Dopamine Beta Hydroxylase Deficiency Clinical Trial
Official title:
Phase III, Multi-Center, Study to Assess the Clinical Effect of Droxidopa in Subjects With Primary Autonomic Failure, Dopamine Beta Hydroxylase Deficiency or Non-Diabetic Neuropathy and Symptomatic NOH
The purpose of this study is to see whether droxidopa is effective in treating symptoms of neurogenic orthostatic hypotension in patients with Primary Autonomic Failure (Pure Autonomic Failure, Multiple System Atrophy, Parkinson's Disease), Non-diabetic neuropathy, or Beta Hydroxylase deficiency.
Systolic blood pressure 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, and thus maintain adequate cerebral perfusion. The
compensatory mechanisms that regulate blood pressure upon standing are dysfunctional in
subjects 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.
The autonomic nervous system has a central role in the regulation of blood pressure. Primary
Autonomic Failure is manifested in a variety of syndromes. Orthostatic hypotension is a
usual presenting symptom. Primary Autonomic Failure may be the primary diagnosis, and
classifications include pure autonomic failure (PAF), also called idiopathic orthostatic
hypotension (Bradbury-Eggleston syndrome) autonomic failure with multiple system atrophy
(Shy-Drager syndrome) and also Parkinson's disease. Regardless of the primary condition,
autonomic dysfunction underlies orthostatic hypotension.
Orthostatic hypotension may be a severely disabling condition which can seriously interfere
with the quality of life of afflicted subjects. Currently available therapeutic options
provide some symptomatic relief in a subset of subjects, but are relatively ineffective and
are often accompanied by severe side effects that limit their usefulness. Support garments
(tight-fitting leotard) may prove useful in some subjects, but is difficult to don without
family or nursing assistance, especially for older subjects. Midodrine, fludrocortisone,
methylphenidate, ephedrine, indomethacin and dihydroergotamine are among 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.
The current withdrawal design study will measure the efficacy of droxidopa on symptoms of
neurogenic orthostatic hypotension in patients randomized to continued droxidopa treatment
versus placebo, following 14 days of double-blind treatment.
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, and
Parkinson's disease. There are four stereoisomers of DOPS; however, only the
L-threo-enantiomer (droxidopa) is biologically active.
The exact mechanism of action of droxidopa in the treatment of symptomatic NOH has not been
precisely defined; however, its NE replenishing properties with concomitant recovery of
decreased noradrenergic activity are considered to be of major importance.
Droxidopa has been marketed in Japan since 1989. Data from clinical studies and
post-marketing surveillance programs conducted in Japan show that the most commonly reported
adverse drug reactions with droxidopa are increased blood pressure, nausea, and headache. In
clinical studies, the prevalence and severity of droxidopa adverse effects appear to be
similar to those reported by the placebo control arm.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
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