1 ANRS 12 180 REFLATE TB SC meeting – 5 April 2011 Trial profile and progress overview (by March...

1ANRS 12 180 REFLATE TB SC meeting – 5 April 2011

Trial profile Trial profile

and progress overviewand progress overview

(by March 30(by March 30th th , 2011), 2011)


INCLUSIONSINCLUSIONS

− 1st patient enrolled in France : July 30th, 2009

− 1st patient enrolled in Brazil : February 22th, 2010

− End of inclusions is postponed to July 2011

10 patients to be included per month 150 patients

Trial profile and progress overviewTrial profile and progress overview


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


Brazilian Sites (2)

Nova Iguaçu – José Henrique PilottoDepartamento de DST – Hospital Geral de Nova Iguaçu- Inclusion (prevision) 30 patients- Pharmacokinetic, Immunological and Genetic Sub-studies yes- Site Initiation (prevision) january, 2010


Brazilian Sites (3)

São Paulo – Jose Valdez MadrugaCentro 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


Brazilian Sites (4)

Porto Alegre – Nêmora BarcelosServiço 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


Brazilian Sites (5)

Salvador – Carlos BritesLaboratório 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


Brazilian Sites (6)

• Hospital Conceição• Dr Breno Riegel Santos• Inclusion (prevision) 20 patients


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


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


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



Activities:• Presentation :

– protocol– study operational precedures– estimates of the patients inclusions – laboratory procedures– randomization procedures



• Presentation:– management medication procedures– central pharmacy procedures– SAEs report procedures– capture System– CRF– monitoring procedures


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



• The following issues were reviewed:– study operational precedures– laboratory procedures– randomization procedures– management medication procedures– central pharmacy procedures– SAEs report procedures– monitoring procedures



• eCRF training was performed

• Site Initiation prevision:Rio de Janeiro december, 2009Nova Iguaçu, São Paulo, Porto

Alegreand Salvador january/february,

2010


Pre-inclusions and inclusions curves Pre-inclusions and inclusions curves

• In France:


Pre-inclusions and inclusions curvesPre-inclusions and inclusions curves

• In Brazil:


Pre-inclusions and inclusions curvesPre-inclusions and inclusions curves • In Brazil and in France (until July 2011):

1st enrollment in France 1st enrollment in Brazil


Number of randomized patients per month Number of randomized patients per month


Distribution per site Distribution per site


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 12 180 REFLATE TB trial Flow diagram of ANRS 12 180 REFLATE TB trial data by 30 March 2011data by 30 March 2011


Withdrawal(s) – Lost to follow up - Strategy discontinuation 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


Sub-studies enrolmentSub-studies enrolment

Trial profile and progress overviewTrial profile and progress overview


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)


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 protocol43 patients have been includedInclusions were stopped in October 2010


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 30th , 2011 :

120 patients agreed (and 4 disagreed) to participate so far


PRESENTING REFLATE TB RESULTS PRESENTING REFLATE TB RESULTS

• 19th Conference on Retroviruses and Opportunistic Infections (CROI) :

- on February-March 2012

- Late breaker abstract on January 2012 (= last patient inclusion should be in June 2011)

• XIX International AIDS Conference :

- on 22-27 July 2012 (Washington DC, USA)

- Abstract submission will open towards the end of 2011

• 52th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) :

- on September 2012

- Abstract soumission deadline : May 2012

Different possibilities (depending on patient recruitment and conference deadlines)


INSERM-Bordeaux

• Implementation of eCRF• Excellent day by day protocol

management• Excellent level of communication and

trouble shooting


ANRS

• All steps implemented so far came along very smoothly

• Nice scientific environment and partnership


Challenges

• Finalize enrollment within the planned timeframe

• Keep very low levels of LFU• Funding for substudies• Next projects?


Obrigada!

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