The goal of this proof-of-concept clinical trial is to determine whether cardiacrehabilitation improves exercise capacity and chronotropic (heart rate) response toexercise among people with Long COVID. The study will include individuals with confirmedSARS-CoV-2 infection, symptoms not present prior to COVID-19 that are persistent for atleast 3 months after acute infection ("Long COVID"), and who have reduced exercisecapacity less than predicted and reduced heart rate response during cardiopulmonaryexercise testing (CPET). In addition to the primary outcome of change in peak VO2,secondary outcomes will include change in symptoms including autonomic symptoms(COMPASS-31), anxiety (GAD-7), depression (PHQ-9), endothelial function with brachialartery flow-mediated dilation, and satisfaction (net-promotor score).
Study Overview
This single-center, proof-of-concept mechanistic study of cardiac rehabilitation will use
a pre-post design to establish whether there is any effect of cardiac rehabilitation on
adjusted heart rate reserve achieved and peak oxygen consumption (peak VO2) in LC.
Once a participant is identified as potentially eligible, they will be contacted by the
study team. Participants will be asked to co-enroll in the Long-term Impact of Infection
with Novel Coronavirus observational cohort ("LIINC" NCT 04362150). If participants do
not agree to be co-enrolled in LIINC (if they are not already included) and the
Cardiovascular Sub-Study, they will not be allowed to enroll.
Participants will be consented by the PI or research team before any procedures take
place. Participants who provide written informed consent and meet the inclusion criteria
will be enrolled into the study. They undergo a series of baseline measurements as
outlined in the Schedule of Events. They will participate in 12 weeks of cardiac
rehabilitation and then undergo follow-up measurements to determine the safety, clinical
impact, and biological impact of the therapy as outlined in the Schedule of Events.
Blood collection will occur at baseline and after completion of cardiac rehabilitation as
per the Schedule of Events and will be timed to stay within Red Cross Guidelines (less
than 480 mL every 8 weeks).
The details of the visit schedule are outlined below. Ultimately, the most up to date
Schedule of Events will be the final guide for what events are to occur at each specific
study visit.
Informed Consent
The study PI or their designee will explain the risks and benefits of the study and
obtain written informed consent. Those who consent to participate in the study will
undergo a Screening Assessment.
Screening Assessment
Assessments performed exclusively to determine eligibility for this study will be
performed only after obtaining informed consent. Assessments performed for clinical
indication (not exclusively to determine study eligibility) or other research studies may
be used for screening even if the studies were performed before informed consent was
obtained. For example, a screening cardiopulmonary exercise test may be used to establish
eligibility that was performed through clinical practice or for research through the
LIINC study or RECOVER. However, these measurements may be repeated at the discretion of
the PI.
Following informed consent, study screening will occur during a period of one or more
visits. The Screening Assessment will include a physical examination by a study clinician
(physician, nurse, or physician assistant). Details of the participant's COVID-19 history
will be reviewed and/or confirmed, and a symptom assessment will be performed.
Baseline Assessments
After consenting but prior to starting cardiac rehabilitation, all participants will
undergo baseline assessments including symptom assessments, cardiopulmonary exercise
testing and vascular function studies.
Intervention
Participants who screen into the study and complete baseline measurements will then start
standard of care cardiac rehabilitation at University of California, San Francisco (UCSF)
Parnassus Campus. Exercise prescriptions will be based on the heart rate performance
during the baseline CPET. Standard clinical assessments will be made to tailor
recommendations during the course of cardiac rehabilitation. The intensity of the
exercise prescription and level of monitoring will be tailored to the individual
participant's performance on their baseline CPET according to guidelines. Exercise will
be prescribed by a Cardiac Exercise Physiologist in accordance with standard cardiac
rehabilitation protocols. Resistance exercise activities will also be incorporated.
Recumbent exercise will be utilized based on assessment by exercise physiologist and
patient. Dietary counseling, smoking cessation counseling for smokers, and medication
counseling will be incorporated according to standard cardiac rehabilitation protocols.
Participants are asked to commit to attending at least 24 sessions, of which 12 (one per
week for 12 weeks) must be in person at UCSF Parnassus. Participants will be allowed to
select a fully in-person approach (36 sessions) or hybrid approach (12-24 in person,
12-24 virtual for up to 36 total sessions).
Duration of intervention: 12 weeks
Follow Up Assessments (Week 12) After completion of cardiac rehabilitation (approximately
12 weeks after start), participants will complete the follow up assessments within 2
weeks, which will include the same assessments as baseline as well as an assessment of
satisfaction with cardiac rehabilitation as measured with the net-promotor score.
Behavioral: Cardiac Rehabilitation
Exercise prescriptions will be based on the heart rate performance during the baseline
CPET. The intensity of the exercise prescription and level of monitoring will be tailored
to the individual participant's performance on their baseline CPET according to
guidelines. Exercise will be prescribed by a Cardiac Exercise Physiologist in accordance
with standard cardiac rehabilitation protocols. Resistance exercise activities will also
be incorporated. Recumbent exercise will be utilized based on assessment by exercise
physiologist and patient. Dietary counseling, smoking cessation counseling for smokers,
and medication counseling will be incorporated according to standard cardiac
rehabilitation protocols. Participants are asked to commit to attending at least 24
sessions, of which 12 (one per week for 12 weeks) must be in person. Participants will be
allowed to select a fully in-person approach (36 sessions) or hybrid approach (12-24 in
person, 12-24 virtual for up to 36 total sessions).
Inclusion Criteria:
1. Age 18 years or older
2. Previously documented SARS-CoV-2 RNA positivity from an oral or nasal swab, as
measured by a nucleic acid amplification test, documented positive antigen testing,
or positive nucleocapsid antibody. Documentation of the positive test is required.
3. Presence of persistent symptoms, defined as at least one COVID-attributed symptom
newly present during acute illness or worse than baseline and reported to still be
present for at least 90 days following symptom onset. This will be ascertained using
study case report forms.
4. Reduced exercise capacity <85% predicted and adjusted heart rate reserve achieved
<80% on maximal CPET (RER>1.05). If there are difficulties with recruitment we may
include individuals with exercise capacity between 85-99% predicted.
5. Willing and able to actively participate in cardiac rehabilitation including
attending at least 12 in person sessions at UCSF Parnassus.
6. Agree to participate in the LIINC Study including the cardiovascular substudy if
they are not already participating.
Exclusion Criteria:
1. Pregnant or intention to become pregnant during study
2. Pre-existing congenital heart disease, heart failure, pulmonary hypertension, heart
or lung transplant, or cardiac valve surgery
3. Myocardial infarction, or coronary artery bypass graft surgery, or new diagnosis of
heart failure with a reduced ejection fraction <40% within 90 days prior to
enrollment (Class I indications for cardiac rehabilitation)
4. Acute myocarditis diagnosed <90 days prior
5. Atrial fibrillation, atrial flutter, or other arrhythmias requiring antiarrhythmic
therapy
6. Use of beta-blockers, non-dihydropyridine calcium channel blockers or ivabradine
7. Implanted pacemaker or defibrillator
8. Chronic lung disease requiring the use of home oxygen therapy
9. Inability to ride a sitting bicycle for CPET
10. Severe post-exertional malaise or symptom worsening that would preclude
participation in cardiac rehabilitation
11. Medical or psychological comorbidities that would prevent safe participation in the
trial, in the opinion of the Principal Investigator
University of California, San Francisco
San Francisco, California, United States
Investigator: Matthew Durstenfeld, MD MAS
Contact: 628-206-5562
matthew.durstenfeld@ucsf.edu
Matthew S Durstenfeld, MD MAS
628-206-5562
matthew.durstenfeld@ucsf.edu
Matthew S Durstenfeld, MD MAS, Principal Investigator
University of California, San Francisco