RECOVER-AUTONOMIC Platform Protocol

Long COVID Clinical Trial

Official title:

RECOVER-AUTONOMIC: A Platform Protocol for Evaluation of Interventions for Autonomic Dysfunction in Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT06305780
• Other study ID #: Pro00112597
• Secondary ID: OTA-21-015G
• Status: Enrolling by invitation
• Phase: Phase 2
• Start date: March 11, 2024
• Est. completion date: March 2026

Study information

• Verified date: April 2024
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 380
• Est. completion date: March 2026
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. = 18 years of age at the time of enrollment

2. Previous suspected, probable, or confirmed SARS-CoV-2 infection, as defined by the Pan American Health Organization12? ? Enrollment of participants with suspected or probable SARS-CoV-2 infection will only be allowed if they occurred before May 1, 2021 and be limited to no more than 10% of the total sample size per Study Drug Appendix. Refer to the Manual of Procedures (MOP) for details. Suspected case of SARS-CoV-2 infection - Three options, A through C: A. Meets the clinical OR epidemiological criteria.

1. Clinical criteria: Acute onset of fever AND cough (influenza-like illness) OR Acute onset of ANY THREE OR MORE of the following signs or symptoms: fever, cough, general, weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, nausea, diarrhea, anorexia.

2. Epidemiological criteria: Contact of a probable or confirmed case or linked to a COVID-19 cluster; or B. Presents with acute respiratory infection with history of fever or measured fever of = 38°C; and cough; with onset within the last 10 days; and who requires hospitalization); or C. Presents with no clinical signs or symptoms, NOR meeting epidemiologic criteria with a positive professional use or self-test SARS-CoV-2 antigen-Rapid Diagnostic Test. Probable case of SARS-CoV-2 infection, defined as meets clinical criteria above AND is a contact of a probable or confirmed case or is linked to a COVID-19 cluster. Confirmed case of SARS-CoV-2 infection - Two options, A through B: A. A person with a positive nucleic acid amplification test, regardless of clinical criteria OR epidemiological criteria; or B. Meeting clinical criteria AND/OR epidemiological criteria (See suspect case A). With a positive professional use or self-test SARS-CoV-2 Antigen-Rapid Diagnostic Test.

3. Moderate, self-identified autonomic symptoms (defined as COMPASS-31 >25) following a SARS-CoV-2 infection that has persisted for at least 12 weeks and is still present at the time of consent

4. OHQ/OIQ, question 1 score >2

Exclusion Criteria:

1. Known pregnancy, breast-feeding, or contemplating pregnancy during the study period

2. Known active acute SARS-CoV-2 infection = 4 weeks from enrollment

3. Known renal failure (eGFR <20ml/1.73 m²)

4. Known atrial fibrillation or significant cardiac arrhythmia

5. Known cardiovascular conditions such as heart failure (Class 3-4), severe valvular disease, symptomatic ischemic coronary artery disease, revascularization for PAD/CAD within the past 6 months

6. Clinically significant atherosclerotic disease, defined as history of stroke or myocardial infarction or revascularization 6 months prior to enrollment and/or current symptomatic angina

7. Existing uncontrolled hypertension

8. History of significant hypercoagulability disorders

9. Active or recent thrombosis

Related Conditions & MeSH terms

• COVID-19
• Long COVID
• Long Covid-19

Intervention

Drug:
• IVIG + Coordinated Care
Participants will receive IVIG for a duration of 9 months and coordinated non-pharmacologic care for a duration of 3 months, concurrent with IVIG administration. Coordinated non-pharmacologic care involves volume expansion through high salt diet, water intake, abdominal binder, exercise/rehabilitation, motivation, education, and assisted care through a care coordinator.
• IVIG Placebo + Coordinated Care
Normal saline given intravenously will be the control (placebo) product. Blinding IV bag and tubing covers will be used for both IVIG and Placebo administration. Participants will receive IVIG placebo for a duration of 9 months and coordinated non-pharmacologic care for a duration of 3 months, concurrent with IVIG placebo administration. Coordinated non-pharmacologic care involves volume expansion through high salt diet, water intake, abdominal binder, exercise/rehabilitation, motivation, education, and assisted care through a care coordinator.
• Ivabradine + Coordinated Care
Participants will receive Ivabradine for a duration of 3 months and 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.
• Ivabradine Placebo + Coordinated Care
The control (placebo) oral tablets will be similar to the study drug, ivabradine. The control packaging matches the packaging. Participants will receive Ivabradine placebo for a duration of 3 months and coordinated non-pharmacologic care for a duration of 3 months, concurrent with ivabradine placebo administration. Coordinated non-pharmacologic care involves volume expansion through high salt diet, water intake, abdominal binder, exercise/rehabilitation, feedback, nutrition counseling, motivation, education, and assisted care through care coordinator.
• IVIG + Usual Care
Participants will receive IVIG for a duration of 9 months and usual non-pharmacologic care (control) for a duration of 3 months. This will be concurrent with scheduled IVIG administration.
• IVIG Placebo + Usual Care
Normal saline given intravenously will be the control (placebo) product. The normal saline will be of similar formulation and appearance to IVIG. Participants will receive IVIG placebo for a duration of 9 months and usual non-pharmacologic care (control) for a duration of 3 months. This will be concurrent with scheduled IVIG placebo administration.
• Ivabradine + Usual Care
Participants will receive Ivabradine for a duration of 3 months and usual non-pharmacologic care (control) for a duration of 3 months, concurrent with ivabradine administration.
• Ivabradine Placebo + Usual Care
The control (placebo) oral tablets will be similar to the study drug, ivabradine. The control packaging matches the packaging. Participants will receive Ivabradine placebo for a duration of 3 months and usual non-pharmacologic care (control) for a duration of 3 months, concurrent with ivabradine placebo administration.

Locations

Country	Name	City	State
United States	University of Colorado Anschutz Medical Campus Clinical and Translational Research Center (CTRC) - Appendix A & B	Aurora	Colorado
United States	St. Lawrence Health Medical Campus - Appendix A & B	Canton	New York
United States	University of Virginia Health System, University Hospital - Appendix A & B	Charlottesville	Virginia
United States	Rush University Medical Center - Appendix A & B	Chicago	Illinois
United States	NorthShore University HealthSystem - Evanston Hospital - Appendix B Only	Evanston	Illinois
United States	University of Kansas Medical Center CTSU Fairway - Appendix A & B	Fairway	Kansas
United States	East Carolina University - Appendix A & B	Greenville	North Carolina
United States	University of Kentucky Medical Center - Appendix A & B	Lexington	Kentucky
United States	Cedars Sinai Medical Center - Appendix A & B	Los Angeles	California
United States	Sentara Norfolk General Hospital - Appendix A & B	Norfolk	Virginia
United States	University of Oklahoma Health Science Center - Oklahoma Clinical and Translational Science Institute - Appendix A & B	Oklahoma City	Oklahoma
United States	Bateman Horne Center - Appendix B Only	Salt Lake City	Utah
United States	Providence Medical Research Center - Appendix A & B	Spokane	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Kanecia Obie Zimmerman

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in Autonomic Function Testing	Head-up tilt (HUT) test; Valsalva maneuver with a pressure of 40 mmHg for 15 seconds; Deep breathing test; Skin biopsy (if applicable as per Appendix); Transcranial doppler (TCD), if available	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Other	Change in Vanderbilt Orthostatic Symptoms Score (VOSS)	The VOSS consists of 9 orthostatic symptoms rated on a scale of 0 (no symptom) to 10 (worst the participant has experienced) at the end of each Head-up Tilt test. Scores range from 0-90 with higher scores representing worse symptoms.	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Other	Change in PASC Symptom Questionnaire	Participants will be asked to complete a questionnaire that asks about the presence of PASC symptoms. This questionnaire includes additional PASC symptoms that are not directly related to autonomic dysfunction.	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Primary	Change in Orthostatic Hypotension Questionnaire (OHQ)/Orthostatic Intolerance Questionnaire (OIQ) Composite Score	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.	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Secondary	Change in Composite Autonomic Symptoms Score 31 (COMPASS-31)	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.	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Secondary	Change in Malmo POTS Symptom Score	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.	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Secondary	Change in Active Stand Test	Participants will remain supine for 10 minutes, and data will be acquired at 5 and 10 minutes. Standing test should be performed with HR and BP monitoring at 1, 3, 5 and 10 minutes	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Secondary	Change in blood pressure	measured from Active stand test	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Secondary	Change in heart rate (HR)	measured from Active stand test	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Secondary	Change in 6-min Walk Test	Normal walking speed will be measured using a standard 6 minute walk	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Secondary	Change in PROMIS-29 + 2 Questionnaire	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.	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Secondary	Change in step count as measured by a wearable device	measured by activity tracker	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Secondary	Change in heart rate as measured by a wearable device	measured by activity tracker	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Secondary	Proportion of participants who experience individual SAEs	These will be analyzed in the safety population.	Baseline to Follow-up (IVIG 12 months, Ivabradine 6 months)
Secondary	Proportion who experience any one or more SAEs	These will be analyzed in the safety population.	Baseline to Follow-up (IVIG 12 months, Ivabradine 6 months)
Secondary	Incidence of SAEs leading to discontinuation	These will be analyzed in the safety population.	Baseline to Follow-up (IVIG 12 months, Ivabradine 6 months)
Secondary	Incidence of Events of Special Interest (ESIs)	Each study drug may have a unique list of ESIs	Baseline to Follow-up (IVIG 12 months, Ivabradine 6 months)

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