Evaluating the Effectiveness of Intravenous Immunoglobulin Therapy in Autoimmune Autonomic Ganglionopathy

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2013 by Beth Israel Deaconess Medical Center
Sponsor:
Collaborators:
Mayo Clinic
Vanderbilt University
New York University School of Medicine
University of Texas Southwestern Medical Center
Information provided by (Responsible Party):
Roy Freeman, MD, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier:
NCT01522235
First received: January 25, 2012
Last updated: July 30, 2013
Last verified: July 2013
  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: IVIG
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
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 Beth Israel Deaconess Medical Center:

Primary Outcome Measures:
  • The effect of intravenous immunoglobulin (IVIG) study treatment on orthostatic hypotension during head up tilt. [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
    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:
  • To determine the effects of 12 weeks of intravenous immunoglobulin (IVIG) study treatment on orthostatic hypotension compared to 6 weeks of IVIG. [ Time Frame: 6 weeks and 12 weeks ] [ Designated as safety issue: No ]
    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).

  • To determine the effects of 12 weeks of intravenous immunoglobulin (IVIG) study treatment on autonomic symptoms. [ Time Frame: baseline, 6 weeks, 12 weeks ] [ Designated as safety issue: No ]
    To determine the change in autonomic symptoms (measured by the composite autonomic symptom score [COMPASS] questionnaire) measured at baseline, 6 and 12 weeks in individuals receiving IVIG.

  • To determine the effects of 12 weeks of intravenous immunoglobulin (IVIG) study treatment on Composite Autonomic Severity Score (CASS). [ Time Frame: baseline, 6 weeks, 12 weeks. ] [ Designated as safety issue: No ]
    To determine the change in autonomic symptoms (measured by the composite autonomic severity score [CASS]) measured at baseline, 6 and 12 weeks in individuals receiving IVIG.

  • To determine the effects of 12 weeks of intravenous immunoglobulin (IVIG) study treatment on change in quality of life. [ Time Frame: baseline, 6 weeks, 12 weeks. ] [ Designated as safety issue: No ]
    To determine the change in quality of life (measured by the EuroQol [EQ-5D]) measured at baseline, 6 and 12 weeks in individuals receiving IVIG.

  • To provide a summary of the adverse events after 12 weeks of intravenous immunoglobulin (IVIG). [ Time Frame: baseline, 6 weeks ,12 weeks. ] [ Designated as safety issue: Yes ]
    To report adverse events experienced after treatment by 6 or 12 weeks of IVIG in patients with autoimmune autonomic ganglionopathy.


Estimated Enrollment: 30
Study Start Date: February 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Group A
4 treatments of IVIG
Drug: IVIG
Participants will be randomized to Group A (2 treatments of IVIG and 2 treatments of placebo), or Group B (4 treatments of IVIG). Placebo is 5% albumin. Study treatment with IVIG, at 2.0 gm/kg over 2-5 consecutive days, and then 1.0 gm/kg over 2-5 consecutive days three weeks later. Placebo 5% at equivalent volume.
Group B
2 treatment of placebo and 2 treatments of IVIG
Drug: IVIG
Participants will be randomized to Group A (2 treatments of IVIG and 2 treatments of placebo), or Group B (4 treatments of IVIG). Placebo is 5% albumin. Study treatment with IVIG, at 2.0 gm/kg over 2-5 consecutive days, and then 1.0 gm/kg over 2-5 consecutive days three weeks later. Placebo 5% at equivalent volume.

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 are 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.
  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
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

Contacts
Contact: Peggy Rose, RN, BSN 617-632-0899 prose1@bidmc.harvard.edu

Locations
United States, Maryland
Nih Ninds Not yet recruiting
Bethesda, Maryland, United States, 20895
Contact: LaToya Sewell, NP    301-496-2103      
Principal Investigator: David Goldstein, MD, PhD         
United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Peggy Rose, RN, BSN    617-632-0899    prose1@bidmc.harvard.edu   
Principal Investigator: Roy Freeman, MD         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Tonette Gehrking    507-284-4462    gehrking.tonette@mayo.edu   
Principal Investigator: Phillip Low, MD         
United States, New York
NYU Medical Center Recruiting
New York, New York, United States, 10016
Contact: Jose Martinez, MD    212-263-7225    jose.martinex@nyumc.org   
Principal Investigator: Horacio Kaufmann, MD         
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37215
Contact: Cindy Dorminy    615-322-2931    cindy.a.dorminy@Vanderbilt.edu   
Principal Investigator: David Robertson, MD         
United States, Texas
UT Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
Contact: Steve Hopkins    214-648-9275    steve.hopkins@utsouthwestern.edu   
Principal Investigator: Steven Vernino, MD, PhD         
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
Mayo Clinic
Vanderbilt University
New York University School of Medicine
University of Texas Southwestern Medical Center
Investigators
Principal Investigator: Roy Freeman, MD Beth Israel Deaconess Medical Center
  More Information

No publications provided

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: 2011P-000397, 1U54NS065736
Study First Received: January 25, 2012
Last Updated: July 30, 2013
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

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

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

ClinicalTrials.gov processed this record on September 18, 2014