Phase I/II Dose Finding and Safety Study of Rifapentine and Isoniazid in HIV-Infected and HIV-Uninfected Children With Latent Tuberculosis Infection
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 69
- 试验地点
- 1
- 主要终点
- Rifapentine exposure among participants by median area under the curve (AUC)
研究概览
简要总结
Hypotheses: Rifapentine (given as water-dispersible monolayer and/or fixed dose combination with isoniazid) dosing in HIV-infected and uninfected children ≤ 12 years of age with latent TB infection (LTBI) or with exposure to Mycobacterium tuberculosis (M. tuberculosis) will require higher mg/kg rifapentine dosing than adults to achieve adult- exposures which are correlated with efficacy in trials of TB prevention. Investigators further hypothesize that rifapentine will be safe and well-tolerated in HIV-infected and uninfected children who require treatment for LTBI.
详细描述
Design: Tuberculosis Trials Consortium Study 35 (TBTC S35) is a Phase I/II, open-label, single arm, exposure-controlled dose finding study using an adaptive design. S35 will evaluate the pharmacokinetics (PK), safety and tolerability of rifapentine given in a new fixed dose combination once-weekly, in combination with isoniazid for 12 weeks, in HIV-infected and HIV-uninfected children aged 0-12 years in whom LTBI treatment is indicated. The study utilizes a modified age de-escalation approach given the extensive PK and safety data already available in children older than 2 years of age. The protocol allows for parallel enrolment of children into cohorts 1 and 2, simultaneously, using a predetermined modeled initial dose for each cohort, separately. Similarly, cohorts 3 and 4 will be enrolled in parallel, using modeled doses for each cohort, based on data from cohorts 1 and 2 and historical data from TBTC trials.
Sample Size: Approximately 72 participants will be required to ensure a minimum number of 60 evaluable participants.
Participants will be enrolled in 4 age cohorts:
Cohort 1: ≥ 4 to ≤ 12 years Cohort 2: ≥ 24 months to < 4 years Cohort 3: ≥ 12 to < 24 months Cohort 4: 0 to <12 months
There will be a minimum of 12 participants each in cohorts 1 and 2, and 18 participants each in cohorts 3 and 4, to allow for 36 participants in the age group below 2 years, given the importance of developmental pharmacology in this youngest age group (Table 1) and the lack of historical data in this age group. Cohorts 3 and 4 will be enrolled once week 1 PK and safety data is available in cohorts 1 and 2.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 0 Years 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged 0 - 12 years
- •Documented close (household or other close exposure) for at least an average 4 hours a day over the past 6 months to a bacteriologically confirmed adult (18 years or older) source case with pulmonary TB. The adult TB source case should have confirmed drug sensitive (sputum culture confirmed or XPERT MTB/Rif [Cepheid] positive TB and without any evidence of drug resistance, i.e., at least XPERT MTB/Rif rifampicin susceptible or an alternative molecular or phenotypic test indicating rifampicin susceptible M. tb) OR:
- •Evidence of M. tb infection (positive TST ≥ 10 mm in HIV-uninfected and TST ≥ 5 mm in HIV-infected participants or a positive commercial interferon-gamma release assay, as defined by the manufacturer)
- •Confirmed HIV status:
- •HIV status will be confirmed by DNA PCR and Plasma HIV-RNA if the participant is <18 months of age.
- •In participants ≥18 month of age HIV-ELISA testing will be completed. If any HIV test is positive in a child participant, regardless of age, the test result needs to be confirmed with a second HIV test, using HIV DNA or RNA PCR, from an independent sample.
- •HIV-infected participants should be on an ART regimen for at least 12 weeks prior to enrolment and should be clinically stable before entering the study, regardless of CD 4 count and HIV viral load. While on study, participants must be on an efavirenz- or raltegravir-based ART regimen which should have been given for at least 14 days prior to enrolment.
- •Caregiver (parent or legal guardian) gives written informed consent and assent from the child where applicable
- •Weight > 2.5 kg but < 40 kg
排除标准
- •Active TB disease (evidenced by: symptoms suggestive of TB, or suggestive findings on clinical examination, or suggestive chest radiographic findings, or positive mycobacterial culture/molecular TB tests -if culture/molecular testing was clinically indicated and was completed-, or currently on TB treatment for active disease).
- •Any documented drug resistant TB (DR TB) in an identified adult source case, defined as rifampicin resistance on Xpert or any other relevant approved molecular test, or phenotypic evidence of rifampicin resistance.
- •Receipt of a once-daily isoniazid regimen for > 30 days which was given for at least 14 consecutive days in the 30 days prior to enrolment.
- •Hb < 10 mg/dl
- •Weight for age z score below 2 or severe clinical malnutrition
- •Known allergy or hypersensitivity to isoniazid or rifapentine
- •Documented hepatic disorder including > 5 fold elevated upper limit of normal (ULN) ALT and/or bilirubin
- •Lansky play score < 50
- •Documentation of Hepatitis A or B infection
- •Female adolescents who have reached menarche will not be eligible.
研究组 & 干预措施
Single Arm Rifapentine and Isoniazid
Single arm, open label and exposure-controlled. Intervention is rifapentine given in a new fixed dose combination once-weekly, in combination with isoniazid for 12 weeks, in HIV-infected and HIV-uninfected children aged 0-12 years in whom LTBI treatment is indicated. The protocol allows for parallel enrolment of children into cohorts 1 and 2, simultaneously, using a predetermined modeled initial dose for each cohort, separately. Similarly, cohorts 3 and 4 will be enrolled in parallel, using modeled doses for each cohort, based on data from cohorts 1 and 2 and historical data from TBTC trials.
干预措施: Isoniazid (Drug)
Single Arm Rifapentine and Isoniazid
Single arm, open label and exposure-controlled. Intervention is rifapentine given in a new fixed dose combination once-weekly, in combination with isoniazid for 12 weeks, in HIV-infected and HIV-uninfected children aged 0-12 years in whom LTBI treatment is indicated. The protocol allows for parallel enrolment of children into cohorts 1 and 2, simultaneously, using a predetermined modeled initial dose for each cohort, separately. Similarly, cohorts 3 and 4 will be enrolled in parallel, using modeled doses for each cohort, based on data from cohorts 1 and 2 and historical data from TBTC trials.
干预措施: Rifapentine (Drug)
结局指标
主要结局
Rifapentine exposure among participants by median area under the curve (AUC)
时间窗: 12 weeks
Target AUC is no more than 25% lower than, and no more than 75% higher than, the target AUC of 522 mcg\*h/L. Data to be used for dose adjustments throughout the study and to create dosing algorithm for pediatric subgroups.
Rifapentine Pharmacokinetic Exposure (AUC) Following Weekly 3HP Administration
时间窗: During the 12-week treatment period, based on pharmacokinetic samples collected during study treatment
Rifapentine exposure was assessed using population pharmacokinetic analysis incorporating pharmacokinetic samples collected during the 12-week treatment period. Reported AUC values are model-derived estimates from the overall pharmacokinetic analysis. The target median AUC was 522 mg·h/L, with an acceptable range of 392-914 mg·h/L.
次要结局
- Number of participants with Grade 3 or 4 adverse events(24 weeks)
- Proportion of participants with Grade 3 or 4 adverse events(24 weeks)
- Number of participants who discontinue study drug due to an adverse event(12 weeks)
- Proportion of participants who discontinue study drug due to an adverse event(12 weeks)
- Estimation of rifapentine absorption rate constant (ka) from plasma drug levels(12 weeks)
- Estimation of rifapentine oral clearance (Cl/F) from plasma drug levels(12 weeks)
- Post-hoc Bayesian prediction of rifapentine and metabolite peak concentration (Cmax)(12 weeks)
- Estimation of rifapentine volume of distribution (Vd) from plasma drug levels(12 weeks)
- Post-hoc Bayesian prediction of rifapentine and metabolite time to peak concentration (Tmax)(12 weeks)
- Post-hoc Bayesian prediction of rifapentine and metabolite area-under-the-curve (AUC0-24)(12 weeks)
- Post-hoc Bayesian prediction of rifapentine and metabolite half life (t 1/2)(12 weeks)
- Palatability scores(12 weeks)
- Acceptability scores(12 weeks)
- Incidence of tuberculosis(24 weeks)
- Estimation of isoniazid absorption rate constant (ka) from plasma drug levels(12 weeks)
- Estimation of isoniazid volume of distribution (Vd) from plasma drug levels(12 weeks)
- Estimation of isoniazid oral clearance (Cl/F) from plasma drug levels(12 weeks)
- Post-hoc Bayesian prediction of isoniazid peak concentration (Cmax)(12 weeks)
- Post-hoc Bayesian prediction of isoniazid time to peak concentration (Tmax)(12 weeks)
- Post-hoc Bayesian prediction of isoniazid area-under-the-curve (AUC0-24)(12 weeks)
- Post-hoc Bayesian prediction of isoniazid half life (t 1/2)(12 weeks)
- Incidence of Grade ≥3 Adverse Events Related to Study Treatment(12-week treatment period and 24-week follow-up)