Clinical Trials for TB in India

Soumya Swaminathan MD, National Institute for Research in TB (formerly Tuberculosis Research Centre), Chennai

Tuberculosis in India
Accounts for > 25% of global TB burden 2 million new cases, 1.5 million in RNTCP ~ 1000 deaths/day ~ 60% adults latently infected with M.tuberculosis ~ 100,000 MDRTB cases each year 90,000 notified pediatric cased (7% of total) Major risk factors
Undernutrition HIV Diabetes mellitus Smoking, indoor air pollution

INH Resistance and MDRTB in New and Re-treatment Cases

MDR (global) New: 3.7%, Retreatment: 20%
Relapse: 32% Failure: 49% Treatment after default: 32%

In India, among new TB cases, INH resistance 11-17%, MDRTB 2-3% Among re-treatment cases, INH resistance 25-40% and MDRTB 15-20%

Clinical Trials for TB in India

New drugs/regimens for drug sensitive and drug resistant TB HIV+ and HIV- patients Immunomodulators/supplementary agents Trials to predict/reduce toxicity Mostly conducted in public hospitals affiliated to academic centres/medical colleges or research organizations

Format of Trial Description

Aim, type of trial Nature of Intervention Primary, secondary outcome measure/s Period, sample size Site/s Sponsor Information obtained from NIH clinical trials registry and Clinical Trials Registry of India

End Points for TB Clinical Trials

Phase II:
early bactericidal activity and extended EBA 2nd month culture conversion and speed of culture conversion Safety

Phase III
Cure at end of treatment (bacteriologic) Recurrence (bacteriologic) Death usually low in HIV negative patients Development of drug resistance esp Rifampin Radiographic changes unreliable

Phase III trials for new TB therapy

Recognised endpoints in Phase III trials: Failure: Culture positive in the last 2 mo of treatment Death: except accidental deaths Recurrences: ~80% occur within 12 months of stopping treatment. Genotyping of strains important to distinguish true relapse (re-activation) from re-infection Endpoint rare (5%-10%) leading to trials involving a large number of participants > 5 years for a phase III trial from conception to presentation of results.

TRC Study 18 Ofloxacin in the intensive phase

months 1 2 3 4 5 6

Intensive phase
INH RIF

Continuation phase

PZA EMB

INH RIF PZA OFX

EDITORIAL OFFICES The New England Journal of Medicine

The authors should be congratulated for their efforts to further shorten chemotherapy for TB.,. The paper convincingly shows that adding a quinolone to the initial intensive phase of therapy permits the regimen to be shortened to 4 or 5 months with no loss in efficacy and no important increase in toxicity. I have no important reservations or suggestions regarding the study design or its results. However, it would be of interest to the world to mention the added cost of ofloxacin . The ICMR has contributed greatly to our understanding of TB. It is good to know that the tradition continues.

Response at end of treatment

(360 patients with drug susceptible TB)
Ind J Tub 2002: 49: 27-38
1% 1% 1% 1%

92%

94%

96%

97%

Relapse after treatment (up to 24 months) (341 patients with drug susceptible TB)
Ind J Tub 2002: 49: 27-38

Regimen Patients O3 O4 O5 O4 (2) 83 81 86 91

Relapse No (%) 7 3 2 12 (8%) (4%) (2%) (13%)

Time of relapse after treatment (in months) 1-6 7-12 > 12 5 3 2 9 1 0 0 3 1 0 0 0

Efficacy and Tolerability of 3- and 4- month regimens containing Moxifloxacin in sputum smear and culture positive pulmonary TB
Randomized, parallel group, multiple arm, open label trial (phase III) Intervention: 4 regimens containing Moxifloxacin Outcomes: Relapse (24 months after completion of treatment), sputum culture conversion at 2nd month, bacteriologic response at end of treatment, adverse reactions Period: 2007-2015, sample size 1650 Site and sponsor: Tuberculosis Research Centre, ICMR

Regimens
Regimen 1 Test Reg 1 Test Reg 2 Test Reg 3 Test Reg 4 Control Months 2 3 RHZEM 4 5 6 3 RHM 4 4 4 6 Month s

RHZEM

RHZEM RHM3 600 mg R Rifampicin 450/

H Isoniazid 300/ 600 mg Z Pyrazinamide mg RHZEM RHEM1500 3 E Ethambutol 800/ 1200 mg M Moxifloxacin 400 mg

RHZE3

RH3

Moxifloxacin 3 and 4-month regimens: 2-mo sputum culture conversion

P 0.06

P 0.001

High Dose Isoniazid Adjuvant therapy for Multi Drug Resistant TB

Randomized double blind placebo control, parallel assignment safety/efficacy study Intervention: INH high (16-18mg/kg/day) and regular dose (5mg/kg/day) vs placebo in addition to standardized MDR regimen (kanamycin, levofloxacin, protionamide, cycloserine, PAS) Outcome: Time to sputum culture conversion, radiological improvement, proportion with peripheral neuropathy, hepatotoxicity Period: 2004-2007, SS 134 Sites: Kanpur and Nagpur, India Sponsor: GSVM Medical college, Kanpur

Antibacterial activity, safety and tolerability of TMC207 in patients with MDRTB

Randomized double blind parallel assignment safety/efficacy study (Phase II) 2 stages: exploratory (I) and proof of effectiveness (II) Intervention: TMC 207 400mg QD for 14 days, 200mg tiw for 6 or 22 weeks vs placebo, in addition to background regimen (national guideline) Outcome: time to sputum culture conversion (8 weeks) and 24 weeks. Pharmacokinetics of TMC 207 and its metabolite M2 in plasma and sputum, PK/PD relationships for activity and safety/efficacy, drug interactions with other drugs in background regimen. Patients will be followed for 96 wks Period: 2007-2012. Sample size 50 for I stage and 150 for stage II Sites: Multicentric (south Africa, Thailand, Brazil, India, Latvia, Peru, Philippines, Russia) Sponsor: Tibotec Virco Virology

STREAM Trial: The Evaluation of a Standardised Treatment Regimen of AntiTuberculosis Drugs for Patients with MDR-TB
Based on short Bangladesh regimen tried under operational/program conditions 4 countries: Ethiopia, India, S Africa, Vietnam Test regimen: moxifloxacin, clofazimine, ethambutol and pyrazinamide given for nine months (40 weeks), supplemented by kanamycin, isoniazid and prothionamide in the first four months (16 weeks). Total max length: 48 weeks Control regimen: Locally used WHO-approved MDRTB treatment regimen Primary Outcomes: proportion of patients with a favourable outcome at 27 months and proportion of patients experiencing Grade III or IV AE

Efficacy of 6- vs 9-month intermittent short course ATT in HIV-infected TB patients

Randomized open label Phase III trial Patients with HIV and pulmonary/ extrapulmonary TB randomized to receive 2EHRZ3/4RH3 or 2EHRZ3/7RH3 ART naive Outcome: cure, relapse rate at 24 months Period: 2001-2008, SS 300 Site: Tuberculosis Research Centre, Chennai Sponsor: Indian Council of Medical Research

Am J Respir Crit Care Med 2010; 181:743-51

300 patients, ART-nave, 70% PTB, median CD4 count 150 Cure rate and mortality no different Recurrences (bacteriologic) significantly lower with 9-month regimen All 19 patients developed acquired Rifampicin resistance at time of failure
Am J Respir Crit Care Med 2010; 181:743-51

 Baseline and recurrence cultures fingerprinted using IS6110, MIRU-VNTR and spoligotyping 20 paired HIV+ and 25 HIV- TB patient specimens Re-activation accounted for 92% of HIV Re-infection accounted for 88% of HIV+ recurrences
J Infect Dis 2010; 201:691-703

Comparing Daily vs intermittent ATT in HIV with Pulmonary TB

Efficacy of 3 different regimens in reducing failures and emergence of acquired rifampicin resistance in HIV/TB Randomized, open label, parallel arm Regimens: 2EHRZ7/4RH7, 2EHRZ7/4RH3 2EHRZ3/4RH3 (control) ART as per national guidelines Outcomes: bacteriologic failure, ARR during treatment period 2009-2015, sample size: 420 Site: Tuberculosis Research Centre, Chennai Sponsor: USAID through WHO

Predictors and Immunologic Characterization of TB-associated IRIS in a cohort of HIVinfected TB patients in Chennai
Objectives: To identify clinical and laboratory predictors of tuberculosis-associated IRIS (TB-IRIS) To study the immunopathogenesis of TB-IRIS among HIV-infected patients initiating anti-TB and anti-retroviral trt
NIH Intramural-to-India Program/US-India JWG Collaborators: Tuberculosis Research Centre, Chennai, India (Soumya Swaminathan, G Narendran, Subhash Babu) NIH/NIAID/LIR & LPD, Bethesda, Maryland (Brian Porter, Irini Sereti, Alan Sher)

Safety and Efficacy of two different oncedaily antiretroviral treatment regimens along with anti-TB treatment
Randomized, open label, active control, parallel assignment safety/efficacy trial Interventions: ddI/3TC/NVP vs ddI/3TC/EFV along with standard intermittent TB regimen, from 2nd month of ATT Outcome: virological suppression at 6 months, adverse events, death, TB cure/relapse 2006-2009, sample size 180 Site: Tuberculosis Research centre clinics at Chennai, Madurai and Vellore, Tamil Nadu Sponsor: National AIDS Control Organization

Intent to Treat Analysis at 24 weeks

(Swaminathan et al Clinical Infectious Diseases 2011;53:716724) Response to ART Efavirenz regimen N = 59
50 (85%) p=0.038 9 6

Nevirapine regimen N = 57
38 (67%) 19 11

Favourable response
(viral load < 400 copies/ml)

Unfavourable responses failure

death
Lost to f/u

5
3

RR of failure with NVP 1.28 (95% CI 1.03-1.6)

Efficacy of a Six-month vs a 36-month regimen for prevention of tuberculosis in HIV-infected persons in India: A Randomized Clinical Trial Randomized, open label clinical trial Interventions: 6EH vs 36H Endpoint: development of TB, death, AE Period: 2001-2008 Site: Tuberculosis Research centre clinics at Chennai, Madurai Sponsor: USAID through WHO In press Plos One

Results
712 patients randomized, 2/3rds female, median CD4 count 350 TB Incidence rate (2.4 and 1.5/100 py) much lower than historical 6.9/100py both regimens highly efficacious in preventing TB No significant difference between 6EH and 36H in efficacy or safety TB and death rates 3-4 times higher in CD4<200 group, regardless of regimen Both regimens equally effective in TST+ and TST- individuals

TB Incidence Rate
6EH 36H

ITT (n= 683) rate/100 py (95% CI)

Per Protocol (n =619)

2.44 1.55 (1.42 3.46) ( 0.73 2.36)

2.03 (1.1 3.0) 1.3 (0.5 - 2.1)

Rate Ratio

1.54 (95% CI 0.72 3.25)

TB Incidence by Immune Status

Within each CD4 stratum, rates not different by regimen

Cost-Effectiveness Results
Life expectancy Strategy (years) Costs ($) Selective 16.85 95 referral Current 16.86 110 standard Routine 16.88 120 referral
India per capita GDP: $1,015

Costeffectiveness ratio ($/YLS) -660 730

Pho, M et al, PLoS One. 2012;7(4):e36001. Epub 2012 Apr 30.

Early vs Delayed initiation of ART for Indian HIV-Infected individuals with TB on ATT
Randomized, open label trial 150 HIV+ TB+ randomized to receive ART (d4T / ZDV + 3TC + EFV) after 2-4 or 8-12 weeks of starting ATT Primary end points: death from any cause & progression of HIV disease No difference in mortality in groups Incidence of ART failure was 31% in delayed versus 16% in early ART arm (p = 0.045) KM - Disease progression free Sinha et al, BMC Infectious Diseases 2012, 12:168 doi:10.1186/1471-2334survival 12-168
At 79%, significantly better for the early ART group, as against 64% for delayed ART group (p = 005)

Immediate versus delayed start of anti-HIV therapy in HIV-infected TB patients with CD4< 250 cells/mm3 (ACTG 5221) N Engl J Med 2011;365:1482-91.
Immediate (within 2 weeks) ART compared to deferred ART (after 8 weeks) of ATT in reducing death and AIDSdefining illness Randomized, open label, active control, parallel assignment, safety/efficacy study TDF/FTC/EFV orally once daily within 2 weeks or at 812 weeks of ATT in patients with CD4 < 200 cells/mm Outcome: proportion of patients surviving without AIDS progression at week 48 Period: 2006-2013, SS 800 Site: multicentric, 22 sites globally. YRG Care, Chennai Sponsor: NIAID, NIH

Results (ACTG 5221)

809 patients, median CD4 77 12.9% of early ART group and 16% of delayed group had AIDS-defining event or death within 48 weeks, ns Among patients with CD4< 50, 15.5% vs 27% developed new illness or died, p=0.02 TB IRIS more common with early (11%) compared to deferred ART (5%) Virological suppression at 48 weeks same (~75%)

Other ACTG/HPTN studies at YRG Care, Chennai or NARI, Pune

HPTN 052: Can TB and other OIs be prevented by starting ART early? ACTG 5253: Diagnostic algorithm for TB using new tools ACTG 5274: Empiric TB treatment in HIV+ patients with CD4< 50 GSK TB vaccine in HIV+ subjects: safety and immunogenecity

Efficacy of Thrice weekly DOTS in HIVassociated tuberculosis

Non-randomized open label active control parallel assignment efficacy study Efficacy of thrice-weekly intermittent short course anti-TB chemotherapy in TB patients with and without HIV 2EHRZ3/4RH3 in HIV+ and HIV- patients Outcome: cure rate, treatment failure, death, relapse, adverse drug reactions Period: 2006-2009, SS 150 Site and Sponsor: All India Institute of Medical Sciences, New Delhi and Ministry of health Study completed, manuscript submitted

Efficacy and Safety of Immunomodulator as an Adjunct Therapy in New Pulmonary TB (Cat I) Patients
Randomized double blind placebo controlled safety/efficacy study (Phase III) 6 doses of Mycobacterium indicus pranii 0.1 ml (100 million bacilli) intradermal Time of sputum conversion and cure rate, relapses and clinical adverse events Period: 2007-2009, sample size 300 Multicentric Sponsor: Dept of Biotechnology, Govt of India Data under analysis

Efficacy and Safety of Immunomodulator as an Adjunct Therapy in Pulmonary TB Retreatment Patients

Randomized double blind placebo controlled safety/efficacy study (Phase III) 6 doses of Mycobacterium indicus pranii in improving sputum conversion and cure rate, reducing relapses and safety issues in Cat II patients Period: 2005-2010, sample size 1020 Multicentric: Delhi, Tamil Nadu, Rajasthan, Andhra Pradesh Sponsor: Dept of Biotechnology, Govt of India Data under analysis

Efficacy of Oral Zinc Administration as an Adjunct Therapy in New Pulmonary TB (Cat I) Patients
Randomized double blind placebo controlled parallel assignment efficacy trial Role of oral zinc (50mg/day) along with ATT among newly diagnosed pulm TB pts 2008-2009, sample size 150 Time of smear conversion, cure rate, relapses, adverse reactions and immunological changes Site: AIIMS, New Delhi Sponsor: Ministry of Science and Technology

Pulmonary TB and vitamin D

Randomized double blind placebo controlled efficacy study (phase III) Role of oral vit D as adjunct therapy in Cat I pulmonary TB along with assessment of immunological parameters Cholecalciferol 60,000IU weekly for 2 months, then monthly, with 1 gm calcium carbonate daily Placebo lactose Time to convert sputum positivity to negativity, effector immune function, safety, relapses Period: 2009-2010, sample size 150 Site: AIIMS, New Delhi Sponsors: Dept Biotechnology, Indian Council of Medical Research

Effect of Addition of Vit D to Conventional Treatment in New Pulmonary TB Patients

Randomized, double blind placebo control, parallel assignment safety/efficacy study 100,000 IU cholecalciferol once every 2 weeks for 2 months, in addition to ATT Time to sputum culture conversion, treatment outcomes (RNTCP), weight gain, performance status, % smear/culture positive at 8 weeks, time to growth in liquid media 2009-2011 (not recruiting yet), SS 250 Site: Christian Medical College, Vellore Sponsor: CMC and Dalhousie Univ, Canada

Micronutrient Supplementation in Pediatric Pulmonary TB

Randomized double blind factorial assignment (Phase III) Intervention: zinc 20mg/day, multimineral 2 RDA, multimineral+zinc, placebo with std ATT in pediatric (6mo-15 yrs) new pulmonary TB Outcome: change in z score for weight, improvement in x-Ray, IFN-gamma activity at 2 and 6 months, symptoms Period: 2008-2011, SS 400 Site: All India Institute of Medical Sciences Sponsor: AIIMS, Univ of Bergen

Immunomodulatory effects of Withania somnifera (Ashwagandha) in pulmonary TB

Proof of concept prospective, randomized, parallel arm, placebo controlled clinical trial to evaluate the effect of PHP-TB in patients with pulmonary TB (phase II) Intervention: Capsule PHP-TB containing hydroalcoholic extracts of Withania somnifera 300mg once daily or placebo for entire 6 months of ATT (2EHRZ3/4RH3) Outcomes: weight gain, improved QOL, sputum AFB clearance, xRay and immune parameters Period: 2008-2009, SS 120 Site and Sponsor: Govt Medical College, Jammu

Role of N-acetyl cysteine in patients with newly detected sputum positive pulm TB
Randomized, parallel group placebo controlled trial Intervention: N-acetyl cysteine 600mg once daily vs placebo, along with standard ATT Outcome: sputum smear conversion rate (1, 2, 4, 6 month), cure and relapse rates Period: 2007-2009, SS 60 Site and sponsor: Christian Medical College, Vellore

Early Prediction of anti-tuberculosis treatment induced hepatitis

Hepatitis most common side effect with short-course ATT, mortality 6-12% if drugs continued Onset 3-135 days, usually within 3 months Pathogenesis and dose relationship not clear (?value of TDM) Case control, prospective study To evaluate plasma levels of hepatotoxic drugs (INH, Rif, PZA plus significant metabolites) among patients on ATT and compare levels among those who develop drug induced hepatitis on follow up and those who do not Cat I and II patients will be enrolled and followed Outcome: plasma levels of INH, Rif and PZA among cases and controls, metabolites Period: 2007-2009, SS 100 Site and Sponsor: All India Institute of Medical Sciences,

Protective effect of curcumin, silymarin and Nacetylcysteine on antitubercular drug-induced hepatotoxicity in an in vitro model
Hum Exp Toxicol. 2012 Aug;31(8):788-97

Aim: to investigate the role of curcumin (CUR), silymarin (SILY) and N-acetylcysteine (N-ACET) on hepatotoxicity by ATT drugs using an in vitro model of human hepatocellular carcinoma cell line (HepG2) Results: (a) increased cell viability, (b) healthy-looking cell morphology as revealed by phase contrast microscopy, (c) active respiring cells as observed with confocal microscopy upon staining with a mitochondrial membrane-specific dye, MitoTracker() Red, and reduction in the sub-G(1) peak in cell cycle analysis by flow cytometry Clinical trials needed

 Hum Exp Toxicol. 2012 Aug;31(8):788-97. doi: 10.1177/0960327111433901. Epub 2012 Feb 8. Singh M, Sasi P, Gupta VH, Rai G, Amarapurkar DN, Wangikar PP. Source Department of Chemical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai, Maharashtra, India.

Study of NAT2 and Cyp2E1 gene as risk factors for hepatitis

Prospective Study of N-acetyltransferase 2 (NAT2) gene and Rifampicin induced cytochrome p4502E1 (Cyp2E1) gene as susceptibility risk factors for anti-tuberculosis drug induced hepatitis Slow acetylator genotype of NAT2 and wild type genotype of Cyp2E1 associated with greater toxicity Design: Case control, prospective Intervention: Newly diagnosed pulmonary TB patients enrolled, genotyped and followed Period: 2005-2008 (completed) Site and sponsor: Maulana Azad Medical College, N Delhi

Efficacy and Safety of Modified Anti-tubercular Regimens in Treatment of Tuberculosis in Patients With Underlying Compensated and Decompensated Chronic Liver Disease
This study is not yet open for participant recruitment. Verified August 2012 by Institute of Liver and Biliary Sciences, India Sponsor: Institute of Liver and Biliary Sciences, India ClinicalTrials.gov Identifier: NCT01677871 Study Type Interventional Study Phase Study Design Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment Condition Chronic Liver Disease With Tuberclosis Intervention

Drug: 2HRZE/4HRIsoniazid + Rifampicin+Pyrazinamide+Ethambutol for initial 2 months followed by Isoniazid + Rifampicin for next 4 months
Drug: 2HRLE/4HRIsoniazid + Rifampicin+ Levofloxacin+Ethambutol for initial 2 months followed by Isonizid + Rifampicin for next 4 months Drug: 9HLEIsoniazid+ Levofloxacin+ Ethambutol for 9 months Drug: 9RLERifampicin + Levofloxacin+ Ethambutol for 9 months Study Arm (s)

Experimental: 2HRZE/4HRIsoniazid + Rifampicin+Pyrazinamide+Ethambutol for initial 2 months floolowed by Isoniazid + Rifampicin for next 4 monthsIntervention: Drug: 2HRLE/4HR
Active Comparator: 2HRLE/4HRIsoniazid + Rifampicin+ Levofloxacin+Ethambutol for initial 2 months followed by Isonizid + Rifampicin for next 4 monthsIntervention: Drug: 2HRZE/4HR Experimental: 9HLEIsoniazid+ Levofloxacin+ Ethambutol for 9 monthsIntervention: Drug: 9RLE Active Comparator: 9RLERifampicin + Levofloxacin+ Ethambutol for 9 monthsIntervention: Drug: 9HLE

Safety and Efficacy of different regimens of reintroduction of anti-TB drugs in anti-TB drug induced liver damage
Randomized open label, dose comparison, parallel assignment safety/efficacy study At time of re-introduction of anti-TB drugs, patients randomized to i) daily INH, Rif, PZA full dose ii) Rif day 1, INH day 8, PZA day 15 full dose iii) gradually increasing doses of INH day 1, Rif day 8 and PZA day 15 Safety, predictors and risk factors for recurrence Liver functions monitored weekly Period: 2006-2008 Sites: Tirupati, AP and New Delhi Sponsor: All India Institute of Medical Sciences, N Delhi

Effect of parasitic worm infections on the immune response to TB bacteria

To determine if pre-existing intestinal helminth infection or filarial infection alters the immune response to mycobacterial antigens or clinical expression of TB Randomized clinical trial TST positive persons randomized to receive DEC+Albendazole or placebo Outcome: Change in TST status, cellular immunological changes Period: 2002-2009, SS 5200 Site: Tuberculosis Research centre, Chengleput district Sponsor: NIAID, NIH

Early bactericidal activity and pharmacokinetic study of LL 3858 among newly diagnosed sputum smear positive pulmonary TB patients
Phase IIa open label single arm study to determine EBA, extended EBA and pharmacokinetics of novel compound LL 3858 of Lupin Ltd Intervention: LL3858 400 mg OD orally for 5 days. 16 hr collection of sputum on day 1,3,4,6 Patients will receive full ATT from day 7 Outcome: Safety, fall in log10 colony forming units (CFU) of M.tuberculosis/ml sputum 0-2 days (EBA) and 2-5 days (extended EBA), PK profile full profile after 1st and 5th dose and a sample on days 7 and 8 Sample size: 40 (20 analyzable) Period: 2009 (not yet recruiting) Sponsor: Lupin Ltd

Gaps and Challenges

Low capacity for Phase I and II (EBA), PK studies Limited capacity for high quality phase III trials of new drugs/diagnostics/vaccines Few well characterized patient/ population cohorts No biological specimen repository from well characterized TB patients Limited research on pediatric TB No national network of centres that can undertake multicentric trials Few studies combining clinical and immunologic/ pathogenesis research (network of basic and

Research Priorities
Efficient and cost-effective point of care diagnostic test for TB (all forms) Shorter treatment regimens for drugsusceptible and drug resistant TB Trials of new and repurposed drugs for TB Adjunct treatment with agents that improve drug efficacy/tolerability Pharmacokinetics of first and second line anti-TB drugs in adults and children Effective TB vaccine