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

Phase 3

Completed

Conditions: Tuberculosis
HIV Infections

Interventions: Drug: Rifapentine (RPT)
Drug: Isoniazid (INH)
Dietary Supplement: Pyridoxine (Vitamin B6)

Registration Number: NCT01404312

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 3000

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RPT plus INH Regimen (Arm A)	Isoniazid (INH)	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 plus INH Regimen (Arm A)	Pyridoxine (Vitamin B6)	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.
INH Regimen (Arm B)	Isoniazid (INH)	Participants received 300 mg of INH and 25 mg or 50 mg of pyridoxine (vitamin B6) each day during Weeks 1 to 36.
INH Regimen (Arm B)	Pyridoxine (Vitamin B6)	Participants received 300 mg of INH and 25 mg or 50 mg of pyridoxine (vitamin B6) each day during Weeks 1 to 36.
RPT plus INH Regimen (Arm A)	Rifapentine (RPT)	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.

Primary Outcome Measures

Name	Time	Method
Incidence of First Diagnosis of Active Tuberculosis, Death Related to Tuberculosis, or Death From Unknown Cause	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Occurrence of One or More Serious Adverse Events (SAEs) Versus no SAEs	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
Number of Participants With a Targeted Adverse Event	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
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	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
Cumulative Incidence of Death From Any Cause	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.
Cumulative Incidence of Death Due to a Non-TB Event	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.
Nevirapine (NVP) Plasma Concentrations in Arm A	Measured at Weeks 0, 2, and 4	Mean and standard deviation
Efavirenz (EFV) Plasma Concentrations in Arm A	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.
Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis	After TB diagnosis	Among MTB-diagnosed participants who underwent drug-susceptibility testing, the number who had any resistance to a particular drug.
EFV Plasma Concentrations in Arm B	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.

Trial Locations

Locations (45): University of Southern California CRS
🇺🇸
Los Angeles, California, United States
University of Washington AIDS CRS
🇺🇸
Seattle, Washington, United States
Trinity Health and Wellness Center CRS
🇺🇸
Dallas, Texas, United States
Kisumu Crs
🇰🇪
Kisumu, Nyanza, Kenya
Molepolole CRS
🇧🇼
Gaborone, Botswana
Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
🇹🇭
Bangkok, Thailand
Moi University Clinical Research Center (MUCRC) CRS
🇰🇪
Eldoret, Kenya
Chapel Hill CRS
🇺🇸
Chapel Hill, North Carolina, United States
Malawi CRS
🇲🇼
Lilongwe, Central, Malawi
Blantyre CRS
🇲🇼
Blantyre, Malawi
The University of Miami AIDS Clinical Research Unit (ACRU) CRS
🇺🇸
Miami, Florida, United States
Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
🇭🇹
Port-au-Prince, Haiti
Nyu Ny Nichd Crs
🇺🇸
New York, New York, United States
Durban International Clinical Research Site CRS
🇿🇦
Durban, KwaZulu-Natal, South Africa
Houston AIDS Research Team CRS
🇺🇸
Houston, Texas, United States
Soweto ACTG CRS
🇿🇦
Johannesburg, Gauteng, South Africa
Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
🇰🇪
Kericho, Rift Valley, Kenya
Univ. of Sao Paulo Brazil NICHD CRS
🇧🇷
Sao Paulo, São Paulo, Brazil
Columbia P&S CRS
🇺🇸
New York, New York, United States
Ucsf Hiv/Aids Crs
🇺🇸
San Francisco, California, United States
Duke University Medical Center CRS
🇺🇸
Durham, North Carolina, United States
Denver Public Health CRS
🇺🇸
Denver, Colorado, United States
Hospital Federal dos Servidores do Estado NICHD CRS
🇧🇷
Rio de Janeiro, Brazil
Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
🇧🇷
Rio de Janeiro, Brazil
Inst de Infectologia Emilio Ribas Sao Paulo Brazil NICHD CRS
🇧🇷
Sao Paulo, Brazil
Parirenyatwa CRS
🇿🇼
Harare, Zimbabwe
San Miguel CRS
🇵🇪
Lima, Peru
GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
🇭🇹
Port-au-Prince, Haiti
Barranco CRS
🇵🇪
Lima, Peru
Chonburi Hosp. CRS
🇹🇭
Chon Buri, Thailand
University of Colorado Hospital CRS
🇺🇸
Aurora, Colorado, United States
University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program
🇺🇸
La Jolla, California, United States
Harbor-UCLA CRS
🇺🇸
Torrance, California, United States
UCSD Antiviral Research Center CRS
🇺🇸
San Diego, California, United States
Northwestern University CRS
🇺🇸
Chicago, Illinois, United States
Boston Medical Center CRS
🇺🇸
Boston, Massachusetts, United States
Cooper Univ. Hosp. CRS
🇺🇸
Camden, New Jersey, United States
New Jersey Medical School Clinical Research Center CRS
🇺🇸
Newark, New Jersey, United States
Bronx-Lebanon Hospital Center NICHD CRS
🇺🇸
Bronx, New York, United States
Gaborone CRS
🇧🇼
Gaborone, Botswana
Hospital Nossa Senhora da Conceicao CRS
🇧🇷
Porto Alegre, Rio Grande Do Sul, Brazil
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
🇹🇭
Chiang Mai, Thailand
Hosp. Geral De Nova Igaucu Brazil NICHD CRS
🇧🇷
Rio de Janeiro, Brazil
Wits Helen Joseph Hospital CRS (Wits HJH CRS)
🇿🇦
Johannesburg, Gauteng, South Africa
Henry Ford Hosp. CRS
🇺🇸
Detroit, Michigan, United States