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

NCT ID: NCT02273765

Last Updated: 2018-12-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 460 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-11
• Study Completion Date: 2018-11-28

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).

Conditions

HIV-1 Infection; Tuberculosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Raltegravir

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

Group Type: ACTIVE_COMPARATOR

Tenofovir + lamivudine + raltegravir

Intervention Type: DRUG

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

Efavirenz

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

Group Type: EXPERIMENTAL

Tenofovir + lamivudine + efavirenz

Intervention Type: DRUG

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.

Interventions

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

Intervention Type: 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.

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Ministry of Health, Brazil

OTHER_GOV

Sponsor Role: collaborator

ANRS, Emerging Infectious Diseases

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Beatriz Grinsztejn, MD, PhD

Role: STUDY_CHAIR

Laboratory on Clinical research on DST/AIDS-IPEC FIOCRUZ Av Brasil, 4365 Manguinhos Rio de Janeiro, Brazil CEP 21040-900

Nathalie De Castro, MD

Role: STUDY_CHAIR

AP-HP Hôpital Saint-Louis 1 avenue Claude Vellefaux, 75010 Paris, France

Locations

Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ

Rio de Janeiro, , Brazil

PACCI / CePReF Centre de Prise en charge de Recherche et de Formation

Abidjan, , Côte d’Ivoire

Hôpital Saint Louis

Paris, , France

Instituto Nacional de Saude / Hospital Geral de Machava

Maputo, , Mozambique

Pham Ngoc Thach Hospital

Ho Chi Minh City, , Vietnam

Countries

Brazil; Côte d’Ivoire; France; Mozambique; Vietnam

References

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.

Reference Type: DERIVED

PMID: 33667406 (View on PubMed)

Other Identifiers

ANRS 12300 REFLATE TB2

Identifier Type: -

Identifier Source: org_study_id