Clinical trial NCT04907682: Pharmacokinetics, Tolerability and Safety of Favipiravir Compared to Ribavirin for the Treatment of Lassa Fever
Official title: Pharmacokinetics, Tolerability and Safety of Favipiravir Compared to Ribavirin for the Treatment of Lassa Fever: A Randomized Controlled Open Label Phase II Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lassa Fever
Keywords: Ribavirin
Favipiravir
viral hemorrhagic fever
Lead sponsor: Bernhard Nocht Institute for Tropical Medicine
Sponsor class: OTHER_GOV
Collaborators: name: University of Hamburg-Eppendorf
name: Alliance for International Medical Action
name: Institut National de la Santé Et de la Recherche Médicale, France
name: University of Bordeaux
name: Federal Medical Centre, Owo
name: Irrua Specialist Teaching Hospital
First posted: 2021-06-01
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Exploratory, prospective, controlled, multisite, open label, randomized clinical trial with two arms
Primary purpose: TREATMENT

Brief summary: This exploratory, prospective, controlled, multisite, open label, randomized clinical trial with two treatment arms aims to compare favipiravir, a new treatment candidate for Lassa fever (LF), with the current standard of care, ribavirin.

The primary endpoints of this research are (1) the description of classical pharmacokinetic parameters of favipiravir in comparison with ribavirin standard treatment in patients suffering from LF and (2) the safety and tolerability of both study drugs in the investigated regimens.

Detailed description: The currently used antiviral for the treatment of LF, which is also recommended by the World Health Organization (WHO) and the Nigeria Center for Disease Control, is ribavirin. However, evidence for ribavirin efficacy in LF patients adds up to the results of a single study with serious limitations. A promising new treatment candidate that showed efficacy against LF in preclinical studies is Favipiravir. It has further been evaluated for the treatment of Ebola Virus disease during the West-African Ebola outbreak and is approved for treatment of pandemic influenza virus infections in Japan.

The study will be conducted at two study sites in Nigeria: the Irrua Specialist Teaching Hospital (ISTH) and the Federal Medical Center of Owo (FMCO). Lassa fever patients of 18 years and older with LF confirmed by reverse-transcription polymerase chain reaction (RT-PCR) hospitalized at either ISTH or FMCO will be asked to participate in this study. A total of 40 evaluable participants will be randomized to two treatment arms (20 participants per arm): intravenous ribavirin standard of care treatment (Irrua regimen), oral favipiravir. Patients will be included in the study after giving written informed consent and if all inclusion criteria and no exclusion criteria are met. Multiple blood draws with the purpose of virologic, serologic and immunological analyses, hematological and biochemical analyses as well as pharmacokinetic analyses will be performed throughout the study duration of ten days. Adverse events (AEs), serious adverse events (SAEs) and pregnancy will be captured, monitored and followed-up. A medical monitor will be available for study investigators to assist with any clinical and safety related questions. An external data safety monitoring board (DSMB) will conduct periodic safety reviews.

Data will be captured on source documents and electronic case report forms (eCRFs). Informed consent forms will be stored in a lockable cabinet. Participants data will only be linked to the unique identifier to ensure pseudonymity.

Statistical analysis of study endpoints and pharmacokinetic parameters will be performed descriptively. Missing data will be treated as such, no imputation will be applied.

The study will be conducted in compliance with the protocol, the Declaration of Helsinki, the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guideline and the Nigerian National Code for Health Research Ethics, in particular concerning the submission to the ethics committees and the protection of personal data as well as other national and regulatory requirements.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* LF confirmed by RT-PCR (reverse-transcription polymerase chain reaction)
* Written informed consent

Exclusion Criteria:

* Inability to give consent (e.g. unconscious patients/ cognitively impaired patients)
* Pregnancy/lactation (evidenced by negative urine pregnancy test in women of child-bearing potential)
* Women who plan to get pregnant within the upcoming 6 months
* Severe malnutrition (BMI\<16)
* Known intolerance to ribavirin or favipiravir
* History of hemoglobinopathies (i.e., sickle-cell anaemia or thalassemia major) and/or haemophilia
* Organ failure as evidenced by:

  * Creatinine ≥ 3x upper limit of normal (ULN)
  * Aspartate aminotransferase (AST/GOT) \> 150 IU/l
  * Alert, confusion, voice, pain, unresponsive (ACVPU) score = V or P or U (corresponds to Glasgow Coma Scale (GCS) ≤ 12)
  * Severe central nervous system features (e.g. seizures, restlessness, confusion and coma)
  * O2 Saturation \< 90%
  * Hematocrit \<30 %
  * Severe anaemia requiring blood transfusion
* Inability to take oral drug (e.g. encephalopathy, severe vomiting)
* Patients who already received ribavirin or favipiravir within the preceding 7 days

Primary outcomes:
measure: Pharmacokinetic parameter of favipiravir: Maximum plasma concentration (Cmax)
timeFrame: Day 1, Day 2, Day 4, Day 6, Day 7, Day 8 and Day 10 of the study conduct
measure: Pharmacokinetic parameter of favipiravir: Time to maximum concentration (Tmax)
timeFrame: Day 1, Day 2, Day 4, Day 6, Day 7, Day 8 and Day 10 of the study conduct
measure: Pharmacokinetic parameter of favipiravir: Area under the concentration-time curve (AUC)
timeFrame: Day 1, Day 2, Day 4, Day 6, Day 7, Day 8 and Day 10 of the study conduct
measure: Pharmacokinetic parameter of favipiravir: Half life (T1/2)
timeFrame: Day 1, Day 2, Day 4, Day 6, Day 7, Day 8 and Day 10 of the study conduct
measure: Proportion of drug related AEs and SAEs of both study treatments
timeFrame: throughout study completion (10 days per participant)
Secondary outcomes:
measure: Mutagenicity
timeFrame: 10 days
measure: Change from baseline in Viral RNA loads
timeFrame: Day of enrollment - Day 10
measure: Change from baseline in Lassa virus titers
timeFrame: Day of enrollment - Day 10
measure: Change from baseline in Lassa virus serological status
timeFrame: 10 days
measure: Pharmacokinetic (PK) modelling and simulations
timeFrame: Day 1, Day 2, Day 4, Day 6, Day 7, Day 8 and Day 10 of the study conduct
measure: Correlation between drug exposure and different parameters
timeFrame: 10 days
measure: Co-variates impacting on drug exposure
timeFrame: 10 days
Other outcomes:
Locations:
city: Irrua
country: Nigeria
facility: Irrua Specialist Teaching Hospital
state: Edo State
city: Owo
country: Nigeria
facility: Federal Medical Center of Owo
state: Ondo State
Study officials:
affiliation: ISTH
name: Peter Akhideno, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: ISTH
name: Sylvanus Okogbenin, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: FMCO
name: Oluwafemi Ayodeji, Dr
role: PRINCIPAL_INVESTIGATOR
References: