Clinical trial NCT06305806: RECOVER-AUTONOMIC: Platform Protocol, Appendix B (Ivabradine)
Official title: RECOVER-AUTONOMIC (Ivabradine): Randomized Trial of the Effect of Ivabradine Versus Placebo on Long COVID Symptoms
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Long COVID
Long Covid19
Long Covid-19
Keywords: PASC
POTS
Lead sponsor: Duke University
Sponsor class: OTHER
First posted: 2024-03-12
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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 (an increase of 30 beats per minute (bpm) or more in HR within 10 minutes upon standing without orthostatic hypotension) and experiencing orthostatic symptoms
2. COMPASS-31 Score \> 25 and not enrolled in the IVIG appendix

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 the following medications: clonidine, tizanidine, amphetamines, and serotonin and norepinephrine reuptake inhibitors (SNRIs) with the exception of modafinil
3. Use of beta-blockers (any formulation), calcium channel blockers, 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.
4. Combination with verapamil or diltiazem which are moderate CYP3A4 inhibitors with heart rate reducing properties
5. Lactating and breast-feeding women
6. Severe hepatic impairment
7. Use of drugs known to prolong the QT-interval (e.g., quinidine, disopyramide, bepridil, sotalol, amiodarone, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine
8. Concomitant use of digoxin
9. Participants who are pacemaker dependent
10. Patients with hypokalemia (serum K+\<3.5 mEq/L)
11. Patients taking potassium-depleting diuretics
12. A history of congenital or acquired long QT syndrome, with or without torsade de pointes
13. Patients with high degree AV block such as Mobitz II

Primary outcomes:
measure: Change in Orthostatic Hypotension Questionnaire (OHQ)/Orthostatic Intolerance Questionnaire (OIQ) Composite Score
timeFrame: Baseline to End of Intervention (3 months)
Secondary outcomes:
measure: Change in Composite Autonomic Symptoms Score 31 (COMPASS-31)
timeFrame: Baseline to End of Intervention (3 months)
measure: Change in Malmo POTS Symptom Score
timeFrame: Baseline to End of Intervention (3 months)
measure: Change in Active Stand Test
timeFrame: Baseline to End of Intervention (3 months)
measure: Change in blood pressure (BP)
timeFrame: Baseline to End of Intervention (3 months)
measure: Change in heart rate (HR)
timeFrame: Baseline to End of Intervention (3 months)
measure: Change in 6-min Walk Test
timeFrame: Baseline to End of Intervention (3 months)
measure: Change in PROMIS-29 + 2 Questionnaire
timeFrame: Baseline to End of Intervention (3 months)
measure: Change in step count as measured by a wearable device
timeFrame: Baseline to End of Intervention (3 months)
measure: Change in heart rate as measured by a wearable device
timeFrame: Baseline to End of Intervention (3 months)
measure: Proportion of participants who experience individual SAEs
timeFrame: Baseline to Follow-up (6 months)
measure: Proportion who experience any one or more SAEs
timeFrame: Baseline to Follow-up (6 months)
measure: Incidence of SAEs leading to discontinuation
timeFrame: Baseline to Follow-up (6 months)
measure: Incidence of Events of Special Interest (ESIs)
timeFrame: Baseline to Follow-up (6 months)
Other outcomes:
measure: Changes in Autonomic Function Testing
timeFrame: Baseline to End of Intervention (3 months)
measure: Change in Vanderbilt Orthostatic Symptoms Score (VOSS)
timeFrame: Baseline to End of Intervention (3 months)
measure: Change in PASC Symptom Questionnaire
timeFrame: Baseline to End of Intervention (3 months)
Locations:
city: Durham
country: United States
facility: All sites listed under NCT06305780
state: North Carolina
Study officials:
affiliation: Duke Clinical Research Institute
name: Christopher Grainger, MD
role: STUDY_CHAIR
affiliation: Vanderbilt University Medical Center
name: Cyndya Shibao, MD
role: STUDY_CHAIR
affiliation: Harvard
name: Peter Novak, MD
role: STUDY_CHAIR
affiliation: University of California, San Diego
name: Pam Taub, MD
role: STUDY_CHAIR
affiliation: Johns Hopkins University
name: Tae Chung, MD
role: STUDY_CHAIR
References: