Efficacy and Safety Evaluation of Human Normal Immunoglobulin (IgPro20) in Adults with Post-COVID-19 Postural Orthostatic Tachycardia Syndrome

The primary objective of this study is to evaluate the **efficacy** of IgPro20, a subcutaneous immunoglobulin, in comparison with placebo in adults diagnosed with post-COVID-19 **Postural Orthostatic Tachycardia Syndrome (POTS)**. This condition is characterized by an abnormal increase in heart rate upon standing, which can significantly impact the quality of life. Assessing the efficacy of IgPro20 is clinically relevant as it may offer a therapeutic option for managing symptoms associated with post-COVID-19 POTS, potentially improving patient outcomes and quality of life.

The clinical trial involves a total of **160 participants** diagnosed with **Post-COVID-19 Postural Orthostatic Tachycardia Syndrome (POTS)**. The study population includes both male and female adults aged 18 years and older. Participants were selected based on their ability to provide written informed consent and adhere to all protocol requirements. The trial does not include a vulnerable population. Participants must have a confirmed historical documentation of a preceding COVID-19 infection, with POTS symptoms developing within four months post-infection. A COMPASS-31 score of at least 40 and a positive confirmatory standardized standing test at the screening visit are required. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** Phase 3 study designed to evaluate the efficacy and safety of IgPro20, a **subcutaneous immunoglobulin**, in adults diagnosed with post-COVID-19 **Postural Orthostatic Tachycardia Syndrome (POTS)**. The trial aims to compare the effects of IgPro20 with a placebo, which is a 2% human albumin solution. The study is expected to commence recruitment on October 1, 2025, and conclude by September 24, 2027, with a maximum treatment period of 53 weeks for the active product and 24 weeks for the placebo.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of post-COVID POTS, and specific test results like the COMPASS-31 score and standardized standing test. Following successful screening, participants will be randomized to receive either IgPro20 or placebo. Regular follow-up visits will be scheduled to monitor the participants' health, assess the primary endpoint of the proportion of participants no longer meeting the diagnostic criteria for post-COVID POTS, and evaluate secondary endpoints, including changes in orthostatic intolerance scores and heart rate measurements.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to gather comprehensive data on the treatment's efficacy and safety. Participants are expected to remain in the study for the entire duration unless specific conditions necessitate early termination, such as the occurrence of serious treatment-emergent adverse events or withdrawal of consent. The trial's design ensures rigorous monitoring and data collection to achieve its primary objective of evaluating IgPro20's efficacy in treating post-COVID POTS.

The clinical trial involves the administration of **Hizentra**, a 200 mg/ml solution for subcutaneous injection, which contains **human normal immunoglobulin** as the active substance. This experimental medication is provided in the form of a solution for injection and is administered subcutaneously. The maximum daily dose is 250 ml, with a total maximum dose of 13,250 ml over a treatment period of up to 53 weeks. The product is manufactured by CSL Behring GmbH and is authorized for use in the European Union. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

The study also includes a placebo comparator, which is a 2% human albumin solution. This placebo is derived from the dilution of CSL Behring's Human Albumin 5% (AlbuRx® 5%) and is also administered subcutaneously. The placebo is provided in the form of a solution for infusion, with a maximum daily dose of 250 ml and a total maximum dose of 6,000 ml over a treatment period of up to 24 weeks. The placebo is designed to match the experimental treatment in appearance and administration to maintain the double-blind nature of the trial. Compliance with the placebo administration schedule will be similarly monitored to ensure the integrity of the study results.

The efficacy of IgPro20 in the treatment of post-COVID-19 **Postural Orthostatic Tachycardia Syndrome (POTS)** will be assessed through a double-blind, randomized, placebo-controlled Phase 3 clinical trial. The primary endpoint for evaluating efficacy is the proportion of participants who no longer meet the diagnostic criteria for post-COVID POTS, as determined by a standardized standing test. This test measures the absence of a heart rate increase of ≥ 30 beats per minute (bpm) without a 20 mmHg decrease in systolic blood pressure, indicating the resolution of orthostatic intolerance symptoms.

Secondary endpoints include changes from baseline in the orthostatic intolerance score and total score of the COMPASS-31, a validated scale for assessing autonomic symptoms. Additional secondary endpoints involve changes in heart rate increase within 10 minutes of the standing test, as well as the number and percentage of participants experiencing treatment-emergent adverse events (TEAEs), related TEAEs, serious TEAEs, and related serious TEAEs. Electrocardiogram (ECG) abnormalities will also be monitored, with assessments including the number and percentage of participants with ECG abnormalities and changes from baseline in these abnormalities.