Highlights
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NIH-sponsored platform RCT in Long COVID postural orthostatic tachycardia syndrome.
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Tests intravenous immunoglobulin and ivabradine vs placebo.
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Factorial design includes coordinated care vs usual care.
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Primary endpoint: change in measured orthostatic intolerance symptoms.
ABSTRACT
Background
Post‑acute sequelae of SARS‑CoV‑2 infection (Long COVID) affect a substantial proportion of individuals, and among the many reported symptom clusters, autonomic dysfunction, particularly postural orthostatic tachycardia syndrome (POTS), represents an important subset. The Researching COVID to Enhance Recovery Clinical Trials (RECOVER-CT) initiative developed by the National Institutes of Health included a platform trial (RECOVER-AUTONOMIC) designed to assess the safety, tolerability, and efficacy of 3 interventions—(1) coordinated nonpharmacologic care, (2) pharmacotherapy with intravenous immunoglobulin (IVIG), and (3) pharmacotherapy with ivabradine—in treating POTS in adults with Long COVID.
Methods
RECOVER-AUTONOMIC is a multicenter, randomized, double-blinded, placebo-controlled, platform trial employing a flexible, adaptive design. Participants are randomized to IVIG or ivabradine with matching placebo, and (in a factorial design) to either coordinated nonpharmacologic care or usual care. The primary endpoint is the change in orthostatic intolerance symptoms measured by the Orthostatic Hypotension Questionnaire/Orthostatic Intolerance Questionnaire from baseline to the end of intervention. Secondary endpoints include quality of life, functional performance, symptom burden, and safety. Exploratory endpoints include autonomic function testing, wearable sensor data, and longitudinal biomarker profiling.
Discussion
RECOVER-AUTONOMIC seeks to determine the benefits and risks of IVIG and of ivabradine, as well as of coordinated nonpharmacologic care, for the treatment of POTS in Long COVID. Results from this trial will offer the largest source of evidence to help guide the medical care of this population.
Trial Registration
ClinicalTrials.gov–Platform: NCT06305780; Appendix A (intravenous immunoglobulin): NCT06305793; Appendix B (ivabradine): NCT06305806. Protocol available at https://trials.recovercovid.org/autonomic .
Background
The COVID-19 pandemic has resulted in a high burden of chronic, multisystem symptoms in a subgroup of individuals after their acute infection. A growing body of evidence indicates that postacute sequelae of SARS-CoV-2 infection (PASC), also known as Long COVID, are characterized by a constellation of persistent symptoms that can involve fatigue, brain fog, dyspnea, orthostatic and exercise intolerance, postexertional malaise, and notably, autonomic dysfunction. , Cardiovascular autonomic manifestations are increasingly recognized as a hallmark of Long COVID and may include postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension, and syncope. ,
POTS is believed to affect between 30% and 80% of individuals with Long COVID, with higher prevalence among women and younger patients. , The pathophysiology is complex and multifactorial, with hypotheses implicating immune dysregulation with autoantibody production, endothelial injury, persistent viral reservoirs, and abnormalities in baroreflex and enhanced sympathetic tone. ,,
Current treatment strategies are largely empirical and have been extrapolated from the non–Long COVID POTS literature, mostly based on nonrandomized studies. These include nonpharmacologic interventions such as increased fluid and salt intake, compression stockings, abdominal binders, and graded physical therapy, as well as pharmacologic agents such as beta-blockers, calcium channel blockers, ivabradine, central sympatholytic agents, midodrine, and pyridostigmine. However, the response to intervention is often incomplete, and large randomized clinical trials are lacking. Anecdotal reports and small case series have suggested potential benefit from intravenous immunoglobulin (IVIG), particularly in Long COVID cases presumed to have an autoimmune basis. , Ivabradine, a heart rate-reducing agent approved by the U.S. Food and Drug Administration (FDA) for systolic heart failure and by the European Medicines Agency for angina, has demonstrated promise in early studies targeting tachycardia in POTS.
The National Institutes of Health (NIH) launched the RECOVER (Researching COVID to Enhance Recovery) initiative to better understand, prevent, and treat Long COVID through comprehensive observational cohorts and interventional randomized platform trials (RECOVER Clinical Trials [RECOVER-CT]). RECOVER-AUTONOMIC is the interventional platform trial focused specifically on Long COVID POTS. This platform trial is designed to test multiple therapeutic strategies in parallel. Initial interventions tested include IVIG and ivabradine, each supported by biologic plausibility and some clinical signals of possible benefit. The integrated design of the RECOVER-CT platforms allows for cross-trial data pooling of patients with Long COVID.
In addition to evaluating medication treatment efficacy, RECOVER-AUTONOMIC incorporates a coordinated nonpharmacologic care versus usual care comparison. There is also advanced phenotyping, including patient-reported outcome measures, autonomic function testing, wearable biosensors, and immune profiling. This approach allows not only for treatment assessment but also for gaining mechanistic insights and potentially identifying patient phenotypes most likely to derive benefit.
In this article, we detail the rationale, methods, and implementation of the RECOVER-AUTONOMIC platform trial, with a specific focus on the IVIG and ivabradine versus placebo comparisons. The trial’s platform design allows parallel and future adaptive testing of multiple candidate interventions under a shared protocol structure. By systematically evaluating both immune-modulating and heart rate-targeting therapies within a robust clinical trial framework, RECOVER-AUTONOMIC aims to provide actionable evidence to inform clinical care and improve outcomes in patients with POTS in Long COVID.
Methods
Study design and overview
RECOVER-AUTONOMIC is a prospective, multicenter, randomized, controlled, platform trial designed to evaluate multiple therapeutic interventions for autonomic dysfunction in patients with Long COVID. The trial uses an adaptive platform structure that allows efficient testing of multiple treatment strategies with shared infrastructure and oversight. The platform features 2 factorial 2 × 2 designs, randomizing patients to receive one of the pharmacologic interventions (IVIG [Appendix A] or ivabradine [Appendix B] and matching placebo) and to either coordinated nonpharmacologic or usual care ( Figure 1 ).
Study design.
IVAB, ivabradine; IVIG, intravenous immunoglobulin.
Eligibility criteria
Inclusion criteria defined for participants included age ≥ 18 years; history of suspected, probable, or confirmed SARS-CoV-2 infection; symptoms of autonomic dysfunction lasting ≥ 12 weeks after acute COVID-19, score >20 (score >25 for IVIG) on the COMPASS-31 (31-question Composite Autonomic Symptom Score) instrument, and Orthostatic Hypotension Questionnaire/Orthostatic Intolerance Questionnaire (OHQ/OIQ) item 1 score >2 (Supplementary Table 1 for the full list of inclusion criteria).
Key exclusion criteria are as follows:
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Active COVID-19 infection within 4 weeks.
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Pregnancy or breastfeeding.
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Severe cardiac disease (e.g., ejection fraction < 30%, New York Heart Association Classes III-IV, severe valvular disease).
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Severe renal impairment (estimated glomerular filtration rate < 20 mL/min/1.73 m²).
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Prior history of POTS or significant autonomic dysregulation before COVID.
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Enrollment in another interventional study within 30 days.
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History of atrial fibrillation or uncontrolled arrhythmia.
Intervention arms
IVIG
IVIG is approved by the FDA for the treatment of various immune deficiency syndromes and autoimmune diseases. IVIG at high dose is thought to neutralize pathogenic autoantibodies and suppresses autoimmune response, and the use of high titers of anti-SARS-CoV-2 antibodies for the treatment of COVID-19 is authorized in the US. Prior use of IVIG on severe cases of POTS indicates that the medication can be associated with improved autonomic symptoms, as well as with decreased overall symptom burden. ,,, IVIG may also improve other, noncardiovascular autonomic dysregulation and has the potential to provide disease-modifying effects. IVIG (manufactured by Grifols USA, LLC) or matching saline infusion will be administered intravenously by a medical professional at the site. The dose will be a total of 2 g/kg every month for 9 months. The initial dosing frequency of 0.5 g/kg once a week is suggested; however, the frequency can be modified based on individual site preference. There will be a dose cap of 80 kg (i.e., if participant weight is >80 kg, dose will be at the 80-kg level). The formulation is 10% IVIG solution. To reduce the occurrence of side effects and to enhance tolerability, fluids and pre- and post-medications are strongly encouraged. Therefore, 500 mL fluids (0.9% NaCl 500 mL IV), acetaminophen 650 mg, and loratadine 10 mg may be given at the primary investigator’s discretion 30 minutes before IVIG (or saline) infusion and after infusion. Some patients may require stronger pre and postmedications or additional fluids. The control arm receives volume-matched normal saline infusions administered on the same schedule. Figure 2 depicts the IVIG study design.
Study schema for Appendix A (intravenous immunoglobulin).
IVIG, intravenous immunoglobulin; LC, Long COVID; OHQ/OIQ, Orthostatic Hypotension Questionnaire/Orthostatic Intolerance Questionnaire; POTS, postural orthostatic tachycardia syndrome.
Ivabradine
Ivabradine was initially approved to treat chronic systolic heart failure with elevated heart rate and is in a class of medications called hyperpolarization-activated cyclic nucleotidegated channel blockers. It is also categorized as an inhibitor of the I(f) (or “funny”) current. Ivabradine reduces heart rate without reducing contractility and blood pressure. The medication has the greatest activity and most potent effect when the heart rate is elevated. It increases coronary flow reserve and collateral perfusion, promoting the development of coronary collaterals and improving endothelial function, and thus is also approved in some countries to treat angina. Ivabradine has been successfully used to treat symptoms such as tachycardia and POTS in a small, randomized trial, and its use has been associated with improvement in symptoms in patients with Long COVID and POTS. The starting dose is 5 mg by mouth twice daily, titrated to 7.5 mg as tolerated. Up-titration is assessed at the 7-day safety visit; dose is reduced to 2.5 mg twice daily if the participant’s resting heart rate is < 60 beats per minute (bpm), or symptomatic bradycardia is present. Participants on beta-blockers or calcium channel blockers can pause their medication 2 days prior to the active stand test at screening/baseline visit (Supplementary Table 2 for the participants’ visit schedule). This is not mandatory, but is highly recommended if the participant is willing to try. In the control arm, placebo tablets are matched in size, color, and dosing schedule. Figure 3 depicts the ivabradine study design. Ivabradine/placebo exposure is 3 months.
Study schema for Appendix B (ivabradine).
LC, Long COVID; OHQ/OIQ, Orthostatic Hypotension Questionnaire/Orthostatic Intolerance Questionnaire; POTS, postural orthostatic tachycardia syndrome.
Nonpharmacologic intervention
The nonpharmacologic intervention or behavioral care arm is a randomized comparison of coordinated versus usual care. With support from a care coordinator, participants in the coordinated care group receive structured guidance to promote adherence to nonpharmacologic interventions, which includes standardized education on fluid and salt loading, use of compression garments, physical counterpressure maneuvers, and individualized activity guidance, delivered via virtual health coaching (design in Figure 4 ). The duration of the nonpharmacological intervention was restricted to 3 months in both the IVIG and ivabradine arm.
Coordinated nonpharmacologic/behavioral care arm.
Participants randomized to the coordinated care intervention receive:
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Home blood pressure monitor and wearable activity tracker (Fitbit).
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Educational booklet and daily logbook.
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Weekly telehealth sessions with a trained care coordinator.
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Personalized feedback and motivational interviewing for adherence.
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Reinforcement of physical counter-pressure maneuvers (e.g., squatting, leg crossing).
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Behavioral strategies to mitigate orthostatic symptoms.
Participants assigned to the usual care group receive an instruction sheet outlining general, nonprescriptive recommendations. These include following a high-salt diet, increasing water intake to individual tolerance, wearing compression garments during physical activity, and engaging in daily exercise as tolerated over a 12-week period. Unlike the coordinated care intervention group, these participants do not receive structured guidance or adherence support from the care coordinator.
Recruitment strategy
Participants are identified from existing NIH RECOVER registries, hospital discharge records, primary care referrals, clinics associated with enrolling sites, and online advertising. Individuals will be recruited from across the US through outreach by community organizations and participating clinic sites as well as the RECOVER observational study. Patient representatives, who were involved in developing this study protocol, were consulted on recruitment and retention strategies. Dropout is minimized through frequent patient visits and phone contact both within the control and intervention groups. Further, this trial is one of the few randomized controlled trials for Long COVID POTS for which many patients have self-referred.
First enrollment occurred in April 2024. The fourth amendment to the protocol enrollment criteria was implemented at the end of 2024 with the intent to increase enrollment. Among the most impactful changes to the inclusion criteria was to allow for a history of documented increase of 30 bpm or more on an active stand test or tilt table in the past year and a standing heart rate above 100 bpm at the screening/baseline visit to qualify the patient. This was implemented in response to feedback from sites indicating that patients with clinically documented POTS had missed the heart rate criterion on the active stand test by a few beats at the time of trial enrollment. Additionally, we provided a clarification and change around the most common screen failure criterion, the active stand test. An abnormal active stand test was now defined as presence of orthostatic tachycardia (an increase of 30 bpm or more in heart rate within 10 minutes upon standing without orthostatic hypotension) and experiencing orthostatic symptoms. The resultant increase in enrollment rates is shown in Figure 5 . The record of all amendments is depicted in Supplementary Table 3.
Changes in enrollment rates in the RECOVER-AUTONOMIC Trial. Trend data indicate an uptake in the enrollment rate and a drop in the screen failure rate following the amendment at the end of 2024 (marked with *). Number of sites = 50.
Randomization
Randomization is conducted centrally via a secure web-based randomization module, using a permuted block design with a 1:1:1:1 allocation to study drug intervention/control combined with coordinated nonpharmacologic care/usual care. Eligibility assessments (active stand test, OHQ/OIQ, and laboratory tests) are completed prior to randomization.
Blinding and masking
Pharmacologic interventions (IVIG and ivabradine) and their matched saline/placebos are administered in a double-blind fashion. Masking is maintained through the use of identical packaging and labeling. IVIG drug preparation and accountability are managed by designated unblinded pharmacists who do not interact with study participants or outcome assessors.
Nonpharmacologic care assignment is not blinded due to the nature of the intervention, but steps are taken to minimize bias. These include standardized training for care coordinators, blinded outcome assessors where possible, and the separation of staff handling intervention delivery from those collecting endpoint data.
Endpoints
The primary endpoint is the change from baseline to the end of intervention (EOI) in OHQ/OIQ composite score ( Table 1 ). Key secondary endpoints are changes in COMPASS-31, Malmö POTS Symptom Score (MAPS), Patient-Reported Outcomes Measurement Information System 29-item profile with 2 additional domains (PROMIS-29 + 2) scores; functional capacity (6-minute walk distance); heart rate changes during active stand test; and safety outcomes—i.e., adverse events, severe adverse events, and events of special interest.
Table 1
Study assessments
| Assessment/instrument | Purpose | Timepoints |
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| OHQ/OIQ (primary endpoint) | Orthostatic intolerance symptoms | Screening; baseline; during intervention; EOI; follow-up |
| COMPASS-31 | Autonomic symptom burden (domains) | Screening; during intervention; EOI; follow-up |
| MAPS | POTS symptom burden | Baseline; during intervention; EOI; follow-up |
| VOSS | Orthostatic symptom rating after active stand test/HUT | Baseline; during intervention; EOI; follow-up |
| Active stand test | Objective HR/BP response to standing | Baseline; appendix-specific follow-ups; EOI; follow-up |
| 6-min walk test | Functional capacity | Baseline; during intervention; EOI; follow-up |
| DSQ-PEM | Postexertional malaise frequency/severity | Baseline (7-d lookback); each visit (since-last-visit) |
| PROMIS-29 + 2 | Global health domains and QoL | Baseline; during intervention; EOI; follow-up |
| Long COVID symptom questionnaire | Broader PASC symptom inventory | Baseline; during intervention; EOI; follow-up |
| Autonomic Function tests (HUT, Valsalva, deep breathing, TCD) | Physiologic autonomic profiling (select sites/substudies) | Baseline (select sites); EOI (appendix/site dependent) |
| Biomarkers/ biospecimens (blood; stool) | Mechanistic/endotyping and biorepository | Baseline; during intervention; EOI; follow-up |
| Wearable (Fitbit) | Step count, HR/HRV (trend) | 7 d predrug; continuous encouraged; 7 d pre-EOI |
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