Long COVID, Long Covid19, Long Covid-19
Conditions
Keywords
PASC, POTS
Brief summary
This study is a platform protocol designed to be flexible so that it is suitable for a wide range of settings within health care systems and in community settings where it can be integrated into COVID-19 programs and subsequent treatment plans. This protocol is a prospective, multi-center, multi-arm, randomized, controlled platform trial evaluating various interventions for use in the treatment of autonomic dysfunction symptoms, including cardiovascular complications and postural orthostatic tachycardia syndrome (POTS), in PASC participants. The interventions tested will include non-pharmacologic care and pharmacologic therapies with study drugs.
Detailed description
The hypothesis is that some of the autonomic dysfunction symptoms are immune-mediated, so immunotherapy and other applicable therapies will result in improvement in autonomic symptoms. Interventions will be added to the platform protocol as appendices. Each appendix will leverage all elements of the platform protocol, with additional elements described in the individual appendix.
Interventions
DRUGIvabradine Placebo
The control (placebo) oral tablets will be similar to the study drug, ivabradine. The control packaging matches the packaging. Participants will receive placebo for 3 months (12 weeks) with a follow-up period for an additional 3 months (total study duration of 6 months).
DRUGIvabradine
Participants will receive ivabradine for 3 months (12 weeks) with a follow-up period for an additional 3 months (total study duration of 6 months).
BEHAVIORALCoordinated Care
Participants will receive coordinated non-pharmacologic care for a duration of 3 months, concurrent with ivabradine administration. Coordinated non-pharmacologic care involves volume expansion through high salt diet, water intake, abdominal binder, exercise/rehabilitation, motivation, education, and assisted care through care coordinator.
BEHAVIORALUsual Care
Participants will receive usual non-pharmacologic care (control) for a duration of 3 months, concurrent with ivabradine administration.
Sponsors
Kanecia Obie Zimmerman
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double blind
Intervention model description
In each Appendix trial, each participant will be assigned with equal probability to one of the factorial combinations based on two factors: (1) a study intervention/control and (2) non-pharmacologic intervention/control if the participant is eligible for the study intervention.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* See NCT06305780 for RECOVER-AUTO: Platform Protocol level inclusion criteria which applies to this appendix (or sub-study) Additional Appendix B (Ivabradine Sub-study) Level Inclusion Criteria: 1\. Abnormal active standing test defined as presence of orthostatic tachycardia and experiencing orthostatic symptoms. Orthostatic tachycardia defined as: Increase of 30 beats per minute (bpm) or more in HR within 10 minutes upon standing without orthostatic hypotension (decline of ≥ 20 mmHg of systolic or ≥ 10 mmHg of diastolic blood pressure after 3 minutes of standing) OR History of documented increase of 30 bpm or more from an active stand test or tilt table test without orthostatic hypotension in the past 1 year AND standing HR above 100 bpm at the Screening/Baseline visit active stand test. Exclusions Criteria: * See NCT06305780 for RECOVER-AUTO: Platform Protocol level inclusion criteria which applies to this appendix (or sub-study) Additional Appendix B (Ivabradine Sub-study) Level
Exclusion criteria
1. A person of child-bearing potential who is not taking effective contraception 2. Use of midodrine, pyridostigmine, fludrocortisone, and guanfacine will be excluded unless participant is on a stable dose (\>4 weeks). Participants on stable doses will be allowed to continue the medication throughout the study 3. Combination with verapamil or diltiazem which are moderate CYP3A4 inhibitors with heart rate reducing properties 4. Severe hepatic impairment 5. Use of drugs known to prolong the QT-interval (e.g., quinidine, disopyramide, bepridil, sotalol, amiodarone, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidineUse of drugs known to prolong the QT-interval (e.g., quinidine, disopyramide, bepridil, sotalol, amiodarone, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine 6. Concomitant use of digoxin or Paxlovid 7. Known history of atrial fibrillation or significant cardiac arrhythmia not due to reversible cause 8. Participants who are pacemaker dependent 9. Patients with hypokalemia (serum K+\<3.5 mEq/L) 10. Patients taking potassium-depleting diuretics, unless potassium level is normal at the baseline CMP, in which case participants may continue taking it during the study. 11. A history of congenital or acquired long QT syndrome, with or without torsade de pointes 12. Patients with high degree AV block such as Type 2 AV block, Mobitz II
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Orthostatic Hypotension Questionnaire (OHQ)/Orthostatic Intolerance Questionnaire (OIQ) Composite Score | Baseline to End of Intervention (3 months) | The OHQ / OIQ is a measure of orthostatic intolerance and includes a 6-item symptom assessment (OHSA) and the 4-item Daily Activity Scale (OHDAS). Each item is scored from 0 (none/no interference) to 10 (worst possible/complete interference), describing the preceding week. The OHSA composite score is the average of the first 6 non-zero items and the OHDAS composite score is the average of the last 4 non-zero items. The OHQ/OIQ composite score is the average of the OHSA and OHDAS composite scores. The OHQ/OIQ scales at post-baseline are calculated using only those items that were included in the baseline scores. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Composite Autonomic Symptoms Score 31 (COMPASS-31) | Baseline to End of Intervention (3 months) | The COMPASS-31 is a patient reported outcome that measures autonomic symptoms across multiple domains commonly seen in patients with PASC. Scores range from 0-100 with higher values representing severe symptoms. |
| Change in Malmo POTS Symptom Score | Baseline to End of Intervention (3 months) | The Malmo POTS symptom score assesses symptom burden in postural orthostatic tachycardia syndrome (POTS). It is a self-rating, 12-item score (0-10 per item, total range 0-120) based on patients' own perception of symptoms through visual analogue scale assessment. Higher scores represent more pronounced symptoms. |
| Change in heart rate (HR) | Baseline to End of Intervention (3 months) | measured during Active Stand Test |
| Change in 6-min Walk Test | Baseline to End of Intervention (3 months) | Normal walking speed will be measured using a standard 6 minute walk |
| Change in PROMIS-29 + 2 Questionnaire | Baseline to End of Intervention (3 months) | The PROMIS-29 consists of 29 items that assess general domains of health and functioning, including overall physical health, mental health, social health, pain, fatigue, and overall perceived quality of life. The PROMIS-29+2 is used to calculate a preference score (PROPr) by the addition of two Cognitive Function Ability items. Scores will be reported as T scores ranging from 0 to 100, with a score of 60 being 1 standard deviation above the mean. Higher scores indicate worse overall health. |
| Characterize the safety and tolerability of study intervention for treatment of PASC | Baseline to Follow-up (6 months) | Adverse events, including serious adverse events (SAEs) and events of special interest (ESIs). Proportion of participants who experience individual SAEs and the proportion who experience any one or more SAEs. Incidence of SAEs leading to discontinuation. Incidence of ESIs. |
Countries
United States
Contacts
STUDY_CHAIRChristopher Grainger, MD
Duke Clinical Research Institute
STUDY_CHAIRCyndya Shibao, MD
Vanderbilt University Medical Center
STUDY_CHAIRPeter Novak, MD
Harvard
STUDY_CHAIRPam Taub, MD
University of California, San Diego
STUDY_CHAIRTae Chung, MD
Johns Hopkins University
Outcome results
None listed