Clinical trial NCT06841614: EBOla Post-Exposure Prophylaxis
Official title: Evaluation of the Efficacy of a Post-exposure Prophylaxis (PEP) Strategy in Contacts At High Risk of Developing Ebola Virus Disease (EVD)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Ebola Virus Disease
Keywords: Ebola Virus Disease
EBOV
High-Risk contact
Post-Exposure Prophylaxis
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Alliance for International Medical Action
name: Centre de Recherche et de Formation en Infectiologie de Guinée (CERFIG)
name: Medecins Sans Frontieres, Netherlands
name: Barcelona Institute for Global Health
name: University of Bordeaux
name: INSERM UMR S 1136
name: Agence Nationale de Sécurité Sanitaire de Guinée (ANSS)
name: National Institute for Biomedical Research DRC
name: Cheikh Anta Diop University, Senegal
name: PACCI Program
name: The PANdemic preparedness plaTform for Health and Emerging infectious Response
name: University of Sierra Leone College of Medicine and Allied Health Sciences
name: National Public Health Institute of Liberia
First posted: 2025-02-24
Enrollment: 160
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomised (1:1) into one of two trial arms:

* ERV: Ervebo vaccine at D1
* ERV+IMZ: Ervebo vaccine at D1 and D56 + Inmazeb on D1 All participants are monitored daily for a minimum of 21 or 60 days. These visits are accompanied by follow-up, in collaboration with the Ministry of Health surveillance team (details described in a specific procedure), at home or by telephone, including at least one daily call.
* ERV arm: If no signs or symptoms suggestive of EVD follow-up stops at D21.
* ERV+IMZ arm: Participants are revaccinated at D56 to compensate for a possible inhibition of the vaccine response when the vaccine is administered concomitantly with Inmazeb (probable negative interaction).
Primary purpose: PREVENTION

Brief summary: EBO-PEP is a multicentre, multi-epidemic, phase III, comparative, controlled, randomised, strict superiority trial in two unblinded parallel arms.

The trial will be open during EVD epidemics and will recruit asymptomatic participants at high risk of developing EVD.

Participants will be randomized (1:1) into one of two trial arms:

* Arm 1 (ERV): Ervebo D0 (72 million PFU IM)
* Arm 2 (ERV+IMZ): Ervebo D0 (72 million PFU IM) + Inmazeb IV (150 mg/kg) D0 + Ervebo D56 (revaccination)

Definition of high-risk:

Direct contact with a person with confirmed EVD presenting with diarrhoea, vomiting or externalized haemorrhages ("wet symptoms"), or with their body fluids; Direct contact with the corpse of a person with confirmed or probable EVD; or child born to or breastfed by an infected mother

Trial follow-up

All participants are monitored daily for a minimum of 21 or 60 days, with face-to-face visits to the investigation site, also known as the Post-Exposure Prophylaxis (PEP) centre:

* at D5, D10, and D21 for the ERV arm,
* at D5, D10, D21 and D56 for the ERV+IMZ and ERV+IMZ arms. These visits are accompanied by follow-up, in collaboration with the Ministry of Health surveillance team (details described in a specific procedure), at home or by telephone, including at least one daily call.
* ERV arm: If no signs or symptoms suggestive of EVD follow-up stops at D21.
* ERV+IMZ arm: Participants are revaccinated at D56 to compensate for a possible inhibition of the vaccine response when the vaccine is administered concomitantly with Inmazeb (probable negative interaction). For safety reasons, a call is made at D60 to check for any adverse events (AEs) after vaccination.

Follow-up after hospitalisation In the event of signs or symptoms suggestive of EVD, the participant enters the Ebola Treatment Centre (ETC) suspected case assessment circuit.

If EVD is confirmed by PCR, the participant is taken into care in the ETC as a confirmed case. They will continue to be monitored by the research team and daily data will be collected during their stay in the ETC.

If the EVD is not confirmed, the participant will continue to be monitored by the PEP centre.

If the participant leaves the ETC before D21, he/she will be recalled for his/her final visit on D21. If the participant leaves the ETC or dies after D21, they are considered to have left the trial.

Detailed description: Since its discovery in the Democratic Republic of Congo (DRC) in 1976, the EBOV virus has been responsible for numerous epidemics. Outbreaks have occurred in the DRC, Gabon, Guinea, Liberia and Sierra Leone. Imported cases were also discovered in 1996 in South Africa, and in 2014 in Mali, Nigeria, Senegal, Italy, Spain, UK and USA (1). To date, the largest EVD epidemic occurred in West Africa between 2014 and 2016. It was responsible for over 28,000 infections and more than 11,000 deaths (2-4). Since this epidemic, EVD has emerged and re-emerged regularly in Sub-Saharan Africa (SSA).

Post-exposure prophylaxis (PEP) is the treatment of people at high risk of EVD. The main aim of PEP is to intervene during the asymptomatic incubation period (2-21 days) to prevent the development of EVD.

In addition to preventing the disease in individuals, an effective PEP strategy could reduce the rate of secondary attacks, thus interrupting transmission chains. If introduced rapidly, this tool could halt the spread of the disease and contribute to the fight against EVD epidemics (5). The particular vulnerability of healthcare personnel has been highlighted during several outbreaks, due to their close contact with infected patients and contaminated equipment (6). With an effective and accessible PEP tool, it will be possible to ensure the safety and protection of these essential personnel and minimize the risk of nosocomial transmission within healthcare establishments. PEP could also benefit contact tracing efforts by providing an appropriate preventive measure. By integrating PEP into comprehensive epidemic response strategies, it will be possible to improve countries' ability to control and mitigate the public health impact of EVD epidemics and prevent future outbreaks.

There is currently no comprehensive PEP strategy, i.e. one that combines several interventions. Several prophylactic interventions have been evaluated, including vaccination and mAb immunotherapy, each with its advantages and limitations (7-9). Although not intended for this use, Ervebo vaccine is currently administered as PEP during EVD epidemics, by being administered to contacts regardless of exposure levels.

MAbs have been administered as PEP on a compassionate basis, to healthcare workers following occupational exposure, in line with WHO expert advice from 2018 (10). In addition, mAbs are recommended as PEP for newborns of Ebola-infected mothers, within seven days of birth (11). PEP can prevent the risk of infection associated with a particular contact, but not the persistent risk of infection during an epidemic. A comprehensive strategy to protect high-risk contacts must therefore be put in place, including both a drug to prevent EVD after contact (mAb or antiviral) and a vaccine for long-term immunity, to guarantee both immediate and prolonged protection.

Inmazeb (REGN-EB3), developed by Regeneron, is a cocktail of 3 neutralizing humanized mAbs directed against 3 EBOV GP epitopes (atoltiviMab, maftiviMab and odesiviMab). It is indicated for the treatment of EVD in adult patients (including pregnant women) and in children, including neonates whose mothers have EVD at the time of delivery. Inmazeb inhibits viral entry into the target cell (12). This mechanism of action makes Inmazeb a promising candidate for PEP (34,40-44). In phase 1, the optimal dose was set at 150 mg/kg as a single intravenous (IV) dose, with good tolerability, except for moderate side effects such as headache and myalgia in 30% and 10% of participants respectively. The longest half-life of the three antibodies was 27.3 days (21.7 and 23.3 for the other two antibodies). At 180 days, the residual concentration of each antibody (administered at 150 mg/kg) is less than 10 mg/l (13). In the PALM trial, overall mortality after a single 150 mg/kg dose was estimated at 33.5% (versus 51.3% in the ZMapp control arm). However, the effect of treatment is strongly influenced by viral load. In patients with a high viral load at inclusion (NP Ct \< 22), mortality was 63.6% (versus 86.2% in the Zmapp subgroup), while in patients with a low viral load at inclusion (NP Ct \> 22), mortality was 11.2% (versus 25.8% in the Zmapp subgroup) (14). Following the PALM trial, Inmazeb was approved by the FDA for the treatment of EVD in adults and children (15).

A study conducted during the 10éme EVD epidemic in the DRC evaluated PEP with mAbs as part of a compassionate program (Post-Exposure Prophylaxis Monitored Emergency Used for Unregistered Intervention - PEP MEURI). In this study, 23 vaccine-naïve high-risk contacts received mAbs (21 Ebanga and 2 Inmazeb) after a median delay of one day between contact and PEP. At D14, none of the participants were symptom-free and their PCR was negative (16).

EBO-PEP is a multicentre, multi-epidemic, phase III, comparative, controlled, randomised, strict superiority trial in two unblinded parallel arms.

The trial will be open during EVD epidemics, and will recruit asymptomatic participants at high risk of developing EVD. Participants will be randomized (1:1) into one of two trial arms:

* Arm 1 (control arm): Ervebo D1 (72 million PFU IM)
* Arm 2: Ervebo D1 (72 million PFU IM) + Inmazeb IV (150 mg/kg) D1 + Ervebo D56 (revaccination)

Definition of high-risk:

Direct contact with a person with confirmed EVD presenting with diarrhoea, vomiting or externalized haemorrhages ("wet symptoms"), or with their body fluids; Direct contact with the corpse of a person with confirmed or probable EVD; or child born to or breastfed by an infected mother

Eligibility criteria: Inclusion Criteria:

* Last high-risk contact within the last 5 days
* No signs or symptoms of EVD
* Age ≥ 6 months
* Signed and dated informed consent (by a representative of parental authority for minors).

Exclusion Criteria:

* Previous vaccination with Ervebo or any other EVD vaccine less than 5 years ago (declared by the participant)
* History of confirmed EVD less than 5 years ago (declared by the participant);
* Hypersensitivity to one of the investigational medicinal products (IMP) or to their excipients (declared by the participant)
* Participation in another therapeutic or vaccination trial for EVD
* Any other reason which, at the investigator's discretion, would compromise the participant's safety and cooperation in the trial.

Primary outcomes:
measure: Proportion of participants with symptomatic and PCR-confirmed EVD
timeFrame: Between Day 1 and Day 21
Secondary outcomes:
measure: Proportion of participants with symptomatic and PCR-confirmed EVD
timeFrame: Between Day 1 and Day 60
measure: Safety and tolerance
timeFrame: Between Day 1 and Day 60
measure: Severity of EVD
timeFrame: Between Day 1 and Day 60
measure: Proportion of participants with asymptomatic EVD
timeFrame: Between Day 1 and Day 60
measure: Proportion of deaths
timeFrame: Between Day 1 and Day 60
measure: Changes in viral load
timeFrame: Between Day 1 and Day 21
measure: Estimating cost-effectiveness
timeFrame: Between Day 1 and up to Day 60
Other outcomes:
Locations:
city: Kinshasa
country: Congo, The Democratic Republic of the
facility: National Institute for Biomedical Research (INRB)
city: Conakry
country: Guinea
facility: Guinea Centre for Research and Training in Infectious Diseases (CERFIG)
city: Monrovia
country: Liberia
facility: National Public Health Institute of Liberia
city: Freetown
country: Sierra Leone
facility: University of Sierra Leone College of Medicine and Allied Health Sciences
Study officials:
affiliation: INRB
name: Placide MBALA, MD, MSPH, PhD
role: STUDY_CHAIR
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