A Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Efficacy of Intravenous Immunoglobulin Therapy in Autoimmune Autonomic Ganglionopathy.
Overview
- Phase
- Phase 2
- Intervention
- Double blinded IVIg
- Conditions
- Autoimmune Autonomic Ganglionopathy (AAG)
- Sponsor
- Beth Israel Deaconess Medical Center
- Enrollment
- 6
- Locations
- 6
- Primary Endpoint
- Change in Systolic Blood Pressure During 60° Tilt (ΔSBP)
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
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).
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).
Investigators
Roy Freeman, MD
Professor of Neurology, Harvard Medical School
Beth Israel Deaconess Medical Center
Eligibility Criteria
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)
Arms & Interventions
IVIg group
Double blinded IVIg and single blinded IVIg
Intervention: Double blinded IVIg
IVIg group
Double blinded IVIg and single blinded IVIg
Intervention: Single Blinded IVIg
Placebo Group
Double blinded Placebo and single blinded IVIg
Intervention: Double blinded Placebo
Placebo Group
Double blinded Placebo and single blinded IVIg
Intervention: Single Blinded IVIg
Outcomes
Primary Outcomes
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 Outcomes
- Composite Autonomic Severity Score (CASS) Questionnaire.(Baseline, 6 weeks)
- EuroQol [EQ-5D] Questionnaire.(Baseline, 6 weeks)
- Composite Autonomic Symptom Score [COMPASS] Questionnaire(Baseline, 6 weeks)
- Orthostatic Hypotension Symptom Assessment Questionnaire(Baseline, 6 weeks)
- Change in Systolic Blood Pressure During 60° Tilt (ΔSBP)(6 weeks and 12 weeks)