UMIT-2 - Adaptive Phase IIb Platform Trial to Determine the Efficacy and Safety of Therapeutics for CCHF

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.

Inclusion criteria

• 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.

Exclusion criteria

• 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 CYP2C8.
• 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.