The Early Bactericidal Activity of High-Dose or Standard-Dose Isoniazid Among Adult Participants With Isoniazid-Resistant or Drug-Sensitive Tuberculosis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 282
- 试验地点
- 2
- 主要终点
- Daily Change in Time to Positivity (TTP)
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Group 1: 5mg Cohort
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
干预措施: Isoniazid (Drug)
Group 1: 5mg Cohort
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
干预措施: Vitamin B6 (Dietary Supplement)
Group 1: 10mg Cohort
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
干预措施: Isoniazid (Drug)
Group 1: 10mg Cohort
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
干预措施: Vitamin B6 (Dietary Supplement)
Group 1: 15mg Cohort
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
干预措施: Isoniazid (Drug)
Group 1: 15mg Cohort
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
干预措施: Vitamin B6 (Dietary Supplement)
Group 2: 5mg Cohort
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
干预措施: Isoniazid (Drug)
Group 2: 5mg Cohort
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
干预措施: Vitamin B6 (Dietary Supplement)
Group 3: 15mg Cohort
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
干预措施: Isoniazid (Drug)
Group 3: 15mg Cohort
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
干预措施: Vitamin B6 (Dietary Supplement)
Group 3: 20mg Cohort
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
干预措施: Isoniazid (Drug)
Group 3: 20mg Cohort
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
干预措施: Vitamin B6 (Dietary Supplement)
结局指标
主要结局
Daily Change in Time to Positivity (TTP)
时间窗: 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.
Daily Change in log10 Colony-forming Unit (CFU)
时间窗: 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.
INH PK Parameter Area Under the Concentration Time Curve (AUC 0-24 Hours)
时间窗: 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
时间窗: 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.
次要结局
- INH PK Parameter Minimum Plasma Concentration (Cmin)(Intensive INH PK samples collected on Day 6 of INH initiation at sample times pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose.)
- INH PK Parameter Maximum Plasma Concentration (Cmax)(Intensive INH PK samples collected on Day 6 of INH initiation at sample times pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h post-dose.)
- INH Minimum Inhibitory Concentration (MIC) Against M. Tuberculosis Isolates(Day 0)
- Proportions of Participants Estimated to Have a Drop in log10 CFU/mL at or Above 0.65 log10 CFU/mL.(From baseline through day 7)
- Daily Change in log10 CFU Measured by Early- (EBA0-2) and Late-phase (EBA2-7) Individual-based Parameter Estimates From Nonlinear Models(At baseline, day 2, and day 7)
- Daily Change in TTP Measured by Early- (EBA0-2) and Late-phase (EBA2-7) Individual-based Parameter Estimates From Nonlinear Models(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(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(From baseline through day 7)