Clinical trial NCT01404312: Brief Rifapentine-Isoniazid Evaluation for TB Prevention (BRIEF TB)
Official title: Phase III Clinical Trial of Ultra-Short-Course Rifapentine/Isoniazid for the Prevention of Active Tuberculosis in HIV-Infected Individuals With Latent Tuberculosis Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tuberculosis
HIV Infections
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2011-07-28
Enrollment: 3000
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of First Diagnosis of Active Tuberculosis, Death Related to Tuberculosis, or Death From Unknown Cause
timeFrame: 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 outcomes:
measure: Number of Participants With Occurrence of One or More Serious Adverse Events (SAEs) Versus no SAEs
timeFrame: 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)
measure: Number of Participants With a Targeted Adverse Event
timeFrame: 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)
measure: 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
timeFrame: From entry to end of treatment (up to 8 weeks for Arm A; up to 54 weeks for Arm B)
measure: Cumulative Incidence of Death From Any Cause
timeFrame: 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)
measure: Cumulative Incidence of Death Due to a Non-TB Event
timeFrame: 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)
measure: Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis
timeFrame: After TB diagnosis
measure: Efavirenz (EFV) Plasma Concentrations in Arm A
timeFrame: Measured at Weeks 0, 2, 4, and 16
measure: Nevirapine (NVP) Plasma Concentrations in Arm A
timeFrame: Measured at Weeks 0, 2, and 4
measure: EFV Plasma Concentrations in Arm B
timeFrame: Measured at weeks 0, 2 and 4
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program
state: California
city: Los Angeles
country: United States
facility: University of Southern California CRS
state: California
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS
state: California
city: San Francisco
country: United States
facility: Ucsf Hiv/Aids Crs
state: California
city: Torrance
country: United States
facility: Harbor-UCLA CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Denver
country: United States
facility: Denver Public Health CRS
state: Colorado
city: Miami
country: United States
facility: The University of Miami AIDS Clinical Research Unit (ACRU) CRS
state: Florida
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Boston
country: United States
facility: Boston Medical Center CRS
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hosp. CRS
state: Michigan
city: Camden
country: United States
facility: Cooper Univ. Hosp. CRS
state: New Jersey
city: Newark
country: United States
facility: New Jersey Medical School Clinical Research Center CRS
state: New Jersey
city: Bronx
country: United States
facility: Bronx-Lebanon Hospital Center NICHD CRS
state: New York
city: New York
country: United States
facility: Nyu Ny Nichd Crs
state: New York
city: New York
country: United States
facility: Columbia P&S CRS
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center CRS
state: North Carolina
city: Dallas
country: United States
facility: Trinity Health and Wellness Center CRS
state: Texas
city: Houston
country: United States
facility: Houston AIDS Research Team CRS
state: Texas
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: Gaborone
country: Botswana
facility: Gaborone CRS
city: Gaborone
country: Botswana
facility: Molepolole CRS
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao CRS
state: Rio Grande Do Sul
city: Sao Paulo
country: Brazil
facility: Univ. of Sao Paulo Brazil NICHD CRS
state: São Paulo
city: Rio de Janeiro
country: Brazil
facility: Hospital Federal dos Servidores do Estado NICHD CRS
city: Rio de Janeiro
country: Brazil
facility: Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
city: Rio de Janeiro
country: Brazil
facility: Hosp. Geral De Nova Igaucu Brazil NICHD CRS
city: Sao Paulo
country: Brazil
facility: Inst de Infectologia Emilio Ribas Sao Paulo Brazil NICHD CRS
city: Port-au-Prince
country: Haiti
facility: Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
city: Port-au-Prince
country: Haiti
facility: GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
city: Kisumu
country: Kenya
facility: Kisumu Crs
state: Nyanza
city: Kericho
country: Kenya
facility: Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
state: Rift Valley
city: Eldoret
country: Kenya
facility: Moi University Clinical Research Center (MUCRC) CRS
city: Lilongwe
country: Malawi
facility: Malawi CRS
state: Central
city: Blantyre
country: Malawi
facility: Blantyre CRS
city: Lima
country: Peru
facility: Barranco CRS
city: Lima
country: Peru
facility: San Miguel CRS
city: Johannesburg
country: South Africa
facility: Soweto ACTG CRS
state: Gauteng
city: Johannesburg
country: South Africa
facility: Wits Helen Joseph Hospital CRS (Wits HJH CRS)
state: Gauteng
city: Durban
country: South Africa
facility: Durban International Clinical Research Site CRS
state: KwaZulu-Natal
city: Bangkok
country: Thailand
facility: Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
city: Chiang Mai
country: Thailand
facility: Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
city: Chon Buri
country: Thailand
facility: Chonburi Hosp. CRS
city: Harare
country: Zimbabwe
facility: Parirenyatwa CRS
Study officials:
affiliation: Johns Hopkins University
name: Richard E. Chaisson, MD
role: STUDY_CHAIR
affiliation: University of Nebraska
name: Susan Swindells, MBBS
role: STUDY_CHAIR
References:
citation: Golub JE, Pronyk P, Mohapi L, Thsabangu N, Moshabela M, Struthers H, Gray GE, McIntyre JA, Chaisson RE, Martinson NA. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort. AIDS. 2009 Mar 13;23(5):631-6. doi: 10.1097/QAD.0b013e328327964f.
citation: Zhang T, Zhang M, Rosenthal IM, Grosset JH, Nuermberger EL. Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection. Am J Respir Crit Care Med. 2009 Dec 1;180(11):1151-7. doi: 10.1164/rccm.200905-0795OC. Epub 2009 Sep 3.
citation: Pham MM, Podany AT, Mwelase N, Supparatpinyo K, Mohapi L, Gupta A, Samaneka W, Omoz-Oarhe A, Langat D, Benson CA, Chaisson RE, Swindells S, Fletcher CV. Population Pharmacokinetic Modeling and Simulation of Rifapentine Supports Concomitant Antiretroviral Therapy with Efavirenz and Non-Weight Based Dosing. Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0238521. doi: 10.1128/aac.02385-21. Epub 2022 Aug 9.
citation: Haas DW, Podany AT, Bao Y, Swindells S, Chaisson RE, Mwelase N, Supparatpinyo K, Mohapi L, Gupta A, Benson CA, Baker P, Fletcher CV. Pharmacogenetic interactions of rifapentine plus isoniazid with efavirenz or nevirapine. Pharmacogenet Genomics. 2021 Jan;31(1):17-27. doi: 10.1097/FPC.0000000000000417.
citation: Miyahara S, Ramchandani R, Kim S, Evans SR, Gupta A, Swindells S, Chaisson RE, Montepiedra G. Applying a Risk-benefit Analysis to Outcomes in Tuberculosis Clinical Trials. Clin Infect Dis. 2020 Feb 3;70(4):698-703. doi: 10.1093/cid/ciz784.
citation: Swindells S, Ramchandani R, Gupta A, Benson CA, Leon-Cruz J, Mwelase N, Jean Juste MA, Lama JR, Valencia J, Omoz-Oarhe A, Supparatpinyo K, Masheto G, Mohapi L, da Silva Escada RO, Mawlana S, Banda P, Severe P, Hakim J, Kanyama C, Langat D, Moran L, Andersen J, Fletcher CV, Nuermberger E, Chaisson RE; BRIEF TB/A5279 Study Team. One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis. N Engl J Med. 2019 Mar 14;380(11):1001-1011. doi: 10.1056/NEJMoa1806808.
citation: Podany AT, Bao Y, Swindells S, Chaisson RE, Andersen JW, Mwelase T, Supparatpinyo K, Mohapi L, Gupta A, Benson CA, Kim P, Fletcher CV; AIDS Clinical Trials Group A5279 Study Team. Efavirenz Pharmacokinetics and Pharmacodynamics in HIV-Infected Persons Receiving Rifapentine and Isoniazid for Tuberculosis Prevention. Clin Infect Dis. 2015 Oct 15;61(8):1322-7. doi: 10.1093/cid/civ464. Epub 2015 Jun 16.