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

NCT01404312 | Completed Phase 3 Results DMC

• 3 other identifiers: A527910848ACTG A5279
• Study Type: interventional
• Target: 3,000
• Locations: 10 countries
• Sites: 45

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.

Conditions

Tuberculosis; HIV Infections

Outcome Measures

Primary Outcomes (1)

• Incidence of First Diagnosis of Active Tuberculosis, Death Related to Tuberculosis, or Death From Unknown Cause

  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 Outcomes (9)

• 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)

• 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)

• 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)

• 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)

• 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)

Study Arms (2)

RPT plus INH Regimen (Arm A)

EXPERIMENTAL

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.

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

INH Regimen (Arm B)

ACTIVE COMPARATOR

Participants received 300 mg of INH and 25 mg or 50 mg of pyridoxine (vitamin B6) each day during Weeks 1 to 36.

Drug: Isoniazid (INH); Dietary Supplement: Pyridoxine (Vitamin B6)

Interventions

Rifapentine (RPT) DRUG

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).

RPT plus INH Regimen (Arm A)

Isoniazid (INH) DRUG

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

INH Regimen (Arm B); RPT plus INH Regimen (Arm A)

Pyridoxine (Vitamin B6) DIETARY_SUPPLEMENT

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.

INH Regimen (Arm B); RPT plus INH Regimen (Arm A)

Eligibility Criteria

• Age: 13 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Absolute neutrophil count (ANC) greater than 750 cells/mm\^3
• Hemoglobin greater than or equal to 7.4 g/dL
• Platelet count greater than or equal to 50,000/mm\^3
• AST (SGOT) and ALT (SGPT) less than or equal to three times the upper limit of normal (ULN)
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (45)

University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program

La Jolla, California, 92093-0672, United States

Location

University of Southern California CRS

Los Angeles, California, 90033-1079, United States

Location

UCSD Antiviral Research Center CRS

San Diego, California, 92103, United States

Location

Ucsf Hiv/Aids Crs

San Francisco, California, 94110, United States

Location

Harbor-UCLA CRS

Torrance, California, 90502, United States

Location

University of Colorado Hospital CRS

Aurora, Colorado, 80045, United States

Location

Denver Public Health CRS

Denver, Colorado, 80204, United States

Location

The University of Miami AIDS Clinical Research Unit (ACRU) CRS

Miami, Florida, 33136, United States

Location

Northwestern University CRS

Chicago, Illinois, 60611, United States

Location

Boston Medical Center CRS

Boston, Massachusetts, 02118, United States

Location

Henry Ford Hosp. CRS

Detroit, Michigan, 48202, United States

Location

Cooper Univ. Hosp. CRS

Camden, New Jersey, 08103, United States

Location

New Jersey Medical School Clinical Research Center CRS

Newark, New Jersey, 07103, United States

Location

Nyu Ny Nichd Crs

New York, New York, 10016, United States

Location

Columbia P&S CRS

New York, New York, 10032-3732, United States

Location

Bronx-Lebanon Hospital Center NICHD CRS

The Bronx, New York, 10457, United States

Location

Chapel Hill CRS

Chapel Hill, North Carolina, 27599, United States

Location

Duke University Medical Center CRS

Durham, North Carolina, 27710, United States

Location

Trinity Health and Wellness Center CRS

Dallas, Texas, 75208, United States

Location

Houston AIDS Research Team CRS

Houston, Texas, 77030, United States

Location

University of Washington AIDS CRS

Seattle, Washington, 98104-9929, United States

Location

Gaborone CRS

Gaborone, Botswana

Location

Molepolole CRS

Gaborone, Botswana

Location

Hospital Nossa Senhora da Conceicao CRS

Porto Alegre, Rio Grande do Sul, 91350-200, Brazil

Location

Univ. of Sao Paulo Brazil NICHD CRS

São Paulo, São Paulo, 14049-900, Brazil

Location

Hospital Federal dos Servidores do Estado NICHD CRS

Rio de Janeiro, 20221-903, Brazil

Location

Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS

Rio de Janeiro, 21040-360, Brazil

Location

Hosp. Geral De Nova Igaucu Brazil NICHD CRS

Rio de Janeiro, 26030, Brazil

Location

Inst de Infectologia Emilio Ribas Sao Paulo Brazil NICHD CRS

São Paulo, 01246-900, Brazil

Location

Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS

Port-au-Prince, 6110, Haiti

Location

GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS

Port-au-Prince, Haiti

Location

Kisumu Crs

Kisumu, Nyanza, 40100, Kenya

Location

Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS

Kericho, Rift Valley, 20200, Kenya

Location

Moi University Clinical Research Center (MUCRC) CRS

Eldoret, 30100, Kenya

Location

Malawi CRS

Lilongwe, Central Region, Malawi

Location

Blantyre CRS

Blantyre, Malawi

Location

Barranco CRS

Lima, 04, Peru

Location

San Miguel CRS

Lima, 32, Peru

Location

Soweto ACTG CRS

Johannesburg, Gauteng, 1862, South Africa

Location

Wits Helen Joseph Hospital CRS (Wits HJH CRS)

Johannesburg, Gauteng, 2092, South Africa

Location

Durban International Clinical Research Site CRS

Durban, KwaZulu-Natal, 4013, South Africa

Location

Thai Red Cross AIDS Research Centre (TRC-ARC) CRS

Bangkok, 10330, Thailand

Location

Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS

Chiang Mai, 50200, Thailand

Location

Chonburi Hosp. CRS

Chon Buri, 20000, Thailand

Location

Parirenyatwa CRS

Harare, Zimbabwe

Location

Related Publications (7)

• 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.

  PMID: 19525621 BACKGROUND

• 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.

  PMID: 19729664 BACKGROUND

• 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.

  PMID: 35943252 DERIVED

• 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.

  PMID: 32815870 DERIVED

• 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.

  PMID: 31414121 DERIVED

• 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.

  PMID: 30865794 DERIVED

• 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.

  PMID: 26082504 DERIVED

Related Links

• DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009
• Manual for Expedited Reporting of Adverse Events to DAIDS

MeSH Terms

Conditions

Tuberculosis; HIV Infections

Interventions

rifapentine; Isoniazid; Pyridoxine; Vitamin B 6

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Picolines

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Richard E. Chaisson, MD

  Johns Hopkins University

  STUDY CHAIR

• Susan Swindells, MBBS

  University of Nebraska

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 26, 2011
• First Posted: July 28, 2011
• Study Start: May 23, 2012
• Primary Completion: November 14, 2017
• Study Completion: November 14, 2017
• Last Updated: November 4, 2021
• Results First Posted: December 6, 2018

Record last verified: 2020-12

Locations

ZA (3); BO (2); ZI (1); HA (2); US (21); BR (6); TH (3); PE (2); MA (2); KE (3)