SOBERANA 02-FaseIII

General information

Section to complete general information about the trial: scientific and public title, protocol identifiers, sponsors and Source(s) of Monetary or Material Support.

Acronym of Public Title:

SOBERANA 02-FaseIII

Scientific title:

Phase III clinical trial, multicenter, adaptive, parallel-group, randomized, placebo-controlled, double-blind study to evaluate the efficacy, safety and immunogenicity of vaccination against SARS-CoV-2 with 2 doses of FINLAY-FR-2 and a heterologous scheme with 2 doses of FINLAY-FR-2 and a booster dose with FINLAY-FR-1A (COVID-19)

Acronym of Scientific Title:

SOBERANA 02-Fase III

Secondary indentifying numbers:

IFV/COR/09

Issuing authority of the secondary identifying numbers:

Finlay Vaccine Institute (IFV)

Source(s) of monetary or material support:

Finlay Vaccine Institute; Cuban Fund for Science and Innovation (FONCI) from Ministry of Science, Technology and Enviroment

Authorization for beginning

Section to complete information about the regulatory approval of clinical trial: regulatory agency name, approval date and reference number in the agency.

Regulatory instance to authorize the initiation of the study:

Center for State Control of Drugs, Medical Devices and Equipment (CECMED)

Authorization date :

03/03/2021

Reference number:

In process

Principal investigator

Section to complete information about Email address, telephone number and postal address of the Principal Investigator.

First name:

Maria

Midle name:

Eugenia

Last name:

Toledo Romani

Medical Specialty :

First degree specialist in Integral General Medicine. Doctor of Medical Science

Affiliation:

Instituto de Medicina Tropical “Pedro Kouri”

Postal address:

Novia del Mediodia avenue, KM 6 1/2, La Lisa

City:

Havana

Country:

Cuba

Zip Code:

11400

Telephone:

+53-72020427

Email address:

mariaeugenia@ipk.sld.cu

Clinical sites to participate

Section to complete the data related to the clinical sites involved in the trial: site and responsible investigator for every site.

Countries of recruitment:

Cuba

Clinical sites:

Havana, Plaza municipality, Policlinic Plaza, Lisi Munniz, MD. Specialist in Integral General Medicine.

Havana, Plaza municipality, Policlinic Moncada, Ingrid Rodriguez Crespo, MD. Specialist in Integral General Medicine.

Havana, Plaza municipality, Policlinic Vedado, Centro Atencion al Diabético, Liz Caballero, MD. Specialist in Integral General Medicine.

Havana, Plaza municipality, Policlinic 19 de Abril, Susel Perez, MD. Specialist in Integral General Medicine.

Havana, Playa municipality, Policlinic 5 de septiembre, Amaury Miranda, MD. Specialist in Integral General Medicine.

Havana, Playa municipality, Policlinic Manuel Fajardo, Yanislaydy Cabriales, MD. Specialist in Integral General Medicine.

Havana, Playa municipality, Policlinic 26 de Julio, Aylin Molina, MD. Specialist in Integral General Medicine.

Havana, Centro Habana municipality, Policlinic Marcio Manduley, Rudrany Rodriguez, MD. Specialist in Integral General Medicine.

Havana, Centro Habana municipality, Policlinic Docente Reina, Marlene Sosa, MD. Specialist in Integral General Medicine.

Havana, Centro Habana municipality, Escuela de Musica Amadeu Roldan, Maura Suarez, MD. Specialist in Integral General Medicine.

Havana, Centro Habana municipality, Casona China, Marlene Sosa, MD. Specialist in Integral General Medicine.

Havana, La Lisa municipality, Policlinic Elpidio Berovides, Carlos Perez, MD. Specialist in Integral General Medicine.

Havana, La Lisa municipality, Policlinic Cristobal Labra, Luis Vivas, MD. Specialist in Integral General Medicine.

Havana, La Lisa municipality, Policlinic Antonio Pulido, Lena Martinez, MD. Specialist in Integral General Medicine.

Havana, Habana Vieja municipality, Policlinic Aballi, Jose Miguel Perez, MD. Specialist in Integral General Medicine.

Havana, Habana Vieja municipality, Policlinic Romay, Yuneisy Cantero, MD. Specialist in Integral General Medicine.

Havana, Habana Vieja municipality, Policlinic Zulueta, Yalilka Obama, MD. Specialist in Integral General Medicine.

Recruitment status

Section to complete information about the recruitment status and the date of first enrolment subject

Recruitment status:

Complete

Date of first enrollment:

08/03/2021

Health condition and Intervention

Section to complete information about the primary medical condition(s) or problem(s) studied and, a characteristics of the intervention(s).

Health condition(s) or Problem(s) studied:

COVID-19

Health condition(s) code:

Disease Prevention

Coronavirus Infections

SARS Virus

Coronaviridae Infections

Betacoronavirus

Health condition keyword:

COVID-19

SARS-CoV2

Intervention(s):

Experimental Group 1: FINLAY-FR-2 25 µg RBD-TT, Intramuscular (IM), 0.5 mL, 0 – 28 days. Presentation: Vial with single dose. Experimental Group 2: FINLAY-FR-2 25 µg RBD-TT, IM, 0.5 mL, 0 – 28 days + FINLAY-FR-1A (50 µg d-RBD+ alumina, IM, 0.5 mL) as booster dose 56 days. Presentation: Vial with single dose. Placebo Group: IM, 0.5 mL, 0 – 28 days. Presentation: Vial with single dose.

Intervention code:

Immunogenicity, Vaccine

Immunotherapy, Active

Vaccination

Injections, Intramuscular

Outcomes and Timepoint

Section to complete information about primary and secondary outcomes including. It includes the metric or method of measurement used and, the time point for every outcome.

Primary outcome(s):

Virologically confirmed symptomatic infection of Covid-19. Measurement time: from 14 days after the last dose of the candidate until 3 months after this evaluation.

Key secondary outcomes:

1. Confirmed Covid-19 infection with signs of severe systemic disease. Measurement time: from 14 days after the last dose of the candidate until 3 months after this evaluation. 2. Confirmed SARS-Cov-2 infection from routine surveillance or determinations of the presence of antigens. Measurement time: from 14 days after the last dose of the candidate until 3 months after this evaluation. 3. Death from causes directly attributable to a complication of COVID-19 Measurement time: from 14 days after the last dose of the candidate until 3 months after this evaluation. 4. Virologically confirmed disease of Covid-19. Measurement time: starting 14 days after the candidate's first dose and up to 28 days. 5. Duration of the disease, measured from: Time to negativization and Duration of symptoms 6. Immunogenicity (IgG antibody concentration, Neutralizing antibody titre, determined by neutralization assay and ACE2-RBD interaction inhibition assay (% inhibition at 1/100 dilution; ID50). Measurement time: from 14 days after the candidate's first dose and until the end of the study (approximately 160 days) 7. Reactogenicity (Incidence of Local and systemic Adverse Events (AE) (They will measure as: -Occurrence of the AE (Yes, No), Duration (Time from onset date until end date of event), Time of onset (Time from the previous dose to the onset of AE), -Intensity of the AE (mild, moderate, severe), -Severe (Serious, not serious), -Result (Recovered, Recovered with sequelae, Persists, Death, Unknown), - Causal relationship (causal association consistent with vaccination, Indeterminate, causal association inconsistent with vaccination, not classifiable)). Measurement time: 3 days after each dose 8. Safety Incidence of Adverse Events (AE) (They will measure as: Description of the AE (name of the event), Duration (Time from onset date until end date of event), Time of onset (Time from the previous dose to the onset of AE), -Intensity of the AE (mild, moderate, severe), -Severe (Serious, not serious), -Result (Recovered, Recovered with sequelae, Persists, Death, Unknown), -Causality relationship (causal association consistent with vaccination, Undetermined, causal association inconsistent with vaccination, not classifiable)). Measurement time: 28 days after each dose

Selection criterias

Section to complete information about the inclusion and exclusion criteria for participant selection, including age and gender.

Gender:

Male/Female

Minimum age:

19 years

Maximum age:

80 years

Inclusion criteria:

1. Subjects who give their informed consent to participate in the study in writing. 2. Subjects aged between 19 and 80 years. 3. Women of childbearing age who use contraceptive methods during the study and are willing to use them up to 3 months after the corresponding vaccination schedule has concluded.

Exclusion criteria:

1. Subjects with acute febrile or infectious disease in the 7 days prior to the administration of the vaccine or at the time of its application. 2. Subjects with diminished mental faculties for decision making. 3. Subjects with a history of hypersensitivity to thiomersal or to some of the components of the formulation. 4. Previous or current history of SARS-CoV-2 infection (questioning) 5. Application of vaccines containing tetanus toxoid in the last 3 months. 6. Subjects previously vaccinated against SARS-CoV-2. 7. Treatment with immunomodulators in the last 30 days, considering steroids (except topical and inhaled), cytostatics, interferon, immunoferon, transfer factor, Biomodulin T, any gamma globulin, Levamisole, Heberferon, thymosin) or other drugs with immunomodulatory action. In addition, those people who, due to their underlying disease, require immunomodulatory treatment during the development of the study. 8. Pregnancy, puerperium or lactation. 9. Subjects with tattoos in the deltoid region on both arms. 10. Decompensated chronic diseases that limit vaccination according to clinical criteria. 11. HIV subjects with detectable viral load, history of opportunistic infection or CD4 less than 200 copies. 12. Subjects with unstabilized malignant disease or who are receiving cytostatic treatment and / or radiotherapy during the time of the study or have been receiving it in the last three months.

Type of population:

Adults

Type of participant:

Healthy volunteers

Study design

Section to complete information about the characteristics of the study design.

Type study:

Interventional

Purpose:

Prevention

Allocation:

Randomized controlled trial

Masking:

Double Blind

Control group:

Placebo

Study design:

Parallel

Phase:

Target sample size:

44010

Contact for public queries

Section to complete information about Email address, telephone number and postal address of the contact who will respond to general queries, including information about current recruitment status

First Name:

Mayra

Last Name:

Garcia Carmenate

Specialty:

Master of Science. 1st Degree Specialist in Comprehensive General Medicine. Assistant teacher. Head of the Department of Trasmisible Diseases

Affiliation:

Provincial Center of Hygiene and Epidemiology of Havana

Postal Address:

Av. 31 y 100. Marianao.

City:

Havana

Country:

Cuba

Zip Code:

11600

Telephone:

+53-772600713

Email :

mayragc@infomed.sld.cu

Contact for scientific queries

Section to complete information about Email address, telephone number and postal address of the contact who will respond to scientific queries.

First Name:

Meiby

Middle Name:

de la Caridad

Last Name:

Rodriguez Gonzalez

Specialty:

1st degree Specialist Physician in General Medicine. Master in Epidemiology

Affiliation:

Finlay Vaccine Institute

Postal Address:

St 21 and 200, Atabey, Playa

City:

Havana

Country:

Cuba

Zip Code:

11600

Telephone:

+53-772718331

Email :

mcrodriguez@finlay.edu.cu

Research Ethics Committees

Section to complete the data related to the review ethics committees.

Name of Research Ethics Committees:

Research Ethics Committee Centralized Extended

Status of evaluation:

Approved

Status of evaluation date of Ethic Committee:

02/03/2021

Postal address of Ethic Committee :

Manuel Fajardo Faculty of Medical Sciences. 29 and C, Vedado, Plaza de la Revolucion. Havana. Cuba

Telephone:

+53-53602191

Email:

About study completion

Section to complete the data related to the study completion.

Final enrolment number:

44031

Study completion date:

07/11/2021

Date of available results:

15/01/2022

Date of first publication:

30/01/2022

Results Study

Section to complete the data related to the summarized results.

Participant flow:

Between 3/4/21 and 03/31/2021, 45 184 subjects were evaluated, including 44 031 (97.4%); in Placebo Group: 14,675, Experimental Group 1 (two doses): 14,679, Experimental Group: 2 (three doses heterologous schedule): 14,677. Subjects not included 1,153 , in general, the main causes of non-inclusion were: No inclusion criteria: 41, Non-voluntary: 191, Exclusion criteria: 766, Other causes: 15 The 44031 subjects included in the ITT population received the first dose of the planned scheme in the protocol, which represents 100%. Of these, 43,268 received the first two doses of the schedule provided for in the protocol, which represents 98.3% of the total included, and from the 3-dose schedule, a total of 13,979 subjects (95.2%) received the 3 planned doses. Placebo group: 14,675, included in efficacy analysis: 13,070 2-dose group: 14,679, included in efficacy analysis: 12,610 3-dose group: 14,677, included in efficacy analysis: 13,843

Baseline characteristics:

The demographic and baseline characteristics of the entire included sample are summarized. The median age in the 3 groups was 50 years; with a slight predominance of the female sex (52%), 59% were white-skinned and 41% had some comorbidity, being arterial hypertension with 31%, Diabetes Mellitus with 8.3% and Bronchial Asthma with a 6.6% the most frequent. In relation to the distribution of subjects by strata, those older than or equal to 65 years old represent 18%, in accordance with what was planned in the protocol and representative of that age in the selected municipalities, those under 65 years old without comorbidity 54%, and those under 65 years of age with comorbidity 54%. For COVID-19, 22 subjects were PCR positive at baseline for 0.1% of all subjects, with a percentage distribution of less than 0.1% in each of the treatment groups. 133 subjects had a positive antigen test that represented 0.3%, with similar behavior between groups.

Outcome measures:

Primary efficacy variable: Vaccine efficacy against symptomatic disease was 69.7% in treatment group 2 (two doses of FINLAY-FR-2 (0-28 d)), and 92.0% in group 3 (FINLAY-FR-2 (0 -28 d) + FINLAY-FR-1A (56 d)). The lower limits of the 95% CI are greater than 55% in both treatments, rejecting the null hypothesis H0: EV* ≤ 30% with a type 1 error probability p<0.001. Secondary efficacy variable: - Efficacy against severe disease and death 28 subjects with severe disease were observed from 14 days after the end of each regimen, which represents 0.07% of the PP population. The percentages of subjects with severe systemic disease were higher in subjects in the placebo group (82%) compared to the 2-dose group (18% and 0% for the 2- and 3-dose schedules, respectively), in this category. no subjects with 3 doses. The efficacy in the prevention of severe systemic disease is 74.9% for the 2-dose schedule and 100% for the 3-dose schedule (6 cases in the placebo group during the comparison period with the 3-dose schedule), with very wide confidence intervals, given the small number of cases. Eight intensive care unit hospitalizations occurred (ICU: 6, 2, 0 in the 2-dose and 3-dose placebo groups). -Efficacy in preventing severe disease leading to ICU hospitalization was 63.6% (95% CI: 103.5, 96.4) for the 2-dose schedule and 100% for the 3-dose schedule. The frequency of deaths due to complications of COVID-19 in the subjects who fell ill 14 days after completion of each regimen was 5 subjects, of whom 3 were in the placebo group and 2 in the two-week treatment group. dose. During the observation period for the efficacy of 3 doses, there were no deceased subjects in either the placebo group or the 3-dose schedule. Of the 5 deceased, 2 were older than 65 years and 3 were younger than 65 years with associated comorbidities, all 3 referred hypertension, and 1 of them diabetes mellitus and obesity. Given the small number of cases in the 3 groups, it is not considered reasonable to estimate the efficacy for this variable. Efficacy against infection: The frequency of subjects reported with SARS-Cov-2 infection is shown in Table 21. 423 PCR-positive subjects were observed, representing 0.99% of the PP population. The percentages of infected subjects were higher in subjects in the placebo group (50%) compared to the group vaccinated with 2 and 3 doses (37 and 13%), respectively. This is also reflected in each stratum separately. Efficacy in preventing infection in the PP population in the stratified Cox regression model, a reduction in the risk of infection greater than 65% compared to the Placebo group is obtained for treatment with 3 doses

Adverse events:

For the analysis of the adverse events, 44 031 subjects were included, of whom 5 225 reported at least one adverse event (11.9%), more frequently in the groups treated with the vaccine, with a total of 8 465 adverse events, of which they were mild. 90.4% and only 2.4% were classified as severe (4.0%, 2.1%, and 1.9% in the placebo, 2-dose, and 3-dose groups, respectively). - 90.8% of the events were consistent with vaccination (more than 70% classified as A1) and 66.3% of the requested type, although only 49.6% in the placebo group. - 98.2% were completely recovered - The number of events decreased with the number of doses up to 0.3% with the third. - Local events predominate, accounting for 52% of all events, with pain being the most frequent with 3,192 reports (37.7% of all reported events). Solicited local adverse events occurred more frequently in the vaccine group than in the placebo group after the first dose (7.7% vs. 2.6%) and the second dose (1.9% vs. 0. 44%). After the third dose, the frequency of subjects with local AEs was reduced to 0.3%. In the vaccinated groups (treatment 2 and treatment 3), local adverse events were predominantly grade 1 (97.5% were of mild intensity) and lasted a median of 2 days after the first, second, and third doses. The most common local AE was pain at the injection site (2.6% vs. 8.2% in placebo and vaccine, respectively). There were 5 serious adverse events consistent with vaccination (<0.1% in each group), 3 in the placebo group (abdominal pain, hypertension, and anaphylactic shock: abdominal pain was disabling, hypertension required hospitalization, and life-threatening anaphylactic shock). life); 1 event of precordial pain after the 1st dose of FINLAY-FR-2 that required hospitalization and one event of cutaneous paresthesia after the 1st dose of FINLAY-FR-2, which also required hospitalization. All of these events were resolved; only anaphylactic shock was classified with type A1 causality. There were 54 grade 3 (severe) systemic events consistent with vaccination in 51 subjects (17, 15, and 19 subjects in the placebo, 2-dose, and 3-dose groups, respectively) and 11 local events in 48 subjects and 11 in placebo groups. local type in 8 subjects (1, 3, and 4 subjects in the placebo, 2-dose, and 3-dose groups, respectively). .

Summary study:

SAFETY RESULTS: The vaccine candidate was generally found to be safe and well tolerated. There was a predominance of local events, with pain being the most frequent, the events generally lasting between 1 to 3 days and the frequency of their appearance decreased in the second and third injections. EFFICACY RESULTS: The per-protocol population efficacy analysis of the FINLAY-FR-2 vaccine candidate based on a randomized, blinded, placebo-controlled trial that included 42,511 subjects from the total study population (44,031), shows a overall efficacy for the prevention of symptomatic disease of 69.7% (95% CI 56.5-78.9) for the two-dose scheme; 92.0% (95% CI 80.4–96.7%) for the three-dose heterologous schedule, considering the analysis performed with respect to the Placebo group from 14 days after completion of the 2-dose vaccination schedule (for the efficacy analysis of 2 dose) and from 42 days after completion of the 2-dose vaccination schedule (for the placebo group in the 3-dose efficacy analysis) to ensure concurrent comparison. Efficacy estimation was also performed according to the analysis originally planned in the protocol, in which the placebo observation period started from 14 days after the 2nd dose (for the efficacy of both schemes) so it was not exactly concurrent with the observation period of the 3-dose schedule. The estimate based on this planned analysis shows that the efficacy of the 2-dose schedule is 70.7% (95% CI: 58.8; 79.1) and 92.4% (95% CI: 86.9-95.6) for the 3-dose schedule. Additionally, and before the appearance of intercurrent events, efficacy was estimated using a synthetic placebo group (based on the incidence of the municipalities where the CT was performed) and this estimate was consistent with the demonstrated clinical efficacy. Efficacy in preventing severe disease is 74.9% (95% CI 33.7-90.5) for the two-dose schedule of the FINLAY-FR-2 candidate, and 63.6% for avoiding hospitalization in intensive care units. In both cases, the efficacy is 100% after completion of the 3-dose heterologous regimen. CONCLUSIONS: This report shows that the FINLAY-FR-2 vaccine candidate was safe and well tolerated, the most frequent adverse event was local pain. The FINLAY-FR-2 vaccine candidate in a two-dose schedule achieved a clinical efficacy of 69.7% in the prevention of symptomatic disease, which increases to 92.0% when the third heterologous dose with FINLAY-FR1A is administered. In both schemes, the efficacy in the prevention of symptomatic disease is higher than what was proposed in the study hypothesis (60%) and the 50% established as the minimum criterion according to the World Health Organization (7) to validate its emergency use in the current COVID-19 pandemic.

Registration and Update

Section to complete information about the name of Primary Registry, date of registration and the unique ID number assigned by the registry (RPCEC).

Primary registry:

RPCEC

Unique ID number:

RPCEC00000354

Date of Registration in Primary Registry:

03/03/2021

Record Verification Date:

2022/06/23

Next update date:

2023/06/23

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SOBERANA 02-FaseIII

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