High-Dose Isoniazid Among Adult Patients With Different Genetic Variants of INH-Resistant Tuberculosis (TB)
Condition: Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Isoniazid; Vitamin B6
Intervention type(s): Drug; Dietary Supplement
Intervention description(s): 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.; Vitamin B6 was administered at >= 25 mg daily and was obtained locally for use by study participants.
Other intervention name(s): INH
Intervention MeSH terms: Vitamin B 6; Pyridoxal; Pyridoxine; Isoniazid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment