TuberculosisPhase 2NCT01936831

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

A Phase 2 study testing Isoniazid and Vitamin B6 in people with Tuberculosis, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 2 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Tuberculosis
What is being tested?: Isoniazid and Vitamin B6
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 282 participants
Where: 2 sitesin 2 countries
Study dates: 13 Aug 2014to 6 Oct 2021
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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.

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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)
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/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.

Who cannot join

-There are no exclusion criteria for Step 1.
-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.

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Known exposure to a person diagnosed with extensively drug-resistant (XDR)-TB or known personal diagnosis of XDR-TB in the past.
Protocol version 1.0: 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.

Trial locations and contacts

2 sites in 2 countries.

Country

City, postcode or hospital

2 sites in 2 countries

Haiti1 site

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

Other trials in Haiti

South Africa1 site

TASK Applied Science CRS (31718)
Bellville, 7531

Other trials in South Africa

About this study

Official title: The Early Bactericidal Activity of High-Dose or Standard-Dose Isoniazid Among Adult Participants With Isoniazid-Resistant or Drug-Sensitive Tuberculosis

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.

Read the detailed description

A5312 was a two-stage, two-step, phase IIa, open-label, randomized clinical trial among adult participants with sputum smear positive pulmonary TB evaluating the early bacterial activity (EBA).

No study drug was administered under Step 1. Data collected in Step 1: (a) determined eligibility to Step 2, and (b) allowed characterization of INH MICs in three groups. Groups 1, 2, and 3 consist of participants infected with TB with inhA mutations, with drug susceptible TB (DS-TB), and with TB with katG resistance-conferring mutations, respectively.

Participants enrolled to Step 2 received the study drug, INH, which was given with vitamin B6 >=25 mg daily, by mouth. During both stages, participants in Group 1 who met Step 2 entry criteria were randomized to receive 5, 10, or 15 mg/kg of INH daily for 7 days. During Stage 2, participants in Group 2 who met Step 2 entry criteria received 5 mg/kg of INH daily for 7 days. Under protocol version 3.0 during Stage 2, participants in Group 3 who met Step 2 entry criteria were randomized to receive 15 or 20 mg/kg of INH daily for 7 days. After completion of 7 days of INH alone, participants were referred to begin standard anti-TB chemotherapy according to local guidelines.

In Step 2, prior to initiation of treatment, sputum was collected for quantitative culture on solid medium (for colony forming units (CFU) for Groups 1 and 2 only) and liquid medium (for determination of time to positivity (TTP) for all groups). Sixteen-hour sputum collections were performed daily during INH treatment, as per standard early bacterial activity (EBA) methodology. Sampling for PK analysis was performed at steady state on Day 6 (±1). Safety and tolerability were monitored via clinical evaluations throughout the study and through scheduled laboratory evaluations.

The study consisted of two stages, as follows:

Stage 1-Pilot study to ensure feasibility:

The goal of Stage 1 was to demonstrate feasibility, not treatment efficacy.

Participants were recruited at a single clinical site. All eligible participants entered Step 1 of the study (determination of INH resistance, measurement of INH minimum inhibitory concentrations (MIC)). Among Group 1 participants who met the Step 2 entry criteria, 15 participants were randomized 1:1:1 to receive 5, 10, or 15 mg/kg daily of INH for 7 days with evaluations performed as described above.

Stage 1 completed March 26, 2015. A total of 15 Group 1, 44 Group 2, and 12 Group 3 participants were enrolled in Step 1 only during Stage 1. These participants did not receive study treatment. They provided sputum samples for MIC determination.

Stage 2-Main study:

During Stage 2, Group 1 participants who met Step 2 entry criteria were randomized 1:1:1 to receive 5, 10, or 15 mg/kg of INH daily for 7 days. Group 2 participants who met Step 2 entry criteria were enrolled and received INH at a dose of 5 mg/kg daily. Group 3 participants who met Step 2 entry criteria were enrolled and randomized 1:1 to receive INH at a dose of 15 or 20 mg/kg daily.

In Stage 1, Group 1 participants who did not meet Step 2 entry criteria, all Group 2 participants and all Group 3 participants were referred to a local TB program for treatment. In Stage 2, Group 1, 2 and 3 participants who did not meet Step 2 entry criteria, were referred to a local TB program for treatment.

Protocol Versions:

Key differences in protocol versions include the following:

Study entry criteria were changed from protocol versions 1.0 to 2.0
No longer excluded individuals for antiretroviral therapy use
Exclusion of individuals with any MDR-TB treatment with second-line anti-TB drugs was relaxed to exclude only those with more than 7 cumulative days of use.
Protocol version 2.0 allowed additional sites to enroll participants.
Under protocol versions 1.0 and 2.0, eligible individuals in Group 1 and Group 2 could enroll in Step 1 and Step 2, and eligible individuals in Group 3 could be enrolled in Step 1 only. Under protocol version 3.0, eligible individuals in Group 3 could enroll in Step 1 and Step 2.
Early bactericidal activity was described using both solid culture CFU and liquid culture TTP under protocol versions 1.0 and 2.0. Under protocol version 3.0, early bactericidal activity was measured by liquid culture TTP only.
There were technical difficulties with measuring the isoniazid minimum inhibitory concentration using 1% agar solution for participants enrolled under protocols versions 1.0 and 2.0. For protocol version 3.0, the Thermo Fisher MYCOTB Sensititre plate was substituted to overcome the technical difficulties.

Conditions: Tuberculosis
Being tested: Isoniazid, Vitamin B6
Medical subject headings: Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

IsoniazidDrug
Also called INH
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.
Vitamin B6Dietary supplement
Vitamin B6 was administered at >= 25 mg daily and was obtained locally for use by study participants.

Study groups in NCT01936831
Study group	Role	What they receive
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 Receives: 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 Receives: 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 Receives: 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 Receives: 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 Receives: 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 Receives: Drug: Isoniazid; Dietary Supplement: Vitamin B6

What is being measured

The primary outcome is the main question the study is designed to answer.

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: 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: 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.
Measured: 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: Measured from entry through Day 21

Secondary outcomes (8)

INH PK Parameter Minimum Plasma Concentration (Cmin)
Cmin defines minimum concentration observed over the 24 hours of the INH dosing interval.
Measured: 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)
Cmax defines maximum concentration observed over the 24 hours of the INH dosing interval.
Measured: 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
MIC are determined by phenotypic drug susceptibility testing (DST) based on spot sputum collected at Step 1 Day 0. For group 3 participants shown, MIC was tested using Thermofisher Sensititre MYCOTB plates.
Measured: Day 0
Proportions of Participants Estimated to Have a Drop in log10 CFU/mL at or Above 0.65 log10 CFU/mL.
Proportions of participants obtained through simulation using the estimated model who have a drop in log10 CFU/mL at or above the threshold of 0.65 log10 CFU/mL; 0.65 is half the drop in log10 CFU/mL observed in participants with DS-TB (Group 2) on day 7. A total of 10000 simulated pseudo-participants per arm were used based on data from the study participants. The NAT2 genotype distribution was based only on Group 1 and 2 participants since NAT2 genotype data was not available for Group 3. The simulations were run repeatedly. The point estimate of the proportion was based on the median proportion of the pseudo-individuals across the repeated simulations and the 90% confidence interval used the 5th and 95th percentiles of the proportion across the repeated simulations.
Measured: 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
Negative daily change in log10 CFU indicate decreases in bacterial burden over the time period. The mean CFU are estimated using all values by fitting a biphasic regression models for each participant. The daily change for the first two days of treatment was calculated as EBA0-2 (CFU)= [Day 2 log10 CFU per mL - baseline log10 CFU per mL]/2. The daily change from day 2 to day 7 was calculated as EBA2-7 (CFU)= [Day 7 log10 CFU per mL - Day 2 log10 CFU per mL]/5. Baseline is the average of pre-entry and entry visits.
Measured: At baseline, day 2, and day 7
Daily Change in TTP Measured by Early- (EBA0-2) and Late-phase (EBA2-7) Individual-based Parameter Estimates From Nonlinear Models
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 time period and is therefore better. The mean log transformed TTP are estimated using all values by fitting a biphasic regression models for each participant. The daily change over the first two days of treatment is calculated as EBA0-2 (TTP)= [Day 2 TTP - baseline TTP]/2. The daily change from Day 2 to Day 7 is calculated as EBA2-7 (TTP)= [Day 7 TTP - Day 2 TTP]/5. Baseline is the average of pre-evaluation and entry visits.
Measured: At baseline, day 2, and day 7
EBA Measured by Individual-based Parameter Estimates From Linear or Nonlinear Models When the Number of Phases Differs Between Every Dosing Cohort
Both TTPs and log10 CFU from the pre-evaluation and entry visits averaged and treated as the baseline TTP and log10 CFU for each participant. This outcome was included for analysis if the number of phases differed between every dosing cohort. Since the number of phases did not differ between dosing cohorts, this outcome was not measured.
Measured: From baseline through day 7
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
This approach utilizes the area between baseline CFU per mL and the CFU curve for each participant, as measured using the trapezoidal rule. This outcome was included for analysis if the number of phases differed between every dosing cohort. Since the number of phases did not differ between dosing cohorts, this outcome was not measured.
Measured: From baseline through day 7

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

13 Aug 20146 Oct 2021

First posted6 Sep 2013 (estimated)
Study start13 Aug 2014
Primary completion22 Sep 2021
Study completion6 Oct 2021

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (3)Papers the sponsor has linked to this study.
Other trials for TuberculosisStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 282 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01936831
Sponsor's protocol ID: ACTG A5312
Other IDs: UM1AI068636
Status last verified: Feb 2023
First submitted: 3 Sep 2013
Last updated: 17 Feb 2023
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

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.
PubMed 38564365
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.
PubMed 34403326
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.
PubMed 31945300

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Tuberculosis trials

Study at a glance

From the registry record, last updated by the sponsor on 17 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: The Early Bactericidal Activity of High-Dose or Standard-Dose Isoniazid Among Adult Participants With Isoniazid-Resistant or Drug-Sensitive Tuberculosis
ClinicalTrials.gov ID: NCT01936831
Acronym / sponsor ID: ACTG A5312
Conditions: Tuberculosis
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 282 participants (actual)
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other InfectionsResearch network
Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
Study start: 13 Aug 2014 (actual)
Primary completion: 22 Sep 2021 (actual)
Study completion: 6 Oct 2021 (actual)
First posted: 6 Sep 2013 (estimated)
Results: Posted 17 Feb 2023

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

A5312 was a two-stage, two-step, phase IIa, open-label, randomized clinical trial among adult participants with sputum smear positive pulmonary TB evaluating the early bacterial activity (EBA).

The study consisted of two stages, as follows:

Stage 1-Pilot study to ensure feasibility:

The goal of Stage 1 was to demonstrate feasibility, not treatment efficacy.

Stage 2-Main study:

Protocol Versions:

Key differences in protocol versions include the following:

Study entry criteria were changed from protocol versions 1.0 to 2.0
No longer excluded individuals for antiretroviral therapy use
Exclusion of individuals with any MDR-TB treatment with second-line anti-TB drugs was relaxed to exclude only those with more than 7 cumulative days of use.
Protocol version 2.0 allowed additional sites to enroll participants.
Under protocol versions 1.0 and 2.0, eligible individuals in Group 1 and Group 2 could enroll in Step 1 and Step 2, and eligible individuals in Group 3 could be enrolled in Step 1 only. Under protocol version 3.0, eligible individuals in Group 3 could enroll in Step 1 and Step 2.
Early bactericidal activity was described using both solid culture CFU and liquid culture TTP under protocol versions 1.0 and 2.0. Under protocol version 3.0, early bactericidal activity was measured by liquid culture TTP only.
There were technical difficulties with measuring the isoniazid minimum inhibitory concentration using 1% agar solution for participants enrolled under protocols versions 1.0 and 2.0. For protocol version 3.0, the Thermo Fisher MYCOTB Sensititre plate was substituted to overcome the technical difficulties.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 6

Arm	Type	Receives
Group 1: 5mg Cohort	Experimental	Drug: Isoniazid, Dietary Supplement: Vitamin B6Group 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
Group 1: 10mg Cohort	Experimental	Drug: Isoniazid, Dietary Supplement: Vitamin B6Group 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
Group 1: 15mg Cohort	Experimental	Drug: Isoniazid, Dietary Supplement: Vitamin B6Group 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
Group 2: 5mg Cohort	Active comparator	Drug: Isoniazid, Dietary Supplement: Vitamin B6Group 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
Group 3: 15mg Cohort	Experimental	Drug: Isoniazid, Dietary Supplement: Vitamin B6Group 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
Group 3: 20mg Cohort	Experimental	Drug: Isoniazid, Dietary Supplement: Vitamin B6Group 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

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (22 listed)

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:
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).

Key exclusion criteria (16 listed)

-There are no exclusion criteria for Step 1.
-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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
IsoniazidAlso: INHINH 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.	Drug	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 B6Vitamin B6 was administered at >= 25 mg daily and was obtained locally for use by study participants.	Dietary supplement	Group 1: 10mg Cohort, Group 1: 15mg Cohort, Group 1: 5mg Cohort, Group 2: 5mg Cohort, Group 3: 15mg Cohort, Group 3: 20mg Cohort

Primary outcome

Daily Change in log10 Colony-forming Unit (CFU)
Time frame: Measured at baseline and Day 7
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.
Daily Change in Time to Positivity (TTP)
Time frame: Measured at baseline and Day 7
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.
INH PK Parameter Area Under the Concentration Time Curve (AUC 0-24 Hours)
Time frame: 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.
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.
Number of Participants With Grade 2 or Higher Drug-related Adverse Clinical or Laboratory Events
Time frame: Measured from entry through Day 21
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.

8 secondary outcomes

INH PK Parameter Minimum Plasma Concentration (Cmin)
Time frame: 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)
Time frame: 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
Time frame: Day 0
Proportions of Participants Estimated to Have a Drop in log10 CFU/mL at or Above 0.65 log10 CFU/mL.
Time frame: 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
Time frame: At baseline, day 2, and day 7
Daily Change in TTP Measured by Early- (EBA0-2) and Late-phase (EBA2-7) Individual-based Parameter Estimates From Nonlinear Models
Time frame: At baseline, day 2, and day 7
EBA Measured by Individual-based Parameter Estimates From Linear or Nonlinear Models When the Number of Phases Differs Between Every Dosing Cohort
Time frame: From baseline through day 7
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: From baseline through day 7

Results and safety

Results posted to the registry on 17 Feb 2023, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Group 1: inhA Mutation	110	110
Group 2: Neither inhA Nor katG Mutations	85	85
Group 3: katG Mutation	87	87
Group 1: 5mg Cohort	0	0
Group 1: 10mg Cohort	0	0
Group 1: 15mg Cohort	0	0
Group 2: 5mg Cohort	0	0
Group 3: 15mg Cohort	0	0
Group 3: 20mg Cohort	0	0

Primary outcome: Daily Change in log10 Colony-forming Unit (CFU)

Time frame: Measured at baseline and Day 7. Mean (Standard Deviation). Unit: log10 CFU per mL sputum per day

Measure	Group 1: 5mg Cohort n = 12	Group 1: 10mg Cohort n = 11	Group 1: 15mg Cohort n = 12	Group 2: 5mg Cohort n = 11
Value	-0.06 (0.14)	-0.18 (0.12)	-0.21 (0.15)	-0.15 (0.11)

Population analysed: Participants who took at least one dose of study treatment in Step 2 in Groups 1 and 2. CFU was not collected for Group 3. Participants who had missing Baseline or Day 7 CFU counts were not included.

Primary outcome: Daily Change in Time to Positivity (TTP)

Time frame: Measured at baseline and Day 7. Mean (Standard Deviation). Unit: hours per day

Measure	Group 1: 5mg Cohort n = 13	Group 1: 10mg Cohort n = 14	Group 1: 15mg Cohort n = 14	Group 2: 5mg Cohort n = 16	Group 3: 15mg Cohort n = 10	Group 3: 20mg Cohort n = 10
Value	3 (8)	8 (6)	10 (8)	10 (4)	2.0 (7.9)	4.6 (7.9)

Population analysed: Participants who took at least one dose of study treatment in Step 2. Participants who had missing Baseline or Day 7 TTP counts were not included.

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

Time frame: 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.. Median (Inter-Quartile Range). Unit: ug*hr/mL

Measure	Group 1: 5mg Cohort n = 13	Group 1: 10mg Cohort n = 14	Group 1: 15mg Cohort n = 15	Group 2: 5mg Cohort n = 16	Group 3: 15mg Cohort n = 11	Group 3: 20mg Cohort n = 10
Value	14.05 (9.27 to 28.73)	53.08 (23.65 to 67.26)	50.24 (42.24 to 89.71)	10.47 (8.04 to 18.09)	54.13 (37.86 to 92.57)	70.54 (66.39 to 89.64)

Population analysed: Participants in each treatment dose arm with intensive PK results in Step 2.

Primary outcome: Number of Participants With Grade 2 or Higher Drug-related Adverse Clinical or Laboratory Events

Time frame: Measured from entry through Day 21. Count of participants. Unit: Participants

Measure	Group 1: 5mg Cohort n = 13	Group 1: 10mg Cohort n = 14	Group 1: 15mg Cohort n = 16	Group 2: 5mg Cohort n = 16	Group 3: 15mg Cohort n = 11	Group 3: 20mg Cohort n = 10
Value	0	4	0	1	1	0

Population analysed: Participants who took at least one dose of study treatment in Step 2.

8 secondary outcomes are reported in the full results.

Adverse events

Time frame: Measured from baseline through Day 21. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Group 1- INH 5mg	0 of 13 (0%)	12 of 13 (92.3%)	0 of 13
Group 1- INH 10mg	1 of 14 (7.1%)	14 of 14 (100%)	0 of 14
Group 1- INH 15mg	0 of 16 (0%)	15 of 16 (93.8%)	0 of 16
Group 2- INH 5mg	1 of 16 (6.3%)	16 of 16 (100%)	0 of 16
Group 3- INH 15mg	0 of 11 (0%)	11 of 11 (100%)	0 of 11
Group 3- INH 20mg	0 of 10 (0%)	10 of 10 (100%)	0 of 10

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 17 Feb 2023.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 38564365Gausi 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.
Derived from this study: PubMed 34403326Gausi 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.
Derived from this study: PubMed 31945300Dooley 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.
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009)Link provided by the sponsor.
Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010Link provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Andreas H Diacon, MD, PhD study chair

TASK Clinical Research Center CRS, Karl Bremer Hospital

Kelly Dooley, MD, PhD study chair

Johns Hopkins Adult AIDS CRS

2 sites in 2 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Isoniazid and Vitamin B6 in people with Tuberculosis, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 2 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 17 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Haiti, South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Feb 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Daily Change in log10 Colony-forming Unit (CFU) (time frame: Measured at baseline and Day 7). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01936831, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2023; AzTrials last refreshed its copy on 7 Nov 2026.