Safety, Tolerability and Immunogenicity Study of 2-dose Heterologous Regimens for Ebola Vaccines Ad26.ZEBOV/MVA-BN-Filo

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, tolerability and immunogenicity of different vaccination schedules of Ad26.ZEBOV and MVA-BN-Filo administered intramuscularly (IM) as 2-dose heterologous regimens in healthy and in HIV-infected adults.

Detailed Description
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This is a randomized, observer-blind, placebo-controlled, parallel-group, multicenter, 2-part, Phase 2 study of Ad26.ZEBOV and MVA-BN-Filo in healthy and HIV infected adults. In part 1, dose 1 vaccination with MVA-Bn-Filo will be followed by dose 2 vaccination with Ad26 14 days later in the US. In part 2, two regimens will be investigated. The first regimen will be Ad26 dose 1 vaccination followed by MVA-BN-Filo dose 2, 28 days later and the second regimen will be MVA-BN-Filo dose 1 vaccination followed by Ad26.ZEBOV dose 2, 14 days later in Africa. The study consists of a Screening phase of up to 8 weeks (starting from the moment the participants signs the ICF), a Vaccination Phase, in which participants will be vaccinated at baseline (Day 1) followed by a dose 2 vaccination on Day 15 or 29, and a post-dose 2 follow-up phase of maximum 1 year post-dose 2 vaccination. Upon completion of 6-month post dose 2 visit those participants who received active vaccine will enter long-term follow-up until the 1 year post dose 2 vaccination visit to assess long-term safety and immunogenicity.

Official Title
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A Randomized, Observer-blind, Placebo-controlled, Two-part, Phase 2 Study to Evaluate the Safety, Tolerability and Immunogenicity of Two Prime-boost Regimens of the Candidate Prophylactic Vaccines for Ebola Ad26.ZEBOV and MVA-BN-Filo

Conditions
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Hemorrhagic Fever, Ebola

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be healthy in the Investigator's clinical judgment on the basis of medical history, physical examination and vital signs performed at Screening Participant must be healthy on the basis of clinical laboratory tests and electrocardiogram (ECG) (only in participants >50 years) performed at Screening. If the results of the laboratory screening tests and ECG are outside the institutional 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 A woman of childbearing potential must have a negative urine β-human chorionic gonadotropin [beta-hCG] pregnancy test at Screening and a negative urine [beta-hCG] pregnancy test immediately prior to each study vaccine administration A man who is sexually active with a woman of childbearing potential must be willing to use condoms for sexual intercourse beginning prior to dose 1 vaccination until at least 3 months after the dose 2 vaccination, unless a vasectomy was performed more than 1 year prior to Screening Participant must pass the test of understanding (TOU) Additional Inclusion Criteria for HIV-infected participants a) participants must have a positive HIV-1 and/or -2 serology test within 6 months of screening, including the day of screening; b) participants must have a Screening CD4+ cell count >200 cells/microliter (mcL); c) in part 1, all participants must be on a stable highly active antiretroviral therapy (HAART) regimen for 4 weeks prior to Screening, in part 2 participants with screening CD4+ cell count <350 cells/mcL must also be on a stable HAART regimen for 4 weeks prior to Screening Exclusion Criteria: Has received any candidate Ebola vaccine Diagnosed with Ebola virus disease, or prior exposure to EBOV, including travel to epidemic Ebola areas less than 1 month prior to Screening Has received any experimental candidate Ad26- or MVA-based vaccine in the past or received any other investigational drug or investigational vaccine or used an invasive investigational medical device within 3 months prior to Screening Known allergy or history of anaphylaxis or other serious adverse reactions to vaccines or vaccine products Presence of significant conditions (eg, history of seizure disorders, (auto)immune disease or deficiency, any spleen disease, active malignancy, ongoing tuberculosis treatment, other systemic infections) or clinically significant findings during screening of medical history, ECG (only in participants >50 years), physical examination, vital signs or laboratory testing for which, in the opinion of the investigator, participation would not be in the best interest of the participants (eg, compromise the safety or well-being) or that could prevent, limit, or confound the protocol-specified assessments

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 (US Participants)<br>Participants will receive MVA-BN-Filo or placebo on Day 1 followed by Ad26.ZEBOV or placebo on Day 15. | Biological: Ad26.ZEBOV<br>* One 0.5 mL intramuscular (IM) injection of (5x10*10 viral particles).<br>Biological: MVA-BN-Filo<br>* One 0.5 mL IM injection of (1x10*8 infectious units).<br>Biological: Placebo<br>* One 0.5 mL IM injection of 0.9 percent (%) saline.<br>|
| Experimental: Part 2 Group 1 (African Participants)<br>Participants will receive Ad26.ZEBOV or placebo on Day 1 followed by MVA-BN-Filo or placebo on Day 29. | Biological: Ad26.ZEBOV<br>* One 0.5 mL intramuscular (IM) injection of (5x10*10 viral particles).<br>Biological: MVA-BN-Filo<br>* One 0.5 mL IM injection of (1x10*8 infectious units).<br>Biological: Placebo<br>* One 0.5 mL IM injection of 0.9 percent (%) saline.<br>|
| Experimental: Part 2 Group 2 (African Participants)<br>Participants will receive MVA-BN-Filo or placebo on Day 1 followed by Ad26.ZEBOV or placebo on Day 15. | Biological: Ad26.ZEBOV<br>* One 0.5 mL intramuscular (IM) injection of (5x10*10 viral particles).<br>Biological: MVA-BN-Filo<br>* One 0.5 mL IM injection of (1x10*8 infectious units).<br>Biological: Placebo<br>* One 0.5 mL IM injection of 0.9 percent (%) saline.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1, Part 2 (Group 2): Number of Participants With Unsolicited Adverse Events | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. 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. As per planned analysis, the data from Parts 1 and 2 (Group 2) of the study was pooled (that is, 14-day interval regimen) and presented separately for the healthy and HIV-infected cohorts. | Up to 28 days post each dose (up to Day 43) | 
| Part 2 (Group 1): Number of Participants With Unsolicited Adverse Events | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. 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 days post dose 2 visit (up to Day 57) | 
| Part 1, Part 2 (Group 2): Number of Participants With Serious Adverse Events (SAEs) | A SAE is an adverse event 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. As per planned analysis, the data from Parts 1 and 2 (Group 2) of the study was pooled (that is, 14-day interval regimen) and presented separately for the healthy and HIV-infected cohorts. | Up to 1 year post dose 2 (up to Day 380) | 
| Part 2 (Group 1): Number of Participants With SAEs | A SAE is an adverse event 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 1 year post dose 2 (up to Day 394) | 
| Part 1, Part 2 (Group 2): Number of Participants With Immediate Reportable Events (IREs) | 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: 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 1 year post dose 2 (up to Day 380) | 
| Part 2 (Group 1): Number of Participants With IREs | 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: 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 1 year post dose 2 (up to Day 394) | 
| Parts 1 and 2: Number of Participants With Solicited Local Adverse Events (AEs) 7 Days Post First Vaccination | 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. As per planned analysis, the data from Parts 1 and 2 (Group 2) of the study was pooled (that is, 14-day interval regimen) and presented separately for the healthy and HIV-infected cohorts. | 7 days post dose 1 (up to Day 8) | 
| Part 1, Part 2 (Group 2): Number of Participants With Solicited Local AEs 7 Days Post Second Vaccination | 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 second vaccination. Solicited local AEs were: injection site pain/tenderness, erythema, induration/swelling, itching at the vaccination site. As per planned analysis, the data from Parts 1 and 2 (Group 2) of the study was pooled (that is, 14-day interval regimen) and presented separately for the healthy and HIV-infected cohorts. | 7 days post dose 2 (up to Day 22) | 
| Part 2 (Group 1): Number of Participants With Solicited Local AEs 7 Days Post Second Vaccination | 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 second 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 36) | 
| Parts 1 and 2: Number of Participants With Solicited Systemic Adverse Events 7 Days Post First Vaccination | 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. As per planned analysis, the data from Parts 1 and 2 (Group 2) of the study was pooled (that is, 14-day interval regimen) and presented separately for the healthy and HIV-infected cohorts. | 7 days post dose 1 (up to Day 8) | 
| Part 1, Part 2 (Group 2): Number of Participants With Solicited Systemic AEs 7 Days Post Second Vaccination | 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. As per planned analysis, the data from Parts 1 and 2 (Group 2) of the study was pooled (that is, 14-day interval regimen) and presented separately for the healthy and HIV-infected cohorts. | 7 days post dose 2 (up to Day 22) | 
| Part 2 (Group 1): Number of Participants With Solicited Systemic AEs 7 Days Post Second Vaccination | 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 36) | 
| Part 1, Part 2 (Group 2): 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) | 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. A sample was considered positive, if the value was above the lower limit of quantification (LLOQ), that is, 36.11 ELISA units/mL. As per planned analysis, the data from Parts 1 and 2 (Group 2) of the study was pooled (that is, 14-day interval regimen) and presented separately for the healthy and HIV-infected cohorts. | 21-days post dose 2 (up to Day 36) | 
| Part 2 (Group 1): GMCs of Binding Antibody Levels Against EBOV GP Measured Using FANG ELISA | 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. A sample was considered positive, if the value was above the LLOQ, that is, 36.11 ELISA units/mL. | 21-days post dose 2 (Day 50) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. As per planned analysis, the data from Parts 1 and 2 (Group 2) of the study was pooled (that is, 14-day interval regimen) and presented separately for the healthy and HIV-infected cohorts. This outcome measure was planned to compare the safety (unsolicited AEs, solicited local and solicited systemic AEs) of Ad26.ZEBOV/MVA-BN-Filo and MVA-BN-Filo/Ad26.ZEBOV regimens in healthy and HIV-infected participants. Therefore, placebo arm is not reported. | Solicited AEs: Up to 7 days post each vaccination (Up to Day 36); Unsolicited AEs: Up to 28 days post each vaccination (Up to Day 57) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy, Vaccine, Ebola viruses, Ebola virus disease (EVD), Filoviruses, Hemorrhagic fever, Monovalent vaccine, Human adenovirus serotype 26 (Ad26) encoding the Ebola virus Mayinga variant glycoprotein (Ad26.ZEBOV), Modified Vaccinia Virus Ankara - Bavarian Nordic (MVA-BN) Filo-vector, Safety, Immunogenicity