Evaluating the Effectiveness of Intravenous Immunoglobulin Therapy in Autoimmune Autonomic Ganglionopathy
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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: Intravenous Immunoglobulin |
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. |
- 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.
- 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
12 weeks of IVIG treatment
|
Drug: Intravenous Immunoglobulin
First Observation Period: Participants will be randomized to receive study treatment with either IVIG or placebo (5% albumin). Participants will receive study treatment with IVIG, at 2.0 gm/kg, or placebo (5% albumin) over 2-5 consecutive days. A maintenance study treatment IVIG, at 1.0 gm/kg, or placebo (5% albumin) will occur three weeks later. Second Observation Period: In a single-blind extension study, all participants will receive study treatment with IVIG, at 2.0 gm/kg over 2-5 consecutive days. A maintenance study treatment at 1.0 gm/kg, over 2-5 consecutive days will occur three weeks later. |
|
Group B
6 weeks of placebo followed by 6 weeks of IVIG
|
Drug: Intravenous Immunoglobulin
First Observation Period: Participants will be randomized to receive study treatment with either IVIG or placebo (5% albumin). Participants will receive study treatment with IVIG, at 2.0 gm/kg, or placebo (5% albumin) over 2-5 consecutive days. A maintenance study treatment IVIG, at 1.0 gm/kg, or placebo (5% albumin) will occur three weeks later. Second Observation Period: In a single-blind extension study, all participants will receive study treatment with IVIG, at 2.0 gm/kg over 2-5 consecutive days. A maintenance study treatment at 1.0 gm/kg, over 2-5 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 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:
- To measure the effect of IVIG treatment on orthostatic hypotension, autonomic symptoms and quality of life scores in patient participants with AAG.
- 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 |
Inclusion Criteria:
- Participants aged 18 to 85
- Participants have neurogenic orthostatic hypotension (fall in systolic blood pressure > 30 mmHg).
- Symptoms of orthostatic intolerance.
- 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.
- 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:
- Women of childbearing potential (WOCP) who are not using a medically accepted contraception
- 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.
- Severe depression and/or anxiety (score of > 29 on the Beck Depression Inventory or score on the Beck Anxiety Inventory of ≥ 36)
- Active psychosis is ineligible, history of psychosis will be eligible, but only after review with the patients PCP and/or treating mental health provider.
- History of asthma
- Other causes of autonomic failure (e.g., diabetes, amyloidosis)
- History of allergic or anaphylactic reaction to humanized or murine antibodies.
- History or presence of recurrent or chronic infection (recurrent infections defined as >4 times per year).
- History of cancer, including solid tumors and hematologic malignancies (except fully resolved and resected cutaneous basal cell and squamous cell carcinomas of the skin)
- 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)
- History of severe, clinically significant central nervous system trauma (e.g., cerebral contusion, spinal cord compression)
- 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)
- History of thromboembolic events or deep vein thrombosis
- Platelet count <100,000/mL, Hemoglobin <8.5 g/dL, Neutrophils <1.5 x 103/mL.
- Serum IgA deficiency: Immunoglobulin A (IgA) level < 7 mg/dL.
- History of immunosuppression or HIV/AIDS
- 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)
- History of renal failure or creatinine >2.0
- History of previous allergic response to albumin.
- Treatment with IVIG or plasma exchange within 6 weeks of study enrollment.
- 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| Contact: Peggy Rose, RN, BSN | 617-632-0899 | prose1@bidmc.harvard.edu |
| 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 | Not yet 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 | Not yet 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 | Not yet 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 | Not yet 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 | Not yet recruiting |
| Dallas, Texas, United States, 75390 | |
| Contact: Steve Hopkins 214-648-9275 steve.hopkins@utsouthwestern.edu | |
| Principal Investigator: Steven Vernino, MD, PhD | |
| 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: | January 27, 2012 |
| Health Authority: | United States: Institutional Review Board United States: Data Safety and Monitoring 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 June 17, 2013