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

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ClinicalTrials.gov Identifier: NCT02273765
Recruitment Status : Completed
First Posted : October 24, 2014
Last Update Posted : December 31, 2018
Sponsor:
Collaborators:
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)

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

Condition or disease Intervention/treatment Phase
HIV-1 Infection Tuberculosis Drug: Tenofovir + lamivudine + raltegravir Drug: Tenofovir + lamivudine + efavirenz Phase 3

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 460 participants
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
Actual Study Start Date : September 11, 2015
Actual Primary Completion Date : November 28, 2018
Actual Study Completion Date : November 28, 2018


Arm Intervention/treatment
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.




Primary Outcome Measures :
  1. 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 :
  1. Time to death [ Time Frame: Week 48 ]
  2. Frequency, type and time to new or recurrent AIDS-defining illnesses [ Time Frame: Week 48 ]
  3. Frequency, type and time to severe HIV-associated non-AIDS defining illnesses [ Time Frame: Week 48 ]
  4. Frequency, type and time to grade 3 or 4 adverse events [ Time Frame: Week 48 ]
  5. 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 ]
  6. Change in plasma HIV-1 RNA from baseline to week 48 [ Time Frame: Week 48 ]
  7. Proportion of patients in virologic success at each time point (HIV-1 RNA<50 copies/mL) [ Time Frame: Week 48 ]
  8. Time to virologic failure during follow-up [ Time Frame: Week 48 ]
  9. Frequency and time to new antiretroviral genotypic resistance in plasma RNA in patients with virologic failure [ Time Frame: Week 48 ]
  10. Change in CD4 cell counts from baseline to week 48 [ Time Frame: Week 48 ]
  11. Frequency, type and time to Immune Reconstitution Inflammatory Syndrome [ Time Frame: Week 48 ]
  12. Frequency of tuberculosis treatment outcomes [ Time Frame: Week 48 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02273765


Locations
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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
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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

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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    
Other Study ID Numbers: ANRS 12300 REFLATE TB2
First Posted: October 24, 2014    Key Record Dates
Last Update Posted: December 31, 2018
Last Verified: December 2018
Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Tenofovir
Lamivudine
Raltegravir Potassium
Efavirenz
Rifampin
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents
HIV Integrase Inhibitors
Integrase Inhibitors
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP3A Inducers
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Leprostatic Agents