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

Primary Purpose

HIV-1 Infection, Tuberculosis

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Tenofovir + lamivudine + raltegravir
Tenofovir + lamivudine + efavirenz
Sponsored by
ANRS, Emerging Infectious Diseases
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV-1 Infection

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ
  • PACCI / CePReF Centre de Prise en charge de Recherche et de Formation
  • Hôpital Saint Louis
  • Instituto Nacional de Saude / Hospital Geral de Machava
  • Pham Ngoc Thach Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Raltegravir

Efavirenz

Arm Description

Tenofovir 300mg QD + lamivudine 300mg QD + raltegravir 400mg BID

Tenofovir 300mg QD + lamivudine 300mg QD + efavirenz 600mg QD

Outcomes

Primary Outcome Measures

Proportion of patients in virologic success
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
Frequency, type and time to new or recurrent AIDS-defining illnesses
Frequency, type and time to severe HIV-associated non-AIDS defining illnesses
Frequency, type and time to grade 3 or 4 adverse events
Frequency, type and time to drug-induced clinical or biological adverse reactions of grade 3 or 4 or leading to treatment interruption
Change in plasma HIV-1 RNA from baseline to week 48
Proportion of patients in virologic success at each time point (HIV-1 RNA<50 copies/mL)
Time to virologic failure during follow-up
Frequency and time to new antiretroviral genotypic resistance in plasma RNA in patients with virologic failure
Change in CD4 cell counts from baseline to week 48
Frequency, type and time to Immune Reconstitution Inflammatory Syndrome
Frequency of tuberculosis treatment outcomes

Full Information

First Posted
October 20, 2014
Last Updated
December 28, 2018
Sponsor
ANRS, Emerging Infectious Diseases
Collaborators
Merck Sharp & Dohme LLC, Ministry of Health, Brazil
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1. Study Identification

Unique Protocol Identification Number
NCT02273765
Brief Title
Raltegravir Versus Efavirenz in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis
Acronym
REFLATE TB2
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2018
Overall Recruitment Status
Completed
Study Start Date
September 11, 2015 (Actual)
Primary Completion Date
November 28, 2018 (Actual)
Study Completion Date
November 28, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ANRS, Emerging Infectious Diseases
Collaborators
Merck Sharp & Dohme LLC, Ministry of Health, Brazil

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV-1 Infection, Tuberculosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
460 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Raltegravir
Arm Type
Active Comparator
Arm Description
Tenofovir 300mg QD + lamivudine 300mg QD + raltegravir 400mg BID
Arm Title
Efavirenz
Arm Type
Experimental
Arm Description
Tenofovir 300mg QD + lamivudine 300mg QD + efavirenz 600mg QD
Intervention Type
Drug
Intervention Name(s)
Tenofovir + lamivudine + raltegravir
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Tenofovir + lamivudine + efavirenz
Intervention Description
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.
Primary Outcome Measure Information:
Title
Proportion of patients in virologic success
Description
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.
Time Frame
Week 48
Secondary Outcome Measure Information:
Title
Time to death
Time Frame
Week 48
Title
Frequency, type and time to new or recurrent AIDS-defining illnesses
Time Frame
Week 48
Title
Frequency, type and time to severe HIV-associated non-AIDS defining illnesses
Time Frame
Week 48
Title
Frequency, type and time to grade 3 or 4 adverse events
Time Frame
Week 48
Title
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
Title
Change in plasma HIV-1 RNA from baseline to week 48
Time Frame
Week 48
Title
Proportion of patients in virologic success at each time point (HIV-1 RNA<50 copies/mL)
Time Frame
Week 48
Title
Time to virologic failure during follow-up
Time Frame
Week 48
Title
Frequency and time to new antiretroviral genotypic resistance in plasma RNA in patients with virologic failure
Time Frame
Week 48
Title
Change in CD4 cell counts from baseline to week 48
Time Frame
Week 48
Title
Frequency, type and time to Immune Reconstitution Inflammatory Syndrome
Time Frame
Week 48
Title
Frequency of tuberculosis treatment outcomes
Time Frame
Week 48

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Beatriz Grinsztejn, MD, PhD
Organizational Affiliation
Laboratory on Clinical research on DST/AIDS-IPEC FIOCRUZ Av Brasil, 4365 Manguinhos Rio de Janeiro, Brazil CEP 21040-900
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Nathalie De Castro, MD
Organizational Affiliation
AP-HP Hôpital Saint-Louis 1 avenue Claude Vellefaux, 75010 Paris, France
Official's Role
Study Chair
Facility Information:
Facility Name
Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ
City
Rio de Janeiro
Country
Brazil
Facility Name
PACCI / CePReF Centre de Prise en charge de Recherche et de Formation
City
Abidjan
Country
Côte D'Ivoire
Facility Name
Hôpital Saint Louis
City
Paris
Country
France
Facility Name
Instituto Nacional de Saude / Hospital Geral de Machava
City
Maputo
Country
Mozambique
Facility Name
Pham Ngoc Thach Hospital
City
Ho Chi Minh City
Country
Vietnam

12. IPD Sharing Statement

Citations:
PubMed Identifier
33667406
Citation
De Castro N, Marcy O, Chazallon C, Messou E, Eholie S, N'takpe JB, Bhatt N, Khosa C, Timana Massango I, Laureillard D, Chau GD, Domergue A, Veloso V, Escada R, Wagner Cardoso S, Delaugerre C, Anglaret X, Molina JM, Grinsztejn B; ANRS 12300 Reflate TB2 study group. Standard dose raltegravir or efavirenz-based antiretroviral treatment for patients co-infected with HIV and tuberculosis (ANRS 12 300 Reflate TB 2): an open-label, non-inferiority, randomised, phase 3 trial. Lancet Infect Dis. 2021 Jun;21(6):813-822. doi: 10.1016/S1473-3099(20)30869-0. Epub 2021 Mar 2.
Results Reference
derived

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Raltegravir Versus Efavirenz in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis

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