Phase 2 Randomized, Multicenter, Double-blinded Safety and Efficacy Study to Evaluate Oral Fexinidazole Dosing Regimens for the Treatment of Adult Patients With Chronic Indeterminate Chagas Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 45
- 试验地点
- 1
- 主要终点
- Incidence and severity of adverse events.
研究概览
简要总结
This study focuses on the evaluation of low doses (600 and 1200 mg) and short treatment duration (at 3, 7 and 10 days) of fexinidazole (Fexi) to determine the minimal efficacious and safe dose for the treatment of adult patients with chronic indeterminate Chagas Disease (CD).
详细描述
Fexi anti-protozoal activity against T. cruzi has been demonstrated by various in vitro and in vivo studies.
Patients will be randomly assigned to receive one of three different treatment regimen arms containing either the active drug or matching placebo tablet
Following conclusion of 12 months of follow-up of DNDi-CH-FEXI-001 clinical trial, unblinded data review showed high sustained parasite clearance rates of FEXI even at the lowest dose tested (1200 mg 2 weeks), including in patients that received < 3days treatment.
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
- Double (Participant, Investigator)
盲法说明
As the study is double-blinded, the patient, investigators, pharmacist(s) and DNDi study team members involved with the clinical trial implementation will remain blinded to treatment allocation for the duration of the clinical trial.
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Following the screening period, patients must also meet all of the following inclusion criteria to be eligible for randomization:
- •Confirmed diagnosis of T. cruzi infection by:
- •Serial qualitative PCR (three samples collected over a single day, at least one of which must be positive),
- •Conventional serology (a minimum of two positive tests must be positive, Conventional ELISA, Recombinant Elisa, Chemiluminescence immunoassays and/or IIF)
- •Women in reproductive age must have a negative serum pregnancy test at screening, must not be breastfeeding, must consistently use a highly effective contraceptive method until end of treatment and estimated FEXI, M1 and M2 clearance (total of 21 days). After this, contraception is no longer required.
- •Normal ECG (Heart rate: 50-100bpm; PR interval ≤200 msec, QRS complex ≤120 msec, and QT interval corrected for heart rate (QTc) ≥350msec and ≤450 msec interval durations) at screening
- •24 hour Holter-monitoring with no clinically relevant arrythmias (defined as Ventricular Tachycardia (defined as >3 ventricular beats with >100bpm); Sustained Accelerated Idio-Ventricular rhythm (defined as >30 seconds duration and Heart Rate (HR): 50bpm<HR<100bpm); frequent Ventricular Premature Beats (10/hour); Atrial Fibrillation/flutter; Mobitz type 2 second degree AV block; High degree and complete AV block; Bradycardia episodes <40bpm)
排除标准
- •Signs and/or symptoms of chronic cardiac and/or digestive form of CD (as per Study Manual of Operations).
- •History of cardiomyopathy, heart failure, or ventricular arrhythmia.
- •History of digestive surgery or mega syndromes.
- •Personal history of mental disability or suicidal tendencies
- •Hospital Anxiety and Depression Scale (HADS - Appendix 1) self-assessment score >11 in each of the sub-scales. (Note: If HADS score >11, retesting would be allowed before after a minimum period of 15 days and referral to counseling/evaluation.)
- •Any other acute or chronic health conditions that, in the opinion of the PI, may interfere with the efficacy and/or safety evaluation of the trial drug (such as acute infections, history of HIV infection, diabetes, uncontrolled systolic/diastolic blood pressure, liver, and renal diseases requiring medical treatment).
- •Laboratory test values considered clinically significant or out of the allowable range at selection period as follows:
- •Total White Blood Count (WBC) must be within the normal range, with an acceptable margin of +/- 5% (3,800 - 10,500 / mm3).
- •Platelets must be within the normal range up to 550,000/mm3
- •Total bilirubin must be within the normal range
- •Transaminases (ALT and AST) must be within the normal range, with an acceptable margin of 25% above the upper limit of normality (ULN), < 1.25 x ULN.
- •Creatinine must be within an acceptable margin of 10% above the ULN, <1.10 x ULN.
- •Alkaline phosphatase must be within the normal range up to Grade 1 CTCAE (<,2.5 x ULN)
- •Gamma-glutamyl Transpeptidase (GGT) must be within the normal range up to 2x ULN.
- •Fasting glucose (minimum of 8 hours from latest meal) must be within the normal range
- •Electrolytes (Ca, Mg, K) must be within the normal range
- •Hepatitis screen must be negative for acute and/or chronic infection (Hepatitis A antibody, Imunoglobulina M (IgM); Hepatitis B surface Ag, Hepatitis B
- •If the results of the blood tests (hematology and biochemistry) are out of the ranges defined above, but within the limits of CTCAE (version 4.03) Grade 1, and this laboratory finding is considered as non-clinically significant, a new sample can be collected for a retest. Only one retest will be allowed within the screening period.
- •If the result of the retest is within the margins defined above, the Investigator will review the parameter(s) together with all other medical information available (medical history, clinical examinations, vital signs, etc.) and upon his/her medical judgement will decide if the patient is eligible or not for trial randomization.
- •Any condition that prevents the patient from taking oral medication.
- •Patients with any contra-indication (known hypersensitivity) to any nitroimidazoles, e.g. metronidazole
- •Patients with history of allergy (serious or not), allergic skin rash, asthma, intolerance, sensitivity or photosensitivity to any drug
- •Any concomitant use of allopurinol, antimicrobial, anti-parasitic agents, and/or of herbal medicines, food supplements and energetic drinks
- •Any concomitant medication with drug known risk of Torsade de Pointe, according AZCERT Scientific Publications and SADS Foundation (www.crediblemeds.org/index.php/new-drug-list)
- •Any planned surgery likely to interfere with the trial conduction and/or treatment evaluation
- •Unlikely to return for study visits, comply with study treatment and co-operate with the trial-related procedures.
- •Any previous participation in any clinical trial for Chagas Disease treatment evaluation
- •Participation in another trial at the same time or within 3 months prior to selection (according to local regulations).
研究组 & 干预措施
Group A
Fexinidazole (FEXI) 600 mg x 10 days in a single daily dose orally (1 fexinidazole 600 mg tablet and 1 fexinidazole matching placebo oral tablet administered in a single daily dose) (total dose: 6.0 g).
干预措施: Fexinidazole (Drug)
Group A
Fexinidazole (FEXI) 600 mg x 10 days in a single daily dose orally (1 fexinidazole 600 mg tablet and 1 fexinidazole matching placebo oral tablet administered in a single daily dose) (total dose: 6.0 g).
干预措施: Placebo Oral Tablet (Drug)
Group B
Fexinidazole (FEXI) 1200 mg x 3 days orally (2 fexinidazole 600 mg tablets administered in a single daily dose for 3 days), to be followed by matching placebo oral tablet for 7 days (2 fexinidazole matching placebo oral tablets administered once daily for 7 days) (total dose: 3.6 g).
干预措施: Fexinidazole (Drug)
Group B
Fexinidazole (FEXI) 1200 mg x 3 days orally (2 fexinidazole 600 mg tablets administered in a single daily dose for 3 days), to be followed by matching placebo oral tablet for 7 days (2 fexinidazole matching placebo oral tablets administered once daily for 7 days) (total dose: 3.6 g).
干预措施: Placebo Oral Tablet (Drug)
Group C
Fexinidazole (FEXI) 600 mg for 3 days, followed by 1200 mg in a single daily dose orally for 4 days (1 fexinidazole 600 mg tablet AND 1 fexinidazole matching placebo oral tablet administered in a single daily dose for 3 days, to be followed by 2 fexinidazole 600 mg tablets for 4 days), then followed by matching placebo oral tablet for 3 days (2 fexinidazole matching placebo tablets administered once daily for 3 days) (total dose: 6.6 g).
干预措施: Fexinidazole (Drug)
Group C
Fexinidazole (FEXI) 600 mg for 3 days, followed by 1200 mg in a single daily dose orally for 4 days (1 fexinidazole 600 mg tablet AND 1 fexinidazole matching placebo oral tablet administered in a single daily dose for 3 days, to be followed by 2 fexinidazole 600 mg tablets for 4 days), then followed by matching placebo oral tablet for 3 days (2 fexinidazole matching placebo tablets administered once daily for 3 days) (total dose: 6.6 g).
干预措施: Placebo Oral Tablet (Drug)
结局指标
主要结局
Incidence and severity of adverse events.
时间窗: 12 months
次要结局
- Pharmacokinetic : measure of blood concentration of fexinidazole, fexinidazole sulfoxide and fexinidazole sulfone in order to determine Cmax values, for all dose levels.(D0 (pre-dose), Day 1, Day 2, Day 3, and at steady-state phase (week 2-10).)
- Pharmacokinetic : measure of blood concentration of fexinidazole, fexinidazole sulfoxide and fexinidazole sulfone in order to determine AUC0-t values, for all dose levels.(D0 (pre-dose), Day 1, Day 2, Day 3, and at steady-state phase (week 2-10).)