RECOVER-AUTONOMIC: Platform Protocol, Appendix A (IVIG)

Phase 2

Recruiting

• Conditions: Long COVID; Long Coronavirus Disease 2019 (Covid19); Long Covid-19
• Interventions: Drug: IVIG (intravenous immunoglobulin); Drug: IVIG Placebo; Behavioral: Usual Care; Behavioral: Coordinated Care

• Registration Number: NCT06305793
• Lead Sponsor: Kanecia Obie Zimmerman

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 Post-Acute Sequelae of SARS-CoV-2 infection (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.

Study Timeline

• Study First Submitted: 2024-03-04
• Study First Submitted QC: 2024-03-08
• Study Start: 2024-03-11
• Study First Posted: 2024-03-12
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-19
• Last Update Posted: 2025-05-20
• Primary Completion: 2026-09
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

• See NCT06305780 for RECOVER-AUTO: Platform Protocol level inclusion criteria which applies to this appendix (or sub-study)

Additional Appendix A (IVIG 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 > 40

Exclusion Criteria

• See NCT06305780 for RECOVER-AUTO: Platform Protocol level exclusion criteria which applies to this appendix (or sub-study)

Additional Appendix A (IVIG Sub-study) Level Exclusion Criteria:

1. Current or previous IVIG treatment
2. Contraindication to intravenous immunoglobulin.
3. Known allergic reactions to blood products including IVIG and/or subcutaneous immunoglobulin (SCIG), such as history of clinically relevant hemolysis after IVIG infusion, aseptic meningitis, recurrent severe headache, hypersensitivity, severe generalized or severe local skin reactions
4. Selective IgA deficiency
5. Current and recent (within 5 half-lives) use of high-dose corticosteroids (for example for prior solid organ transplant), omalizumab, anti-TNF-alpha inhibitors
6. Use of immunosuppressants such as Plaquenil, or low-dose steroid (prednisone, no more than 10mg a day) will be excluded unless the participant is on stable (>4 weeks) dose
7. Significant thrombotic events after the acute phase of COVID-19 and/or within 6 months of enrollment
8. Veins that are not viable for infusions
9. Not willing to adhere to dosing schedule for IVIG infusions for 9 months

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IVIG Placebo + Usual Care	Usual Care	Saline: Same dosage as IVIG; monthly for 9 months (36 weeks)
IVIG + Usual Care	IVIG (intravenous immunoglobulin)	IVIG (Gamunex); 2g /kg monthly for 9 months (36 weeks)
IVIG + Coordinated Care	IVIG (intravenous immunoglobulin)	IVIG (Gamunex); 2g /kg monthly for 9 months (36 weeks)
IVIG + Usual Care	Usual Care	IVIG (Gamunex); 2g /kg monthly for 9 months (36 weeks)
IVIG + Coordinated Care	Coordinated Care	IVIG (Gamunex); 2g /kg monthly for 9 months (36 weeks)
IVIG Placebo + Coordinated Care	Coordinated Care	Saline: Same dosage as IVIG; monthly for 9 months (36 weeks)
IVIG Placebo + Coordinated Care	IVIG Placebo	Saline: Same dosage as IVIG; monthly for 9 months (36 weeks)
IVIG Placebo + Usual Care	IVIG Placebo	Saline: Same dosage as IVIG; monthly for 9 months (36 weeks)

Primary Outcome Measures

Name	Time	Method
Change in Orthostatic Hypotension Questionnaire (OHQ)/Orthostatic Intolerance Questionnaire (OIQ) Composite Score	Baseline to End of Intervention (9 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 Outcome Measures

Name	Time	Method
Incidence of Events of Special Interest (ESIs)	Baseline to Follow-up (12 months)	Each study drug may have a unique list of ESIs
Proportion of participants who experience individual (SAEs	Baseline to Follow-up (12 months)	These will be analyzed in the safety population.
Proportion who experience any one or more ( Serious Adverse Event) SAEs	Baseline to Follow-up (12 months)	These will be analyzed in the safety population.
Change in heart rate (HR)	Baseline to End of Intervention (9 months)	measured during Active Stand Test
Change in Active Stand Test	Baseline to End of Intervention (9 months)	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
Change in blood pressure	Baseline to End of Intervention (9 months)	measured during Active Stand Test
Change in 6-min Walk Test	Baseline to End of Intervention (9 months)	Normal walking speed will be measured using a standard 6 minute walk
Change in heart rate as measured by a wearable device	Baseline to End of Intervention (9 months)	measured by activity tracker
Change in Composite Autonomic Symptoms Score 31 (COMPASS-31)	Baseline to End of Intervention (9 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 Patient-Reported Outcomes Measurement Information System (PROMIS-29) + 2 Questionnaire	Baseline to End of Intervention (9 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.
Change in step count as measured by a wearable device	Baseline to End of Intervention (9 months)	measured by activity tracker
Change in Malmo POTS Symptom Score	Baseline to End of Intervention (9 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.
Incidence of SAEs leading to discontinuation	Baseline to Follow-up (12 months)	These will be analyzed in the safety population.

Trial Locations

Locations (1)

All sites listed under NCT06305780; 🇺🇸 Durham, North Carolina, United States