Pharmacokinetics of the antiviral drug ribavirin in Lassa fever treatment
| ISRCTN | ISRCTN11104750 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11104750 |
| Secondary identifying numbers | v03 06DEC2019, amended version of v02 25OCT2019 |
- Submission date
- 02/02/2020
- Registration date
- 06/02/2020
- Last edited
- 05/10/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
Lassa fever (LF) is a severe and often fatal systemic disease in humans. It is caused by Lassa virus (LASV) which belongs to the segmented negative-strand RNA viruses of the family Arenaviridae. LF affects a large number of countries in West Africa. The currently used antiviral, which is also recommended by WHO, is ribavirin. However, evidence for ribavirin efficacy in LF patients is poor and pharmacokinetic (PK) data for currently used regimens are not available. This study will describe blood concentrations of ribavirin and will provide evidence for further dose optimization studies with the ultimate goal of improving patient care.
Who can participate?
Patients aged 18 years or older, suffering from Lassa fever.
What does the study involve?
Participants will receive ribavirin treatment using the Irrua hospital dosing regimen.
Blood samples will be collected at 0.5, 1, 3, 5, 8, 12 and 24 hours after doses on day 1, day 4 and day 10.
What are the possible benefits and risks of participating?
Benefits: Participants will be provided with protein bars and long-lasting insecticide-treated bednets as compensation for taking part in this observational study.
Risks: Participants may experience side effects from taking the drug.
Where is the study run from?
Irrua Specialist Teaching Hospital (Nigeria)
When is the study starting and how long is it expected to run for?
February 2020 to September 2021
Who is funding the study?
Federal German Ministry for Health (Germany)
Who is the main contact?
Dr Mirjam Groger
groger@bnitm.de
Contact information
Public
Bernhard Nocht Institute for Tropical Medicine
Hamburg
20359
Germany
 ORCID ID |
0000-0001-7375-3685 |
|---|---|
| Phone | +49 4042818511 |
| groger@bnitm.de |
Study information
| Study design | Prospective observational clinical study |
|---|---|
| Primary study design | Observational |
| Secondary study design | Longitudinal study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Part of the informed consent form |
| Scientific title | Prospective observational study on the pharmacokinetic properties of the Irrua ribavirin regimen used in routine clinical practice in Lassa fever patients in Nigeria |
| Study acronym | PAIRR |
| Study objectives | Evaluating the pharmacokinetic (PK) characteristics of ribavirin when administered as per local standard in a national reference centre for treatment of Lassa fever (LF). Descriptive analysis of drug exposure and viral kinetics will be performed to elucidate the PK/PD (pharmacodynamic) profile of ribavirin in the treatment of LF. |
| Ethics approval(s) | Approved 07/11/2019, Human Research Ethics Committee of ISTH (Irrua Specialist Teaching Hospital, km87 Benin Auchi Road, Irrua, P.M.B. 8 Edo State, Nigeria; +234 815 299 8878; isth.rec.2015@gmail.com), ref: ISTH/HREC/20190104/009 |
| Health condition(s) or problem(s) studied | Lassa fever |
| Intervention | Pharmacokinetic analysis of ribavirin treatment Blood samples will be collected at 0.5, 1, 3, 5, 8, 12 and 24 hours after doses on day 1, day 4 and day 10 of ribavirin treatment using the Irrua dosing regimen. Additionally, blood will be collected during screening before the first dose of ribavirin. Blood samples will be centrifuged and the plasma supernatant will be frozen at -80° C within 2 h after blood sampling. Plasma samples will be inactivated using a validated protocol. The samples will then be shipped frozen to the bioanalysis site (Dept. of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Germany). Ribavirin plasma concentrations will be determined using liquid chromatography coupled to tandem mass spectrometry (LCMS/ MS). PCR analyses Blood for RT-PCR, LASV serology and metagenomic sequencing will be sampled at inclusion, 24 hours after first drug administration and then every second day until end of treatment. Two RT-PCR assays for the detection of LASV, Altona Diagnostics (Hamburg, Germany) and an inhouse assay will be used to determine the viral load. These analyses will be performed at site in Irrua. Biochemistry and hematology Blood for biochemical safety and tolerability will be collected every second day starting with screening. Biochemistry and hematology analyses will be performed using automated systems at ISTH. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Ribavirin |
| Primary outcome measure | Pharmacokinetic parameters (maximum concentration (Cmax), maximum time (Tmax), area under the curve (AUC), half-life time (T1/2), volume of distribution) using blood samples will be collected at 0.5, 1, 3, 5, 8, 12 and 24 hours after doses on day 1, day 4 and day 10 of ribavirin treatment using the Irrua dosing regimen |
| Secondary outcome measures | 1. Safety and tolerability of the Irrua Ribavirin regimen measured using clinical, hematological, and biochemical parameters: 1.1. Clinical: every day from day 0 to day 10 1.2. Haematology: standarad full blood count (hb; wbc; pla; diff) every 48 hours 1.3. Biochemistry: creatinine; alt; ast; bun; ldh every 48 hours 2. Viral kinetics in patients measured using at day 0, 5, 10 3. LASV genome changes under the Irrua ribavirin regimen measured at day 0, 5, 10 |
| Overall study start date | 01/06/2019 |
| Completion date | 01/09/2021 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 20 |
| Total final enrolment | 20 |
| Key inclusion criteria | 1. Age ≥ 18 years 2. Lassa fever confirmed by RT-PCR 3. Written informed consent 4. Anticipated treatment with intravenous ribavirin |
| Key exclusion criteria | 1. Inability to give consent (e.g. unconscious patients/ cognitively impaired patients) 2. Critical illness (based on investigator’s clinical evaluation) 3. Severe malnutrition 4. Hemodialysis 5. History of hemophilia / bleeding disorder 6. Hematocrit <30 % 7. History of hemoglobinopathies (i.e., sickle-cell anaemia or thalassemia major) 8. Known intolerance to ribavirin 9. Known pregnancy 10. Women who plan to get pregnant within the upcoming 3 months 11. Patients who already received ribavirin within the last 7 days |
| Date of first enrolment | 03/02/2020 |
| Date of final enrolment | 18/03/2021 |
Locations
Countries of recruitment
- Nigeria
Study participating centre
Irrua
P.M.B. 8 Edo State
Nigeria
Sponsor information
Research organisation
Bernhard Nocht Strasse 74
Hamburg
20359
Germany
| Phone | +49 40 42818-930 |
|---|---|
| GUENTHER@BNITM.DE | |
| Website | https://www.tropmed-hamburg.de |
"ROR" |
https://ror.org/01evwfd48 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- Federal Ministry of Health, Germany, Federal Ministry of Health, BMG
- Location
- Germany
Results and Publications
| Intention to publish date | 01/06/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request, Published as a supplement to the results publication |
| Publication and dissemination plan | All results will be published in agreement between the Sponsor and the PI in international peer-reviewed scientific journals with preference to open access journals. |
| IPD sharing plan | Relevant data are within the manuscript and its supporting information files. The data underlying the results presented in the study are available from the corresponding author on reasonable request. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 16/04/2020 | 21/04/2020 | Yes | No |
| Results article | outcome measures | 26/07/2022 | 05/10/2022 | Yes | No |
Editorial Notes
05/10/2022: Publication reference added.
13/01/2022: The following changes were made to the trial record:
1. The recruitment start date was changed from 06/02/2020 to 03/02/2020.
2. The recruitment end date was changed from 31/12/2021 to 18/03/2021.
3. The overall trial end date was changed from 31/12/2021 to 01/09/2021.
4. The intention to publish date was changed from 31/12/2022 to 01/06/2022.
5. IPD sharing statement and total final enrolment added.
6. Ther acronym was changed from PAIR to PAIRR.
21/04/2020: Publication reference added.
07/02/2020: Internal review.
05/02/2020: Trial’s existence confirmed by Human Research Ethics Committee of ISTH (Irrua Specialist Teaching Hospital)
