High-Dose Isoniazid Among Adult Patients With Different Genetic Variants of INH-Resistant Tuberculosis (TB)
Study Details
Study Description
Brief Summary
Isoniazid (INH) is a drug commonly used to treat 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 will treat people with INH-resistant TB with different doses of INH to see if INH can still fight the bacteria if we just increase the dose. We will compare how well the drug works at higher doses for participants who have resistant TB to how well the drug works at regular doses for participants who have TB that is not resistant. The study will also compare 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.
This study will be done in two stages. Stage 1 is a pilot study to determine the feasibility of enrolling enough participants into Stage 2, the larger stage of this study. If Stage 1 is successful, then Stage 2 will begin.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Early Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Group 1: Participants with a TB strain that has an inhA mutation Participants who meet Step 2 entry criteria will be randomized 1:1:1 to receive the following treatments for 7 days: 5 mg cohort: Isoniazid 5 mg/kg daily plus vitamin B6 ≥25 mg daily 10 mg cohort: Isoniazid 10 mg/kg daily plus vitamin B6 ≥25 mg daily 15 mg cohort: Isoniazid 15 mg/kg daily plus vitamin B6 ≥25 mg daily |
Drug: Isoniazid
INH is available in 100 mg tablets. INH will be administered orally daily in the morning on an empty stomach. Doses of INH will be given according to the weight bands.
Other Names:
Dietary Supplement: Vitamin B6
Vitamin B6 will be administered at >\= 25 mg daily and will be obtained locally for use by study participants.
|
| Experimental: Group 2: Participants with TB without inhA nor katG mutations Participants who meet Step 2 entry criteria will receive Isoniazid 5 mg/kg daily plus vitamin B6 ≥25 mg daily for 7 days |
Drug: Isoniazid
INH is available in 100 mg tablets. INH will be administered orally daily in the morning on an empty stomach. Doses of INH will be given according to the weight bands.
Other Names:
Dietary Supplement: Vitamin B6
Vitamin B6 will be administered at >\= 25 mg daily and will be obtained locally for use by study participants.
|
| Experimental: Group 3: Participants with an MTB isolate with a katG mutation with or without an inhA mutation Participants with an M. tuberculosis isolate with a katG mutation with or without an inhA mutation who meet Step 2 entry criteria will be randomized to receive either Isoniazid 15 mg/kg or 20 mg/kg daily, plus vitamin B6 ≥25 mg daily for 7 days. |
Drug: Isoniazid
INH is available in 100 mg tablets. INH will be administered orally daily in the morning on an empty stomach. Doses of INH will be given according to the weight bands.
Other Names:
Dietary Supplement: Vitamin B6
Vitamin B6 will be administered at >\= 25 mg daily and will be obtained locally for use by study participants.
|
Outcome Measures
Primary Outcome Measures
- Daily decline in log10 Colony-forming unit (CFU) per mL sputum from baseline to Day 7 of study treatment (Groups 1 and 2) [7 days]
Defined as EBA0-7(CFU)=[baseline log10 CFU per mL (mean of the pre-entry visit and entry visit sputum colony counts) - Day 7 log10 CFU per mL]/7 (Groups 1 and 2)
- Daily log10 CFU per mL sputum and TTD from baseline to Day 7 of study treatment; area under the time-concentration curve (AUC) for INH; MIC of M. tuberculosis isolates against INH (Group 1 for CFU and TTD, Group 3 for TTD only) [7 days]
Daily log10 CFU per mL sputum and TTD from baseline to Day 7 of study treatment; area under the time-concentration curve (AUC) for INH; MIC of M. tuberculosis isolates against INH (Group 1 for CFU and TTD, Group 3 for TTD only)
- Grade 2 or higher drug-related adverse clinical or laboratory events (all groups) [approximately 23 days]
Grade 2 or higher drug-related adverse clinical or laboratory events (all groups)
- Daily decline in TTD from baseline to day 7 of study treatment (all groups) [7 days]
defined as EBA0-7 (TTD) = [baseline TTD (mean of the pre-entry visit and entry visit TTDs) - Day 7 TTD]/7
Secondary Outcome Measures
- Steady state Pharmacokinetic (PK) parameters measured from PK sampling at Day 6 [1 day]
Including max concentration (Cmax), area under plasma concentration-time curve in one dosing interval over 24 hours (AUC0-24), & T1/2; N-acetyltransferase 2 (NAT2) acetylator status determined on specimens collected at Step 2 Day 0 (all groups)
- INH minimum inhibitory concentration (MIC) against M. tuberculosis isolates as determined by phenotypic drug susceptibility testing (DST) based on spot sputum collected at Step 1 Day 0 (all groups) [1 day]
INH minimum inhibitory concentration (MIC) against M. tuberculosis isolates as determined by phenotypic drug susceptibility testing (DST) based on spot sputum collected at Step 1 Day 0 (all groups)
- AUC/MICs which reach 50% of the mean EBA0-7(CFU) and EBA0-7(TTD) among Group 2 participants (Group 1 CFU and TTD, Group 3 TTD only) with MIC will be determined from spot sputum collected at Step 1 Day 0, AUC will be measured from Day 6 PK sampling [2 days]
EBA0-7(CFU) is defined as [baseline log10 CFU per mL (mean of the pre-entry visit and entry visit sputum colony counts) - Day 7 log10 CFU per mL]/7, and EBA0- 7(TTD) is defined as [baseline TTD (mean of the pre-entry visit and entry visit TTDs) - Day 7 TTD]/7
- EBA measured by early- (EBA0-2) and late-phase (EBA2-7) individual-based parameter estimates from nonlinear mixed effect models when the number of phases is the same for every dosing cohort (all groups) [7 days]
Both TTDs and log10 CFU from the pre-evaluation and entry visits will be averaged and treated as the baseline TTD and log10 CFU (all groups)
- EBA measured by individual-based parameter estimates from linear or nonlinear mixed effect models when the number of phases differs between every dosing cohort [7 days]
Both TTDs and log10 CFU from the pre-evaluation and entry visits will be averaged and treated as the baseline TTD and log10 CFU for each participant
- 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 [7 days]
This approach utilizes the area between baseline CFU per mL and the CFU curve for each participant, as measured using the trapezoidal rule
- Daily decline in TTD from baseline to Day 7 of study treatment for every cohort in Group 1 and Group 2 [7 days]
EBA0-7 (TTD) is defined as [baseline TTD (mean of the pre-entry visit and entry visit TTDs) - Day 7 TTD]/7 (Groups 1 and 2)
Eligibility Criteria
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.
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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)
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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)
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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)
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Ability and willingness of the participant or legal guardian/representative to provide informed consent.
Inclusion Criteria for Step 2:
-
Entry into Step 1.
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During Stage 1 of the protocol: inhA promoter or functional mutation only (Group 1).
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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).
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Body weight: 40 kg to 90 kg, inclusive.
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Laboratory values obtained within 30 days prior to entry:
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Absolute neutrophil count (ANC) >/=750 cells/mm3
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Hemoglobin >/= 7.4 g/dL
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Platelet count >/= 50,000/mm3
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Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 X upper limit of normal (ULN)
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Total bilirubin ≤2.5 X ULN
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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.
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For HIV-positive candidates only: CD4+ cell count of ≥50 cells/mm3, performed within 7 days prior to entry at a DAIDS-approved laboratory
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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.
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Willingness to be hospitalized for a minimum of 9 consecutive days.
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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. \
-
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, 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.
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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.
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Known exposure to a person diagnosed with XDR-TB or known personal diagnosis of Extensively drug-resistant (XDR)-TB in the past.
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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.
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Breastfeeding.
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Known allergy/sensitivity to INH.
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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).
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Any of the following co-morbidities, complications, or underlying medical conditions:
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Known current neurological TB (eg, TB of the spine, TB meningitis)
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Peripheral neuropathy ≥Grade 2 within 14 days prior to entry
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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
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (31730) | Port Au Prince | Haiti | ||
| 2 | TASK Applied Science CRS (31718) | Bellville | South Africa | 7531 |
Sponsors and Collaborators
- AIDS Clinical Trials Group
- National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
- Study Chair: Andreas H Diacon, MD, PhD, TASK Clinical Research Center CRS, Karl Bremer Hospital
- Study Chair: Kelly Dooley, MD, PhD, Johns Hopkins Adult AIDS CRS
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ACTG A5312
- UM1AI068636