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

NCT02273765 | Completed Phase 3 DMC

• 1 other identifier: ANRS 12300 REFLATE TB2
• Study Type: interventional
• Target: 460
• Locations: 5 countries
• Sites: 5

Brief Summary

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

Conditions

HIV-1 Infection; Tuberculosis

Outcome Measures

Primary Outcomes (1)

• 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.

  Week 48

Secondary Outcomes (12)

• Time to death

  Week 48

• Frequency, type and time to new or recurrent AIDS-defining illnesses

  Week 48

• Frequency, type and time to severe HIV-associated non-AIDS defining illnesses

  Week 48

• Frequency, type and time to grade 3 or 4 adverse events

  Week 48

• Frequency, type and time to drug-induced clinical or biological adverse reactions of grade 3 or 4 or leading to treatment interruption

  Week 48

Study Arms (2)

Raltegravir

ACTIVE COMPARATOR

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

Drug: Tenofovir + lamivudine + raltegravir

Efavirenz

EXPERIMENTAL

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

Drug: Tenofovir + lamivudine + efavirenz

Interventions

Tenofovir + lamivudine + raltegravir 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

Raltegravir

Tenofovir + lamivudine + efavirenz 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.

Efavirenz

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• For French patients, affiliation to a Social Security program

You may not qualify if:

• 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)
• Person under guardianship, or deprived of freedom by a judicial or administrative decision

Sponsors & Collaborators

• ANRS, Emerging Infectious Diseases: lead
• Merck Sharp & Dohme LLC: collaborator
• Ministry of Health, Brazil: collaborator

Study Sites (5)

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

Rio de Janeiro, Brazil

Location

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

Abidjan, Côte d’Ivoire

Location

Hôpital Saint Louis

Paris, France

Location

Instituto Nacional de Saude / Hospital Geral de Machava

Maputo, Mozambique

Location

Pham Ngoc Thach Hospital

Ho Chi Minh City, Vietnam

Location

Related Publications (1)

• 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.

  PMID: 33667406 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

Tenofovir; Lamivudine; Raltegravir Potassium; efavirenz

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides; Pyrrolidinones; Pyrrolidines

Study Officials

• 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

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 20, 2014
• First Posted: October 24, 2014
• Study Start: September 11, 2015
• Primary Completion: November 28, 2018
• Study Completion: November 28, 2018
• Last Updated: December 31, 2018

Record last verified: 2018-12

Locations

BR (1); MO (1); CÔ (1); VN (1); FR (1)