Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0835 or +27 21 938 0967
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202312770983740 Date of Registration: 22/12/2023
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title The INTEGRATE study: an adaptive platform trial for the development of new interventions to combat Lassa Fever in West Africa.
Official scientific title Efficacy, tolerability and safety of new or repurposed drugs against Lassa Fever in West African countries: an adaptative phase II-III platform trial
Brief summary describing the background and objectives of the trial Lassa fever (LF) is a viral haemorrhagic fever responsible of 18000 deaths per year in West Africa, with in-hospital mortality at 12%. Transmission to humans occurs mainly via direct or indirect exposure to excreta from the rodent reservoir, mainly made up of Mastomys natalensis. Less frequently, Lassa virus (LASV) may also be transmitted from human to human and cause nosocomial outbreaks. Ribavirin is the only treatment available with worrying toxicity, questionable efficacy and low access because of its high cost. Consequently, there is an urgent need for new drugs to treat LF patients. The Research and Development (R&D) Blueprint of the World Health Organization (WHO) has included LF in the list of priority diseases for urgent research and development. The INTEGRATE study is a platform, multinational, multicentre, sequential, seamless phase II-III, controlled, randomised, superiority trial in open-label parallel arms. Its primary objective is to compare the efficacy of each Investigational Medical Product (IMP) to Standard of Care Drug (SCD) to prevent death or organ failure in hospitalized patients with confirmed LF. The primary objective of the trial is to compare the efficacy of each IMP and SCD to prevent death or organ failure in hospitalized participants with confirmed LF. Secondary objectives are i) to compare the safety and tolerability of each IMP and SCD, ii) to compare the efficacy of each IMP and SCD on clinical, virological and biological parameters, iii) to describe the pharmacokinetics of each IMP and iv) to develop a pharmacokinetics / pharmacodynamics model for each IMP informing about optimal dosing regimens and dose-response relationship.
Type of trial RCT
Acronym (If the trial has an acronym then please provide)
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Lassa Fever
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/07/2024
Actual trial start date
Anticipated date of last follow up 29/06/2027
Actual Last follow-up date
Anticipated target sample size (number of participants) 732
Actual target sample size (number of participants) 732
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Stratified allocation where factors such as age, gender, center, or previous treatment are used in the stratification Central randomisation by phone/fax Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Ribavirin 100 mg/kg Day 1 (two doses) 25 mg/kg single dose days 2-7 12.5 mg/kg single dose days 8-10 10 Days Intravenous ribavirin (Irrua regimen – 100 mg/kg Day 1 (dose is divided: 2/3 stat, 1/3 8 hours later, maximum dose is 7g/day) then 25 mg/kg single dose days 2-7, 12.5 mg/kg single dose days 8-10). 183 Active-Treatment of Control Group
Experimental Group Favipiravir 1600 Loading dose :2400 mg BID D1 1600 mg BID D2-D10 10 days Oral favipiravir: 2400 mg BID D1; 1600 mg BID D2-D10 183
Experimental Group Combinaison Favipiravir and Ribavirin Oral favipiravir: 2400 mg BID D1; 1200 mg BID D2-D10 IV ribavirin :Irrua regimen 10 days Oral favipiravir: 2400 mg BID D1; 1200 mg BID D2-D10 in association with IV ribavirin: 100 mg/kg Day 1 (dose is divided: 2/3 stat, 1/3 8 hours later, maximum dose is 7g/day) then 25 mg/kg single dose days 2-7, 12.5 mg/kg single dose days 8-10) 183
Experimental Group Combinaison Ribavirin and Dexamethasone IV ribavirin: Irrua regimen in association with IV or oral dexamethasone 6mg/day 10 days IV ribavirin: Irrua regimen in association with IV or oral dexamethasone 6mg/day (For the first 48 hours, dexamethasone will be given intravenously (i.v.). Afterwards, a switch to oral dexamethasone (same dosage) is permitted at the discretion of the study physician.) 183
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
General Inclusion Criteria: ● Clinical disease with signs and symptoms suggestive for LF ● Positive plasma LASV RT-PCR ● Participant requires hospitalization per the local guidelines ● Participant or their legally authorized representative is able and willing to sign the informed consent Each intervention arm has specific eligibility criteria -->Favipiravir: specific inclusion criteria • Age ≥ 18 years old -->Combinaison Favipiravir and Ribavirin specific inclusion criteria • Age ≥ 18 years old --> Combinaison Ribavirin and Dexamethasone specific inclusion criteria • Age ≥ 12 years old General Exclusion criteria: ● Unwilling to provide informed consent ● Positive pregnancy test ● History of allergic reaction or other contra-indication to ribavirin according to the Reference safety document ● Received drug therapy for Lassa fever (excluding supportive care) prior to inclusion Each intervention arm has have specific eligibility criteria --> Favipiravir: specific exclusion criteria • Pregnancy (evidenced by positive urine pregnancy test in women of child-bearing potential) • Treatment contraindicated with favipiravir according to the Reference safety document • Pre-existing liver failure • Severe symptomatic gout/hyperuricemia • History of QT prolongation or arrhythmia or other cardiac disorders • PR interval ≥ 200 ms • Hypersensitivity to excipients • Inability to take oral drug (e.g. encephalopathy, severe vomiting) --> Combinaison Favipiravir and Ribavirin specific exclusion criteria • Pregnancy (evidenced by positive urine pregnancy test in women of child-bearing potential) • Treatment contraindicated with favipiravir according to the Reference safety document • Pre-existing liver failure • Severe symptomatic gout/hyperuricemia • History of QT prolongation or arrhythmia or other cardiac disorders • PR interval ≥ 200 ms • Hypersensitivity to excipients • Inability to take oral drug (e.g. encephalopathy, severe vomiting) --> Combinaison Ribavirin and Dexamethasone specific exclusion criteria • Pregnancy (evidenced by positive urine pregnancy test in women of child-bearing potential) • Known intolerance and contra-indications to ribavirin or dexamethasone • Patients who already received a corticosteroid within the preceding 7 days 80 and over: 80+ Year,Adolescent: 13 Year(s)-17 Year(s),Adult: 18 Year(s)-44 Year(s),Aged: 65 Year(s)-79 Year(s),Child: 6 Year-12 Year,Middle Aged: 45 Year(s)-64 Year(s) 12 Year(s) 100 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 31/01/2024 National Health Research Ethics Committee Nigeria
Ethics Committee Address
Street address City Postal code Country
Federal Ministry of Health, Federal Secretariat Complex Shehu Shagari Way, Garki Abuja PMB 083 Nigeria
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome The primary endpoint is the proportion of patients meeting any one of the components of the below composite endpoint - Death - New onset of acute kidney failure - New onset of acute respiratory failure - New onset of shock The composite endpoint assesses the new onset of an event from D0. Death will be measured between D0-D28 and New onset of acute kidney failure , New onset of acute respiratory failure and New onset of shock will be measured between D0-D10
Secondary Outcome Safety Adverse Event grade 3 and higher will be collected between D0-10, Serious Adverse Event and Adverse Event of Special Interest collected between D0-D28
Secondary Outcome Acute Kidney Injury Proportion of participants meeting KDIGO grade 2 or above or an initiation of renal replacement therapy will be collected between D0 and D10
Secondary Outcome Encephalopathy Proportion of participants with CVPU or seizure will be collected between D0-D10
Secondary Outcome Bleeding Proportion of participants meeting WHO bleeding scale grade 2 or above will be collected between D0-D10
Secondary Outcome Severe anaemia Proportion of participants with Hb level inferior to 80 g/L will be collected between D0-D10
Secondary Outcome Liver failure Proportion of participants with AST or ALT level above or equal to 3N or more will be collected between D0-D10
Secondary Outcome Clinical severity score Proportion of participants with a NEWS2 score up to 7 will be collected between D0-D10
Secondary Outcome Intensive care strategies Proportion of participants having received oxygen therapy and/or having received RRT and/or having received blood transfusion and/or having received inotropes will be collected between D0-D10
Secondary Outcome Viral clearance Change in LF RT-PCR Ct value from D0 and/or change in LASV viral titer from D0 and/or Proportion of participants with LASV RT-PCR less than LLQ will be collected at D3, D5, D7 and D9
Secondary Outcome Pharmacokinetics (phase II only) Description of the PK following PK parameters: peak concentration, time to peak concentration, area under the curve, half-life, clearance and volume of distribution will be collected between D0-D10
Secondary Outcome PK/PD (phase II only) The prediction of initial viral load and slope of decline and the optimal dosing regimen with PK/PD modelling will be calculated between D0-D10
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Irrua Specialist Teaching Hospital KM 87 Benin Auchi Rd Irrua 310115 Nigeria
Federal Medical Centre Owo Michael Adekunle Ajasin Road Owo PMB 1053 Nigeria
ABUBAKAR TAFAWA BALEWA UNIVERSITY TEACHING HOSPITAL Hospital Road off Yandoka Rd Bauchi Nigeria
FUNDING SOURCES
Name of source Street address City Postal code Country
European Union EDCTP3 program Global Health EDCTP3 JU TO56 Brussels 1049 Belgium
Agency for research on AIDS and viral hepatitis Emerging infectious diseases 2 rue d Oradour sur Glane Paris 75015 France
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Irrua Specialist Teaching Hospital KM 87 Benin Auchi Rd Irrua 310115 Nigeria Hospital
Secondary Sponsor Agency for research on AIDS and viral hepatitis Emerging infectious diseases 2 rue d Oradour sur Glane Paris 75015 France Funding Agency
COLLABORATORS
Name Street address City Postal code Country
Alliance for International Medical Action Rte des Almadies Dakar Senegal
Bernhard Nocht Institute for Tropical Medicine BERNHARD NOCHT STRASSE 74 Hamburg 20359 Germany
Federal Medical Centre Owo Michael Adekunle Ajasin Road Owo PMB 1053 Nigeria
University of Bordeaux 35 place Pey Berland Bordeaux 33000 France
Program PACCI CHU Treichville Abidjan Cote Divoire
Alex Ekwueme Federal UniversityTeaching Hospital Abakaliki Aefutha road Department of Community Medicine,AEFUTHA Abakaliki 480001 Nigeria
Medecins sans Frontieres Belgium Rue de l arbre benit 46 Brussels 1050 Brussels Belgium
Phebe Hospital Suokoko District, Bong County Phebe Liberia
University North Carolina 321 S Columbia St Chapel Hill NC 27599 United States of America
University of Hamburg Mittelweg 177 Hamburg 20148 Germany
Medical Research Center of Lambarene Lambarene Lambarene 242 Gabon
Scientific Research Fondation Scientific Research Fondation Cotonou BP88 Benin
Donka Hospital Hopital de Donka Conakry G8P8 6GW Guinea
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Sylvanus Okogbenin okogbenins@yahoo.com +2348060476179 KM 87 Benin Auchi Rd
City Postal code Country Position/Affiliation
Irrua 310115 Nigeria Consultant Obstetrician and Gynecologist
Role Name Email Phone Street address
Scientific Enquiries Marie Jaspard marie.jaspard@coral.alima.ngo +33658809012 1 rue Philidor
City Postal code Country Position/Affiliation
Paris 75020 France Coordinator of the emerging infectious disease department
Role Name Email Phone Street address
Principal Investigator Michael Ramharter ramharter@bnitm.de +491733915608 Bernhard Nocht Strasse 74
City Postal code Country Position/Affiliation
Hamburg 20359 Germany Head of Division of Tropical Medicine
Role Name Email Phone Street address
Public Enquiries Camille Fritzell camille.fritzell@coral.alima.ngo +33783676824 35 place Pey Berland
City Postal code Country Position/Affiliation
Bordeaux 33000 France International Project Manager at ALIMA
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes All specific individual participant data that underlie results in a publication, after deidentification will be shared. Informed Consent Form,Study Protocol Data will be available beginning 9 months and ending 36 months following the article publication Researchers who provide a methodologically sound proposal will be able to submit it to marie.jaspard@coral.alima.ngo. To gain access, data requestors will need to sign a data access agreement.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information