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: May 17, 2021
• 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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Postural Tachycardia Syndrome	Drug: IVIG; Drug: Albumin	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 32 participants
• 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
• Official Title: IVIG (Gamunex-C) Study of Treatment for Autoimmune Neuropathic Dysautonomia/Postural Tachycardia (POTS)
• Actual Study Start Date: October 29, 2018
• Estimated Primary Completion Date: October 2021
• Estimated Study Completion Date: March 2022

Arms and Interventions

Arm	Intervention/treatment
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).	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
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	Drug: Albumin; This will be the matching placebo used in the study.

Outcome Measures

Primary Outcome Measures :

1. Improvement in symptoms measured by change in COMPASS-31 score. [ Time Frame: 12 weeks ]
   Primary outcome with POTS symptoms

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Texas

UT Southwestern Medical Center

Dallas, Texas, United States, 75208

Sponsors and Collaborators

University of Texas Southwestern Medical Center

Grifols Biologicals, LLC

Dysautonomia International

Investigators

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

More Information

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.

• Responsible Party: Steven Vernino, PROFESSOR, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT03919773
• Other Study ID Numbers: STU-2018-0005
• First Posted: April 18, 2019
• Last Update Posted: May 17, 2021
• Last Verified: May 2021

Individual Participant Data (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.

• 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

Additional relevant MeSH terms:

Postural Orthostatic Tachycardia Syndrome; Tachycardia; Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Pathologic Processes; Orthostatic Intolerance; Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Immunoglobulins; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin; Immunologic Factors; Physiological Effects of Drugs