A Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Efficacy of Intravenous Immunoglobulin Therapy in Autoimmune Autonomic Ganglionopathy.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 6
- 试验地点
- 6
- 主要终点
- Change in Systolic Blood Pressure During 60° Tilt (ΔSBP)
研究概览
简要总结
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).
详细描述
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:
- 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
IVIg group
Double blinded IVIg and single blinded IVIg
干预措施: Double blinded IVIg (Drug)
IVIg group
Double blinded IVIg and single blinded IVIg
干预措施: Single Blinded IVIg (Other)
Placebo Group
Double blinded Placebo and single blinded IVIg
干预措施: Double blinded Placebo (Other)
Placebo Group
Double blinded Placebo and single blinded IVIg
干预措施: Single Blinded IVIg (Other)
结局指标
主要结局
Change in Systolic Blood Pressure During 60° Tilt (ΔSBP)
时间窗: 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.
次要结局
- 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)
研究者
Roy Freeman, MD
Professor of Neurology, Harvard Medical School
Beth Israel Deaconess Medical Center