PHOENIX

Overview

Status: Recruiting
Keywords: Symptomatic nOH , Parkinson's Disease (PD) , Multiple System Atrophy (MSA) , Pure Autonomic Failure (PAF) , Dopamine Beta Hydroxylase (DBH) , PHOENIX , Droxidopa , Orthostatic hypotension
IRB Number: 00071707
Specialty: Neurology, Neurology, Neurology, Neurology, Neurology
Sub Specialties: Multiple System Atrophy, Movement Disorders, Parkinson's Disease, Neurodegenerative Disorders

Brief Summary

PURPOSE

The purpose of this research study is to determine whether a drug called droxidopa can relieve the symptoms of nOH and whether it causes any side effects in people with symptomatic nOH over a long-term (17 weeks) treatment period. Droxidopa is a drug that is changed in the body to a chemical called norepinephrine. Norepinephrine is a chemical in your body that is used by your nervous system to signal nerves that control blood pressure.

OBJECTIVE

The primary objective is to evaluate the clinical efficacy of droxidopa versus placebo, as
demonstrated by improvements in dizziness (OHSA Item #1) from randomization over a
12 week (maximum) treatment period in patients with symptomatic nOH.
 
Secondary objectives will further evaluate the clinical efficacy of droxidopa versus placebo using
endpoints derived from the OHQ, Clinical Global Impression-Improvement (CGI-I), Clinical
Global Impression-Severity (CGI-S) and Boston University Activity Measure For Post-Acute
Care (AM-PAC) Basic Mobility Outpatient Short Form questionnaires, as well as assessment of
patient-reported falls, and BP measurements during the orthostatic standing tests. The safety of
droxidopa versus placebo will be assessed by AEs, vital sign assessments, ECGs, and laboratory
assessments.

Detailed Description

BACKGROUND Systolic blood pressure (SBP) is transiently and minimally decreased in healthy individuals upon standing. Normal physiologic feedback mechanisms work through neurally-mediated pathways to maintain the standing blood pressure (BP), and thus maintain adequate cerebral perfusion. The compensatory mechanisms that regulate BP upon standing are dysfunctional in patients with orthostatic hypotension (OH), a condition that may lead to inadequate cerebral perfusion with accompanying symptoms of syncope, dizziness or lightheadedness, unsteadiness and blurred or impaired vision, among other symptoms. Orthostatic hypotension may be a severely disabling condition which can seriously interfere with the quality of life of afflicted patients. Currently available therapeutic options provide some symptomatic relief in a subset of patients, but are relatively ineffective and are often accompanied by severe side effects that limit their usefulness. Support garments (e.g., tight-fitting leotards) may prove useful in some patients, but are difficult to don without family or nursing assistance, especially for older patients. Midodrine, fludrocortisone, methylphenidate, ephedrine, indomethacin and dihydroergotamine are some of the pharmacological interventions that have been used to treat orthostatic hypotension, although only midodrine is specifically approved for this indication. The limitations of these currently available therapeutic options, and the incapacitating nature and often progressive downhill course of disease, point to the need for an improved therapeutic alternative. Droxidopa Droxidopa [also, known as L-threo-3,4-dihydroxyphenylserine, L-threo-DOPS, or L-DOPS] is the International Non-proprietary Name (INN) for a synthetic amino acid precursor of norepinephrine (NE), which was originally developed by Sumitomo Pharmaceuticals Co., Limited, Japan. It has been approved for use in Japan since 1989. Droxidopa has been shown to improve symptoms of orthostatic hypotension that result from a variety of conditions including Shy-Drager syndrome (Multiple System Atrophy), Pure Autonomic Failure (PAF), and Parkinson’s disease (PD). There are four stereoisomers of DOPS; however, only the L-threoenantiomer (droxidopa) is biologically active.

Principal Investigator: David Shprecher
Department: Neurology
Co Investigator:

Contact Information

Name:Stacey Larrinaga
Phone: 801-585-9266
Email: stacey.larrinaga@hsc.utah.edu

Inclusion Criteria

Inclusion Criteria

1. 18 years or older and ambulatory (defined as being able to walk at least 10 meters)
2. Clinical diagnosis of symptomatic orthostatic hypotension associated with Primary
Autonomic Failure (PD, MSA, and PAF) or Dopamine Beta Hydroxylase Deficiency
3. At their Baseline Visit (Visit 2), patients must demonstrate:
            a. a score of at least 4 or greater on OHSA Item #1
            b. a fall of at least 20 mmHg in their systolic blood pressure, within 3 minutes of standing
4. Provide written informed consent to participate in the study and understand that they may
withdraw their consent at any time without prejudice to their future medical care

Exclusion Criteria

Exclusion Criteria

1. Score of 23 or lower on the mini-mental state examination (MMSE)
2. Concomitant use of vasoconstricting agents for the purpose of increasing blood pressure;
          a. Patients taking vasoconstricting agents such as ephedrine, dihydroergotamine, or midodrine                      must stop taking these drugs at least 2 days or 5 half-lives (whichever is longer) prior to their                    baseline visit (Visit 2) and throughout the duration of the study
3. Known or suspected alcohol or substance abuse within the past 12 months (Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) definition of alcohol or substance abuse)
4. Women who are pregnant or breastfeeding
5. Women of childbearing potential (WOCP) who are not using at least one method of contraception with their partner
6. Sustained supine hypertension greater than or equal to 180 mmHg systolic or 110 mmHg diastolic, or have these measurements at their Baseline Visit (Visit 2). Sustained is defined as measurements persistently greater at 2 separate measurements at least 10 minutes apart with the subject supine and at rest for at least 5 minutes
7. Untreated closed angle glaucoma
8. Diagnosis of hypertension that requires treatment with antihypertensive medications (short-acting antihypertensives to treat nocturnal supine hypertension are allowed in this study)
9. Any significant uncontrolled cardiac arrhythmia
10. History of myocardial infarction, within the past 2 years
11. Current unstable angina
12. Congestive heart failure (New York Heart Association (NYHA) Class 3 or 4)
13. Diabetic autonomic neuropathy
14. History of cancer within the past 2 years other than a successfully treated, non-metastatic cutaneous squamous cell or basal cell carcinoma or cervical cancer in situ
15. Gastrointestinal condition that may affect the absorption of study drug (e.g., ulcerative
colitis, gastric bypass)
16. Any major surgical procedure within 30 days prior to the Baseline visit (Visit 2)
17. Previously treated with droxidopa within 30 days prior to the Baseline visit (Visit 2)
18. Currently receiving any other investigational drug or have received an investigational drug within 30 days prior to the Baseline visit (Visit 2)
19. Any condition or laboratory test result, which in the Investigator's judgment, might result in an increased risk to the patient, or would affect their participation in the study
20. The Investigator has the ability to exclude a patient if for any reason they feel the subject is not a good candidate for the study or will not be able to follow study procedures