Open-Label Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension (NOH)

NCT ID: NCT00738062

Last Updated: 2014-05-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 103 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-01-31
• Study Completion Date: 2010-12-31

Brief Summary

The purpose of this study is to assess the durability of effect of Droxidopa 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.

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.

Conditions

Neurogenic Orthostatic Hypotension; Non-Diabetic Autonomic Neuropathy; Multiple System Atrophy; Dopamine Beta Hydroxylase Deficiency

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Droxidopa

Study medication

Group Type: ACTIVE_COMPARATOR

Droxidopa

Intervention Type: DRUG

100 mg, oral, three times per day 200 mg, oral, three times per day 300 mg, oral, three times per day 400 mg, oral, three times per day 500 mg, oral, three times per day 600 mg, oral, three times per day

Placebo

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

100 mg, oral, three times per day 200 mg, oral, three times per day 300 mg, oral, three times per day 400 mg, oral, three times per day 500 mg, oral, three times per day 600 mg, oral, three times per day

Interventions

Droxidopa

100 mg, oral, three times per day 200 mg, oral, three times per day 300 mg, oral, three times per day 400 mg, oral, three times per day 500 mg, oral, three times per day 600 mg, oral, three times per day

Intervention Type: DRUG

Placebo

100 mg, oral, three times per day 200 mg, oral, three times per day 300 mg, oral, three times per day 400 mg, oral, three times per day 500 mg, oral, three times per day 600 mg, oral, three times per day

Intervention Type: DRUG

Other Intervention Names

Inactive drug (to look like Droxidopa)

Eligibility Criteria

Inclusion Criteria

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

• Participated in Droxidopa Protocol 302;
• 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

Patients are not eligible for this study if they fulfill one or more of the following criteria:

• Currently taking ephedrine or midodrine;
• Patients taking ephedrine or midodrine must stop taking these drugs at least 2 days prior to their study entry visit (Visit 1).
• Currently taking anti-hypertensive medication;

• 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;

• Reproductive potential:
• Female subjects should be either post-menopausal (amenorrhea for at least 12 consecutive months), surgically sterile, or women of child-bearing potential (WOCP) who are using or agree to use acceptable methods of contraception.
• Acceptable contraceptives include intrauterine devices (IUDs), hormonal contraceptives (oral, depot, patch or injectable) and double barrier methods such as condoms or diaphragms with spermicidal gel or foam.
• For WOCP a urine pregnancy test must be conducted at each study visit.
• WOCP must be advised to use acceptable contraceptives throughout the study period and for 30 days after the last dose of investigational product.
• If hormonal contraceptives are used they should be taken according to the package insert.
• WOCP who are not currently sexually active must agree to use acceptable contraception, as defined above, if they decide to become sexually active during the period of the study and for 30 days after the last dose of investigational product.
• 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 umol/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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chelsea Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Horacio Kaufmann Kaufmann, MD

Role: PRINCIPAL_INVESTIGATOR

NYU School of Medicine

Christopher J. Mathias, MD

Role: PRINCIPAL_INVESTIGATOR

Imperial School of Medicine

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Dedicated Clinical Research

Litchfield Park, Arizona, United States

Xenoscience Inc.

Phoenix, Arizona, United States

Sun Health Research Institute

Sun City, Arizona, United States

The Parkinson's and Movement Disorders Institute

Fountain Valley, California, United States

Pacific Neuroscience Medical Group

Oxnard, California, United States

The Parkinson's Institute

Sunnyvale, California, United States

Electrophysiology Associates

Colorado Springs, Colorado, United States

Parkinson's Disease & Movment Disorder Center

Boca Raton, Florida, United States

Southeastern Integrated Medical

Gainesville, Florida, United States

Mayo Jacksonville Florida Department of Neurology

Jacksonville, Florida, United States

University of Miami Miller School of Medicine

Miami, Florida, United States

University of South Florida

Tampa, Florida, United States

Medical Associates of North Georgia

Canton, Georgia, United States

Saint Mary of Nazareth Hospital Center

Chicago, Illinois, United States

North Chicago VA Medical Center

North Chicago, Illinois, United States

Indiana Medical Research

Elkhart, Indiana, United States

JWM Neurology

Indianapolis, Indiana, United States

Kansas City Bone and Joint, PA

Overland Park, Kansas, United States

University of Louisville

Louisville, Kentucky, United States

University of Maryland Hospital

Baltimore, Maryland, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

University of Massachusetts Worcester

Worcester, Massachusetts, United States

Henry Ford Health System

Southfield, Michigan, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

Washington University Medical Center

St Louis, Missouri, United States

New Jersey Neuroscience Institute

Edison, New Jersey, United States

Kingston Neurological Associates, PC

Kingston, New York, United States

NYU Medical Center

New York, New York, United States

Columbia University Neurological institute of NY

New York, New York, United States

University of Rochester

Rochester, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Wake Forest University

Winston-Salem, North Carolina, United States

University of Cincinnati

Cincinnati, Ohio, United States

University Hospitals Case Medical Center

Cleveland, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

COR Clinical Research, LLC

Oklahoma City, Oklahoma, United States

The Oregon Clinic

Portland, Oregon, United States

Vanderbilt University

Nashville, Tennessee, United States

Jacinto Medical Group, PA

Baytown, Texas, United States

UT Southwestern Medical Center

Dallas, Texas, United States

Scott & White Healthcare - Round Rock

Round Rock, Texas, United States

Scott & White Memorial Hospital & Clinic

Temple, Texas, United States

East Texas Medical Center - Neurological Institute Movment Disorders Center

Tyler, Texas, United States

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Baker Heart Research Institute

Melbourne, Victoria, Australia

Austin Hospital

Heidelburg, , Australia

McMaster University

Hamilton, Ontario, Canada

Centre for Movement Disorders

Markham, Ontario, Canada

Parkinson's & Neurodegenerative Disorders Clinic

Ottawa, Ontario, Canada

SMBD Jewish General Hospital - Department of Neurology

Montreal, Quebec, Canada

Quebec Memory and Motor Skills Disorders Clinic

Québec, Quebec, Canada

Auckland Hospital

Grafton Auckland, Private Bag, New Zealand

Van der Veer Institute for Parkinson's Disease and Movement Disorders

Christchurch, , New Zealand

Countries

United States; Australia; Canada; New Zealand

Other Identifiers

Droxidopa NOH303

Identifier Type: -

Identifier Source: org_study_id