TB new treatments and new methodological challenges

TB new treatments and new methodological challenges

Dr Corinne Merle

Outline

Current pipeline of new TB drugs

Methodological challenges for designing TB trials (using the OFLOTUB project as an example)

Challenges in TB regimen development

TB drug development: to set the scene

1882

Description of the agent of TB

1940 1950 1960 1970 1980 1990 2000

1943Streptomycine (S)

1952Isoniazid (H)

1954Pyrazinamide (Z)

1961Ethambutol (E)

1963Rifampicin (R)

1952: 1st regimen: S/PAS/H

18-24 months therapy

1970s: short course regimen: S/H/R or S/H/Z -9 months

therapy

1980s: modern short-course regimen:

E (S) H R Z6 months of therapy

1946: 1st drug: S Montotherapy led to S resistance

2010

TB drug development: to set the scene

1882

Description of the agent of TB

1940 1950 1960 1970 1980 1990 2000

1943Streptomycine (S)

1952Isoniazid (H)

1954Pyrazinamide (Z)

1961Ethambutol (E)

1963Rifampicin (R)

1952: 1st regimen: S/PAS/H

18-24 months therapy

1970s: short course regimen: S/H/R or S/H/Z -9 months

therapy

1980s: modern short-course regimen:

E (S) H R Z6 months of therapy

1946: 1st drug: S Montotherapy led to S resistance

Effective treatment: 95% of treatment efficacyBut... 6 months treatment regimen problem of treatment adherence Emergence of MDRTB 8.8 millions new TB cases in 2010

2010

Development pipeline for new TB drugs Shortening TB treatment recognised as a major target for the improvement of

TB control Since the late 90s: new agents discovered Significant target diversity and potential for better combinations

Development pipeline for new TB drugs

Drugs at a Phase III stage Both gatifloxacin and moxifloxacin have

emerged as candidates from the 8-methoxyfluoroquinolones drug class and are proposed for shortened treatment of pan-susceptible TB.

Gatifloxacin was chosen based on its bactericidal activity and its generic status

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35 years after the East African/British Medical Research Council trials, 3 new drugs currently assessed in large Phase III trials RIFAQUIN trial (Rifapentine) REMoxTB trial (Moxifloxacin) OFLOTUB trial (Gatifloxacin)

Gatifloxacin Product Development Plan

Pre-Clinical Toxicology studies Phase I Pharmacokinetic study (J Antimicrob Chemother.

2007 Dec;60(6):1398-401)

Phase II SSCC study (Int J Tuberc Lung Dis. 2008 Feb;12(2):128-38. ).

Phase III pivotal trial with a nested PK/PD

also called OFLOTUB

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More than 10 years in

development

Overview of OFLOTUB project: Phase III/PK

Objective

To evaluate the efficacy and safety of 4-month gatifloxacin containing regimen compared to the standard WHO-recommended 6-month regimen

Study design A randomized (1:1), open-label, non-inferiority, multi-centre controlled trial with

a nested Pharmacokinetic (PK/PD) study

PatientsNewly diagnosed microbiologically confirmed TB sensitive adults patients in 5 countries in Africa

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Follow-up 2 years after completion of TB treatment Patients seen at 1, 2, 4, 6, 9, 12, 15, 18 and 24 months after treatment Clinical examination, 2 sputum samples collected for smear & culture

Treatment Test arm : 2 months GHRZ / 2 months GHR Control arm: 2 months EHRZ / 4 months RH Daily DOT during the 1st 2 months of treatment, Weekly drug delivery during the continuation

phase

Overview of OFLOTUB project: Phase III/PK

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Trial setting and OFLOTUB partners

Institute for Research & Development (Marseille)

PNLTB (Dakar, Senegal)

St George’s Hospital Medical School, (London)

KEMRI (Nairobi, Kenya)

Tropical Medical Institute (Antwerp)

Hôpital Raymond Poincaré (Paris)

PNLTB (Cotonou, Benin)

PNLTB (Conakry, Guinea)

MRC SA (Durban, South Africa)

WHO / TDR

(Geneva)

LUPIN Pharma

(India)

Thamassat University

(Bangkok)

London School of Hygiene and Tropical Medicine (London)

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Trial setting and OFLOTUB partners

Institute for Research & Development (Marseille)

PNLTB (Dakar, Senegal)

St George’s Hospital Medical School, (London)

KEMRI (Nairobi, Kenya)

Tropical Medical Institute (Antwerp)

Hôpital Raymond Poincaré (Paris)

PNLTB (Cotonou, Benin)

PNLTB (Conakry, Guinea)

MRC SA (Durban, South Africa)

WHO / TDR

(Geneva)

LUPIN Pharma

(India)

Thamassat University

(Bangkok)

London School of Hygiene and Tropical Medicine (London)

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Trial setting and OFLOTUB partners

Institute for Research & Development (Marseille)

PNLTB (Dakar, Senegal)

St George’s Hospital Medical School, (London)

KEMRI (Nairobi, Kenya)

Tropical Medical Institute (Antwerp)

Hôpital Raymond Poincaré (Paris)

PNLTB (Cotonou, Benin)

PNLTB (Conakry, Guinea)

MRC SA (Durban, South Africa)

WHO / TDR

(Geneva)Thamassat University

(Bangkok)

London School of Hygiene and Tropical Medicine (London) LUPIN Pharma

(India)

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Trial setting and OFLOTUB partners

Institute for Research & Development (Marseille)

St George’s Hospital Medical School, (London)

KEMRI (Nairobi, Kenya)

Tropical Medical Institute (Antwerp)

Hôpital Raymond Poincaré (Paris)

PNLTB (Cotonou, Benin)

PNLTB (Conakry, Guinea)

MRC SA (Durban, South Africa)

WHO / TDR

(Geneva)Thamassat University

(Bangkok)

PNLTB (Dakar, Senegal)

London School of Hygiene and Tropical Medicine (London) LUPIN Pharma

(India)

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Trial setting and OFLOTUB partners

London School of Hygiene and Tropical Medicine (London)

Institute for Research & Development (Marseille)

St George’s Hospital Medical School, (London)

KEMRI (Nairobi, Kenya)

Tropical Medical Institute (Antwerp)

Hôpital Raymond Poincaré (Paris)

PNLTB (Cotonou, Benin)

PNLTB (Conakry, Guinea)

MRC SA (Durban, South Africa)

WHO / TDR

(Geneva)Thamassat University

(Bangkok)

PNLTB (Dakar, Senegal)

LUPIN Pharma

(India)

1836 patients recruited 316 in Benin, 452 in Guinea, 200 in Kenya,

358 in Senegal and 510 in South Africa Last patient completed treatment end of

April 2009 Last patient last visit: April 2011 (i.e. 24

months of follow-up following the end of treatment)

Percentage of patients LTFU estimated to be around 10 %

First results should be released in November 2012

Progress status

Overview of OFLOTUB project: Phase III/PK

Non-inferiority design

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Rationale for Choice of Non-inferiority design

Highly efficient current TB treatment (95% cure rate) Unlikely that a new regimen will demonstrate superiority Interest lies with showing whether a new regimen is not inferior

Non-inferiority design is an excellent choice for current TB sensitive drug development (A. Nunn et al, Tuberculosis(2008))

Non-inferiority design

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Rationale for Choice of Non-inferiority design

Highly efficient current TB treatment (95% cure rate) Unlikely that a new regimen will demonstrate superiority Interest lies with showing whether a new regimen is not inferior

NI design is an excellent choice for current TB sensitive drug development (A. Nunn et al, Tuberculosis(2008))

Implication of NI design on trial population to be analysed Intention-To-Treat (ITT) Vs Per-Protocol (PP) ITT approach tends to minimise differences by including protocol deviations PP is biased because not including all randomised patients

In fact, both are equally important and require similar conclusions in order to support final result (Piaggio G, Elbourne DR, et al. JAMA 2006;295(10):1152-60.)

Choice & measurement of the endpoints

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In 1947, endpoint of BMRC Streptomycin trial: Survival or Chest Xray

Nowadays, bacteriological endpoints TB recurrence main outcome of interest But restricted to patients cured at the end of the treatment

A composite “unfavourable outcome” endpoint including: - treatment failure - Death - TB recurrences

Choice & measurement of the endpoints Bacteriological diagnosis: Cultures Solid Vs liquid media False-positive cultures results from

Misidentification of the strain Laboratory cross-contamination Clerical error reporting More than 3 % of false positive (Burman et al Clin Infect Dis 2000,

31(6):1390-1395)

Necessity to take 2 sputum samples per visit, per patient to minimise unavailability or false positive culture results

Solid medium is the gold standard

Recurrence, relapse and re-infection

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Relapse : Reactivation of the original infection Re-infection: Infection with a new TB strain Effective treatment should prevent relapse but have no effect on re-

infection Context of TB and HIV, proportion of re-infection can be high Non-inferiority design context

Necessity to differentiate relapse from re-infection using molecular method (e.g. MIRU-VNTR)

Recurrence considered to allow comparison with previous trials

Length of patient follow-up

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For a TB regimen to be acceptable: • Patient must convert to culture negative by

the end of treatment• most importantly, it must demonstrate

clearance of bacteria by keeping patients relapse-free

How long is long enough?

When to start the clock…after the end of treatment (equal follow-up between arms)? or post randomization (unequal follow-up)?

Conservative approach: 24 months after the end of the treatment

In the light of BMRC trials: 1 year follow-up could be enough (Nunn AJ et al. Int J Tuberc Lung Dis 2010, 14(2):241-242)

Discussion on when to start the clock (even more important for shorter treatment regimen trial)

Blinded design versus Open-label design

Options i) non-blinded design: an arm with 4 months of test regimen vs an arm with 6

months of standard regimen ii) blinded design : 2-months placebo added to the test arm

Discussion Double blinding design favoured in many trial situations For a shorter regimen, one of the mechanisms for treatment efficacy might

be better adherence to treatment Aspect not captured in blinded design Pro and Cons

Requirements if Open-label designLaboratory staff are blinded to the treatment regimen the patient is receivingStrict & objective endpoint definitions and a blinded endpoint committee

Sample size calculation

Sample size calculation for a constant 2.5% 1-sided level of significance and variable values for primary outcome percentage, power and delta

‘Event’ percentage in control group

Number per group for given delta and power

Delta=3% Delta=5% Delta=6%

80% 90% 80% 90% 80% 90%

5% 828 1110 298 399 207 277

10% 1570 2102 565 757 392 525

15% 2224 2977 801 1072 556 744

Sample size calculation

OFLOTUB

Major Efficacy Outcome “Unfavourable” events

% events in control arm 20%

1-sided significance level 2.5%

Power 80%

Non-inferiority margin δ 6%

# of patients overall 1,394 (2 arms)

Adjustment for non assessable patients 15%

Grand total 1,640

Importance of being powered for both ITT and PP analysis

TB Drug development challenges

Objective is to get new TB treatment regimen not only new TB drug Novel 3-drug combinations that have potential to:

Shorten treatment to 2 months or less Be co-administered with ARVs Be effective against MDR- and XDR-TB

ABFE

AB

ABCE

ABCD GFEE

D

CF

G

Conventional approach would need 24-30 years to develop a combination that contains ≥ 3 new drugs

Adaptive multi-arm multistage (MAMS) trial design, which has been successfully used in cancer — is under discussion.

Even if MAMS, TB drug trial are long and costly

8-10 years

8-10 Years

8-10 years

24-30 Years

Gatifloxacin product development Length

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Dec 2002, Grant approval (P III)

Nov 2012, 1st efficacy results

Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD

Design of the phase III study & set-up,

capacity building +++

Phase III: last patient recruited: 31 Oct 2008

Follow-up period

Phase III: April 2011, last patient FU

In total 10 to 11 years

Phase I, Phase II, Phase III & PK/PD

July 2004, Phase II SSCC

August 2003, Phase I & PK

Phase III Recruitment period

Gatifloxacin product development Length

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Dec 2002, Grant approval (P III)

Nov 2012, 1st efficacy results

Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD

Design of the phase III study & set-up,

capacity building +++

Phase III: last patient recruited: 31 Oct 2008

Follow-up period

Phase III: April 2011, last patient FU

Phase I, Phase II, Phase III & PK/PD

July 2004, Phase II SSCC

August 2003, Phase I & PK

Phase III Recruitment period

2.5 years

Gatifloxacin product development Length

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Dec 2002, Grant approval (P III)

Nov 2012, 1st efficacy results

Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD

Design of the phase III study & set-up,

capacity building +++

Phase III: last patient recruited: 31 Oct 2008

Follow-up period

Phase III: April 2011, last patient FU

Phase I, Phase II, Phase III & PK/PD

July 2004, Phase II SSCC

August 2003, Phase I & PK

Phase III Recruitment period

2.5 years

Gatifloxacin product development Length

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Dec 2002, Grant approval (P III)

Nov 2012, 1st efficacy results

Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD

Design of the phase III study & set-up,

capacity building +++

Phase III: last patient recruited: 31 Oct 2008

Follow-up period

Phase III: April 2011, last patient FU

Phase I, Phase II, Phase III & PK/PD

July 2004, Phase II SSCC

August 2003, Phase I & PK

Phase III Recruitment period

3.5 years

Gatifloxacin product development Length

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Dec 2002, Grant approval (P III)

Nov 2012, 1st efficacy results

Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD

Design of the phase III study & set-up,

capacity building +++

Phase III: last patient recruited: 31 Oct 2008

Follow-up period

Phase III: April 2011, last patient FU

Phase I, Phase II, Phase III & PK/PD

July 2004, Phase II SSCC

August 2003, Phase I & PK

Phase III Recruitment period

2 years ?

Gatifloxacin product development Length

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Dec 2002, Grant approval (P III)

Nov 2012, 1st efficacy results

Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD

Design of the phase III study & set-up,

capacity building +++

Phase III: last patient recruited: 31 Oct 2008

Follow-up period

Phase III: April 2011, last patient FU

Phase I, Phase II, Phase III & PK/PD

July 2004, Phase II SSCC

August 2003, Phase I & PK

Phase III Recruitment period

Data management

To reduce the length of TB drug development

Set-up phase Enhancing local capacity; training & re-training…..

Huge capacity building investment, important that it is being capitalised and optimised

Necessity to ensure continuity of the research investments in these sites

Necessity to adopt common guidelines for designing TB treatment trials

Recruitment period

Patient follow-up & outcome of interest Reduced to 12 months post treatment Necessity to validate surrogate markers

Datamanagement

Conclusion

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Shortening the duration of TB treatment is the major target There are TB drug development challenges There are methodological challenges when designing phase III TB

sensitive RCT We are advocating for:

a non-inferiority design, a non-blinded design, a composite unfavourable endpoint, a follow-up of 12 months post treatment completion, added trial procedures specifically aiming at minimizing

unavailability of endpoints, and distinguishing between relapse and re-infection.

Conclusion

1882

Description of the agent of TB

1940 1950 1960 1970 1980 1990 2000

1943Streptomycine (S)

1952Isoniazid (H)

1954Pyrazinamide (Z)

1961Ethambutol (E)

1963Rifampicin (R)

1952: 1st regimen: S/PAS/H

18-24 months therapy

1970s: short course regimen: S/H/R or S/H/Z -9 months

therapy

1980s: modern short-course regimen:

E (S) H R Z6 months of therapy

1946: 1st drug: S Montotherapy led to S resistance

2010

?

Conclusion

1882

Description of the agent of TB

1940 1950 1960 1970 1980 1990 2000

1943Streptomycine (S)

1952Isoniazid (H)

1954Pyrazinamide (Z)

1961Ethambutol (E)

1963Rifampicin (R)

1952: 1st regimen: S/PAS/H

18-24 months therapy

1970s: short course regimen: S/H/R or S/H/Z -9 months

therapy

1980s: modern short-course regimen:

E (S) H R Z6 months of therapy

1946: 1st drug: S Montotherapy led to S resistance

2010

?

TB Alliance is instrumental (www.tballiance.org)

Conclusion

1882

Description of the agent of TB

1940 1950 1960 1970 1980 1990 2000

1943Streptomycine (S)

1952Isoniazid (H)

1954Pyrazinamide (Z)

1961Ethambutol (E)

1963Rifampicin (R)

1952: 1st regimen: S/PAS/H

18-24 months therapy

1970s: short course regimen: S/H/R or S/H/Z -9 months

therapy

1980s: modern short-course regimen:

E (S) H R Z6 months of therapy

1946: 1st drug: S Montotherapy led to S resistance

2010

?

Ignoring the vulnerable Children TB/HIV co-infected

patients