Clinical Trials

MainTitle

Raltegravir Versus Efavirenz in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis (REFLATE TB2)

This study has been completed
Sponsor
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)

Collaborator
Merck Sharp & Dohme Corp.
Ministry of Health, Brazil

Information provided by (Responsible Party)
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
ClinicalTrials.gov Identifier
NCT02273765

First received: October 20, 2014
Last updated: December 28, 2018
Last Verified: December 2018
History of Changes
Purpose

Purpose

Phase III trial evaluating raltegravir as an alternative to efavirenz for antiretroviral treatment of HIV-infected patients with tuberculosis.

Condition Intervention Phase
HIV-1 Infection
Tuberculosis

Drug : Tenofovir + lamivudine + raltegravir
Drug : Tenofovir + lamivudine + efavirenz
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase III Open-label Randomized Multicenter Trial to Assess the Non-inferiority of Raltegravir Compared With EFavirenz, Both in Combination With LAmivudine and TEnofovir, in ART-naïve HIV-1-infected Patients Receiving Rifampin for Active TuBerculosis

Further study details as provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):

Primary Outcome Measures

  • Proportion of patients in virologic success [ Time Frame: Week 48 ]
    Virologic success, defined as plasma HIV-1 RNA <50 copies/mL, at week 48 with a window period of 42 to 54 weeks (snapshot algorithm). Discontinuation of the strategy (ie. permanent discontinuation of EFV, RAL), missing values, loss to follow-up and death will be considered as failure.
Secondary Outcome Measures:
  • Time to death [ Time Frame: Week 48 ]
  • Frequency, type and time to new or recurrent AIDS-defining illnesses [ Time Frame: Week 48 ]
  • Frequency, type and time to severe HIV-associated non-AIDS defining illnesses [ Time Frame: Week 48 ]
  • Frequency, type and time to grade 3 or 4 adverse events [ Time Frame: Week 48 ]
  • Frequency, type and time to drug-induced clinical or biological adverse reactions of grade 3 or 4 or leading to treatment interruption [ Time Frame: Week 48 ]
  • Change in plasma HIV-1 RNA from baseline to week 48 [ Time Frame: Week 48 ]
  • Proportion of patients in virologic success at each time point (HIV-1 RNA<50 copies/mL) [ Time Frame: Week 48 ]
  • Time to virologic failure during follow-up [ Time Frame: Week 48 ]
  • Frequency and time to new antiretroviral genotypic resistance in plasma RNA in patients with virologic failure [ Time Frame: Week 48 ]
  • Change in CD4 cell counts from baseline to week 48 [ Time Frame: Week 48 ]
  • Frequency, type and time to Immune Reconstitution Inflammatory Syndrome [ Time Frame: Week 48 ]
  • Frequency of tuberculosis treatment outcomes [ Time Frame: Week 48 ]

Enrollment: 460
Study Start Date: September 11, 2015
Study Completion Date: November 28, 2018
Primary Completion Date: November 28, 2018 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Active Comparator: Raltegravir
Tenofovir 300mg QD + lamivudine 300mg QD + raltegravir 400mg BID
Drug: Tenofovir + lamivudine + raltegravir
    In this arm, patients will receive the following medications :
    • Tenofovir disoproxil fumarate (TDF) 300 mg / Lamivudine (3TC) 300 mg FDC once a day (1 tablet qd)
    • Raltegravir (RAL) 400 mg (Isentress®): twice daily (1 tablet bid), with food
    In countries where TDF/3TC FDC is not available, the following separate drugs will be used:
    • Tenofovir disoproxil fumarate (TDF) 300 mg (Viread® 245 mg): once a day (1 tablet qd)
    • Lamivudine (3TC) : 300 mg once a day (300 mg, 1 tablet qd or 150 mg 2 tablets qd)
    • Raltegravir (RAL) 400 mg (Insentress®): twice daily (1 tablet bid), with food

    Experimental: Efavirenz
    Tenofovir 300mg QD + lamivudine 300mg QD + efavirenz 600mg QD
    Drug: Tenofovir + lamivudine + efavirenz
      In this arm, patients will receive the following medications, in accordance with treatment guidelines in all countries:
      • Tenofovir disoproxil fumarate (TDF) 300 mg / lamivudine (3TC) 300 mg FDC once a day (1 tablet qd)
      • Efavirenz (EFV) 600 mg: once a day, at night (1 tablet qd)
      OR:
      • • Tenofovir disoproxil fumarate (TDF) 245 300 mg / lamivudine (3TC) 300 mg / efavirenz (EFV) 600 mg: once a day (1 tablet qd), at night, if possible without food
      In countries where TDF/3TC FDC is not available, the following separate drugs will be used:
      • Tenofovir disoproxil fumarate (TDF) 300 mg (Viread® 245 mg): once a day (1 tablet qd)
      • Lamivudine (3TC): 300 mg once a day (300 mg, 1 tablet qd or 150 mg 2 tablets qd)
      • Efavirenz (EFV) 600 mg: once a day, at night (1 tablet qd), if possible without food. The dose will not be adapted to the patient's body weight.

      Detailed Description:

      Phase III multicenter, international, open-label, randomized trial evaluating non-inferiority of raltegravir at dose of 400mg BID compared to efavirenz 600mg QD, both in association with tenofovir disoproxil fumarate and lamivudine in ART-naïve HIV-1 infected patients with active TB disease receiving a rifampin-based TB treatment initiated <8 weeks before inclusion. Patients will be randomized between 2 arms: the raltegravir (RAL) 400 mg bid arm or the efavirenz (EFV) 600 mg qd arm, each in combination with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) and will be followed for 48 weeks after entry in the trial (ART initiation).

      Eligibility

      Eligibility

      Ages Eligible for Study: 18 Years and older  
      Sexes Eligible for Study: All  
      Accepts Healthy Volunteers: No  

      Criteria

      Inclusion Criteria:

      • Signed informed consent form
      • Aged 18 years or more
      • Confirmed HIV-1 infection as documented at any time prior to trial entry per national HIV testing procedures
      • ART naïve
      • For women of childbearing potential i.e. women of childbearing age who are not menopausal, or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) or not refraining from sexual activity: negative urinary test for pregnancy and acceptance to use contraceptive methods
      • Confirmed or probable active TB disease of any location, except neurological (meningitis or encephalitis), according to the following criteria based on WHO updated definitions:
        • Bacteriologically confirmed pulmonary TB (PTB) or extrapulmonary TB (EPTB), e.g. TB with a biological specimen positive by smear microscopy, culture or nucleic acid amplification test (such as Xpert MTB/RIF).
        • Clinically diagnosed PTB or EPTB with typical histological evidence of TB (caseous or granulomatous) on biopsy specimen or positive urinary LAM test OR a significant improvement on TB treatment
      • Ongoing standard rifampin-containing TB treatment for ≤8 weeks at inclusion
      • For French patients, affiliation to a Social Security program


      Exclusion Criteria:
      • HIV-2 co-infection
      • Impaired hepatic function (icterus or ALT (SGPT) > 5ULN)
      • Hemoglobin < 6.5 g/dl
      • Creatinine clearance <60ml/min (assessed by the Cockroft and Gault formula)
      • Mycobacterium tuberculosis strain resistant to rifampin (current or past history).
      • Neurological TB (meningitis or encephalitis)
      • Severe associated diseases requiring specific treatment (including all specific AIDS defining illnesses other than TB, and any severe sepsis)
      • Any condition which might, in the investigator's opinion, compromise the safety of treatment and/or patient's adherence to trial procedures including very severe TB-related clinical condition
      • Concomitant treatments including phenytoin or phenobarbital (compounds interacting with UGT1A1)
      • For HCV co-infected patients, need to start specific treatment for hepatitis during the trial duration
      • For women of childbearing potential:
        • Pregnancy or breastfeeding
        • Refusal to use a contraceptive method
        • Any history of ARV intake for prevention of mother to child transmission of HIV (pMTCT)
      • Subjects participating in another clinical trial evaluating therapies and including an exclusion period that is still in force during the screening phase
      • Person under guardianship, or deprived of freedom by a judicial or administrative
      decision

      contacts and locations

      Contacts and Locations

      Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

      Please refer to this study by its ClinicalTrials.gov identifier: NCT02273765

      Locations

      Brazil
      Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ
      Rio de Janeiro, Brazil
      Côte D'Ivoire
      PACCI / CePReF Centre de Prise en charge de Recherche et de Formation
      Abidjan, Côte D'Ivoire
      France
      Hôpital Saint Louis
      Paris, France
      Mozambique
      Instituto Nacional de Saude / Hospital Geral de Machava
      Maputo, Mozambique
      Vietnam
      Pham Ngoc Thach Hospital
      Ho Chi Minh City, Vietnam

      Sponsors and Collaborators

      French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
      Merck Sharp & Dohme Corp.
      Ministry of Health, Brazil

      Investigators

      Study Chair: Beatriz Grinsztejn, MD, PhD Laboratory on Clinical research on DST/AIDS-IPEC FIOCRUZ Av Brasil, 4365 Manguinhos Rio de Janeiro, Brazil CEP 21040-900
      Study Chair: Nathalie De Castro, MD AP-HP Hôpital Saint-Louis 1 avenue Claude Vellefaux, 75010 Paris, France
      More Information

      More Information


      Responsible Party: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)  
      ClinicalTrials.gov Identifier: NCT02273765   History of Changes  
      Other Study ID Numbers: ANRS 12300 REFLATE TB2  
      Study First Received: October 20, 2014  
      Last Updated: December 28, 2018  

      Additional relevant MeSH terms:
      Tuberculosis
      Tenofovir
      Lamivudine
      Efavirenz
      Raltegravir Potassium

      ClinicalTrials.gov processed this data on May 24, 2020
      This information is provided by ClinicalTrials.gov.