Phase 2 Randomized, Multicenter, Placebo-controlled, Safety and Efficacy Study to Evaluate Three Oral E1224 Dosing Regimens and Benznidazole 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
- 230
- 试验地点
- 1
- 主要终点
- Serial negative qualitative Polymerase Chain Reaction (PCR) results (3 negative PCR results from 3 samples to be collected over 7 days) as a measure of parasitological cure at end of treatment
研究概览
简要总结
This study will assess the safety and efficacy of E1224, a pro-drug of ravuconazole, in individuals with chronic indeterminate Chagas disease recruited in research centres in Tarija and Cochabamba, Bolivia.
详细描述
Chagas disease (CD) ranks among the world's most neglected diseases. In Latin America, 21 countries are endemic for CD with an estimated 108 million people at risk of contracting the disease. Estimates from the 1980s indicated that some 16 million to 18 million individuals were infected. In the 1990s, after a series of multinational control initiatives, estimates of the number of infected people were revised to 9.8 million in 2001. The estimated burden of disease in terms of disability-adjusted life years (DALYs) declined from 2.7 million in 1990 to 586,000 in 2001. Recent estimates from Pan American Health Organization (PAHO, 2006) indicate 7.54 million infected people and 55,185 new cases per year.
The only two medicines available - benznidazole (BZN) and nifurtimox (NFX) - are known to cause serious toxicity with unsatisfactory cure rates, especially when used in adult chronic CD patients.
Novel antifungal triazole derivatives have arisen as alternative treatments for CD. They inhibit T. cruzi ergosterol biosynthesis, which is essential for parasite growth and survival, and have pharmacokinetic properties suitable for the treatment of this disseminated intracellular infection. Several triazole derivatives have been tested in animal models of CD, including D08701, posaconazole, ravuconazole (RAV), albaconazole, and TAK-187. In particular, RAV has previously been shown to have potent in vitro and in vivo activities, inducing parasitological cure in mice with acute infections, including those caused by benznidazole-resistant strains of T. cruzi. Suppressive activity was also seen in dog models.
E1224 is a water-soluble monolysine salt form of the RAV pro-drug. It is a broad-spectrum triazole antifungal with in vitro activity against most Candida and Aspergillus species, some non-Aspergillus species of filamentous fungi, Cryptococcus, dermatophytes, and fungi that cause the endemic mycoses.
RAV was evaluated extensively in animal models and in human trials including Phase 2 safety and efficacy trials in oropharyngeal and esophageal candidiasis and onychomycosis, and for prevention of invasive fungal infections in hematopoietic stem cell transplant recipients.
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)
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
- •Confirmed diagnosis of T. cruzi infection by serial qualitative PCR AND Conventional serology
- •Women in reproductive age must have a negative serum pregnancy test at screening, must not be breastfeeding, and consistently use and/or have partner consistently use an adequate contraceptive method
- •Normal ECG at screening
排除标准
- •Abnormal laboratory test values at screening for the following parameters: total White Blood Cells (WBC) count, platelet count, alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin, or creatinine; or gamma-glutamyl transferase (GGT)
- •History of alcohol abuse or any other drug addiction (as specified in the Study Manual of Operations)
- •Any condition that prevents the patient from taking oral medication
- •Any concomitant use of antimicrobial or antiparasitic agents
研究组 & 干预措施
High Dose E1224
High Dose (HD - 8weeks) Group
干预措施: E1224 (Drug)
Low Dose E1224
Low Dose (LD - 8 weeks) Group
干预措施: E1224 (Drug)
Short Dose E1224
Short Dose (SD - 4 weeks) Group
干预措施: E1224 (Drug)
Placebo
Placebo (8 weeks) Group
干预措施: Placebo (Drug)
Benznidazol
BZN (Laboratório do Estado de Pernambuco -LAFEPE, tablet 100mg), 5 mg/Kg/day PO divided in two daily doses, for 60 days
干预措施: Benznidazole (Drug)
结局指标
主要结局
Serial negative qualitative Polymerase Chain Reaction (PCR) results (3 negative PCR results from 3 samples to be collected over 7 days) as a measure of parasitological cure at end of treatment
时间窗: Day 65 (end of treatment)
To determine whether at least one of three dosing regimens of orally administered E1224 is more efficacious than placebo in individuals with chronic indeterminate CD, by determining the number of patients who convert from positive to negative in serial, qualitative PCR test results
次要结局
- Consistently negative serial qualitative PCR as a measure of sustained parasitological eradication(4, 6 and 12 months follow-up)
- Qualitative PCR as a measure of parasite eradication(Day 8, 15, 36 , 65 and at 4, 6 and 12 months follow-up)
- Quantitative PCR as a measure of change in parasite load over time(Day 8, 15, 36, 65 and at 4, 6 and 12 months follow-up)
- Incidence of serological conversion to negative and changes in titers over time as measured by conventional and non-conventional serologies(Day 65 and at 4, 6 and 12 months after treatment)
- Changes in the levels of biomarkers over time: brain natriuretic peptide, troponin T, selected prothrombotic factors, lytic antibodies, apolipoprotein A1 and multiplex serodiagnostic assay(Day 36 , 65 and at 4, 6 and 12 months follow-up)
- Area under the plasma concentration versus time curve (AUC), Peak Plasma Concentration (Cmax), Minimum Plasma Concentration (Cmin), Clearance, Volume of Distribution , and Plasma Terminal Half-Life (t1/2) of ravuconazole and benznidazole(Day 0 (pre-dose), Day 1 (after 1st dose), Day 2, Day 3, steady-state phase (D8-D50), at the end of treatment (D65) and at the 4 months follow-up visit)
- Incidence and severity of adverse events (clinical and laboratory)(Up to 12 months follow-up)
- Incidence of Serious Adverse Events and/or adverse events leading to treatment discontinuation(Up to 12 months follow-up)
- Early and late predictors of sustainable response to treatments(Up to 12 months follow-up)
- Correlation of pharmacokinetic parameters with parasitological response, changes in biomarkers and safety outcomes(Day 8, 15, 36, 65, and at 4, 6 months and 12 months follow-up)