1 ANRS REFLATE TB SC meeting – 5 April 2011 Trial profile and progress overview (by March 30 th, 2011)

2 ANRS REFLATE TB SC meeting – 5 April 2011 INCLUSIONS 1 st patient enrolled in France : July 30 th, st patient enrolled in Brazil : February 22 th, 2010 End of inclusions is postponed to July patients to be included per month 150 patients Trial profile and progress overview

3 ANRS REFLATE TB SC meeting – 5 April 2011 Brazilian Sites (1) Rio de Janeiro – Beatriz Grinsztejn Laboratório de Pesquisa Clínica em DST e Aids - IPEC / FIOCRUZ - Inclusion (prevision) 30 patients - Pharmacokinetic, Immunological and Genetic Sub-studies yes - Site Initiation (prevision) december, 2009

4 ANRS REFLATE TB SC meeting – 5 April 2011 Brazilian Sites (2) Nova Iguaçu – José Henrique Pilotto Departamento de DST – Hospital Geral de Nova Iguaçu - Inclusion (prevision) 30 patients - Pharmacokinetic, Immunological and Genetic Sub-studies yes - Site Initiation (prevision) january, 2010

5 ANRS REFLATE TB SC meeting – 5 April 2011 Brazilian Sites (3) São Paulo – Jose Valdez Madruga Centro de Referência e Treinamento em DST/Aids – SES/SP - Inclusion (prevision) 25 patients - Pharmacokinetic and Immunological Sub- studies no - Genetic Sub-study yes - Site Initiation (prevision) january, 2010

6 ANRS REFLATE TB SC meeting – 5 April 2011 Brazilian Sites (4) Porto Alegre – Nêmora Barcelos Serviço de Atenção Terapêutica – Hospital Sanatório Partenon - Inclusion (prevision) 25 patients - Pharmacokinetic and Immunological Sub-studies no - Genetic Sub-study yes - Site Initiation (prevision) january, 2010

7 ANRS REFLATE TB SC meeting – 5 April 2011 Brazilian Sites (5) Salvador – Carlos Brites Laboratório de Pesquisa Clínica em Infectologia – Hospital Universitário Prof. Edgar Santos - Inclusion (prevision) 25 patients - Pharmacokinetic and Immunological Sub-studies no - Genetic Sub-study yes - Site Initiation (prevision) january, 2010

8 ANRS REFLATE TB SC meeting – 5 April 2011 Brazilian Sites (6) Hospital Conceição Dr Breno Riegel Santos Inclusion (prevision) 20 patients

9 ANRS REFLATE TB SC meeting – 5 April 2011 Brasil Coordinating site activities Clinical Sites identification and contact Financial agreements with the sites Conduction of local regulatory process Conduction of Drug importation and distribution to the clinical sites Laboratory contracts development Protocol training(lab,eCRFs,pharmacy) Site initiation Randomization Site monitoring Assistance with any protocol related issues Repository

10 ANRS REFLATE TB SC meeting – 5 April 2011 ANVISA Submissions and Approvals (Protocol and Import License) Submission Date 30/07/2009 Registration Error at ANVISA 09/09/2009 New registration 09/09/2009 First questions received from ANVISA 10/11/2009 Answers protocolled at ANVISA 18/11/2009 Protocol and import license approval (prevision) dezembro/2009

11 ANRS REFLATE TB SC meeting – 5 April 2011 First Training Performed (1) Date: 24 and 25/09/2009, in Rio de Janeiro Participants: - Brazilian PI - Brazilian Coordination - Subinvestigators, study coordinators and pharmacists of all sites - Loboratory cooordinators - Central Pharmacy Team

12 ANRS REFLATE TB SC meeting – 5 April 2011 First Training Performed (2) Activities: Presentation : –protocol –study operational precedures –estimates of the patients inclusions –laboratory procedures –randomization procedures

13 ANRS REFLATE TB SC meeting – 5 April 2011 First Training Performed (3) Presentation: –management medication procedures –central pharmacy procedures –SAEs report procedures –capture System –CRF –monitoring procedures

14 ANRS REFLATE TB SC meeting – 5 April 2011 Initiation Visit at Sites (1) Visit performed by Project Manager, Monitor, Data Manager, Pharmacyst and Laboratory Coordinator Visits took place in the clinical department, all laboratories and the hospital pharmacy ANRS opening of clinical sites procedures were formalized

15 ANRS REFLATE TB SC meeting – 5 April 2011 Initiation Visit at Sites (2) The following issues were reviewed: –study operational precedures –laboratory procedures –randomization procedures –management medication procedures –central pharmacy procedures –SAEs report procedures –monitoring procedures

16 ANRS REFLATE TB SC meeting – 5 April 2011 Initiation Visit at Sites (3) eCRF training was performed Site Initiation prevision: Rio de Janeiro december, 2009 Nova Iguaçu, São Paulo, Porto Alegre and Salvador january/february, 2010

17 ANRS REFLATE TB SC meeting – 5 April 2011 Pre-inclusions and inclusions curves In France:

18 ANRS REFLATE TB SC meeting – 5 April 2011 Pre-inclusions and inclusions curves In Brazil:

19 ANRS REFLATE TB SC meeting – 5 April 2011 Pre-inclusions and inclusions curves In Brazil and in France (until July 2011): 1st enrollment in France1st enrollment in Brazil

20 ANRS REFLATE TB SC meeting – 5 April 2011 Number of randomized patients per month

21 ANRS REFLATE TB SC meeting – 5 April 2011 Distribution per site

22 ANRS REFLATE TB SC meeting – 5 April 2011 Pre-included N = 149 France N = 8 Brazil N = 141 To be included into the analysis N = 124 Excluded from the analysis N = 0 Randomized N = 124 France N = 8 Brazil N = 116 Treated N = 124 Non treated N = 0 Lost to follow up N = 2 withdrawal N = 3 Strategy discontinuation N = 6 Non included N = 17 France N = 0 Brazil N = 17 Flow diagram of ANRS REFLATE TB trial data by 30 March 2011

23 ANRS REFLATE TB SC meeting – 5 April 2011 Withdrawal(s) – Lost to follow up - Strategy discontinuation Withdrawals : N=3 Lost-to-follow up : N=2 Strategy discontinuations : N=6 anti-TB : N=2 ARV : N=3 ARV and anti-TB : N=1

24 ANRS REFLATE TB SC meeting – 5 April 2011 Sub-studies enrolment Trial profile and progress overview

25 ANRS REFLATE TB SC meeting – 5 April 2011 Pharmacokinetic sub-study Objectives –To study the pharmacokinetic interactions between rifampin and raltegravir (at the doses of either 400 mg bid and 800 mg bid Endpoint –Evolution of pharmacokinetic parameters of raltegravir between week 4 (with rifampin) and at least 1 month after rifampin discontinuation (before dose decrease for patients in the raltegravir 800 mg arm)

26 ANRS REFLATE TB SC meeting – 5 April 2011 Immunological sub-study Objective –To assess the incidence of immune reconstitution inflammatory syndrome (IRIS) and to identify potential predictors of IRIS Endpoint –Rate and predictors of immune reconstitution inflammatory syndrome (IRIS) 40 patients planned by the protocol 43 patients have been included Inclusions were stopped in October 2010

27 ANRS REFLATE TB SC meeting – 5 April 2011 Genetic sub-study Objective : To assess relationship between genetic polymorphism of genes involved in the metabolization and transport of ARV or anti-TB drugs (UGT1A1, CYP2B6, acetylase, MDR1) and plasma concentrations, efficacy and tolerance By March 30 th, 2011 : 120 patients agreed (and 4 disagreed) to participate so far

28 ANRS REFLATE TB SC meeting – 5 April 2011 PRESENTING REFLATE TB RESULTS 19th Conference on Retroviruses and Opportunistic Infections (CROI) : - on February-March Late breaker abstract on January 2012 (= last patient inclusion should be in June 2011) XIX International AIDS Conference : - on July 2012 (Washington DC, USA) - Abstract submission will open towards the end of th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) : - on September Abstract soumission deadline : May 2012 Different possibilities (depending on patient recruitment and conference deadlines)

29 ANRS REFLATE TB SC meeting – 5 April 2011 INSERM-Bordeaux Implementation of eCRF Excellent day by day protocol management Excellent level of communication and trouble shooting

30 ANRS REFLATE TB SC meeting – 5 April 2011 ANRS All steps implemented so far came along very smoothly Nice scientific environment and partnership

31 ANRS REFLATE TB SC meeting – 5 April 2011 Challenges Finalize enrollment within the planned timeframe Keep very low levels of LFU Funding for substudies Next projects?

32 ANRS REFLATE TB SC meeting – 5 April 2011 Obrigada!