REMEMBER: Reducing Early Mortality & Morbidity by Empiric Tuberculosis (TB) Treatment

NCT01380080 | Completed Phase 4 Results DMC

• 2 other identifiers: ACTG A52741U01AI068636
• Study Type: interventional
• Target: 851
• Locations: 9 countries
• Sites: 17

Brief Summary

People with HIV have a high chance of becoming infected with TB, especially when they live in areas where TB infection is common. It can be difficult to diagnose TB in people who need to start HIV treatment right away. Within about 6 months after starting HIV treatment, some of these people can become very sick with TB and can even die from it. This study was being done in people who were starting HIV treatment and who lived in areas where the TB infection rate is high. The purpose of this study was to test an experimental approach to TB treatment to see if it is better than the usual approach. The experimental approach was to start TB treatment at the same time as HIV treatment, even when TB infection had not been found. The usual approach was to start TB treatment only if TB infection was found. In this study, half of the people started TB treatment at the same time as they started their HIV treatment. The other half started TB treatment only if TB infection was found. The study also tested how safe and effective it was to start TB treatment at about the same time as HIV treatment even when TB infection had not been found. The study collected information about diet, whether (and when) people in the study became sicker or died, how well their HIV was controlled, how they were feeling, how they were taking their medications, whether it mattered where they lived or what kind of HIV and TB care was standard, how many people were diagnosed with TB while in the study, and how the cost of the two treatment options on a national level could be compared.

Conditions

HIV Infection

Outcome Measures

Primary Outcomes (1)

• Cumulative Probability of Death or Unknown Vital Status by Week 24

  The Kaplan-Meier estimate of the cumulative probability of death or unknown vital status by week 24. The vital status was considered unknown at week 24 if a participant prematurely discontinued from the study before week 24 and no vital status was obtained at week 48.

  From study entry to week 24

Secondary Outcomes (15)

• Cumulative Probability of Death by Week 24

  From study entry to week 24

• Cumulative Probability of First AIDS Progression by Week 96

  From study entry to week 96

• Cumulative Probability of Death or AIDS Progression by Week 24

  From study entry to week 24

• Proportion of Participants With HIV-1 RNA Level <400 Copies/mL

  At weeks 0, 4, 24, and 48

• CD4+ T-cell Count

  At weeks 0, 4, 24, and 48

Study Arms (2)

Arm A: Empiric

EXPERIMENTAL

Study treatment for Arm A participants is the strategy of initiating study-provided or other FDA-approved or tentatively approved antiretroviral treatment as soon as possible following randomization and within no more than 3 days following randomization plus a 4-drug anti-tuberculosis treatment (ATT) regimen (defined as rifampin/isoniazid/ethambutol/pyrazinamide) as soon as possible following randomization and within no more than 7 days following initiation of antiretroviral therapy. After 2 months (or 8 weeks), the 4-drug ATT will be followed with 4 months (or 16 weeks) of 2-drug ATT (defined as rifampin/isoniazid). All participants will be followed through week 96. Drug provision by or through the study will be through week 48 only

Drug: Atripla (r); Drug: Efavirenz; Drug: Truvada; Drug: Rifampin/isoniazid/pyrazinamide/ethambutol FDC; Drug: Rifampin/isoniazid FDC

Arm B: IPT

EXPERIMENTAL

Study treatment for Arm B participants is the strategy of initiating study-provided or other FDA-approved or tentatively approved antiretroviral therapy as soon as possible following randomization and within no more than 3 days following randomization and of initiating anti-TB treatment (ATT) only when indicated according to local standard practice and at the discretion of the site investigator. All participants will be followed through week 96. Drug provision by or through the study will be through week 48 only. Pyridoxine is provided by the sites to all participants while they are receiving isoniazid (INH).

Drug: Atripla (r); Drug: Efavirenz; Drug: Truvada; Drug: Isoniazid

Interventions

Atripla (r) DRUG

Patients are administered one tablet of Efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (EFV/FTC/TDF, Atripla) to taken be taken orally once daily at bedtime without food.

Arm A: Empiric; Arm B: IPT

Efavirenz DRUG

Participants will take one 600 mg tablet administered orally once daily without food.

Also known as: EFV

Arm A: Empiric; Arm B: IPT

Truvada DRUG

Participants will take one tablet of Emtricitabine 200mg/tenofovir disoproxil fumarate 300mg (FTC/TDF, Truvada) administered orally once daily with or without food.

Arm A: Empiric; Arm B: IPT

Rifampin/isoniazid/pyrazinamide/ethambutol FDC DRUG

Participants will be administered Rifampin/isoniazid/pyrazinamide/ethambutol FDC tablets orally, once daily; dose by weight as determined in Table 5.1-1 of the protocol, for the first 8 weeks.

Arm A: Empiric

Rifampin/isoniazid FDC DRUG

Participants will be administered rifampin/isoniazid FDC tablets orally, once daily; dose by weight as determined in Table 5.1-1 in the protocol, for 16 weeks following the first 8 weeks.

Arm A: Empiric

Isoniazid DRUG

INH 300 mg orally once daily

Arm B: IPT

Eligibility Criteria

• Age: 13 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV-1 infection
• Willingness to start efavirenz-based ART as soon as possible and within no more than 3 days following randomization.
• CD4+ cell count \<50 cells/mm\^3 obtained within 45 days prior to study entry
• Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT), and total bilirubin ≤ 2.5 X ULN within 30 days prior to study entry.
• Creatinine clearance ≥30 mL/min either measured or estimated using values obtained within 30 days prior to study entry.
• Results from a hepatitis B surface antigen test performed within 30 days prior to study entry.
• Agreement not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization).
• Female candidates of reproductive potential must have a negative serum or urine (15-25 mIU/mL) pregnancy test result within 7 days prior to study entry.
• Female candidates of reproductive potential who are participating in sexual activity that could lead to pregnancy must use two reliable methods of contraception while on study.
• Karnofsky performance score \>/= 30 at time of study entry.
• Ability to swallow medications.
• Ability and willingness of participant or legal guardian/representative to provide informed consent.
• Intention to remain in the same general geographic region for the duration of study participation.

You may not qualify if:

• Presence of any confirmed or probable TB based on criteria listed in the current ACTG diagnosis appendix within 30 days prior to study entry and following completion of study-specific screening algorithm.
• Use of single-dose NVP for prevention of mother-to-child transmission (pMTCT) within 24 months prior to study entry.
• Use of prohibited medications within 30 days prior to study entry.
• Known allergy/sensitivity or any hypersensitivity to components of study-required ART or TB treatment.
• Current receipt of treatment for active TB or receipt of \>14 days cumulative treatment for active TB within 96 weeks prior to study entry.
• Receipt of \>30 days cumulative of INH prophylaxis within 48 weeks prior to study entry.
• Receipt at any time prior to study entry of \>7 days cumulative treatment with any ARV or combination of ARVs (except for ARVs taken for any length of time during pregnancy for pMTCT, or ARVs taken for occupational exposure).
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Current Grade ≥2 neuropathy.
• History of multi-drug-resistant (MDR) TB.
• Within 12 weeks prior to entry, exposure to a household member or co-worker with known MDR TB.

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (18)

Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS

Rio de Janeiro, 21045-900, Brazil

Location

Les Centres GHESKIO CRS

Port-au-Prince, 6110, Haiti

Location

GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS

Port-au-Prince, Haiti

Location

YRG CARE Medical Ctr., VHS Chennai CRS

Rajiv Gandhi Salai Taramani, Chennai, 600113, India

Location

BJ Medical College CRS

Pune, Maharashtra, 411001, India

Location

AMPATH at Moi Univ. Teaching Hosp. Eldoret CRS

Eldoret, 30100, Kenya

Location

Walter Reed Project - Kenya Med. Research Institute Kericho CRS

Kericho, 20200, Kenya

Location

College of Med. JHU CRS (30301)

Blantyre, Malawi

Location

University of North Carolina Lilongwe CRS (12001)

Lilongwe, Malawi

Location

San Miguel CRS

San Miguel, Lima region, Peru

Location

Barranco CRS (11301)

Lima, 18 PE, Peru

Location

Wits HIV CRS

Johannesburg, Gauteng, South Africa

Location

CAPRISA eThekwini CRS

Durban, KwaZulu-Natal, 4011, South Africa

Location

Durban Adult HIV CRS

Durban, KwaZulu-Natal, South Africa

Location

Soweto ACTG CRS (12301)

Johannesburg, South Africa

Location

Joint Clinical Research Centre (JCRC) (12401)

Kampala, Uganda

Location

Kalingalinga Clinic CRS (12801)

Lusaka, Zambia

Location

UZ-Parirenyatwa CRS

AIDS Research Unit P.O. Box A178, Harare, Zimbabwe

Location

Related Publications (5)

• M. Hosseinipour, G. Bisson, S., et al. Empiric TB therapy does not decrease early mortality compared to Isoniazid Preventive therapy in adults with advanced HIV initiating ART: Results of ACTG A5274 (REMEMBER study). Program and abstracts of the 8th IAS Conference on HIV Pathogenesis, Treatment and prevention; July 19-22, 2015; Vancouver, Canada. Abstract A-729-0105-03495

  BACKGROUND

• Johnstone Kumwenda, Amita Gupta, et al. Empiric TB therapy versus IPT in HIV-infected persons initiating ART (ACTG A5274 48 week results). Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 16-1383

  BACKGROUND

• Gregory P. Bisson, Amita Gupta, et al. Urine LAM Testing in Advanced HIV-Infected Adults in a Trial of Empiric TB Therapy. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 16-1650

  BACKGROUND

• Manabe YC, Andrade BB, Gupte N, Leong S, Kintali M, Matoga M, Riviere C, Samaneka W, Lama JR, Naidoo K, Zhao Y, Johnson WE, Ellner JJ, Hosseinipour MC, Bisson GP, Salgame P, Gupta A. A Parsimonious Host Inflammatory Biomarker Signature Predicts Incident Tuberculosis and Mortality in Advanced Human Immunodeficiency Virus. Clin Infect Dis. 2020 Dec 17;71(10):2645-2654. doi: 10.1093/cid/ciz1147.

  PMID: 31761933 DERIVED

• Hosseinipour MC, Bisson GP, Miyahara S, Sun X, Moses A, Riviere C, Kirui FK, Badal-Faesen S, Lagat D, Nyirenda M, Naidoo K, Hakim J, Mugyenyi P, Henostroza G, Leger PD, Lama JR, Mohapi L, Alave J, Mave V, Veloso VG, Pillay S, Kumarasamy N, Bao J, Hogg E, Jones L, Zolopa A, Kumwenda J, Gupta A; Adult AIDS Clinical Trials Group A5274 (REMEMBER) Study Team. Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial. Lancet. 2016 Mar 19;387(10024):1198-209. doi: 10.1016/S0140-6736(16)00546-8.

  PMID: 27025337 DERIVED

Related Links

• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009)
• Manual for Expedited Reporting of Adverse Events to DAID, Version 2.0, January 2010

MeSH Terms

Conditions

HIV Infections

Interventions

Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; efavirenz; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Rifampin; Isoniazid

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Tenofovir; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Emtricitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Drug Combinations; Pharmaceutical Preparations; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Pyridines

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social & Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Mina C Hosseinipour, MD

  University of North Carolina Lilongwe CRS

  STUDY CHAIR

• Johnstone Kumwenda, MBChB, FRCP

  College of Med. JHU CRS

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 22, 2011
• First Posted: June 27, 2011
• Study Start: October 1, 2011
• Primary Completion: January 31, 2015
• Study Completion: April 1, 2016
• Last Updated: October 15, 2024
• Results First Posted: February 23, 2016

Record last verified: 2024-10

Locations

ZA (4); ZI (1); MA (2); KE (2); HA (2); PE (2); IN (2); BR (1); UG (1)