Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension (NOH) (NOH302)

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

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.

Study Overview

• Status: Completed
• Conditions: Primary Autonomic Failure; Dopamine Beta Hydroxylase Deficiency; Symptomatic Neurogenic Orthostatic Hypotension (NOH); Non-diabetic Neuropathy
• Intervention / Treatment: Drug: Droxidopa; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 181
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Heidelburg, Australia, 3084
    • Austin Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Baker Heart Research Institute
• Canada
  • Quebec, Canada, G1R 3X5
    • Quebec Memory and Motor Skills Disorders Clinic
  • Ontario
    • Hamilton, Ontario, Canada, L8L2X2
      • McMaster University
    • Markham, Ontario, Canada, L6B1C9
      • Centre for Movement Disorders
    • Ottawa, Ontario, Canada, K1G4G3
      • Parkinson's & Neurodegenerative Disorders Clinic
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • SMBD Jewish General Hospital
• New Zealand
  • Christchurch, New Zealand
    • Van der Veer Institute for Parkinson's Disease and Movement Disorders
  • Private Bag
    • Grafton Auckland, Private Bag, New Zealand
      • Auckland Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Litchfield Park, Arizona, United States, 85340
      • Dedicated Clinical Research
    • Phoenix, Arizona, United States, 85004
      • Xenoscience Inc.
    • Sun City, Arizona, United States, 85351
      • Sun Health Research Institute
  • California
    • Fountain Valley, California, United States, 92708
      • The Parkinson's and Movement Disorders Institute
    • Oxnard, California, United States, 93030
      • Pacific Neuroscience Medical Group
    • Sunnyvale, California, United States, 94085
      • The Parkinson's Institute
  • Colorado
    • Colorado Springs, Colorado, United States, 80910
      • Electrophysiology Associates
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Parkinson's Disease & Movment Disorder Center
    • Gainesville, Florida, United States, 32607
      • Southeastern Integrated Medical
    • Jacksonville, Florida, United States, 32224
      • Mayo Jacksonville Florida Department of Neurology
    • Miami, Florida, United States, 33136
      • University of Miami
    • Tampa, Florida, United States, 33606
      • University of South Florida
  • Georgia
    • Canton, Georgia, United States, 30114
      • Medical Associates of North Georgia
  • Illinois
    • Chicago, Illinois, United States, 60622
      • Saint Mary of Nazareth Hospital Center
    • North Chicago, Illinois, United States, 60064
      • North Chicago VA Medical Center
  • Indiana
    • Elkhart, Indiana, United States, 46514
      • Indiana Medical Research
    • Indianapolis, Indiana, United States, 46237
      • JWM Neurology
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • Kansas City Bone and Joint, PA
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Worcester
  • Michigan
    • Southfield, Michigan, United States, 48034
      • Henry Ford Health System
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University Medical Center
  • New Jersey
    • Edison, New Jersey, United States, 08818
      • New Jersey Neuroscience Institute
  • New York
    • Kingston, New York, United States, 12401
      • Kingston Neurological Associates, PC
    • New York, New York, United States, 10032
      • Columbia University
    • New York City, New York, United States, 10016
      • NYU Medical Center
    • Rochester, New York, United States, 14618
      • University of Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
    • Winston Salem, North Carolina, United States, 27157
      • Wake Forest University
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • COR Clinical Research, LLC
  • Oregon
    • Portland, Oregon, United States, 97213
      • The Oregon Clinic
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University
  • Texas
    • Baytown, Texas, United States, 77521
      • Jacinto Medical Group, PA
    • Dallas, Texas, United States, 75390-9036
      • UT Southwestern Medical Center
    • Round Rock, Texas, United States, 78665
      • Scott & White Healthcare - Round Rock
    • Temple, Texas, United States, 76508
      • Scott & White Memorial Hospital & Clinic
    • Tyler, Texas, United States, 75701
      • East Texas Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

PATIENT INCLUSION 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.

MAIN PATIENT EXCLUSION CRITERIA:

• Taking ephedrine or midodrine; Patients taking ephedrine or midodrine may enroll after a minimum 7 day washout period;
• Taking anti-hypertensive medication;
• Have a history of more than moderate alcohol consumption;
• Women who are pregnant or lactating;
• Have a history of closed angle glaucoma;
• Have 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;
• In the investigator's opinion, have any other significant systemic, hepatic, cardiac or renal illness;
• Have diabetes mellitus or insipidus;
• Have a known or suspected malignancy;
• Have 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;
• Have a serum creatinine level > 130 µmol/L;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Droxidopa; Double-blind	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 Names: L-threo-DOPS; L-DOPS; Northera
Placebo Comparator: Placebo; Double-blind	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Dizziness/ Lightheadedness/ Feeling Faint/ or Feeling Like You Might Blackout (OHSA Item 1)	OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. In this withdrawal design, a positive score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug) .	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Fatigue (OHSA Item 4)	OHSA item 4 scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. In this withdrawal design, a positive score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug) .	14 days
Change in Weakness (OHSA Item 3)	OHSA item 3 scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. In this withdrawal design, a positive score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug) .	14 days
Change in Vision (OHSA Item 2)	OHSA item 2 scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. In this withdrawal design, a positive score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug) .	14 days
Change in Concentration (OHSA Item 5)	OHSA item 5 scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. In this withdrawal design, a positive score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug) .	14 days
Change in Head/Neck Discomfort (OHSA Item 6)	OHSA item 6 scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. In this withdrawal design, a positive score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug) .	14 days
Change in Ability to Conduct Activities of Daily Living Score (OHDAS Composite Score)	The OHDAS scale is the average of four items: 1) Standing for a short time; 2) Standing for a long time; 3) Walking for a short time; and 4) Walking for a long time. Each asks the patient to rate their disease impact over the past week. Each item is scored on a Likert scale from 0 to 10, with 10 being the most severe. Change: score at end of study minus score at randomization. In this withdrawal design, a positive score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug) .	14 days
Change in Orthostatic Hypotension Symptom Assessment Score (OHSA Composite)	The OHSA scale is the average of six items: 1) Dizziness, lightheadedness, feeling faint or feeling like you might black out; 2) Problems with vision; 3) Weakness; 4) Fatigue; 5) Trouble concentrating; and 6) Head/neck discomfort. Each asks the patient to rate their symptoms over the past week. Each item is scored on a Likert scale from 0 to 10, with 10 being the most severe. Change: score at end of study minus score at randomization. In this withdrawal design, a positive score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug) .	14 days
Change in Orthostatic Hypotension Symptom Scores Excluding Dizziness (OHSA Composite Items 2-6)	OHSA composite scale (items 2-6) is the average of five OHSA items: 2) Problems with vision; 3) Weakness; 4) Fatigue; 5) Trouble concentrating; and 6) Head/neck discomfort. Each asks the patient to rate their symptoms over the past week. Each item is scored on a Likert scale from 0 to 10, with 10 being the most severe. Change: score at end of study minus score at randomization. In this withdrawal design, a positive score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug) .	14 days
Change in Systolic Blood Pressure (SBP) Measurements 3 Minutes Post Standing;	Change: standing systolic blood pressure at end of study minus standing systolic blood pressure at randomization. In this withdrawal design, a negative score indicates worsening during the double-blind randomized phase relative to value at randomization (on open-label drug) .	14 days

Collaborators and Investigators

• Sponsor: Chelsea Therapeutics
• Collaborators: Chiltern International Inc.
• Investigators: Principal Investigator: Christopher J Mathias, MD, Imperial School of Medicine; Principal Investigator: Roy Freeman, MD, Harvard Medicine School; Principal Investigator: Phillip A Low, MD, Mayo Foundation

Publications and helpful links

General Publications

• 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.
• 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.
• Biaggioni I, Freeman R, Mathias CJ, Low P, Hewitt LA, Kaufmann H; Droxidopa 302 Investigators. Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension. 2015 Jan;65(1):101-7. doi: 10.1161/HYPERTENSIONAHA.114.04035. Epub 2014 Oct 27.

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): August 1, 2009
• Study Completion (Actual): September 1, 2009

Study Registration Dates

• First Submitted: March 5, 2008
• First Submitted That Met QC Criteria: March 11, 2008
• First Posted (Estimate): March 12, 2008

Study Record Updates

• Last Update Posted (Estimate): May 20, 2014
• Last Update Submitted That Met QC Criteria: April 22, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Parkinson; MSA; NOH; Dopamine; Neuropathy; Multiple System Atrophy; Orthostatic hypotension; Autonomic Failure; PAF; Neurogenic Orthostatic Hypotension; Droxidopa; Pure Autonomic Failure; Dopamine Deficiency
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Primary Dysautonomias; Orthostatic Intolerance; Hypotension; Hypotension, Orthostatic; Autonomic Nervous System Diseases; Pure Autonomic Failure; Antiparkinson Agents; Anti-Dyskinesia Agents; Droxidopa
• Other Study ID Numbers: Droxidopa NOH302