COVID-19 Vaccine-induced Inflammatory Heart Disease Prevalence Registry (COVID-VIHPR)

• ClinicalTrials.gov Identifier: NCT05046002
• Recruitment Status: Recruiting
• First Posted: September 16, 2021
• Last Update Posted: May 31, 2023
• Sponsor: Ottawa Heart Institute Research Corporation
• Information provided by (Responsible Party): Ottawa Heart Institute Research Corporation

Tracking Information

• First Submitted Date: August 16, 2021
• First Posted Date: September 16, 2021
• Last Update Posted Date: May 31, 2023
• Actual Study Start Date: August 11, 2021
• Estimated Primary Completion Date: December 30, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 14, 2022)

• Proportion of patients with autoimmune disease [ Time Frame: 30 days ]
  To identify how many patients (in each group) have a history of autoimmune disease
• Composite of MACE [ Time Frame: 30 days ]
  To identify major cardiovascular events - death, ventricular arrhythmia, heart block, heart failure, LV dysfunction (LVEF<55%), cardiac tamponade, re-hospitalization for cardiac reasons

Original Primary Outcome Measures (submitted: September 14, 2021)

• Proportion of patients with autoimmune disease [ Time Frame: 30 days ]
  To identify how many patients (in each group) have a history of autoimmune disease
• Composite of MACE [ Time Frame: 30 days ]
  To identify major cardiovascular events - death, ventricular arrhythmia, heart block, cardiomyopathy, heart failure
• Relationship between severity, duration of hospitalization, and degrees of organ involvement between those who develop symptoms following one dose versus those following two doses of the mRNA vaccine. [ Time Frame: 3 months ]
  To assess the relationship between severity, duration of hospitalization, and degrees of organ involvement between those who develop symptoms following one dose versus those following two doses of the mRNA vaccine.
• Relationship between the dosing interval of vaccine and incidence of inflammatory heart disease. [ Time Frame: 30 days ]
  To assess the relationship between the dosing interval of vaccine and incidence of inflammatory heart disease.
• The potential predictors of severe disease [ Time Frame: 3 months ]
  To identify predictors as indicated by prolonged hospitalization, evidence of ventricular dysfunction or extensive inflammation will be identified.
• Analysis of immune cell profiles [ Time Frame: 30 days ]
  Blood samples for those who develop myocarditis/pericarditis vs those who are free from these adverse events, as controls.

Current Secondary Outcome Measures (submitted: March 14, 2022)

• Recurrence of myocarditis/pericarditis [ Time Frame: 3 months, 6 months, 12 months, every year for 4 years ]
  similar symptoms compared to baseline
• Atrial arrhythmias [ Time Frame: 3 months, 6 months, 12 months, every year for 4 years ]
  irregular atrial heart rhythms
• Cardiovascular mortality [ Time Frame: 3 months, 6 months, 12 months, every year for 4 years ]
  death from any cardiac cause
• Quality of life data [ Time Frame: 3 months, 6 months, 12 months, every year for 4 years ]
  EQ-5D-5L questionnaires

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: COVID-19 Vaccine-induced Inflammatory Heart Disease Prevalence Registry
• Official Title: COVID-19 Vaccine-induced Inflammatory Heart Disease Prevalence Registry (COVID-VIHPR)

Brief Summary

Myocarditis and pericarditis are inflammatory diseases of the myocardium and pericardium, and can be related to different causes, including vaccines. In the past, some people developed inflammatory heart disease after receiving a live or inactive virus vaccine (smallpox vaccine or flu vaccine). Myocarditis was also seen in people with COVID-19. More recently, many countries reported that some people have developed an inflammatory condition of the myocardium or pericardium after receiving a vaccine for COVID-19.

After the COVID-19 vaccination campaigns, doctors have noticed more people presenting to the Emergency Department with chest pain and shortness of breath after receiving the vaccine, symptoms that resemble myocarditis or pericarditis. These symptoms may start between 2 to 10 days following vaccination and are frequently noticed after the second dose of the vaccines. While pericarditis seems to affect people of various age groups and gender, myocarditis is more commonly seen in young males.

The study will consist of three components. First, the vaccine-induced inflammatory heart disease registry will be established. It will include a retrospective cohort study (chart review). Second, patients with persistent symptoms will be invited to participate in additional research-blood work and a 3-month telephone interview, as some of the patients may display chronic symptoms after developing the condition. Third, there will be a prospective, pragmatic design case-control study. We will collect clinical information and include blood samples for biomarkers twice for cases and once for controls and retrospective patients with persistent symptoms. Follow-up telephone interview will be conducted at the 3 months, 6 months, 12 months and yearly up to 4 years. A record search will also be performed at 6 months, 12 months and yearly for 4 years.

The retrospective component of the study will be conducted by identifying patients previously diagnosed with this condition at participating centres.

Detailed Description

The study will consist of three components. First, the vaccine-induced inflammatory heart disease registry will be established. This will include a retrospective chart review in provinces across Canada. Second, patients with persistent symptoms, identified in the retrospective chart review, will be asked to participate in research bloodwork and phone call follow-ups. Third, there will be a prospective, pragmatic design case-control study.

This will be a multi-center study conducted in centers in Canada that treat post-vaccine inflammatory heart disease in both the inpatient and outpatient settings. In Ontario, the major hospitals will include CHEO, London, Toronto, Hamilton, and Kingston.

Patients will be invited to participate in the Registry when they present to the Emergency Department, during inpatient admission, or in the Cardiology Outpatient Clinic. Patients will be invited to ask a relative or friend to contact the research site to serve as controls. The retrospective component of the study will be conducted by identifying patients previously diagnosed with this condition at participating centers.

At some centers, we will collect clinical information and include blood samples for biomarkers at the baseline/recruitment visit and first follow-up visit for cases and at a research study visit for controls. The follow-up visit is expected to be between 4 and 12 weeks after the initial visit. The research blood samples will be stored and processed at the Ottawa Heart Institute.

The UOHI will see the patients for clinical purposes and the research data will be captured at the same time points. These are expected at baseline/initial visit and then a 4-12-weeks follow-up visit. Clinical assessments and bloodwork will be conducted at the two visits. Subsequent follow-up via telephone interview will be conducted after 6 months, 12 months and every year for 4 years, with a script-based questionnaire to ascertain the patient's clinical status and the achievement of clinical endpoints. Patients will be asked to complete a quality-of-life questionnaire.

For the case-control study, we will establish a surveillance clinic to assess identified controls. The surveillance clinic will evaluate the clinical aspect of controls and assess whether they are at higher risk of developing post-vaccine myocarditis, myopericarditis, or pericarditis. We will draw clinical bloodwork and request a clinical Holter monitor to assess for subclinical myocarditis and arrhythmias. The Holter monitor duration can be determined by local availability, but the goal will be the shortest duration possible, for example 24-48 hrs. We will draw clinical and research bloodwork only once rather than the two time-points in the cases. We will request a research cardiac MRI for the controls to assess for subclinical myocarditis.

• Study Type: Observational [Patient Registry]
• Study Design: Observational Model: Case-Control; Time Perspective: Prospective
• Target Follow-Up Duration: 4 Years

Biospecimen

Retention:   Samples With DNA

Description:

At the time of standard-of-care bloodwork collection, additional research blood samples for biomarker assessment will be collected. Analysis of serum biomarkers such as hs-CRP, ESR, TNF-alpha, IL-1 beta IL-6, and IL-10 may help shed light on the pathway of inflammation. Antibody titres response to mRNA vaccination in younger patients will be of particular interest.

• Sampling Method: Probability Sample

Study Population

Patients who have developed symptoms after receiving a COVID-19 vaccine and meet the inclusion and exclusion criteria are eligible to participate in the registry.

Family members, vaccinated in a similar timeframe, with similar technology vaccine (e.g. any mRNA) but did not experience myocarditis side-effects - as a negative controls. If a relative is not available, voluntary controls who received the same type of COVID-19 vaccine in a similar time frame can be recruited (friends, roommates) Alternatively, if family members also had similar reactions, they can be recruited as positive controls.

For the retrospective registry, we would also collect data on COVID-19 myocarditis and pericarditis and all other etiologies of myocarditis or pericarditis.

Condition

• Myocarditis
• Pericarditis

• Intervention: Not Provided

Study Groups/Cohorts

• Prospective (cases)
  Patients who develop new symptoms of suspected myocarditis/pericarditis within 42 days of receiving a COVID-19 vaccination. The clinical symptoms include chest pain, pressure, or discomfort; dyspnea, shortness of breath, or pain with breathing; palpitations; diaphoresis or sudden death. The symptoms can also be non-specific, including fatigue, abdominal pain, dizziness or syncope, edema, cough or irritability, vomiting, poor feeding, tachypnea or lethargy in young children
• Prospective (Control Positive)
  Family members/relatives who have been vaccinated in a similar timeframe with the participant and had similar reactions
• Prospective (Control Negative)

  Family members/relatives who have been vaccinated in a similar timeframe with the participants but did not experience myocarditis side-effects.

  If a relative is not available, then a voluntary control who has received the same COVID-19 vaccine in a similar time frame can be recruited.

• Retrospective
  Identified patients, previously diagnosed with the condition, at participating centers

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 14, 2022): 400
• Original Estimated Enrollment (submitted: September 14, 2021): 318
• Estimated Study Completion Date: December 31, 2026
• Estimated Primary Completion Date: December 30, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. All patients eligible for vaccination with a COVID-19 vaccine,

2. At least one cardiac symptom of suspected myocarditis/pericarditis within 42 days of receiving a COVID-19 vaccination. The clinical symptoms include chest pain, pressure, or discomfort; dyspnea, shortness of breath/dyspnea/pain with breathing, palpitations, diaphoresis, syncope, or sudden death.

   OR At least two non-specific symptoms within 42 days of receiving a COVID-19 vaccination. These symptoms include fatigue, abdominal pain, dizziness or syncope, edema, or cough.

   OR In infants and young children, can also have at least two non-specific symptoms within 42 days of receiving a COVID-19 vaccination. These symptoms include irritability, vomiting, poor feeding, tachypnea, or lethargy.

   OR No symptoms, but abnormal histopathology or a combination of abnormal cardiac biomarkers with abnormal cardiac imaging (echo or MRI)

3. At least one of the following:

   1. a. Elevations in Troponin T, Troponin I, or CK-MB (above threshold of normal)
   2. Abnormal MRI (per Brighton Criteria Case Definitions, see Appendix 2 and 3)
   3. Any new or worsening cardiac arrhythmias on ECG or telemetry or Holter monitor (per Brighton Criteria Case Definitions, see Appendix 2 and 3) including those that normalize on recovery.
   4. Abnormal Echocardiographic findings (per Brighton Criteria Case Definitions, see Appendix 2 and 3)
   5. Physical exam finding: Pericardial friction rub or pulsus paradoxus
   6. Pericardial fluid or inflammation by imaging (echo, MRI, or CT) or at least one of the following elevated biomarkers of inflammation: ESR, CRP, hs-CRP, or D-Dimer.
   7. Enlarged heart on chest radiograph.
   8. Histopathologic examination of myocardial tissue (autopsy or endomyocardial biopsy) showed myocardial inflammation

Exclusion Criteria:

1. Clear alternative diagnosis or explanation for the symptoms and findings (e.g. infectious myocarditis such as Lyme carditis). Note: Work-up of alternative diagnosis is dependent on clinical presentation e.g. Lyme carditis (e.g. endemic area, season, bullseye rash) or autoimmune heart disease (e.g. arthritis, rash, recurrence).
2. Symptoms after 42 days of vaccination.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 5 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Peter Liu, MD; 6136967351; pliu@ottawaheart.ca

Contact: Ermina Moga; 6136967000 ext 10945; emoga@ottawaheart.ca

• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT05046002
• Other Study ID Numbers: CTO 3740
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided
• Plan Description: To be determined

• Current Responsible Party: Ottawa Heart Institute Research Corporation
• Original Responsible Party: Same as current
• Current Study Sponsor: Ottawa Heart Institute Research Corporation
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Peter Liu, MD; Ottawa Heart Institute Research Corporation

• PRS Account: Ottawa Heart Institute Research Corporation
• Verification Date: May 2023