| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10084465 |
| E.1.2 | Term | COVID-19 vaccination |
| E.1.2 | System Organ Class | 100000004865 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 3 portion
The primary objective of the Phase 3 portion of the study is:
Efficacy:
• To evaluate the efficacy of the CoVLP formulation, compared to placebo, in the prevention of laboratory confirmed symptomatic SARS-CoV-2 infection (virologic method) starting 7 days after the second vaccination in Period 1 and prior to the cross-over. |
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| E.2.2 | Secondary objectives of the trial |
Phase 3 portion
The secondary objectives of the Phase 3 portion of the study are:
Efficacy:
• To evaluate the efficacy of the CoVLP formulation, compared to placebo, in the prevention of laboratory confirmed asymptomatic SARS-CoV-2 infection (serologic method) starting 7 days after the second vaccination in Period 1 and prior to the cross-over;
• To evaluate the efficacy of the CoVLP formulation, compared to placebo, in the prevention of severe COVID-19 disease starting 7 days after the second vaccination in Period 1 and prior to the cross-over;
Please refer the protocol for further details.
Immunogenicity:
• To assess the immunogenicity of the CoVLP formulation, compared to placebo, in a subset of subjects, as determined by the protocol
Safety:
• To assess the safety and tolerability of the CoVLP formulation, compared to placebo, up to the end of the study. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria at the Screening (Visit 1) and/or Vaccination (Visit 2) visits to be eligible for participation in this study; no protocol waivers are allowed. All Investigator assessment-based judgements must be carefully and fully documented in the source documents:
1. Subjects must have read, understood, and signed the informed consent form (ICF) prior to participating in the study; subjects must also complete study-related procedures and the subjects must communicate with the study staff at visits and by phone during the study;
2. At the Screening visit (Visit 1), male and female subjects must be:
• Study Populations #1: 18 to 64 (has not yet had his/her 65th birthday) years of age, inclusive;
• Study Population #2: 65 years of age or older;
• Study Population #3: 18 years of age or older;
3. At Screening (Visit 1) and Vaccination (Visit 2), study populations #1 and #2 must have a body mass index (BMI) of ≥ 18.5 and < 30 kg/m2 for the Phase 2 portion of the study and a BMI of ≥ 18.5 and < 35 kg/m2 for the Phase 3 portion of the study;
4. Subjects are considered by the Investigator to be reliable and likely to cooperate with the assessment procedures and be available for the duration of the study;
5. Study Populations #1: Subjects must be in good general health prior to study participation, with no clinically relevant abnormalities that could jeopardize subject safety or interfere with study assessments, as determined by medical history, physical examination, and vital signs. Investigator discretion will be permitted with this inclusion criterion;
6. Study Populations #1 and #3: Female subjects of childbearing potential must have a negative serum pregnancy test result at Screening (Visit 1 for the Phase 2 portion) and/or a negative urine pregnancy test result at Vaccination (Visit 2 for the Phase 2 portion; Visit 1 for the Phase 3 portion):
Non-childbearing females are defined as:
• Surgically-sterile (defined as bilateral tubal ligation, hysterectomy or bilateral oophorectomy performed more than one month prior to the first study vaccination); or
• Post-menopausal (absence of menses for 12 consecutive months and age consistent with natural cessation of ovulation);
7. Study Populations #1 and #3: Female subjects of childbearing potential must use an effective method of contraception for one month prior to vaccination (Visit 2) and agree to continue employing highly effective birth control measures for at least one month after the last study vaccination (or in the case of early termination, she must not plan to become pregnant for at least one month after her last study vaccination).
The following relationship or methods of contraception are considered to be highly effective:
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal;
• Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable;
• Intra-uterine device with or without hormonal release;
• Credible self-reported history of heterosexual vaginal intercourse abstinence prior to and for at least one month after the last study vaccination. Abstinent subjects who are ovulating should be asked what method(s) they would use should their circumstances change, and subjects without a well-defined plan should be excluded;
• Female partner;
• All regions except the US: Vasectomised partner, provided that this partner is the sole sexual partner of the study participant and that the vasectomised partner has received a medical assessment of the surgical success;
• Bilateral tubal occlusion.
8. Study Population #2: Subjects must be non-institutionalized and have no acute or evolving medical problems prior to study participation and no clinically relevant abnormalities that could jeopardize subject safety or interfere with study assessments, as assessed by the Principal Investigator or sub-Investigator and determined by medical history, physical examination, vital signs and, only for the Phase 2 portion, serology, clinical chemistry and haematology tests and urinalysis. Investigator discretion will be permitted with this inclusion criterion.
9. Study Population #3: Subjects must have one or more co-morbid conditions that puts them at higher risk for severe COVID-19 disease
Please, see protocol for further inclusion criteria details |
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| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria at the Screening (Visit 1) and/or Vaccination (Visit 2) visits will not be eligible for participation in this study; no protocol waivers are allowed.
All Investigator assessment-based judgements must be thoroughly documented in the source documents:
1. Study Populations #1 and #2: According to the Investigator’s opinion, significant acute or chronic, uncontrolled medical or neuropsychiatric illness. Acute disease is defined as presence of any moderate or severe acute illness with or without a fever within 48 hours prior to the Screening (Visit 1) and/or Vaccination visit (Visit 2).
‘Uncontrolled’ is defined as:
• Requiring a new medical or surgical treatment during the three months prior to study vaccine administration;
Requiring any significant change in a chronic medication (i.e. drug, dose, frequency) during the three months prior to study vaccine administration due to uncontrolled symptoms or drug toxicity unless the innocuous nature of the medication change meets the criteria outlined in inclusion criterion no. 5(Study Population #1) or no. 8 (Study Population #2) and is appropriately justified and documented by the Investigator.
Investigator discretion is permitted with this exclusion criterion and must be carefully and fully documented in the source documents;
2. Study Populations #1 and #2: Any chronic medical condition associated with elevated risk of severe outcomes of COVID-19, including obesity, diabetes (type I/II), significant cardiovascular or respiratory disease including asthma, chronic renal failure, disorders of bleeding/coagulation, chronic inflammatory or autoimmune conditions, immunosuppressive conditions (including HIV), and hypertension;
3. Study Populations #1 and #2: Any confirmed or suspected current immunosuppressive condition or immunodeficiency, including cancer, human immunodeficiency virus (HIV), hepatitis B or C infection (subjects with a history of cured hepatitis B or C infection without any signs of immunodeficiency at present time are allowed). Investigator discretion is permitted with this exclusion criterion;
4. Study Populations #1 and #2: Current autoimmune disease (such as rheumatoid arthritis, systemic lupus erythematosus,
multiple sclerosis or narcolepsy). Investigator discretion is permitted with this exclusion criterion, and subjects may be eligible to participate with appropriate written justification in the source document(i.e. subjects with a history of autoimmune disease who are diseasefree without treatment for three years or more, or on stable thyroid replacement therapy, mild psoriasis [i.e. a small number of minor plaques requiring no systemic treatment], etc.);
5. Study Populations #1 and #2: Administration of any medication or treatment that may alter the vaccine immune responses, such as:
• Systemic glucocorticoids at a dose exceeding 10 mg of prednisone (or equivalent) per day for more than seven consecutive days or for 10 or more days in total, within one month prior to the Vaccination visit (Visit 2). Inhaled, nasal, ophthalmic, dermatological, and other topical glucocorticoids are permitted;
• Cytotoxic, antineoplastic, or immunosuppressant drugs - within 36 months prior to Vaccination (Visit 2);
• Any immunoglobulin preparations or blood products, blood transfusion – within 6 months prior to Vaccination (Visit 2);
6. Study Population #3: Acute disease defined as presence of any moderate or severe acute illness with or without a fever within 48 hours prior to the Screening (V1) and/or Vaccination visit (V2);
7. Administration of any vaccine within 14 days prior to Vaccination (V2); planned administration of any vaccine during the study (up to Day 28 of the study). Immunization on an emergency basis during the study will be evaluated on case-by-case basis by the Investigator;
8. Administration of any other SARS-CoV-2 / COVID-19, or other experimental coronavirus vaccine at any time prior to or during the study;
9. History of virologically-confirmed COVID-19;
10. Use of any investigational or non-registered product within 30 days or 5 half-lives, whichever is longer, prior to Vaccination (V2) or planned use during the study period.
Subjects who are in a prolonged post-administration observation period of another investigational or marketed drug clinical study, for which there is no ongoing exposure to the investigational or marketed product and all scheduled on-site visits are completed, will be allowed to take part in this study, if all other eligibility criteria are met;
11. Have a rash, dermatological condition, tattoos, muscle mass, or any other abnormalities at injection site that may interfere with injection site reaction rating. Investigator discretion will be permitted with this exclusion criterion;
Please, refer to protocol for further exclusion criteria |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 2 portion
In the Phase 2 portion, the primary endpoints are:
Safety:
• Occurrence, intensity, and relationship to vaccination of immediate AEs (30 minutes after each vaccination);
• Occurrence and intensity of solicited local and systemic AEs (for seven days following each vaccine administration);
• Occurrence, intensity, and relationship of unsolicited AEs for 21 days following each vaccine administration;
• Number and percentage of subjects with normal and abnormal clinically significant urine, haematological and biochemical values prior to and three days following each vaccination;
• Occurrences of SAEs, MAAEs, AEs leading to withdrawal, AESIs (including VED), and deaths up to 21 days following each vaccine administration;
Immunogenicity:
• Nab response induced in each Study Population against the SARS-CoV-2 virus on Days 0, 21, and 42 will be analyzed using the following parameter: geometric mean titers (GMT), seroconversion (SC) rate, and geometric mean fold rise (GMFR);
• Specific Th1 CMI response induced in each Study Population against the SARS-CoV-2 virus on Days 0, 21, and 42, as measured by IFN-γ ELISpot.
Phase 3 portion
In the Phase 3 portion, the primary endpoint is:
Efficacy:
• First occurrence, in a subject, of laboratory-confirmed (virologic method) symptomatic SARS-CoV-2 infection (≥ 7 days post-second vaccination) in Period 1 and prior to cross-over. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Phase 2 portion
In the Phase 2 portion, the secondary endpoints are:
Immunogenicity:
• Relative neutralizing antibody response between the healthy adults (Study Population #1) and the healthy elderly populations (Study Population #2; each age strata) induced at 21 days after the second vaccination will be analyzed using the following parameter: GMT;
• Relative neutralizing antibody response for the combination of healthy adults (Study Population #1) and healthy elderly adults (Study Population #2) compared to adults and elderly adults with significant comorbidities (Study Population #3) induced at 21 days after the second vaccination will be analyzed using the following parameter: GMT;
• Persistence of the Nab antibody response induced in each Study Population against the SARS-CoV-2 virus at Day 128, Day 201, and Day 386 will be analyzed using the following parameters: GMT, SC rate, and GMFR;
• Specific antibody response induced in each Study Population against the SARS-CoV-2 virus will be measured by the total IgG levels on Days 0, 21, and 42, and the persistence of these antibodies at Days 128, 201, and 386 and analyzed using the following parameters: GMT, SC rate, and GMFR;
• The ratio of neutralizing antibody titers: IgG (ELISA) antibody titers at Day 21, Day 42, Day 128, Day 201, and Day 386;
• Specific Th1 CMI response induced in each Study Population against the SARS-CoV-2 virus on Day 201 and Day 386, as measured by IFN-γ ELISpot;
• Specific T helper 2 (Th2) CMI response induced in each Study Population against the SARS-CoV-2 virus on Days 0, 21, 42, 201, and 386, as measured by IL-4 ELISpot;
Safety:
• Relative occurrence of solicited local and systemic AEs by intensity grades for seven days following each vaccine administration between the healthy adults (Study Population #1) and each healthy elderly population (Study Population #2);
• Relative occurrence of solicited local and systemic AEs by intensity grades for seven days following each vaccine administration for the combination of healthy adults (Study Population #1) and the healthy elderly adults (Study Population #2) compared to adults and elderly adults with significant comorbidities (Study Population #3);
• Occurrences of SAEs, MAAEs, AEs leading to withdrawal, AESIs (including VED), and deaths from Day 43 to Day 201;
• Occurrences of SAEs, MAAEs, AEs leading to withdrawal, AESIs (including VED), and deaths from Day 202 to Day 386.
Efficacy:
• First occurrence, in a subject, of laboratory-confirmed (virologic method) symptomatic SARS-CoV-2 infection (≥ 7 days post-second vaccination);
• Occurrences of severe COVID-19 disease (≥ 7 days post-second vaccination). Refer to the definition of severe COVID-19 disease in the Secondary Objectives section above.
Phase 3 portion
In the Phase 3 portion, the secondary endpoints are:
Efficacy:
• Occurrences of laboratory-confirmed (confirmed by the ELISA method for the N protein) asymptomatic SARSCoV-2 infection starting 7 days after the second vaccination in Period 1 and prior to the cross-over;
• Occurrences of severe COVID-19 disease (≥ 7 days post-second vaccination) in Period 1 and prior to crossover. Refer to the definition of severe COVID-19 disease in the Secondary Objectives section above;
• Occurrence and intensity of COVID-19-related symptoms in virologically-confirmed cases up until resolution of the symptoms in Period 1 compared to subjects administered the placebo and compared to subjects administered CoVLP at the time of cross-over in Period 2;
• First occurrence, in a subject, of laboratory-confirmed (virologic method) symptomatic SARS-CoV-2 infection (≥ first vaccination) in Period 1 and prior to cross-over;
• First occurrence, in a subject, of laboratory-confirmed (virologic method) symptomatic SARS-CoV-2 infection (≥ first vaccination and < second vaccination) in Period 1 and prior to cross-over;
• First occurrence, in a subject, of laboratory-confirmed (virologic method) symptomatic SARS-CoV-2 infection (≥ second vaccination and < 7 days post-second vaccination) in Period 1 and prior to cross-over;
• Occurrences of laboratory-confirmed (confirmed by the ELISA method for the N protein) asymptomatic SARSCoV-2 infection starting 7 days after the vaccination in Period 1 and prior to the cross-over in subjects who only received a single vaccination;
• Duration and intensity of viral shedding after virologically-confirmed SARS-CoV-2 infection in Period 1 and prior to cross-over;
• First occurrence, in a subject, of laboratory-confirmed (virologic method) symptomatic SARS-CoV-2 infection (≥ 7 days post-second vaccination) in Period 1 by strain and prior to cross-over;
Please, refer to protocol for further secondary endpoints (Immunogenicity and safety secondary endpoints in the Phase 3 portion).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| as defined in the endpoints |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity & tolerability |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Brazil |
| Canada |
| Colombia |
| Mexico |
| Peru |
| United States |
| Hungary |
| Poland |
| Spain |
| United Kingdom |
| Argentina |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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