High-Dose Isoniazid Among Adult Patients With Different Genetic Variants of INH-Resistant Tuberculosis (TB)
Condition: Tuberculosis
MeSH terms: Tuberculosis
Intervention: Isoniazid; Vitamin B6
Intervention description: 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.
Intervention MeSH terms: Vitamin B 6; Pyridoxal; Pyridoxine; Isoniazid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 282.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria for Step 1:

          -  New or recurrent pulmonary TB with sputum positive for acid-fast bacilli on direct
             microscopy of at least grade 1+ (International Union Against Tuberculosis and Lung
             Disease [IUATLD] scale) at the study laboratory on at least one pre-treatment sputum
             sample within 14 days prior to entry.

          -  Infected with an M. tuberculosis strain for which Hain GenoType MTBDRplus genotype,
             performed at the study laboratory within 14 days prior to study entry, reveals one of
             the following results for INH susceptibility testing:

               -  inhA promoter or functional mutation only (Group 1 participants, eligible for
                  Steps 1 and 2)

               -  No mutations in the inhA or katG genes (Group 2 participants, eligible for Step 1
                  and, during Stage 2 of the study, also eligible for Step 2)

               -  katG mutation with or without an inhA mutation (Group 3 participants, eligible
                  for Step 1 and, during Stage 2 of the study, also eligible for Step 2)

          -  Ability and willingness of the participant or legal guardian/representative to provide
             informed consent.

        Inclusion Criteria for Step 2:

          -  Entry into Step 1.

          -  During Stage 1 of the protocol: inhA promoter or functional mutation only (Group 1).

          -  During Stage 2 of the protocol: inhA promoter or functional mutation only (Group 1) OR
             mutations in neither inhA nor katG genes (Group 2) or mutation in the katG gene, with
             or without mutations in inhA promoter or functional genes (Group 3).

          -  Body weight: 40 kg to 90 kg, inclusive.

          -  Laboratory values obtained within 30 days prior to entry:

               -  Absolute neutrophil count (ANC) >=750 cells/mm^3

               -  Hemoglobin >= 7.4 g/dL

               -  Platelet count >= 50,000/mm^3

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=3 X upper
                  limit of normal (ULN)

               -  Total bilirubin <=2.5 X ULN

          -  HIV infection status must be documented as either absent or present, as defined below:

        Absence of HIV-1 infection within 30 days prior to Step 2 entry OR HIV-1 infection at any
        time prior to Step 2 entry.

          -  For HIV-positive candidates only: CD4+ cell count of >=50 cells/mm^3, performed within
             7 days prior to entry at a DAIDS-approved laboratory

          -  For females of reproductive potential, negative serum or urine pregnancy test within 7
             days prior to entry. Female participants who are participating in sexual activity that
             could lead to pregnancy must agree to use one reliable non-hormonal method of
             contraception (condoms or an IUD), or another method (diaphragm or cervical cap) if it
             is approved by the national regulatory authority and used according to package insert,
             while receiving study medications.

          -  Willingness to be hospitalized for a minimum of 9 consecutive days.

          -  Ability to produce an overnight sputum sample of sufficient quality and quantity.

        Exclusion Criteria for Step 1:

        -There are no exclusion criteria for Step 1.

        Exclusion Criteria for Step 2:

        -Current treatment with INH or receipt of INH during the 7 days prior to Step 2 entry.

        NOTE: Participants who have been started on INH-containing anti-TB treatment and have
        received this treatment for less than or equal to 2 weeks, but for whom TB drugs have been
        discontinued because of resistance to INH (with or without resistance to RIF), can
        participate in the study, but may need to be hospitalized, at the discretion of the
        investigator, while these drugs wash out; the minimum washout period for these drugs is 7
        days.

          -  Protocol versions 1.0 and 2.0 only: Any prior history of treatment for MDR-TB with
             second-line anti-TB drugs. This includes all drugs with anti-TB activity, except INH,
             RIF, ethambutol, pyrazinamide, and streptomycin.

          -  Protocol versions 1.0 and 2.0 only: Receipt of more than 7 cumulative days of
             antibiotics intended for bacterial treatment that may have anti-TB activity, including
             amoxicillin/clavulanate (Augmentin), linezolid, metronidazole, or drugs from the
             quinolone class, with any of those days falling within the 14 days prior to Step 1
             screening sputum collection.

          -  Protocol version 3.0 only: Receipt of more than 7 cumulative days of second-line
             anti-TB drugs (including all drugs with anti-TB activity, except INH, RIF, ethambutol,
             pyrazinamide, and streptomycin) and/or antibiotics intended for bacterial treatment
             that may have anti-TB activity, including amoxicillin/clavulanate (Augmentin),
             linezolid, metronidazole, or drugs from the quinolone class, with any of those days
             falling within the 14 days prior to Step 1 screening sputum collection. The minimum
             washout period for these drugs is 7 days prior to Step 2 pre-entry sputum collection.

          -  Known exposure to a person diagnosed with extensively drug-resistant (XDR)-TB or known
             personal diagnosis of XDR-TB in the past.

          -  Protocol version 1.0: For HIV+ participants only: Current treatment, or treatment
             within 30 days prior to entry, with antiretroviral therapy (ART) or expected to
             initiate ART within 8 days after Step 2 entry. Prior receipt of ART for the prevention
             of mother-to-child-transmission is not exclusionary.

          -  Breastfeeding.

          -  Known allergy/sensitivity to INH.

          -  Karnofsky score <60 or poor general condition where any delay in full TB treatment
             cannot be tolerated in the opinion of the investigator (at screening).

          -  Any of the following co-morbidities, complications, or underlying medical conditions:

               -  Known current neurological TB (eg, TB of the spine, TB meningitis)

               -  Peripheral neuropathy >=Grade 2 within 14 days prior to entry

               -  Current or history of epilepsy, defined as seizure disorder requiring current
                  treatment with an antiepileptic medicine or history of any seizures within the
                  prior year

          -  Any condition as determined by physical examination, medical history, laboratory data,
             or chest x-ray which, in the opinion of the investigator, would interfere with
             participation in the study.