Clinical trial NCT01380080: REMEMBER: Reducing Early Mortality & Morbidity by Empiric Tuberculosis (TB) Treatment
Official title: Reducing Early Mortality and Early Morbidity by Empiric Tuberculosis Treatment Regimens (REMEMBER)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2011-06-27
Enrollment: 851
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Cumulative Probability of Death or Unknown Vital Status by Week 24
timeFrame: From study entry to week 24
Secondary outcomes:
measure: Cumulative Probability of Death by Week 24
timeFrame: From study entry to week 24
measure: Cumulative Probability of First AIDS Progression by Week 96
timeFrame: From study entry to week 96
measure: Cumulative Probability of Death or AIDS Progression by Week 24
timeFrame: From study entry to week 24
measure: Proportion of Participants With HIV-1 RNA Level <400 Copies/mL
timeFrame: At weeks 0, 4, 24, and 48
measure: CD4+ T-cell Count
timeFrame: At weeks 0, 4, 24, and 48
measure: CD4+ T-cell Count Change From Baseline
timeFrame: Weeks 0, 4, 24 and 48
measure: Time to Initiation of TB Treatment by Week 96
timeFrame: From study entry to week 96
measure: Proportion of Participants With TB Diagnosis by Week 96
timeFrame: From study entry to week 96
measure: Proportion of Participants With at Least One New Grade 3 or 4 Adverse Event That is at Least a One-grade Increase From Baseline by Week 48
timeFrame: From study entry to week 48
measure: Proportion of Participants With at Least One New Grade 3 or 4 Targeted Laboratory Value That is at Least a One-grade Increase From Baseline by Week 48
timeFrame: From study entry to week 48. The lab events were collected at study entry, weeks 2, 4, 8, 12, 16, 20, 24, and 48.
measure: Proportion of Participants With Immune Reconstitution Inflammatory Syndrome (IRIS) by Week 48
timeFrame: From study entry to week 48
measure: Proportion of Participants With Reportable Hospitalization by Week 48
timeFrame: From study entry to week 48
measure: Proportion of Participants Who Prematurely Discontinued Any Component of TB Treatment by Week 48
timeFrame: From study entry to week 48
measure: Proportion of Participants Who Prematurely Discontinued Antiretroviral Therapy by Week 48
timeFrame: From study entry to week 48
measure: Cumulative Probability of Death or AIDS Progression by Week 48
timeFrame: From study entry to week 48
Other outcomes:
Locations:
city: Rio de Janeiro,
country: Brazil
facility: Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
city: Port Au Prince
country: Haiti
facility: GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
city: Port-au-Prince
country: Haiti
facility: Les Centres GHESKIO CRS
city: Rajiv Gandhi Salai Taramani
country: India
facility: YRG CARE Medical Ctr., VHS Chennai CRS
state: Chennai
city: Pune
country: India
facility: BJ Medical College CRS
state: Maharashtra
city: Eldoret
country: Kenya
facility: AMPATH at Moi Univ. Teaching Hosp. Eldoret CRS
city: Kericho
country: Kenya
facility: Walter Reed Project - Kenya Med. Research Institute Kericho CRS
city: Blantyre
country: Malawi
facility: College of Med. JHU CRS (30301)
city: Lilongwe
country: Malawi
facility: University of North Carolina Lilongwe CRS (12001)
city: San Miguel
country: Peru
facility: San Miguel CRS
state: Lima
city: Lima
country: Peru
facility: Barranco CRS (11301)
city: Johannesburg
country: South Africa
facility: Wits HIV CRS
state: Gauteng
city: Durban
country: South Africa
facility: CAPRISA eThekwini CRS
state: KwaZulu-Natal
city: Durban
country: South Africa
facility: Durban Adult HIV CRS
state: KwaZulu-Natal
city: Johannesburg
country: South Africa
facility: Soweto ACTG CRS (12301)
city: Kampala
country: Uganda
facility: Joint Clinical Research Centre (JCRC) (12401)
city: Lusaka
country: Zambia
facility: Kalingalinga Clinic CRS (12801)
city: AIDS Research Unit P.O. Box A178
country: Zimbabwe
facility: UZ-Parirenyatwa CRS
state: Harare
Study officials:
affiliation: University of North Carolina Lilongwe CRS
name: Mina C Hosseinipour, MD
role: STUDY_CHAIR
affiliation: College of Med. JHU CRS
name: Johnstone Kumwenda, MBChB, FRCP
role: STUDY_CHAIR
References:
citation: 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
citation: 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
citation: 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
citation: 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.
citation: 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.