Clinical trial NCT00782340: A Clinical Study for Patients With Neurogenic Orthostatic Hypotension (NOH) Using Droxidopa
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Symptomatic Neurogenic Orthostatic Hypotension (NOH)
Non-diabetic Neuropathy
Primary Autonomic Failure
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
Collaborators: name: Chiltern International Inc.
First posted: 2008-10-31
Enrollment: 263
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 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.

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:

* 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.

Primary outcomes:
measure: Change in Orthostatic Hypotension Questionnaire Score (OHQ)
timeFrame: 7 days
Secondary outcomes:
measure: Change in Ability to Conduct Activities of Daily Living Score (OHDAS Composite Score)
timeFrame: 7 days
measure: Change in Orthostatic Hypotension Symptom Assessment (OHSA Composite) Score
timeFrame: 7 days
measure: Change in Activities Involving Standing a Short Time (OHDAS Item 1)
timeFrame: 7 days
measure: Change in Activities Involving Walking a Short Time (OHDAS Item 3)
timeFrame: 7 days
measure: Change in Dizziness/ Lightheadedness/ Feeling Faint/ or Feeling Like You Might Blackout (OHSA Item 1)
timeFrame: 7 days
measure: Patient-Reported Clinical Global Improvement - Severity Scores
timeFrame: 7 days
measure: Clinician-Reported Clinical Global Improvement - Severity Scores
timeFrame: 7 days
measure: Change in Systolic Blood Pressure (SBP) Measurements 3 Minutes Post Standing
timeFrame: 7 days
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: North Alabama Neuroscience
state: Alabama
city: Scottsdale
country: United States
facility: Mayo Clinic-Arizona
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Cardiology
state: Arkansas
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Bradenton
country: United States
facility: Bradenton Neurology, Inc
state: Florida
city: St. Petersburg
country: United States
facility: Suncoast Neuroscience Associates, Inc
state: Florida
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Bethesda
country: United States
facility: Cncs, Ninds,Nih
state: Maryland
city: Hattiesburg
country: United States
facility: Nerological Reserch Center at Hattiesburg
state: Mississippi
city: Manshasette
country: United States
facility: North Shore Hospital
state: New York
city: Philadelphia
country: United States
facility: Pennsylvania Hospital of the University of PA Health System- Department of Neurology
state: Pennsylvania
city: Upland
country: United States
facility: HAN Neurological Associates
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Kirkland
country: United States
facility: Evergreen Hospital Medical Center; Booth Gardner Parkinson's Care Center
state: Washington
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Winnipeg
country: Canada
facility: Movment Disorder Clinic Deer lodge Centre
state: Manitoba
city: Halifax
country: Canada
facility: David B. King, - Private Clinic
state: Nova Scotia
city: London
country: Canada
facility: London Health Sciences Centre, UH
state: Ontario
city: Toranto
country: Canada
facility: UHNresearch
state: Ontario
city: Montreal
country: Canada
facility: IRCM
state: Quebec
Study officials:
affiliation: Arkansas Cardiology
name: Stephen Greer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Suncoast Neuroscience
name: Alberto Vasquez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: North Alabama Neuroscience
name: Richard Hull, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Brent Goodman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Bradenton Neurology, Inc
name: Alvin McElveen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Kansas Medical Center
name: Mazen Dimachkie, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Biaggioni I, Arthur Hewitt L, Rowse GJ, Kaufmann H. Integrated analysis of droxidopa trials for neurogenic orthostatic hypotension. BMC Neurol. 2017 May 12;17(1):90. doi: 10.1186/s12883-017-0867-5.
citation: Francois C, Rowse GJ, Hewitt LA, Vo P, Hauser RA. Analysis of number needed to treat for droxidopa in patients with symptomatic neurogenic orthostatic hypotension. BMC Neurol. 2016 Aug 18;16(1):143. doi: 10.1186/s12883-016-0665-5.