Droxidopa / Pyridostigmine in Orthostatic Hypotension

Study Overview
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Brief Summary
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This study is being done to study the combination of pyridostigmine and low-dose Droxidopa for the treatment of orthostatic hypotension.

Official Title
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Treatment Trial of Droxidopa and Pyridostigmine to Improve Orthostatic Hypotension Without Aggravating Supine Hypertension

Conditions
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Orthostatic Hypotension

Intervention / Treatment
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* Drug: Droxidopa
* Drug: Pyridostigmine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria The presence of OH (fall in systolic BP >=30 mm Hg) is required for this study. Autonomic testing and clinical evaluation demonstrates OH to be of neurogenic etiology. Exclusion Criteria: Pregnant or lactating females. Chronic illnesses or the presence of other conditions that potentially involve the CNS or affect autonomic testing. These include congestive heart failure, recent (<6 months) myocardial infarct, severe anemia, diabetes mellitus, alcoholism, malignant neoplasms, amyloidosis, hypothyroidism, sympathectomy, cerebrovascular accidents, and neurotoxins or neuroactive drug exposure. Orthopedic problems or cardiopulmonary disease, sufficient to compromise mobility and activity of daily living. Any known concurrent infection or severe liver or kidney disease. Medications that could affect autonomic function are suspended prior to autonomic testing. Therapy with midodrine, alpha and beta adrenergic antagonists, or other medications that affect autonomic function will be withdrawn 48 hours prior to autonomic evaluations. Fludrocortisone doses up to 0.2 mg per day will be permitted. Stable doses of antidepressants (tricyclics, SSRIs, SNRIs) will also be permitted. The 48h medication withdrawal is reviewed on a case by case basis - if felt unsafe by the investigators, the withdrawal period may be shortened. This will be documented in the study documents. Occasional use of a neuroleptic as an anti-emetic in the past is allowed, but none can have been used within 3 weeks prior to this study. Use of methylphenidate, cinnarizine, reserpine, amphetamine, atypical antipsychotics such as risperidone, olanzapine, and quetiapine or a MAO-A inhibitor within 3 weeks prior to this study. Dementia (DSM-IV criteria - Amer. Psych. Assoc., 1994). The score on the Mini-Mental State Examination must be >24. History of stroke (diagnosed on clinical grounds as an acute deterioration of neurological function typical of a stroke; confirmatory CT or MRI evidence of stroke will be useful but not necessary). History of electroconvulsive therapy. History of brain surgery for Parkinson's disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Placebo-controlled, double-blind, randomized four-way crossover
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo, Then Pyridostigmine<br>participants first receive placebo by mouth 3 times a day, for treatment day 1. Then participants receive pyridostigmine by mouth 3 times a day for treatment day 2. | Drug: Pyridostigmine<br>* 60 mg tablets by mouth three times a day<br>Other: Placebo<br>* Looks exactly like the study drug but contains no active ingredients<br>|
| Active Comparator: Pyridostigmine, Then Placebo<br>participants first receive pyridostigmine by mouth 3 times a day, for treatment day 1. Then participants receive placebo by mouth 3 times a day for treatment day 2. | Drug: Pyridostigmine<br>* 60 mg tablets by mouth three times a day<br>Other: Placebo<br>* Looks exactly like the study drug but contains no active ingredients<br>|
| Experimental: Drioxidopa and Placebo, Then Drioxidopa and Pyridostigmine<br>participants first receive placebo by mouth 3 times a day, for treatment day 3. Then participants receive Droxidopa by mouth 3 times a day for treatment day 4. | Drug: Droxidopa<br>* 100 mg tablets by mouth three times a day<br>Drug: Pyridostigmine<br>* 60 mg tablets by mouth three times a day<br>Other: Placebo<br>* Looks exactly like the study drug but contains no active ingredients<br>|
| Experimental: Droxidopa and Pyridostigmine, Then Droxidopa and Placebo<br>participants first receive Droxidopa by mouth 3 times a day, for treatment day 3. Then participants receive Placebo by mouth 3 times a day for treatment day 4. | Drug: Droxidopa<br>* 100 mg tablets by mouth three times a day<br>Drug: Pyridostigmine<br>* 60 mg tablets by mouth three times a day<br>Other: Placebo<br>* Looks exactly like the study drug but contains no active ingredients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in orthostatic diastolic blood pressure | diastolic blood pressure measured upon standing reported in mm/Hg | 1 hour after medication administration, 2 hours after medication administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in orthostatic systolic blood pressure | systolic blood pressure measured upon standing reported in mm/Hg | 1 hour after medication administration, 2 hours after medication administration | 
| Change in absolute supine diastolic blood pressure | diastolic blood pressure measured while lying flat reported in mm/Hg | 1 hour after medication administration, 2 hours after medication administration | 
| Change in absolute supine systolic blood pressure | systolic blood pressure measured while lying flat reported in mm/Hg | 1 hour after medication administration, 2 hours after medication administration | 
| Change in supine norepinephrine levels | measure of serum norepinephrine levels while lying flat reported in pg/mL | 1 hour after medication administration, 2 hours after medication administration | 
| Change in orthostatic symptoms | measured during tilt study, the patient will be asked to score orthostatic symptoms on a symptom scale ranging from 0 = no symptoms to 10 = near syncope | 1 hour after medication administration, 2 hours after medication administration |