Comparison of the safety and efficacy of Razi SARS-CoV-2 recombinant Spike protein (Razi Cov Pars) and Sinopharm vaccines in adults aged 18 and over, a phase III randomised, double blind, non-inferiority clinical trial

Comparison of safety and efficacy of recombinant spike protein COVID-19 vaccine developed by RAZI institute (Razi Cov Pars) and Sinopharm vaccine

Phase III, two parallel and equal groups, randomized, double blind, non-inferiority design; will be conducted on 41128 volunteers.

1. Razi Vaccine and Serum Research Institute, Hesarak, Karaj 2. Kharazi Highway, Iran Mall Shopping Center, Business Negotiation Center, Tehran 3. Shahrara, Rasoul, Tehran 4. Mobile unit

Inclusion criteria: 18 years old and over; Access to Internet and smart phone; No current COVID -19; Non pregnant (women); Signed informed consent. Exclusion criteria: Any ongoing or new diagnose of symptomatic, acute or chronic illness requiring continuous ongoing medical or surgical care; Breastfeeding; received any type of COVID-19 vaccine; History of sever allergic diseases or history of anaphylaxis to any drug, vaccine or food; History of uncontrolled serious psychiatric disorder; Current substance or alcohol abuse; Splenectomy for any reason; Close contact with a confirmed COVID-19 within the last two weeks

The two study groups consists of a vaccine group receiving Razi Cov Pars vaccine, and a group receiving Sinopharm vaccine. They will receive two vaccine injections on day 0 and 21 followed by intranasal spray on day 51.

Occurrence of COVID-19 disease confirmed by PCR test 2 weeks after the 2nd vaccine dose; Occurrence of moderate and severe Covid-19 disease or death due to it 2 weeks after the 2nd vaccine dose; Immediate abnormal vital signs & anaphylactic reactions following vaccination; Local & Systemic adverse events within the first week post vaccination; SAEs, SUSARs, MAAEs, up to 6 months after the second vaccine dose; and Specific secretory IgA level in blood and saliva samples.

Add 3 new centers; Add two non-random arms; Change some inclusion and exclusion criteria

This study uses both randomized and non-randomized arms. Block randomization method with variable block sizes of 4 and 6 in STATA will be used to create the random sequence in randomized arms. For the purpose of concealment, a unique code will be assigned to each intervention the participants receive, and all subjects will be identified with this code until the end of the study (concealment code).

In this study, the control group will receive the Sinopharm vaccine, which has different color, volume and packaging from Razi Cov Pars. Therefore, blinding will be performed by a person who will be responsible for preparing and inoculating the vaccine. This is the only person who will not be blind to the intervention given. Once the participant becomes eligible to receive the vaccine, a concealment/randomization code will be assigned to the volunteer and the vaccine type will be displayed on the screen of the vaccinator until the inoculation is confirmed. To protect the blinding in the participant, the syringe's cylinder will be covered to conceal the content of the syringe. Non-randomized arms that were added to the study later on, are not blind.

Deidentified IPD related to outcome will be shared.

The access period will begin once the study is complete and the main results have been published in peer reviewed journals.

The data that have been published in peer reviewed journals, will be available just for academic researchers.

The proposed study protocol should be submitted to RAZI vaccine and serum research institute and approved by its scientific and technical advisory committee.

Researchers will submit their request to Dr. Mohammad Hossein Fallah at the following email address (mhf2480@yahoo.com )

Data will be made available after consideration and approval by the relevant authorities from Razi Vaccine and Serum Research Institute.

Background: We conducted a phase III, non-inferiority trial comparing safety and efficacy of RCP recombinant spike protein Covid-19 vaccine to BBIBP (Sinopharm). Methods: Adult Iranian population received RCP or BBIBP in a randomized, double blind and an additional non-randomized open labeled trial arms. Eligible participants signed a written informed consent and received two intramuscular injections three weeks apart. In the randomized arm, an intranasal dose of vaccine or adjuvant-only preparation were given to the RCP and BBIBP recipients at day 51 respectively. Participants were actively followed for up to 4 months for safety and efficacy outcomes. Primary outcome was PCR + symptomatic Covid-19 disease two weeks after the second dose. The non-inferiority margin was 10% of reported BBIBP vaccine efficacy (HR = 1.36). Results: We recruited 23,110 participants (7224 in the randomized and 15,886 in the nonrandomized arm). We observed 604 primary outcome events during 4 months of active followup including 121 and 133 in the randomized and 157 and 193 cases in the non-randomized arms among recipients of RCP and BBIBP respectively. Adjusted hazard ratios for the primary outcome in those receiving RCP compared with BBIBP interval were 0.91 (0.71–1.16) and 0.62 (0.49–0.77) in the randomized and non-randomized arms respectively. The upper boundary of 99.1% confidence interval of HR = 0.91 (0.67–1.22) remained below the margin of noninferiority in the randomized arm after observing the early stopping rules using O’Brien Fleming method. Conclusion: Our study showed that the RCP efficacy is non-inferior and its safety profile is comparable to the BBIBP.