Brief Rifapentine-Isoniazid Evaluation for TB Prevention (BRIEF TB)

Phase III Clinical Trial of Ultra-Short-Course Rifapentine/Isoniazid for the Prevention of Active Tuberculosis in HIV-Infected Individuals With Latent Tuberculosis Infection

HIV-infected people have an increased risk of developing active tuberculosis (TB). At the time the study was designed, the standard course of treatment for TB was 6 to 9 months of isoniazid (INH).This study compared the safety and effectiveness of a 4-week regimen of rifapentine (RPT) plus INH versus a standard 9-month regimen of INH in HIV-infected people who are at risk of developing active TB.

Study Overview

Detailed Description

The World Health Organization (WHO) estimated that in 2017 there were 10 million new cases of TB, and 1.6 million people died as a result of TB. Among new TB cases, it is estimated that 920,000 occurred in people who were HIV-coinfected, and 23% of TB deaths were among HIV-coinfected individuals. In Africa, TB is the leading AIDS-related opportunistic infection. Latent TB infection occurs when people are infected with the bacteria that cause TB, but they do not have any symptoms of TB infection. Latent TB can develop into active TB, and HIV-infected people have an increased risk of progressing from latent TB to active TB. INH is a medication that is prescribed for people with latent TB to help prevent active TB from developing. The standard INH treatment regimen is 6 to 9 months; a shorter treatment regimen of 3 months of once-weekly RPT plus INH has proven to be as effective and improved adherence. The purpose of this study was to compare the safety and effectiveness of a 4-week daily regimen of RPT plus INH to a standard 9-month daily INH regimen for TB prevention in HIV-infected individuals.

This study enrolled HIV-infected people who did not have evidence of active TB but who were at high risk of developing active TB. Participants were randomly assigned to receive RPT and INH once a day for 4 weeks or INH once a day for 9 months. All participants received pyridoxine (vitamin B6) with each dose of INH to help prevent possible side effects. Study visits occurred at baseline and Weeks 2, 4, 8, 12, 16, 20, 24, and 36. At select study visits, participants had a physical exam, clinical assessment, blood collection, and a chest radiograph or chest computed tomography (CT) scan (if needed). Some participants had their blood stored for future testing. Follow-up study visits occurred every 12 weeks starting at Week 48 and continued for 3 years after the last participant enrolled.

Study Type

Interventional

Enrollment (Actual)

3000

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Gaborone, Botswana
        • Gaborone CRS
      • Gaborone, Botswana
        • Molepolole CRS
      • Rio de Janeiro, Brazil, 21040-360
        • Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
      • Rio de Janeiro, Brazil, 20221-903
        • Hospital Federal dos Servidores do Estado NICHD CRS
      • Rio de Janeiro, Brazil, 26030
        • Hosp. Geral De Nova Igaucu Brazil NICHD CRS
      • Sao Paulo, Brazil, 01246-900
        • Inst de Infectologia Emilio Ribas Sao Paulo Brazil NICHD CRS
    • Rio Grande Do Sul
      • Porto Alegre, Rio Grande Do Sul, Brazil, 91350-200
        • Hospital Nossa Senhora da Conceicao CRS
    • São Paulo
      • Sao Paulo, São Paulo, Brazil, 14049-900
        • Univ. of Sao Paulo Brazil NICHD CRS
      • Port-au-Prince, Haiti, 6110
        • Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
      • Port-au-Prince, Haiti
        • GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
      • Eldoret, Kenya, 30100
        • Moi University Clinical Research Center (MUCRC) CRS
    • Nyanza
      • Kisumu, Nyanza, Kenya, 40100
        • Kisumu Crs
    • Rift Valley
      • Kericho, Rift Valley, Kenya, 20200
        • Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
      • Blantyre, Malawi
        • Blantyre CRS
    • Central
      • Lilongwe, Central, Malawi
        • Malawi CRS
      • Lima, Peru, 04
        • Barranco CRS
      • Lima, Peru, 32
        • San Miguel CRS
    • Gauteng
      • Johannesburg, Gauteng, South Africa, 1862
        • Soweto ACTG CRS
      • Johannesburg, Gauteng, South Africa, 2092
        • Wits Helen Joseph Hospital CRS (Wits HJH CRS)
    • KwaZulu-Natal
      • Durban, KwaZulu-Natal, South Africa, 4013
        • Durban International Clinical Research Site CRS
      • Bangkok, Thailand, 10330
        • Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
      • Chiang Mai, Thailand, 50200
        • Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
      • Chon Buri, Thailand, 20000
        • Chonburi Hosp. CRS
    • California
      • La Jolla, California, United States, 92093-0672
        • University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program
      • Los Angeles, California, United States, 90033-1079
        • University of Southern California CRS
      • San Diego, California, United States, 92103
        • UCSD Antiviral Research Center CRS
      • San Francisco, California, United States, 94110
        • Ucsf Hiv/Aids Crs
      • Torrance, California, United States, 90502
        • Harbor-UCLA CRS
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado Hospital CRS
      • Denver, Colorado, United States, 80204
        • Denver Public Health CRS
    • Florida
      • Miami, Florida, United States, 33136
        • The University of Miami AIDS Clinical Research Unit (ACRU) CRS
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Northwestern University CRS
    • Massachusetts
      • Boston, Massachusetts, United States, 02118
        • Boston Medical Center CRS
    • Michigan
      • Detroit, Michigan, United States, 48202
        • Henry Ford Hosp. CRS
    • New Jersey
      • Camden, New Jersey, United States, 08103
        • Cooper Univ. Hosp. CRS
      • Newark, New Jersey, United States, 07103
        • New Jersey Medical School Clinical Research Center CRS
    • New York
      • Bronx, New York, United States, 10457
        • Bronx-Lebanon Hospital Center NICHD CRS
      • New York, New York, United States, 10016
        • Nyu Ny Nichd Crs
      • New York, New York, United States, 10032-3732
        • Columbia P&S CRS
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • Chapel Hill CRS
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center CRS
    • Texas
      • Dallas, Texas, United States, 75208
        • Trinity Health and Wellness Center CRS
      • Houston, Texas, United States, 77030
        • Houston AIDS Research Team CRS
    • Washington
      • Seattle, Washington, United States, 98104-9929
        • University of Washington AIDS CRS
      • Harare, Zimbabwe
        • Parirenyatwa CRS

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

11 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • HIV-1 infection
  • Tuberculin skin test (TST) reactivity greater than or equal to 5 mm or a positive interferon gamma release assay (IGRA) at any time prior to study entry, OR living in a high TB burden area. More information on this criterion can be found in the protocol.
  • Laboratory values obtained within 30 days prior to study entry:

    1. Absolute neutrophil count (ANC) greater than 750 cells/mm^3
    2. Hemoglobin greater than or equal to 7.4 g/dL
    3. Platelet count greater than or equal to 50,000/mm^3
    4. AST (SGOT) and ALT (SGPT) less than or equal to three times the upper limit of normal (ULN)
    5. Total bilirubin less than or equal to 2.5 times the ULN
  • Chest radiograph or chest CT scan without evidence of active tuberculosis, unless one has been performed within 30 days prior to entry
  • Female participants of reproductive potential must have a negative serum or urine pregnancy test performed within 7 days prior to study entry. More information on this criterion can be found in the protocol.
  • All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization) while receiving RPT and for 6 weeks after stopping this drug
  • Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal form of contraceptive while receiving RPT and for 6 weeks after stopping this drug. More information on this criterion can be found in the protocol.
  • Weight of greater than or equal to 30 kg
  • Participant or legal guardian is able and willing to provide informed consent

Exclusion Criteria:

  • Treatment for active or latent TB (pulmonary or extrapulmonary) within 2 years prior to study entry or, at screening, presence of any confirmed or probable TB based on criteria listed in the current ACTG Diagnosis Appendix
  • History of multi-drug resistant (MDR) or extensively-drug resistant (XDR) TB at any time prior to study entry
  • Known exposure to MDR or XDR TB (e.g., household member of a person with MDR or XDR TB) at any time prior to study entry
  • Treatment for more than 14 consecutive days with a rifamycin or more than 30 consecutive days with INH at any time during the 2 years prior to enrollment
  • For participants taking antiretroviral therapy (ART) at study entry, only approved nucleoside reverse transcriptase inhibitors (NRTIs) with efavirenz (EFV) or nevirapine (NVP) for at least 4 weeks were permitted
  • History of liver cirrhosis at any time prior to study entry.
  • Evidence of acute hepatitis, such as abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to study entry
  • Diagnosis of porphyria at any time prior to study entry
  • Peripheral neuropathy greater than or equal to Grade 2 according to the December 2004 (Clarification, August 2009) Division of AIDS (DAIDS) Toxicity Table, within 90 days prior to study entry
  • Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation
  • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
  • Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry
  • Breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: RPT plus INH Regimen (Arm A)
Participants received RPT (dosage based on their weight), 300 mg of INH, and 25 mg or 50 mg of pyridoxine (vitamin B6) each day during Weeks 1 to 4. During Weeks 5 to 36, participants did not receive any study medications.

RPT dosing was be based on participants' weight:

Participants who weighed 30 kg to less than 35 kg received 300 mg once daily (administered as two 150-mg tablets).

Participants who weighed 35 kg to less than 45 kg received 450 mg once daily (administered as three 150-mg tablets).

Participants who weighed greater than 45 kg received 600 mg once daily (administered as four 150-mg tablets).

Participants received one 300-mg tablet or three 100-mg tablets of INH once daily.

Participants received 25 mg or 50 mg of pyridoxine, based on the current local, national, or international dosing guidelines.

Participants who received 25 mg of pyridoxine took one 25-mg tablet once daily with INH.

Participants who received 50 mg of pyridoxine took two 25-mg tablets once daily with INH.

Active Comparator: INH Regimen (Arm B)
Participants received 300 mg of INH and 25 mg or 50 mg of pyridoxine (vitamin B6) each day during Weeks 1 to 36.
Participants received one 300-mg tablet or three 100-mg tablets of INH once daily.

Participants received 25 mg or 50 mg of pyridoxine, based on the current local, national, or international dosing guidelines.

Participants who received 25 mg of pyridoxine took one 25-mg tablet once daily with INH.

Participants who received 50 mg of pyridoxine took two 25-mg tablets once daily with INH.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of First Diagnosis of Active Tuberculosis, Death Related to Tuberculosis, or Death From Unknown Cause
Time Frame: From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Incidence rate (events per 100 person-years) was estimated, and 95.1% confidence interval used to account for interim analysis of primary efficacy outcome.
From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Occurrence of One or More Serious Adverse Events (SAEs) Versus no SAEs
Time Frame: From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Occurrence of any SAE that meets the ICH definition of an SAE
From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Number of Participants With a Targeted Adverse Event
Time Frame: From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Targeted adverse events include each new grade 3 or 4 laboratory value or sign or symptom that is at least one grade increase from baseline for the following: nausea and vomiting; cutaneous; drug-associated fever; elevated aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]), or bilirubin; and peripheral neuropathy
From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Number of Participants in Each Category of Ordered Categorical Variable Indicating Most Stringent Level of Study Drug Management Due to Toxicity That Was Required Over the Treatment Period
Time Frame: From entry to end of treatment (up to 8 weeks for Arm A; up to 54 weeks for Arm B)

Ordered categories include:

  1. Premature permanent treatment discontinuation
  2. Treatment hold for more than 7 consecutive days
  3. None of the above
From entry to end of treatment (up to 8 weeks for Arm A; up to 54 weeks for Arm B)
Cumulative Incidence of Death From Any Cause
Time Frame: From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Data table estimates for percentage who died by each time point were estimated using Kaplan-Meier at 1, 2, 3, and 4 years post-entry.
From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Cumulative Incidence of Death Due to a Non-TB Event
Time Frame: From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Cumulative incidence function estimated nonparametrically, treating TB-related deaths as competing risks.
From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis
Time Frame: After TB diagnosis
Among MTB-diagnosed participants who underwent drug-susceptibility testing, the number who had any resistance to a particular drug.
After TB diagnosis
Efavirenz (EFV) Plasma Concentrations in Arm A
Time Frame: Measured at Weeks 0, 2, 4, and 16

Mean and standard deviation.

Week 16 samples have not yet been analyzed because the metabolite assay is being validated, and requires submission for approval by the Clinical Pharmacology Quality Assurance Program. Analysis of week 16 samples are anticipated to be available in September 2019.

Measured at Weeks 0, 2, 4, and 16
Nevirapine (NVP) Plasma Concentrations in Arm A
Time Frame: Measured at Weeks 0, 2, and 4
Mean and standard deviation
Measured at Weeks 0, 2, and 4
EFV Plasma Concentrations in Arm B
Time Frame: Measured at weeks 0, 2 and 4

For Version 2.0 of the protocol only, measured in the first 90 participants randomized to Arm B who enter the study taking EFV and who meet dose timing criteria.

Outcome measure was not assessed because no participants enrolled under version 2.0 of the protocol were on Efavirenz at study entry.

Measured at weeks 0, 2 and 4

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Chair: Susan Swindells, MBBS, University of Nebraska
  • Study Chair: Richard E. Chaisson, MD, Johns Hopkins University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 23, 2012

Primary Completion (Actual)

November 14, 2017

Study Completion (Actual)

November 14, 2017

Study Registration Dates

First Submitted

July 26, 2011

First Submitted That Met QC Criteria

July 26, 2011

First Posted (Estimate)

July 28, 2011

Study Record Updates

Last Update Posted (Actual)

November 4, 2021

Last Update Submitted That Met QC Criteria

November 2, 2021

Last Verified

December 1, 2020

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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