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

NCT01936831 | Completed Phase 2 Results DMC

• 2 other identifiers: ACTG A5312UM1AI068636
• Study Type: interventional
• Target: 282
• Locations: 2 countries
• Sites: 2

Brief 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.

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (4)

• Daily Change in log10 Colony-forming Unit (CFU)

  Negative daily change in log10 CFU indicate decreases in bacterial burden over the 7 day period. Defined as EBA0-7(CFU) = \[Day 7 log10 CFU per mL - baseline log10 CFU per mL\]/7. The baseline measure is the mean of the pre-entry visit and entry visit sputum colony counts.

  Measured at baseline and Day 7

• Daily Change in Time to Positivity (TTP)

  The time to positivity (TTP) measures growth of mycobacterium tuberculosis using MGIT assay in hours. Higher values of daily change in TTP indicate greater decrease in bacterial burden over the 7 day period and is therefore better. Daily change is defined as EBA0-7(TTP) = \[Day 7 TTP - Baseline TTP\]/7. Baseline is the mean of the pre-entry visit and entry visit TTPs.

  Measured at baseline and Day 7

• INH PK Parameter Area Under the Concentration Time Curve (AUC 0-24 Hours)

  AUC 0-24h defines area under the concentration-time curve over the period of 24 hours post-dose, estimated through non-compartmental methods using the linear trapezoidal rule.

  Intensive INH PK samples collected on Day 6 of INH initiation at sample times pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose.

• Number of Participants With Grade 2 or Higher Drug-related Adverse Clinical or Laboratory Events

  Post-entry, all new diagnoses, signs/symptoms and laboratory events of ≥Grade 2 that were assessed by the site as drug related. The DAIDS AE Grading Table (V1.0) and EAE Manual (V2.0) were used.

  Measured from entry through Day 21

Secondary Outcomes (8)

• INH PK Parameter Minimum Plasma Concentration (Cmin)

  Intensive INH PK samples collected on Day 6 of INH initiation at sample times pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose.

• INH PK Parameter Maximum Plasma Concentration (Cmax)

  Intensive INH PK samples collected on Day 6 of INH initiation at sample times pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose.

• INH Minimum Inhibitory Concentration (MIC) Against M. Tuberculosis Isolates

  Day 0

• Proportions of Participants Estimated to Have a Drop in log10 CFU/mL at or Above 0.65 log10 CFU/mL.

  From baseline through day 7

• Daily Change in log10 CFU Measured by Early- (EBA0-2) and Late-phase (EBA2-7) Individual-based Parameter Estimates From Nonlinear Models

  At baseline, day 2, and day 7

Study Arms (6)

Group 1: 5mg Cohort

EXPERIMENTAL

Group 1 participants had an M. tuberculosis strain with an inhA mutation only. 5 mg cohort received Isoniazid 5 mg/kg daily plus vitamin B6 \>=25 mg daily for 7 days

Drug: Isoniazid; Dietary Supplement: Vitamin B6

Group 1: 10mg Cohort

EXPERIMENTAL

Group 1 participants had an M. tuberculosis strain with an inhA mutation only. 10 mg cohort received Isoniazid 10 mg/kg daily plus vitamin B6 \>=25 mg daily for 7 days

Drug: Isoniazid; Dietary Supplement: Vitamin B6

Group 1: 15mg Cohort

EXPERIMENTAL

Group 1 participants had an M. tuberculosis strain with an inhA mutation only. 15 mg cohort received Isoniazid 15 mg/kg daily plus vitamin B6 \>=25 mg daily for 7 days

Drug: Isoniazid; Dietary Supplement: Vitamin B6

Group 2: 5mg Cohort

ACTIVE COMPARATOR

Group 2 participants had an M. tuberculosis strain with neither inhA nor katG mutations. All Group 2 participants received Isoniazid 5 mg/kg daily plus vitamin B6 \>=25 mg daily for 7 days

Drug: Isoniazid; Dietary Supplement: Vitamin B6

Group 3: 15mg Cohort

EXPERIMENTAL

Group 3 participants had an M. tuberculosis strain with a katG mutation with or without an inhA mutation. 15mg cohort received Isoniazid 15 mg/kg daily plus vitamin B6 \>=25 mg daily for 7 days

Drug: Isoniazid; Dietary Supplement: Vitamin B6

Group 3: 20mg Cohort

EXPERIMENTAL

Group 3 participants had an M. tuberculosis strain with a katG mutation with or without an inhA mutation. 20mg cohort received Isoniazid 20 mg/kg daily plus vitamin B6 \>=25 mg daily for 7 days

Drug: Isoniazid; Dietary Supplement: Vitamin B6

Interventions

Isoniazid DRUG

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.

Also known as: INH

Group 1: 10mg Cohort; Group 1: 15mg Cohort; Group 1: 5mg Cohort; Group 2: 5mg Cohort; Group 3: 15mg Cohort; Group 3: 20mg Cohort

Vitamin B6 DIETARY_SUPPLEMENT

Vitamin B6 was administered at \>= 25 mg daily and was obtained locally for use by study participants.

Group 1: 10mg Cohort; Group 1: 15mg Cohort; Group 1: 5mg Cohort; Group 2: 5mg Cohort; Group 3: 15mg Cohort; Group 3: 20mg Cohort

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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)

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (2)

GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (31730)

Port-au-Prince, Haiti

Location

TASK Applied Science CRS (31718)

Bellville, 7531, South Africa

Location

Related Publications (3)

• Gausi K, Ignatius EH, De Jager V, Upton C, Kim S, McKhann A, Moran L, Wiesner L, von Groote-Bidlingmaier F, Marzinek P, Vanker N, Yvetot J, Pierre S, Rosenkranz SL, Swindells S, Diacon AH, Nuermberger EL, Denti P, Dooley KE. High-Dose Isoniazid Lacks EARLY Bactericidal Activity against Isoniazid-resistant Tuberculosis Mediated by katG Mutations: A Randomized Phase II Clinical Trial. Am J Respir Crit Care Med. 2024 Aug 1;210(3):343-351. doi: 10.1164/rccm.202311-2004OC.

  PMID: 38564365 DERIVED

• Gausi K, Ignatius EH, Sun X, Kim S, Moran L, Wiesner L, von Groote-Bidlingmaier F, Hafner R, Donahue K, Vanker N, Rosenkranz SL, Swindells S, Diacon AH, Nuermberger EL, Dooley KE, Denti P. A Semimechanistic Model of the Bactericidal Activity of High-Dose Isoniazid against Multidrug-Resistant Tuberculosis: Results from a Randomized Clinical Trial. Am J Respir Crit Care Med. 2021 Dec 1;204(11):1327-1335. doi: 10.1164/rccm.202103-0534OC.

  PMID: 34403326 DERIVED

• Dooley KE, Miyahara S, von Groote-Bidlingmaier F, Sun X, Hafner R, Rosenkranz SL, Ignatius EH, Nuermberger EL, Moran L, Donahue K, Swindells S, Vanker N, Diacon AH; A5312 Study Team. Early Bactericidal Activity of Different Isoniazid Doses for Drug-Resistant Tuberculosis (INHindsight): A Randomized, Open-Label Clinical Trial. Am J Respir Crit Care Med. 2020 Jun 1;201(11):1416-1424. doi: 10.1164/rccm.201910-1960OC.

  PMID: 31945300 DERIVED

Related Links

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009)
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

Tuberculosis

Interventions

Isoniazid; Vitamin B 6

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Picolines

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, a DLH Holdings Company

ACTGCT.gov@fstrf.org

(301) 628-3348

Study Officials

• 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 CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2013
• First Posted: September 6, 2013
• Study Start: August 13, 2014
• Primary Completion: September 22, 2021
• Study Completion: October 6, 2021
• Last Updated: February 17, 2023
• Results First Posted: February 17, 2023

Record last verified: 2023-02

Locations

ZA (1); HA (1)