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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01380080
First received: June 22, 2011
Last updated: February 29, 2016
Last verified: February 2016

June 22, 2011
February 29, 2016
October 2011
January 2015   (final data collection date for primary outcome measure)
Cumulative Probability of Death or Unknown Vital Status by Week 24 [ Time Frame: From study entry to week 24 ] [ Designated as safety issue: No ]

The Kaplan-Meier estimate of the cumulative probability of death or unknown vital status by week 24.

Vital status at week 48 and again at weeks 60, 72, 84, and 96 was determined for participants who do not complete study follow-up, including those who are prematurely discontinued from the study before week 24 without coming in to the clinic. Vital status for participants who are not discontinued from the study whenever a scheduled visit of any type is missed was also obtained. 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.

Survival status at 24 weeks post randomization [ Time Frame: Randomization to 24 weeks ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01380080 on ClinicalTrials.gov Archive Site
  • Cumulative Probability of Death by Week 24 [ Time Frame: From study entry to week 24 ] [ Designated as safety issue: Yes ]
    The Kaplan-Meier estimate of cumulative probability of death by week 24
  • Cumulative Probability of First AIDS Progression by Week 96 [ Time Frame: From study entry to week 96 ] [ Designated as safety issue: Yes ]
    The Kaplan-Meier estimate of the cumulative probability of first AIDS progression which was defined as the identification of a new World Health Organization (WHO) stage 3 or 4 condition
  • Cumulative Probability of Death or AIDS Progression by Week 24 [ Time Frame: From study entry to week 24 ] [ Designated as safety issue: Yes ]

    The Kaplan-Meier estimate of the cumulative probability of death or AIDS progression by week 24

    The result of cumulative probability of death or AIDS progression by week 48 will be submitted after the study is completed. AIDS progression was defined as new WHO stage 3 or 4 conditions occurred after study entry.

  • Proportion of Participants With HIV-1 RNA Level <400 Copies/mL [ Time Frame: At weeks 0, 4, 24, and 48 ] [ Designated as safety issue: No ]
    Proportion of participants with HIV-1 RNA level <400 copies/mL at weeks 0, 4, and 24. The results at week 48 will be submitted after the study is completed
  • CD4+ T-cell Count [ Time Frame: At weeks 0, 4, 24, and 48 ] [ Designated as safety issue: No ]
    The absolute levels of CD4+ T-cell counts (cells/mm^3) at weeks 0, 4, and 24. The results at week 48 will be submitted after the study is completed
  • CD4+ T-cell Count Change From Baseline [ Time Frame: From study entry to weeks 4, 24 and 48 ] [ Designated as safety issue: No ]
    Change was calculated as the CD4+ T-cell count at week (4 and 24) minus the baseline CD4+ T-cell count. The results at week 48 will be submitted after the study is completed
  • Time to Initiation of TB Treatment by Week 96 [ Time Frame: From study entry to week 96 ] [ Designated as safety issue: No ]
    Median time to TB treatment initiation by week 96
  • Proportion of Participants With TB Diagnosis Per Current ACTG Diagnosis Appendix by Week 96 [ Time Frame: From study entry to week 96 ] [ Designated as safety issue: Yes ]
    Proportion of participants with TB diagnosis per current ACTG Diagnosis Appendix 60 by week 96
  • 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 [ Time Frame: From study entry to week 48 ] [ Designated as safety issue: Yes ]
    Proportion of participants with at least one new Grade 3 or 4 laboratory or sign or symptom that is at least a one-grade increase from baseline by Week 48
  • Proportion of Participants With at Least One New Grade 3 or 4 That is at Least a One-grade Increase From Baseline for the Following Targeted Laboratory Values by Week 48 [ Time Frame: From study entry to week 48 ] [ Designated as safety issue: Yes ]

    Proportion of participants with at least one new Grade 3 or 4 that is at least a one-grade increase from baseline for the following targeted laboratory values by Week 48

    The targeted laboratory events include hemoglobin, serum creatinine, ALT and AST

  • Proportion of Participants With IRIS (Using Current ACTG Definition) by Week 48 [ Time Frame: From study entry to week 48 ] [ Designated as safety issue: Yes ]
    Proportion of participants with IRIS (using current ACTG definition Appendix 60) by Week 48
  • Proportion of Participants With Reportable Hospitalization by Week 48 [ Time Frame: From study entry to week 48 ] [ Designated as safety issue: Yes ]
    Proportion of participants with any hospitalization reported by Week 48
  • Proportion of Participants Who Prematurely Discontinued Any Component of TB Treatment by Week 48 [ Time Frame: From study entry to week 48 ] [ Designated as safety issue: No ]
    Proportion of participants with premature discontinuation of any component of TB treatment by Week 48
  • Proportion of Participants Who Prematurely Discontinued Antiretroviral Therapy by Week 48 [ Time Frame: From study entry to week 48 ] [ Designated as safety issue: No ]
    Proportion of participants with premature discontinuation of antiretroviral therapy (ART) by Week 48
  • Time from randomization to death [ Time Frame: Randomization to 96 weeks ] [ Designated as safety issue: No ]
  • Time from randomization to AIDS progression (defined as the identification of a new WHO stage 3 or 4 condition) [ Time Frame: Randomization to 96 weeks ] [ Designated as safety issue: No ]
  • AIDS-free survival status at 24 and 48 weeks (cumulative) [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • HIV-1 RNA level (<400 vs. ≥400 copies/mL) at weeks 4, 24, and 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Safety and tolerability status at 24 and 48 weeks (cumulative) [ Time Frame: 48 weeks ] [ Designated as safety issue: Yes ]

    Safety endpoints-

    1. new Grade 3 or 4 laboratory or sign or symptom that is at least a one-grade increase from baseline
    2. new Grade 3 or 4 that is at least a one-grade increase from baseline for the following targeted laboratory values: hemoglobin, serum creatinine, ALT and AST
    3. IRIS (using current ACTG definition)
    4. reportable hospitalization

    Tolerability endpoints-

    1. premature discontinuation of any component of TB treatment
    2. premature discontinuation of ART
  • Time to initiation of TB treatment [ Time Frame: Randomization to 96 weeks ] [ Designated as safety issue: No ]
  • CD4+ cell count and change from baseline at weeks 4, 24, and 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • TB diagnosis per current ACTG Diagnosis Appendix [ Time Frame: Randomization to 96 weeks ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
REMEMBER: Reducing Early Mortality & Morbidity by Empiric Tuberculosis (TB) Treatment
Reducing Early Mortality and Early Morbidity by Empiric Tuberculosis Treatment Regimens (REMEMBER)

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 is being done in people who are starting HIV treatment and who live in areas where the TB infection rate is high. The purpose of this study is to test an experimental approach to TB treatment to see if it is better than the usual approach. The experimental approach is to start TB treatment at the same time as HIV treatment, even when TB infection has not been found. The usual approach is to start TB treatment only if TB infection is found.

In this study, half of the people will start TB treatment at the same time as they start their HIV treatment. The other half will start TB treatment only if TB infection is found.

The study will also test how safe and effective it is to start TB treatment at about the same time as HIV treatment even when TB infection has not been found. The study will collect information about diet, whether (and when) people in the study become sicker or die, how well their HIV is controlled, how they are feeling, how they are taking their medications, whether it matters where they live or what kind of HIV and TB care is standard, how many people are diagnosed with TB while in the study, and how the cost of the two treatment options on a national level could be compared.

This was a randomized, open-label, phase IV strategy trial for participants from resource-limited settings (RLS) who present with advanced HIV disease and no probable or confirmed tuberculosis (TB), as defined in the current ACTG diagnosis appendix, and who are initiating antiretroviral treatment (ART) will be 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 are followed for 96 weeks. Participants attended study visits at screening, enrollment, and weeks 1, 2, 4, 8, 12, 16, 20, and 24. 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 and 24 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.

The current results submission included data up to the primary outcome time point (week 24), and that after study completion, there will be a second results submission to include the data from the later visits up to week 96.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
HIV Infection
  • Drug: 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.
  • Drug: Efavirenz
    Participants will take one 600 mg tablet administered orally once daily without food.
    Other Name: EFV
  • 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.
  • 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.
  • 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.
  • Drug: Isoniazid
    INH 300 mg orally once daily
  • Experimental: 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
    Interventions:
    • Drug: Atripla (r)
    • Drug: Efavirenz
    • Drug: Truvada
    • Drug: Rifampin/isoniazid/pyrazinamide/ethambutol FDC
    • Drug: Rifampin/isoniazid FDC
  • Experimental: 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).
    Interventions:
    • Drug: Atripla (r)
    • Drug: Efavirenz
    • Drug: Truvada
    • Drug: Isoniazid

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
851
April 2016
January 2015   (final data collection date for primary outcome measure)

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 at any laboratory that has a CLIA certification or its equivalent.
  • 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.
  • Males and females age >/= 13 years.
  • 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 (see list in A5274/REMEMBER MOPS, section 3.2.1) 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.
Both
13 Years and older   (Child, Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Brazil,   Haiti,   India,   Kenya,   Malawi,   Peru,   South Africa,   Uganda,   Zambia,   Zimbabwe
Tanzania
 
NCT01380080
ACTG A5274, 1U01AI068636
Yes
Not Provided
Not Provided
AIDS Clinical Trials Group
AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
Study Chair: Mina C Hosseinipour, MD University of North Carolina Lilongwe CRS
Study Chair: Johnstone Kumwenda, MD, MBBS, MMED College of Med. JHU CRS
AIDS Clinical Trials Group
February 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP