Phase II/III Study of the AVX/COVID-12 Vaccine Against COVID-19 Applied as a Booster.

Sponsor

Laboratorio Avi-Mex, S.A. de C.V. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05710783

Collaborator

National Council of Science and Technology, Mexico (Other), Instituto Nacional de Enfermedades Respiratorias (Other)

3,000

Enrollment

Locations

Arms

10.7

Anticipated Duration (Months)

214.3

Patients Per Site

20.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a phase II/III parallel, double-blind, active-controlled, non-inferiority study to evaluate immunogenicity and safety of a booster immunization scheme of a single intramuscular dose of the recombinant vaccine against SARS-CoV-2 (AVX/COVID-12 vaccine) based on live recombinant Newcastle disease virus (rNDV) vector in healthy adults with a history of vaccination against COVID-19. The study is divided into two phases with immuno-bridging and 3000 healthy subjects showing evidence of prior immunity to SARS-CoV-2 are estimated to enrol. To verify non-inferiority in a determined number of subjects an intramuscular dose of the COVID-19 vaccine (ChAdOx-1-S[recombinant]) shall be used as active control in originally randomised subjects. The study shall be carried out in several sites of clinical research in Mexico.

Condition or Disease	Intervention/Treatment	Phase
SARS-CoV-2 Infection	Biological: AVX-COVID/12 Biological: ChAdOx-1-S[recombinant]	Phase 2/Phase 3

Detailed Description

General objective:

To demonstrate immunogenicity and safety of the AVX/COVID-12 vaccine (108.0 EID50/dose) as a single intramuscular booster shot in previously vaccinated subjects and prove non-inferiority producing neutralizing antibodies anti-COVID-19 from 14 days after administration in comparison to the active control, whose efficacy has been formerly established in a placebo-controlled clinical study.

Primary objective:

Phase II:

To demonstrate immunogenicity of the AVX/COVID-12 vaccine (108.0 EID50/dose) as a single intramuscular booster shot to increase levels of Spike protein to ACE2 binding-inhibitory antibodies, as well as to increase titres of neutralizing antibodies anti-COVID-19 from 14 days after vaccine administration.

Phase III:

To demonstrate non-inferiority of the AVX/COVID-12 vaccine (108.0 EID50/dose) as a single intramuscular booster shot for seroconversion and production of neutralizing antibodies anti-COVID-19 from 14 days after vaccine administration compared to active control, whose efficacy has been formerly established in a placebo-controlled clinical study.

Secondary objectives:

Phase II:

To evaluate the extent of the increase in the neutralizing titres after 0, 14, 90 and 180 days of administration of the AVX/COVID-12 vaccine (108.0 EID50/dose) as a single intramuscular booster shot.

To evaluate production of interferon-gamma by peripheral blood T lymphocytes in response to the Spike protein or its derivatives peptides stimulation following 0, 14, 90 and 180 days of administration of the AVX/COVID-12 vaccine (108.0 EID50/dose) as a single intramuscular booster shot in a subgroup of subjects randomly selected among the study population.

To compare production of interferon-gamma by peripheral blood T lymphocytes in response to the Spike protein or its derivatives peptides stimulation following 0, 14, 90 and 180 days of administration of the AVX/COVID-12 vaccine (108.0 EID50/dose) as a single intramuscular booster shot in a subgroup of subjects randomly selected among the study population to production in subjects vaccinated with active control.

Phase III:

To document the incidence of symptomatic COVID-19 disease cases in both groups (experimental vaccine and active control) from 14 days after administration.

To document the incidence of severe or mortality COVID-19 disease cases in both groups (experimental vaccine and active control) from 14 days after administration.

Safety objective (primary):

Both Phases:

To evaluate safety of AVX/COVID-12 vaccine immunization as a single intramuscular booster shot in comparison to the active control.

Exploratory objectives:

Phase II:

To evaluate the extent of the increase in following neutralizing titres 0, 14, 90 and 180 days of administration of the AVX/COVID-12 vaccine (108.0 EID50/dose) as a single intramuscular booster shot as per the history of immunization/infection at the time of enrolment.

To evaluate the neutralizing capacity of anti-SARS-CoV-2 antibodies gained following 0, 14, 90 and 180 days of administration of the AVX/COVID-12 vaccine (108.0 EID50/dose) as a single intramuscular booster shot in neutralization tests of pseudovirus expressing Spike proteins derived from SARS-CoV-2 variants of concern.

To evaluate production of cytokines by peripheral blood T lymphocytes in response to the Spike protein or its derivatives (peptides) stimulation following 0, 14, 90 and 180 days of administration of the AVX/COVID-12 vaccine (108.0 EID50/dose) as a single intramuscular booster shot in a subgroup of subjects randomly selected among the population study.

To compare production of cytokines by peripheral blood T lymphocytes in response to the Spike protein or its derivatives (peptides) stimulation following 0, 14, 90 and 180 days of administration of the AVX/COVID-12 vaccine (108.0 EID50/dose) as a single intramuscular booster shot in a subgroup of subjects randomly selected among the population study to production in subjects vaccinated with active control.

Phase III:

To compare geometric means of neutralizing titres after AVX/COVID-12 (108.0 EID50/dose) vaccination as a single intramuscular booster shot in the following active-controlled subgroups:

Subjects younger than 65 years.
Subjects older than 65 years.
Subjects with at least one comorbidity (any).
Subjects with obesity (BMI >30).
Subjects with Diabetes Mellitus.
Subjects with hypertension.
Subjects with smoking history.
Subjects with asthma.
Subjects with cardiovascular disease.
Subjects with chronic obstructive pulmonary disease.
Subjects with chronic renal disease.
Subjects with liver disease.
Subjects with cancer history.

Clinical trial hypothesis:

Phase II:

In subjects with prior anti-SARS-CoV-2 vaccination longer than 4 months ago, 14 days after intramuscular administration of the AVX/COVID-12 vaccine, ≥80% of the subjects showed an inhibitory capacity of the receptor-binding domain (spike protein binds to ACE2) above 95% and levels of neutralizing titres statistically greater than baseline tires (vaccination day).

Phase III:

Immunogenicity assessed as seroconversion rate and production of neutralizing antibodies after administration of the AVX/COVID-12 vaccine as a single intramuscular booster shot of 108.0 EID50/dose showed non-inferiority to active control from 14 days after administration.

Justification of the product use in clinical research.

Nonclinical studies and Phase I clinical study have shown safety of the AVX/COVID-12 vaccine by intramuscular route. Signs of immunogenicity in several animals are clear. Evaluation of the immune response in healthy volunteers in the Phase I clinical study after administration of the vaccine by intramuscular route as a single dose of 108.0 EID50/dose showed immunogenicity of the vaccine. Partial reports from a Phase II boosting study in subjects with low levels of immunity at the time of enrolment strongly suggest the vaccine is safe and immunogenic in this population. Altogether, these data justify the continuation of the AVX/COVID-12 vaccine development program. Due to the advanced stage of the pandemics and vaccination programs worldwide, it is important to assess the capacity of the AVX/COVID-12 vaccine to boost the pre-existing immunity in open previously vaccinated population.

Study design:

A phase II/III parallel, double-blind, active-controlled, non-inferiority study to evaluate immunogenicity and safety of a booster immunization scheme with a single intramuscular dose of the recombinant vaccine against SARS-CoV-2 (AVX/COVID-12 vaccine) based on live recombinant Newcastle disease virus (rNDV) vector in healthy adults with a history of vaccination against COVID-19.

Summarised description of Phase II design:

Subjects who meet the study inclusion and not exclusion criteria shall be randomised (1:1) to receive the AVX/COVID-12 vaccine or active control.

From the first 400 subjects of study samples corresponding to the efficacy criteria for Phases II and III shall be collected (including samples to determine cell response in a randomly-defined subgroup).

If at the end of the main endpoint assessment of the study phase corresponding to Phase II (day 14) it is determined the intervention with AVX-COVID-12 vaccine did not meet the specified objective (i. e., neutralizing capacity above 95% was not showed in 80% of the population vaccinated in surrogate testing and a significant change when comparing the geometric means of population neutralizing antibodies titres from days 0 to 14) the enrolment shall be stopped in order to meet the criteria related to the Phase III objectives, otherwise the enrolment shall continue consecutively.

Additionally, the first 400 subjects enrolled (corresponding to Phase II (200 vaccinated with the experimental vaccine and 200 with the active control)) shall be evaluated 90 and 180 days after vaccination to determine the humoral immune response performance at these moments.

A sub-sample of 100 subjects randomly selected (50 experimental vaccine and 50 active control) shall be evaluated regarding cell-mediated immune response in addition to the humoral response at the time of enrolment and 14, 90 and 180 days after vaccination.

Comparison of the safety evaluation related to Phase II shall be carried out with the population receiving active control as reference.

An interim futility analysis shall be carried out for non-inferiority criteria of Phase III at the end of enrolment corresponding to Phase II by Fleming-alpha spending function.

Summarised description of Phase III design:

In total 3832 subjects shall be enrolled divided into 3000 subjects to receive the experimental vaccine (2168 + 832 (632 Phase III + 200 from Phase II/III)) and 832 subjects (632 Phase II + 200 from Phase II/III) will receive active control.

The first 1664 subjects enrolled shall be randomised 1:1 to receive the experimental vaccine or active control and at the end of this phase the subsequent number of subjects enrolled shall receive only the experimental vaccine up to 3000 subjects.

From the first 1664 subjects of study (832 randomised to receive the experimental vaccine and 832 vaccinated with active control) samples shall be collected on days 0 and 14 to determine total titres of anti-S IgG, total titres of anti-N IgG and anti-SARS-CoV-2 neutralizing titres.

Three thousand subjects from safety population and 832 subjects vaccinated with active control shall be followed-up to 180 days to detect symptomatic cases of COVID-19 proved with genetic material detection from nasal/mouth mucus by PCR.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

3000 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Immuno-bridgingImmuno-bridging

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

Randomization of patients shall be carried out by a computerized system. Once the informed consent signed, the patient shall be allocated with a number coding with all his/her pseudonymously information during collection and completely anonymised during analysis. The randomization of the first 400 study subjects will include, in addition to 1:1 randomization (experimental vaccine: active control), randomization to participate as a subsample subject for cellular immune response determinations. Once the 1664 subjects have been randomised, the following study subjects shall be designated as experimental vaccine receptors until have enrolled all the study subjects.

Primary Purpose:

Prevention

Official Title:

Phase II/III Parallel, Double-blind, Non-inferiority Study With Active Control, to Evaluate the Immunogenicity and Safety of a Booster Immunization Scheme With a Single Intramuscular Dose of the Recombinant Vaccine Against SARS-CoV-2

Actual Study Start Date :

Nov 9, 2022

Anticipated Primary Completion Date :

Sep 9, 2023

Anticipated Study Completion Date :

Sep 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase II - Experimental AVX-COVID/12 Dose: 10^8.0 EID50/ intramuscular dose Study parameters: Safety, Serological response, Cellular response	Biological: AVX-COVID/12 Single dose IM administration of a Recombinant Newcastle Disease Virus Vectored Vaccine for SARS-CoV-2 Other Names: Recombinant NDV Vectored Vaccine for SARS-CoV-2
Active Comparator: Phase II - Active Control ChAdOx-1-S[recombinant]) intramuscular Study parameters: Safety, Serological response, Cellular response	Biological: ChAdOx-1-S[recombinant] Single dose IM administration of ChAdOx1 nCOV-19 (Astra-Zeneca) adenovirus-vectored vaccine Other Names: AstraZeneca COVID vaccine
Experimental: Phase III - Experimental AVX-COVID/12 Intramuscular Dose: 10^8.0 EID50/ intramuscular dose Study parameters: Safety, Serological response	Biological: AVX-COVID/12 Single dose IM administration of a Recombinant Newcastle Disease Virus Vectored Vaccine for SARS-CoV-2 Other Names: Recombinant NDV Vectored Vaccine for SARS-CoV-2
Active Comparator: Phase III - Active Control ChAdOx-1-S[recombinant]) intramuscular Study parameters: Safety, Serological response	Biological: ChAdOx-1-S[recombinant] Single dose IM administration of ChAdOx1 nCOV-19 (Astra-Zeneca) adenovirus-vectored vaccine Other Names: AstraZeneca COVID vaccine
Experimental: Phase III - Security AVX-COVID/12 Intramuscular Dose: 10^8.0 EID50/ intramuscular dose Study parameters: Safety.	Biological: AVX-COVID/12 Single dose IM administration of a Recombinant Newcastle Disease Virus Vectored Vaccine for SARS-CoV-2 Other Names: Recombinant NDV Vectored Vaccine for SARS-CoV-2
Experimental: Phase II- Experimental AVX-COVID/12 Dose: 10^8.0 EID50/ intramuscular dose Study parameters: Safety, Serological response.	Biological: AVX-COVID/12 Single dose IM administration of a Recombinant Newcastle Disease Virus Vectored Vaccine for SARS-CoV-2 Other Names: Recombinant NDV Vectored Vaccine for SARS-CoV-2
Active Comparator: Phase II- Active Control ChAdOx-1-S[recombinant]) intramuscular Study parameters: Safety, Serological response.	Biological: ChAdOx-1-S[recombinant] Single dose IM administration of ChAdOx1 nCOV-19 (Astra-Zeneca) adenovirus-vectored vaccine Other Names: AstraZeneca COVID vaccine

Outcome Measures

Primary Outcome Measures

Phase II - Increase in titres of neutralizing anti SARS-CoV-2 IgG antibodies in serum [14 to 17 days after vaccination]
Serum IgG, neutralizing antibodies
Phase II - T-cell elicited responses [Day 14]
Percentage of cells expressing IL2, TNF-alpha and IFN-gamma by Flow cytometry after challenge with spike protein.
Phase III - Increase in titres of neutralizing anti SARS-CoV-2 IgG antibodies in serum [14 to 17 days after vaccination]
Serum IgG, neutralizing antibodies

Secondary Outcome Measures

Phase II - Increase in titres of neutralizing anti SARS-CoV-2 IgG antibodies in serum [Day 0 (day of vaccination)]
Serum IgG, neutralizing antibodies
Phase II - Increase in titres of neutralizing anti SARS-CoV-2 IgG antibodies in serum [Day 90 after vaccination]
Serum IgG, neutralizing antibodies
Phase II - Increase in titres of neutralizing anti SARS-CoV-2 IgG antibodies in serum [Day 180 after vaccination]
Serum IgG, neutralizing antibodies
Phase II - T-cell elicited responses [Day 0 (day of vaccination)]
Percentage of cells expressing IL2, TNF-alpha and IFN-gamma by Flow cytometry after challenge with spike protein.
Phase II - T-cell elicited responses [Day 90 after vaccination]
Percentage of cells expressing IL2, TNF-alpha and IFN-gamma by Flow cytometry after challenge with spike protein.
Phase II - T-cell elicited responses [Day 180 after vaccination]
Percentage of cells expressing IL2, TNF-alpha and IFN-gamma by Flow cytometry after challenge with spike protein.
Phase III - Incidence of symptomatic COVID-19 disease cases [From 14 days after vaccination]
Document the incidence of COVID-19 disease symptomatic cases in both groups (experimental vaccine and active control).
Phase III - Incidence of severe COVID-19 disease cases or mortality [From 14 days after vaccination]
Document the incidence of severe or mortality COVID-19 disease cases in both groups (experimental vaccine and active control).

Other Outcome Measures

Phase II/Phase III - Safety: Adverse Events [After Day 14 after vaccination]
Incidence of adverse events
Phase II -Basal titers of Anti-N and anti-S antibodies, distribution of anti-N and anti-S antibodies within study population [Day 0 (day of vaccination)]
Appearance of anti-N and anti-S antibodies
Phase II - Increase in titers of Anti-N and anti-S antibodies, distribution of anti-N and anti-S antibodies within study population [Day 14 after vaccination]
Appearance of anti-N and anti-S antibodies
Phase II - Increase in titers of Anti-N and anti-S antibodies, distribution of anti-N and anti-S antibodies within study population [Day 90 after vaccination]
Appearance of anti-N and anti-S antibodies
Phase II - Increase in titers of Anti-N and anti-S antibodies, distribution of anti-N and anti-S antibodies within study population [Day 180 after vaccination]
Appearance of anti-N and anti-S antibodies
Phase II - Incidence of confirmed cases of SARS-CoV-2 infection [Day 28 until the end of the study.]
Evaluation of the incidence of confirmed cases of SARS-CoV-2 infection in study subjects from systematic vaccination.
Increase in titres of neutralizing anti SARS-CoV-2 IgG antibodies in serum in selected subpopulations [From 14 and up to 180 days after vaccination]
Subjects younger than 65 years. Subjects older than 65 years. Subjects with at least one comorbidity (any). Subjects with obesity (BMI >30). Subjects with Diabetes Mellitus. Subjects with hypertension. Subjects with smoking history. Subjects with asthma. Subjects with cardiovascular disease. Subjects with chronic obstructive pulmonary disease. Subjects with chronic renal disease. Subjects with liver disease. Subjects with cancer history.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

People ≥18 years old.
Any genre.
Have received their informed consent.
Negative PCR test for SARS-CoV-2 during the screening visit.
Negative pregnancy test in women with child-bearing potential.
Commitment to maintain adequate prevention measures to avoid contagion by SARS-CoV-2 throughout their participation in the study considering their strict following for the first 14 days after the baseline visit (use of face masks in closed places, social distancing measures in open spaces and frequent handwashing).
Have been vaccinated with any of the approved vaccines against SARS-CoV-2 (at least once).

Exclusion Criteria:

History of hypersensibility or allergy to any of the vaccine compounds.
History of severe anaphylactic reactions of any cause.
Fever at the baseline visit.
Active participation in any other clinical trial or experimental intervention within last 3 months.
Have received any vaccine (experimental or approved) within 30 days before baseline visit, except for influenza vaccine.
The last anti-COVID vaccination was less than 4 months ago.
SARS-CoV-2 infection occurred in less than 1 month ago.
Pregnant or nursing women.
Child-bearing potential and sexually active women who do not use highly effective birth control methods (oral contraceptives, intrauterine device, subcutaneous implant, transdermal patch used at least within 3 months) at the time of enrolment. Fertile and sexually active men not willing to strictly use (in all relationships) barrier methods of birth control throughout study. Those participants (both sexes) not sexually active can participate in the study if they are committed to avoid sexual intercourse throughout study (6 months).
Chronic diseases that require use of immunosuppressive agents or immune response modulators (for instance: systemic corticosteroids, cyclosporine, rituximab, among others).
Cancer under active chemotherapy treatment.
Subjects with HIV infection history.
Subjects with chronic renal or liver disease who have shown an infectious condition that required hospitalization or treatment with intravenous drugs within the last year prior baseline visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CAIMED Investigación en Salud S.A. de C.V.	Mexico City	Cdmx	Mexico	06760
2	Centro de Investigación Clínica Chapultepec S.A. de C.V.	Coyoacán	Ciudad De México	Mexico	04100
3	Unidad de Medicina Familiar No. 20 - IMSS	Gustavo A Madero	Ciudad De México	Mexico	07760
4	Centro de Investigación Clínica Acelerada, S.C.	Gustavo A. Madero	Ciudad De México	Mexico	07369
5	Clinical Research Institute S.C.	Tlalnepantla	Estado De México	Mexico	54055
6	Centro de Investigación Clínica del Pacífico, S.A. de C.V.	Acapulco	Guerrero	Mexico	39670
7	Sociedad Administradora de Servicios de Salud, S.C.	Morelia	Michoacán	Mexico	58260
8	Centro de Investigación y Avances Médicos Especializados / RED OSMO Cancún	Cancún	Quintana Roo	Mexico	77506
9	Centro Multidisciplinario para el Desarrollo Especializado de la Investigación Clinica en Yucatán S.C.P.	Mérida	Yucatán	Mexico	97070
10	Jules Bordet Medical Service, S.C.P. / Khöler & Milstein Research	Mérida	Yucatán	Mexico	97070
11	Unidad de Atención Médica e Investigación en Salud, S.C.P.	Mérida	Yucatán	Mexico	97070
12	Promotora Médica Aguascalientes, S.A. de C.V.	Aguascalientes		Mexico	20230
13	Oaxaca Site Management Organization, S.C.	Oaxaca		Mexico	68000
14	Profesionales Médicos Desarrollados, S.C. (Instituto Veracruzano de Investigación Clínica)	Veracruz		Mexico	91855