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

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

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

Study Overview

• Status: Recruiting
• Conditions: CCHF
• Intervention / Treatment: Drug: Favipiravir; Drug: Ribavirin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Lucy Read; Phone Number: +447743438383; Email: lucy.read@lstmed.ac.uk
• Study Contact Backup: Name: Umit-1 Study; Email: umit@lstmed.ac.uk

Study Locations

• Turkey
  • Yenimahalle
    • Ankara, Yenimahalle, Turkey, 06200
      • Recruiting
      • Ankara Oncology Training and Research Center
      • Contact: Mustafa Ertek; Email: ertekmustafa@hotmail.com
      • Contact: Mehmet Yildiz; Email: mehmet.yildiz@medex-smo.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cohort 1; 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; Small molecule antiviral
Active Comparator: Cohort 2; 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; Small molecule antiviral
Active Comparator: Cohort 3; 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; Small molecule antiviral; Drug: Ribavirin; Small molecule antiviral
Active Comparator: Cohort 4; 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; Small molecule antiviral; Drug: Ribavirin; Small molecule antiviral

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	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.	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)

Collaborators and Investigators

• Sponsor: Liverpool School of Tropical Medicine
• Investigators: Study Director: Lucy E Read, PhD, MRCP, Liverpool School of Tropical Medicine

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2023
• Primary Completion (Estimated): September 30, 2023
• Study Completion (Estimated): December 31, 2023

Study Registration Dates

• First Submitted: May 3, 2023
• First Submitted That Met QC Criteria: July 7, 2023
• First Posted (Actual): July 11, 2023

Study Record Updates

• Last Update Posted (Actual): October 5, 2023
• Last Update Submitted That Met QC Criteria: October 3, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Favipiravir; Ribavirin
• Other Study ID Numbers: 22-021

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No