Phase 2
N=282
High-Dose Isoniazid Among Adult Patients With Different Genetic Variants of INH-Resistant Tuberculosis (TB)
Tuberculosis
Bottom Line
View on ClinicalTrials.gov: NCT01936831 ↗Enrolled (actual)
282
Serious AEs
2.5%
Results posted
Feb 2023
Primary outcome: Primary: Daily Change in log10 Colony-forming Unit (CFU) — -0.06; -0.18; -0.21; -0.15 log10 CFU per mL sputum per day
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Isoniazid (Drug); Vitamin B6 (Dietary_supplement)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
- Primary completion
- Sep 2021
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Daily Change in log10 Colony-forming Unit (CFU) |
-0.06; -0.18; -0.21; -0.15 | — |
| PRIMARY Daily Change in Time to Positivity (TTP) |
3; 8; 10; 10; 2.0; 4.6 | — |
| PRIMARY INH PK Parameter Area Under the Concentration Time Curve (AUC 0-24 Hours) |
14.05; 53.08; 50.24; 10.47; 54.13; 70.54 | — |
| PRIMARY Number of Participants With Grade 2 or Higher Drug-related Adverse Clinical or Laboratory Events |
0; 4; 0; 1; 1; 0 | — |
| SECONDARY INH PK Parameter Minimum Plasma Concentration (Cmin) |
0.053; 0.053; 0.053; 0.053; 0.053; 0.053 | — |
| SECONDARY INH PK Parameter Maximum Plasma Concentration (Cmax) |
5.26; 10.4; 15.1; 4.55; 15; 22.15 | — |
| SECONDARY INH Minimum Inhibitory Concentration (MIC) Against M. Tuberculosis Isolates |
1; 0; 0; 0; 0; 1 | — |
| SECONDARY Proportions of Participants Estimated to Have a Drop in log10 CFU/mL at or Above 0.65 log10 CFU/mL. |
0.17; 0.50; 0.64; 0.88; 0.01; 0.05 | — |
| SECONDARY Daily Change in log10 CFU Measured by Early- (EBA0-2) and Late-phase (EBA2-7) Individual-based Parameter Estimates From Nonlinear Models |
-0.23; -0.17; -0.13; -0.41; -0.01; -0.17 | — |
| SECONDARY Daily Change in TTP Measured by Early- (EBA0-2) and Late-phase (EBA2-7) Individual-based Parameter Estimates From Nonlinear Models |
7.78; 11.03; 7.35; 22.39; 2.91; -1.36 | — |
| SECONDARY EBA Measured by Individual-based Parameter Estimates From Linear or Nonlinear Models When the Number of Phases Differs Between Every Dosing Cohort |
— | — |
| SECONDARY Mean EBA Measured by Ratio of the Following Areas: Numerator = AUC of Observed log10 CFU Over 7 Days and Denominator = Baseline log10 CFU for Every Dosing Cohort in Groups 1 and 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.
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) =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 d
Data sourced from ClinicalTrials.gov (NCT01936831). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.