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

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01404312
• Other study ID #: A5279
• Secondary ID: 10848ACTG A5279
• Status: Completed
• Phase: Phase 3
• Start date: May 23, 2012
• Est. completion date: November 14, 2017

Study information

• Verified date: December 2020
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 3000
• Est. completion date: November 14, 2017
• Est. primary completion date: November 14, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Years and older

Eligibility

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

Related Conditions & MeSH terms

• HIV Infections
• Infections
• Tuberculosis

Intervention

Drug:
• Rifapentine (RPT)
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).
• Isoniazid (INH)
Participants received one 300-mg tablet or three 100-mg tablets of INH once daily.

Dietary Supplement:
• Pyridoxine (Vitamin B6)
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.

Locations

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

Sponsors (1)

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

Countries where clinical trial is conducted

United States,  Zimbabwe,  Botswana,  Brazil,  Haiti,  Kenya,  Malawi,  Peru,  South Africa,  Thailand, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Number of Participants With Occurrence of One or More Serious Adverse Events (SAEs) Versus no SAEs	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)
Secondary	Number of Participants With a Targeted Adverse Event	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)
Secondary	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	Ordered categories include: Premature permanent treatment discontinuation; Treatment hold for more than 7 consecutive days; None of the above	From entry to end of treatment (up to 8 weeks for Arm A; up to 54 weeks for Arm B)
Secondary	Cumulative Incidence of Death From Any Cause	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)
Secondary	Cumulative Incidence of Death Due to a Non-TB Event	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)
Secondary	Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis	Among MTB-diagnosed participants who underwent drug-susceptibility testing, the number who had any resistance to a particular drug.	After TB diagnosis
Secondary	Efavirenz (EFV) Plasma Concentrations in Arm A	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
Secondary	Nevirapine (NVP) Plasma Concentrations in Arm A	Mean and standard deviation	Measured at Weeks 0, 2, and 4
Secondary	EFV Plasma Concentrations in Arm B	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

External 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