African-Canadian Study of HIV-Infected Adults and a Vaccine for Ebola - ACHIV-Ebola

Study Overview
=================
Brief Summary
-----------------
This is a randomized, placebo-controlled, multi-site, double-blind trial of V920 (rVSVΔG-ZEBOV-GP) Ebola Virus vaccine candidate in subjects with HIV infection to be conducted in conformance with Good Clinical Practices. The study will take place at 2 Canadian sites (Centre Hospitalier de l'Université de Montréal and Ottawa General Hospital) and 2 African sites (Centre MURAZ, Burkina Faso and Centre Hospitalier National Aristide Le Dantec, Dakar, Senegal). The Duration of Study: 365 days for each participant not including screening.

Detailed Description
-----------------
The study will enroll approximately 250 participants,  100 at 2 sites in Canada and  100 at 2 sites in Africa. Overall  200 participants will receive the study vaccine and 50 will receive a placebo . Sequential enrollment of five study cohorts will occur over time at each study site according to CD4 T-cell counts: Group 1 will include adult subjects with CD4 ≥ 500 cells/mm3, Group 2 CD4 > 350 and < 500 cells/mm3, Group 3 CD4 ≥ 200 and ≤ 350 cells/mm3, Group 4 adolescents CD4 ≥ 200 cells/mm3, and Group 5 adults and adolescents CD4 ≥ 200 cells/mm3. Enrolment and vaccine administration will begin with the group with the highest CD4 count. When the D42 post-vaccination period is completed for all subjects in Group 1, and the Data Safety Monitoring Board (DSMB) has reviewed the safety data and determined that there are no concerns, enrolment and vaccination of the next CD4 cohort may begin. Similarly, when the D42 safety data for Group 2 has been reviewed/approved by the DSMB, enrolment and vaccination of participants in Group 3 may begin. Adolescents 13-17 years of age (inclusive) with CD4 ≥ 200 will be enrolled after D42 safety is reviewed in adults with CD4 ≥ 200. Adolescents 13-17 years of age (inclusive) and adults with CD4 ≥ 200 will be enrolled after D42 safety is reviewed in adolescents with CD4 ≥ 200.Within each group, participants will be randomly assigned to receive one dose of ≥2 x 107 pfu of the study vaccine or the placebo in a ratio of 4 to 1 (160:40). Participants will complete memory aids for 42 days following vaccination. Specific procedures to be performed during the trial, as well as their prescribed times and associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each procedure are provided in Section 7.0 - Trial Procedures. This trial will use an adaptive design based on pre-specified criteria, using an independent, external DSMB to monitor safety and immunogenicity. There will be 3 formal safety analyses performed by the DSMB. Data for at least 75% of participants must be available for each analysis. The first safety analysis will be conducted when the first group (CD4 ≥ 500 cells/mm3) will have completed 42 days of follow-up post vaccination. The second safety analysis will be conducted when the second group (CD4 > 350 and < 500 cells/mm3) will have completed 42 days of follow-up post vaccination. The third safety analysis will be conducted when the third group (Adults CD4 ≥ 200 and ≤ 350 cells/mm3) will have completed 42 days of follow-up post vaccination. The fourth safety analysis will be conducted when the fourth group (Adolescents CD4 ≥ 200) will have completed 42 days of follow-up post vaccination. Results of the safety analysis will be reviewed by the DSMB, which will make recommendations to the Sponsor to continue, modify or end the trial according to the plan described briefly in Section 2.2 - Trial Diagram and in detail in Section 8.0 - Statistical Analysis Plan. In case of an outbreak of Ebola Zaire the DSMB may recommend to vaccinate subjects randomized to receive placebo with V920 provided at least 84 days of SAE follow-up is conducted.

Official Title
-----------------
A Phase 2 Randomized, Multi-Center Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Immunogenicity of the V920 (rVSVΔG-ZEBOV-GP) Ebola Virus Vaccine Candidate in HIV-Infected Adults and Adolescents

Conditions
-----------------
Ebola

Intervention / Treatment
-----------------
* Biological: V920 (rVSVΔG-ZEBOV-GP) Ebola Virus Vaccine
* Other: Saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HIV-infected adult or adolescent male or non-pregnant, non-breastfeeding female, ages 13 to 65 (inclusive) at the time of screening; On antiretroviral therapy with an undetectable viral load (< 40 c/ml); CD4 T cell counts ≥ 200 cells/mm3; Written informed consent (subject or parent) and assent (adolescent), after reading the consent form and having adequate opportunity to discuss the study with an investigator or a qualified designee Free of clinically significant health problems that could affect the safety of the participant, as determined by the Investigator by pertinent medical history and clinical examination prior to entry into the study; Available, able, and willing to participate for all study visits and procedures; Males and females who are willing to practice abstinence from sexual intercourse, or are willing to use effective methods of contraception, from at least 30 days prior to vaccination until 2 months after vaccination. If the female partner is NOT of childbearing potential, the couple will only be required to use condoms, without other adjunctive contraception. For this study, a woman is considered of childbearing potential unless postmenopausal (≥ 1 year without menses) or surgically sterilized (tubal ligation, bilateral oophorectomy, or hysterectomy) Effective contraception is defined as a contraceptive method with failure rate of less than 1% per year when used consistently and correctly and when applicable, in accordance with the product label for example: i. Male condoms PLUS: ii. Oral contraceptives, either combined or progestogen alone iii. injectable progestogen iv. implants of etenogestrel or levonorgestrel v. oestrogenic vaginal ring vi. percutaneous contraceptive patches vii. intrauterine device or intrauterine system Be willing to minimize blood and body fluid exposure of others for 6 weeks after vaccination Use of effective barrier prophylaxis, such as latex condoms, during penetrative sexual intercourse Avoiding the sharing of needles, razors, or toothbrushes Avoiding open-mouth kissing Exclusion Criteria: History of prior infection with a filovirus or prior participation in a filovirus vaccine trial; History of prior infection with VSV or receipt of a VSV-vectored vaccine; Is a healthcare worker who has direct contact with patients Presence of any febrile illness or any known or suspected acute illness on the day of any first immunization (subject may be rescheduled); Clinical manifestations of systemic diseases considered by the investigator to impact safety or immunogenicity Receipt of systemic glucocorticoids (a dose ≥ 20 mg/day prednisone or equivalent) within one month, or any other cytotoxic or immunosuppressive drug within six months; Receipt of any investigational drug within 12 months of vaccination; Receipt of any live virus vaccine within 42 days prior to study entry or any other (non-live virus) vaccine within 14 days prior to study entry. History of sensitivity to any component of study vaccines per investigator brochure or package insert; Any baseline laboratory screening tests which is outside of acceptable range as defined in the protocol: ALT, AST, creatinine, hemoglobin, platelet count, total white blood cell count, urine protein, urine occult blood, urine glucose (Appendix 2). To exclude transient abnormalities, the investigator may repeat a test up to twice, and if the repeat test is normal, subject may be enrolled; Have an active malignancy or history of metastatic or hematologic malignancy except non-melanoma skin cancers; Suspected or known alcohol and/or illicit drug abuse within the past 5 years; Moderate or severe illness and/or fever >101°F (38.3ºC) within one week prior to vaccination; Pregnant or breastfeeding female, or female who intends to become pregnant during the study period; Administration of immunoglobulins and/or any blood products within the 120 days preceding study entry or planned administration during the study period; Any other significant finding that in the opinion of the investigator would increase the risk of the individual having an adverse outcome from participating in this study.

Ages Eligible for Study
-----------------
Minimum Age: 13 Years
Maximum Age: 65 Years

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

Accepts Healthy Volunteers
-----------------
No

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1: 50 HIV-infected adults CD4 ≥ 500 cells/mm^3<br>Participants will be randomly assigned to receive one dose of ≥2 x 107 pfu of the V920 (rVSVΔG-ZEBOV-GP) Ebola Virus Vaccine or the placebo | Biological: V920 (rVSVΔG-ZEBOV-GP) Ebola Virus Vaccine<br>* The rVSVΔG-ZEBOV-GP vaccine is a live attenuated recombinant virus consisting of a single recombinant VSV isolate (11481 nt, strain Indiana) with the gene for the Zaire ebolavirus GP (ZEBOV GP), Kikwit strain replacing the gene for the VSV GP, which has been deleted. This results in a VSV backbone with the ZEBOV GP constituting the envelope of the virus.<br>Other: Saline<br>* Normal saline (0.9%) has been chosen as an inert substance to serve as placebo control.<br>|
| Active Comparator: Group 2: 50 HIV-infected adults CD4 > 350 and < 500 cells/mm^3<br>Participants will be randomly assigned to receive one dose of ≥2 x 107 pfu of the V920 (rVSVΔG-ZEBOV-GP) Ebola Virus Vaccine or the placebo | Biological: V920 (rVSVΔG-ZEBOV-GP) Ebola Virus Vaccine<br>* The rVSVΔG-ZEBOV-GP vaccine is a live attenuated recombinant virus consisting of a single recombinant VSV isolate (11481 nt, strain Indiana) with the gene for the Zaire ebolavirus GP (ZEBOV GP), Kikwit strain replacing the gene for the VSV GP, which has been deleted. This results in a VSV backbone with the ZEBOV GP constituting the envelope of the virus.<br>Other: Saline<br>* Normal saline (0.9%) has been chosen as an inert substance to serve as placebo control.<br>|
| Active Comparator: Group 3: 50 HIV-infected adults CD4 ≥ 200 and ≤ 350 cells/mm^3<br>Participants will be randomly assigned to receive one dose of ≥2 x 107 pfu of theV920 (rVSVΔG-ZEBOV-GP) Ebola Virus Vaccine or the placebo | Biological: V920 (rVSVΔG-ZEBOV-GP) Ebola Virus Vaccine<br>* The rVSVΔG-ZEBOV-GP vaccine is a live attenuated recombinant virus consisting of a single recombinant VSV isolate (11481 nt, strain Indiana) with the gene for the Zaire ebolavirus GP (ZEBOV GP), Kikwit strain replacing the gene for the VSV GP, which has been deleted. This results in a VSV backbone with the ZEBOV GP constituting the envelope of the virus.<br>Other: Saline<br>* Normal saline (0.9%) has been chosen as an inert substance to serve as placebo control.<br>|
| Active Comparator: Group 4: HIV infected adolescents CD4 ≥ 200 cells/mm^3<br>Participants will be randomly assigned to receive one dose of ≥2 x 107 pfu of the V920 (rVSVΔG-ZEBOV-GP) Ebola Virus Vaccine or the placebo | Biological: V920 (rVSVΔG-ZEBOV-GP) Ebola Virus Vaccine<br>* The rVSVΔG-ZEBOV-GP vaccine is a live attenuated recombinant virus consisting of a single recombinant VSV isolate (11481 nt, strain Indiana) with the gene for the Zaire ebolavirus GP (ZEBOV GP), Kikwit strain replacing the gene for the VSV GP, which has been deleted. This results in a VSV backbone with the ZEBOV GP constituting the envelope of the virus.<br>Other: Saline<br>* Normal saline (0.9%) has been chosen as an inert substance to serve as placebo control.<br>|
| Active Comparator: Group 5: HIV infected adults and adolescents CD4 ≥ 200 cells/mm^3 with 2 doses<br>Participants will be randomly assigned to receive two dosse of ≥2 x 107 pfu of the V920 (rVSVΔG-ZEBOV-GP) Ebola Virus Vaccine or the placebo | Biological: V920 (rVSVΔG-ZEBOV-GP) Ebola Virus Vaccine<br>* The rVSVΔG-ZEBOV-GP vaccine is a live attenuated recombinant virus consisting of a single recombinant VSV isolate (11481 nt, strain Indiana) with the gene for the Zaire ebolavirus GP (ZEBOV GP), Kikwit strain replacing the gene for the VSV GP, which has been deleted. This results in a VSV backbone with the ZEBOV GP constituting the envelope of the virus.<br>Other: Saline<br>* Normal saline (0.9%) has been chosen as an inert substance to serve as placebo control.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure number of adverse events following V920 vaccination in HIV-infected adults and adolescents | The number of general solicited local (at the injection site) and systemic adverse events during a 14-day follow-up period following vaccination will be summarized. Each participant will record if they had any symptoms and the severity (mild, moderate, or severe). The following local AES will be solicited: i. Pain at injection site ii. Redness at injection site iii. Swelling at injection site The number of AEs of fever, arthritis, arthralgia, rash and blisters/vesicular lesions during a 42-day follow -up period following vaccination will be collected and summarized. Each participant will record if they had any symptoms (yes/no) and the severity (mild, moderate, or severe) This data will be collected on participants memory aids and then entered into an electronic case report form for analysis. | The number of vaccine related SAE's from signing the consent form to day 365 will be recorded and summarized. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure the immunogenicity of V920 via ZEBOV- specific antibody responses induced by V920 at D28 | Measure the immunogenicity of V920 via ZEBOV- specific antibody responses induced by V920 at D28 in HIV-infected adults and adolescents. The V920 vaccine candidate is a live recombinant vesicular stomatitis virus (VSV) expressing the glycoprotein (GP) of Zaire Ebola virus (ZEBOV). Two independent assays are currently being utilized in the clinical development program to clinically evaluate the immunogenicity of V920: GP-ELISA measures the total IgG antibody response and can also be correlated to the plaque reduction neutralization assay (PRNT) titer result. Plaque reduction neutralization assay (PRNT) is a functional assay and a gold standard platform in the field for quantitating the neutralizing antibody response elicited by the vaccine. | ZEBOV-specific antibody responses measured by ELISA and neutralization on Day 28 |