NCT01936831

High-Dose Isoniazid Among Adult Patients With Different Genetic Variants of INH-Resistant Tuberculosis (TB)

The Early Bactericidal Activity of High-Dose or Standard-Dose Isoniazid Among Adult Participants With Isoniazid-Resistant or Drug-Sensitive Tuberculosis

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 282 (actual)
• Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections · Network
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Not accepted

Summary

Isoniazid (INH) is a drug commonly used to treat tuberculosis (TB) worldwide. Sometimes, the bacteria that cause TB can become resistant to INH. Resistance means that bacteria have adapted to a drug and are able to live in the presence of the drug. When TB becomes resistant to INH, INH does not work as well at fighting the bacteria. This study treated people with INH-resistant TB with different doses of INH to see if INH can still fight the bacteria if the dose is increased. We evaluated how well the drug works at higher doses for participants who have resistant TB as well as how well the drug works at regular doses for participants who have TB that is not resistant. The study also evaluated the safety and tolerability of the different doses of INH. Tolerability is how well people can put up with the side effects of a drug. Using increased doses of INH to treat TB that is resistant to INH is experimental and has not been approved by regulatory authorities. While there is some evidence that this approach will work, this has not yet been proven.

Detailed description

A5312 was a two-stage, two-step, phase IIa, open-label, randomized clinical trial among adult participants with sputum smear positive pulmonary TB evaluating the early bacterial activity (EBA). No study drug was administered under Step 1. Data collected in Step 1: (a) determined eligibility to Step 2, and (b) allowed characterization of INH MICs in three groups. Groups 1, 2, and 3 consist of participants infected with TB with inhA mutations, with drug susceptible TB (DS-TB), and with TB with katG resistance-conferring mutations, respectively. Participants enrolled to Step 2 received the study drug, INH, which was given with vitamin B6 \>=25 mg daily, by mouth. During both stages, participants in Group 1 who met Step 2 entry criteria were randomized to receive 5, 10, or 15 mg/kg of INH daily for 7 days. During Stage 2, participants in Group 2 who met Step 2 entry criteria received 5 mg/kg of INH daily for 7 days. Under protocol version 3.0 during Stage 2, participants in Group 3 who met Step 2 entry criteria were randomized to receive 15 or 20 mg/kg of INH daily for 7 days. After completion of 7 days of INH alone, participants were referred to begin standard anti-TB chemotherapy according to local guidelines. In Step 2, prior to initiation of treatment, sputum was collected for quantitative culture on solid medium (for colony forming units (CFU) for Groups 1 and 2 only) and liquid medium (for determination of time to positivity (TTP) for all groups). Sixteen-hour sputum collections were performed daily during INH treatment, as per standard early bacterial activity (EBA) methodology. Sampling for PK analysis was performed at steady state on Day 6 (±1). Safety and tolerability were monitored via clinical evaluations throughout the study and through scheduled laboratory evaluations. The study consisted of two stages, as follows: Stage 1-Pilot study to ensure feasibility: The goal of Stage 1 was to demonstrate feasibility, not treatment efficacy. Participants were recruited at a single clinical site. All eligible participants entered Step 1 of the study (determination of INH resistance, measurement of INH minimum inhibitory concentrations (MIC)). Among Group 1 participants who met the Step 2 entry criteria, 15 participants were randomized 1:1:1 to receive 5, 10, or 15 mg/kg daily of INH for 7 days with evaluations performed as described above. Stage 1 completed March 26, 2015. A total of 15 Group 1, 44 Group 2, and 12 Group 3 participants were enrolled in Step 1 only during Stage 1. These participants did not receive study treatment. They provided sputum samples for MIC determination. Stage 2-Main study: During Stage 2, Group 1 participants who met Step 2 entry criteria were randomized 1:1:1 to receive 5, 10, or 15 mg/kg of INH daily for 7 days. Group 2 participants who met Step 2 entry criteria were enrolled and received INH at a dose of 5 mg/kg daily. Group 3 participants who met Step 2 entry criteria were enrolled and randomized 1:1 to receive INH at a dose of 15 or 20 mg/kg daily. In Stage 1, Group 1 participants who did not meet Step 2 entry criteria, all Group 2 participants and all Group 3 participants were referred to a local TB program for treatment. In Stage 2, Group 1, 2 and 3 participants who did not meet Step 2 entry criteria, were referred to a local TB program for treatment. Protocol Versions: Key differences in protocol versions include the following: * Study entry criteria were changed from protocol versions 1.0 to 2.0 * No longer excluded individuals for antiretroviral therapy use * Exclusion of individuals with any MDR-TB treatment with second-line anti-TB drugs was relaxed to exclude only those with more than 7 cumulative days of use. * Protocol version 2.0 allowed additional sites to enroll participants. * Under protocol versions 1.0 and 2.0, eligible individuals in Group 1 and Group 2 could enroll in Step 1 and Step 2, and eligible individuals in Group 3 could be enrolled in Step 1 only. Under protocol version 3.0, eligible individuals in Group 3 could enroll in Step 1 and Step 2. * Early bactericidal activity was described using both solid culture CFU and liquid culture TTP under protocol versions 1.0 and 2.0. Under protocol version 3.0, early bactericidal activity was measured by liquid culture TTP only. * There were technical difficulties with measuring the isoniazid minimum inhibitory concentration using 1% agar solution for participants enrolled under protocols versions 1.0 and 2.0. For protocol version 3.0, the Thermo Fisher MYCOTB Sensititre plate was substituted to overcome the technical difficulties.

Conditions

• Tuberculosis

Interventions

Type	Name	Description
DRUG	Isoniazid	INH was available in 100 mg tablets. INH was administered orally daily in the morning on an empty stomach. Doses of INH were given according to the weight bands and by cohort.
DIETARY_SUPPLEMENT	Vitamin B6	Vitamin B6 was administered at \>= 25 mg daily and was obtained locally for use by study participants.

Timeline

• Start date: 2014-08-13
• Primary completion: 2021-09-22
• Completion: 2021-10-06
• First posted: 2013-09-06
• Last updated: 2023-02-17
• Results posted: 2023-02-17

Locations

2 sites across 2 countries: Haiti, South Africa