Evaluating the Effectiveness of Intravenous Immunoglobulin Therapy in Autoimmune Autonomic Ganglionopathy

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.

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.