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

NCT ID: NCT01380080

Last Updated: 2024-10-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 851 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-10-31
• Study Completion Date: 2016-04-30

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.

Detailed Description

This was a randomized, open-label, phase IV strategy trial for participants from resource-limited settings (RLS) who presented with advanced HIV disease and no probable or confirmed tuberculosis (TB), and who were initiating antiretroviral treatment (ART).

Participants were randomized to one of two strategy arms: immediate, empiric TB treatment (Empiric arm) or local standard of care TB treatment (IPT arm).

Randomization was balanced by clinical trial unit and stratified according to CD4+ T cell count (<25 vs. ≥25 cells/mm^3) and presence of any of the following prognostic factors: reportable hospitalization within the past 30 days, BMI <18.5 kg/m^2, or anemia (hemoglobin <8 g/dl).

Participants were followed for 96 weeks. Participants attended study visits at screening, enrollment, and weeks 1, 2, 4, 8, 12, 16, 20, 24 and 48. Signs and symptoms, ART modifications, concomitant medications, and clinical events as defined by AIDS Clinical Trials Group (ACTG) Appendix 60 were collected at each visit. Blood was collected for CD4 and HIV-1 RNA at study entry, weeks 4, 24 and 48, and blood for safety laboratories (liver function, hematology, and renal function) was collected at all visits except week 1. A sputum sample was collected and stored at study entry. Phone contact was conducted at weeks 60, 72, 84 and 96 to obtain information about vital status, reportable hospitalization, TB status (including screening and follow-up), TB and HIV treatment modifications, and quality of life.

Conditions

HIV Infection

Study Design

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

Study Groups

Arm A: Empiric

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

Group Type: EXPERIMENTAL

Atripla (r)

Intervention Type: 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.

Efavirenz

Intervention Type: DRUG

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

Truvada

Intervention Type: DRUG

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

Rifampin/isoniazid/pyrazinamide/ethambutol FDC

Intervention Type: 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.

Rifampin/isoniazid FDC

Intervention Type: 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 B: IPT

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).

Group Type: EXPERIMENTAL

Atripla (r)

Intervention Type: 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.

Efavirenz

Intervention Type: DRUG

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

Truvada

Intervention Type: DRUG

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

Isoniazid

Intervention Type: DRUG

INH 300 mg orally once daily

Interventions

Atripla (r)

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.

Intervention Type: DRUG

Efavirenz

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

Intervention Type: DRUG

Truvada

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

Intervention Type: DRUG

Rifampin/isoniazid/pyrazinamide/ethambutol FDC

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.

Intervention Type: DRUG

Rifampin/isoniazid FDC

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.

Intervention Type: DRUG

Isoniazid

INH 300 mg orally once daily

Intervention Type: DRUG

Other Intervention Names

EFV

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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.

• Minimum Eligible Age: 13 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mina C Hosseinipour, MD

Role: STUDY_CHAIR

University of North Carolina Lilongwe CRS

Johnstone Kumwenda, MBChB, FRCP

Role: STUDY_CHAIR

College of Med. JHU CRS

Locations

Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS

Rio de Janeiro, , Brazil

Les Centres GHESKIO CRS

Port-au-Prince, , Haiti

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

Port-au-Prince, , Haiti

YRG CARE Medical Ctr., VHS Chennai CRS

Rajiv Gandhi Salai Taramani, Chennai, India

BJ Medical College CRS

Pune, Maharashtra, India

AMPATH at Moi Univ. Teaching Hosp. Eldoret CRS

Eldoret, , Kenya

Walter Reed Project - Kenya Med. Research Institute Kericho CRS

Kericho, , Kenya

College of Med. JHU CRS (30301)

Blantyre, , Malawi

University of North Carolina Lilongwe CRS (12001)

Lilongwe, , Malawi

San Miguel CRS

San Miguel, Lima region, Peru

Barranco CRS (11301)

Lima, , Peru

Wits HIV CRS

Johannesburg, Gauteng, South Africa

CAPRISA eThekwini CRS

Durban, KwaZulu-Natal, South Africa

Durban Adult HIV CRS

Durban, KwaZulu-Natal, South Africa

Soweto ACTG CRS (12301)

Johannesburg, , South Africa

Joint Clinical Research Centre (JCRC) (12401)

Kampala, , Uganda

Kalingalinga Clinic CRS (12801)

Lusaka, , Zambia

UZ-Parirenyatwa CRS

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

Countries

Brazil; Haiti; India; Kenya; Malawi; Peru; South Africa; Uganda; Zambia; Zimbabwe

References

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

Reference Type: 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

Reference Type: 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

Reference Type: 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.

Reference Type: DERIVED

PMID: 31761933 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27025337 (View on PubMed)

Related Links

http://rsc.tech-res.com/safetyandpharmacovigilance/

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)

http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual

Manual for Expedited Reporting of Adverse Events to DAID, Version 2.0, January 2010

Other Identifiers

1U01AI068636

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ACTG A5274

Identifier Type: -

Identifier Source: org_study_id