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| ID | Type | Description | Link |
|---|---|---|---|
| OTA-21-015G | Other Identifier | NIH Grant to RTI; RTI subcontracting with DCRI |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IVIG + Coordinated Care | Experimental | IVIG (Gamunex); 2g /kg monthly for 9 months (36 weeks) |
|
| IVIG Placebo + Coordinated Care | Experimental | Saline: Same dosage as IVIG; monthly for 9 months (36 weeks) |
|
| IVIG + Usual Care | Experimental | IVIG (Gamunex); 2g /kg monthly for 9 months (36 weeks) |
|
| IVIG Placebo + Usual Care | Experimental | Saline: Same dosage as IVIG; monthly for 9 months (36 weeks) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IVIG (intravenous immunoglobulin) | Drug | 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). |
| 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) |
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Autonomic Function Testing |
| Baseline to End of Intervention (9 months) |
| Change in Vanderbilt Orthostatic Symptoms Score (VOSS) |
Inclusion Criteria:
Additional Appendix A (IVIG Sub-study) Level Inclusion Criteria:
Exclusion Criteria:
Additional Appendix A (IVIG Sub-study) Level Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| 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 | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| All sites listed under NCT06305780 | Durham | North Carolina | 27710 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41720282 | Derived | Fudim M, Novak P, Taub PR, Chung T, Zimmerman KO, Moy OV, Fissler HZ, Wen J, Freeman NLB, O'Brien S, Marti H, Cook D, Low P, Kim DY, Rosenberg Y, Granger CB, Shibao CA. Design and rationale of RECOVER-AUTONOMIC: A randomized platform trial evaluating interventions for Long COVID postural orthostatic tachycardia syndrome. Am Heart J. 2026 Jun;296:107384. doi: 10.1016/j.ahj.2026.107384. Epub 2026 Feb 18. |
| Label | URL |
|---|---|
| Related Info | View source |
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The summary of results will be shared on the study website: https://recovercovid.org/
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| ICF | No | No | Yes | Informed Consent Form | Jan 15, 2024 | Jul 11, 2025 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D000094024 | Post-Acute COVID-19 Syndrome |
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D016756 | Immunoglobulins, Intravenous |
| ID | Term |
|---|---|
| D007074 | Immunoglobulin G |
| D007132 | Immunoglobulin Isotypes |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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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.
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Double blind
| IVIG Placebo | Drug | 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). |
|
| Coordinated Care | Behavioral | 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. |
|
| Usual Care | Behavioral | Participants will receive usual non-pharmacologic care (control) for a duration of 3 months, concurrent with IVIG administration. |
|
| 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) |
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) |
| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D000094025 | Post-Infectious Disorders |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |