Phase 2 Randomized, Multicenter, Safety and Efficacy Trial to Evaluate Different Oral Benznidazole Monotherapy and Benznidazole/E1224 Combination Regimens for the Treatment of Adult Patients With Chronic Indeterminate Chagas Disease
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 210
- 试验地点
- 1
- 主要终点
- Parasitological response as determined by serial negative qualitative PCR results (3 negative PCR results, from 3 samples to be collected in the same day) at EOT and sustained parasitological clearance until 6 months follow-up.
研究概览
简要总结
Recent scientific advances have provided further impetus to develop new therapeutic approaches for Chagas Disease (CD) using different doses and duration of BZN, as well as combinations directed at multiple therapeutic targets to improve treatment response and tolerability and reduce the potential for development of resistance.
This project focuses on the proof-of-concept evaluation of improved treatment regimens of BZN, with the assessment of new BZN-sparing regimens in monotherapy and in combination with E1224.
详细描述
The current treatment for Chagas disease has significant limitations, including long treatment durations, safety and tolerability concerns and is currently limited to two nitro-heterocyclic drugs, nifurtimox and benznidazole (BZN). BZN, a nitroimidazole introduced by Roche in 1971, is marketed by Laboratório Farmacêutico do Estado de Pernambuco S/A - LAFEPE and Laboratorio ELEA - Argentina. It is supplied in tablets strengths of 12.5, 50 and 100 mg, administered twice daily at a dose of 5 mg/kg body weight/day for adults and 5-10 mg/kg body weight/day for children for 30-60 days. Notably, the current regimens with BZN for the treatment of adults with CD likely represent the maximum dosing case scenario in terms of dose, duration and schedule of administration (Chagas expert meeting DNDi. January 2014. GVA).
Doses and duration of treatment for CD have not been evaluated systematically. Current treatment regimens and dosing intervals have been derived from decades-old patient series and with very limited direct comparisons. Data from recently concluded trials suggest existing opportunities for optimisation of the treatment regimens of BZN.
A (Drugs for Neglected Disease initiative) DNDi-sponsored Phase 2, proof-of-concept clinical trial on E1224 and Benznidazole (BZN) in adults with chronic indeterminate CD, conducted between 2011 and 2013 in Bolivia, showed that all BZN-treated patients had cleared parasite DNA after 2 weeks of treatment and 81% sustained the parasite clearance at 12 months after treatment. At end-of treatment (EOT, Day 65), E1224 was found to be efficacious in clearing T. cruzi parasites when compared to placebo. However, at 12 months less than one third of patients sustained parasite clearance. The trial safety data also indicated a proportion of patients (10-20%) who do not complete treatment in conditions of use, the majority due to adverse drug reactions (ADRs) and the long treatment duration.
Taking into consideration the efficacy gap with about 80% sustained response and a tolerability gap, with a proportion of patients (10-20%) who do not complete treatment, two approaches for Chagas treatment optimization are to be pursued:
- A change in the current adult dosing regimen for BNZ to reduce exposure and improve tolerability while maintaining efficacy; and
- The development of a combination therapy to improve efficacy while maintaining or improving tolerability. The combination therapy aims to address the efficacy gap and may or may not address tolerability gap.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double Dummy
入排标准
- 年龄范围
- 18 Years 至 50 Years（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
BZN STD Regimen
Benznidazole (100 mg and 50 mg) tablets by mouth, every 12 hours for 8 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: E1224 Placebo (Drug)
BZN STD Regimen
Benznidazole (100 mg and 50 mg) tablets by mouth, every 12 hours for 8 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: Benznidazole (Drug)
BZN 300 mg - 4 wks
Benznidazole (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks, followed by:
Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: Benznidazole (Drug)
BZN 300 mg - 4 wks
Benznidazole (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks, followed by:
Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: E1224 Placebo (Drug)
BZN 300 mg - 4 wks
Benznidazole (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks, followed by:
Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: Benznidazole Placebo (Drug)
BZN 300 mg - 2 wks
Benznidazole (100 mg and 50 mg) tablets by mouth, every 12 hours for 2 weeks, followed by:
Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 6 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: Benznidazole (Drug)
BZN 300 mg - 2 wks
Benznidazole (100 mg and 50 mg) tablets by mouth, every 12 hours for 2 weeks, followed by:
Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 6 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: E1224 Placebo (Drug)
BZN 300 mg - 2 wks
Benznidazole (100 mg and 50 mg) tablets by mouth, every 12 hours for 2 weeks, followed by:
Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 6 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: Benznidazole Placebo (Drug)
BZN 150 mg - 4 wks
Benznidazole (100 mg and 50 mg) tablets and Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, in two separate daily doses for 4 weeks, followed by:
Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: Benznidazole (Drug)
BZN 150 mg - 4 wks
Benznidazole (100 mg and 50 mg) tablets and Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, in two separate daily doses for 4 weeks, followed by:
Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: E1224 Placebo (Drug)
BZN 150 mg - 4 wks
Benznidazole (100 mg and 50 mg) tablets and Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, in two separate daily doses for 4 weeks, followed by:
Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: Benznidazole Placebo (Drug)
BZN 150 mg - 4 wks / E1224 300 mg
Benznidazole (100 mg and 50 mg) tablets and Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, in two separate daily doses for 4 weeks, followed by:
Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks.
Three E1224 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks. (total dose: 3000 mg).
干预措施: Benznidazole (Drug)
BZN 150 mg - 4 wks / E1224 300 mg
Benznidazole (100 mg and 50 mg) tablets and Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, in two separate daily doses for 4 weeks, followed by:
Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks.
Three E1224 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks. (total dose: 3000 mg).
干预措施: E1224 (Drug)
BZN 150 mg - 4 wks / E1224 300 mg
Benznidazole (100 mg and 50 mg) tablets and Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, in two separate daily doses for 4 weeks, followed by:
Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, every 12 hours for 4 weeks.
Three E1224 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks. (total dose: 3000 mg).
干预措施: Benznidazole Placebo (Drug)
BZN 300 mg (weekly) 8 wks / E1224 300 mg
Benznidazole (100 mg and 50 mg) tablets by mouth, once weekly for 8 weeks (total 8 days of intermittent treatment) and Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, in the other 6 days of the week for 8 weeks
Three E1224 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks. (total dose: 3000 mg).
干预措施: Benznidazole (Drug)
BZN 300 mg (weekly) 8 wks / E1224 300 mg
Benznidazole (100 mg and 50 mg) tablets by mouth, once weekly for 8 weeks (total 8 days of intermittent treatment) and Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, in the other 6 days of the week for 8 weeks
Three E1224 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks. (total dose: 3000 mg).
干预措施: E1224 (Drug)
BZN 300 mg (weekly) 8 wks / E1224 300 mg
Benznidazole (100 mg and 50 mg) tablets by mouth, once weekly for 8 weeks (total 8 days of intermittent treatment) and Benznidazole Placebo (100 mg and 50 mg) tablets by mouth, in the other 6 days of the week for 8 weeks
Three E1224 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks. (total dose: 3000 mg).
干预措施: Benznidazole Placebo (Drug)
Placebo
Benznidazole Placebo (100 mg and 50mg) tablets by mouth, every 12 hours for 8 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: E1224 Placebo (Drug)
Placebo
Benznidazole Placebo (100 mg and 50mg) tablets by mouth, every 12 hours for 8 weeks.
Three E1224 Placebo 100 mg capsules by mouth, everyday on days 1 to 3, followed by three E1224 Placebo 100 mg capsules by mouth, once weekly (starting on week 2) for 7 weeks.
干预措施: Benznidazole Placebo (Drug)
结局指标
主要结局
Parasitological response as determined by serial negative qualitative PCR results (3 negative PCR results, from 3 samples to be collected in the same day) at EOT and sustained parasitological clearance until 6 months follow-up.
时间窗: From the end of the treatment period up to 6 months.
To determine the efficacy of different dosing regimens of orally administered BZN and BZN/E1224 in individuals with chronic indeterminate CD, by determining the proportion of patients who convert from positive to negative in serial, qualitative PCR test results (3 negative PCR results) at end of treatment (EOT) and sustain parasitological clearance at 6 months of follow-up, in comparison to placebo. For efficacy assessments, the EOT of each treatment arm will be defined in accordance to the duration of the treatment regimen. Sustained response will be assessed in all treatment arms using the same number of PCR samples (i.e., EOT; 12 weeks; 4 and 6 months).
次要结局
- Parasite clearance as measured by qualitative PCR(Weeks 1, 2, 3, 4, 6, 10, 12, and at 4, 6, and 12 months follow-up)
- Sustained parasitological clearance at 12 weeks and 12 months of follow-up(From the end of the treatment period up to 12 months.)
- Incidence of Adverse Events (AEs)(Through study completion, i.e up to 12 months.)
- Incidence of Serious Adverse Events (SAEs) and/or adverse events leading to treatment discontinuation(Through study completion, i.e up to 12 months)
- Severity of Adverse Events (AEs)(Through study completion, i.e up to 12 months.)
- Change in parasite load over time assessed as measured by quantitative PCR(Weeks 1, 2, 3, 4, 6, 10, 12, and at 4, 6, and 12 months follow-up.)
- Serological response by conventional serology assessed at 12 months of follow up and non-conventional serology assessed at W12, 4, 6, and 12 months of follow up. (changes in titters over time)(From the end of the treatment period up to 12 months.)