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Evaluating the Effectiveness of Intravenous Immunoglobulin Therapy in Autoimmune Autonomic Ganglionopathy

This study has been completed.
Sponsor:
Collaborators:
Mayo Clinic
Vanderbilt University
New York University School of Medicine
University of Texas Southwestern Medical Center
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Roy Freeman, MD, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier:
NCT01522235
First received: January 25, 2012
Last updated: June 2, 2017
Last verified: June 2017
  Purpose
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).

Condition Intervention Phase
Autoimmune Autonomic Ganglionopathy (AAG) Drug: Double blinded IVIg Other: Double blinded Placebo Other: Single Blinded IVIg Phase 2 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Masking Description:
To prevent unblinding because of observed efficacy, adverse events or changes in laboratory values, each site will have both a treating investigator and an examining investigator. The treating investigator will assess the participant's clinical response and laboratory findings. The treating investigator will make all clinical treatment decisions. The examining investigator will monitor only the clinical autonomic symptoms and quality of life scores, and autonomic tests. Both the treating and examining investigators should be physicians. To prevent infusion unblinding, infusions of IVIG and placebo will occur in opaque bags.
Primary Purpose: Treatment
Official Title: A Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Efficacy of Intravenous Immunoglobulin Therapy in Autoimmune Autonomic Ganglionopathy.

Resource links provided by NLM:


Further study details as provided by Roy Freeman, MD, Beth Israel Deaconess Medical Center:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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).

  • 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.

  • 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.


  • 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".

  • 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.



Enrollment: 6
Study Start Date: February 2012
Study Completion Date: September 2015
Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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.
Placebo Group
Double blinded Placebo and single blinded IVIg
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.
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.

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).

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01522235

Locations
United States, Maryland
Nih Ninds
Bethesda, Maryland, United States, 20895
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
NYU Medical Center
New York, New York, United States, 10016
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37215
United States, Texas
UT Southwestern Medical Center
Dallas, Texas, United States, 75390
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
Mayo Clinic
Vanderbilt University
New York University School of Medicine
University of Texas Southwestern Medical Center
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Principal Investigator: Roy Freeman, MD Beth Israel Deaconess Medical Center
  More Information

Publications:

Responsible Party: Roy Freeman, MD, Professor of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT01522235     History of Changes
Other Study ID Numbers: 2011P000397
1U54NS065736 ( U.S. NIH Grant/Contract )
Study First Received: January 25, 2012
Results First Received: April 14, 2017
Last Updated: June 2, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

Keywords provided by Roy Freeman, MD, Beth Israel Deaconess Medical Center:
Autoimmune autonomic neuropathy
Orthostatic hypotension
Dysautonomia
Autonomic failure
Peripheral autonomic neuropathy

Additional relevant MeSH terms:
Immunoglobulins
Antibodies
Immunoglobulins, Intravenous
gamma-Globulins
Rho(D) Immune Globulin
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 27, 2017