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

Phase 2

Completed

• Conditions: Postural Orthostatic Tachycardia Syndrome
• Interventions: Drug: Placebo; Drug: Efgartigimod

• Registration Number: NCT05633407
• Lead Sponsor: argenx

Brief Summary

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

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.

Study Timeline

• Study Start: 2022-09-23
• Study First Submitted: 2022-11-08
• Study First Submitted QC: 2022-11-29
• Study First Posted: 2022-12-01
• Primary Completion: 2024-04-18
• Study Completion: 2024-04-18
• Results First Submitted: 2025-04-18
• Status Verified: 2025-05
• Results First Submitted QC: 2025-05-08
• Last Update Submitted: 2025-05-08
• Results First Posted: 2025-05-23
• Last Update Posted: 2025-05-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 53

Inclusion Criteria

1. Reached the age of consent when signing the informed consent form

2. Capable of providing signed informed consent and complying with protocol requirements

3. Diagnosed with new-onset POTS post-COVID-19 established by the following:

   1. 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
   2. 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)
   3. 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

4. COMPASS 31 ≥35 at screening

5. Agree to use contraceptives consistent with local regulations regarding the methods of contraception for those participating in clinical studies and the following:

   Male participants: No male contraception is required 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.

6. Body mass index (BMI) <35 kg/m2

Exclusion Criteria

1. 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

2. 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

3. 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

4. Known HIV disease or common variable immunodeficiency

5. 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:

   1. Basal cell or squamous cell skin cancer
   2. Carcinoma in situ of the cervix
   3. Carcinoma in situ of the breast
   4. Incidental histological finding of prostate cancer (TNM stage T1a or T1b)

6. Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection or positive SARS-CoV-2 PCR test at screening

7. Positive serum test at screening for an active infection with any of the following:

   1. 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
   2. Hepatitis C virus (HCV) based on HCV antibody assay unless a negative RNA test is available
   3. HIV

8. A medical condition that could confound the results of the study or put the participant at undue risk in the investigator's judgment

9. 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

10. Total IgG <4 g/L at screening

11. Received within 12 weeks or 5 half-lives (whichever is longer) before screening an investigational product

12. Received within 12 weeks before screening either intravenous immunoglobulin (Ig) IV or SC or plasmapheresis/plasma exchange (PLEX)

13. Received a live or live-attenuated vaccine less than 4 weeks before screening

14. Known hypersensitivity to IMP or 1 of its excipients

15. Previously participated in an efgartigimod clinical study and received at least 1 dose of IMP

16. Currently participating in another interventional clinical study

17. History (within 12 months of screening) of or current alcohol, drug, or medication abuse

18. Pregnant or lactating or intends to become pregnant during the study

19. Unwilling to remain on a stable regimen of medications during the study

20. Unwilling to avoid initiation of new physical rehabilitation or other physician-prescribed exercise programs during the 24-week treatment period

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Receive a matching placebo during weekly infusions during a treatment period of 24 weeks
Efgartigimod	Efgartigimod	Receive efgartigimod IV 10mg/kg during weekly infusions during a treatment period of 24 weeks

Primary Outcome Measures

Name	Time	Method
Change From Baseline to Week 24 in the COMPASS 31 (2-week Recall Version)	Baseline (Day 1) and Week 24	Composite Autonomic Symptom Score (COMPASS) 31 modified version (2-week recall) is a self-rated questionnaire to evaluate the severity and distribution of autonomic symptoms in various autonomic nerve disorders. It consists of 31 questions in 6 weighted domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal {GI}-mixed upper and diarrhea, bladder, and pupillomotor). A weighted total score of 0 (mild) to 100 (severe) was determined by adding a maximum raw score for each domain. Higher scores indicated a more severe degree of autonomic symptoms.
Change From Baseline to Week 24 in the MaPS	Baseline (Day 1) and Week 24	The Malmö POTS Symptom Score (MaPS) score is a dedicated POTS symptom scoring questionnaire. The score consists of 12 questions that assess symptom burden related (tachycardia, palpitations, dizziness, presyncope) and unrelated to orthostatic intolerance (GI symptoms, insomnia, concentration difficulties). Participants graded their symptoms for the past 7 days using a visual analog scale ranging from 0 (no symptoms) to 10 (worst possible). The total score was calculated by summing up the items/individual items and range was 0 to 120 points, with higher scores indicating more severe symptoms.
Number of Participants With TEAEs and TESAEs	From the first dose of study drug (Day 1) up to 60 days post last dose of study drug, up to 236 days	An adverse event (AE) was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. A serious adverse event (SAE) was any untoward medical occurrence that at any dose resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or any other medically important event. Treatment-emergent adverse events (TEAEs) were defined as AEs with onset on or after the first administration of study drug up to and including 60 days after the last study drug administration.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Improved PGI-S at Week 24	Baseline (Day 1) and Week 24	The Patient Global Impression-Severity (PGI-S) is a participant-rated, single-item scale to assess the severity of a health condition. The scale was used to assess the severity of symptoms over the past week (1-week recall) and overall experience of symptoms over the past 2 weeks (2-week recall). Both were rated on a 4-point type Likert scale, with scores ranging from 1 (none), 2 (mild), 3 (moderate), and 4 (severe). Higher scores indicate greater symptom severity. An "improved PGI-S" was defined by a change from baseline of -3, -2 and -1.
Percentage of Participants With Improved in PGI-C at Week 24	Baseline (Day 1) and Week 24	The Patient Global Impression-Change (PGIC) is a single-item scale to capture the participant's perception of a change in their overall symptom severity. Overall change in symptoms was rated on a 7-point Likert scale, with scores ranging from 1 (much better), 2 (somewhat better), 3 (a little better), 4 (no change), 5 (a little worse), 6 (somewhat worse), and 7 (much worse). Higher PGI-C scores signify worse outcome. An "improved PGI-C" was defined by a change from baseline of 1, 2 and 3.
Change From Baseline to Week 24 in the PROMIS Fatigue Short Form 8a	Baseline (Day 1) and Week 24	The Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 8a assesses the impact and perceived fatigue during the last 7 days. This validated 8-question scale has 5 response options, with scores ranging from 1 (not at all) to 5 (very much). Total scores ranged from 8 to 40; higher scores indicated higher fatigue levels and were converted to a T-score with a mean of 50 and standard deviation of 10. A decrease in T-score (negative change from baseline) indicated improvement in fatigue.
Change From Baseline to Week 24 in the PROMIS Cognitive Function Short Form 6a	Baseline (Day 1) and Week 24	PROMIS Cognitive Function Short Form 6a assesses the frequency of cognitive difficulties experienced in the past 7 days. The questionnaire comprises 6 questions on subjective cognitive difficulties regarding a participant's concentration, memory, language, mental acuity, and perceived changes in cognitive functioning. The participant marks their response on a 5-point Likert scale (1: never and 5: very often). Scores ranged from 6 to 30; higher scores indicated worse perceived cognitive functioning and were converted to a T-score with a mean of 50 and standard deviation of 10. An increase in T-score (positive change from baseline) indicated better cognitive function.
Percent Change From Baseline in Total IgG Levels at Week 24	Baseline (Day 1) and Week 24	Blood samples for immunoglobulin G (IgG) analysis were collected at specified time points. Total IgG concentrations were quantified using validated methods at a central laboratory.
Serum Concentration of Efgartigimod	Pre-dose and post-dose at Baseline (Day 1), Weeks 1, 4, 12 and at Week 24	Serum samples were collected at specified timepoints to determine the concentration of efgartigimod.
Number of Participants With ADAs Against Efgartigimod	Up to Week 24	Blood samples were collected at specified timepoints to assess anti-drug antibodies (ADAs) against efgartigimod. ADA incidence reported here was defined as total number of participants with treatment-induced and treatment-boosted ADA. Treatment-induced ADA was defined as a baseline negative sample and at least 1 positive post-baseline sample. Treatment-boosted ADA was defined as a baseline positive sample and the titer value increased 4-fold or more compared to baseline.

Trial Locations

Locations (11)

University of California, San Diego Sulpizio Cardiovascular Center; 🇺🇸 La Jolla, California, United States

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

Stanford Movement Disorder Center; 🇺🇸 Palo Alto, California, United States

Northshore University Health System; 🇺🇸 Glenview, Illinois, United States

Harvard Medical School, Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

Texas Institute of Cardiology; 🇺🇸 McKinney, Texas, United States

Apex Trials Croup, LLC; 🇺🇸 Fort Worth, Texas, United States

Case Western Reserve University; 🇺🇸 Cleveland, Ohio, United States

Pioneer Clinical Research; 🇺🇸 Rosharon, Texas, United States

Metrodora Institute; 🇺🇸 West Valley City, Utah, United States

Vandetbilt University Medical Center / Clinical Research Center; 🇺🇸 Nashville, Tennessee, United States