Interaction Between High Dose Rifampicine and Efavirenz in Pulmonary Tuberculosis and HIV Co-infection
试验速览
- 阶段
- 2 期
- 入组人数
- 105
- 试验地点
- 1
- 主要终点
- Efavirenz Cmin; Cmax; Tmax; AUC0-24
研究概览
简要总结
We propose a first interaction study between efavirenz (EFV) and R20mg/Kg taking into consideration the absence of data about R induction at this dose. Due to an important inter-patient variability of the CYP2B6 polymorphism, the EFV pharmacokinetic (Pk) will be compared in same patients with and without TB treatment.
The main objective is to compare the Pk parameters of EFV in HIV-TB co-infected patients, with and without TB treatment, using R at 10 and 20mg/Kg/day and EFV at 600 and 800mg/day.
详细描述
Justification: In vitro and animal studies have shown that increasing the dose of rifampicin (R) improves the R sterilising effect. If a similar effect can be demonstrated in the clinical setting, this could allow shortening treatment duration from 6 to 4 months, with good tolerance. Several phase 2 trials in HIV-negative patients are ongoing. We propose a first interaction study between efavirenz (EFV) and R20mg/Kg taking into consideration the absence of data about R induction at this dose. Due to an important inter-patient variability of the CYP2B6 polymorphism, the EFV pharmacokinetic (Pk) will be compared in same patients with and without TB treatment.
Principal objective: To compare the Pk parameters of EFV in HIV-TB co-infected patients, with and without TB treatment, using R at 10 and 20mg/Kg/day and EFV at 600 and 800mg/day.
Secondary objectives: To describe the Pk parameters of R and isoniazid (H); the TB treatment réponse (Mycobacterium tuberculosis culture conversion after 8 weeks(w) and cure after 24w) ; the virological response; the occurrence of severe adverse events, especially hepatic and neurological events; the treatment adherence; the genes involved in the EFV metabolism of EFV, R and H, and its relation with the Pk parameters.
Primary endpoint: AUC0-24, Cmax, Cmin, Tmax of EFV after 4w of TB treatment + ARV, and 4w after interruption of TB treatment.
Study design : phase 2 randomized, open label 3 arms therapeutic trial:
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged of 18 years or more
- •Diagnosis of new pulmonary tuberculosis confirmed by a XpertMTB/RIF test
- •Positive HIV antibody test, naïve of ART with CD4 cell count between 50 and 250cells/mm3
- •For women of childbearing age, to have a negative urine test for pregnancy on the day of enrolment and to accept to take a barrier contraception during the period of the trial
- •Participants well enough to receive ambulatory treatment
- •Weight > 45Kg
- •Home address readily accessible
- •Participants providing informed consent to participate in the trial
排除标准
- •Rifampicin drug resistance based on the XpertMTB/RIF result confirmed by the GenotypeMTBDRplus assay
- •Concomitant opportunistic infection requiring additional infectious medication
- •Karnofsky score <80%
- •ALAT or bilirubin > 5.0 x ULN (hepatitis grade 3 or 4)
- •Haemoglobin < 7.5g/dL (grade 3 or 4)
- •Grade 4 clinical sign or biological result according to the ANRS for grading the intensity of adverse events
- •Patient not able to give his informed consent or is unlikely or unable to cooperate with sampling procedures
- •Patient suffering of psychiatric illness, which may prevent follow-up according to the protocol
- •Patients receiving or requiring medications that may interfere with study drugs
研究组 & 干预措施
Arm 1
8 weeks R20mg/Kg + HZE and efavirenz 600mg
干预措施: drug administration (Drug)
Arm 2
8 weeks R20mg/Kg + HZE and efavirenz 800mg
干预措施: drug administration (Drug)
Standard arm
8 weeks R10mg/Kg + HZE and efavirenz 600mg
干预措施: drug administration (Drug)
结局指标
主要结局
Efavirenz Cmin; Cmax; Tmax; AUC0-24
时间窗: Week 28
Efavirenz through concentration before drug intake (Cmin); maximal concentration (Cmax); time to achieve the Cmax (Tmax) and area under the curve of concentrations vs time at steady state during a 24-hour dosing interval (AUC0-24)
时间窗: Week 8
次要结局
- Pharmacokinetic parameters of R and H (Cmin, Cmax and AUC0-24)(Week 8)
- Grade 3 and 4 adverse events(0-28 weeks)
- Plasma HIV-1 RNA(week 28)
- Mycobacterium tuberculosis culture of sputum(week 8)