SOLIDARITY TRIAL PLUS

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SOLIDARITY TRIAL PLUS Standard Operating Procedures

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SOLIDARITY TRIAL PLUS

World Health Organization

An international randomised trial of additional

treatments for COVID-19 in hospitalised patients

who are all receiving the local standard of care

Standard Operating Procedures and

Appendixes

Version 1.0

April 5, 2021

This SOPs are confidential to trial investigators. It should not be disclosed to others

without permission from the WHO, except to seek the consent of collaborators or

participants.

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Contents

SOP-1 APPROVAL OF HOSPITALS TO JOIN THE TRIAL AND ACCESS TRIAL DRUGS ....................... 3

SOP-2 ACCESS TO GLOBAL ENROLMENT AND RANDOMIZATION CENTER ...................................... 4

SOP-3 INFORMED CONSENT FORM ......................................................................................................... 5

SOP-4 PHARMACY MANUAL FOR ARTESUNATE .................................................................................... 9

SOP-5 PHARMACY MANUAL FOR IMATINIB ........................................................................................... 11

SOP-6 PHARMACY MANUAL FOR INFLIXIMAB ...................................................................................... 13

SOP-7 REPORTING OF MAIN OUTCOMES WHILE A PATIENT IS IN HOSPITAL ................................. 16

SOP-8 REPORTING SAES AND SUSARS ................................................................................................ 17

SOP-9 REPORTING OF PROTOCOL DEVIATIONS AND VIOLATIONS ................................................. 19

APPENDIX 1. GLOBAL DATA AND SAFETY MONITORING COMMITTEE ............................................. 20

APPENDIX 2. SOLIDARITY TRIAL GOVERNANCE ................................................................................. 21

APPENDIX 3. PROTOCOL AMENDMENT HISTORY ............................................................................... 22

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SOP-1 Approval of hospitals to join the trial and access trial drugs WHO Director-General has invited all the Ministers of Health to participate in the trial,

and the Minister decides if the country should join the trial. Then, two high-level

representatives are chosen by the country, one for the Health Ministry (or Medical

Research Council) and one for local clinical investigators. These two National

Representatives will work together to get all necessary approvals rapidly, to select as

potential collaborating centres major hospitals that already have, or are expected

soon to have, substantial numbers of inpatient admissions for COVID, and to facilitate

local ethical approval on behalf of willing local collaborators. The following steps should

ensure the trial can start promptly in each collaborating hospital. They should happen in

parallel and not in sequential fashion.

Step What? Who? How? Remarks

1 Officially confirm

interest to participate

Minister of Health or

authorised Delegate of

the Minister of Health

Communication to

WHO Secretariat

[email protected]

2 Appoint two National

Representatives, one

Governmental and

one Clinical

Within-country choice

by Ministry of Health or

main Research Council

and a leading clinical

investigator

Communication to

WHO Secretariat

[email protected]

These two National

Representatives should

both be senior within

their Ministry or profession

3 Identify which

hospitals will have

substantial numbers

and will collaborate

The two National

Representatives, with

one lead doctor per

selected hospital

Communication to

WHO Secretariat

[email protected]

Selected hospitals should

have basic GCP

knowledge

4 Facilitate Approval -

or not - by national

authority and local

ethics committees

The two National

Representatives

High-level national

decisions, not just

local applications by

each collaborator

No modification of the

protocol is possible, as

very large numbers of

hospitals are involved.

5 Establish which study

drugs are available in

each location

Clinical National

Representative, helped

by WHO focal point

Bilateral

interactions

WHO will facilitate study

drug provision where this

is needed

6 Facilitate import

permits for study

drugs, as pertinent

The two National

Representatives

Depends on national

guidelines and

regulations

After permits for initial

amounts, resupply will

depend on entry rate

7 Set up personnel and

logistics for study

implementation

Appoint small central

administrative staff for

the Clinical National

Representative

Make use of existing

p.a. and other staff

of known reliability to

disseminate study

Local centres will need

help on approvals, drug

supplies, getting going,

and maximising accrual

8 Within local hospitals,

move quickly into

rapid recruitment

Lead doctor and lead

pharmacist motivate

and train colleagues

Local leads explain

and discuss study

with colleagues

Local leads motivates &

ensures full compliance,

rapid entry & discipline

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SOP-2 Access to global enrolment and randomization center To facilitate collaboration even in overloaded hospitals, patient enrolment and

randomisation (via a cloud-based GCP-compliant platform) and all other trial

procedures are greatly simplified.

Within each country, the national co-ordinator invites selected hospitals and

helps them get ethical and regulatory approval and study drugs then patient

entry can begin. Access is via the WHO study website

https://data.castoredc.com/.

Each doctor has access to the platform using an individual secured password. A

study ID for the patient is then generated and displayed.

Eligibility: Adults (age ≥ 18 years), hospitalised with laboratory-confirmed COVID,

not expecting transfer within 72 hours, and, in the view of their doctors, with no

contra-indication to any potentially relevant study drug.

Consent: The study website https://data.castoredc.com/studies has printable

patient information in some UN official languages. Once the information has

been explained to patients, obtaining consent takes only a few minutes. An

electronic image of the signature page is kept (or, if national regulations forbid

this, a note to file), and the printed information and original consent stays with

the patient or legal representative.

Data collected electronically immediately before randomisation:

• Country, hospital (from a list of approved hospitals) and randomising doctor

• Confirmation that informed consent was obtained from the patient (or a

surrogate/ representative)

Age, sex and (yes/no): smoking, diabetes, heart disease, chronic liver

disease, chronic lung disease, asthma, HIV, obesity

• Date of onset of symptoms, date of hospitalization, and (yes/no)

current/planned use of a few drugs

• Respiratory support (highest level currently being given): A. No oxygen, B.

Low-flow oxygen, C. High-flow nasal oxygen, D. Non-invasive ventilation, E.

Invasive ventilation, F. ECMO

• SpO2 (%) and, if not ventilated, respiratory rate

• Any major bilateral lung abnormality? (not imaged/no major

abnormality/infiltrations/patchy shadowing)

• Which relevant study drugs are locally available? (yes/no: artesunate,

infliximab, imatinib; confirm that none of these locally available drug(s) is, in

the doctor’s view, definitely contra-indicated)

Trial entry; randomization: Once electronic data collection has been completed

the patient automatically enters the trial and a random allocation of their trial

treatment is generated (by an algorithm that ensures eventual balance in the

characteristics just recorded between each study drug and its controls) and

displayed. The patients will be randomly allocated either to Standard of Care

(SoC) or to one of the study drugs.

https://data.castoredc.com/

https://data.castoredc.com/studies

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SOP-3 Informed consent form

Coronavirus-induced disease (COVID-19, or COVID)

Informed consent to join the WHO Solidarity randomised trial

To the health worker: We are inviting hospitalised adults 18 years or older to

consent to join a research study. All who participate will receive the usual care

offered in this hospital, and in addition some but not all will be given one extra

treatment chosen at random from a few untested treatments or a placebo. The

aim is to discover whether any of these treatments slows disease progression or

improves survival.

To the patient: You have a lung disease called COVID. Several medicines for it have

been proposed. These medicines may have no effect or a moderate effect on the

disease, but none is expected to have a big effect. This hospital is collaborating through

the World Health Organization and hospitals in many other countries in a study to help

discover whether any of these treatments can help.

Whether or not you choose to join, you will still receive the usual standard of care at this

hospital. If you do not join the study, you will receive whatever your doctor thinks is best.

If you decide to join, you may receive one untested treatment chosen by chance, as if

on the roll of a dice. This form has two parts:

1. To share information about the treatments being tested.

2. For your signature, if you do decide to take part

PART 1: Information Sheet

Introduction

I am _____________________________, working for the _________________________.

You have a lung disease called COVID that recently spread across the world. Most

people recover fully from COVID, but a few die. This hospital is collaborating in an

international research study to help discover whether some untested treatments could

help treat COVID. I am going to tell you about the study, then invite you to join it.

Before you decide, you can talk to anyone about it. If there are any words you don’t

understand, please ask me to stop and explain. If you have questions later, I’ll be

available to answer them, and so will the study doctors.

Principal Investigator

Study Sponsor Ministry of Health and WHO

Name of protocol and version Solidarity Trial PLUS

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Purpose of the research

The disease is called COVID-19 because it was first discovered in 2019, but I’ll just call it

COVID. It’s caused by a new virus that can be passed between people touching or

passed through the air when an infected person coughs or sneezes, so the hospital staff

wears protective clothing. Most people with COVID get better without coming to the

hospital, and most who come to the hospital also get better, although they may get

worse before they get better. But, a few of those in the hospital die from the illness. The

Ministry of Health and the World Health Organization are organizing a study in many

countries in which various treatments are studied, to see whether they are of any use for

treating COVID. The study treatments are listed briefly below.

During the study, some treatments may get removed from this list, and others may get

added to it. Each patient will receive at most one of the treatments.

Invitation to participate

Adults admitted to this hospital with COVID can join this study. If you join, you will be

asked to sign that you understand that there are possible risks and benefits and consent

to join the study. Your doctor will check whether you are eligible to join, and whether

any of the study treatments would definitely be unsuitable for you.

After those checks, brief details identifying you and any other conditions you have are

put into the computer, and you are then randomly allocated to receive the care you

normally would receive in this hospital alone or with one of the drugs being evaluated

in the study. Neither you nor the medical staff can choose which of the study options

you will receive, as the computer makes this allocation at random, as if on the roll of a

dice.

Any study treatment should start promptly unless you or your doctor decide for any

reason that it should stop. In addition, you will still receive what is already being done

for COVID patients in this hospital. No additional visits after you leave the clinic/hospital

are required. You or our doctor can stop the untested treatment at any time before it

has been completed, and you are free at any time to change your mind and stop

participating.

Joining is voluntary and will not affect the care you receive at this hospital. You have

the right to withdraw consent to participate at any time without reprisal. but could still

remain in the study, with the outcome of your disease being reported by the study

team. You will not be paid for your participation, and neither will the medical staff. Your

identifying details will be shared confidentially with international researchers, along with

information about the course of your illness, and we would like to use your identifying

details to link your treatment to your future medical records for long enough to know

whether you are properly cured. The findings will be made freely available worldwide

to help future patients, but your details will not be identifiable.

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I’ve got a list describing the possible side-effects of each of the study drugs briefly. We

could either read it now, or you could join the study, find out immediately whether

you’d be taking one of these drugs, and then just learn about that one and decide

whether or not you want to take it.

Risks and benefits

Any study treatment you receive may or may not help you personally, but this study

could help future patients. This study has been reviewed and approved by

__________________________________________________, a committee (contact details) set

up to make sure research participants are protected.

Some of the study treatments are given as infusions in the vein and some orally.

Artesunate is a medication used in the treatment of malaria. Artesunate is part of the

standard treatment for malaria globally. The dose that will be administered is the

standard dose recommended for the treatment of severe malaria. It will involve an

initial infusion and then additional injections after 12 hours, and 24 hours and thereafter

every 24 hours for maximum 7 days.

Infliximab is a medication used to treat a number of diseases of the immune system.

The dose that will be administered is the standard dose that is given repeatedly for the

treatment of psoriasis (a skin disease that causes red, itchy scaly patches, most

commonly on the knees, elbows, trunk and scalp). This will be given as an infusion in the

vein given only once only. The administration takes about 2 hours.

Imatinib is an oral medication used to treat cancer. The dose that will be given is the

standard maintenance dose administered for several years to patients with cancers of

the blood. However, in this study it will be given orally, once daily, for a maximum 14

days.

Before administering you any of these drugs your doctor will review if any of these drugs

is not appropriate for you. There are a few specific contraindications:

Artesunate will not be given to you if you have a history of allergic reaction to it or other

drugs of the same family (called artemisinins), or to any of the components of the drug.

In people with malaria, the doctor will monitor the red blood cell counts after about 2

weeks to evaluate if you have developed anemia.

Infliximab will not be administered if you have a history of allergic reaction to it or to any

of the components of this drug. The doctor may also decide not to give this drug to you

if you have moderate or severe heart failure, tuberculosis or certain severe infections. A

test to determine if you may have latent tuberculosis or hepatitis B may be necessary. If

one of them is positive, the doctor will refer you for treatment if necessary. Receiving

the treatment of the study drug does not have to wait for these results.

Imatinib will not be administered if you have a history of allergic reaction to it or to any

of the components of the drug. This drug may affect the functioning of your liver and

therefore the doctor will not administer it to you if you have certain liver diseases.

There is limited data on its use during pregnancy and breastfeeding, so the doctor will

discuss with you to decide if the potential benefits are greater than the unknown risks.

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PART II: Certificate of consent

Clinic/Hospital : City/Town:

Province/Region: Country:

Participant:

I read the information, or had it read to

me.

I could ask any questions I wanted and

had any questions answered satisfactorily.

I consent voluntarily to participate in this

study.

Literate Witness (if the participant is illiterate):

I witnessed the information sheet being read

verbatim.

The participant could ask any questions

and got satisfactory replies.

I confirm that they gave their consent freely.

First & last name First & last name

Signature Signature

Date Date

Thumb-print

(if illiterate*)

Deferred consent Check this if randomization is done at the investigator's

discretion according to criteria that have been explicit

during national ethical approval of the protocol.

This must be followed by the request for patient's (deferred

subject consent) or representative's (deferred proxy consent)

informed consent in a later phase, as per national

regulations.

If the patient previously declined to consent, then deferred

consent is not applicable and will not be pursued. *Illiterate participants include their thumbprint, and a literate witness countersigns the form.

Statement by the researcher/person taking consent/or documenting deferred consent

I read verbatim the information sheet to the participant and made sure they

understand what the study entails. The participant could ask questions about the study,

and all questions asked were answered correctly to the best of my ability. Consent was

given freely and voluntarily, and a copy of this form has been given to the participant.

Person taking the consent:

First & last name

Signature

Date

This study has been reviewed by ethics experts at the World Health Organization (WHO),

which is co-sponsoring it. The study has been reviewed and approved locally by

___________________________________________________________________ .

This committee exists to make sure research participants are protected from harm.

If you want to contact them about it, now or later, their contact details are

___________________________________________________________________ .

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SOP-4 Pharmacy manual for Artesunate

1. Drug product

Artesunate for injection is a sterile white crystalline powder, in clear, transparent, Type 1

(5 ml) vial. In addition to the Artesunate vial, the package contains: 1 ml type 1

ampoule with 50mg/ml sodium bicarbonate as a sterile clear colourless liquid and a 5

ml type1 ampoule with 9 mg/ml sodium chloride as a sterile clear colourless liquid.

2. Drug receipt

Artesunate must be shipped at temperature below 30˚C. Upon receipt, the recipient

should check all vials and ensure no vials are broken. If vials are broken, the vials should

be discarded. Receipt and accountability of the product on site should be

documented according to the study procedures and the appropriate persons should

be notified.

3. Storage and handling

Store vials of Artesunate for Injection and sterile diluent in the carton at 20°C to 25°C

(68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not freeze. Avoid

exposure to heat. Keep protected from light. Do not use beyond the expiration date.

4. Dose preparation

The Artesunate white powder needs to be reconstituted with the sodium bicarbonate

solution and diluted with the sodium chloride solution. The reconstituted Artesunate

solution should always be used immediately and discarded if not used within 1.5 hours.

Artesunate is to be administered at a dose of 2.4 mg/kg body weight, by intravenous

(IV) at 0, 12 and 24 hours and then once daily. The total duration of the treatment is 7

days. The required dose in mg of Artesunate should be calculated and the number of

vials of Artesunate needed should be determined prior to reconstituting the Artesunate

powder.

Preparation of the solution of Artesunate for injection:

1. Artesunate for Injection must be constituted with the supplied diluent prior to

administration. A diluent consisting of 12 mL of sterile 0.3 M pH 8.0 sodium phosphate

buffer is provided with Artesunate for Injection.

2. To constitute Artesunate for Injection, withdraw 11 mL of this diluent with a needle

and syringe and inject into the artesunate vial (when constituted the final

concentration of artesunate is 10 mg/mL).

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3. Swirl gently (do not shake) for up to 5 to 6 minutes until the powder is fully dissolved

and no visible particles remain.

4. Parenteral drug products should be inspected visually for particulate matter and

discoloration prior to administration, whenever solution and container permit. Do not

administer Artesunate for Injection if particulate matter and/or discoloration is

observed.

5. After constitution, inject the constituted solution intravenously (through an

established intravenous line or needle) as a slow bolus over 1 to 2 minutes. Discard

the vial and any unused portion of the drug product after use.

6. The volume of the solution required (mL) will be: Volume(mL)= (dose(mg)):10.

7. The Artesunate solution should NOT be administrated as an intravenous drip.

5. Disposition of unused product

Records of doses dispensed should be kept and provided to study staff on request. If

any unopened study packages remain at the end of the study, the local study PI

should be contacted for further instructions regarding the disposition of these vials.

Opened, partially unused packages should be destroyed at study end in consultation

with study staff after proper accountability has been performed.

6. Maintenance of inventory logs

The use of doses should be tracked and recorded on drug disposition logs for use

during accountability procedures by study staff. Records of when doses were

dispensed or destroyed must be kept in these logs.

7. Emergency contact

In the event of an emergency or the need for immediate information regarding

product preparation, handling, storage or administration, contact the study’s local

investigator.

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SOP-5 Pharmacy manual for Imatinib

1. Drug product

Imatinib is available as brown-orange film coated Imatinib Mesylate tablets of 400 mg in

PVD C/ aluminium blisters to be administered orally. The tablet is breakable to get 200

mg. It contains the following main excipients: cellulose microcrystalline, crospovidone,

hypomellose, magnesium stearate, silicia colloidal anhydrous, Iron oxide red and

yellow, macrogol, talc.

2. Drug receipt

Imatinib must be shipped at temperature below 30˚C. Upon receipt, the recipient

should check the integrity of the package. If packages are broken, they should be

discarded. Receipt and accountability of the product on site should be documented

according to the study procedures and the appropriate persons should be notified.


Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture.

4. Dose preparation

The recommended dosage for the study is 400mg to be administered orally once daily

for a total duration of 14 days. The dose should be taken orally with a meal and a large

glass of water. For patients unable to swallow, the tablets may be dispersed in a glass of

still water or apple juice.

The required number of tablets should be placed in the appropriate volume (200 mL for

400 mg tablet). The suspension should be administered immediately after the complete

disintegration of the tablets.


Records of doses dispensed should be kept and provided to study staff on request. If any

unopened study packages remain at the end of the study, the local study PI should be

contacted for further instructions regarding the disposition of these vials.



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The use of doses should be tracked and recorded on drug disposition logs for use during

accountability procedures by study staff. Records of when doses were dispensed or

destroyed must be kept in these logs.

7. Emergency Contact



investigator.

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SOP-6 Pharmacy manual for Infliximab

1. Drug product

Infliximab is available as a freeze-dried white pellet powder in a type 1 glass vial with

rubber stopper and aluminium crimp protected by a plastic bag. Each vial contains

100 mg of infliximab and the following main excipients: sucrose, polysorbate 80,

monobasic sodium phosphate, dibasic sodium phosphate.

2. Drug receipt

Infliximab could be shipped at temperature up to a maximum of 25˚C (recommended

storage temperature 2˚C - 8˚C). The product may be at a temperature up to 25˚C for a

period of 6 months, but not exceeding the original expiry date. Upon removal from

refrigerated storage, Infliximab must not be returned to refrigerated storage.

Upon receipt, the recipient should check the integrity of the package. If packages are

broken, they should be discarded. Receipt and accountability of the product on site

should be documented according to the study procedures and the appropriate

persons should be notified.


Before reconstitution, the recommended storage temperature is between 2˚C - 8˚C.

However, the product may be stored up to 25˚C (refer to section 2).

After reconstitution, from a microbiological point of view, the infusion solution should be

administered immediately. If not possible, it should not be kept no longer than 24 hours

at 2˚C - 8˚C. Unless, if the reconstitution/ dilution is done in a controlled and validated

aseptic conditions. From a physical and chemical point of view, the infusion solution is

stable for up to 28 days at 2˚C - 8˚C and for an additional 24 hours at 25˚C after

removal from the refrigerator.

4. Dose preparation

The proposed dosing schedule of this study is 5mg/Kg/dose to be administered as a

single IV infusion.

Infliximab powder reconstitution:

The reconstituted infusion solution should be prepared by a trained medical

professional using aseptic technique by the following procedure:

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1. Calculate the dose, total volume of reconstituted INFLIXIMAB solution

required and the number of INFLIXIMAB vials needed. Each INFLIXIMAB vial

contains 100 mg of the infliximab antibody.

2. Reconstitute each INFLIXIMAB vial with 10 mL of Sterile Water for Injection,

USP, using a syringe equipped with a 21-gauge or smaller needle as follows:

o Remove the flip-top from the vial and wipe the top with an alcohol swab.

Insert the syringe needle into the vial through the center of the rubber

stopper and direct the stream of Sterile Water for Injection, USP, to the

glass wall of the vial.

o Gently swirl the solution by rotating the vial to dissolve the lyophilized

powder. Avoid prolonged or vigorous agitation.

o DO NOT SHAKE.

o Foaming of the solution on reconstitution is not unusual.

o Allow the reconstituted solution to stand for 5 minutes. The solution should

be colorless to light yellow and opalescent, and the solution may develop

a few translucent particles as infliximab is a protein.

o Do not use if the lyophilized cake has not fully dissolved or if opaque

particles, discoloration, or other foreign particles are present.

Infusion solution preparation:

3. Dilute the total volume of the reconstituted INFLIXIMAB solution dose to 250

mL with sterile 0.9% Sodium Chloride Injection, USP, by withdrawing a volume

equal to the volume of reconstituted INFLIXIMAB from the 0.9% Sodium

Chloride Injection, USP, 250 mL bottle or bag.

4. Slowly add the total volume of reconstituted INFLIXIMAB solution to the 250

mL infusion bottle or bag.

5. Gently mix.

6. The resulting infusion concentration should range between 0.4 mg/mL and 4

mg/mL.

Infusion solution administration:

7. The INFLIXIMAB infusion should begin within 3 hours of reconstitution and

dilution.

8. The infusion must be administered over a period of not less than 2 hours and

must use an infusion set with an in-line, sterile, non-pyrogenic, low-protein-

binding filter (pore size of 6 of 58 Reference ID: 3403013 1.2 µm or less).

9. The vials do not contain antibacterial preservatives. Therefore, any unused

portion of the infusion solution should not be stored for reuse.

10. No physical biochemical compatibility studies have been conducted to

evaluate the coadministration of INFLIXIMAB with other agents. INFLIXIMAB

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should not be infused concomitantly in the same intravenous line with other

agents.

11. Parenteral drug products should be inspected visually before and after

reconstitution for particulate matter and discoloration prior to administration,

whenever solution and container permit. If visibly opaque particles,

discoloration or other foreign particulates are observed, the solution should

not be used.

12. Observe patients for at least 1-2 hours post infusion for acute infusions related

reactions.

13. Emergency equipment must be available: adrenaline, antihistamine, corticosteroids,

and artificial airway.

14. Pre-treatment with an antihistamine, hydrocortisone and/ or paracetamol is

possible. The infusion rate may be slowed in order to decrease the risk of infusion

related reactions.


Records of doses dispensed should be kept and provided to study staff on request. If any

unopened study packages remain at the end of the study, the local study PI should be

contacted for further instructions regarding the disposition of these vials.




The use of doses should be tracked and recorded on drug disposition logs for use during

accountability procedures by study staff. Records of when doses were dispensed or

destroyed must be kept in these logs.

7. Emergency Contact



investigator.

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SOP-7 Reporting of main outcomes while a patient is in hospital

To facilitate collaboration even in hospitals that have become overloaded, patient

enrolment and randomization (via the internet) and all other trial procedures are

greatly simplified, and no paperwork at all is required.

Withdrawal from the treatment that was randomly allocated at study entry need not

imply withdrawal from information on outcome in hospital being reported to the WHO

at the end of the hospital stay. But, if the patient (or a legal representative) decides the

patient will withdraw and that no further data will be sent to the WHO study office, then

only the date of withdrawal will be reported; no further information will be given, unless

an adverse drug reaction report is legally required.

At discharge or death, the study doctor will log into the study website

https://data.castoredc.com/and enter:

When patients die or are discharged, follow-up ceases and it is reported:

• Which study drug was given (and for how long?)

• Which of a few selected other drugs were given (and for how long?)

• What respiratory support was given (and first and last dates used?) A No oxygen,

B Low-flow supplemental oxygen, C High-flow nasal oxygen, D Non-invasive

ventilation, E Invasive ventilation, F ECMO upplemental oxygen, high-flow nasal

oxygen, non-invasive ventilation, invasive ventilation, ECMO

• Date and cause of death in hospital or date discharged alive (and, if discharged

alive but still at appreciable risk of death from COVID, give details)

• Pregnant? Yes/No/unknown

Patient information will be encrypted and held securely by the at the cloud database.

Those analysing it will use only anonymized data, and no identifiable patient details will

be released to any unauthorized third party. Patient confidentiality will be maintained

when study results are disseminated.


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SOP-8 Reporting SAEs and SUSARS

An adverse event is any undesirable experience associated with the use of a medical

product in a patient. Serious Adverse Events (SAEs) associated with the study drug

(possibly related to the treatment), and any suspected unexpected serious adverse

reactions (SUSARs) that are life-threatening must be reported within 24 hours.

The event is a SAE and should be reported when the patient outcome is:

o Death : Report if you suspect that the death was an outcome of the adverse event,

and include the date if known.

o Life-threatening : Report if suspected that the patient was at substantial risk of dying

at the time of the adverse event or use or continued use of the device or other

medical product might have resulted in the death of the patient.

o Hospitalization (prolonged) : Report if admission to the hospital or prolongation of

hospitalization was a result of the adverse event.

o Disability or Permanent Damage : Report if the adverse event resulted in a

substantial disruption of a person's ability to conduct normal life functions, i.e., the

adverse event resulted in a significant, persistent or permanent change, impairment,

damage or disruption in the patient's body function/structure, physical activities

and/or quality of life.

o Congenital Anomaly/Birth Defect : Report if you suspect that exposure to a medical

product prior to conception or during pregnancy may have resulted in an adverse

outcome in the child.

o Required Intervention to Prevent Permanent Impairment or Damage (Devices) :

Report if you believe that medical or surgical intervention was necessary to

preclude permanent impairment of a body function, or prevent permanent

damage to a body structure, either situation suspected to be due to the use of a

medical product.

o Other Serious (Important Medical Events) : Report when the event does not fit the

other outcomes, but the event may jeopardize the patient and may require

medical or surgical intervention (treatment) to prevent one of the other outcomes.

Serious Adverse Events possibly related to the study drug with causality assessment must

be reported. Report includes only SAEs possibly related to the treatment. SAEs must be

reported promptly by logging into the study website https://data.castoredc.com/.

The local doctor reporting the event enters a narrative description of the event and its

seriousness that includes the patient’s trial identification number. Include in the report

results of relevant lab tests and other examinations performed outside protocol

scheduled visits.


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SUSARS are Suspected Unexpected Serious Adverse Reactions that are fatal or life-

threatening, such as Stevens-Johnson syndrome, anaphylaxis, aplastic anemia, or

anything comparably uncommon.

Suspected Unexpected Serious Adverse Reaction (SUSAR) includes:

o serious adverse reactions not listed in the Investigator’s Brochure (IB), or

o not listed in the IB at the specificity or severity observed, or

o mentioned in IB as anticipated due to pharmacokinetic properties of the drug, or

o occurred with other drugs in this class, but not with the trial study drug.

SUSARS should be uncommon but must be reported promptly by logging into the study

website https://data.castoredc.com/.

The local doctor reporting the event then enters a narrative description of the event

and its seriousness that includes the patient’s trial identification number.

SAEs (only those possibly related to the treatment)and SUSARs entered onto the study

website are reviewed promptly and, unless refuted, will be reported by the trial center

to the Global Data and Safety Monitoring Committee (Appendix 1), the appropriate

National Regulatory Agency, and the local Ethics Review Committee, the WHO Ethics

Review Committee and the National Regulatory Agency holding the investigational

new drug application via the drug developer within 24 hours of having been entered.

The trial center may need to seek further clarification of the nature and outcome of the

event, and any new information on it that is considered significant on the central review

will be sent as a follow-up report within 15 days.


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SOP-9 Reporting of protocol deviations and violations

A protocol deviation is generally considered to be a departure from the study protocol,

or other study-related documents, that has not been approved by the Ethics Review

Committee.

The investigator should not implement any deviation from, or changes of the protocol

without agreement by the sponsor and prior review and documented approval/

favourable opinion from the Ethics Review Committee of such amendment, except

where:

o it is necessary to eliminate an immediate hazard(s) to trial subjects (because the

protocol leaves the local doctor fully responsible for all decisions about patient

care, including discontinuing study medication if considered appropriate), or

o when the change(s) involves only logistical or administrative aspects of the trial

(e.g., change in monitor(s), change of telephone number(s)

A protocol violation is a divergence from the protocol that materially (a) reduces the

quality or completeness of the data, (b) makes the Informed Consent Form inaccurate,

or (c) impacts a subject's safety, rights, or welfare.

When investigators are aware that a deviation is likely to take place, they may take a

prior approval of the sponsor in the form of a waiver for the deviation, but when the

deviation is discovered after it has taken place, and then the incident is a deviation

and not a waiver.

The local monitor may grant waivers (in writing) for deviations that are not likely to

impact either the data quality or safety of the subject. Since waivers are preapproved

deviations, no action is necessary to be taken.

Major protocol deviations and protocol violation should be uncommon but must be

reported promptly by logging into the study website https://data.castoredc.com/.

The investigator reporting the event then enters a narrative description of the event and

its seriousness that includes the trial identification number patient’s affected and the

corrective actions taken.


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Appendix 1. Global Data and Safety Monitoring Committee

Global Data and Safety Monitoring Committee (DSMC): This independent committee

will not include representatives of the trial sponsors, trial committees or trial centers, and

will not include any doctors who are directly responsible for the treatment of individual

COVID patients.

Interim trial analyses will be monitored by the DSMC. Otherwise, the WHO, collaborators,

and administrative staff (except those who produce the confidential analyses) will

remain ignorant of the interim results.

The DSMC will, at intervals decided by itself, examine confidential interim analyses of

safety and efficacy, reporting them to the executive group only if the DSMC considers

them likely to require publication or a change in the conduct of the trial. Otherwise, the

trial sponsors, trial committees, and trial centers will remain blind to the interim findings.

The protocol states that the evidence on mortality must be strong enough, and the range

of uncertainty around the results must be narrow enough to affect national and global

treatment strategies. It also states that realistic, appropriate sample sizes could not be

estimated at the start of the trial; that it may be possible to enter several thousand

hospitalized patients with the relatively mild disease when admitted and a few thousand

with severe disease, yielding results that are separately reliable for each; and that the

response to certain treatments may differ substantially between different populations or

sub-populations (e.g., patients with particular prior conditions, older adults, patients in

one or another large country).

In the light of this, the DSMC will independently evaluate the interim analyses and will

inform the Executive Group of the Steering Committee if at any stage the results are, in

the judgement of the DSMC, sufficiently robust for general release (ie, strong enough

and with a sufficiently narrow range of uncertainty around the findings to affect

national and global treatment strategies). The DMSC will decide independently how

best to respond to interim analyses of safety and apparent efficacy, and what further

such analyses to require.

Although the DSMC will be informed of each such SAE and SUSAR and major protocol

violations as the trial office deals with reporting it, the DSMC may chiefly be concerned

not with each individual event, but with the confidential analyses of the accumulated

evidence on all such events. In light of this, the DMSC will decide independently how

best to respond to the evidence on adverse reactions.

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Appendix 2. Solidarity Trial Governance

The Director-General of the WHO will invite the Ministries of Health of selected member

states to join the trial. Within each country, the WHO and the Ministry of Health would

act as co-sponsors of the trial.

International Steering Committee: This will govern the conduct of the trial in accordance

with the agreed international protocol, amended as necessary during the study.

Governments that do decide to join will, in consultation with WHO, appoint two members

to the international steering committee. One will be a Governmental representative of

the Ministry of Health (or national Medical Research Council, or equivalent), and the

other will be a leading clinician who would act as the national PI of the trial, and who

would seek the collaboration of appropriate local clinicians at major hospitals. These two

members from each country would be jointly responsible for obtaining rapidly, at national

and at the local hospital level, ethical approval and any other relevant permissions, and

for encouraging whole-hearted participation by the collaborating hospitals.

Executive group of the steering committee: For practicality, a smaller executive group

of about 5-9 members of this committee will be set up in consultation with WHO. They

will confer electronically at frequent intervals with WHO to ensure the study is being

conducted appropriately by the team within WHO and to ensure the trial steering

committee is appropriately informed and consulted.

WHO trial center (Geneva): This will be responsible for the conduct of the trial. It will

establish and maintain a web-based service for randomization, for receiving electronic

reports of any SAEs and SUSARs for entry of follow-up information, and for sending

reminders when follow-up is overdue. The trial center will help deal with obtaining all

necessary approvals, recruiting and motivating centers, ensuring drug supplies, and

reporting SUSARS. It will monitor recruitment rates, follow-up rates, data plausibility, and

overdue follow-up, describing and regularly discussing with the executive group all

aspects of the progress of the trial, but not conducting interim analyses of trial results.

Global Data and Safety Monitoring Committee (DSMC): This independent committee

will examine confidential interim analyses of safety and efficacy, reporting them to the

executive group only if the DSMC considers them likely to require publication or a

change in the conduct of the trial. Otherwise, the trial sponsors, trial committees, and

trial centers will remain blind to the interim findings.

Add-on studies: The trial involves only a simple characterization of patients and outcomes.

So, within particular countries, some hospitals participating in the trial may choose to

collaborate with each other in more detailed studies. Such add-on studies should not

analyze trial treatment allocation in relation to the main trial outcomes of the duration of

hospital stay, ventilation, and mortality until after the main trial findings have been

published in the names of all collaborators. Apart from that, the planning, conduct, and

reporting of any such studies are wholly independent of WHO trial governance.

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Appendix 3. Protocol amendment history

Version Date Description of main amendments o

o

o

o

Documents

SOLIDARITY TRIAL PLUS