Trial no.:	PACTR202005681895696	Date of Approval:	11/05/2020
Trial Status:	Registered in accordance with WHO and ICMJE standards

TRIAL DESCRIPTION

Public title

A study to determine if a new vaccine safely generates good immune responses to protect adults in Kenya from Coronavirus Disease

Official scientific title

A phase Ib/II single-blinded, randomised, controlled study to determine safety, immunogenicity and efficacy of the candidate Coronavirus Disease (COVID-19) vaccine ChAdOx1 nCoV-19 in adults in Kenya (COV004)

Brief summary describing the background and objectives of the trial

As of 11th February 2020, the coronavirus disease (COVID-19) pandemic has affected over 106 million people globally, with over 2 million deaths. The disease has been reported in over 200 countries, including Kenya where over 102,000 cases have been reported. Some of the vaccines approved for emergency use in different regions for use against COVID-19 include Pfizer/BioNTech, Moderna, Sinovac, and ChAdOx1 nCoV-19 among others. As the number of cases continue to rise globally, use of effective vaccines remains the best way to control the pandemic and to safely relax physical distancing and other restrictions. There are over 170 COVID-19 vaccine candidates in development, with 63 of these currently undergoing evaluation in human clinical trials(as of 9th February 2021). Of the 63 vaccines, ChAdOx1 nCoV-19, a candidate vaccine developed by our longstanding collaborators at the University of Oxford in partnership with AstraZeneca, is among the most advanced and has received Emergency Use Authorisation from various national and international regulators, including the World Health Organization (WHO). ChAdOx1 nCoV-19 has shown promise in a range of animal models of COVID-19 disease and has already been administered to over 10,000 adult volunteers in the United Kingdom, Brazil and South Africa (Registration numbers: NCT04324606, NCT04400838, ISRCTN89951424 and NCT04444674). The vaccine has been found to be safe and to provide protection against COVID-19 in these studies. In this single-blinded randomized controlled phase Ib/II study we plan to evaluate the safety and immunogenicity of ChAdOx1 nCoV-19 (5x1010 vp) as compared to rabies vaccine among 400 adults aged ≥18 years. The study will take place in the coastal counties of Kilifi and Mombasa, where high numbers of COVID-19 cases have been detected. The study will enrol frontline staff such as; healthcare workers, allied health professionals, truckers, security personnel, banking personnel, supermarket staff, police, security personnel, prison workers, laboratory technicians, scientists, logistics personnel, public transport workers including aviation industry amongst others. These populations have been prioritised due to their high risk of occupational exposure to COVID-19, hence their urgent need for protection. However, due to the risk of infection from ongoing community SARS-CoV-2 transmission in Kenya, other members of public will also be eligible for the study. Participants will be randomized to receive two doses of either ChAdOx1 nCoV-19 (n=200) or rabies vaccine (n=200). Out of these, 40 will be enrolled in the phase Ib trial, and the remainder to the phase II trial (180 per vaccine). The time interval between the two doses will be 3 months for both phase Ib and phase II. After each vaccination, participants will be required to complete diary cards (paper or electronic) and record any solicited and unsolicited adverse events experienced for 6 days following vaccination while at home. Each participant will have 10 clinic visits in the course of the study and some of the activities that will be carried out will include; physical assessment, checking vital signs, phlebotomy and safety assessment. If found to be safe and effective in generating protective immune responses, the ChAdOx1 nCoV-19 will be further developed for use in controlling COVID-19, including in populations in Kenya and other countries in Africa.

Type of trial

RCT

Acronym (If the trial has an acronym then please provide)

COV004

Disease(s) or condition(s) being studied

Infections and Infestations

Sub-Disease(s) or condition(s) being studied

COVID-19 Disease

Purpose of the trial

Prevention: Vaccines

Anticipated trial start date

01/10/2020

Actual trial start date

Anticipated date of last follow up

01/10/2022

Actual Last follow-up date

31/05/2022

Anticipated target sample size (number of participants)

400

Actual target sample size (number of participants)

Recruitment status

Recruiting

Publication URL

Secondary Ids	Issuing authority/Trial register

STUDY DESIGN
Intervention assignment	Allocation to intervention	If randomised, describe how the allocation sequence was generated	Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms	Masking	If masking / blinding was used
Parallel: different groups receive different interventions at same time during study	Randomised	Simple randomization using a randomization table created by a computer software program	Sealed opaque envelopes	Masking/blinding used	Care giver/Provider,Outcome Assessors,Participants

INTERVENTIONS
Intervention type	Intervention name	Dose	Duration	Intervention description	Group size	Nature of control
Experimental Group	COVID19 vaccine	Two doses of ChAdOx1 nCoV-19 vaccine 5x10^10 vp that will be administered at a 8- to 12-week interval in both phase Ib and II. A longer interval between doses results in better immune responses and higher efficacy and this has informed WHO’s recommendation that two standard doses of ChAdOx1 nCoV-19 be administered at an 8- to 12-week interval.	Phase Ib-1 year follow-up Phase II-1 year follow-up Phase Ib and II will be conducted within the same trial, phase II beginning after DSMB review of phase I day 28 data.	ChAdOx1 nCoV-19 vaccine consists of the replication-deficient simian adenovirus vector ChAdOx1, containing the structural surface glycoprotein (Spike protein) antigen of the SARS CoV-2 (nCoV-19), with a leading tissue plasminogen activator (tPA) signal sequence. ChAdOx1 nCoV-19 expresses a codon-optimised coding sequence for the Spike protein from genome sequence accession GenBank: MN908947. The tPA leader sequence has been shown to be beneficial in enhancing immunogenicity of another ChAdOx1 vectored CoV vaccine (ChAdOx1 MERS) [5]. Following vaccination, the Spike glycoprotein (S) primes the host immune system to attack the coronavirus in case of any infections. The ChAdOx1 vaccine vector was selected due to its non-replicating nature, making it impossible to cause an infection in vaccinated individuals. As a result, the vaccine would be safe in individuals with pre-existing conditions and age groups at risk of getting the SARS-CoV-2 infection.	200
Control Group	Rabies vaccine	0.5 mL of Verorab (rabies vaccine) via the intramuscular route. Two doses that are at an 8-12 week interval.	Phase Ib-1 year follow-up Phase II-1 year follow-up Phase Ib and II will be conducted within the same trial, phase II beginning after DSMB review of phase I day 28 data.	Verorab (from Sanofi) will be used as the rabies vaccine and it is registered and licensed for use in Kenya. One dose consists in the administration of 0.5 mL of vaccine via the intramuscular route.	200	Active-Treatment of Control Group

ELIGIBILITY CRITERIA
List inclusion criteria	List exclusion criteria	Age Category	Minimum age	Maximum age	Gender
• Frontline Staff as defined by the Government of Kenya (including healthcare workers, allied health professionals, truckers, security personnel, banking personnel, supermarket staff, police, security personnel, prison workers, laboratory technicians, scientists, logistics personnel, public transport workers including aviation industry amongst others) and other members of public. • Healthy adults aged 18-55 years for phase Ib, ≥18 years for phase II. • Able and willing (in the Investigators’ opinion) to comply with all study requirements, including making visits to KEMRI CGMRC or other designated study health facility for follow up under conditions with limited transport. • Agreement to refrain from blood donation during the course of the study • Use of effective method of contraception for duration of study for female participants. They should use effective contraception for 30 days prior to vaccination. For female participants, we will ask them to attend with their family planning records for verification. Effective contraception is defined as a contraceptive method with failure rate of less than 1% per year when used consistently and correctly, in accordance with the product label. Examples of these include: combined oral contraceptives; injectable progestogen; implants of etenogestrel or levonorgestrel; intrauterine device or intrauterine system; male partner sterilisation at least 6 months prior to the female subject’s entry into the study, and the relationship is monogamous; male condom combined with a vaginal spermicide (foam, gel, film, cream or suppository); and male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository). • Provide written informed consent. • Plan to remain resident in the study area for 1 year following vaccination	• Prior receipt of any vaccines (licensed or investigational) ≤30 days before enrolment • Volunteer who is not literate. • Planned receipt of any vaccine other than the study intervention within 30 days before or after study vaccination. • Prior receipt of an investigational or licensed vaccine likely to impact on interpretation of the trial data (e.g. Adenovirus vectored vaccines, any coronavirus vaccines). • Planned or ongoing participation in any other interventional studies (of licensed or investigational products) ≤30 days before enrolment and for the duration of the study. • Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate. • Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent severe infections and chronic use (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed). • History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. • Any history of hereditary or idiopathic angioedema. • Pregnancy, lactation or willingness/intention to become pregnant during the study. • History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ). • History of serious psychiatric condition likely to affect participation in the study. • Bleeding disorder (e.g. factor deficiency, coagulopathy or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venepuncture. • Any other serious chronic illness requiring hospital specialist supervision. • Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 42 units every week (e.g. more than 2 bottles of 500mls Tusker (beer) a day, more than 2 large glasses of 12% wine per day)	Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Middle Aged: 45 Year(s)-64 Year(s)	18 Year(s)	55 Year(s)	Both

ETHICS APPROVAL

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

24/08/2020

KEMRI Scientific and Ethics Review Unit

Ethics Committee Address
Street address	City	Postal code	Country
Kenya Medical Research Institute, Off Mbagathi Way Nairobi. Postal address P.O. BOX 54840	Nairobi	00200	Kenya

OUTCOMES
Type of outcome	Outcome	Timepoint(s) at which outcome measured
Primary Outcome	A. To assess the safety, tolerability and reactogenicity profile of the candidate vaccine ChAdOx1nCoV-19 1. Occurrence of serious adverse events (SAEs) throughout the study duration 2. Occurrence of solicited local and systemic reactogenicity signs and symptoms for 7 days following vaccination 3. Occurrence of unsolicited adverse events (AEs) at all scheduled visits; 4. Change from baseline for safety laboratory measures and; 5. Occurrence of SAE of special interest: disease enhancement episodes B. To assess immunogenicity of ChAdOx1 nCoV-19 1. ELISA to quantify IgG antibodies against SARSCoV-2 spike protein (seroconversion rates)	A1- Throughout the study, A2- Days 0 to 7 post first and second vaccination, A3 and A5-Throughout the study, A4-day 7 and 28 post primary and booster dose, B1-day 0 and 28 post primary and booster dos
Secondary Outcome	A. To assess humoral immunogenicity of ChAdOx1 nCoV-19 at early and late timepoints 1. ELISA to quantify IgG antibodies against SARS-CoV-2 spike protein (seroconversion rates) B. To assess cellular immunogenicity of ChAdOx1 nCoV-19 1. IFN-γ ELISpot responses to SARS-CoV-2 spike protein; C. To assess efficacy of ChAdOx1 nCoV-19 against COVID-19 1. Virologically confirmed (PCR positive) symptomatic cases of COVID-19 2. Hospital admissions associated with COVID-19 3. Deaths associated with COVID-19 4. Seroconversion against non-Spike antigens measured by ELISA 5. Asymptomatic SARS-CoV2 carriage	day 0,14, 28, 84, 91, 112, 182, 365

RECRUITMENT CENTRES
Name of recruitment centre	Street address	City	Postal code	Country
KEMRI Wellcome Trust Research Programme Centre for Geographic Medicine Coast KWTRP CGMRC	Hospital Grounds, Off Bofa Road, PO Box 230	Kilifi Kenya	80108	Kenya

FUNDING SOURCES
Name of source	Street address	City	Postal code	Country
Wellcome Trust	Gibbs Building 215 Euston Road London NW1 2BE UK	London		United Kingdom
Medical Sciences Division University of Oxford	Level 3, John Radcliffe Hospital, Oxford OX3 9DU, UK	UK		United Kingdom
Innovate UK and Dept of Health and Social Care	Polaris House, North Star Avenue, Swindon, Wiltshire SN2 1FL, UK	Wiltshire		United Kingdom

SPONSORS
Sponsor level	Name	Street address	City	Postal code	Country	Nature of sponsor
Primary Sponsor	University of Oxford	University of Oxford, University Offices, Wellington Square, Oxford, OX1 2JD, UK	Oxford		United Kingdom	University

COLLABORATORS
Name	Street address	City	Postal code	Country
Chief Administrative Secretary Rashid Aman	Ministry of Health	Nairobi		Kenya

CONTACT PEOPLE
Role	Name	Email	Phone	Street address
Principal Investigator	George Warimwe	GWarimwe@kemri-wellcome.org	+254709983000	KEMRI-Wellcome Trust Research Programme CGMRC, PO Box 230-
City	Postal code	Country	Position/Affiliation
Kilifi	80108	Kenya	Principal Investigator
Role	Name	Email	Phone	Street address
Scientific Enquiries	Philip Bejon	pbejon@kemri-wellcome.org	+254709983000	KEMRI-Wellcome Trust Research Programme CGMRC, PO Box 230
City	Postal code	Country	Position/Affiliation
Kilifi	80108	Kenya	Executive Director
Role	Name	Email	Phone	Street address
Public Enquiries	Marianne Munene	MMunene@kemri-wellcome.org	+254709983436	KEMRI-Wellcome Trust Research Programme CGMRC, PO Box 230
City	Postal code	Country	Position/Affiliation
Kilifi	80108	Kenya	Research Governance Manager

REPORTING
Share IPD	Description	Additional Document Types	Sharing Time Frame	Key Access Criteria
Yes	Individual-level anonymized data will be shared with the Sponsor. For wider stakeholder engagement and the medical community, summary-level statistical analyses will be shared. Information collected or generated during this study may be anonymised for use to support new research on coronavirus vaccines and immunology. Any future research using information from this study must first be approved by a local or national expert committee to make sure that the interests of participants and their communities are protected. Data will be managed by KEMRI CGMRC.	Analytic Code,Informed Consent Form,Statistical Analysis Plan,Study Protocol	At the end of the study (2 years)	On completion of the trial and submission of the manuscript. De-identified trial data that underlies the results reported in the publication will be uploaded onto the KWTRP data repository on Harvard Dataverse as per the curation policy. This data will be uploaded under managed access. Requests for access to data will be submitted via email through a form available on the repository and reviewed by the KWTRP Data Governance Committee (DGC) who will also determine whether further approvals are required before data is shared.
URL	Results Available	Results Summary	Result Posting Date	First Journal Publication Date
https://wellcome.ac.uk/grant-funding/guidance/data-software-materials-management-and-sharing-policy	No
Result Upload 1:	Result Upload 2:	Result Upload 3:	Result Upload 4:	Result Upload 5:

Result URL Hyperlinks	Link To Protocol
Result URL Hyperlinks

Changes to trial information

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