A Phase 2 interventional study of Isoniazid and Vitamin B6 in Tuberculosis, sponsored by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections. Completed at 2 sites in 2 countries. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2023-02-17.
Sponsored by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections · Phase 2, Interventional, and Treatment
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.
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
1,170 studies on the registry are indexed under Tuberculosis; 175 are open to participants now.
This study's enrollment of 282 is above the median of 150 across 820 interventional studies indexed under Tuberculosis.
Browse Tuberculosis studies →Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections is the lead sponsor of 70 studies on the registry; 3 are open to participants now.
Of its 7 completed or terminated interventional studies of FDA-regulated products, 6 (86%) have results posted.
Counted across the registry records on this site, refreshed daily.
Inclusion Criteria for Step 1:
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:
Inclusion Criteria for Step 2:
Laboratory values obtained within 30 days prior to entry:
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.
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 for these drugs is 7 days.
Any of the following co-morbidities, complications, or underlying medical conditions:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
The number of CD4 cells, a type of white blood cell, in a given amount of blood. It is used to follow how well the immune system is doing in HIV.
Able to have children. For women this usually means from the first period until menopause, unless permanently unable to through surgery; for men, unless permanently sterile. Read who the line is about — participants, women, men, or their partners.
Criteria about it usually ask for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
A planned gap after a treatment, so that its effects can lessen before the study treatment or a study assessment. Ask the study team and the doctor who prescribed it before changing any medicine.
A line of therapy is one course of treatment, which may combine several drugs. First-line is the first course given; second-line follows when that stops working or is not tolerated.
“Two prior lines” means two courses that count separately under the study’s rules — not simply two drugs. Ask the study team if you are unsure how yours are counted.
A 0–100 scale of how well someone can carry out everyday activities. 100 is no complaints and no signs of illness; 70 is able to look after yourself but not to work or keep up normal activity; 50 is needing considerable help and frequent medical care.
Studies often ask for 60 or 70 and above. Your doctor gives the score.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CD4 count
The number of CD4 cells, a type of white blood cell, in a given amount of blood. It is used to follow how well the immune system is doing in HIV.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Reproductive potential
Able to have children. For women this usually means from the first period until menopause, unless permanently unable to through surgery; for men, unless permanently sterile. Read who the line is about — participants, women, men, or their partners.
Criteria about it usually ask for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Washout period
A planned gap after a treatment, so that its effects can lessen before the study treatment or a study assessment. Ask the study team and the doctor who prescribed it before changing any medicine.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Line of therapy
A line of therapy is one course of treatment, which may combine several drugs. First-line is the first course given; second-line follows when that stops working or is not tolerated.
“Two prior lines” means two courses that count separately under the study’s rules — not simply two drugs. Ask the study team if you are unsure how yours are counted.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Karnofsky performance status (KPS)
A 0–100 scale of how well someone can carry out everyday activities. 100 is no complaints and no signs of illness; 70 is able to look after yourself but not to work or keep up normal activity; 50 is needing considerable help and frequent medical care.
Studies often ask for 60 or 70 and above. Your doctor gives the score.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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 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 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 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 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 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
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
Drug pages: Vitamin B 6 · Pyridoxine
Vitamin B6 was administered at \>= 25 mg daily and was obtained locally for use by study participants.
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.
Time frame: 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.
Time frame: 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.
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.
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.
Time frame: Measured from entry through Day 21
INH PK Parameter Minimum Plasma Concentration (Cmin)
Cmin defines minimum concentration observed over the 24 hours of the INH dosing interval.
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)
Cmax defines maximum concentration observed over the 24 hours of the INH dosing interval.
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
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.
Time frame: 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.
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
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.
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
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.
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
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.
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
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.
Time frame: From baseline through day 7
No drug was administered under Step 1. Data collected in Step 1 determined eligibility to Step 2. Participants in Steps 1 and 2 were enrolled from August 2014 to September 2021 at 2 non-US clinical research sites.
| Milestone | Group 1: inhA Mutation | Group 2: Neither inhA Nor katG Mutations | Group 3: katG Mutation | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort |
|---|---|---|---|---|---|---|---|---|---|
| Started | 110 | 85 | 87 | 0 | 0 | 0 | 0 | 0 | 0 |
| Completed | 110 | 85 | 87 | 0 | 0 | 0 | 0 | 0 | 0 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Milestone | Group 1: inhA Mutation | Group 2: Neither inhA Nor katG Mutations | Group 3: katG Mutation | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort |
|---|---|---|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 13 | 14 | 16 | 16 | 11 | 10 |
| Completed | 0 | 0 | 0 | 13 | 14 | 15 | 16 | 11 | 10 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
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.
| log10 CFU per mL sputum per day | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort |
|---|---|---|---|---|
| Daily Change in log10 Colony-forming Unit (CFU) | -0.06 ± 0.14 | -0.18 ± 0.12 | -0.21 ± 0.15 | -0.15 ± 0.11 |
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.
| hours per day | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort |
|---|---|---|---|---|---|---|
| Daily Change in Time to Positivity (TTP) | 3 ± 8 | 8 ± 6 | 10 ± 8 | 10 ± 4 | 2.0 ± 7.9 | 4.6 ± 7.9 |
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.
| ug*hr/mL | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort |
|---|---|---|---|---|---|---|
| INH PK Parameter Area Under the Concentration Time Curve (AUC 0-24 Hours) | 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) |
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.
| Participants | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort |
|---|---|---|---|---|---|---|
| Number of Participants With Grade 2 or Higher Drug-related Adverse Clinical or Laboratory Events | 0 | 4 | 0 | 1 | 1 | 0 |
Cmin defines minimum concentration observed over the 24 hours of the INH dosing interval.
| ug/mL | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort |
|---|---|---|---|---|---|---|
| INH PK Parameter Minimum Plasma Concentration (Cmin) | 0.053 (0.053 to 0.053) | 0.053 (0.053 to 0.179) | 0.053 (0.053 to 0.099) | 0.053 (0.053 to 0.053) | 0.053 (0.053 to 0.329) | 0.053 (0.053 to 0.221) |
Cmax defines maximum concentration observed over the 24 hours of the INH dosing interval.
| ug/mL | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort |
|---|---|---|---|---|---|---|
| INH PK Parameter Maximum Plasma Concentration (Cmax) | 5.26 (4.41 to 7.13) | 10.4 (8.26 to 11.90) | 15.1 (12.30 to 17.90) | 4.55 (3.62 to 6.00) | 15 (13.05 to 20.10) | 22.15 (18.10 to 23.75) |
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.
| Participants | Step 1 Group 3 Version 3 |
|---|---|
| 0.03 μg/mL | 1 |
| 0.06 μg/mL | 0 |
| 0.12 μg/mL | 0 |
| 0.25 μg/mL | 0 |
| 0.5 μg/mL | 0 |
| 1 μg/mL | 1 |
| 2 μg/mL | 4 |
| 4 μg/mL | 9 |
| >4 μg/mL | 3 |
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.
| proportion of simulated participants | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort |
|---|---|---|---|---|---|---|
| Proportions of Participants Estimated to Have a Drop in log10 CFU/mL at or Above 0.65 log10 CFU/mL. | 0.17 (0.00 to 0.60) | 0.50 (0.06 to 0.84) | 0.64 (0.18 to 0.91) | 0.88 (0.78 to 0.99) | 0.01 (0.00 to 0.30) | 0.05 (0.00 to 0.41) |
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.
| log10 CFU per mL sputum per day | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort |
|---|---|---|---|---|
| EBA(0-2) | -0.23 ± 0.30 | -0.17 ± 0.22 | -0.13 ± 0.39 | -0.41 ± 0.33 |
| EBA(2-7) | -0.01 ± 0.15 | -0.17 ± 0.13 | -0.25 ± 0.17 | -0.07 ± 0.19 |
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.
| hours per day | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort |
|---|---|---|---|---|---|---|
| EBA(0-2) | 7.78 ± 17.22 | 11.03 ± 6.40 | 7.35 ± 14.73 | 22.39 ± 11.44 | 2.91 ± 3.57 | -1.36 ± 7.59 |
| EBA(2-7) | 1.77 ± 9.61 | 5.45 ± 7.39 | 12.01 ± 8.29 | 5.09 ± 6.43 | 2.69 ± 12.21 | 5.45 ± 8.36 |
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.
No measurements were reported for this outcome.
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.
No measurements were reported for this outcome.
Collected over Measured from baseline through Day 21. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Group 1- INH 5mg | 0/13 (0%) | 0/13 (0%) | 12/13 (92.3%) |
| Group 1- INH 10mg | 0/14 (0%) | 1/14 (7.1%) | 14/14 (100%) |
| Group 1- INH 15mg | 0/16 (0%) | 0/16 (0%) | 15/16 (93.8%) |
| Group 2- INH 5mg | 0/16 (0%) | 1/16 (6.3%) | 16/16 (100%) |
| Group 3- INH 15mg | 0/11 (0%) | 0/11 (0%) | 11/11 (100%) |
| Group 3- INH 20mg | 0/10 (0%) | 0/10 (0%) | 10/10 (100%) |
| Event | Group 1- INH 5mg | Group 1- INH 10mg | Group 1- INH 15mg | Group 2- INH 5mg | Group 3- INH 15mg | Group 3- INH 20mg |
|---|---|---|---|---|---|---|
| Pneumothorax spontaneousRespiratory, thoracic and mediastinal disorders | 0/13 | 1/14 | 0/16 | 0/16 | 0/11 | 0/10 |
| PneumothoraxRespiratory, thoracic and mediastinal disorders | 0/13 | 0/14 | 0/16 | 1/16 | 0/11 | 0/10 |
| Event | Group 1- INH 5mg | Group 1- INH 10mg | Group 1- INH 15mg | Group 2- INH 5mg | Group 3- INH 15mg | Group 3- INH 20mg |
|---|---|---|---|---|---|---|
| Blood albumin decreasedInvestigations | 11/13 | 14/14 | 15/16 | 16/16 | 11/11 | 10/10 |
| Haemoglobin decreasedInvestigations | 4/13 | 6/14 | 5/16 | 4/16 | 6/11 | 4/10 |
| Aspartate aminotransferase increasedInvestigations | 0/13 | 5/14 | 4/16 | 4/16 | 0/11 | 1/10 |
| Alanine aminotransferase increasedInvestigations | 1/13 | 3/14 | 5/16 | 2/16 | 0/11 | 0/10 |
| Blood alkaline phosphatase increasedInvestigations | 1/13 | 3/14 | 4/16 | 1/16 | 0/11 | 3/10 |
| Drug-induced liver injuryHepatobiliary disorders | 0/13 | 2/14 | 0/16 | 0/16 | 0/11 | 0/10 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 0/13 | 2/14 | 0/16 | 0/16 | 0/11 | 0/10 |
| Blood albuminInvestigations | 0/13 | 0/14 | 0/16 | 0/16 | 0/11 | 1/10 |
| Abdominal painGastrointestinal disorders | 0/13 | 0/14 | 0/16 | 0/16 | 1/11 | 0/10 |
| Blood potassium decreasedInvestigations | 0/13 | 0/14 | 0/16 | 0/16 | 1/11 | 0/10 |
All participants
| Age, Continuous(years) | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort | Step 1 Group 1 | Step 1 Group 2 | Step 1 Group 3 | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Median | 31 (20 to 58) | 32 (20 to 58) | 34 (18 to 55) | 30 (19 to 58) | 36 (23 to 61) | 39 (20 to 54) | 36 (19 to 59) | 32 (18 to 63) | 35 (18 to 62) | 35 (18 to 63) |
| Sex: Female, Male(Participants) | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort | Step 1 Group 1 | Step 1 Group 2 | Step 1 Group 3 | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Female | 3 | 3 | 6 | 4 | 3 | 3 | 26 | 27 | 22 | 97 |
| Male | 10 | 11 | 10 | 12 | 8 | 7 | 41 | 42 | 44 | 185 |
| Race/Ethnicity, Customized(Participants) | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort | Step 1 Group 1 | Step 1 Group 2 | Step 1 Group 3 | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| White Non-Hispanic | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 3 |
| Black Non-Hispanic | 13 | 14 | 16 | 15 | 10 | 10 | 66 | 69 | 66 | 279 |
| Region of Enrollment(Participants) | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort | Step 1 Group 1 | Step 1 Group 2 | Step 1 Group 3 | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Haiti | 0 | 0 | 0 | 0 | 7 | 5 | 0 | 0 | 2 | 14 |
| South Africa | 13 | 14 | 16 | 16 | 4 | 5 | 67 | 69 | 64 | 268 |
| Karnofsky Score(units on a scale) | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort | Step 1 Group 1 | Step 1 Group 2 | Step 1 Group 3 | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Median | 90 (70 to 90) | 90 (70 to 90) | 80 (70 to 90) | 90 (80 to 90) | 80 (70 to 90) | 90 (80 to 90) | — | — | — | 90 (70 to 90) |
| BMI(kg/m^2) | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort | Step 1 Group 1 | Step 1 Group 2 | Step 1 Group 3 | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Median | 18.1 (16.2 to 30.9) | 17.7 (14.6 to 23.6) | 18.5 (15.4 to 30.1) | 18.0 (15.2 to 29.7) | 19.3 (16.0 to 24.4) | 17.6 (14.5 to 24.3) | — | — | — | 18.1 (14.5 to 30.9) |
| HIV Status(Participants) | Group 1: 5mg Cohort | Group 1: 10mg Cohort | Group 1: 15mg Cohort | Group 2: 5mg Cohort | Group 3: 15mg Cohort | Group 3: 20mg Cohort | Step 1 Group 1 | Step 1 Group 2 | Step 1 Group 3 | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Living without HIV | 11 | 11 | 12 | 13 | 9 | 8 | — | — | — | 64 |
| Living with HIV | 2 | 3 | 4 | 3 | 2 | 2 | — | — | — | 16 |
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Studies of the drug tested here: Isoniazid
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections