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

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ClinicalTrials.gov Identifier: NCT01936831
Recruitment Status : Recruiting
First Posted : September 6, 2013
Last Update Posted : October 20, 2021
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group

Tracking Information
First Submitted Date  ICMJE September 3, 2013
First Posted Date  ICMJE September 6, 2013
Last Update Posted Date October 20, 2021
Actual Study Start Date  ICMJE August 13, 2014
Estimated Primary Completion Date November 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 2, 2021)
  • Daily decline in log10 Colony-forming unit (CFU) per mL sputum from baseline to Day 7 of study treatment (Groups 1 and 2) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 7 days ]
    defined as EBA0-7 (TTD) = [baseline TTD (mean of the pre-entry visit and entry visit TTDs) - Day 7 TTD]/7
Original Primary Outcome Measures  ICMJE
 (submitted: September 3, 2013)
  • Daily decline in log10 Colony-forming unit (CFU) per mL sputum from baseline to Day 7 of study treatment [ Time Frame: 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) [ Time Frame: 7 days ]
  • Grade 2 or higher drug-related adverse clinical or laboratory events (Groups 1 and 2) [ Time Frame: approximately 23 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 2, 2021)
  • Steady state Pharmacokinetic (PK) parameters measured from PK sampling at Day 6 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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)
Original Secondary Outcome Measures  ICMJE
 (submitted: September 3, 2013)
  • Steady state PK parameters measured from the PK sampling at Day 6, including maximum concentration (Cmax), area under the plasma concentration-time curve in one dosing interval over 24 hours (AUC0-24), and T1/2; NAT2 acetylator status de [ Time Frame: 1 day ]
  • INH minimum inhibitory concentration (MIC) against M. tuberculosis isolates as determined by phenotypic DST based on spot sputum collected at Step 1 Day 0 (all groups) [ Time Frame: 1 day ]
  • AUC/MICs which reach 50% of the mean EBA0-7(CFU) and EBA0-7(TTD) among Group 2 participants (Group 1) with MIC will be determined from spot sputum collected at Step 1 Day 0 and AUC will be measured from the PK sampling at Day 6 [ Time Frame: 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 in Groups1 and 2 [ Time Frame: 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 (Groups 1 and 2)
  • EBA measured by individual-based parameter estimates from linear or nonlinear mixed effect models when the number of phases differs between every dosing cohort in Groups 1 and 2 [ Time Frame: 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
  • 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 [ Time Frame: 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 [ Time Frame: 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)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE High-Dose Isoniazid Among Adult Patients With Different Genetic Variants of INH-Resistant Tuberculosis (TB)
Official Title  ICMJE The Early Bactericidal Activity of High-Dose or Standard-Dose Isoniazid Among Adult Participants With Isoniazid-Resistant or Drug-Sensitive Tuberculosis
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Tuberculosis
Intervention  ICMJE
  • 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 Name: INH
  • Dietary Supplement: Vitamin B6
    Vitamin B6 will be administered at >\= 25 mg daily and will be obtained locally for use by study participants.
Study Arms  ICMJE
  • 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
    Interventions:
    • Drug: Isoniazid
    • Dietary Supplement: Vitamin B6
  • 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
    Interventions:
    • Drug: Isoniazid
    • Dietary Supplement: Vitamin B6
  • 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.
    Interventions:
    • Drug: Isoniazid
    • Dietary Supplement: Vitamin B6
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 2, 2020)
299
Original Estimated Enrollment  ICMJE
 (submitted: September 3, 2013)
64
Estimated Study Completion Date  ICMJE December 14, 2021
Estimated Primary Completion Date November 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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/mm3
    • Hemoglobin >/= 7.4 g/dL
    • Platelet count >/= 50,000/mm3
    • 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/mm3, 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. \

  • 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.
  • 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.
  • Known exposure to a person diagnosed with XDR-TB or known personal diagnosis of Extensively drug-resistant (XDR)-TB in the past.
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Haiti,   South Africa
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01936831
Other Study ID Numbers  ICMJE ACTG A5312
UM1AI068636 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AIDS Clinical Trials Group
Study Sponsor  ICMJE AIDS Clinical Trials Group
Collaborators  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Investigators  ICMJE
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
PRS Account AIDS Clinical Trials Group
Verification Date October 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP