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

Study Overview
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Brief Summary
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UMIT-1: A Randomised Phase Ib Study to Determine the Phase II dose and to Evaluate the Safety and Efficacy of intravenous (IV) Favipiravir & Ribavirin for the Treatment of CCHF

Detailed Description
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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.

Official Title
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UMIT-1 Trial: Favipiravir & Ribavirin Phase IB A Randomised Phase Ib Study to Determine the Phase II Dose and to Evaluate the Safety and Efficacy of Intravenous (IV) Favipiravir & Ribavirin

Conditions
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CCHF

Intervention / Treatment
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* Drug: Favipiravir
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult in-patients (≥18 years) with laboratory confirmed CCHF infection by positive polymerase chain reaction (PCR) test. Ability to provide informed consent signed by study patient or legally acceptable representative 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. Severity Grading System (SGS) for CCHF - mild/moderate. Less than or equal to 7 days from onset of CCHF symptoms Exclusion Criteria: Stage 4 severe chronic kidney disease or requiring dialysis (i.e., estimated glomerular filtration (eGFR) rate <30 mL/min/1.73 m2) 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. Positive COVID-19 PCR Previous intolerance of Favipiravir or Ribavirin Haemoglobinopathies Unstable cardiac diseases within 6 months Any participants deemed not suitable, based on investigators opinion. Patients taking the drugs listed in section 8.11 within 30 days or 5 times the half-life (whichever is longer) of enrolment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1<br>6 patients will be randomised to starting dose of favipiravir 1800 mg BD (day 1), then 800mg BD Day 2 to 10, or standard of care. | Drug: Favipiravir<br>* Small molecule antiviral<br>|
| Active Comparator: Cohort 2<br>6 patients will be randomised to starting dose of favipiravir 2600 mg BD (day 1), then 1200mg BD day 2 to 10, or standard of care. | Drug: Favipiravir<br>* Small molecule antiviral<br>|
| Active Comparator: Cohort 3<br>6 patients will be randomised to starting dose of favipiravir 1800 mg BD (day 1), then 800mg BD Day 2 to 10 plus Ribavirin, or standard of care. | Drug: Favipiravir<br>* Small molecule antiviral<br>Drug: Ribavirin<br>* Small molecule antiviral<br>|
| Active Comparator: Cohort 4<br>6 patients will be randomised to starting dose of favipiravir 2600mg BD (day 1), then 1200mg BD day 2 to 10 plus Ribavirin, or standard of care. | Drug: Favipiravir<br>* Small molecule antiviral<br>Drug: Ribavirin<br>* Small molecule antiviral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety objective To determine the safety and tolerability of multiple doses of IV Favipiravir in patients with CCHF | 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) | Up to day 8 | 
| To determine the safety and tolerability of multiple doses of IV Favipiravir in combination with Ribavirin in patients with CCHF | 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) | up to day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic objective: To characterise the plasma pharmacokinetics of multiple doses of IV Favipiravir and IV Favipiravir in combination with Ribavirin | 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. | up to Day 8 | 
| Virologic objective | To investigate the effect of IV Favipiravir alone and in combination with Ribavirin on CCHF viral load | Change from baseline over time, up to Day 29, in viral load | 
| Clinical objective | To investigate the ability of IV Favipiravir and in combination with Ribavirin to reduce the duration of signs and symptoms of CCHF in-patients. | Mortality at Days 15 and 29 | 
| Clinical objective | To investigate the ability of IV Favipiravir and in combination with Ribavirin to reduce the duration of signs and symptoms of CCHF in-patients. | Time from randomisation to death (up to day 29) |