IVIG (Gamunex-C) Treatment Study for POTS Subjects (iSTAND)

• ClinicalTrials.gov Identifier: NCT03919773
• Recruitment Status: Enrolling by invitation
• First Posted: April 18, 2019
• Last Update Posted: January 24, 2022
• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: Grifols Biologicals, LLC; Dysautonomia International
• Information provided by (Responsible Party): Steven Vernino, University of Texas Southwestern Medical Center

Tracking Information

• First Submitted Date: February 5, 2019
• First Posted Date: April 18, 2019
• Last Update Posted Date: January 24, 2022
• Actual Study Start Date: October 29, 2018
• Estimated Primary Completion Date: September 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 9, 2019)

Improvement in symptoms measured by change in COMPASS-31 score. [ Time Frame: 12 weeks ]

Primary outcome with POTS symptoms

Original Primary Outcome Measures (submitted: April 14, 2019)

Our primary aim is to evaluate the number of research participants that are treated with IVIG (Gammunex-C) versus active placebo (intravenous albumin) with improving the symptoms of POTS using the COMPASS-31 score. [ Time Frame: 12 weeks ]

Primary outcome with POTS symptoms

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: IVIG (Gamunex-C) Treatment Study for POTS Subjects
• Official Title: IVIG (Gamunex-C) Study of Treatment for Autoimmune Neuropathic Dysautonomia/Postural Tachycardia (POTS)
• Brief Summary: The purpose of this trial is to evaluate the symptomatic benefits of immunomodulatory treatment with IVIG for POTS (postural tachycardia syndrome) patients with evidence of autoimmunity.

Detailed Description

Gammunex-C, a form of intravenous immunoglobulin (IVIG), is approved for the treatment of chronic inflammatory demyelinating neuropathy (CIDP) or idiopathic thrombocytopenic purpura (ITP). IVIG has been in use for many decades in the treatment of these disorders and many other inflammatory/autoimmune diseases. It is generally very safe and well tolerated. More recently, IVIG has been proposed as an effective treatment for presumed inflammatory neurological disorders which do not meet the criteria for CIDP. Specifically, case reports and cases series have indicated therapeutic responses to IVIG in autonomic neuropathies.

Intravenous Albumin is approved for the treatment of hypovolemia (see attached package insert). The use of albumin to increase plasma volume in patients with POTS has been suggested. In this study, albumin will be used as an active control treatment to provide the same volume and protein load as IVIG but without the immunomodulatory effects.

There have been few well designed clinical therapy trials aimed at POTS patients and even fewer that are aimed at a particular pathophysiological subtype of POTS. Evidence suggests that POTS is a heterogeneous disorder with differing underlying mechanisms. Several uncontrolled case series have suggested a benefit of IVIG for POTS, but the volume expansion associated with infusion of IVIG make it difficult to assess the immunomodulatory effects of this treatment. We propose to evaluate the efficacy of IVIG using a double-blind randomized cross over design that will determine efficacy while reducing effects of inter-subject variability and placebo effect which are common problems in POTS therapy research. Even with the statistical advantages of a crossover design, the treatment cohort will be small, and this study is designed to be a pilot (phase II) study to evaluate the feasibility, tolerability and potential benefits of treatment. The results of this pilot study will provide the impetus and rationale for a larger multicenter clinical trial to definitively evaluate immunomodulatory treatment in POTS.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

double-blind randomized controlled crossover pilot study

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

double-blind

Primary Purpose: Treatment

• Condition: Postural Tachycardia Syndrome

Intervention

• Drug: IVIG

  If you participate in this study there will be 18 scheduled treatment infusions during the 30 week study period. All the study visits and treatment visits will be outpatient visits.

  Once you qualify to participate in the study and begin treatment, there will be two 12 week treatment periods separated by a 6 week washout period. The infusion visits will take approximately 3-4 hours each.

  Other Name: intravenous immunoglobulin
• Drug: Albumin
  This will be the matching placebo used in the study.

Study Arms

• Active Comparator: Treatment IVIG Arm
  IVIG (Gammunex-C) infusion (0.4 gm/kg) every week for 4 weeks, then every 2 weeks for 8 weeks (12 weeks total).
  Intervention: Drug: IVIG
• Placebo Comparator: Treatment Albumin Arm
  albumin infusion (0.4 gm/kg) every week for 4 weeks then every 2 weeks for 8 weeks (12 weeks total) during
  Intervention: Drug: Albumin

• Publications *: Goodman BP, Crepeau A, Dhawan PS, Khoury JA, Harris LA. Spectrum of Autonomic Nervous System Impairment in Sjögren Syndrome. Neurologist. 2017 Jul;22(4):127-130. doi: 10.1097/NRL.0000000000000134.

Recruitment Information

• Recruitment Status: Enrolling by invitation
• Estimated Enrollment (submitted: May 14, 2021): 32
• Original Estimated Enrollment (submitted: April 14, 2019): 20
• Estimated Study Completion Date: December 2023
• Estimated Primary Completion Date: September 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 18 years of age or older, and able to provide informed consent
• Diagnosis of POTS (see Table 1)
• COMPASS-31 symptom score showing moderate to severe autonomic symptoms

• At least 3 of the following clinical or laboratory features of autoimmunity

  • One or more serum autoantibodies (ANA ≥ 1:160, gAChR antibody > 0.2 nmol/L, positive ENA, aPL, TTG, gliadin) or inflammatory markers (ESR > 30, CRP > 2, low C3 complement or low immunoglobulin IgG level)
  • Confirmed personal history or family history of defined autoimmune disease including Hashimoto's thyroiditis, celiac disease, antiphospholipid syndrome, rheumatoid arthritis, SLE, or Sjogren's syndrome
  • Clear history of acute or subacute onset following infection, immunization, injury/concussion, surgery or pregnancy.
  • Evidence of esophageal, gastric or intestinal dysmotility (with weight loss)
  • Evidence of small fiber neuropathy (abnormal QSART or IENFD)
• Stable oral medical therapy for past 3 months
• Ambulatory at time of screening

Exclusion Criteria:

• Current or previous immunosuppression therapy or IVIG treatment
• Contraindication to intravenous immunoglobulin or intravenous albumin
• Known allergic reactions to blood products including intravenous immunoglobulin (IVIG) and/or subcutaneous immunoglobulin (SCIG), such as history of clinically relevant hemolysis after IVIG infusion, aseptic meningitis, recurrent severe headache, hypersensitivity, severe generalized or severe local skin reaction.
• Inadequate peripheral venous access
• Evidence of renal insufficiency (Cr > 1.5 x elevated) or liver disease (transaminases > 2.5x upper limit) at screening
• History of thrombotic episode within 3 years of enrollment
• Other major medical issue which, in investigators opinion, increases risk for adverse event over the next 12 months or may require separate management.
• Female patients who are premenopausal and are (a) pregnant based on serum pregnancy test, or (b) breast-feeding.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03919773
• Other Study ID Numbers: STU-2018-0005
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: All patient information will be de-identified if sent out. Any AE and/or SAE will be sent out for review.

• Current Responsible Party: Steven Vernino, University of Texas Southwestern Medical Center
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Texas Southwestern Medical Center
• Original Study Sponsor: Same as current

Collaborators

• Grifols Biologicals, LLC
• Dysautonomia International

Investigators

• Principal Investigator: Steven Vernino, MD, PhD; UT Southwestern Medical Center

• PRS Account: University of Texas Southwestern Medical Center
• Verification Date: January 2022