A Clinical Study for Patients With Neurogenic Orthostatic Hypotension (NOH) Using Droxidopa (NOH301)

This study has been completed.
Sponsor:
Collaborator:
Chiltern International Inc.
Information provided by (Responsible Party):
Chelsea Therapeutics
ClinicalTrials.gov Identifier:
NCT00782340
First received: October 29, 2008
Last updated: March 21, 2013
Last verified: March 2013
  Purpose

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.


Condition Intervention Phase
Symptomatic Neurogenic Orthostatic Hypotension (NOH)
Non-diabetic Neuropathy
Primary Autonomic Failure
Dopamine Beta Hydroxylase Deficiency
Drug: Placebo
Drug: Droxidopa
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Chelsea Therapeutics:

Primary Outcome Measures:
  • To evaluate the efficacy of droxidopa in patients with symptomatic NOH as measured by the relative change in mean score of the composite Orthostatic Hypotension Questionnaire(OHQ) 7 days following randomization to treatment with droxidopa or placebo. [ Time Frame: 7 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Evaluate efficacy of droxidopa as measured by changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements 3 minutes post standing; [ Time Frame: 7 days ] [ Designated as safety issue: No ]

Enrollment: 168
Study Start Date: September 2008
Study Completion Date: September 2010
Primary Completion Date: September 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 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
Drug: 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
Other Name: Droxidopa
Placebo Comparator: 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
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
Other Name: Placebo

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00782340

  Show 21 Study Locations
Sponsors and Collaborators
Chelsea Therapeutics
Chiltern International Inc.
Investigators
Principal Investigator: Stephen Greer, MD Arkansas Cardiology
Principal Investigator: Alberto Vasquez, MD Suncoast Neuroscience
Principal Investigator: Richard Hull, MD North Alabama Neuroscience
Principal Investigator: Brent Goodman, MD Mayo Clinic
Principal Investigator: Alvin McElveen, MD Bradenton Neurology, Inc
Principal Investigator: Mazen Dimachkie, MD University of Kansas
  More Information

Additional Information:
No publications provided

Responsible Party: Chelsea Therapeutics
ClinicalTrials.gov Identifier: NCT00782340     History of Changes
Obsolete Identifiers: NCT00879567
Other Study ID Numbers: Droxidopa NOH301
Study First Received: October 29, 2008
Last Updated: March 21, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Chelsea Therapeutics:
NOH
Neurogenic Orthostatic Hypotension
Orthostatic hypotension
PAF
Pure Autonomic Failure
MSA
Multiple System Atrophy
Neuropathy
Autonomic Failure
Parkinson
Dopamine Deficiency
Dopamine
Droxidopa

Additional relevant MeSH terms:
Hypotension
Hypotension, Orthostatic
Autonomic Nervous System Diseases
Pure Autonomic Failure
Vascular Diseases
Cardiovascular Diseases
Orthostatic Intolerance
Primary Dysautonomias
Nervous System Diseases
Droxidopa
Dopamine
Antiparkinson Agents
Anti-Dyskinesia Agents
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Cardiotonic Agents
Cardiovascular Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Protective Agents

ClinicalTrials.gov processed this record on April 15, 2014