UMIT-2: a randomized, multi-country, adaptive phase iib platform trial to determine the efficacy and safety of therapeutics for crimean-congo haemorrhagic fever
Adult in-patients (≥18 years) hospitalised with laboratory confirmed CHFV infection by positive polymerase chain reaction (PCR) test.
Description of randomisation: Participants will be randomised in a 1:1:1 ratio to one of three initial trial arms: standard of care, investigational antiviral A, or investigational antiviral B. Randomisation will be stratified by country to account for potential geographic differences in disease presentation, healthcare delivery, or standard treatment practices. Arm A: Optimised Standard of Care Arm B: Favipiravir: 6-fluoro-3-hydroxypyrazine-2-carboxamide, T-705 (Intravenous and oral tablet formulations). IV Favipiravir 2400mg BD on day 1, Day 2 IV Favipiravir 1200mg BD, Day 3-7 PO Favipiravir 1200mg BD Arm C: Ribavirin: 1-3,4-dihydroxy-5-1,2,4-triazole-3-carboxamide (tablet formulation). Ribavirin will be given at standard dosing: Day 1 PO Ribavirin 33mg/kg (load dose) then 16mg/kg QDS, Day 2 PO Ribavirin 16mg/kg QDS, Day 3-5 PO Ribavirin 16mg/kg QDS, Day 6 to 7 PO Ribavirin 8mg/kg TDS.
1. Adult in-patients (≥18 years) at the time of screening. 2. Confirmed CCHF infection: Laboratory confirmed CCHF infection defined as positive polymerase chain reaction (PCR) test within 5 days prior to randomisation 3. Ability to provide informed consent signed by study patient or legally acceptable representative (for illiterate individuals). 4. Women of childbearing potential (WOCBP) and male patients who are sexually active with WOCBP must agree to use a highly effective method of contraception. 5. Severity Grading System (SGS) for CCHF – Low/moderate risk. (Appendix 15) 6. Less than or equal to 7 days from onset of CCHF symptoms 7. Willingness to participate in the full protocol 8. Requirement to be hospitalised for treatment
1. Severe renal impairment: Stage 4 severe chronic kidney disease or requiring dialysis (i.e., estimated glomerular filtration (eGFR) rate <30 mL/min/1.73 m2) 2. Pregnant or breast feeding 3. Anticipated transfer to another hospital which is not a study site within 72 hours 4. Known Allergy to any study medication 5. Patients participating in another clinical trial of an investigational medicinal product (CTIMP) within the last 30 days. 6. 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. 7. 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). 8. 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. 9. Severity Grading System (SGS) for CCHF – High risk (Appendix 15) 10. Patients taking the drugs listed below within 30 days or 5 times the half-life (whichever is longer) of enrolment: 10.1. Pyrazinamide 10.2. Repaglinide 10.3. Theophylline 10.4. Famciclovir, Sulindac