EBOla Post-Exposure Prophylaxis

Phase 3

Not yet recruiting

• Conditions: Ebola Virus Disease
• Interventions: Biological: Ervebo; Biological: Inmazeb

• Registration Number: NCT06841614
• Lead Sponsor: ANRS, Emerging Infectious Diseases

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 EBOV PCR-confirmed EVD with diarrhea, vomiting or external bleeding ("wet symptoms"), or with their body fluids; Direct contact with the dead body of a person with confirmed or probable EVD; Needlestick with a syringe contaminated by the blood of a person with confirmed or probable EVD; Or a child born to or breastfed by an individual with EVD

Trial follow-up All participants are monitored daily for a minimum of 21 days.

Some visits are conducted in person at the investigation site, also called the Post-Exposure Prophylaxis (PEP) center:

* at Day 5, Day 10, and Day 21 for the ERV arm,

* at Day 5, Day 10, Day 21, and Day 56 for the ERV+IMZ arm. Other visits are conducted at home or by phone, in collaboration with the Ministry of Health's surveillance team.

Participants in the ERV+IMZ arm have an in-person visit at Day 56 to be revaccinated with the Ervebo vaccine to compensate for potential inhibition of the vaccine response when Ervebo is administered simultaneously with Inmazeb.

Participants in the ERV arm have a phone visit at Day 56. For all participants, a phone visit is scheduled at Day 60. It corresponds to the last visit for all trial participants.

Follow-up in Case of Hospitalisation In case of clinical signs suggestive of EVD, participants enter the suspected case management pathway at the Ebola Treatment Center (ETC).

If EVD is confirmed by EBOV PCR, participants are allowed at the ETC, and their study samples are discontinued. They continue to be followed by the research team, and daily data are collected throughout their stay at the ETC until they are discharged alive or deceased. The day of discharge from the ETC marks the end of follow-up in the study for these participants.

Of note, participants in the ERV+IMZ arm who have confirmed EVD are not revaccinated at day 56.

Of note, participants in the ERV+IMZ arm who have confirmed EVD are not revaccinated at day 56.

If EVD is not confirmed, participants continue to be followed up by the PEP center according to the protocol.

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 EBOV PCR-confirmed EVD with diarrhea, vomiting or external bleeding ("wet symptoms"), or with their body fluids; Direct contact with the dead body of a person with confirmed or probable EVD; Needlestick with a syringe contaminated by the blood of a person with confirmed or probable EVD; Or a child born to or breastfed by an individual with EVD

Study Timeline

• Study First Submitted: 2025-01-28
• Study First Submitted QC: 2025-02-18
• Study First Posted: 2025-02-24
• Status Verified: 2025-10
• Study Start: 2025-10-01
• Last Update Submitted: 2025-10-03
• Last Update Posted: 2025-10-08
• Primary Completion: 2027-08-01
• Study Completion: 2028-08-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 160

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ervebo + Inmazeb	Inmazeb	Administration of Ervebo vaccine (72 million PFU IM) and Inmazeb IV (150 mg/kg) at day 1 and Inmazeb IV (150 mg/kg) at day 56
Ervebo vaccine alone	Ervebo	Administration of Ervebo vaccine (72 million PFU IM) at day 1
Ervebo + Inmazeb	Ervebo	Administration of Ervebo vaccine (72 million PFU IM) and Inmazeb IV (150 mg/kg) at day 1 and Inmazeb IV (150 mg/kg) at day 56

Primary Outcome Measures

Name	Time	Method
Proportion of participants with EBOV PCR-confirmed symptomatic EVD	Between Day 1 and Day 21	EVD rate

Secondary Outcome Measures

Name	Time	Method
Proportion of participants with EBOV PCR-confirmed symptomatic EVD	Between Day 1 and Day 60	EVD rate
Safety and tolerance	Between Day 1 and Day 60	Proportion of participants with a grade 3 or higher Adverse Event
Severity of EVD	Between Day 1 and Day 60	Proportion of participants admitted to the Ebola Treatment Center with confirmed EVD meeting at least one of the following criteria: * Nucleoprotein cycle threshold (NP Ct) \< 22; * KDIGO stage 3; * ASAT or ALAT \> 5N; * External bleeding; * AVPU score; * NEWS2 score ≥ 7
Proportion of participants with asymptomatic EVD	Between Day 1 and Day 21	Rate of PCR-confirmed EVD
Proportion of deaths	Between Day 1 and Day 60	Proportion of participants who died (all causes combined)
Changes in viral load	Between Day 1 and Day 21	NP Ct curve (nucleoprotein cycle threshold)
Estimating cost-effectiveness	Between Day 1 and up to Day 60	Incremental cost-effectiveness ratio (ICER) for ERV+IMZ arm vs ERV

Trial Locations

Locations (4)

National Institute for Biomedical Research (INRB); 🇨🇩 Kinshasa, Democratic Republic of the Congo

Guinea Centre for Research and Training in Infectious Diseases (CERFIG); 🇬🇳 Conakry, Guinea

National Public Health Institute of Liberia; 🇱🇷 Monrovia, Liberia

University of Sierra Leone College of Medicine and Allied Health Sciences; 🇸🇱 Freetown, Sierra Leone