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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 1961 Ethambutol (E) 1952 Isoniazid (H) 1963 Rifampicin (R) 1943 Streptomycine (S) 1954 Pyrazinamide (Z) 1882 Description of the agent of TB 1940 1950 1960 1970 1980 1990 1970s: short course regimen: S/H/R or S/H/Z -9 months therapy 1st 1946: drug: S Montotherapy led to S resistance 1952: 1st regimen: S/PAS/H 18-24 months therapy 1980s: modern shortcourse regimen: E (S) H R Z 6 months of therapy 2000 2010 TB drug development: to set the scene 1961 Ethambutol (E) 1952 Isoniazid (H) Effective treatment: 95% of treatment efficacy But... 6 months treatment regimen problem of treatment adherence Emergence of MDRTB 8.8 millions new TB cases in 2010 1963 Rifampicin (R) 1943 Streptomycine (S) 1954 Pyrazinamide (Z) 1882 Description of the agent of TB 1940 1950 1960 1970 1980 1990 1970s: short course regimen: S/H/R or S/H/Z -9 months therapy 1st 1946: drug: S Montotherapy led to S resistance 1952: 1st regimen: S/PAS/H 18-24 months therapy 1980s: modern shortcourse regimen: E (S) H R Z 6 months of therapy 2000 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 8methoxyfluoroquinolones drug class and are proposed for shortened treatment of pan-susceptible TB. Gatifloxacin was chosen based on its bactericidal activity and its generic status 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) flotub 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. ). More than 10 years in development flotub Phase III pivotal trial with a nested PK/PD also called OFLOTUB 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 Patients Newly diagnosed microbiologically confirmed TB sensitive adults patients in 5 countries in Africa flotub Overview of OFLOTUB project: Phase III/PK 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 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 flotub Trial setting and OFLOTUB partners London School of Hygiene and Tropical Medicine (London) Hôpital Raymond Tropical Medical Institute LUPIN Pharma Poincaré (Paris) (Antwerp) (India) St George’s Hospital Medical School, (London) WHO / TDR Institute for Research & Development (Marseille) (Geneva) Thamassat University (Bangkok) PNLTB (Dakar, Senegal) KEMRI (Nairobi, Kenya) PNLTB (Conakry, Guinea) PNLTB (Cotonou, Benin) flotub MRC SA (Durban, South Africa) Trial setting and OFLOTUB partners London School of Hygiene and Tropical Medicine (London) Hôpital Raymond Tropical Medical Institute LUPIN Pharma Poincaré (Paris) (Antwerp) (India) St George’s Hospital Medical School, (London) WHO / TDR Institute for Research & Development (Marseille) (Geneva) Thamassat University (Bangkok) PNLTB (Dakar, Senegal) KEMRI (Nairobi, Kenya) PNLTB (Conakry, Guinea) PNLTB (Cotonou, Benin) flotub MRC SA (Durban, South Africa) Trial setting and OFLOTUB partners London School of Hygiene and Tropical Medicine (London) Hôpital Raymond Tropical Medical Institute LUPIN Pharma Poincaré (Paris) (Antwerp) (India) St George’s Hospital Medical School, (London) WHO / TDR Institute for Research & Development (Marseille) (Geneva) Thamassat University (Bangkok) PNLTB (Dakar, Senegal) KEMRI (Nairobi, Kenya) PNLTB (Conakry, Guinea) PNLTB (Cotonou, Benin) flotub MRC SA (Durban, South Africa) Trial setting and OFLOTUB partners London School of Hygiene and Tropical Medicine (London) Hôpital Raymond Tropical Medical Institute LUPIN Pharma Poincaré (Paris) (Antwerp) (India) St George’s Hospital Medical School, (London) WHO / TDR Institute for Research & Development (Marseille) (Geneva) Thamassat University (Bangkok) PNLTB (Dakar, Senegal) KEMRI (Nairobi, Kenya) PNLTB (Conakry, Guinea) PNLTB (Cotonou, Benin) flotub MRC SA (Durban, South Africa) Trial setting and OFLOTUB partners London School of Hygiene and Tropical Medicine (London) Hôpital Raymond Tropical Medical Institute LUPIN Pharma Poincaré (Paris) (Antwerp) (India) St George’s Hospital Medical School, (London) WHO / TDR Institute for Research & Development (Marseille) (Geneva) Thamassat University (Bangkok) PNLTB (Dakar, Senegal) KEMRI (Nairobi, Kenya) PNLTB (Conakry, Guinea) PNLTB (Cotonou, Benin) flotub MRC SA (Durban, South Africa) Overview of OFLOTUB project: Phase III/PK Progress status 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 Non-inferiority design 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)) flotub Non-inferiority design 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.) flotub Choice & measurement of the endpoints 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 flotub 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 Relapse : Reactivation of the original infection Re-infection: Infection with a new TB strain Effective treatment should prevent relapse but have no effect on reinfection 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 flotub Length of patient follow-up 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) flotub 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 design Laboratory staff are blinded to the treatment regimen the patient is receiving Strict & 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 Number per group for given delta and power Delta=3% Delta=5% Delta=6% ‘Event’ percentage in control group 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 24-30 Be effective against MDR- and XDR-TB Years Conventional approach would need 24-30 years to develop a combination that contains ≥ 3 new drugs ABCD E D GFE 8-10 years 8-10 years ABCE 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 ABFE F 8-10 C Years AB G Gatifloxacin product development Length Dec 2002, Grant approval (P III) August 2003, Phase I & PK Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD July 2004, Phase II SSCC Phase III: April 2011, last patient FU Phase I, Phase II, Phase III & PK/PD Design of the phase III study & set-up, capacity building +++ Phase III Recruitment period In total 10 to 11 years flotub Follow-up period Nov 2012, 1st efficacy results Phase III: last patient recruited: 31 Oct 2008 Gatifloxacin product development Length Dec 2002, Grant approval (P III) August 2003, Phase I & PK Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD July 2004, Phase II SSCC Phase III: April 2011, last patient FU Phase I, Phase II, Phase III & PK/PD Design of the phase III study & set-up, capacity building +++ 2.5 years flotub Phase III Recruitment period Follow-up period Nov 2012, 1st efficacy results Phase III: last patient recruited: 31 Oct 2008 Gatifloxacin product development Length Dec 2002, Grant approval (P III) August 2003, Phase I & PK Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD July 2004, Phase II SSCC Phase III: April 2011, last patient FU Phase I, Phase II, Phase III & PK/PD Design of the phase III study & set-up, capacity building +++ 2.5 years flotub Phase III Recruitment period Follow-up period Nov 2012, 1st efficacy results Phase III: last patient recruited: 31 Oct 2008 Gatifloxacin product development Length Dec 2002, Grant approval (P III) August 2003, Phase I & PK Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD July 2004, Phase II SSCC Phase III: April 2011, last patient FU Phase I, Phase II, Phase III & PK/PD Design of the phase III study & set-up, capacity building +++ Phase III Recruitment period Follow-up period 3.5 years Nov 2012, 1st efficacy results Phase III: last patient recruited: 31 Oct 2008 flotub Gatifloxacin product development Length Dec 2002, Grant approval (P III) August 2003, Phase I & PK Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD July 2004, Phase II SSCC Phase III: April 2011, last patient FU Phase I, Phase II, Phase III & PK/PD Design of the phase III study & set-up, capacity building +++ Phase III Recruitment period Follow-up period Nov 2012, 1st efficacy results 2 years ? Phase III: last patient recruited: 31 Oct 2008 flotub Gatifloxacin product development Length Dec 2002, Grant approval (P III) August 2003, Phase I & PK Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD July 2004, Phase II SSCC Phase I, Phase II, Phase III & PK/PD Design of the phase III study & set-up, capacity building +++ Phase III: April 2011, last patient FU Data management Phase III Recruitment period Follow-up period Nov 2012, 1st efficacy results Phase III: last patient recruited: 31 Oct 2008 flotub To reduce the length of TB drug development Set-up phase Enhancing local capacity; training & retraining….. 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 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. flotub Conclusion 1961 Ethambutol (E) 1952 Isoniazid (H) ? 1963 Rifampicin (R) 1943 Streptomycine (S) 1954 Pyrazinamide (Z) 1882 Description of the agent of TB 1940 1950 1960 1970 1980 1990 1970s: short course regimen: S/H/R or S/H/Z -9 months therapy 1st 1946: drug: S Montotherapy led to S resistance 1952: 1st regimen: S/PAS/H 18-24 months therapy 1980s: modern shortcourse regimen: E (S) H R Z 6 months of therapy 2000 2010 Conclusion TB Alliance is instrumental (www.tballiance.org) 1961 Ethambutol (E) 1952 Isoniazid (H) ? 1963 Rifampicin (R) 1943 Streptomycine (S) 1954 Pyrazinamide (Z) 1882 Description of the agent of TB 1940 1950 1960 1970 1980 1990 1970s: short course regimen: S/H/R or S/H/Z -9 months therapy 1st 1946: drug: S Montotherapy led to S resistance 1952: 1st regimen: S/PAS/H 18-24 months therapy 1980s: modern shortcourse regimen: E (S) H R Z 6 months of therapy 2000 2010 Conclusion Ignoring the vulnerable Children TB/HIV co-infected 1961 Ethambutol (E) patients 1952 Isoniazid (H) ? 1963 Rifampicin (R) 1943 Streptomycine (S) 1954 Pyrazinamide (Z) 1882 Description of the agent of TB 1940 1950 1960 1970 1980 1990 1970s: short course regimen: S/H/R or S/H/Z -9 months therapy 1st 1946: drug: S Montotherapy led to S resistance 1952: 1st regimen: S/PAS/H 18-24 months therapy 1980s: modern shortcourse regimen: E (S) H R Z 6 months of therapy 2000 2010