Clinical trial NCT06860334: UMIT-2 - Adaptive Phase IIb Platform Trial to Determine the Efficacy and Safety of Therapeutics for CCHF
Official title: UMIT-2: A Randomized, Multi-country, Adaptive Phase IIb Platform Trial to Determine the Efficacy and Safety of Therapeutics for Crimean-Congo Haemorrhagic Fever
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Crimean-Congo Hemorrhagic Fever
Keywords: CCHF
Favipiravir
Ribavirin
Crimean Congo Hemorrhagic Fever
Lead sponsor: Liverpool School of Tropical Medicine
Sponsor class: OTHER
First posted: 2025-03-06
Enrollment: 378
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1:1:1 randomised open-label phase 2b trial
Primary purpose: TREATMENT

Brief summary: CCHF has a wide geographical distribution with cases mainly occurring in Asia, the Middle East, South-Eastern Europe and Africa. Since its emergence in 2002, Turkiye has been the epicentre of activity worldwide reporting up to more than 1000 cases annually. CCHF case management relies on the provision of optimised supportive care; therapeutic options lack a robust evidence base

The UMIT-2 Trial (UMIT = 'Hope' in Turkish) will be the first large randomised controlled trial of novel therapeutics in CCHF, undertaken in multiple trial sites in Turkiye and Iraq. It uses an efficient adaptive platform design (Phase IIb), focussed on antiviral efficacy with interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

Adult in-patients (≥18 years)

Laboratory confirmed CCHF infection by positive polymerase chain reaction (PCR) test within 5 days prior to randomisation

Capacity 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 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

Willingness to participate in the full protocol

Requirement to be hospitalised for treatment-

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.

Previous intolerance of Favipiravir or Ribavirin

Any participants deemed not suitable, based on investigators opinion.

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.

Paracetamol: Coadministration of paracetamol (650 mg once daily) and favipiravir (1200 mg twice daily or 800 mg twice daily) increased paracetamol Cmax and AUC by 3% and 16% (1200 mg doses) and by 8% and 14% (800 mg doses). In the UMIT-2 trial after screening and randomisation the daily dose of paracetamol in adults should be no more than 3000 mg/day (rather than 4000 mg/day) -

Primary outcomes:
measure: Virologic objective: To compare CCHFV viral dynamics of investigational therapeutics relative to the control arm
timeFrame: Day 5 from treatment start
Secondary outcomes:
measure: Safety Objective: To determine the safety and tolerability of investigational therapeutics relative to the control arm
timeFrame: Day 29
measure: Clinical Objective: To compare time to successful hospital discharge between participants receiving investigational therapeutics, relative to the control arm
timeFrame: Day 29
measure: Antiviral Objective: To evaluate antiviral efficacy of investigational therapeutics (1)
timeFrame: Day 10
measure: Antiviral Objective: To evaluate antiviral efficacy of investigational therapeutics (2)
timeFrame: Day 10
measure: Safety Objective: To compare the overall mortality in patients with CCHF who receive different investigational therapeutics with those who receive the control arm
timeFrame: Day 28
measure: 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.
timeFrame: Day 28
measure: Pharmacokinetic objective:To characterise the plasma pharmacokinetics (PK) of therapeutics in CCHF
timeFrame: Day 29
Other outcomes:
measure: To characterise virus, host immune response and viral resistance over time
timeFrame: Day 29
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