Clinical trial NCT01522235: Evaluating the Effectiveness of Intravenous Immunoglobulin Therapy in Autoimmune Autonomic Ganglionopathy
Official title: A Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Efficacy of Intravenous Immunoglobulin Therapy in Autoimmune Autonomic Ganglionopathy.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Autoimmune Autonomic Ganglionopathy (AAG)
Keywords: Autoimmune autonomic neuropathy
Orthostatic hypotension
Dysautonomia
Autonomic failure
Peripheral autonomic neuropathy
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: Mayo Clinic
name: Vanderbilt University
name: NYU Langone Health
name: University of Texas Southwestern Medical Center
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2012-01-31
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility 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.

Primary outcomes:
measure: Change in Systolic Blood Pressure During 60° Tilt (ΔSBP)
timeFrame: Baseline and 6 weeks
Secondary outcomes:
measure: Change in Systolic Blood Pressure During 60° Tilt (ΔSBP)
timeFrame: 6 weeks and 12 weeks
measure: Composite Autonomic Symptom Score [COMPASS] Questionnaire
timeFrame: Baseline, 6 weeks
measure: Composite Autonomic Severity Score (CASS) Questionnaire.
timeFrame: Baseline, 6 weeks
measure: EuroQol [EQ-5D] Questionnaire.
timeFrame: Baseline, 6 weeks
measure: Orthostatic Hypotension Symptom Assessment Questionnaire
timeFrame: Baseline, 6 weeks
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Nih Ninds
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: NYU Medical Center
state: New York
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Roy Freeman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vernino S, Sandroni P, Singer W, Low PA. Invited Article: Autonomic ganglia: target and novel therapeutic tool. Neurology. 2008 May 13;70(20):1926-32. doi: 10.1212/01.wnl.0000312280.44805.5d.
citation: Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med. 2000 Sep 21;343(12):847-55. doi: 10.1056/NEJM200009213431204.
citation: Gibbons CH, Freeman R. Antibody titers predict clinical features of autoimmune autonomic ganglionopathy. Auton Neurosci. 2009 Mar 12;146(1-2):8-12. doi: 10.1016/j.autneu.2008.11.013. Epub 2009 Jan 13.
citation: Klein CM, Vernino S, Lennon VA, Sandroni P, Fealey RD, Benrud-Larson L, Sletten D, Low PA. The spectrum of autoimmune autonomic neuropathies. Ann Neurol. 2003 Jun;53(6):752-8. doi: 10.1002/ana.10556.
citation: Gibbons CH, Vernino SA, Kaufmann H, Freeman R. L-DOPS therapy for refractory orthostatic hypotension in autoimmune autonomic neuropathy. Neurology. 2005 Oct 11;65(7):1104-6. doi: 10.1212/01.wnl.0000178980.83477.14.
citation: Gibbons CH, Vernino SA, Freeman R. Combined immunomodulatory therapy in autoimmune autonomic ganglionopathy. Arch Neurol. 2008 Feb;65(2):213-7. doi: 10.1001/archneurol.2007.60.
citation: Iodice V, Kimpinski K, Vernino S, Sandroni P, Fealey RD, Low PA. Efficacy of immunotherapy in seropositive and seronegative putative autoimmune autonomic ganglionopathy. Neurology. 2009 Jun 9;72(23):2002-8. doi: 10.1212/WNL.0b013e3181a92b52.
citation: Modoni A, Mirabella M, Madia F, Sanna T, Lanza G, Tonali PA, Silvestri G. Chronic autoimmune autonomic neuropathy responsive to immunosuppressive therapy. Neurology. 2007 Jan 9;68(2):161-2. doi: 10.1212/01.wnl.0000251194.82212.75. No abstract available.
citation: Young RR, Asbury AK, Adams RD, Corbett JL. Pure pan-dysautonomia with recovery. Trans Am Neurol Assoc. 1969;94:355-7. No abstract available.
citation: Vernino S, Ermilov LG, Sha L, Szurszewski JH, Low PA, Lennon VA. Passive transfer of autoimmune autonomic neuropathy to mice. J Neurosci. 2004 Aug 11;24(32):7037-42. doi: 10.1523/JNEUROSCI.1485-04.2004.
citation: Malik U, Oleksowicz L, Latov N, Cardo LJ. Intravenous gamma-globulin inhibits binding of anti-GM1 to its target antigen. Ann Neurol. 1996 Jan;39(1):136-9. doi: 10.1002/ana.410390121.
citation: Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med. 2001 Sep 6;345(10):747-55. doi: 10.1056/NEJMra993360. No abstract available.
citation: Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004 May 19;291(19):2367-75. doi: 10.1001/jama.291.19.2367.
citation: Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science. 2001 Jan 19;291(5503):484-6. doi: 10.1126/science.291.5503.484.
citation: Dalakas MC. Blockade of blocking antibodies in Guillain-Barre syndromes: "unblocking" the mystery of action of intravenous immunoglobulin. Ann Neurol. 2002 Jun;51(6):667-9. doi: 10.1002/ana.10259. No abstract available.
citation: Hughes RA, Cornblath DR. Guillain-Barre syndrome. Lancet. 2005 Nov 5;366(9497):1653-66. doi: 10.1016/S0140-6736(05)67665-9.
citation: Eftimov F, Winer JB, Vermeulen M, de Haan R, van Schaik IN. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2013 Dec 30;(12):CD001797. doi: 10.1002/14651858.CD001797.pub3.
citation: Leger JM, Viala K, Cancalon F, Maisonobe T, Gruwez B, Waegemans T, Bouche P. Intravenous immunoglobulin as short- and long-term therapy of multifocal motor neuropathy: a retrospective study of response to IVIg and of its predictive criteria in 40 patients. J Neurol Neurosurg Psychiatry. 2008 Jan;79(1):93-6. doi: 10.1136/jnnp.2007.121756.
citation: Slee M, Selvan A, Donaghy M. Multifocal motor neuropathy: the diagnostic spectrum and response to treatment. Neurology. 2007 Oct 23;69(17):1680-7. doi: 10.1212/01.wnl.0000277697.55288.d0.
citation: Federico P, Zochodne DW, Hahn AF, Brown WF, Feasby TE. Multifocal motor neuropathy improved by IVIg: randomized, double-blind, placebo-controlled study. Neurology. 2000 Nov 14;55(9):1256-62. doi: 10.1212/wnl.55.9.1256.
citation: Gorson KC, Ropper AH, Weinberg DH, Weinstein R. Efficacy of intravenous immunoglobulin in patients with IgG monoclonal gammopathy and polyneuropathy. Arch Neurol. 2002 May;59(5):766-72. doi: 10.1001/archneur.59.5.766.
citation: Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology. 2007 Mar 13;68(11):837-41. doi: 10.1212/01.wnl.0000256698.69121.45.
citation: Maddison P, Newsom-Davis J. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003279. doi: 10.1002/14651858.CD003279.pub2.
citation: Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, Dinsmore ST, McCrosky S. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med. 1993 Dec 30;329(27):1993-2000. doi: 10.1056/NEJM199312303292704.
citation: Gold R, Dalakas MC, Toyka KV. Immunotherapy in autoimmune neuromuscular disorders. Lancet Neurol. 2003 Jan;2(1):22-32. doi: 10.1016/s1474-4422(03)00264-3.
citation: Linker RA, Gold R. Use of intravenous immunoglobulin and plasma exchange in neurological disease. Curr Opin Neurol. 2008 Jun;21(3):358-65. doi: 10.1097/WCO.0b013e3282ff5b8f.
citation: Donofrio PD, Berger A, Brannagan TH 3rd, Bromberg MB, Howard JF, Latov N, Quick A, Tandan R. Consensus statement: the use of intravenous immunoglobulin in the treatment of neuromuscular conditions report of the AANEM ad hoc committee. Muscle Nerve. 2009 Nov;40(5):890-900. doi: 10.1002/mus.21433.
citation: Heafield MT, Gammage MD, Nightingale S, Williams AC. Idiopathic dysautonomia treated with intravenous gammaglobulin. Lancet. 1996 Jan 6;347(8993):28-9. doi: 10.1016/s0140-6736(96)91559-7.
citation: Mericle RA, Triggs WJ. Treatment of acute pandysautonomia with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry. 1997 May;62(5):529-31. doi: 10.1136/jnnp.62.5.529.