Efficacy and Safety Study of Efgartigimod in Adults With Post-COVID-19 POTS

Study Overview
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Brief Summary
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The study aims to investigate the safety, tolerability, efficacy, pharmacodynamics (PD), pharmacokinetics (PK), and immunogenicity of efgartigimod compared to placebo in participants with post-COVID-19 postural orthostatic tachycardia syndrome (POTS) (post-COVID-19 POTS).

Detailed Description
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The study aims to investigate the safety, tolerability, efficacy, pharmacodynamics (PD), pharmacokinetics (PK), and immunogenicity of efgartigimod compared to placebo in participants with post-COVID-19 postural orthostatic tachycardia syndrome (POTS) (post-COVID-19 POTS). Efgartigimod may be a viable treatment option for individuals diagnosed with post-COVID-19 POTS because it has been shown to reduce IgG levels, including IgG autoantibodies, which may underlie some of the autonomic disease manifestations in these patients.

Official Title
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A Phase 2 Randomized, Double-blinded, Placebo-controlled Study to Evaluate the Efficacy and Safety of Efgartigimod IV in Adult Patients With Post-COVID-19 Postural Orthostatic Tachycardia Syndrome (POTS)

Conditions
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Postural Orthostatic Tachycardia Syndrome

Intervention / Treatment
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* Drug: Efgartigimod
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Reached the age of consent when signing the informed consent form Capable of providing signed informed consent and complying with protocol requirements Diagnosed with new-onset POTS post-COVID-19 established by the following: History of COVID-19 based on a previous positive test result from either laboratory-confirmed COVID-19 test (eg, a PCR test) or non-laboratory-confirmed COVID-19 test (eg, rapid antigen test); this positive result may be either documented or patient-reported Tilt table or orthostatic vital sign measurements during screening consistent with consensus criteria: sustained HR increase of ≥30 bpm within 10 min of standing or head up tilt (≥40 bpm for individuals aged 18 to 19 years) and/or HR reaching >120 bpm within 10 min; absence of sustained 20 mmHg decrease in systolic blood pressure (SBP) Ongoing symptoms of POTS confirmed by the investigator with at least 3 symptoms in each of the following areas lasting longer than 12 weeks after either diagnosis of COVID-19 or after hospital discharge for COVID-19: i. Vasomotor symptoms: fatigue, orthostatic intolerance, brain fog, exertional dyspnea, difficulty with concentration, venous pooling, and exercise intolerance ii. Sympathetic over-compensation symptoms: palpitation, heat intolerance, nausea with or without vomiting, insomnia, anxiety, lack of appetite, chest pain, and diaphoresis COMPASS 31 ≥35 at screening Agree to use contraceptives consistent with local regulations regarding the methods of contraception for those participating in clinical studies and the following: Male participants Female participants of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline before receiving IMP. Contraceptive requirements. Body mass index (BMI) <35 kg/m2 Exclusion Criteria: Diagnosis of or receiving treatment for the following conditions before COVID-19: peripheral neuropathy, POTS, myalgic encephalomyelitis encephalitis/chronic fatigue syndrome, Ehlers Danlos syndrome confirmed by genetic testing, autonomic neuropathy, multiple sclerosis, stroke, spinal cord injury, or any known lesions in the central nervous system by imaging or neurological exam History of or currently being treated for clinically significant ongoing cardiac arrythmia, heart failure, myocarditis, pulmonary embolism requiring anticoagulation, pulmonary fibrosis, or critical illness-related polyneuropathy or myopathy Known autoimmune disease that, in the investigator's judgment, would interfere with an accurate assessment of clinical symptoms of post-COVID-19 POTS or puts the participant at undue risk Known HIV disease or common variable immunodeficiency History of malignancy unless considered cured by adequate treatment with no evidence of recurrence for ≥3 years before the first administration of IMP. Adequately-treated participants with the following cancers may be included at any time: Basal cell or squamous cell skin cancer Carcinoma in situ of the cervix Carcinoma in situ of the breast Incidental histological finding of prostate cancer (TNM stage T1a or T1b) Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection or positive SARS-CoV-2 PCR test at screening Positive serum test at screening for an active infection with any of the following: Hepatitis B virus (HBV) that is indicative of an acute or chronic infection, unless associated with a negative HB surface antigen (HBsAg) or negative HBV DNA test Hepatitis C virus (HCV) based on HCV antibody assay unless a negative RNA test is available HIV A medical condition that could confound the results of the study or put the participant at undue risk in the investigator's judgment Clinically significant disease, recent major surgery (within 3 months of screening), or intends to have surgery during the study; or any other condition that in the opinion of the investigator could confound the results of the study or put the participant at undue risk Total IgG <4 g/L at screening Received within 12 weeks or 5 half-lives (whichever is longer) before screening an investigational product Received within 12 weeks before screening either intravenous immunoglobulin (Ig) IV or SC or plasmapheresis/plasma exchange (PLEX) Received a live or live-attenuated vaccine less than 4 weeks before screening Known hypersensitivity to IMP or 1 of its excipients Previously participated in an efgartigimod clinical study and received at least 1 dose of IMP Currently participating in another interventional clinical study History (within 12 months of screening) of or current alcohol, drug, or medication abuse Pregnant or lactating or intends to become pregnant during the study Unwilling to remain on a stable regimen of medications during the study Unwilling to avoid initiation of new physical rehabilitation or other physician-prescribed exercise programs during the 24-week treatment period

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Efgartigimod<br>Receive efgartigimod IV 10mg/kg during weekly infusions during a treatment period of 24 weeks | Drug: Efgartigimod<br>* Efgartigimod IV 10 mg/kg infusion qw for 24 weeks. Participants will be randomized to receive efgartigimod IV 10 mg/kg or matching placebo in a 2:1 ratio, respectively<br>|
| Placebo Comparator: Placebo<br>Receive a matching placebo during weekly infusions during a treatment period of 24 weeks | Drug: Placebo<br>* Receive a matching placebo during weekly infusions during a treatment period of 24 weeks. Participants will be randomized to receive efgartigimod IV 10 mg/kg or matching placebo in a 2:1 ratio, respectively<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the efficacy of efgartigimod in reducing the severity of post-COVID-19 POTS symptoms | Change from baseline to week 24 in the Composite Autonomic Symptom Score 31 (COMPASS 31). | Outcome measure is assessed at baseline and week 24. | 
| Evaluate the efficacy of efgartigimod in reducing the severity of post-COVID-19 POTS symptoms | Change from baseline to week 24 in the Malmo POTS Symptom Score (MaPS). | Outcome measure is assessed at baseline and week 24. | 
| Evaluate the safety and tolerability of efgartigimod in patients with post-COVID-19 POTS | Incidence and severity of adverse events (AEs), incidence of serious adverse events (SAEs), changes in laboratory test results, vital sign measurements, and electrocardiogram (ECG) results. | Up to 31 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the efficacy of efgartigimod on patient global assessment of disease activity and fatigue | Change from baseline to week 24 in the Patient Global Impression of Severity (PGI-S) | Change from baseline to week 24 | 
| Evaluate the efficacy of efgartigimod on patient global assessment of disease activity and fatigue | Change from baseline to week 24 in the Patient Global Impression of Change (PGI-C) | Change from baseline to week 24 | 
| Evaluate the efficacy of efgartigimod on patient global assessment of disease activity and fatigue | Change from baseline to week 24 in the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 8a | Change from baseline to week 24 | 
| Evaluate the efficacy of efgartigimod on patient global assessment of disease activity and fatigue | Change from baseline to week 24 in the PROMIS Cognitive Function Short Form 6a | Change from baseline to week 24 | 
| Assess the pharmacodynamic (PD) effect of efgartigimod | Absolute values, changes from baseline, and percent reduction from baseline in total IgG levels | From Baseline to week 24 | 
| Assess the pharmacokinetic (PK) profile of efgartigimod | Efgartigimod serum concentration-time profile | From Baseline to week 24 | 
| Assess the immunogenicity of efgartigimod | Incidence and prevalence of antidrug antibodies (ADA) against efgartigimod | From Baseline to week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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POTS, Long COVID, Postural Orthostatic Tachycardia Syndrome, efgartigimod