Objectives for the Randomized Observe-Blinded Phase:Primary Objectives:Primary Efficacy Objective• To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the prevention of first episodes of virologically-confirmed cases of COVID-19 of any…
ID
Source
Brief title
Condition
- Other condition
- Viral infectious disorders
Synonym
Health condition
SARS-CoV-2
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoint
• Occurrence of first episodes of virologically-confirmed (RT-PCR positive)
cases of COVID-19 of any severity meeting the case definition for the primary
efficacy analysis.
Primary Safety Endpoints
All safety endpoints will be analyzed in all subjects, in subjects seronegative
at baseline, and in subjects seropositive at baseline.
• Occurrence, intensity, and relationship of medically-attended AEs collected
through 6 months after the second trial vaccination in all subjects.
• Occurrence, intensity, and relationship of SAEs and AESIs collected
throughout the trial in all subjects.
• Occurrence of fatal SAEs throughout the trial in all subjects.
• Occurrence, intensity, and duration of each solicited local AE within 7 days
after each trial vaccination in Phase 2b subjects.
• Occurrence, intensity, duration of each solicited systemic AE within 7 days
after each trial vaccination in Phase 2b subjects.
• Occurrence, intensity and relationship of unsolicited AEs occurring within 28
days after each trial vaccination in Phase 2b subjects.
• Occurrence of AEs leading to vaccine withdrawal or trial discontinuation
throughout the trial in all subjects.
Secondary outcome
Key Secondary Efficacy Endpoints
• Occurrence of first episodes of virologically-confirmed (RT-PCR positive)
cases of moderate to severe COVID-19 meeting the case definition for the
primary efficacy analysis (moderate and severe COVID-19 is defined in Appendix
3 and Appendix 4).
• Occurrence of first episodes of virologically-confirmed (RT-PCR positive)
severe cases of COVID-19 meeting the case definition for the primary efficacy
analysis (severe COVID-19 defined in Appendix 3).
• Occurrence of first episodes of virologically-confirmed (RT-PCR positive)
cases of COVID-19 of any severity meeting the case definition due to infection
with *wild type* (i.e., WT/D614G lineages A.1/B.1 without VOC B.1.1.7 [Alpha],
B.1.351 [Beta], B.1.429 [Epsilon]) and *UK* (B.1.1.7 [Alpha]) SARS CoV 2
strains in SARS CoV 2 naïve subjects.
.
Other Secondary Efficacy Endpoints
• In subjects >= 61 years of age, occurrence of first episodes of virologically
confirmed (RT-PCR positive) cases of COVID-19 of any severity meeting the case
definition for the primary efficacy analysis.
• Occurrence of virologically-confirmed (RT-PCR positive) SARS CoV 2 infection,
with or without symptoms.
If subject was symptomatic, onset of symptoms must have occurred >= 15 days
following the second trial vaccination; if subject was asymptomatic, the
positive RT-PCR test must have occurred >= 15 days following the second trial
vaccination.
• BoD scores calculated based on first episodes of virologically confirmed
(RT-PCR positive) cases of COVID-19 of any severity meeting the case definition
for the primary efficacy analysis.
o BoD #1 - no disease (not infected or asymptomatic infection) = 0; mild or
moderate disease = 1; severe disease = 2.
o BoD #2 - no disease (not infected or asymptomatic infection) = 0; disease
without hospitalization = 1; disease with hospitalization = 2; death = 3.
• Occurrence of first episodes of virologically-confirmed (RT-PCR positive)
cases of COVID-19 of any severity with symptom onset at any time after the
first trial vaccination.
Secondary Immunogenicity Endpoints (Phase 2b Immunogenicity Subset)
SARS-CoV-2 RBD of S protein antibody responses
On Days 1, 29, 43, 120, and 211:
• Serum antibodies to SARS-CoV-2 RBD of S protein.
• Occurrence of seroconversion to SARS-CoV-2 RBD of S protein.
Seroconversion is defined as detectable SARS-CoV-2 RBD of S protein antibodies
in the serum of subjects who tested seronegative at baseline.
SARS-CoV-2 viral neutralizing antibody responses
On Days 1, 29, 43, 120, and 211:
• Serum neutralizing antibodies to SARS-CoV-2 virus, as measured by a viral
neutralizing antibody assay.
• Occurrence of seroconversion to SARS-CoV-2 virus, as measured by a viral
neutralizing antibody assay.
Seroconversion is defined as detectable SARS-CoV-2 viral neutralizing
antibodies in the serum of subjects who tested seronegative at baseline.
Background summary
Coronaviruses are a large family of zoonotic ribonucleic acid (RNA) viruses
causing respiratory disease, ranging from a common cold to severe diseases such
as Middle East respiratory syndrome (MERS) and severe acute respiratory
syndrome (SARS) in humans. In December 2019, an outbreak of respiratory disease
caused by a novel coronavirus strain was reported in Wuhan City, Hubei
Province, China. The novel coronavirus was named *severe acute respiratory
syndrome coronavirus 2* (SARS-CoV-2), while the disease associated with it was
referred to as COVID-19 (coronavirus disease 2019). The virus spread to
different parts of China and an increasing number of countries worldwide and on
30 January 2020 the World Health Organization (WHO) announced the outbreak
under International Health Regulations as a public health emergency of
international concern (the WHO's highest level of alarm). On 12 March 2020, the
WHO announced the outbreak as a pandemic.
In view of the severity of respiratory disease caused by emerging
coronaviruses, development of a vaccine has been undertaken by several
pharmaceutical companies, and there are now vaccines available with emergency
authorization/conditional marketing authorization for prevention of COVID 19 in
several countries worldwide. CureVac AG is developing a novel SARS-CoV-2
vaccine referred to as CVnCoV. CVnCoV is a messenger RNA (mRNA) based COVID-19
vaccine in which the mRNA is protected and delivered by encapsulation within
lipid nanoparticles (LNPs). The mRNA encodes the stabilized full-length spike
(S) protein from the SARS-CoV-2 virus. Following intramuscular (IM) injection
of CVnCoV, the S protein is translated from the mRNA stimulating an antigen
specific humoral and cellular immune response to the S protein. Importantly,
functional viral neutralizing titers (VNTs) are induced following vaccination
with CVnCoV.
Phase 1 and 2a trials are being conducted to generate initial data on the
safety, reactogenicity, and immunogenicity of 2 doses of CVnCoV, administered
28 days apart, to adults 18 years of age and older. In a subset of subjects, a
booster dose at 2 or 6 months after the first dose will be investigated. The
first-in-human (FIH) Phase 1 trial, CV-NCOV-001, is evaluating different dose
levels of CVnCoV in seronegative and seropositive adults 18 to 60 years of age.
Following review of the FIH data, a Phase 2a trial, CV-NCOV-002, was initiated
and is evaluating CVnCoV at selected dose levels in adults >= 61 years of age.
Following the first part of Trial CV NCOV 002, expansion cohorts of 220
subjects aged 18 to 60 years and 220 subjects aged >= 61 years are being
enrolled and treated to generate additional safety and immunogenicity data in
preparation of Phase 2b/3 trials. Dose level selection for subsequent trials
will be performed based on the safety and immunogenicity data from these 2
trials. In the FIH Phase 1 trial, a dose of 12 µg elicited the same immune
response as that seen in patients who are recovering from having been infected
with the real virus. Therefore, this dose was selected to be used in this trial.
The present trial CV-NCOV-004 is designed as a Phase 2b/3 pivotal efficacy and
safety trial in adults 18 years of age and older. The trial will have a
randomized, observer-blinded, placebo-controlled design. Subjects will be
enrolled at multiple sites globally and will be randomized in a 1:1 ratio to
receive a 2-dose schedule of either CVnCoV at a dose level of 12 µg mRNA or
placebo {normal saline (0.9% NaCl)} as the control.
The above described randomized, observer-blinded phase will be followed by an
open label phase. The open-label phase has been added to inform all subjects
about the trial treatment they received and to allow follow-up of subjects who
received at least 1 dose of CVnCoV, including those who decide(d) after
unblinding to receive an authorized/licensed vaccine for preventing COVID-19
(AV) through their national vaccination program. Placebo subjects do not
require further follow-up and will discontinue the trial.
Study objective
Objectives for the Randomized Observe-Blinded Phase:
Primary Objectives:
Primary Efficacy Objective
• To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the prevention
of first episodes of virologically-confirmed cases of COVID-19 of any severity
in SARS-CoV-2 naïve subjects.
Primary Safety Objectives
• To evaluate the safety of CVnCoV administered as a 2-dose schedule to
subjects 18 years of age and older.
• To evaluate the reactogenicity of CVnCoV administered as a 2-dose schedule to
subjects 18 years of age and older participating in Phase 2b of the trial.
Secondary Objectives:
Key Secondary Efficacy Objectives
• To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the prevention
of first episodes of virologically-confirmed moderate to severe cases of
COVID-19 in SARS-CoV-2 naïve subjects.
• To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the prevention
of first episodes of virologically-confirmed severe cases of COVID-19 in
SARS-CoV-2 naïve subjects.
• To demonstrate the efficacy of a 2-dose schedule of CVnCoV in the prevention
of first episodes of virologically-confirmed cases of COVID-19 of any severity
caused by *wild type* (i.e., WT/D614G lineages A.1/B.1 without the variant of
concern [VOC] B.1.1.7 [Alpha], B.1.351 [Beta], B.1.429 [Epsilon]) and *UK* (B.
1.1.7 [Alpha]) SARS CoV 2 strains in SARS CoV 2 naïve subjects.
Other Secondary Efficacy Objectives
To evaluate in SARS-CoV-2 naïve subjects:
• The efficacy of a 2-dose schedule of CVnCoV in the prevention of first
episodes of virologically-confirmed cases of COVID-19 of any severity in
subjects >= 61 years of age.
• The efficacy of a 2-dose schedule of CVnCoV in the prevention of first
episodes of virologically-confirmed cases of SARS-CoV-2 infection, with or
without symptoms.
• The efficacy of a 2-dose schedule of CVnCoV in reducing the Burden of disease
(BoD) from COVID-19.
• The efficacy of CVnCoV after the first dose in the prevention of first
episodes of virologically-confirmed cases of COVID-19 of any severity.
Secondary Immunogenicity Objectives
• To assess antibody responses to the receptor binding domain (RBD) of S
protein of SARS-CoV-2 after 1 and 2 doses of CVnCoV in a subset of subjects
participating in Phase 2b of the trial.
• To assess SARS-CoV-2 viral neutralizing antibody responses after 1 and 2
doses of CVnCoV in a subset of subjects participating in Phase 2b of the
trial.
Exploratory Efficacy Objectives
To investigate in SARS-CoV-2 naïve subjects:
• The efficacy of a 2-dose schedule of CVnCoV in the prevention of first
episodes of virologically-confirmed cases of COVID-19 of any severity caused by
individual VOCs (see Section 9.2.1.6).
• If cases of COVID-19 are milder in severity in subjects receiving a 2-dose
schedule of CVnCoV compared to those administered placebo.
• If the need for supplemental oxygenation due to COVID-19 is reduced in
subjects receiving a 2-dose schedule of CVnCoV compared to those administered
placebo.
• If the need for mechanical ventilation due to COVID-19 is reduced in subjects
receiving a 2-dose schedule of CVnCoV compared to those administered placebo.
• If hospitalization due to COVID-19 is reduced in subjects receiving a 2 dose
schedule of CVnCoV compared to those administered placebo.
• If mortality due to COVID-19 is reduced in subjects receiving a 2-dose
schedule of CVnCoV compared to those administered placebo.
• If all-cause mortality is reduced in subjects receiving a 2-dose schedule of
CVnCoV compared to those administered placebo.
• To investigate the cell-mediated immune response of a 2-dose schedule of
CVnCoV from approximately 200 subjects at selected site(s).
To investigate in SARS-CoV-2 naïve and non-naïve subjects:
• The efficacy of a 2-dose schedule of CVnCoV in the prevention of first
episodes of virologically-confirmed cases of COVID-19 of any severity in all
subjects, regardless of SARS-CoV-2 serological status at baseline.
• The efficacy of CVnCoV after the first dose in the prevention of first
episodes of virologically-confirmed cases of COVID-19 of any severity in all
subjects, regardless of SARS-CoV-2 serological status at baseline.
To investigate in subjects with first episodes of virologically confirmed
COVID-19 during the trial:
• The occurrence of second episodes of COVID-19 in subjects receiving a 2-dose
schedule of CVnCoV compared to those administered placebo.
• To explore correlates of protective immunity induced by CVnCoV vaccination.
Objectives for the Open-label Phase:
• To evaluate safety in all subjects >= 18 years of age remaining in the trial
after unblinding.
Open-label Exploratory Objective:
• To describe the number of first episodes of symptomatic virologically
confirmed cases of mild, moderate, and severe COVID-19 as assessed by the
Investigator.
Study design
Trial CV-NCOV-004 will start with an initial Phase 2b part followed by a large
Phase 3 efficacy part. Both Phase 2b and Phase 3 parts will be randomized,
observer-blinded, and placebo controlled. Adult subjects 18 years of age or
older will be enrolled at multiple sites globally and will receive a 2-dose
schedule of either CVnCoV at a dose level of 12 µg mRNA or placebo {normal
saline (0.9% NaCl)} in a 1:1 ratio. Both Phase 2b and Phase 3 parts of the
trial are consistent in design (e.g., for COVID-19 case ascertainment and case
definition) so that cases of COVID-19 occurring in Phase 2b can be pooled with
those in Phase 3 for the primary analysis of vaccine efficacy (VE).
For subjects participating in Phase 2b Immunogenicity Subset (see Table 1):
o 7 protocol-scheduled site visits on Day 1, Day 29, Day 43, Day 57, Day 120,
Day 211, and Day 393.
o 3 protocol-scheduled phone contacts (safety calls) on Day 2, Day 30 and Day
302.
For subjects participating in Phase 2b non-immunogenicity (see Table 2):
o 6 protocol-scheduled site visits on Day 1, Day 29, Day 43, Day 120, Day 211,
and Day 393.
o 4 protocol-scheduled phone contacts (safety calls) on Day 2, Day 30, Day 57,
and Day 302.
For subjects participating in Phase 3 (see Table 3):
o 5 protocol-scheduled site visits on Day 1, Day 29, Day 43, Day 211 and Day
393.
o 3 protocol-scheduled phone contacts (safety calls) on Day 57, Day 120 and Day
302.
This randomized observer-blinded phase will be followed by a Phase 3 open label
phase. The trial will be unblinded on country/site level after receipt of
Competent Authority/Ethics Committee approval of Protocol version 4.0.
Subjects of the placebo treatment arm will be notified of the trial treatment
they received by a Subject Information Letter and will be withdrawn after an
EOT phone call. Subjects of the CVnCoV treatment arm will be notified of the
trial treatment they received at the next planned trial visit/phone call.
For subjects participating in the Open-label Phase:
Cohort A: CVnCoV-AV (Table 4) and Cohort B: CVnCoV only (Table 5):
o Phone calls or clinic visits will be performed after trial unblinding on Day
302 and Day 393/EOT of the original Phase 2b/3 schedule.
Cohort A: CVnCoV-AV (See Table 4 for the Schedule of Trial Assessments and
Procedures): Subjects >= 18 years who received at least 1 dose of CVnCoV and
choose to receive an AV are included in this cohort and will be recommended to
procure AV as standard of care per their national vaccination program, if not
already done. Subjects will be requested to remain in the trial for safety
follow up until the EOT (Day 393 of the original Phase 2b/3 schedule). Subjects
who were individually unblinded and already received an AV before
implementation of Protocol version 4.0 will also be included in this cohort.
Cohort B: CVnCoV only (See Table 5 for the Schedule of Trial Assessments and
Procedures): Subjects >= 18 years who received at least 1 dose of CVnCoV and
choose to remain in the trial without receiving any AV will continue follow up
until EOT (Day 393 of the original Phase 2b/3 schedule). Subjects who were
individually unblinded during the randomized observer-blinded phase and who
received CVnCoV but did not receive an AV before implementation of Protocol
version 4.0 and do not intend to receive an AV will also be included in this
cohort. Subjects who initially intend to complete the trial without receiving
an AV and later decide to receive an AV within the open-label phase will be
switched to Cohort A.
Placebo subjects do not require further follow up and will discontinue the
trial.
The open-label phase will provide additional safety data, including data from
subjects who receive an AV after CVnCoV. COVID-19 cases will continue to be
documented, but there will no longer be any inferential efficacy analysis in
the open-label phase (only descriptive summary of cases). Subjects will undergo
passive surveillance for COVID-19.
Intervention
2 doses of CvnCoV (12 µg dose) or saline placebo, 28 days apart, administered
via intermuscular injection
Study burden and risks
We do not know all the possible side effects of CVnCoV. Like all vaccines,
CVnCOV can cause side effects, although not everybody gets them. Most side
effects are mild to moderate. However, some people may experience serious side
effects and may require treatment.
This CVnCoV vaccine is currently being assessed in humans in a parallel study.
The final data are not yet available, but so far, no safety concerns have been
reported. Some participants experienced reactions that kept them from doing
their routine daily activity during one or maximum two days* in most cases.
Other side effects that may occur: Allergic reactions, immune response,
reaction to the blood collection or nose swab.
For a more detailed overview of the potential side effects please consult the
Protocol, Investigator's Brochure and Informed Consent Form provided with this
inititial submission.
Schumannstr. 27
Frankfurt 60325
DE
Schumannstr. 27
Frankfurt 60325
DE
Listed location countries
Age
Inclusion criteria
Inclusion criteria for all subjects:
Subjects will be enrolled in this trial only if they meet all of the following
criteria:
1. Male or female subjects 18 years of age or older.
2. Be willing and able to provide written informed consent prior to initiation
of any trial procedures..
3. Expected compliance with protocol procedures and availability for clinical
follow-up through the last planned visit.
4. Females of non-childbearing potential defined as follows: surgically sterile
(history of bilateral tubal ligation/occlusion, bilateral oophorectomy or
hysterectomy) or postmenopausal {defined as amenorrhea for >= 12 consecutive
months prior to screening (Day 1)} without an alternative medical cause). A
follicle-stimulating hormone (FSH) level may be measured at the discretion of
the Investigator to confirm postmenopausal status.
5. Females of childbearing potential: negative pregnancy test {human chorionic
gonadotropin (hCG)} within 24 hours prior to each trial vaccination on Day 1
and Day 29.
6. Females of childbearing potential must use highly effective methods of birth
control from 2 weeks before the first administration of the trial vaccine until
3 months following the last administration. The following methods of birth
control are considered highly effective when used consistently and correctly:
• Combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation (oral, intravaginal or transdermal);
• Progestogen-only hormonal contraception associated with inhibition of
ovulation (oral, injectable or implantable);
• Intrauterine devices;
• Intrauterine hormone-releasing systems;
• Bilateral tubal ligation;
• Vasectomized or infertile partner;
7. Sexual abstinence {periodic abstinence (e.g., calendar, ovulation,
symptothermal and post-ovulation methods) and withdrawal are not acceptable}.
Exclusion criteria
Subjects will not be enrolled in this trial if they meet any of the following
criteria:
1. History of virologically-confirmed COVID-19 illness.
2. For females: pregnancy or lactation.
3. Use of any investigational or non-registered product (vaccine or drug)
within 28 days preceding the administration of the first trial vaccine or
planned use during the trial.
4. Receipt of licensed vaccines within 28 days (for live vaccines) or 14 days
(for inactivated or any other vaccines) prior to the administration of the
first trial vaccine.
5. Prior administration of any investigational SARS-CoV-2 vaccine or another
coronavirus (SARS-CoV, MERS-CoV) vaccine or planned use during the trial.
6. Any treatment with immunosuppressants or other immune-modifying drugs
(including but not limited to anabolic steroids, corticosteroids, biologicals
and methotrexate) for > 14 days total within 6 months preceding the
administration of trial vaccine or planned use during the trial. For
corticosteroid use, this means prednisone or equivalent, 0.5 mg/kg/day for 14
days or more. The use of inhaled, topical, or localized injections of
corticosteroids (e.g., for joint pain/inflammation) is permitted.
7. Any medically diagnosed or suspected immunosuppressive or immunodeficient
condition based on medical history and physical examination including known
infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or
hepatitis C virus (HCV); current diagnosis of or treatment for cancer including
leukemia, lymphoma, Hodgkin disease, multiple myeloma, or generalized
malignancy; chronic renal failure or nephrotic syndrome; and receipt of an
organ or bone marrow transplant.
8. History of angioedema (hereditary or idiopathic) or history of any
anaphylactic reaction.
9. History of pIMD.
10. History of allergy to any component of CVnCoV vaccine.
11. Administration of immunoglobulins or any blood products within 3 months
prior to the administration of trial vaccine or planned receipt during the
trial.
12. Subjects with a significant acute or chronic medical or psychiatric illness
that, in the opinion of the Investigator, precludes trial participation (e.g.,
may increase the risk of trial participation, render the subject unable to meet
the requirements of the trial, or may interfere with the subject*s trial
evaluations). These include severe and/or uncontrolled cardiovascular disease,
gastrointestinal disease, liver disease, renal disease, respiratory disease,
endocrine disorder, and neurological and psychiatric illnesses. However, those
with controlled and stable cases can be included in the trial.
13. Subjects with impaired coagulation or any bleeding disorder in whom an IM
injection or a blood draw is contraindicated.
14. Foreseeable non-compliance with the trial procedures as judged by the
Investigator.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2020-003998-22-NL |
CCMO | NL75450.000.20 |