Trial Information

Summary: Study to Evaluate Efficacy of Droxidopa in Symptomatic Neurogenic Orthostatic Hypotension

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.

Inclusion Criteria

• Diagnosis of orthostatic hypotension associated with:
  • Primary Autonomic Failure (Parkinson’s Disease, Multiple System Atrophy, Pure Autonomic Failure)
  • Dopamine Beta Hydroxylase Deficiency
  • Non-Diabetic Autonomic Neuropathy
• A documented fall in systolic blood pressure or in diastolic blood pressure within 3 min of standing Provide written informed consent to participate in the study

Main Exclusion Criteria

• Taking ephedrine or midodrine;
  • Patients taking ephedrine or midodrine must stop taking these drugs at least 2 days prior to their baseline visit (Visit 2);
• Taking anti-hypertensive medication;
  • The use of short-acting anti-hypertensive medications at bedtime is permitted
• Have a history of more than moderate alcohol consumption;
• Women who are pregnant or lactating;
• Have a history of closed angle glaucoma;
• Have pre-existing sustained severe hypertension (BP ³ 180/110 mmHg in the sitting position);
• Have atrial fibrillation or, in the investigator’s opinion, have any other significant cardiac arrhythmia;
• In the investigator’s opinion, have any other significant systemic, hepatic, cardiac or renal illness;
• Have diabetes mellitus or insipidus;
• Have a known or suspected malignancy;
• Have known gastrointestinal illness or other gastrointestinal disorder that may, in the investigator’s opinion, affect the absorption of study drug;
• In the investigator’s opinion, have clinically significant abnormalities on clinical examination or laboratory testing;
• Have a serum creatinine level > 130 µmol/L.

If you would like to learn more about participating in this study, please send an e-mail message using the form below.