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.

• Favipiravir (Drug): 6-fluoro-3-hydroxypyrazine-2-carboxamide, T-705
• Ribavin (Drug): 1-3,4-dihydroxy-5-1,2,4-triazole-3-carboxamide
• Optimised Standard of Care (Other): 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.

Primary outcomes

• Virologic objective: To compare CCHFV viral dynamics of investigational therapeutics relative to the control arm [Day 5 from treatment start]: Comparison of CCHFV viral load clearance by Day 5 for treatment arms compared to Standard of Care arm.

Secondary outcomes

• Safety Objective: To determine the safety and tolerability of investigational therapeutics relative to the control arm [Day 29]: Comparison of incidence of serious adverse events in treatment arms compared to standard of care arm. Comparison of the frequency and characterisation of clinically significant adverse events related to study agent administration (Safety and Tolerability of Favipiravir and Ribavirin CTCAE v5 Grade ≥3 adverse events)
• Clinical Objective: To compare time to successful hospital discharge between participants receiving investigational therapeutics, relative to the control arm [Day 29]: Time from Randomisation to discharge from hospital
• Antiviral Objective: To evaluate antiviral efficacy of investigational therapeutics (1) [Day 10]: Comparison of CCHFV viral load reduction between for treatment arms compared to Standard of Care arm
• Antiviral Objective: To evaluate antiviral efficacy of investigational therapeutics (2) [Day 10]: Comparison of Viral load reduction by PCR test for treatment arms compared to Standard of Care arm
• 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]: Mortality at Days 14 and 28 (time from date of randomisation to death) for treatment arms compared to Standard of Care arm
• 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]: Mortality at Days 14 and 28 (time from date of randomisation to death) in different SGS groups for treatment arms compared to Standard of Care arm
• Pharmacokinetic objective:To characterise the plasma pharmacokinetics (PK) of therapeutics in CCHF [Day 29]: To investigate the exposure-response relationship of Favipiravir on CCHF viral dynamics by analysing concentrations of investigation therapeutics in plasma

Other outcomes

• To characterise virus, host immune response and viral resistance over time [Day 29]: Change in host immune response, CCHFV culture and sequencing related to study agent administration

Sex: All, ages: 18 Years to any

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.