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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified June 2014 by AIDS Clinical Trials Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01936831
First received: September 3, 2013
Last updated: June 5, 2014
Last verified: June 2014
  Purpose

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 Intervention Phase
Tuberculosis
Drug: Isoniazid
Dietary Supplement: Vitamin B6
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Early Bactericidal Activity of High-Dose or Standard-Dose Isoniazid Among Adult Participants With Isoniazid-Resistant or Drug-Sensitive Tuberculosis

Resource links provided by NLM:


Further study details as provided by AIDS Clinical Trials Group:

Primary Outcome Measures:
  • Daily decline in log10 Colony-forming unit (CFU) per mL sputum from baseline to Day 7 of study treatment [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • Grade 2 or higher drug-related adverse clinical or laboratory events (Groups 1 and 2) [ Time Frame: approximately 23 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Steady state Pharmacokinetic (PK) parameters measured from PK sampling at Day 6 [ Time Frame: 1 day ] [ Designated as safety issue: No ]
    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 (Groups 1 & 2)

  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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)


Estimated Enrollment: 64
Study Start Date: June 2014
Estimated Study Completion Date: February 2016
Estimated Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1: Patients 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
Other Name: INH
Dietary Supplement: Vitamin B6
Experimental: Group 2: Patients 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
Other Name: INH
Dietary Supplement: Vitamin B6
No Intervention: Group 3: Patients with an MTB isolate with a katG mutation
Participants with an M. tuberculosis isolate with a katG mutation will not receive study drug.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 only (Group 3 participants, eligible for Step 1 only)
  • 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).
  • 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 ≥200 cells/mm3 within 7 days prior to entry.
  • 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.

  • Any prior history of treatment for Multidrug-resistant (MDR)-TB with second-line anti-TB drugs. This includes all drugs with anti-TB activity, except INH, RIF, ethambutol, pyrazinamide, and streptomycin.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01936831

Sponsors and Collaborators
AIDS Clinical Trials Group
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
  More Information

No publications provided

Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT01936831     History of Changes
Other Study ID Numbers: ACTG A5312, UM1AI068636
Study First Received: September 3, 2013
Last Updated: June 5, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Tuberculosis
Actinomycetales Infections
Bacterial Infections
Gram-Positive Bacterial Infections
Mycobacterium Infections
Isoniazid
Pyridoxal
Pyridoxine
Vitamin B 6
Vitamin B Complex
Vitamins
Anti-Bacterial Agents
Anti-Infective Agents
Antimetabolites
Antitubercular Agents
Fatty Acid Synthesis Inhibitors
Growth Substances
Hypolipidemic Agents
Lipid Regulating Agents
Micronutrients
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014