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

RECOVER-AUTONOMIC (IVIG): Randomized Trial of the Effect of IVIG Versus Placebo on Long COVID Symptoms

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Long COVID; Long Covid-19; Long Coronavirus Disease 2019 (Covid19)
• Intervention / Treatment: Drug: IVIG (intravenous immunoglobulin); Behavioral: Coordinated Care; Drug: IVIG Placebo; Behavioral: Usual Care

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 Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Orshi Moy; Phone Number: 919-668-7520; Email: recoverresearch@duke.edu
• Study Contact Backup: Name: Barrie L Harper, BSMT(ASCP)PMP; Email: recoverresearch@duke.edu

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • All sites listed under NCT06305780

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IVIG + Coordinated Care; IVIG (Gamunex); 2g /kg monthly for 9 months (36 weeks)	Drug: IVIG (intravenous immunoglobulin); Participants will receive IVIG for 9 months (36 weeks) with a follow-up period for an additional 3 months (total study duration for 12 months).; Behavioral: Coordinated Care; Participants will receive 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 care coordinator.
Experimental: IVIG Placebo + Coordinated Care; Saline: Same dosage as IVIG; monthly for 9 months (36 weeks)	Behavioral: Coordinated Care; Participants will receive 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 care coordinator.; Drug: IVIG Placebo; Normal saline given intravenously will be the control (placebo) product. Blinding IV bag and tubing covers will be used for both IVIG and Placebo. Participants will receive placebo for 9 months (36 weeks) with a follow-up period for an additional 3 months (total study duration for 12 months).
Experimental: IVIG + Usual Care; IVIG (Gamunex); 2g /kg monthly for 9 months (36 weeks)	Drug: IVIG (intravenous immunoglobulin); Participants will receive IVIG for 9 months (36 weeks) with a follow-up period for an additional 3 months (total study duration for 12 months).; Behavioral: Usual Care; Participants will receive usual non-pharmacologic care (control) for a duration of 3 months, concurrent with IVIG administration.
Experimental: IVIG Placebo + Usual Care; Saline: Same dosage as IVIG; monthly for 9 months (36 weeks)	Drug: IVIG Placebo; Normal saline given intravenously will be the control (placebo) product. Blinding IV bag and tubing covers will be used for both IVIG and Placebo. Participants will receive placebo for 9 months (36 weeks) with a follow-up period for an additional 3 months (total study duration for 12 months).; Behavioral: Usual Care; Participants will receive usual non-pharmacologic care (control) for a duration of 3 months, concurrent with IVIG administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 (9 months)

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 (9 months)
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 (9 months)
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 (9 months)

Collaborators and Investigators

• Sponsor: Kanecia Obie Zimmerman
• Investigators: Study Chair: Christopher Grainger, MD, Duke Clinical Research Institute; Study Chair: Cyndya Shibao, MD, Vanderbilt University Medical Center; Study Chair: Peter Novak, MD, Harvard; Study Chair: Pam Taub, MD, University of California, San Diego; Study Chair: Tae Chung, MD, Johns Hopkins University

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: March 4, 2024
• First Submitted That Met QC Criteria: March 8, 2024
• First Posted (Actual): March 12, 2024

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 5, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: POTS; PASC
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; Chronic Disease; Post-Infectious Disorders; COVID-19; Post-Acute COVID-19 Syndrome; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin
• Other Study ID Numbers: Pro00112597_A; OTA-21-015G (Other Identifier: NIH Grant to RTI; RTI subcontracting with DCRI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The summary of results will be shared on the study website: https://recovercovid.org/

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No