A Clinical Study for Patients With Neurogenic Orthostatic Hypotension (NOH) Using Droxidopa

Condition(s) targeted: Symptomatic Neurogenic Orthostatic Hypotension (NOH); Non-Diabetic Neuropathy; Primary Autonomic Failure; Dopamine Beta Hydroxylase Deficiency

Intervention: Placebo (Drug); Droxidopa (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Chelsea Therapeutics

Official(s) and/or principal investigator(s):
Stephen Greer, MD, Principal Investigator, Affiliation: Arkansas Cardiology
Alberto Vasquez, MD, Principal Investigator, Affiliation: Suncoast Neuroscience
Richard Hull, MD, Principal Investigator, Affiliation: North Alabama Neuroscience
Brent Goodman, MD, Principal Investigator, Affiliation: Mayo Clinic Arizona
Alvin McElveen, MD, Principal Investigator, Affiliation: Bradenton Neurology, Inc
Mazen Dimachkie, MD, Principal Investigator, Affiliation: University of Kansas

Overall contact:
Michelle Anthony, Phone: 5122250240, Email: michelle.anthony@chiltern.com

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.

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

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: To evaluate the efficacy of droxidopa in patients with symptomatic NOH as measured by the relative change in mean score of Item 1 of the (OHSA) 7 days following randomization to continued therapy with droxidopa or placebo.

Secondary outcome: Evaluate efficacy of droxidopa as measured by changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements 3 minutes post standing;

Detailed description: 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

To be eligible for inclusion, each patient must fulfill the following criteria:

- Male or female and aged 18 years or over

- Clinical diagnosis of orthostatic hypotension associated with Primary Autonomic

Failure (PD, MSA and PAF), Dopamine Beta Hydroxylase Deficiency or Non-Diabetic Autonomic Neuropathies

- A documented fall in systolic blood pressure of at least 20 mmHg, or in diastolic

blood pressure of at least 10 mmHg, within 3 minutes after standing;

- 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:

- Currently 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).

- The use of short-acting anti-hypertensive medications at bedtime is permitted.

- Currently taking tri-cyclic antidepressant medication or other norepinephrine

re-uptake inhibitors;

- Have changed dose, frequency and or type of prescribed medication, within two weeks of

study start (excluding ephedrine and midodrine)

- History of more than moderate alcohol consumption

- History of known or suspected drug or substance abuse

- Women of childbearing potential who are not using a medically accepted contraception

- For WOCP a serum beta HCG pregnancy test must be conducted at screening, and a urine

pregnancy test must be conducted at baseline and study termination; the results must be negative at screening and at baseline for the patient to receive study medication.

- Sexually active males whose partner is a WOCP and who do not agree to use condoms for

the duration of the study and for 30 days after the last dose;

- Women who are pregnant or breast feeding

- Known or suspected hypersensitivity to the study medication or any of its ingredients

- Pre-existing sustained severe hypertension (BP 180/110 mmHg in the sitting position)

- Have atrial fibrillation or, in the investigator's opinion, have any other significant

cardiac arrhythmia

- Any other significant systemic, hepatic, cardiac or renal illness

- Diabetes mellitus or insipidus

- Have a history of closed angle glaucoma

- Have a known or suspected malignancy

- Have a serum creatinine level > 130 mmol/L

- Patients with 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

- In the investigator's opinion, are unable to adequately co-operate because of

individual or family situation

- In the investigator's opinion, are suffering from a mental disorder that interferes

with the diagnosis and/or with the conduct of the study, e. g. schizophrenia, major depression, dementia

- Are not able or willing to comply with the study requirements for the duration of the

study

- Have participated in another clinical trial with an investigational agent (including

named patient or compassionate use protocol) within 4 weeks before the start of the study

- Previous enrolment in the study.

Michelle Anthony, Phone: 5122250240, Email: michelle.anthony@chiltern.com

North Alabama Neuroscience, Huntsville, Alabama 35801, United States; Recruiting
Amanda Wright, Phone: 256-533-3552, Email: awright@clinicforneurology.com
Richard Hull, MD, Principal Investigator

Mayo Clinic-Arizona, Scottsdale, Arizona 85340, United States; Recruiting
Marlene Lind, Phone: 480-301-7644, Email: lind.marlene@mayo.com
Brent Goodman, MD, Principal Investigator

Arkansas Cardiology, Little Rock, Arkansas 72205, United States; Recruiting
Michael Seamon, Phone: 501-227-7596, Email: michael.seamon@arcard.org
Stephen Greer, MD, Principal Investigator

Bradenton Neurology, Inc, Bradenton, Florida 34205, United States; Recruiting
Brandy Dunnett, Phone: 941-708-0005, Email: brandydunnet@bradentonresearch.com
Alvin McElveen, MD, Principal Investigator

Suncoast Neuroscience Associates, Inc, St. Petersburg, Florida 33701, United States; Recruiting
Michele Richardson, Phone: 727-824-7135, Email: mrichardson@suncoast.com
Suzanne Lash, Phone: 727-824-7180, Email: slash@suncoastmed.com
Alberto Vasquez, MD, Principal Investigator

University of Kansas Medical Center, Kansas City, Kansas 66160, United States; Not yet recruiting
Mimi Michaels, Phone: 913-588-0678, Email: mmichaels@kumc.edu
Laura Herbelin, Phone: 913-588-0609, Email: lherbelin@kumc.edu
Mazen Dimachkie, MD, Principal Investigator

Sponsor's website

Study Website

Starting date: September 2008
Ending date: August 2010
Last updated: October 29, 2008