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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Tuberculosis, HIV Infections

Intervention / Treatment
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* Drug: Rifapentine (RPT)
* Drug: Isoniazid (INH)
* Dietary Supplement: Pyridoxine (Vitamin B6)


Participation Criteria
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Eligibility Criteria
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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: 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 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

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RPT plus INH Regimen (Arm A)<br>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)<br>* 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).<br>Drug: Isoniazid (INH)<br>* Participants received one 300-mg tablet or three 100-mg tablets of INH once daily.<br>Dietary Supplement: Pyridoxine (Vitamin B6)<br>* 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.<br>|
| Active Comparator: INH Regimen (Arm B)<br>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)<br>* Participants received one 300-mg tablet or three 100-mg tablets of INH once daily.<br>Dietary Supplement: Pyridoxine (Vitamin B6)<br>* 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.<br>|

What is the study measuring?
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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 | 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 | 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 | 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 | 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) | 
| 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) | 
| 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) | 
| 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 | 
| 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 | 
| Nevirapine (NVP) Plasma Concentrations in Arm A | Mean and standard deviation | Measured at Weeks 0, 2, and 4 | 
| 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 |