Evaluating the Effectiveness of Intravenous Immunoglobulin Therapy in Autoimmune Autonomic Ganglionopathy

June 2, 2017 updated by: Roy Freeman, MD, Beth Israel Deaconess Medical Center

A Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Efficacy of Intravenous Immunoglobulin Therapy in Autoimmune Autonomic Ganglionopathy.

The purpose of the study is to see if administering intravenous immune globulin (IVIG) (putting immune globulin directly into your blood) helps to improve the symptoms of orthostatic hypotension (sudden fall in blood pressure when a person stands up) and quality of life in men and women who have autoimmune autonomic ganglionopathy (AAG).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Autoimmune autonomic ganglionopathy (AAG) is a rare disease that results in severe dysautonomia (disorder of autonomic nervous system function). Many patients are unable to carry out activities of daily living due to autonomic symptoms that do not respond well to therapy (such as drops in blood pressure while standing). The recent discovery of antibodies that cause AAG has stimulated interest in immunomodulatory therapy (therapies that modify the functioning of the immune system). Studies in which a positive clinical response to these therapies have been reported in patients with AAG using immunomodulatory therapy as a treatment.

The investigators plan to carry out a blinded, randomized trial using IVIG. There have been no reported randomized clinical trials with any immunosuppressive agent in AAG. The proposed studies, if successful, will provide the first reliable clinical evidence, that therapy with IVIG is an effective treatment of AAG.

Treatment for the symptoms of autonomic failure is only effective in mild cases. Most patients require therapy that would change the course of the disease, but at present there is no established therapeutic regimen. The natural course of untreated AAG is not known.

To address these unresolved issues, this clinical trial has the following goals:

  1. To measure the effect of IVIG treatment on orthostatic hypotension, autonomic symptoms and quality of life scores in patient participants with AAG.
  2. To determine the durability of IVIG (how long the treatment is effective) on orthostatic hypotension, autonomic symptoms and quality of life scores in patient participants with AAG.

Participants enrolled in the study will receive two courses of intravenous immunoglobulin or placebo separated by 3 weeks. During the First Observation Period, participants will be evaluated after 6 weeks to determine the clinical response and natural history of the disorder.

All the participants will then move to a single blinded second observation period.

All patients enrolled in the study (IVIG group and placebo group) will receive two infusions of intravenous immunoglobulin, i.e., both cohorts will receive IVIG (although participants will not know this, and physicians will not be aware if this treatment is to IVIG naïve or IVIG continued participants).

Study Type

Interventional

Enrollment (Actual)

6

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20895
        • Nih Ninds
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Beth Israel Deaconess Medical Center
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic
    • New York
      • New York, New York, United States, 10016
        • NYU Medical Center
    • Tennessee
      • Nashville, Tennessee, United States, 37215
        • Vanderbilt University
    • Texas
      • Dallas, Texas, United States, 75390
        • UT Southwestern Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Participants aged 18 to 85
  2. Participants have neurogenic orthostatic hypotension (fall in systolic blood pressure > 30 mmHg).
  3. Symptoms of orthostatic intolerance.
  4. Antibodies to the neuronal AChR of the autonomic ganglia of >0.2nmol/l. Results must be within 6 months of the screening visit and there may not have been any immunomodulatory interventions since the time of the antibody measurement or the sample will need to be reconfirmed at screening.
  5. Participants must be willing to withdraw from medications that affect vasoactive and autonomic function for 5 half-lives during testing (with the exception of stable doses of fludrocortisone up to 0.2 mg/day) and adhere to a regular diet

Exclusion Criteria:

  1. Women of childbearing potential (WOCP) who are not using a medically accepted contraception
  2. Pregnant or lactating females- if participants become pregnant during the trial they will no longer receive IVIG, but will be followed as part of the intention to treat protocol.
  3. Severe depression and/or anxiety (score of > 29 on the Beck Depression Inventory or score on the Beck Anxiety Inventory of ≥ 36)
  4. Active psychosis is ineligible, history of psychosis will be eligible, but only after review with the patients PCP and/or treating mental health provider.
  5. History of asthma
  6. Other causes of autonomic failure (e.g., diabetes, amyloidosis)
  7. History of allergic or anaphylactic reaction to humanized or murine antibodies.
  8. History or presence of recurrent or chronic infection (recurrent infections defined as >4 times per year).
  9. History of cancer, including solid tumors and hematologic malignancies (except fully resolved and resected cutaneous basal cell and squamous cell carcinomas of the skin)
  10. History or presence of vascular disease potentially affecting brain or spinal cord (e.g., stroke, transient ischemic attack, carotid stenosis (greater than 80%), aortic aneurysm, intracranial aneurysm, hemorrhage, arteriovenous malformation)
  11. History of severe, clinically significant central nervous system trauma (e.g., cerebral contusion, spinal cord compression)
  12. History or presence of infectious causes of encephalopathy or myelopathy (e.g., syphilis, Lyme disease, human T-cell lymphotropic virus type 1 [HTLV-1], herpes zoster myelopathy)
  13. History of thromboembolic events or deep vein thrombosis
  14. Platelet count <100,000/mL, Hemoglobin <8.5 g/dL, Neutrophils <1.5 x 103/mL.
  15. Serum IgA deficiency: Immunoglobulin A (IgA) level < 7 mg/dL.
  16. History of immunosuppression or HIV/AIDS
  17. History of cardiac arrhythmia or angina, electrocardiogram (ECG) showing significant abnormality that the treating investigator determines may jeopardize the participant's health (i.e., acute ischemia, left bundle branch, or bifascicular block)
  18. History of renal failure or creatinine >2.0
  19. History of previous allergic response to albumin.
  20. Treatment with IVIG or plasma exchange within 6 weeks of study enrollment.
  21. Active adjustments of other immunomodulatory treatments. Patients that are on stable doses of immunomodulatory medications (no dose changes within 4 months -including, but not limited to prednisone, mycophenolate mofetil or azathioprine) but still have elevated antibody titers and meet criteria for inclusion will be allowed to participate in the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: IVIg group
Double blinded IVIg and single blinded IVIg
Drug: Double blinded IVIg
Participants will receive study treatment with IVIg, at 2.0 gm/kg over 2-4 consecutive days. A maintenance study treatment IVIg, at 1.0 gm/kg, over 1-2 consecutive days will occur three weeks later. All participants will proceed to the single blind Second Observation Period.
Other Names:
  • Gammagard
Other: Single Blinded IVIg
This is the single blind Second Observation Period. All participants will receive study treatment with IVIg, at 2.0 gm/kg over 2-4 consecutive days. A maintenance study treatment at 1.0 gm/kg, over 1-2 consecutive days will occur three weeks later.
Other: Placebo Group
Double blinded Placebo and single blinded IVIg
Other: Single Blinded IVIg
This is the single blind Second Observation Period. All participants will receive study treatment with IVIg, at 2.0 gm/kg over 2-4 consecutive days. A maintenance study treatment at 1.0 gm/kg, over 1-2 consecutive days will occur three weeks later.
Other: Double blinded Placebo
Participants will receive placebo (5% albumin) at 2.0 gm/kg over 2-4 consecutive days. A maintenance treatment with placebo (5% albumin) at 1.0 gm/kg, over 1-2 consecutive days will occur three weeks later. All participants will proceed to the single blind Second Observation Period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Systolic Blood Pressure During 60° Tilt (ΔSBP)
Time Frame: Baseline and 6 weeks
The primary outcome, the change in systolic blood pressure during 60 degree tilt (ΔSBP), will be assessed in all study participants at baseline and at 6 weeks.
Baseline and 6 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Systolic Blood Pressure During 60° Tilt (ΔSBP)
Time Frame: 6 weeks and 12 weeks
To compare the change in systolic blood pressure during 60 degree head up tilt table test after 6 and 12 weeks of IVIG (the within-patient difference in ΔSBP at 12 and 6 weeks among treated patients).
6 weeks and 12 weeks
Composite Autonomic Symptom Score [COMPASS] Questionnaire
Time Frame: Baseline, 6 weeks
To determine the change in autonomic symptoms (measured by the composite autonomic symptom score [COMPASS] questionnaire) measured at baseline and 6 weeks. Minimum and maximum score possible: 0-100. We have reported the Total score. Higher values represent worse outcome.
Baseline, 6 weeks
Composite Autonomic Severity Score (CASS) Questionnaire.
Time Frame: Baseline, 6 weeks

To determine the change in autonomic symptoms (measured by the composite autonomic severity score [CASS]) measured at baseline and 6 weeks in individuals receiving IVIg.

Is a 10-point composite autonomic scoring scale of autonomic function. This scale allots 4 points for adrenergic and 3 points each for sudomotor and cardiovagal failure. Subjects with a score of 3 or less on have a mild autonomic failure, 4-6 have moderate autonomic failure and those with scores of 7 to 10 have severe failure. The minimum score possible is 3 and maximum is 10.
Baseline, 6 weeks
EuroQol [EQ-5D] Questionnaire.
Time Frame: Baseline, 6 weeks
To determine the change in quality of life (measured by the EuroQol [EQ-5D]) measured at baseline and 6 weeks in individuals receiving IVIg. We have reported the subscale (EQ-VAS). The minimum score is 0 and maximum score is 100. (0) corresponds to " the worst health you can imagine", and the highest rate (100) corresponds to "the best health you can imagine".
Baseline, 6 weeks
Orthostatic Hypotension Symptom Assessment Questionnaire
Time Frame: Baseline, 6 weeks

To determine the change in orthostatic Hypotension symptom (measured by the orthostatic hypotension symptom assessment questionnaire) measured at baseline and 6 weeks in individuals receiving IVIG. This is a 60 point orthostatic hypotenstion symptom assessment questionnaire. The minimum score possible is 0 and maximum is 60.

Higher values represent worse outcome. We are reporting the total score.
Baseline, 6 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Beth Israel Deaconess Medical Center

Collaborators

Mayo Clinic
National Institute of Neurological Disorders and Stroke (NINDS)
NYU Langone Health
Vanderbilt University
University of Texas Southwestern Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2012

Primary Completion (Actual)

May 1, 2014

Study Completion (Actual)

September 1, 2015

Study Registration Dates

First Submitted

January 25, 2012

First Submitted That Met QC Criteria

January 27, 2012

First Posted (Estimate)

January 31, 2012

Study Record Updates

Last Update Posted (Actual)

July 2, 2017

Last Update Submitted That Met QC Criteria

June 2, 2017

Last Verified

June 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2011P000397
  • 1U54NS065736 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

The investigators will adhere to the NIH Grant Policy on Sharing of Unique Research Resources including the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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