Clinical trial NCT00738062: Open-Label Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension (NOH)
Official title: An Open-label Study, to Assess the Long-term Safety and Clinical Benefit of Droxidopa in Subjects With PAF, Dopamine Beta Hydroxylase Deficiency or Non-diabetic Neuropathy and Symptomatic Neurogenic Orthostatic Hypotension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neurogenic Orthostatic Hypotension
Non-Diabetic Autonomic Neuropathy
Multiple System Atrophy
Dopamine Beta Hydroxylase Deficiency
Keywords: NOH
Neurogenic Orthostatic Hypotension
Orthostatic hypotension
PAF
Pure Autonomic Failure
MSA
Multiple System Atrophy
Neuropathy
Autonomic Failure
Parkinson
Dopamine Deficiency
Dopamine
Droxidopa
Lead sponsor: Chelsea Therapeutics
Sponsor class: INDUSTRY
First posted: 2008-08-20
Enrollment: 103
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change in Orthostatic Hypotension Questionnaire Composite Score (OHQ)
timeFrame: 14 days
Secondary outcomes:
measure: Change in Orthostatic Hypotension Daily Activities (OHDAS) Score
timeFrame: 14 days
measure: Change in Orthostatic Hypotension Symptom Assessment (OHSA) Composite Score
timeFrame: 14 days
measure: Change in Systolic Blood Pressure (SBP) Measurements 3 Minutes Post Standing
timeFrame: 14 days
measure: Patient Reported Clinical Global Impression - Severity
timeFrame: 14 days
measure: Clinician Recorded Clinical Global Impression - Severity
timeFrame: 14 days
measure: Patient Reported Clinical Global Impression - Improvement
timeFrame: 14 days
measure: Clinician Rated Clinical Global Impressions - Improvement
timeFrame: 14 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Litchfield Park
country: United States
facility: Dedicated Clinical Research
state: Arizona
city: Phoenix
country: United States
facility: Xenoscience Inc.
state: Arizona
city: Sun City
country: United States
facility: Sun Health Research Institute
state: Arizona
city: Fountain Valley
country: United States
facility: The Parkinson's and Movement Disorders Institute
state: California
city: Oxnard
country: United States
facility: Pacific Neuroscience Medical Group
state: California
city: Sunnyvale
country: United States
facility: The Parkinson's Institute
state: California
city: Colorado Springs
country: United States
facility: Electrophysiology Associates
state: Colorado
city: Boca Raton
country: United States
facility: Parkinson's Disease & Movment Disorder Center
state: Florida
city: Gainesville
country: United States
facility: Southeastern Integrated Medical
state: Florida
city: Jacksonville
country: United States
facility: Mayo Jacksonville Florida Department of Neurology
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Canton
country: United States
facility: Medical Associates of North Georgia
state: Georgia
city: Chicago
country: United States
facility: Saint Mary of Nazareth Hospital Center
state: Illinois
city: North Chicago
country: United States
facility: North Chicago VA Medical Center
state: Illinois
city: Elkhart
country: United States
facility: Indiana Medical Research
state: Indiana
city: Indianapolis
country: United States
facility: JWM Neurology
state: Indiana
city: Overland Park
country: United States
facility: Kansas City Bone and Joint, PA
state: Kansas
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland Hospital
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Worcester
state: Massachusetts
city: Southfield
country: United States
facility: Henry Ford Health System
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: St. Louis
country: United States
facility: Washington University Medical Center
state: Missouri
city: Edison
country: United States
facility: New Jersey Neuroscience Institute
state: New Jersey
city: Kingston
country: United States
facility: Kingston Neurological Associates, PC
state: New York
city: New York City
country: United States
facility: NYU Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Neurological institute of NY
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Oklahoma City
country: United States
facility: COR Clinical Research, LLC
state: Oklahoma
city: Portland
country: United States
facility: The Oregon Clinic
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Baytown
country: United States
facility: Jacinto Medical Group, PA
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Round Rock
country: United States
facility: Scott & White Healthcare - Round Rock
state: Texas
city: Temple
country: United States
facility: Scott & White Memorial Hospital & Clinic
state: Texas
city: Tyler
country: United States
facility: East Texas Medical Center - Neurological Institute Movment Disorders Center
state: Texas
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Baker Heart Research Institute
state: Victoria
city: Heidelburg
country: Australia
facility: Austin Hospital
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: Markham
country: Canada
facility: Centre for Movement Disorders
state: Ontario
city: Ottawa
country: Canada
facility: Parkinson's & Neurodegenerative Disorders Clinic
state: Ontario
city: Montreal
country: Canada
facility: SMBD Jewish General Hospital - Department of Neurology
state: Quebec
city: Quebec
country: Canada
facility: Quebec Memory and Motor Skills Disorders Clinic
city: Grafton Auckland
country: New Zealand
facility: Auckland Hospital
state: Private Bag
city: Christchurch
country: New Zealand
facility: Van der Veer Institute for Parkinson's Disease and Movement Disorders
Study officials:
affiliation: NYU School of Medicine
name: Horacio Kaufmann Kaufmann, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Imperial School of Medicine
name: Christopher J. Mathias, MD
role: PRINCIPAL_INVESTIGATOR
References: