COVID-19: A Study to Evaluate Safety, Reactogenicity and Immunogenicity of the SARS-CoV-2 mRNA Vaccine CVnCoV in Adults With Co-morbidities

Study Overview
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Brief Summary
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The primary objectives of this study are to evaluate the safety and reactogenicity profile after 1 and 2 dose administrations of investigational SARS-CoV-2 mRNA vaccine CVnCoV, and to evaluate the humoral immune responses 14 days after 2 dose administrations of CVnCoV.

Detailed Description
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Study participants with the following mild to moderate per protocol defined co-morbidities will be recruited: chronic kidney disease (CKD); cardiovascular disease (CVD), chronic obstructive pulmonary disease (COPD), type-2-diabetes. After safety data review, recruitment for severe cases will be opened. No severity classification will be done for study participants with chronic human immunodeficiency virus (HIV) infection with stable aviremia 12 months prior enrollment, for renal transplant patients if stable under medication for at least 6 months prior enrollment, and for study participants with a body mass index > 32 kg/m^2. This clinical trial information was submitted voluntarily under the applicable law and, therefore, certain submission deadlines may not apply. (That is, clinical trial information for this applicable clinical trial was submitted under section 402(j)(4)(A) of the Public Health Service Act and 42 CFR 11.60 and is not subject to the deadlines established by sections 402(j)(2) and (3) of the Public Health Service Act or 42 CFR 11.24 and 11.44.).

Official Title
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COVID-19: A Phase 3 Multicenter Clinical Trial to Evaluate the Safety, Reactogenicity and Immunogenicity of the Investigational SARS-CoV-2 mRNA Vaccine CVnCoV in Adults 18 Years of Age and Above With Co-morbidities

Conditions
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Coronavirus, Covid19, SARS-CoV-2, Severe Acute Respiratory Syndrome

Intervention / Treatment
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* Biological: CVnCoV Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants ≥18 years of age with 1 or more co-morbidities. For the co-morbidities chronic kidney disease, chronic obstructive pulmonary disease (COPD), chronic cardiovascular disease and diabetes mellitus, the first 25 participants per co-morbidity should include only mild to moderate cases. Thereafter, more severe conditions may be recruited following Internal Safety Review Committee (iSRC) and Data Safety Monitoring Board (DSMB) Chair approval. Participant has no overt clinical signs or symptoms of COVID-19. Participant has to sign the informed consent form (ICF) before any trial procedures. Participants with a life expectancy of at least 1 year as per the Investigator's assessment. Expected to be compliant with protocol procedures and available for clinical follow-up through the last planned visit. Physical examination without acute clinically significant findings according to the Investigator's assessment. Female participants: At the time of enrollment, negative human chorionic gonadotropin (hCG) pregnancy test (serum) for women presumed to be of childbearing potential on the day of enrollment. On Day 1 (pre vaccination): negative urine pregnancy test (hCG) (only required if serum pregnancy test was performed more than 3 days before). Note: Women that are postmenopausal (defined as amenorrhea for ≥ 12 consecutive months prior to screening without an alternative medical cause) or permanently sterilized will be considered as not having reproductive potential. Female participants 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. Exclusion Criteria: A previous clinical and laboratory-confirmed diagnosis of COVID-19 within the last six months prior to screening. Use of any investigational or non-registered product (vaccine or drug) other than the trial vaccine within 28 days preceding the administration of the trial vaccine, or planned use during the trial period. Receipt of any other vaccines within 28 days prior to enrollment in this trial or planned receipt of any vaccine within 28 days of trial vaccine administration. Planned vaccination with an inactivated influenza vaccine is permitted. Receipt of any investigational, authorized or licensed SARS-CoV-2, other coronavirus vaccine or any other lipid nanoparticles (LNP)-containing messenger ribonucleic acid vaccine prior to the administration of the trial vaccine. For authorized or licensed SARS-CoV-2: planned administration during the trial up to 6 weeks after the foreseen date of second dose administration of CVnCoV. Any treatment with immunosuppressants or other immune-modifying drugs (including, but not limited to, corticosteroids, biologicals, and methotrexate) for >14 days in total within 6 months prior to the administration of the 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. Note: This exclusion does not apply to the renal transplant cases and is at the Investigator's discretion for participants with other co-morbidities (e.g., COPD). Participants with chronic human immunodeficiency virus (HIV) infection with controlled Hepatitis B infection with therapy or aviremic Hepatitis C may be eligible for the trial, based on the Investigator's judgment. History of immune-mediated or autoimmune disease. History of anaphylaxis or allergy to any component of CVnCoV or aminoglycoside antibiotics. History of or current alcohol and/or drug abuse. History of confirmed severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS) disease. Administration of immunoglobulins and/or any blood products within the 3 months preceding the administration of any dose of the trial vaccine. Presence or evidence of significant uncontrolled acute or chronic medical or psychiatric illness, excluding the co-morbidities specified in the protocol. Significant medical or psychiatric illnesses include but are not limited to: Uncontrolled respiratory disease. Uncontrolled neurological disorders or Guillain-Barré syndrome or history of seizure, except for febrile seizures during childhood. Current or past malignancy, unless completely resolved without sequelae for >5 years Foreseeable non-compliance with protocol, as judged by the Investigator. For female participants: pregnancy or lactation. Participants with impaired coagulation or any bleeding disorder in whom an IM injection or a blood draw is contraindicated. This includes participants on treatment with anticoagulants (e.g., vitamin K antagonists, novel oral anticoagulants, and heparin). Use of platelet aggregation inhibitors is not exclusionary. However, use of anticoagulants is accepted in certain co-morbidities according to the clinical Investigator's judgment and if the international normalized ratio (INR) remains ≤3. Participants employed by the Sponsor, Investigator, or trial site, or relatives of research staff working on this trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CVnCoV Vaccine<br>Participants will be vaccinated with CVnCoV 12 µg mRNA on Day 1 and Day 29. | Biological: CVnCoV Vaccine<br>* Intramuscular (IM) injection in the deltoid area, preferably in the non-dominant arm.<br>* Other names: CV07050101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced a Solicited Adverse Event (AE) Occurring on the Day of Vaccination and the Following 7 Days After Any Dose | Reactogenicity was assessed daily via collection of solicited local AEs (injection site pain, redness, swelling, and itching) and solicited systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia, nausea/vomiting, and diarrhea) using paper diary cards. By definition, all solicited local AEs occurring from the time of first vaccination were considered related to trial vaccination. For solicited systemic AEs, the Investigator assessed the relationship between trial vaccine and each occurrence of each AE. | Up to 7 days after vaccination (Days 1 to 8 and Days 29 to 36) | 
| Intensity of Solicited AEs Per US Food and Drug Administration (FDA) Toxicity Grading Scale Occurring on the Day of Vaccination and the Following 7 Days After Any Dose | Reactogenicity was assessed daily via collection of solicited local AEs (injection site pain, redness, swelling, and itching) and solicited systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia, nausea/vomiting, and diarrhea) using paper diary cards. Intensity of solicited local AEs and solicited systemic AEs were graded per the FDA Toxicity Grading Scale at Grades 1-3, where higher grades indicate a worse outcome. | Up to 7 days after vaccination (Days 1 to 8 and Days 29 to 36) | 
| Duration of Solicited AEs Occurring on the Day of Vaccination and the Following 7 Days After Any Dose | Reactogenicity was assessed daily via collection of solicited local AEs (injection site pain, redness, swelling, and itching) and solicited systemic AEs (fever, headache, fatigue, chills, myalgia, arthralgia, nausea/vomiting, and diarrhea) using paper diary cards. Duration was calculated as consecutive days with a respective solicited AE regardless of the grade of the AE. AEs ongoing after Day 8 were included. | Up to 7 days after vaccination (Days 1 to 8 and Days 29 to 36) | 
| Number of Participants Who Experienced an Unsolicited AE Occurring on the Day of Vaccination and the Following 28 Days After Any Dose | Diaries were used for collection of unsolicited AEs on each vaccination day and the following 28 days. In addition, participants were contacted by phone to verify whether they had any health concerns since the last visit. The Investigator assessed the relationship between trial vaccine and each occurrence of each AE. | Up to 28 days after vaccination (Days 1 to 29 and Days 29 to 57) | 
| Intensity of Unsolicited AEs Per the Investigator's Assessment Occurring on the Day of Vaccination and the Following 28 Days After Any Dose | Diaries were used for collection of unsolicited AEs on each vaccination day and the following 28 days. In addition, participants were contacted by phone to verify whether they had any health concerns since the last visit. Participants were included only once, at the maximum severity. The Investigator made an assessment of intensity for each AE reported during the trial and assigned it to one of the following categories: Mild: an event that was easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities. Moderate: an event that caused sufficient discomfort to interfere with normal everyday activities. Severe: an event that prevented normal everyday activities. | Up to 28 days after vaccination (Days 1 to 29 and Days 29 to 57) | 
| Number of Participants Who Experienced a Serious Adverse Event (SAE) During the Trial | An SAE was defined as any untoward medical occurrence that, at any dose: Resulted in death. Was life-threatening. Required inpatient hospitalization or prolongation of existing hospitalization. Resulted in persistent disability/incapacity. Was a congenital anomaly/birth defect in the offspring of the participant. Was an important medical event. The Investigator assessed the relationship between trial vaccine and each occurrence of each AE. | Up to Day 57 | 
| Number of Participants Who Experienced an Adverse Event of Special Interest (AESI) During the Trial | AESIs included: AEs with a suspected immune-mediated etiology including potential immune-mediated diseases. Other AEs relevant to SARS-CoV-2 vaccine development or the target disease. Non-serious intercurrent medical conditions that may affect the immune response to vaccination was collected throughout the trial. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine. The Investigator assessed the relationship between trial vaccine and each occurrence of each AE. | Up to Day 57 | 
| Number of Participants Seroconverting for SARS-CoV-2 Spike Protein Receptor-Binding Domain (RBD) Antibodies on Day 43 | Seroconversion was defined as any increase in titer in antibodies against SARS-CoV-2 RBD versus baseline. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/ authorized vaccine. | Baseline and Day 43 | 
| Geometric Mean Titers (GMTs) of Serum SARS-CoV-2 Spike Protein RBD Antibodies on Day 43 | The SARS-CoV-2 spike RBD protein-specific antibodies are expressed as GMT (geometric mean of reciprocal duplicate dilutions). Concentration/titers marked as below the lower limit of quantification (LLOQ) were arbitrary replaced by half of the LLOQ for GMT computations purpose. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine. | Day 43 | 
| Subset Participants: Number of Participants Seroconverting for SARS-CoV-2 Neutralizing Antibodies on Day 43 | Seroconversion was defined as any increase in titer of SARS-CoV-2 neutralizing antibodies versus baseline. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine. | Baseline and Day 43 | 
| Subset Participants: GMTs of Serum SARS-CoV-2 Neutralizing Antibodies on Day 43 | The SARS-CoV-2 neutralizing antibodies are expressed as GMT (geometric mean of reciprocal duplicate dilutions). Concentrations/titers marked as below the LLOQ were arbitrary replaced by half of the LLOQ for GMT computations purpose. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine. | Day 43 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Seroconverting for SARS-CoV-2 Spike Protein RBD Antibodies on Days 29, 120, 211 and 393 | Seroconversion was defined as any increase in titer in antibodies against SARS-CoV-2 RBD versus baseline. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/ authorized vaccine. | Baseline and Days 29, 120, 211 and 393 | 
| GMTs of Serum SARS-CoV-2 Spike Protein RBD Antibodies on Days 29, 120, 211 and 393 | The SARS-CoV-2 spike RBD protein-specific antibodies are expressed as GMT (geometric mean of reciprocal duplicate dilutions). Concentrations/titers marked as below the LLOQ were arbitrary replaced by half of the LLOQ for GMT computations purpose. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine. | Days 29, 120, 211 and 393 | 
| Subset Participants: Number of Participants Seroconverting for SARS-CoV-2 Neutralizing Antibodies on Days 29 and 120 | Seroconversion was defined as any increase in titer of SARS-CoV-2 neutralizing antibodies versus baseline. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine. | Baseline and Days 29 and 120 | 
| Subset Participants: GMTs of Serum SARS-CoV-2 Neutralizing Antibodies on Days 29 and 120 | The SARS-CoV-2 neutralizing antibodies are expressed as GMT (geometric mean of reciprocal duplicate dilutions). Concentrations/titers marked as below the LLOQ were arbitrary replaced by half of the LLOQ for GMT computations purpose. Participants who received a licensed/authorized vaccine were censored at the day after receiving the licensed/authorized vaccine. | Days 29 and 120 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Covid19, CVnCoV, SARS-CoV-2 mRNA vaccine, Vaccine, SARS, COVID, Safety, Reactogenicity, Immunogenicity