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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1 | Active Comparator | 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. |
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| Cohort 2 | Active Comparator | 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. |
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| Cohort 3 | Active Comparator | 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. |
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| Cohort 4 | Active Comparator | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Favipiravir | Drug | Small molecule antiviral |
|
| 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 |
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetic objective: To investigate the exposure-response relationship of IV Favipiravir on CCHF viral dynamics. | Change in host immune response | At End of study (6 Months) |
| Pharmacokinetic objective: To investigate the exposure-response relationship of IV Favipiravir on CCHF viral dynamics. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Lucy Read | Contact | +447743438383 | lucy.read@lstmed.ac.uk | |
| Umit-1 Study | Contact | umit@lstmed.ac.uk |
| Name | Affiliation | Role |
|---|---|---|
| Lucy E Read, PhD, MRCP | Liverpool School of Tropical Medicine | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ankara Oncology Training and Research Center | Recruiting | Ankara | Yenimahalle | 06200 | Turkey (Türkiye) |
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| ID | Term |
|---|---|
| C462182 | favipiravir |
| D012254 | Ribavirin |
| ID | Term |
|---|---|
| D012263 | Ribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
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| Ribavirin | Drug | Small molecule antiviral |
|
| 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) |
Change in CCHFV culture and sequencing |
| At End of study (6 Months) |
| Pharmacokinetic objective: To characterise virus and host immune response. | Change in host immune response | At End of study (6 Months) |
| Pharmacokinetic objective: To characterise virus and host immune response. | Change in CCHFV culture and sequencing | At End of study (6 Months) |
| Measure immune response by aldehyde oxidase (AO) / xanthine oxidase (XO) activity. | 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) | At End of study (6 Months) |