UMIT-2: A Randomized, Multi-country, Adaptive Phase IIb Platform Trial to Determine the Efficacy and Safety of Therapeutics for Crimean-Congo Haemorrhagic Fever
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 378
- 试验地点
- 3
- 主要终点
- Virologic objective: To compare CCHFV viral dynamics of investigational therapeutics relative to the control arm
研究概览
简要总结
CCHF has a wide geographical distribution with cases mainly occurring in Asia, the Middle East, South-Eastern Europe and Africa. Since its emergence in 2002, Turkiye has been the epicentre of activity worldwide reporting up to more than 1000 cases annually. CCHF case management relies on the provision of optimised supportive care; therapeutic options lack a robust evidence base
The UMIT-2 Trial (UMIT = 'Hope' in Turkish) will be the first large randomised controlled trial of novel therapeutics in CCHF, undertaken in multiple trial sites in Turkiye and Iraq. It uses an efficient adaptive platform design (Phase IIb), focussed on antiviral efficacy with interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety
详细描述
This will be a 1:1:1 randomised open-label phase 2b trial of Favipiravir (IV & PO) and Ribavirin (IV & PO) vs optimised standard of care in CCHF aimed at evaluating virological efficacy. This is an adaptive multi-arm Phase II platform for patients with CCHF. Key design features are:
Treatment arms can be added or removed.
Shared standard of care (SoC, control) arm so that a greater proportion of more patients receive experimental therapeutics. Eligibility to randomisation to specific treatment arms is based on treatment specific inclusion/exclusion criteria and all comparisons to SoC are within the same eligibility set and concurrent randomisation.
Timing of interim analyses flexible to make use of the seasonality of CCHF to ensure they take place during low recruitment periods.
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
- •Adult in-patients (≥18 years) at the time of screening.
- •Confirmed CCHF infection: Laboratory confirmed CCHF infection defined as positive polymerase chain reaction (PCR) test within 5 days prior to randomisation.
- •Ability to provide informed consent signed by study patient or legally acceptable representative (for illiterate individuals).
- •Women of childbearing potential (WOCBP) and male patients who are sexually active with WOCBP must agree to use a highly effective method of contraception (as outlined in Protocol section 5.4) from the first administration of trial treatment, throughout trial treatment and for the duration outlined.
- •Severity Grading System (SGS) for CCHF - Low/moderate risk. (Appendix 15).
- •Less than or equal to 7 days from onset of CCHF symptoms.
- •Willingness to participate in the full protocol.
- •Requirement to be hospitalised for treatment.
排除标准
- •Severe renal impairment: Stage 4 severe chronic kidney disease or requiring dialysis (i.e., estimated glomerular filtration (eGFR) rate <30 mL/min/1.73 m^2).
- •Pregnant or breast feeding.
- •Anticipated transfer to another hospital which is not a study site within 72 hours.
- •Known Allergy to any study medication.
- •Patients participating in another clinical trial of an investigational medicinal product (CTIMP) within the last 30 days.
- •Known hypersensitivity or allergy to any component of the investigational medicinal product (IMP) or its excipients or documented previous intolerance or significant adverse reaction to the active IMP.
- •Participation in another clinical trial involving an investigational medicinal product (CTIMP) within 30 days or five half-lives of the prior IMP (whichever is longer).
- •Any condition or circumstance which, in the opinion of the Investigator, would place the participant at undue risk, compromise safety, or interfere with trial participation or interpretation of results.
- •Severity Grading System (SGS) for CCHF - High risk (Appendix 15).
- •Patients taking the drugs listed below within 30 days or 5 times the half-life (whichever is longer) of enrolment:
- •Pyrazinamide: Pyrazinamide administration with favipiravir examined possible renal urate transporter interactions. Pyrazinamide increased blood uric acid levels 2 to 9 mg/dL over baseline. The addition of favipiravir increased blood uric acid levels 4 to 11 mg/dL over baseline, indicating a moderate additive effect.
- •Repaglinide: Favipiravir administration with repaglinide, an anti-diabetic agent that is extensively metabolized by CYP2C8 and CYP3A4, increased repaglinide plasma AUC 30 to 50% due to inhibition of CYP2C
- •Theophylline: Theophylline administration with favipiravir increases plasma Cmax and AUC of favipiravir through xanthine oxidase (XO) interaction. The primary metabolite of theophylline is known to be metabolized by XO which is partially involved in metabolism of favipiravir.
- •Famciclovir, Sulindac: Famciclovir and Sulindac are converted to active metabolite by Aldehyde Oxidase (AO). Favipiravir inhibits AO and decrease the concentration of active metabolite of Famciclovir and Sulindac.
研究组 & 干预措施
Arm C: Ribavirin
Day 1 (First 24 hours): IV Ribavirin (33mg/kg) loading dose followed by IV Ribavirin 16mg/kg every 6 hours Day 2 (24-48 hours): IV Ribavirin 16mg/kg four times daily (QDS) Days 3-5: Oral (PO) Ribavirin 16mg/kg four times daily (QDS) Days 6 -7: Oral (PO) Ribavirin 8mg/kg four times daily (QDS) until hospital discharge
Plus any additional supportive care deemed necessary by the study investigator
干预措施: Ribavin (Drug)
Optimised standard of care (oSOC)
Optimised standard of care will include treatment per national guidelines for CCHF case management in Turkiye and Iraq, and any other supportive medication or therapies as required. The standard of care arm will exclude any medicine defined as investigation arms of this study. Any supportive medication or therapies will be recorded on the patient CRFs.
干预措施: Optimised Standard of Care (Other)
Arm B: Favipiravir
Day 1 (First 24 hours): IV Favipiravir 2600 mg twice daily (BD) Day 2 (24-48 hours): IV Favipiravir 1200 mg twice daily (BD) Day 3 -7 (Post 48 hours): Oral (PO) Favipiravir 1200 mg twice daily (BD)1 until hospital discharge up to 7 days (14 doses) whichever is soonest.
Plus any additional supportive care deemed necessary by the study investigator
干预措施: Favipiravir (Drug)
结局指标
主要结局
Virologic objective: To compare CCHFV viral dynamics of investigational therapeutics relative to the control arm
时间窗: Day 5 from treatment start
Comparison of CCHFV viral load clearance by Day 5 for treatment arms compared to Standard of Care arm.
次要结局
- Safety Objective: To determine the safety and tolerability of investigational therapeutics relative to the control arm(Day 29)
- Clinical Objective: To compare time to successful hospital discharge between participants receiving investigational therapeutics, relative to the control arm(Day 29)
- Antiviral Objective: To evaluate antiviral efficacy of investigational therapeutics (1)(Day 10)
- Antiviral Objective: To evaluate antiviral efficacy of investigational therapeutics (2)(Day 10)
- Safety Objective: To compare the overall mortality in patients with CCHF who receive different investigational therapeutics with those who receive the control arm(Day 28)
- Safety Objective: To compare mortality rates among patients whose baseline predictors of disease place them in different categories for disease severity, who receive different investigational therapeutics.(Day 28)
- Pharmacokinetic objective:To characterise the plasma pharmacokinetics (PK) of therapeutics in CCHF(Day 29)