important to public health response to COVID-19

REMAP-COVID

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

Changed definitions

ICU

bull During a pandemic an ICU is defined as an area that is capable of providing ICU-level carebull [NIV with a sealed mask] invasive mechanical ventilation or

vasopressors via continuous infusion

bull Existing wards which provide sealed mask NIV which do not have expanded capabilities do not qualify

bull May be a physical ICU or an area not usually designated as an ICU which has been re-purposed

Primary end-point

Days alive and out of ICU at Day 21

bull Censored at hospital discharge (no need to follow-up after hospital discharge until usual D90)

Statistical Model

bull Domains considered relevant to the pandemic are analyzed using a separate statistical model

bull RAR occurs separately for patients with and without pandemic infection

PISOP patients = Pandemic Infection Suspected or ProvenPINSNP patients = Pandemic Infection Neither Suspected Nor Proven

Analysis and RAR during pandemic

bull Statistical model evaluates all pandemic domainsbull Evaluates patients who are confirmed COVID-19

and not confirmed COVID-19 separately with borrowing between stratum as appropriate

bull Reduction in statistical trigger from 099 to 095 probability of superiority

bull RAR driven off confirmed COVID-19 for future suspected and confirmed patients

bull Assesses safety in suspected patients who turn out to be non-COVID patients

Current Domains in pandemic model

bull Corticosteroid strategybull Sites can choose different set of interventions for

pandemic and non-pandemic patients

bull Macrolide durationbull Important given French uncontrolled case-seriesbull Only accessible if allocated to a beta-lactam + macrolide

combination in antibiotic domain

bull Can still get assignment for antibiotics and antiviral analyzed in non-pandemic statistical model

COVID-19 Specific Domains

bull COVID-19 Antiviral Domainbull No antiviral for COVID-19 (no placebo)

bull Lopinavirritonavir (ldquoKaletrardquo)

bull Hydroxychloroquine

bull COVID-19 Immune Modulation Domainbull No immune modulation for COVID-19 (no placebo)

bull Interferon-β-1a

bull Anakinra (Interleukin-1 receptor antagonist - not available at launch in all regions)

bull Tocilizumab + sarulumab in UK

bull COVID19 Anticoagulationbull Therapeutic Heparin

bull Routine thromboprophylaxis

bull Vitamin C

bull Convalescent Plasma

Consent processes during pandemic

bull Have requested permission to use phone electronic confirmation of agreement to participate from person responsible

bull Verbal consent from participant if competent to consent

Role of DSMB

bull Granted more flexibility

bull Can ask for additional analyses that might be relevant

bull Permitted to contact public health authorities direct with any information that they believe is important to public health response to COVID-19

REMAP-COVID

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

Primary end-point

Days alive and out of ICU at Day 21

bull Censored at hospital discharge (no need to follow-up after hospital discharge until usual D90)

Statistical Model

bull Domains considered relevant to the pandemic are analyzed using a separate statistical model

bull RAR occurs separately for patients with and without pandemic infection

PISOP patients = Pandemic Infection Suspected or ProvenPINSNP patients = Pandemic Infection Neither Suspected Nor Proven

Analysis and RAR during pandemic

bull Statistical model evaluates all pandemic domainsbull Evaluates patients who are confirmed COVID-19

and not confirmed COVID-19 separately with borrowing between stratum as appropriate

bull Reduction in statistical trigger from 099 to 095 probability of superiority

bull RAR driven off confirmed COVID-19 for future suspected and confirmed patients

bull Assesses safety in suspected patients who turn out to be non-COVID patients

Current Domains in pandemic model

bull Corticosteroid strategybull Sites can choose different set of interventions for

pandemic and non-pandemic patients

bull Macrolide durationbull Important given French uncontrolled case-seriesbull Only accessible if allocated to a beta-lactam + macrolide

combination in antibiotic domain

bull Can still get assignment for antibiotics and antiviral analyzed in non-pandemic statistical model

COVID-19 Specific Domains

bull COVID-19 Antiviral Domainbull No antiviral for COVID-19 (no placebo)

bull Lopinavirritonavir (ldquoKaletrardquo)

bull Hydroxychloroquine

bull COVID-19 Immune Modulation Domainbull No immune modulation for COVID-19 (no placebo)

bull Interferon-β-1a

bull Anakinra (Interleukin-1 receptor antagonist - not available at launch in all regions)

bull Tocilizumab + sarulumab in UK

bull COVID19 Anticoagulationbull Therapeutic Heparin

bull Routine thromboprophylaxis

bull Vitamin C

bull Convalescent Plasma

Consent processes during pandemic

bull Have requested permission to use phone electronic confirmation of agreement to participate from person responsible

bull Verbal consent from participant if competent to consent

Role of DSMB

bull Granted more flexibility

bull Can ask for additional analyses that might be relevant

bull Permitted to contact public health authorities direct with any information that they believe is important to public health response to COVID-19

REMAP-COVID

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

Statistical Model

bull Domains considered relevant to the pandemic are analyzed using a separate statistical model

bull RAR occurs separately for patients with and without pandemic infection

PISOP patients = Pandemic Infection Suspected or ProvenPINSNP patients = Pandemic Infection Neither Suspected Nor Proven

Analysis and RAR during pandemic

bull Statistical model evaluates all pandemic domainsbull Evaluates patients who are confirmed COVID-19

and not confirmed COVID-19 separately with borrowing between stratum as appropriate

bull Reduction in statistical trigger from 099 to 095 probability of superiority

bull RAR driven off confirmed COVID-19 for future suspected and confirmed patients

bull Assesses safety in suspected patients who turn out to be non-COVID patients

Current Domains in pandemic model

bull Corticosteroid strategybull Sites can choose different set of interventions for

pandemic and non-pandemic patients

bull Macrolide durationbull Important given French uncontrolled case-seriesbull Only accessible if allocated to a beta-lactam + macrolide

combination in antibiotic domain

bull Can still get assignment for antibiotics and antiviral analyzed in non-pandemic statistical model

COVID-19 Specific Domains

bull COVID-19 Antiviral Domainbull No antiviral for COVID-19 (no placebo)

bull Lopinavirritonavir (ldquoKaletrardquo)

bull Hydroxychloroquine

bull COVID-19 Immune Modulation Domainbull No immune modulation for COVID-19 (no placebo)

bull Interferon-β-1a

bull Anakinra (Interleukin-1 receptor antagonist - not available at launch in all regions)

bull Tocilizumab + sarulumab in UK

bull COVID19 Anticoagulationbull Therapeutic Heparin

bull Routine thromboprophylaxis

bull Vitamin C

bull Convalescent Plasma

Consent processes during pandemic

bull Have requested permission to use phone electronic confirmation of agreement to participate from person responsible

bull Verbal consent from participant if competent to consent

Role of DSMB

bull Granted more flexibility

bull Can ask for additional analyses that might be relevant

bull Permitted to contact public health authorities direct with any information that they believe is important to public health response to COVID-19

REMAP-COVID

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

Analysis and RAR during pandemic

bull Statistical model evaluates all pandemic domainsbull Evaluates patients who are confirmed COVID-19

and not confirmed COVID-19 separately with borrowing between stratum as appropriate

bull Reduction in statistical trigger from 099 to 095 probability of superiority

bull RAR driven off confirmed COVID-19 for future suspected and confirmed patients

bull Assesses safety in suspected patients who turn out to be non-COVID patients

Current Domains in pandemic model

bull Corticosteroid strategybull Sites can choose different set of interventions for

pandemic and non-pandemic patients

bull Macrolide durationbull Important given French uncontrolled case-seriesbull Only accessible if allocated to a beta-lactam + macrolide

combination in antibiotic domain

bull Can still get assignment for antibiotics and antiviral analyzed in non-pandemic statistical model

COVID-19 Specific Domains

bull COVID-19 Antiviral Domainbull No antiviral for COVID-19 (no placebo)

bull Lopinavirritonavir (ldquoKaletrardquo)

bull Hydroxychloroquine

bull COVID-19 Immune Modulation Domainbull No immune modulation for COVID-19 (no placebo)

bull Interferon-β-1a

bull Anakinra (Interleukin-1 receptor antagonist - not available at launch in all regions)

bull Tocilizumab + sarulumab in UK

bull COVID19 Anticoagulationbull Therapeutic Heparin

bull Routine thromboprophylaxis

bull Vitamin C

bull Convalescent Plasma

Consent processes during pandemic

bull Have requested permission to use phone electronic confirmation of agreement to participate from person responsible

bull Verbal consent from participant if competent to consent

Role of DSMB

bull Granted more flexibility

bull Can ask for additional analyses that might be relevant

bull Permitted to contact public health authorities direct with any information that they believe is important to public health response to COVID-19

REMAP-COVID

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

Current Domains in pandemic model

bull Corticosteroid strategybull Sites can choose different set of interventions for

pandemic and non-pandemic patients

bull Macrolide durationbull Important given French uncontrolled case-seriesbull Only accessible if allocated to a beta-lactam + macrolide

combination in antibiotic domain

bull Can still get assignment for antibiotics and antiviral analyzed in non-pandemic statistical model

COVID-19 Specific Domains

bull COVID-19 Antiviral Domainbull No antiviral for COVID-19 (no placebo)

bull Lopinavirritonavir (ldquoKaletrardquo)

bull Hydroxychloroquine

bull COVID-19 Immune Modulation Domainbull No immune modulation for COVID-19 (no placebo)

bull Interferon-β-1a

bull Anakinra (Interleukin-1 receptor antagonist - not available at launch in all regions)

bull Tocilizumab + sarulumab in UK

bull COVID19 Anticoagulationbull Therapeutic Heparin

bull Routine thromboprophylaxis

bull Vitamin C

bull Convalescent Plasma

Consent processes during pandemic

bull Have requested permission to use phone electronic confirmation of agreement to participate from person responsible

bull Verbal consent from participant if competent to consent

Role of DSMB

bull Granted more flexibility

bull Can ask for additional analyses that might be relevant

bull Permitted to contact public health authorities direct with any information that they believe is important to public health response to COVID-19

REMAP-COVID

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

COVID-19 Specific Domains

bull COVID-19 Antiviral Domainbull No antiviral for COVID-19 (no placebo)

bull Lopinavirritonavir (ldquoKaletrardquo)

bull Hydroxychloroquine

bull COVID-19 Immune Modulation Domainbull No immune modulation for COVID-19 (no placebo)

bull Interferon-β-1a

bull Anakinra (Interleukin-1 receptor antagonist - not available at launch in all regions)

bull Tocilizumab + sarulumab in UK

bull COVID19 Anticoagulationbull Therapeutic Heparin

bull Routine thromboprophylaxis

bull Vitamin C

bull Convalescent Plasma

Consent processes during pandemic

bull Have requested permission to use phone electronic confirmation of agreement to participate from person responsible

bull Verbal consent from participant if competent to consent

Role of DSMB

bull Granted more flexibility

bull Can ask for additional analyses that might be relevant

bull Permitted to contact public health authorities direct with any information that they believe is important to public health response to COVID-19

REMAP-COVID

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

Consent processes during pandemic

bull Have requested permission to use phone electronic confirmation of agreement to participate from person responsible

bull Verbal consent from participant if competent to consent

Role of DSMB

bull Granted more flexibility

bull Can ask for additional analyses that might be relevant

bull Permitted to contact public health authorities direct with any information that they believe is important to public health response to COVID-19

REMAP-COVID

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

Role of DSMB

bull Granted more flexibility

bull Can ask for additional analyses that might be relevant

bull Permitted to contact public health authorities direct with any information that they believe is important to public health response to COVID-19

REMAP-COVID

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

REMAP-COVID

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

SOLIDARITY

ldquoMultiple small trials with different

methodologies may not give us the

clear strong evidence we need about

which treatments help to save livesrdquo ndash

Dr Tedros

March 18 2020

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

A global lsquomegatrialrsquo with the aim of enrolling (tens of) thousands of patients with a common analytic sethttpwwwisrctncomISRCTN83971151Population Hospitalized adults with confirmed COVID19Randomized to one of 1) Remdesivir + Optimized supportive care2) Hydroxychloroquine + Optimized supportive care3) Kaletra+ Optimized supportive care4) Kaletra + IFN-B1a + Optimized Supportive care5) Optimized supportive carePrimary outcome of hospital mortality

SOLIDARITY

bull No sample size

bull No pre-specified stopping rules

bull No pre-determined interim efficacy analyses

bull Embedded within care as much as possible

Data collected Baseline demographics Minimal baseline severity Drug given Outcome at discharge

Will adapt to new interventions as they become available Others dropped for harmfutility

Mapping the evidence

4272020 Cytel Inc 22

1 2 3 4 5

Craig Rayner President Certara

The 5 Lessons Apply what we have learned from history

4272020 Cytel Inc 24

Know what weare up against

Begin with multiple audiences in mind

A strategy an integrated team amp agile implementation are essential

Smarter drug development is necessary to accelerate therapeutics

We must build and sustain collaboration and coordination

1 2 3 4 5

Refer to Accelerating Therapeutics for COVID-19 Webinar httpswwwyoutubecomwatchv=aXpBjfemexQ

Mapping the evidence

4272020 Cytel Inc 22

1 2 3 4 5

Craig Rayner President Certara

The 5 Lessons Apply what we have learned from history

4272020 Cytel Inc 24

Know what weare up against

Begin with multiple audiences in mind

A strategy an integrated team amp agile implementation are essential

Smarter drug development is necessary to accelerate therapeutics

We must build and sustain collaboration and coordination

1 2 3 4 5

Refer to Accelerating Therapeutics for COVID-19 Webinar httpswwwyoutubecomwatchv=aXpBjfemexQ

The 5 Lessons Apply what we have learned from history

4272020 Cytel Inc 24

Know what weare up against

Begin with multiple audiences in mind

A strategy an integrated team amp agile implementation are essential

Smarter drug development is necessary to accelerate therapeutics

We must build and sustain collaboration and coordination

1 2 3 4 5

Refer to Accelerating Therapeutics for COVID-19 Webinar httpswwwyoutubecomwatchv=aXpBjfemexQ

The 5 Lessons Apply what we have learned from history

4272020 Cytel Inc 25

Know what weare up against

Begin with multiple audiences in mind

A strategy an integrated team amp agile implementation are essential

Smarter drug development is necessary to accelerate therapeutics

We must build and sustain collaboration and coordination

1 2 3 4 5

Refer to Accelerating Therapeutics for COVID-19 Webinar httpswwwyoutubecomwatchv=aXpBjfemexQ

Itrsquos like weather forecasting with global consequences

4272020 Cytel Inc 26

In the chaos of COVID-19 who is thinking about optimal dose regimen

4272020 Cytel Inc 27

Optimal dose regimen

- Every mg above optimal is less for others

- Every mg below optimal potential for resistance

Clinical translational and

quantitative pharmacology

is foundational to the

ldquosciencerdquo of dosing

2

8

C19 Peloton

Pharmacology Plausibility amp Proof of Hope

Clinical Proof of Concept amp Dose Determination

Clinical Confirmation amp Real World Application

C19 Peloton Ivermectin

Pharmacology Plausibility amp Proof of Hope

C19 Peloton Ivermectin is unlikely to be clinically effective

Pharmacology Plausibility amp Proof of Hope

IC50 gt21-fold lung tissue Cmax

Simulated concentrations in plasma

(black) and lung tissue (blue) following

ivermectin 600microgkg QD for 3days

Yeo K et al Antiviral Research 2020 (accepted)

Improved ldquosamerdquo is not enough - Smarter drug development is

required to accelerate therapeutics for COVID-19

4272020 Cytel Inc

Make use of diverse approaches and evidence to drive faster and higher

quality decisions on optimal dose regimens for COVID-19

PKPD enriched HECT RCT run-in and Compassionate Use

PK to define dosing in subpops comorbidities DDI disease course

Pharmaco-epi models to explore impact on transmission

RWE registry examining associations on dose regimens

Many quant methods to ldquointerrogaterdquo gray data amp simulate scenarios

Covid-19 clinical trials tracker

wwwcovid-trialsorg

4272020 Cytel Inc 34

Louis Dron Director Cytel

4272020 Cytel Inc 35

Global tracker wwwcovid-trialsorg

Global data

sources

Visualization

4272020wwwcovid-trialsorg

Cytel Inc36

Ways to filterhellip By included treatment(s)

By countries

Filtered data

download

By participant context

A fragmented landscape

4272020 Cytel Inc

bull ~50 of these trials are

investigating one intervention only

(2-arm trials) with sample size lt100

participants

bull Certain treatments are particularly

often investigated and repeated

bull For example chloroquine or

hydroxychloroquine (HCQ) features

as a treatment in 118 separate trials

0

50

100

150

200

10 or less 11 to 30 31 to 100 101 to250

251 to500

501 to1000

1000 ormore

To

tal n

um

ber

of

tria

ls

Anticipated sample size

Distribution of planned sample size

020406080

100120

232020 332020 432020

Cu

mu

lati

ve

tri

al

N

Date

Trials with HCQ

Regions of interest ndash United States

38

0

10

20

30

40

50

60

70

80

Cum

ula

tive t

rial num

ber

Date

Cumulative US trials over time

The United States is the country with the

second largest number of registered trials

at 77 (with 47 trials actively recruiting)

More than half of the trials registered in the

United States have done so within the first

weeks of April

Close to a third of registered trials with

sites in the US (32) include

chloroquine or hydroxychloroquine

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

In the chaos of COVID-19 who is thinking about optimal dose regimen

4272020 Cytel Inc 27

Optimal dose regimen

- Every mg above optimal is less for others

- Every mg below optimal potential for resistance

Clinical translational and

quantitative pharmacology

is foundational to the

ldquosciencerdquo of dosing

2

8

C19 Peloton

Pharmacology Plausibility amp Proof of Hope

Clinical Proof of Concept amp Dose Determination

Clinical Confirmation amp Real World Application

C19 Peloton Ivermectin

Pharmacology Plausibility amp Proof of Hope

C19 Peloton Ivermectin is unlikely to be clinically effective

Pharmacology Plausibility amp Proof of Hope

IC50 gt21-fold lung tissue Cmax

Simulated concentrations in plasma

(black) and lung tissue (blue) following

ivermectin 600microgkg QD for 3days

Yeo K et al Antiviral Research 2020 (accepted)

Improved ldquosamerdquo is not enough - Smarter drug development is

required to accelerate therapeutics for COVID-19

4272020 Cytel Inc

Make use of diverse approaches and evidence to drive faster and higher

quality decisions on optimal dose regimens for COVID-19

PKPD enriched HECT RCT run-in and Compassionate Use

PK to define dosing in subpops comorbidities DDI disease course

Pharmaco-epi models to explore impact on transmission

RWE registry examining associations on dose regimens

Many quant methods to ldquointerrogaterdquo gray data amp simulate scenarios

Covid-19 clinical trials tracker

wwwcovid-trialsorg

4272020 Cytel Inc 34

Louis Dron Director Cytel

4272020 Cytel Inc 35

Global tracker wwwcovid-trialsorg

Global data

sources

Visualization

4272020wwwcovid-trialsorg

Cytel Inc36

Ways to filterhellip By included treatment(s)

By countries

Filtered data

download

By participant context

A fragmented landscape

4272020 Cytel Inc

bull ~50 of these trials are

investigating one intervention only

(2-arm trials) with sample size lt100

participants

bull Certain treatments are particularly

often investigated and repeated

bull For example chloroquine or

hydroxychloroquine (HCQ) features

as a treatment in 118 separate trials

0

50

100

150

200

10 or less 11 to 30 31 to 100 101 to250

251 to500

501 to1000

1000 ormore

To

tal n

um

ber

of

tria

ls

Anticipated sample size

Distribution of planned sample size

020406080

100120

232020 332020 432020

Cu

mu

lati

ve

tri

al

N

Date

Trials with HCQ

Regions of interest ndash United States

38

0

10

20

30

40

50

60

70

80

Cum

ula

tive t

rial num

ber

Date

Cumulative US trials over time

The United States is the country with the

second largest number of registered trials

at 77 (with 47 trials actively recruiting)

More than half of the trials registered in the

United States have done so within the first

weeks of April

Close to a third of registered trials with

sites in the US (32) include

chloroquine or hydroxychloroquine

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

2

8

C19 Peloton

Pharmacology Plausibility amp Proof of Hope

Clinical Proof of Concept amp Dose Determination

Clinical Confirmation amp Real World Application

C19 Peloton Ivermectin

Pharmacology Plausibility amp Proof of Hope

C19 Peloton Ivermectin is unlikely to be clinically effective

Pharmacology Plausibility amp Proof of Hope

IC50 gt21-fold lung tissue Cmax

Simulated concentrations in plasma

(black) and lung tissue (blue) following

ivermectin 600microgkg QD for 3days

Yeo K et al Antiviral Research 2020 (accepted)

Improved ldquosamerdquo is not enough - Smarter drug development is

required to accelerate therapeutics for COVID-19

4272020 Cytel Inc

Make use of diverse approaches and evidence to drive faster and higher

quality decisions on optimal dose regimens for COVID-19

PKPD enriched HECT RCT run-in and Compassionate Use

PK to define dosing in subpops comorbidities DDI disease course

Pharmaco-epi models to explore impact on transmission

RWE registry examining associations on dose regimens

Many quant methods to ldquointerrogaterdquo gray data amp simulate scenarios

Covid-19 clinical trials tracker

wwwcovid-trialsorg

4272020 Cytel Inc 34

Louis Dron Director Cytel

4272020 Cytel Inc 35

Global tracker wwwcovid-trialsorg

Global data

sources

Visualization

4272020wwwcovid-trialsorg

Cytel Inc36

Ways to filterhellip By included treatment(s)

By countries

Filtered data

download

By participant context

A fragmented landscape

4272020 Cytel Inc

bull ~50 of these trials are

investigating one intervention only

(2-arm trials) with sample size lt100

participants

bull Certain treatments are particularly

often investigated and repeated

bull For example chloroquine or

hydroxychloroquine (HCQ) features

as a treatment in 118 separate trials

0

50

100

150

200

10 or less 11 to 30 31 to 100 101 to250

251 to500

501 to1000

1000 ormore

To

tal n

um

ber

of

tria

ls

Anticipated sample size

Distribution of planned sample size

020406080

100120

232020 332020 432020

Cu

mu

lati

ve

tri

al

N

Date

Trials with HCQ

Regions of interest ndash United States

38

0

10

20

30

40

50

60

70

80

Cum

ula

tive t

rial num

ber

Date

Cumulative US trials over time

The United States is the country with the

second largest number of registered trials

at 77 (with 47 trials actively recruiting)

More than half of the trials registered in the

United States have done so within the first

weeks of April

Close to a third of registered trials with

sites in the US (32) include

chloroquine or hydroxychloroquine

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

C19 Peloton

Pharmacology Plausibility amp Proof of Hope

Clinical Proof of Concept amp Dose Determination

Clinical Confirmation amp Real World Application

C19 Peloton Ivermectin

Pharmacology Plausibility amp Proof of Hope

C19 Peloton Ivermectin is unlikely to be clinically effective

Pharmacology Plausibility amp Proof of Hope

IC50 gt21-fold lung tissue Cmax

Simulated concentrations in plasma

(black) and lung tissue (blue) following

ivermectin 600microgkg QD for 3days

Yeo K et al Antiviral Research 2020 (accepted)

Improved ldquosamerdquo is not enough - Smarter drug development is

required to accelerate therapeutics for COVID-19

4272020 Cytel Inc

Make use of diverse approaches and evidence to drive faster and higher

quality decisions on optimal dose regimens for COVID-19

PKPD enriched HECT RCT run-in and Compassionate Use

PK to define dosing in subpops comorbidities DDI disease course

Pharmaco-epi models to explore impact on transmission

RWE registry examining associations on dose regimens

Many quant methods to ldquointerrogaterdquo gray data amp simulate scenarios

Covid-19 clinical trials tracker

wwwcovid-trialsorg

4272020 Cytel Inc 34

Louis Dron Director Cytel

4272020 Cytel Inc 35

Global tracker wwwcovid-trialsorg

Global data

sources

Visualization

4272020wwwcovid-trialsorg

Cytel Inc36

Ways to filterhellip By included treatment(s)

By countries

Filtered data

download

By participant context

A fragmented landscape

4272020 Cytel Inc

bull ~50 of these trials are

investigating one intervention only

(2-arm trials) with sample size lt100

participants

bull Certain treatments are particularly

often investigated and repeated

bull For example chloroquine or

hydroxychloroquine (HCQ) features

as a treatment in 118 separate trials

0

50

100

150

200

10 or less 11 to 30 31 to 100 101 to250

251 to500

501 to1000

1000 ormore

To

tal n

um

ber

of

tria

ls

Anticipated sample size

Distribution of planned sample size

020406080

100120

232020 332020 432020

Cu

mu

lati

ve

tri

al

N

Date

Trials with HCQ

Regions of interest ndash United States

38

0

10

20

30

40

50

60

70

80

Cum

ula

tive t

rial num

ber

Date

Cumulative US trials over time

The United States is the country with the

second largest number of registered trials

at 77 (with 47 trials actively recruiting)

More than half of the trials registered in the

United States have done so within the first

weeks of April

Close to a third of registered trials with

sites in the US (32) include

chloroquine or hydroxychloroquine

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

C19 Peloton Ivermectin

Pharmacology Plausibility amp Proof of Hope

C19 Peloton Ivermectin is unlikely to be clinically effective

Pharmacology Plausibility amp Proof of Hope

IC50 gt21-fold lung tissue Cmax

Simulated concentrations in plasma

(black) and lung tissue (blue) following

ivermectin 600microgkg QD for 3days

Yeo K et al Antiviral Research 2020 (accepted)

Improved ldquosamerdquo is not enough - Smarter drug development is

required to accelerate therapeutics for COVID-19

4272020 Cytel Inc

Make use of diverse approaches and evidence to drive faster and higher

quality decisions on optimal dose regimens for COVID-19

PKPD enriched HECT RCT run-in and Compassionate Use

PK to define dosing in subpops comorbidities DDI disease course

Pharmaco-epi models to explore impact on transmission

RWE registry examining associations on dose regimens

Many quant methods to ldquointerrogaterdquo gray data amp simulate scenarios

Covid-19 clinical trials tracker

wwwcovid-trialsorg

4272020 Cytel Inc 34

Louis Dron Director Cytel

4272020 Cytel Inc 35

Global tracker wwwcovid-trialsorg

Global data

sources

Visualization

4272020wwwcovid-trialsorg

Cytel Inc36

Ways to filterhellip By included treatment(s)

By countries

Filtered data

download

By participant context

A fragmented landscape

4272020 Cytel Inc

bull ~50 of these trials are

investigating one intervention only

(2-arm trials) with sample size lt100

participants

bull Certain treatments are particularly

often investigated and repeated

bull For example chloroquine or

hydroxychloroquine (HCQ) features

as a treatment in 118 separate trials

0

50

100

150

200

10 or less 11 to 30 31 to 100 101 to250

251 to500

501 to1000

1000 ormore

To

tal n

um

ber

of

tria

ls

Anticipated sample size

Distribution of planned sample size

020406080

100120

232020 332020 432020

Cu

mu

lati

ve

tri

al

N

Date

Trials with HCQ

Regions of interest ndash United States

38

0

10

20

30

40

50

60

70

80

Cum

ula

tive t

rial num

ber

Date

Cumulative US trials over time

The United States is the country with the

second largest number of registered trials

at 77 (with 47 trials actively recruiting)

More than half of the trials registered in the

United States have done so within the first

weeks of April

Close to a third of registered trials with

sites in the US (32) include

chloroquine or hydroxychloroquine

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

C19 Peloton Ivermectin is unlikely to be clinically effective

Pharmacology Plausibility amp Proof of Hope

IC50 gt21-fold lung tissue Cmax

Simulated concentrations in plasma

(black) and lung tissue (blue) following

ivermectin 600microgkg QD for 3days

Yeo K et al Antiviral Research 2020 (accepted)

Improved ldquosamerdquo is not enough - Smarter drug development is

required to accelerate therapeutics for COVID-19

4272020 Cytel Inc

Make use of diverse approaches and evidence to drive faster and higher

quality decisions on optimal dose regimens for COVID-19

PKPD enriched HECT RCT run-in and Compassionate Use

PK to define dosing in subpops comorbidities DDI disease course

Pharmaco-epi models to explore impact on transmission

RWE registry examining associations on dose regimens

Many quant methods to ldquointerrogaterdquo gray data amp simulate scenarios

Covid-19 clinical trials tracker

wwwcovid-trialsorg

4272020 Cytel Inc 34

Louis Dron Director Cytel

4272020 Cytel Inc 35

Global tracker wwwcovid-trialsorg

Global data

sources

Visualization

4272020wwwcovid-trialsorg

Cytel Inc36

Ways to filterhellip By included treatment(s)

By countries

Filtered data

download

By participant context

A fragmented landscape

4272020 Cytel Inc

bull ~50 of these trials are

investigating one intervention only

(2-arm trials) with sample size lt100

participants

bull Certain treatments are particularly

often investigated and repeated

bull For example chloroquine or

hydroxychloroquine (HCQ) features

as a treatment in 118 separate trials

0

50

100

150

200

10 or less 11 to 30 31 to 100 101 to250

251 to500

501 to1000

1000 ormore

To

tal n

um

ber

of

tria

ls

Anticipated sample size

Distribution of planned sample size

020406080

100120

232020 332020 432020

Cu

mu

lati

ve

tri

al

N

Date

Trials with HCQ

Regions of interest ndash United States

38

0

10

20

30

40

50

60

70

80

Cum

ula

tive t

rial num

ber

Date

Cumulative US trials over time

The United States is the country with the

second largest number of registered trials

at 77 (with 47 trials actively recruiting)

More than half of the trials registered in the

United States have done so within the first

weeks of April

Close to a third of registered trials with

sites in the US (32) include

chloroquine or hydroxychloroquine

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Improved ldquosamerdquo is not enough - Smarter drug development is

required to accelerate therapeutics for COVID-19

4272020 Cytel Inc

Make use of diverse approaches and evidence to drive faster and higher

quality decisions on optimal dose regimens for COVID-19

PKPD enriched HECT RCT run-in and Compassionate Use

PK to define dosing in subpops comorbidities DDI disease course

Pharmaco-epi models to explore impact on transmission

RWE registry examining associations on dose regimens

Many quant methods to ldquointerrogaterdquo gray data amp simulate scenarios

Covid-19 clinical trials tracker

wwwcovid-trialsorg

4272020 Cytel Inc 34

Louis Dron Director Cytel

4272020 Cytel Inc 35

Global tracker wwwcovid-trialsorg

Global data

sources

Visualization

4272020wwwcovid-trialsorg

Cytel Inc36

Ways to filterhellip By included treatment(s)

By countries

Filtered data

download

By participant context

A fragmented landscape

4272020 Cytel Inc

bull ~50 of these trials are

investigating one intervention only

(2-arm trials) with sample size lt100

participants

bull Certain treatments are particularly

often investigated and repeated

bull For example chloroquine or

hydroxychloroquine (HCQ) features

as a treatment in 118 separate trials

0

50

100

150

200

10 or less 11 to 30 31 to 100 101 to250

251 to500

501 to1000

1000 ormore

To

tal n

um

ber

of

tria

ls

Anticipated sample size

Distribution of planned sample size

020406080

100120

232020 332020 432020

Cu

mu

lati

ve

tri

al

N

Date

Trials with HCQ

Regions of interest ndash United States

38

0

10

20

30

40

50

60

70

80

Cum

ula

tive t

rial num

ber

Date

Cumulative US trials over time

The United States is the country with the

second largest number of registered trials

at 77 (with 47 trials actively recruiting)

More than half of the trials registered in the

United States have done so within the first

weeks of April

Close to a third of registered trials with

sites in the US (32) include

chloroquine or hydroxychloroquine

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Covid-19 clinical trials tracker

wwwcovid-trialsorg

4272020 Cytel Inc 34

Louis Dron Director Cytel

4272020 Cytel Inc 35

Global tracker wwwcovid-trialsorg

Global data

sources

Visualization

4272020wwwcovid-trialsorg

Cytel Inc36

Ways to filterhellip By included treatment(s)

By countries

Filtered data

download

By participant context

A fragmented landscape

4272020 Cytel Inc

bull ~50 of these trials are

investigating one intervention only

(2-arm trials) with sample size lt100

participants

bull Certain treatments are particularly

often investigated and repeated

bull For example chloroquine or

hydroxychloroquine (HCQ) features

as a treatment in 118 separate trials

0

50

100

150

200

10 or less 11 to 30 31 to 100 101 to250

251 to500

501 to1000

1000 ormore

To

tal n

um

ber

of

tria

ls

Anticipated sample size

Distribution of planned sample size

020406080

100120

232020 332020 432020

Cu

mu

lati

ve

tri

al

N

Date

Trials with HCQ

Regions of interest ndash United States

38

0

10

20

30

40

50

60

70

80

Cum

ula

tive t

rial num

ber

Date

Cumulative US trials over time

The United States is the country with the

second largest number of registered trials

at 77 (with 47 trials actively recruiting)

More than half of the trials registered in the

United States have done so within the first

weeks of April

Close to a third of registered trials with

sites in the US (32) include

chloroquine or hydroxychloroquine

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

4272020 Cytel Inc 35

Global tracker wwwcovid-trialsorg

Global data

sources

Visualization

4272020wwwcovid-trialsorg

Cytel Inc36

Ways to filterhellip By included treatment(s)

By countries

Filtered data

download

By participant context

A fragmented landscape

4272020 Cytel Inc

bull ~50 of these trials are

investigating one intervention only

(2-arm trials) with sample size lt100

participants

bull Certain treatments are particularly

often investigated and repeated

bull For example chloroquine or

hydroxychloroquine (HCQ) features

as a treatment in 118 separate trials

0

50

100

150

200

10 or less 11 to 30 31 to 100 101 to250

251 to500

501 to1000

1000 ormore

To

tal n

um

ber

of

tria

ls

Anticipated sample size

Distribution of planned sample size

020406080

100120

232020 332020 432020

Cu

mu

lati

ve

tri

al

N

Date

Trials with HCQ

Regions of interest ndash United States

38

0

10

20

30

40

50

60

70

80

Cum

ula

tive t

rial num

ber

Date

Cumulative US trials over time

The United States is the country with the

second largest number of registered trials

at 77 (with 47 trials actively recruiting)

More than half of the trials registered in the

United States have done so within the first

weeks of April

Close to a third of registered trials with

sites in the US (32) include

chloroquine or hydroxychloroquine

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

4272020wwwcovid-trialsorg

Cytel Inc36

Ways to filterhellip By included treatment(s)

By countries

Filtered data

download

By participant context

A fragmented landscape

4272020 Cytel Inc

bull ~50 of these trials are

investigating one intervention only

(2-arm trials) with sample size lt100

participants

bull Certain treatments are particularly

often investigated and repeated

bull For example chloroquine or

hydroxychloroquine (HCQ) features

as a treatment in 118 separate trials

0

50

100

150

200

10 or less 11 to 30 31 to 100 101 to250

251 to500

501 to1000

1000 ormore

To

tal n

um

ber

of

tria

ls

Anticipated sample size

Distribution of planned sample size

020406080

100120

232020 332020 432020

Cu

mu

lati

ve

tri

al

N

Date

Trials with HCQ

Regions of interest ndash United States

38

0

10

20

30

40

50

60

70

80

Cum

ula

tive t

rial num

ber

Date

Cumulative US trials over time

The United States is the country with the

second largest number of registered trials

at 77 (with 47 trials actively recruiting)

More than half of the trials registered in the

United States have done so within the first

weeks of April

Close to a third of registered trials with

sites in the US (32) include

chloroquine or hydroxychloroquine

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

A fragmented landscape

4272020 Cytel Inc

bull ~50 of these trials are

investigating one intervention only

(2-arm trials) with sample size lt100

participants

bull Certain treatments are particularly

often investigated and repeated

bull For example chloroquine or

hydroxychloroquine (HCQ) features

as a treatment in 118 separate trials

0

50

100

150

200

10 or less 11 to 30 31 to 100 101 to250

251 to500

501 to1000

1000 ormore

To

tal n

um

ber

of

tria

ls

Anticipated sample size

Distribution of planned sample size

020406080

100120

232020 332020 432020

Cu

mu

lati

ve

tri

al

N

Date

Trials with HCQ

Regions of interest ndash United States

38

0

10

20

30

40

50

60

70

80

Cum

ula

tive t

rial num

ber

Date

Cumulative US trials over time

The United States is the country with the

second largest number of registered trials

at 77 (with 47 trials actively recruiting)

More than half of the trials registered in the

United States have done so within the first

weeks of April

Close to a third of registered trials with

sites in the US (32) include

chloroquine or hydroxychloroquine

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Regions of interest ndash United States

38

0

10

20

30

40

50

60

70

80

Cum

ula

tive t

rial num

ber

Date

Cumulative US trials over time

The United States is the country with the

second largest number of registered trials

at 77 (with 47 trials actively recruiting)

More than half of the trials registered in the

United States have done so within the first

weeks of April

Close to a third of registered trials with

sites in the US (32) include

chloroquine or hydroxychloroquine

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Regions of interest ndash China

39

0

50

100

150

200

250

300

350

Cum

ula

tive t

rial num

ber

Date

Cumulative trials in ChinaChina is the country with the largest number

of registered trials at 318

Of trials in China a substantial proportion

(n=100 31) involved the use of

Traditional Chinese Medicine

Other interventions of interest include

lopinavirritonavir (n=29 9) stem cell

therapies (n=25 8) and

hydroxychloroquine (n=20 6)

The flattening of newly added trials over

time appears to reflect the reduction in

reported active cases

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Geographical Spread of registered COVID-19 trials

4272020 Cytel Inc 40

North America 94

Europe 114

East Asia 334

Middle East 41

Africa 11

South Asia 7 South America 12

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Dynamic Trial Designs for

COVID-19 Interventions

4272020 Cytel Inc 41

Kristian Thorlund SVP Cytel

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Cytel Inc 42

The Evidence Lines between treatments indicate

direct comparisons in clinical trials

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Cytel Inc 43

Representation of Outcomes

- Viral LoadClearance (140)

- Mortality (126)

- Invasive Ventilation (109)

- Clinical Improvement (102)

- ICU Admission (93)

- Fever (91)

- Hospitalization 86)

- Non-invasive Ventilation (84)

- Pneumonia or ARDS (68)

- Radiographic findings (64)

- Inflammatory biomarkers (62)

- Organ failuredysfunction (40)

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Cytel Inc44

Hospitalized Healthcare

Workers

Healthcare

Workers

Outpatients HealthyProphylaxis

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Cytel Inc 45

Three parallel clinical trials embedded as a triage platform trial

Trial I Exposed patients

Trial 2 Lower-risk PCR+ Covid-19 outpatients

Trial 3 Higher-risk PCR+ Covid-19

outpatients

H

H

HH

H

H

H

Eligible individuals or patients permitted to enter different sub-trials established within the

master protocol ndash this offers benefits of capturing patient journey throughout

Transfer to

collaborator trial

Once eligible patientrsquos can be

transferred to other trials on

hospitalized or ICU admitted

CoVID-19 populations

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Last updated April 27 2020

46

PICOS criteria

Criteria Sub-trial 1 Sub-trial 2 Sub-trial 3

Population Exposed individualsLower-risk PCR+ Covid-19 outpatients

Higher-risk PCR+ Covid-19 outpatients

InterventionsAny post-exposure prophylaxis (PEP) therapeutics

Any treatment therapeutics

Any treatment therapeutics

Comparator Placebo or standard-of-care as they become available

Primary outcome

bull Any outcome bull Any outcome bull Any outcome

Study design A triage platform clinical trial

Stratification of PCR+ Covid-19 into lower-risk and higher-risk can be defined by the clinical experts

Up to three arms simultaneously evaluated at once

Primary outcome of each sub-trials will be defined by the clinical experts

Patients from this trial can be transferred to other key master protocols evaluating hospitalized Covid-19 patients if and when they

become eligible

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Cytel Inc 47

Your 2-arm Stem Cell

Therapy Trial

Assess External + Interim Data

- Stop if the answer is already in

- Bayesian Predictive Probabilities

- Sample Size Reassessment

NIH advises against

Hydroxychloroquine +

Azithromyzin combination

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Cytel Inc 48

Master Protocols and Platform Trials CoViD vs non-CoViD

0

10

20

30

40

50

60

70

80

90

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Basket trials Umbrella trials

Platform trials

Number of Master Protocols over Time

Basket Trials Umbrella Trials and Platform Trials

Non-CoViD

Master Protocols

Umbrella

Platform

Basket

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Examples of registered master protocols in COVID-19

4272020

Trial name (ID) Master protocol

category

Therapeutic area(s)(listed as of mid-April)

Countries Patient context

ACOVACT

(NCT04351724)

Basket trial RAS blockade antiviral

immune modulation

Austria Outpatients renal

impaired critically ill

(separate sub studies)

PRINCIPLE

(ISRCTN86534580)

Platform trial Hydroxychloroquine United Kingdom High risk patients

primary care

REMAP-CAP

(REMAP-COVID)

(NCT02735707)

Platform trial (sub-

platform)

Antiviral immune

modulation macrolide

corticosteroid

Thirteen countries Critically Ill

SOLIDARITY

(ISRCTN83971151)

Platform trial with

umbrella component

Vaccine antiviral

immune modulation

Thirteen countries five

continents

Multiple planned

U-WASH

(NCT04354428)

Platform trial Hydroxychloroquine

azithromycin

United States High risk outpatients

U-DEPLOY

(NCT04331665 ndash single

sub trial registration)

Umbrella trial Cellular products

immune modulation

Canada Critically ill non-critically

ill

Note this is not intended to be an exhaustive list of master protocols in COVID-19 It is intended to demonstrate several efforts identified through routine surveillance of clinical trial registries as of April 19 2020

Design description not taken from study investigators

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

Cytel Inc 50

Concluding Remarks

Consider what has been accomplished in such a short timehellip

hellip let us not forget how much non-CoViD patients will benefit from

upholding this new standard

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA

COVID-19 Trials Designs and

Tools for Promising Results

4272020 Cytel Inc 51

1 2 3 4 5

Panel discussion

Audience QampA