IVIG (Gamunex-C) Treatment Study for POTS Subjects

Study Overview
=================
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.

Official Title
-----------------
IVIG (Gamunex-C) Study of Treatment for Autoimmune Neuropathic Dysautonomia/Postural Tachycardia (POTS)

Conditions
-----------------
Postural Tachycardia Syndrome

Intervention / Treatment
-----------------
* Drug: IVIG
* Drug: Albumin


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: double-blind randomized controlled crossover pilot study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment IVIG Arm<br>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<br>* 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.<br>* Other names: intravenous immunoglobulin;|
| Placebo Comparator: Treatment Albumin Arm<br>albumin infusion (0.4 gm/kg) every week for 4 weeks then every 2 weeks for 8 weeks (12 weeks total) during | Drug: Albumin<br>* This will be the matching placebo used in the study.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in symptoms measured by change in COMPASS-31 score. | Primary outcome with POTS symptoms | 12 weeks |