A Study to Assess Safety, Tolerability, and Immunogenicity of Three Heterologus 2-dose Regimens of the Candidate Prophylactic Vaccines for Ebola in Healthy Adults

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety, tolerability, and immunogenicity of 3 vaccination schedules of Ad26.ZEBOV and MVA-BN-Filo administered intramuscularly (IM) as 2-dose heterologous regimens.

Detailed Description
-----------------
This is a randomized, observer-blind, placebo-controlled, parallel-group, multicenter, Phase 2 study evaluating the safety, tolerability and immunogenicity of 2-dose heterologous regimens using Ad26.ZEBOV and MVA-BN-Filo administered to healthy adults participants in Europe. The study involves a screening period of up to 12 weeks, a vaccination period in which participants will be vaccinated with Ad26.ZEBOV (dose 1) followed by vaccination with MVA-BN-Filo (dose 2) 28, 56 or 84 days later, and a post-vaccination phase until 6 months post dose 2 visit (Days 209, 237 or 265). After unblinding, only participants who received Ad26.ZEBOV and/or MVA-BN-Filo will continue the study until the Day 365 visit (or until the start of the roll-over study or for an additional 12 months [whichever comes first] for participants in France who agree to continue the long-term follow-up after Day 365) to assess long-term safety and immunogenicity. Participants will enroll into 3 cohorts: that is, Cohort 1 (Participants will receive Ad26.ZEBOV and MVA-BN-Filo in an open-label fashion), Cohort 2 (Participants will be randomized to receive the 2-dose heterologous vaccine regimen with either Ad26.ZEBOV followed by MVA-BN-Filo, or placebo in a 14:1 ratio) and Cohort 3 (Participants will be randomized to receive the 2-dose heterologous vaccine regimen with either Ad26.ZEBOV followed by MVA-BN-Filo, or placebo in a 10:3 ratio). In Cohorts 2 and 3, core immunogenicity assessments (humoral and cellular assays) will be performed. In Cohort 2, additional immunogenicity assessments will be done. In Cohort 1, plasma blast response kinetics will be evaluated. Safety will be monitored during the study.

Official Title
-----------------
A Randomized, Observer-Blind, Placebo-Controlled, Phase 2 Study to Evaluate the Safety, Tolerability and Immunogenicity of Three Prime-Boost Regimens of the Candidate Prophylactic Vaccines for Ebola Ad26.ZEBOV and MVA-BN-Filo in Healthy Adults in Europe

Conditions
-----------------
Ebola Viral Disease

Intervention / Treatment
-----------------
* Biological: MVA-BN-Filo
* Biological: Ad26.ZEBOV
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must be healthy in the Investigator's clinical judgment on the basis of medical history, physical examination, electrocardiogram (ECG) and vital signs performed at Screening Must be healthy on the basis of clinical laboratory tests performed at Screening. If the results of the laboratory screening tests are outside the normal reference ranges, the participant may be included only if the Investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study Before randomization, a woman must be either of childbearing potential and practicing (or intending to practice) a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for participants participating in clinical studies, beginning at least 28 days prior to vaccination OR not of childbearing potential: postmenopausal (greater than [>] 45 years of age with amenorrhea for at least 2 years or lesser than or equal to [<=] 45 years of age with amenorrhea for at least 6 months, and a serum follicle stimulating hormone (FSH) level >40 international unit per milliliter [IU/L]); permanently sterilized (for example, bilateral tubal occlusion [which includes tubal ligation procedures as consistent with local regulations], hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy Woman of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) at Screening and a negative urine beta-hCG pregnancy test immediately prior to each study vaccine administration Man who is sexually active with a woman of childbearing potential and has not had a vasectomy performed more than 1 year prior to screening must be willing to use condoms for sexual intercourse beginning prior to enrollment Exclusion Criteria: Having received any candidate Ebola vaccine Diagnosed with Ebola virus disease, or prior exposure to Ebola virus, including travel to West Africa less than 1 month prior to screening. West Africa includes but is not limited to the countries of Guinea, Liberia, Mali, and Sierra Leone Having received any experimental candidate adenovirus serotype 26 (vector: Ad26) or Modified Vaccinia Ankara (MVA-) based vaccine in the past Known allergy or history of anaphylaxis or other serious adverse reactions to vaccines or vaccine products (including any of the constituents of the study vaccines including known allergy to egg, egg products and aminoglycosides Presence of acute illness or temperature greater than or equal to 38.0 C on Day 1

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Participants will receive intramuscular (IM) injection of Ad26.ZEBOV/Placebo on Day 1 followed by IM injection of MVA-BN-Filo/Placebo on Day 29. | Biological: MVA-BN-Filo<br>* One 0.5 mL intramuscular (IM) injection of 1E8 Infectious Unit [Inf. U.] on Day 29, 57, or 85.<br>Biological: Ad26.ZEBOV<br>* One 0.5 mL IM injection of 5E10 viral particles (vp) on Day 1.<br>Biological: Placebo<br>* One 0.5 mL IM injection of 0.9% saline on Day 1 and Day 29, 57, or 85.<br>|
| Experimental: Group 2<br>Participants will receive IM injection of Ad26.ZEBOV/Placebo on Day 1 followed by IM injection of MVA-BN-Filo/Placebo on Day 57. | Biological: MVA-BN-Filo<br>* One 0.5 mL intramuscular (IM) injection of 1E8 Infectious Unit [Inf. U.] on Day 29, 57, or 85.<br>Biological: Ad26.ZEBOV<br>* One 0.5 mL IM injection of 5E10 viral particles (vp) on Day 1.<br>Biological: Placebo<br>* One 0.5 mL IM injection of 0.9% saline on Day 1 and Day 29, 57, or 85.<br>|
| Experimental: Group 3<br>Participants will receive IM injection of Ad26.ZEBOV/Placebo on Day 1 followed by IM injection of MVA-BN-Filo/Placebo on Day 85. | Biological: MVA-BN-Filo<br>* One 0.5 mL intramuscular (IM) injection of 1E8 Infectious Unit [Inf. U.] on Day 29, 57, or 85.<br>Biological: Ad26.ZEBOV<br>* One 0.5 mL IM injection of 5E10 viral particles (vp) on Day 1.<br>Biological: Placebo<br>* One 0.5 mL IM injection of 0.9% saline on Day 1 and Day 29, 57, or 85.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Unsolicited Adverse Events (Groups 1, 2 and 3) | An adverse event (AE) is any untoward medical occurrence in a clinical study subject administered a medicinal product, it does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal product. Unsolicited adverse events were events which were reported by the participant voluntarily or obtained by means of interviewing the participant in a nondirected manner at study visits. | Up to 42-day post dose 2 visit (Day 1 to Day 127) | 
| Number of Participants With Serious Adverse Events (Groups 1, 2 and 3) | A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Up to Day 365 | 
| Number of Participants With Immediate Reportable Events (Groups 1, 2 and 3) | The following neuroinflammatory disorders were considered immediate reportable events and which had to be reported to the sponsor within 24 hours of becoming aware of the event. Neuroinflammatory disorders included: cranial nerve disorders including paralyses/paresis (example: bell's palsy), optic neuritis, multiple sclerosis, transverse myelitis, guillain-barre syndrome including miller fisher syndrome, bickerstaff's encephalitis and other variants, acute disseminated encephalomyelitis, including site-specific variants (example: non-infectious encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitis), myasthenia gravis and lambert-eaton myasthenic syndrome, immune-mediated peripheral neuropathies and plexopathies, including chronic inflammatory, demyelinating polyneuropathy, multifocal motor neuropathy, and polyneuropathies associated with monoclonal gammopathy, narcolepsy, isolated paresthesia of more than 7 days duration. | Up to Day 365 | 
| Number of Participants With Solicited Local Adverse Events (Groups 1, 2 and 3) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. Solicited local AEs were pre-defined local (at the injection site) AEs for which participants were specifically questioned and which were noted by participants in their diary for 7 days post first vaccination. Solicited local AEs were: injection site pain/tenderness, erythema, induration/swelling, itching at the vaccination site. | 7 days post-dose 1 (Day 8) | 
| Number of Participants With Solicited Local Adverse Events (Groups 1, 2 and 3) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. Solicited local AEs were pre-defined local (at the injection site) AEs for which participants were specifically questioned and which were noted by participants in their diary for 7 days post first vaccination. Solicited local AEs were: injection site pain/tenderness, erythema, induration/swelling, itching at the vaccination site. | 7 days post-dose 2 (Up to Day 92) | 
| Number of Participants With Solicited Systemic Adverse Events (Groups 1, 2 and 3) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. Participants were instructed on how to note signs and symptoms in the diary on a daily basis for 7 days post-vaccination (Day of vaccination and the subsequent 7 days) for solicited systemic AEs. Solicited systemic events included fever, headache, fatigue/malaise, myalgia, nausea/vomiting, arthralgia and chills. | 7 days post-dose 1 (Day 8) | 
| Number of Participants With Solicited Systemic Adverse Events (Groups 1, 2 and 3) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. Participants were instructed on how to note signs and symptoms in the diary on a daily basis for 7 days post-vaccination (Day of vaccination and the subsequent 7 days) for solicited systemic AEs. Solicited systemic events included fever, headache, fatigue/malaise, myalgia, nausea/vomiting, arthralgia and chills. | 7 days post-dose 2 (Up to Day 92) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Unsolicited Adverse Events (Group 4) | An AE is any untoward medical occurrence in a clinical study subject administered a medicinal product, it does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal product. Unsolicited adverse events were events which were reported by the participant voluntarily or obtained by means of interviewing the participant in a nondirected manner at study visits. | Up to 28-day post dose 1 (Day 29) | 
| Number of Participants With Serious Adverse Events (Group 4) | A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Up to Day 180 | 
| Number of Participants With Immediate Reportable Events (Group 4) | The following neuroinflammatory disorders were considered immediate reportable events which had to be reported to the sponsor within 24 hours of becoming aware of the event. Neuroinflammatory disorders included: cranial nerve disorders including paralyses/paresis (example: bell's palsy), optic neuritis, multiple sclerosis, transverse myelitis, guillain-barre syndrome including miller fisher syndrome, bickerstaff's encephalitis and other variants, acute disseminated encephalomyelitis, including site-specific variants (example: non-infectious encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitis), myasthenia gravis and lambert-eaton myasthenic syndrome, immune-mediated peripheral neuropathies and plexopathies, including chronic inflammatory, demyelinating polyneuropathy, multifocal motor neuropathy, and polyneuropathies associated with monoclonal gammopathy, narcolepsy, isolated paresthesia of more than 7 days duration. | Up to Day 180 | 
| Number of Participants With Solicited Local Adverse Events (Group 4) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. Solicited local AEs were pre-defined local (at the injection site) AEs for which participants were specifically questioned and which were noted by participants in their diary for 7 days post first vaccination. Solicited local AEs were: injection site pain/tenderness, erythema, induration/swelling, itching at the vaccination site. | 7 days after each vaccination (Up to Day 8) | 
| Number of Participants With Solicited Systemic Adverse Events (Group 4) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. Participants were instructed on how to note signs and symptoms in the diary on a daily basis for 7 days post-vaccination (Day of vaccination and the subsequent 7 days) for solicited systemic AEs. Solicited systemic events included fever, headache, fatigue/malaise, myalgia, nausea/vomiting, arthralgia and chills. | 7 days after each vaccination (Up to Day 8) | 
| Geometric Mean Concentrations (GMCs) of Binding Antibody Levels Against Ebola Virus Glycoprotein (EBOV GP) Measured Using Filovirus Animal Non-Clinical Group (FANG) Enzyme-linked Immunosorbent Assay (ELISA) (Groups 1, 2 and 3) | GMCs of antibodies binding to EBOV GP using FANG ELISA were reported and were measured in ELISA unit per milliliter (EU/mL). Serum samples were collected for analysis of binding antibodies against EBOV GP using FANG ELISA to determine humoral responses following vaccination. For ELISA binding antibody responses, values below the lower limit of quantification (LLOQ) (36.11 ELISA units/mL). The outcome measure was planned to be reported at 21-day post dose 2. Therefore, the results are reported for Group 1, 2 and 3 only. | At 21-days post dose 2 (Day 50 for Group 1; Day 78 for Group 2; and Day 106 for Group 3) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ebola Viral Disease (EVD), Healthy, Ebola viruses, Filoviruses, Monovalent vaccine, Human adenovirus serotype 26 (Ad26) encoding the Ebola virus Mayinga variant glycoprotein (Ad26.ZEBOV), Modified Vaccinia Virus Ankara - Bavarian Nordic Filo-vector (MVA-BN Filo), Safety, Immunogenicity, Inserm and University of Oxford