Revisions for SOBERANA 02A | Registro Público Cubano de Ensayos Clínicos

--- 17 December 2020 - 6:15pm by Gladys
+++ 24 March 2023 - 7:15am by Gladys
+-12-17 00:00:00
-In process
+.019.20BA
-Pending
+Complete
-No
+Yes
+The immunological individual data, and other supporting clinical documents, including study protocol, statistical analysis plan, and the informed consent form will be available after publication in specialized journals. Proposals should be sent to: dagarcia@finlay.edu.cu or: vicente.verez@finlay.edu.cu. These proposals must be reviewed and approved by the sponsor and investigator. Finally, data access agreement must be signed.
+The Study protocol, statistical analysis plan, and the informed consent form will be available after publication.
+https://www.finlay.edu.cu/blog/category/sala-cientifica/
 Serious Adverse Events-SAE (It will measure as: -Occurrence of the SAE (Yes, No), - Duration (Time from start date until end date of event), -Description of the event, Result (Recovered, Recovered with squeals, Persists, Death, Unknown), - Causality (Causal association consistent with vaccination, Undetermined, Inconsistent causal association with vaccination, not classifiable). Measurement time: daily for 28 days after each dose.
 Stage IIb:
-Concentration of specific anti-RBD IgG antibodies (Percentage of subjects with seroconversion 4-fold to pre-vaccination). Measurement time: Day 0, 14, 28, 42 and 56.
+Concentration of specific anti-RBD IgG antibodies (Percentage of subjects with seroconversion 4-fold to pre-vaccination). Measurement time: Day 0, 14, 42, 56, 70, 84.
 Stage IIa:
-) Solicited Local and systemic Adverse Events (AE) (They will measure as: -Occurrence of the AE (Yes, No), Duration (Time from start date until end date of event), -Intensity of the AE (mild, moderate, severe), -Severe (Serious, not serious), -Result (Recovered, Recovered with sequelae, Persists, Death, Unknown), -Causation (causal association consistent with vaccination, Indeterminate, causal association inconsistent with vaccination, not classifiable)). Measurement time: daily for 3 days after each dose.
+) Solicited Local and systemic Adverse Events (AE) (They will measure as: -Occurrence of the AE (Yes, No), Duration (Time from start date until end date of event), -Intensity of the AE (mild, moderate, severe), -Severe (Serious, not serious), -Result (Recovered, Recovered with sequelae, Persists, Death, Unknown), -Causation (causal association consistent with vaccination, Indeterminate, causal association inconsistent with vaccination, not classifiable)). Measurement time: daily for 7 days after each dose.
 ) Unsolicited Adverse Events (AE) (They will measure as: Description of the AE (name of the event), Duration (Time from start date until end date of event), -Intensity of the AE (mild, moderate, severe), -Severe (Serious, not serious) , -Result (Recovered, Recovered with sequelae, Persists, Death, Unknown), -Causality (causal association consistent with vaccination, Undetermined, causal association inconsistent with vaccination, not classifiable)). Measurement time: daily for 28 days after each dose .
-) Concentration of specific anti-RBD IgG antibodies (Percentage of subjects with seroconversion 4-fold to pre-vaccination). Measurement time: Day 0, 14, 28, 42 and 56. 4) Neutralizing antibody titer: Measurement time: Day 0 and 56. 5) % ACE2-RBD inhibition: Measurement time: Day 0, 14, 28, 42 and 56.
+) Concentration of specific anti-RBD IgG antibodies (Percentage of subjects with seroconversion 4-fold to pre-vaccination). Measurement time: Day 0, 14,  42, 56, 70, 84. 4) Neutralizing antibody titer: Measurement time: Day 0 (only IgG positive), 56, 70, 84 (Sample subset). 5) % ACE2-RBD inhibition: Measurement time: Day 0 (only IgG positive), 14,  42, 56, 70, 84.
 Stage IIb:
 ) Serious Adverse Events-SAE (It will measure as: -Occurrence of the SAE (Yes, No), - Duration (Time from start date until end date of event), -Description of the event, Result (Recovered, Recovered with squeals, Persists, Death, Unknown), - Causality (Causal association consistent with vaccination, Undetermined, Inconsistent causal association with vaccination, not classifiable). Measurement time: daily for 28 days after each dose.
-) Solicited Local and systemic Adverse Events (AE) (They will measure as: -Occurrence of the AE (Yes, No), Duration (Time from start date until end date of event), -Intensity of the AE (mild, moderate, severe), -Severe (Serious, not serious), -Result (Recovered, Recovered with sequelae, Persists, Death, Unknown), -Causation (causal association consistent with vaccination, Indeterminate, causal association inconsistent with vaccination, not classifiable)). Measurement time: daily for 3 days after each dose.
+) Solicited Local and systemic Adverse Events (AE) (They will measure as: -Occurrence of the AE (Yes, No), Duration (Time from start date until end date of event), -Intensity of the AE (mild, moderate, severe), -Severe (Serious, not serious), -Result (Recovered, Recovered with sequelae, Persists, Death, Unknown), -Causation (causal association consistent with vaccination, Indeterminate, causal association inconsistent with vaccination, not classifiable)). Measurement time: daily for 7 days after each dose.
 ) Unsolicited Adverse Events (AE) (They will measure as: Description of the AE (name of the event), Duration (Time from start date until end date of event), -Intensity of the AE (mild, moderate, severe), -Severe (Serious, not serious) , -Result (Recovered, Recovered with sequelae, Persists, Death, Unknown), -Causality (causal association consistent with vaccination, Undetermined, causal association inconsistent with vaccination, not classifiable)). Measurement time: daily for 28 days after each dose .
-) Neutralizing antibody titer: Measurement time: Day 0 and 56.
+) Neutralizing antibody titer: Measurement time: Day 0 (only IgG positive), 56, 70, 84 (sample subset).
-) % ACE2-RBD inhibition: Measurement time: Day 0, 14, 28, 42 and 56.
+) % ACE2-RBD inhibition: Measurement time: Day 0 (only IgG positive), 14, 42, 56, 70, 84
 Stage IIa:
-Group 1- FINLAY-FR-2 (Experimental): high dose RBD conjugated to TT (batch 1) + adjuvant; 0.5 mL by intramuscular route. Treatment scheme: 0-28 days. Presentation: Vial with single dose.
+Group 1- FINLAY-FR-2 (Experimental): high dose RBD conjugated to TT (batch 1) + adjuvant; 0.5 mL by intramuscular route. Treatment scheme: 0-28 days.   Booster dose 56 days: 25 subjects with FINLAY-FR-2 (Experimental batch 1): high dose of conjugated RBD+adjuvant; 0,5 mL, intramuscular (IM) and 25 subjects with FINLAY-FR-1A 50 ug dRBD/alumina, 0,5 mL,intramuscular (IM) Presentation: Vial with single dose.
-Group 2- FINLAY-FR-2 (Experimental): high dose RBD conjugated to TT (batch 2) + adjuvant; 0.5 mL by intramuscular route. Treatment scheme: 0-28 days. Presentation: Vial with single dose.
+Group 2- FINLAY-FR-2 (Experimental): high dose RBD conjugated to TT (batch 2) + adjuvant; 0.5 mL by intramuscular route. Treatment scheme: 0-28 days. Booster dose 56 days: 25 subjects with FINLAY-FR-2 (Experimental batch 2): high dose of conjugated RBD+adjuvant; 0,5 mL, intramuscular (IM) and 25 subjects with FINLAY-FR-1A 50 ug dRBD/alumina, 0,5 mL,intramuscular (IM)  Presentation: Vial with single dose.
 Stage IIb:
-Group 1- FINLAY-FR-2 (Experimental): high dose RBD conjugated to TT (batch 1) + adjuvant; 0.5 mL,by intramuscular route. Treatment scheme: 0-28 days. Presentation: Vial with single dose.
+Group 1- FINLAY-FR-2 (Experimental): high dose RBD conjugated to TT (batch 1) + adjuvant; 0.5 mL,by intramuscular route. Treatment scheme: 0-28 days. Booster dose 56 days: FINLAY-FR-1A 50 ug dRBD/alumina, 0,5 mL,intramuscular (IM)  Presentation: Vial with single dose.
-Group 2- FINLAY-FR-2 (Experimental): high dose RBD conjugated to TT (batch 2) + adjuvant; 0.5 mL by intramuscular route. Treatment scheme: 0-28 days. Presentation: Vial with single dose.
+Group 2- FINLAY-FR-2 (Experimental): high dose RBD conjugated to TT (batch 2) + adjuvant; 0.5 mL by intramuscular route. Treatment scheme: 0-28 days. Booster dose 56 days: FINLAY-FR-1A 50 ug dRBD/alumina, 0,5 mL,intramuscular (IM) Presentation: Vial with single dose.
 Group 3 Placebo (control): 0.5 mL by intramuscular route. Treatment scheme: 0-28 days. Presentation: Vial with single dose.
 Vaccination
 Injections, Intramuscular
+Placebos
-/12/17
+/01/28
-/12/17
+/01/28
+Period studied:
+Date of first subject recruited: 11/21/2021 (Phase IIa), 01/18/21 (Phase IIb)
+Date of last subject recruited: 01/13/21 (Phase IIa), 01/19/21 (Phase IIb)
+Date of last completed subject (28 days after last dose): 08/04/2021 (Phase IIa), 06/05/2021 (Phase IIb)
+All subjects planned, included and who received at least one dose of the investigational products were analyzed by intention to treat and for safety: 910 subjects. In phase IIa, of 100 patients included, 5 subjects at T42 were independently excluded from the intention-to-treat and per-protocol efficacy analysis according to time intervals; 6 in T56; 7 in T70 and 7 in T84; from phase IIb, 4 were excluded (T14); 8 (T42); 24 (T56), 30 (T70) and 24 (T84). The results of phase IIa are presented in a separate report (Annex). Given that in phase IIb the heterologous scheme was continued; the rest of the analyzes are restricted to the 860 subjects who received the heterologous regimen during phase IIa/IIb (758 with the vaccine candidate and 102 with placebo).
+Male or female subjects, apparently healthy, between 19 and 80 years of age and Cuban nationality who met the following inclusion criteria: They gave their informed consent in writing, women of childbearing age who used safe contraceptive methods during the study, physical examination general, regional and by devices: normal or without clinically significant alterations and laboratory results within the range of reference values or outside them but not clinically significant (for phase IIa).
+Demographic characteristics are summarized in Table 21 of the final report. The groups were homogeneous with respect to all demographic characteristics. Overall, a slightly higher proportion of women, a higher proportion of subjects with fair skin color (72.6%), median age of 48 years, and BMI around 26 kg/m2 were observed.
+EFFICACY RESULTS:
+The proportion of subjects who seroconverted was significantly higher in the group that received the vaccine candidate compared to the group that received placebo, detecting a difference between the groups greater than 69% after the second dose. After the booster dose, seroconversion was achieved in 96% of the subjects. No differences were found when comparing the formulations with different IFAs. With respect to the kinetics of antibodies, a similar result is observed: from 14 days after the first dose is administered, differences are detected globally and in each IFA with respect to the Placebo group. In the group treated with the vaccine candidate, there was a significant increase after the booster dose with respect to T56, which shows the booster effect of this dose. The proportion of subjects who exceed the median observed in the concentration of IgG anti-RBD antibodies in the convalescent panel increases with the number of doses, being even higher than this after the booster dose. The percentage of inhibition of the RBD: ACE2 interaction, a variable that shows a high correlation (r2  mayor que 0.8) with the neutralizing activity, shows significant differences from 14 days after the second dose compared to the Placebo group.
+After the administration of the booster dose with SOBERANA Plus, the median significantly exceeds the convalescent panel (86.4% and 83.0% at 70 and 84 days). Regarding the neutralizing activity of the antibodies, significantly higher values of molecular neutralization are detected in the vaccinated group compared to the Placebo group from 14 days after the second dose and a significant effect of the booster dose, where it exceeds the median observed in the convalescent panel. Similar results were found for viral neutralization, where it was found that after the second dose, (T56) 98.7% of the subjects had Ac. neutralizing (97.5% and 100% in IFA1 and IFA2, respectively). A significant increase in MGT was detected after the booster dose compared to the second dose (overall and in each IFA). The confidence interval for the MGT from the booster dose was very similar to the confidence interval for the panel of Cuban convalescents (overall and in each IFA). When considering the non-responders, the MGT after the booster dose was 1.9 times higher than the panel of Cuban convalescents. After two doses with FINLAY-FR-2, the presence of specific IFNγ-producing T cells was detected, evidencing the induction of a Th1 pattern, which changes to a mixed Th1/Th2 when the booster dose is administered (results of stage IIa). The presence of neutralizing antibodies was demonstrated up to 7-8 months after the booster dose.
+SAFETY RESULTS: Of the total of 860 subjects who received the heterologous scheme, 43.7% presented some adverse event (AE) for a total of 978 of 81 different types. The most frequently requested AE was pain at the injection site in both the vaccinated and placebo groups (35.0% vs. 8.8%, respectively). The most frequent systemic solicited AE in both treatment groups was malaise (4.2% and 2.9%, respectively). The frequency of subjects with each adverse event was similar between formulations with different APIs. The most frequent systemic unsolicited AEs were headache and hypertension (the latter with similar frequency in vaccinated and placebo: 4.4% vs. 3.9%, respectively). Most of the AEs occurred in the first 24 hours, were mild in intensity, solicited, and 73.8% were consistent with vaccination, 68.1% were related to the investigational product. An EAG consistent with vaccination was presented (an erythema multiforme, due to conditions inherent to the vaccinated); Two AEs of severe intensity not consistent with vaccination occurred in one subject (right lung and pancreas neoplasia and right middle lobe pneumonia).
+The Cuban vaccine candidate FINLAY-FR-2 was found to be safe, well tolerated and immunogenic in a two-dose schedule. Administration of a third heterologous dose with FINLAY-FR-1A significantly increases immunogenicity.
+The heterologous scheme that combines two doses of FINLAY-FR-2 or SOBERANA 02 and a booster dose with FINLAY-FR-1A or SOBERANA PLUS was immunogenic even after the two doses corresponding to the primary vaccination, with no differences between IFA. With all the variables studied (antibody titers and concentration, percentage of inhibition and neutralizing, molecular and viral activity), significant differences were detected between the study group and the control group. The booster effect of SOBERANA PLUS is verified in the comparisons with the panel of Cuban convalescents.
+The induction of specific T cells was demonstrated, evidencing the induction of a Th1 pattern, which changes to a Th1/Th2 mixture when the booster dose is administered. The persistence of neutralizing antibodies up to 7-8 months after the booster dose is demonstrated.
+Only one serious adverse event consistent with vaccination was reported, and no AEs of severe intensity consistent with vaccination occurred. The probability of exceeding the predicted level of toxicity was low. Most of the AEs were local and solicited. The most common AE was pain at the injection site, which occurred in approximately one-third of vaccinated individuals and less than one-tenth of placebo recipients.

Revision of 24 March 2023 - 7:15am:

SOBERANA 02A

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 02A

Scientific title:

Phase II study, multicenter and adaptive for evaluating the immunogenicity, safety and reactogenicity of the Anti-SARS Prophylactic Vaccine Candidate - CoV - 2, FINLAY- FR-2 (COVID-19)

Acronym of Scientific Title:

SOBERANA 02A

Secondary indentifying numbers:

IFV/COR/08

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 EnviromentCITMA

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 :

17/12/2020

Reference number:

05.019.20BA

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:

Institute of Tropical Medicine "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, Clinic 1 La Lisa, Leslyhana Verdecia Sanchez, MD. Specialist in Internal Medicine

Havana, "April 19" Polyclinic, Mayra Garcia Carmenate, MD. First degree 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:

21/12/2020

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:

Coronavirus Infections

SARS Virus

Coronaviridae Infections

Betacoronavirus

Disease Prevention

Health condition keyword:

COVID-19

SARS-CoV2

Intervention(s):

Stage IIa: Group 1- FINLAY-FR-2 (Experimental): high dose RBD conjugated to TT (batch 1) + adjuvant; 0.5 mL by intramuscular route. Treatment scheme: 0-28 days. Booster dose 56 days: 25 subjects with FINLAY-FR-2 (Experimental batch 1): high dose of conjugated RBD+adjuvant; 0,5 mL, intramuscular (IM) and 25 subjects with FINLAY-FR-1A 50 ug dRBD/alumina, 0,5 mL,intramuscular (IM) Presentation: Vial with single dose. Group 2- FINLAY-FR-2 (Experimental): high dose RBD conjugated to TT (batch 2) + adjuvant; 0.5 mL by intramuscular route. Treatment scheme: 0-28 days. Booster dose 56 days: 25 subjects with FINLAY-FR-2 (Experimental batch 2): high dose of conjugated RBD+adjuvant; 0,5 mL, intramuscular (IM) and 25 subjects with FINLAY-FR-1A 50 ug dRBD/alumina, 0,5 mL,intramuscular (IM) Presentation: Vial with single dose. Stage IIb: Group 1- FINLAY-FR-2 (Experimental): high dose RBD conjugated to TT (batch 1) + adjuvant; 0.5 mL,by intramuscular route. Treatment scheme: 0-28 days. Booster dose 56 days: FINLAY-FR-1A 50 ug dRBD/alumina, 0,5 mL,intramuscular (IM) Presentation: Vial with single dose. Group 2- FINLAY-FR-2 (Experimental): high dose RBD conjugated to TT (batch 2) + adjuvant; 0.5 mL by intramuscular route. Treatment scheme: 0-28 days. Booster dose 56 days: FINLAY-FR-1A 50 ug dRBD/alumina, 0,5 mL,intramuscular (IM) Presentation: Vial with single dose. Group 3 Placebo (control): 0.5 mL by intramuscular route. Treatment scheme: 0-28 days. Presentation: Vial with single dose.

Intervention code:

Immunogenicity, Vaccine

Immunotherapy, Active

Vaccination

Injections, Intramuscular

Placebos

Intervention keyword:

FINLAY-FR-2

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):

Stage IIa: Serious Adverse Events-SAE (It will measure as: -Occurrence of the SAE (Yes, No), - Duration (Time from start date until end date of event), -Description of the event, Result (Recovered, Recovered with squeals, Persists, Death, Unknown), - Causality (Causal association consistent with vaccination, Undetermined, Inconsistent causal association with vaccination, not classifiable). Measurement time: daily for 28 days after each dose. Stage IIb: Concentration of specific anti-RBD IgG antibodies (Percentage of subjects with seroconversion 4-fold to pre-vaccination). Measurement time: Day 0, 14, 42, 56, 70, 84.

Key secondary outcomes:

Stage IIa: 1) Solicited Local and systemic Adverse Events (AE) (They will measure as: -Occurrence of the AE (Yes, No), Duration (Time from start date until end date of event), -Intensity of the AE (mild, moderate, severe), -Severe (Serious, not serious), -Result (Recovered, Recovered with sequelae, Persists, Death, Unknown), -Causation (causal association consistent with vaccination, Indeterminate, causal association inconsistent with vaccination, not classifiable)). Measurement time: daily for 7 days after each dose. 2) Unsolicited Adverse Events (AE) (They will measure as: Description of the AE (name of the event), Duration (Time from start date until end date of event), -Intensity of the AE (mild, moderate, severe), -Severe (Serious, not serious) , -Result (Recovered, Recovered with sequelae, Persists, Death, Unknown), -Causality (causal association consistent with vaccination, Undetermined, causal association inconsistent with vaccination, not classifiable)). Measurement time: daily for 28 days after each dose . 3) Concentration of specific anti-RBD IgG antibodies (Percentage of subjects with seroconversion 4-fold to pre-vaccination). Measurement time: Day 0, 14, 42, 56, 70, 84. 4) Neutralizing antibody titer: Measurement time: Day 0 (only IgG positive), 56, 70, 84 (Sample subset). 5) % ACE2-RBD inhibition: Measurement time: Day 0 (only IgG positive), 14, 42, 56, 70, 84. Stage IIb: 1) Serious Adverse Events-SAE (It will measure as: -Occurrence of the SAE (Yes, No), - Duration (Time from start date until end date of event), -Description of the event, Result (Recovered, Recovered with squeals, Persists, Death, Unknown), - Causality (Causal association consistent with vaccination, Undetermined, Inconsistent causal association with vaccination, not classifiable). Measurement time: daily for 28 days after each dose. 2) Solicited Local and systemic Adverse Events (AE) (They will measure as: -Occurrence of the AE (Yes, No), Duration (Time from start date until end date of event), -Intensity of the AE (mild, moderate, severe), -Severe (Serious, not serious), -Result (Recovered, Recovered with sequelae, Persists, Death, Unknown), -Causation (causal association consistent with vaccination, Indeterminate, causal association inconsistent with vaccination, not classifiable)). Measurement time: daily for 7 days after each dose. 3) Unsolicited Adverse Events (AE) (They will measure as: Description of the AE (name of the event), Duration (Time from start date until end date of event), -Intensity of the AE (mild, moderate, severe), -Severe (Serious, not serious) , -Result (Recovered, Recovered with sequelae, Persists, Death, Unknown), -Causality (causal association consistent with vaccination, Undetermined, causal association inconsistent with vaccination, not classifiable)). Measurement time: daily for 28 days after each dose . 4) Neutralizing antibody titer: Measurement time: Day 0 (only IgG positive), 56, 70, 84 (sample subset). 5) % ACE2-RBD inhibition: Measurement time: Day 0 (only IgG positive), 14, 42, 56, 70, 84

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 using contraceptive methods during the study. 4. General, regional and apparatus physical examination: normal or without clinically significant alterations. 5. Laboratory results within or outside the range of reference values but not clinically significant (for stage IIa)

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 antimicrobial treatment in the 7 days prior to the administration of the vaccine. 3. Subjects with Poor Weight (BMI <18.5) and Obesity (BMI ≥ 34.9). 4. Subjects with non-communicable chronic diseases not controlled according to clinical or laboratory criteria (eg bronchial asthma, chronic obstructive pulmonary disease, diabetes mellitus, thyroid diseases, ischemic heart disease, arterial hypertension, psychiatric disease at the psychotic, neurological, system level hemolymphopoietic). 5. Subjects with congenital or acquired immune system disease. 6. Subjects with a history of unresolved neoplastic disease. 7. Subjects with a personal history of liver or kidney failure. 8. Subjects with a history of substance abuse during the last 30 days or addictive illness to toxic substances, except if the subject is in abstinence, in the case of alcoholics, and smoking. 9. Subjects with diminished mental faculties for decision making. 10. Subjects with a history of severe allergic disease (anaphylactic shock, angioneurotic edema, glottis edema, severe urticaria). 11. Subjects with a history of hypersensitivity to thiomersal or to some of the components of the formulation. 12. Subjects with a history of SARS and COVID-19 who meet any of the following criteria: a) Previous or current history of SARS-CoV-2 infection. b) Be declared in the category of contact or suspect at the time of inclusion. c) Subject with positive test for Anti-SARS-CoV-2 Antibodies. d) Subject with positive PCR at the time of inclusion. 13. Participation in another clinical trial in the last 3 months. 14. Application of vaccines containing tetanus toxoid in the last 3 months. 15. Application of other vaccines in the last 30 days. 16. Treatment with immunomodulators in the last 30 days, considering steroids (except topical and inhaled), cytostatics, interferon, immunoferon, transfer factor, monoclonal antibody, Biomodulin T, any ganmaglobulin, Levamisole, Heberferon, thymosin) or other drugs with action immunomodulatory. In addition, those people who, due to their underlying disease, require immunomodulatory treatment during the development of the study. 17. Transfusion of blood or blood products in the last 3 months. 18. Subjects with difficulties in attending the planned follow-up consultations. 19. Splenectomy or splenic dysfunction. 20. Pregnancy, puerperium or lactation. 21. Subjects with tattoos in the deltoid region on both arms. 22. Subjects with positive results for HIV, Hepatitis B Surface Antigen, Hepatitis C Antibody and VDRL Serology. (For stage IIa). 23. Women with a positive pregnancy test.

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:

910

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:

Beatriz

Last Name:

Paredes Moreno

Specialty:

Pharmaceutical Sciences

Affiliation:

Finlay Vaccine Institute

Postal Address:

21 avenue bw/ 198 and 200 Atabey, Playa

City:

Havana

Country:

Cuba

Zip Code:

11600

Telephone:

+53-7271833

Email :

bparedes@finlay.edu.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:

First degree specialist in Integral General Medicine. Master in Epidemiology

Affiliation:

Finlay Vaccine Institute

Postal Address:

21 avenue bw/ 198 and 200 Atabey, Playa

City:

Havana

Country:

Cuba

Zip Code:

11600

Telephone:

+53-72718331

Email :

mcrodriguez@finlay.edu.cu

Research Ethics Committees

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

Name of Research Ethics Committees:

Ad hoc centralized Research Ethic Committee for development of COVID-19 vaccines

Status of evaluation:

Approved

Status of evaluation date of Ethic Committee:

15/12/2020

Postal address of Ethic Committee :

Calle D e/ 29 y Zapata. Vedado. Havana, Cuba

Telephone:

+53-78330171

Email:

orlelibre@infomed.sld.cu

About study completion

Section to complete the data related to the study completion.

Study completion date:

12/03/2021

Date of available results:

22/04/2021

Date of first publication:

30/04/2021

Results Study

Section to complete the data related to the summarized results.

Participant flow:

Period studied: Date of first subject recruited: 11/21/2021 (Phase IIa), 01/18/21 (Phase IIb) Date of last subject recruited: 01/13/21 (Phase IIa), 01/19/21 (Phase IIb) Date of last completed subject (28 days after last dose): 08/04/2021 (Phase IIa), 06/05/2021 (Phase IIb) All subjects planned, included and who received at least one dose of the investigational products were analyzed by intention to treat and for safety: 910 subjects. In phase IIa, of 100 patients included, 5 subjects at T42 were independently excluded from the intention-to-treat and per-protocol efficacy analysis according to time intervals; 6 in T56; 7 in T70 and 7 in T84; from phase IIb, 4 were excluded (T14); 8 (T42); 24 (T56), 30 (T70) and 24 (T84). The results of phase IIa are presented in a separate report (Annex). Given that in phase IIb the heterologous scheme was continued; the rest of the analyzes are restricted to the 860 subjects who received the heterologous regimen during phase IIa/IIb (758 with the vaccine candidate and 102 with placebo).

Baseline characteristics:

Male or female subjects, apparently healthy, between 19 and 80 years of age and Cuban nationality who met the following inclusion criteria: They gave their informed consent in writing, women of childbearing age who used safe contraceptive methods during the study, physical examination general, regional and by devices: normal or without clinically significant alterations and laboratory results within the range of reference values or outside them but not clinically significant (for phase IIa). Demographic characteristics are summarized in Table 21 of the final report. The groups were homogeneous with respect to all demographic characteristics. Overall, a slightly higher proportion of women, a higher proportion of subjects with fair skin color (72.6%), median age of 48 years, and BMI around 26 kg/m2 were observed.

Outcome measures:

EFFICACY RESULTS: The proportion of subjects who seroconverted was significantly higher in the group that received the vaccine candidate compared to the group that received placebo, detecting a difference between the groups greater than 69% after the second dose. After the booster dose, seroconversion was achieved in 96% of the subjects. No differences were found when comparing the formulations with different IFAs. With respect to the kinetics of antibodies, a similar result is observed: from 14 days after the first dose is administered, differences are detected globally and in each IFA with respect to the Placebo group. In the group treated with the vaccine candidate, there was a significant increase after the booster dose with respect to T56, which shows the booster effect of this dose. The proportion of subjects who exceed the median observed in the concentration of IgG anti-RBD antibodies in the convalescent panel increases with the number of doses, being even higher than this after the booster dose. The percentage of inhibition of the RBD: ACE2 interaction, a variable that shows a high correlation (r2 mayor que 0.8) with the neutralizing activity, shows significant differences from 14 days after the second dose compared to the Placebo group. After the administration of the booster dose with SOBERANA Plus, the median significantly exceeds the convalescent panel (86.4% and 83.0% at 70 and 84 days). Regarding the neutralizing activity of the antibodies, significantly higher values of molecular neutralization are detected in the vaccinated group compared to the Placebo group from 14 days after the second dose and a significant effect of the booster dose, where it exceeds the median observed in the convalescent panel. Similar results were found for viral neutralization, where it was found that after the second dose, (T56) 98.7% of the subjects had Ac. neutralizing (97.5% and 100% in IFA1 and IFA2, respectively). A significant increase in MGT was detected after the booster dose compared to the second dose (overall and in each IFA). The confidence interval for the MGT from the booster dose was very similar to the confidence interval for the panel of Cuban convalescents (overall and in each IFA). When considering the non-responders, the MGT after the booster dose was 1.9 times higher than the panel of Cuban convalescents. After two doses with FINLAY-FR-2, the presence of specific IFNγ-producing T cells was detected, evidencing the induction of a Th1 pattern, which changes to a mixed Th1/Th2 when the booster dose is administered (results of stage IIa). The presence of neutralizing antibodies was demonstrated up to 7-8 months after the booster dose.

Adverse events:

SAFETY RESULTS: Of the total of 860 subjects who received the heterologous scheme, 43.7% presented some adverse event (AE) for a total of 978 of 81 different types. The most frequently requested AE was pain at the injection site in both the vaccinated and placebo groups (35.0% vs. 8.8%, respectively). The most frequent systemic solicited AE in both treatment groups was malaise (4.2% and 2.9%, respectively). The frequency of subjects with each adverse event was similar between formulations with different APIs. The most frequent systemic unsolicited AEs were headache and hypertension (the latter with similar frequency in vaccinated and placebo: 4.4% vs. 3.9%, respectively). Most of the AEs occurred in the first 24 hours, were mild in intensity, solicited, and 73.8% were consistent with vaccination, 68.1% were related to the investigational product. An EAG consistent with vaccination was presented (an erythema multiforme, due to conditions inherent to the vaccinated); Two AEs of severe intensity not consistent with vaccination occurred in one subject (right lung and pancreas neoplasia and right middle lobe pneumonia).

Summary study:

The Cuban vaccine candidate FINLAY-FR-2 was found to be safe, well tolerated and immunogenic in a two-dose schedule. Administration of a third heterologous dose with FINLAY-FR-1A significantly increases immunogenicity. The heterologous scheme that combines two doses of FINLAY-FR-2 or SOBERANA 02 and a booster dose with FINLAY-FR-1A or SOBERANA PLUS was immunogenic even after the two doses corresponding to the primary vaccination, with no differences between IFA. With all the variables studied (antibody titers and concentration, percentage of inhibition and neutralizing, molecular and viral activity), significant differences were detected between the study group and the control group. The booster effect of SOBERANA PLUS is verified in the comparisons with the panel of Cuban convalescents. The induction of specific T cells was demonstrated, evidencing the induction of a Th1 pattern, which changes to a Th1/Th2 mixture when the booster dose is administered. The persistence of neutralizing antibodies up to 7-8 months after the booster dose is demonstrated. Only one serious adverse event consistent with vaccination was reported, and no AEs of severe intensity consistent with vaccination occurred. The probability of exceeding the predicted level of toxicity was low. Most of the AEs were local and solicited. The most common AE was pain at the injection site, which occurred in approximately one-third of vaccinated individuals and less than one-tenth of placebo recipients.

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:

RPCEC00000347

Date of Registration in Primary Registry:

17/12/2020

Record Verification Date:

2022/01/28

Next update date:

2023/01/28

Link to the spanish version:

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Registered Trials

Registration process

SOBERANA 02A

About the RPCEC

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