UMIT-1 Trial Favipiravir & Ribavirin for the Treatment of CCHF

This will be a 2:1 randomised open-label phase I trial of IV Favipiravir and IV Favipiravir plus Ribavirin vs optimised standard of care in CCHF. The phase Ib will be carried out to test the safety and tolerability of IV Favipiravir in hospitalised patients. Following review of safety, tolerability and PK data from evaluated phase I doses, an IV Favipiravir doses will be selected to progress to phase II. virological efficacy.

• Favipiravir (Drug): Small molecule antiviral
• Ribavirin (Drug): Small molecule antiviral

Primary outcomes

• Safety objective To determine the safety and tolerability of multiple doses of IV Favipiravir in patients with CCHF [Up to day 8]: Adverse events and serious adverse events Dose limiting toxicities (Safety and Tolerability of IV Favipiravir and IV Favipiravir/Ribavirin- CTCAE v5 Grade ≥3 adverse events)
• To determine the safety and tolerability of multiple doses of IV Favipiravir in combination with Ribavirin in patients with CCHF [up to day 8]: Adverse events and serious adverse events Dose limiting toxicities (Safety and Tolerability of IV Favipiravir and IV Favipiravir/Ribavirin- CTCAE v5 Grade ≥3 adverse events)

Secondary outcomes

• Pharmacokinetic objective: To characterise the plasma pharmacokinetics of multiple doses of IV Favipiravir and IV Favipiravir in combination with Ribavirin [up to Day 8]: Evaluation of favipiravir in VHFs is limited by the predicted high-pill burden (up to 30 tablets per day) required and uncertainty around dose and PK. Favipiravir injection (IV favipiravir) is a novel formulation of favipiravir for intravenous drip infusion, with Cmax levels 4-fold higher following administration of multiple doses in cynomolgus monkeys compared to oral (Toyama IB). The favipiravir activity is derived from the intracellular ribofuranosyl-5'-triphosphate (RTP) metabolite that has a longer half-life intracellularly than the parent drug in plasma. Therefore, transiently higher Cmax values are expected to translate into sustained higher intracellular RTP concentrations and thus activity.
• Virologic objective [Change from baseline over time, up to Day 29, in viral load]: To investigate the effect of IV Favipiravir alone and in combination with Ribavirin on CCHF viral load
• Clinical objective [Mortality at Days 15 and 29]: To investigate the ability of IV Favipiravir and in combination with Ribavirin to reduce the duration of signs and symptoms of CCHF in-patients.
• Clinical objective [Time from randomisation to death (up to day 29)]: To investigate the ability of IV Favipiravir and in combination with Ribavirin to reduce the duration of signs and symptoms of CCHF in-patients.

Other outcomes

• Pharmacokinetic objective: To investigate the exposure-response relationship of IV Favipiravir on CCHF viral dynamics. [At End of study (6 Months)]: Change in host immune response
• Pharmacokinetic objective: To investigate the exposure-response relationship of IV Favipiravir on CCHF viral dynamics. [At End of study (6 Months)]: Change in CCHFV culture and sequencing
• Pharmacokinetic objective: To characterise virus and host immune response. [At End of study (6 Months)]: Change in host immune response
• Pharmacokinetic objective: To characterise virus and host immune response. [At End of study (6 Months)]: Change in CCHFV culture and sequencing
• Measure immune response by aldehyde oxidase (AO) / xanthine oxidase (XO) activity. [At End of study (6 Months)]: To investigate the exposure-response relationship of IV Favipiravir and IV Favirpiravir/Ribavirin on CCHF viral dynamics (Favipiravir inhibits AO and XO is partially involved in metabolism of favipiravir)

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Adult in-patients (≥18 years) with laboratory confirmed CCHF infection by positive polymerase chain reaction (PCR) test.
2. Ability to provide informed consent signed by study patient or legally acceptable representative
3. 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 section 5.4 below) from the first administration of trial treatment, throughout trial treatment and for the duration outlined in trial protocol as well as addition 14 days for women and 7 days for men after the last dose of trial treatment.
4. Severity Grading System (SGS) for CCHF - mild/moderate.
5. Less than or equal to 7 days from onset of CCHF symptoms

Exclusion Criteria:

1. 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. Positive COVID-19 PCR
7. Previous intolerance of Favipiravir or Ribavirin
8. Haemoglobinopathies
9. Unstable cardiac diseases within 6 months
10. Any participants deemed not suitable, based on investigators opinion.
11. Patients taking the drugs listed in section 8.11 within 30 days or 5 times the half-life (whichever is longer) of enrolment

• Lucy E Read, PhD, MRCP, Study director, Liverpool School of Tropical Medicine