Sustained Effect of Droxidopa in Symptomatic Neurogenic Orthostatic Hypotension

Phase 4

Completed

Conditions: Symptomatic Neurogenic Orthostatic Hypotension

Interventions: Drug: Droxidopa capsules
Drug: Placebo capsules

Registration Number: NCT02586623

Lead Sponsor: H. Lundbeck A/S

Brief Summary: To evaluate the time to treatment intervention in patients with Parkinson's Disease (PD), Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), Non-Diabetic Autonomic Neuropathy (NDAN) or Dopamine Beta Hydroxylase (DBH) Deficiency who have been previously stabilized with droxidopa therapy for symptoms of neurogenic orthostatic hypotension (NOH) (dizziness, light-headedness, or feelings that they are about to black out)

Detailed Description: This is a multi-site, placebo-controlled, double-blind, randomized withdrawal, time to intervention study with a duration of up to 36 weeks, consisting of 5 periods:

Screening Period: up to 4 weeks duration; Open-Label Titration Period (Titration Period): up to 4 weeks duration; Open-Label Treatment Period (Open-Label Period): 12 weeks duration; Double-Blind Treatment Period (Double-Blind Period): 12 weeks duration; Safety Follow-Up Period: 4 weeks duration

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 453

Inclusion Criteria

18 years or older and able to stand (with or without limited assistance)
Clinical diagnosis of symptomatic orthostatic hypotension associated with Primary Autonomic Failure (PD, MSA or PAF) or NDAN or DBH Deficiency
Score of at least 4 or greater on Orthostatic Hypotension Symptom Assessment (OHSA) Item #1 (measured at Screening [Visit 1] and the first Titration Visit [Visit 2a] prior to dosing)
A documented drop of at least 20 millimeters of mercury (mmHg) in SBP, within 3 minutes of standing. This can either be documented in the patient history or assessed during Screening prior to the first Titration Visit (Visit 2a)
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

Additional inclusion criteria for patients taking prescribed droxidopa prior to study entry:

Patients who are taking prescribed droxidopa therapy are eligible to participate in the study if they meet the other inclusion criteria and also have been on a stable dose of prescribed droxidopa for at least 2 weeks prior to the Screening Visit (Visit 1). In addition, they must meet either of the following at the Screening Visit (Visit 1):

The patient's Visit 1 OHSA Item #1 score is ≥ 7 AND the prescribed dose is ≤ 300 mg three times daily (TID); OR
The patient's Visit 1 OHSA Item #1 score is ≤6 AND worsens by ≥ 2 units when retested after washing out of droxidopa for at least 3 days

Exclusion Criteria

In the investigator's opinion, the patient is not able to understand or cooperate with study procedures
Known or suspected alcohol or substance use disorder within the past 12 months (DSM-5 criteria)
Women who are pregnant or breastfeeding
Women of childbearing potential (WOCP) who are not using at least one method of contraception with their partner
Sustained supine hypertension greater than or equal to 180 mmHg systolic or 110 mmHg diastolic. Sustained is defined as the average of 3 observations each at least 10 minutes apart with the patient having been supine and at rest for at least 5 minutes prior to each measurement.
Untreated closed angle glaucoma
Diagnosis of hypertension that requires treatment with antihypertensive medications (short-acting antihypertensives to treat nocturnal supine hypertension are allowed in this study)
Any significant uncontrolled cardiac arrhythmia
History of myocardial infarction or stroke, within the past 2 years
Current unstable angina
Congestive heart failure (NYHA Class 3 or 4)
Diabetic autonomic neuropathy
History of cancer within the past 2 years other than a successfully treated, non-metastatic cutaneous squamous cell or basal cell carcinoma or cervical cancer in situ
Any major surgical procedure within the past 30 days
Currently receiving any investigational drug or have received an investigational drug within the past 28 days

Additional protocol defined exclusion criteria do apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Open Label Period	Droxidopa capsules	Active droxidopa 100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally. During the Open Label Titration Period, patients will first receive 100 mg TID and their dose will be raised (in 100 mg increments) at subsequent visits until optimal dose is determined. During the Open Label Treatment Period, patients will receive active droxidopa100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally (equal to the patient's individual dose at the end of the Open-Label Titration Period).
Randomized Period	Placebo capsules	Active droxidopa 100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally (equal to patients individual dose at the end of the Open-Label Period) or matching placebo.
Randomized Period	Droxidopa capsules	Active droxidopa 100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally (equal to patients individual dose at the end of the Open-Label Period) or matching placebo.

Primary Outcome Measures

Name	Time	Method
Time To Intervention	Randomization (Day 0) up to Week 12	Kaplan-Meier estimates are presented for time to treatment intervention. The estimates represent the quartiles of the survival time, where 50% corresponds to the median time to need for treatment intervention. Need for intervention is defined as meeting ANY of the following criteria during the Double-Blind Treatment Period: * OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of efficacy as judged by the investigator; OR * OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive visits; OR * OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before early discontinuation; OR * participant stops IMP or withdraws from study for patient-reported lack of efficacy.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Needed Intervention During the 12-week Double-Blind Treatment Period	Randomization (Day 0) up to Week 12	Need for intervention is defined as meeting ANY of the following criteria during the Double-Blind Treatment Period: * OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of efficacy as judged by the investigator; OR * OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive visits; OR * OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before early discontinuation; OR * participant stops IMP or withdraws from study for patient-reported lack of efficacy.
Clinician-rated Clinical Global Impressions - Severity (CGI-S)	Weeks 2 to 12	The CGI-S was developed to provide global measures of the severity of a participant's clinical condition during clinical studies. The CGI-S was utilized by both the clinician and the participant to provide an impression of the participant's current state of OH. The severity of the participant's current illness was rated by the clinician on a 7-point scale ranging from 1 (normal, no OH) to 7 (among those patients most extremely ill with OH).
Time To All-cause Discontinuation	Randomization (Day 0) up to Week 12	Kaplan-Meier estimates are presented for time to all-cause discontinuation. The estimates represent the quartiles of the survival time, where 50% corresponds to the median time to discontinuation. Time to all-cause discontinuation was defined as the time from randomization to withdrawal or last contact date.
Change From Randomization To All Post-randomization Visits in Orthostatic Hypotension Symptom Assessment (OHSA) Item #1 Score	Randomization (Day 0); Weeks 2 to 12	The OHSA scale was designed to rate symptoms occurring specifically as a result of low blood pressure (BP), on average, over the past week using an 11-point scale (0 to 10), with more severe symptoms scoring higher. A score of zero indicates that the symptom was not experienced, and 10 is the worst possible. The scale was used to assess six symptoms: 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. Scores for each activity and a composite score for all six activities were tabulated. A mean negative change from baseline means that symptoms have improved. A mean positive change from baseline means that symptoms have gotten worse.
Change From Randomization To All Post-randomization Visits in Orthostatic Hypotension Questionnaire (OHQ) Composite Score	Randomization (Day 0); Weeks 2 to 12	The OHQ composite score was a mean of the OHSA composite and the Orthostatic Hypotension Daily Activity Scale (OHDAS) composite scores. The OHDAS was designed as a measure of quality of life. It uses an 11-point scale to assess whether orthostatic hypotension (OH) "interfered" with four types of activities: 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. A zero rating means that over the preceding week the activity was performed with no interference and a 10 rating means that orthostatic hypotension completely interfered with the activity. Scores for each activity and a composite score for all four activities were tabulated. A mean negative change from baseline means that symptoms have improved. A mean positive change from baseline means that symptoms have gotten worse.
Participant-rated CGI-S	Weeks 2 to 12	The CGI-S was developed to provide global measures of the severity of a participant's clinical condition during clinical studies. The CGI-S was utilized by both the clinician and the participant to provide an impression of the participant's current state of OH. The severity of the participant's current illness was rated by the participant on a 7-point scale ranging from 1 (normal, no OH) to 7 (most extremely ill with OH).

Trial Locations

Locations (167): Sutter East Bay Medical Foundation
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Berkeley, California, United States
New Life Medical Research Center
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Miami Lakes, Florida, United States
Nothern Michigan Neurology
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Traverse City, Michigan, United States
Drexel Neurosciences Institute
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Philadelphia, Pennsylvania, United States
Parkinson's Institute and Clinical Center
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Mountain View, California, United States
Detroit Clinical Research Center
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Farmington Hills, Michigan, United States
Northern Michigan Neurology
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Traverse City, Michigan, United States
University of Pittsburgh, Department of Neurology
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Pittsburgh, Pennsylvania, United States
Neurology Offices Of South Florida
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Boca Raton, Florida, United States
Mir Neurology
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Hagerstown, Maryland, United States
Tufts Medical Center
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Boston, Massachusetts, United States
Alpha Neurology
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Staten Island, New York, United States
The Ohio State University
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Columbus, Ohio, United States
University Of Miami - Jackson Memorial Hospital, Dept. of Neurology
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Miami, Florida, United States
Anchor Medical Research, LLC
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Miami, Florida, United States
Novel Clinical Research Center, LLC
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Miami, Florida, United States
Cleveland Clinic - Taussig Cancer Institute
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Cleveland, Ohio, United States
Riverhills Healthcare, Inc.
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Cincinnati, Ohio, United States
Northwestern Medicine Central DuPage Hospital
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Winfield, Illinois, United States
American Health Network of Indiana
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Avon, Indiana, United States
The Neurological Institute, PA
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Charlotte, North Carolina, United States
Mid America Cardiology - University of Kansas
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Kansas City, Kansas, United States
University Of Southern California
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Los Angeles, California, United States
Movement Disorders Center of Arizona
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Scottsdale, Arizona, United States
Parkinson's Disease Treatment Center of Southwest Florida
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Port Charlotte, Florida, United States
Neurostudies, Inc.
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Port Charlotte, Florida, United States
Autonomic and Movement Disorders
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Boston, Massachusetts, United States
Georgetown University
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Washington, District of Columbia, United States
Neurology Associates
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Maitland, Florida, United States
Geodyssey Research, LLC
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Vero Beach, Florida, United States
Henry Ford West Bloomfield Hospital
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West Bloomfield, Michigan, United States
Movement Disorders Clinic
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Boston, Massachusetts, United States
Michigan Center of Medical Research
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Farmington Hills, Michigan, United States
Project 4 Research
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Miami, Florida, United States
Innovative Research of West Florida
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Clearwater, Florida, United States
Carilion Clinic
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Roanoke, Virginia, United States
Maine Medical Partners Technology
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Scarborough, Maine, United States
Coral Way Research
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Miami, Florida, United States
Michigan State University, Department of Neurology
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East Lansing, Michigan, United States
Dartmouth-Hitchcock Medical Center
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Lebanon, New Hampshire, United States
Platte Valley Medical Group
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Kearney, Nebraska, United States
Louisiana Heart Center
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Covington, Louisiana, United States
Florida Research Center
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Miami, Florida, United States
Brigham and Women's Faulkner Hospital (BWFH) - Brigham & Women's Foot & Ankle Center
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Boston, Massachusetts, United States
Aurora Medical Center
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Grafton, Wisconsin, United States
Grafton Medical Office
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Grafton, Wisconsin, United States
21st Century Neurology
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Phoenix, Arizona, United States
Methodist Physicians Clinic - Heart Consultants
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Omaha, Nebraska, United States
Eminance Medical & Clinical Research
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Tampa, Florida, United States
University Of South Florida
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Tampa, Florida, United States
USF Parkinson's & Movement Disorders Center
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Tampa, Florida, United States
MPC Heart Consultants
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Omaha, Nebraska, United States
Vanderbilt University Autonomic Dysfunction Center - Clinical Trials Center
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Nashville, Tennessee, United States
University Of Nebraska Medical Center
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Omaha, Nebraska, United States
The Nebraska Medical Center
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Omaha, Nebraska, United States
COR Clinical Research, LLC
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Oklahoma City, Oklahoma, United States
Legacy / Oregon Clinic Neurology
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Portland, Oregon, United States
The Oregon Clinic
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Portland, Oregon, United States
Bateman Home Center
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Salt Lake City, Utah, United States
Aurora St. Luke's Medical Center
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Milwaukee, Wisconsin, United States
Medical College of Wisconsin, Department of Neurology
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Milwaukee, Wisconsin, United States
Aurora Sinai Medical Center-Arrhythmia Center
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Milwaukee, Wisconsin, United States
MDFirst Research - Chandler
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Chandler, Arizona, United States
Movement Disorder Clinic - The University of Arizona
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Tucson, Arizona, United States
Center For Neurosciences
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Tucson, Arizona, United States
Arkansas Cardiology Clinic
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Little Rock, Arkansas, United States
University of Arizona Health Sciences Center, Department Of Neurology
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Tucson, Arizona, United States
The Parkinson's and Movement Disorder Institute
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Fountain Valley, California, United States
East Bay Physicians Medical Group
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Berkeley, California, United States
Behavioral Research Specialists, LLC
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Glendale, California, United States
Diverse Research Solutions, LLC
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Oxnard, California, United States
Focilmed
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Oxnard, California, United States
Neurosearch, Inc. - Pasedena
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Pasadena, California, United States
Parkinsons Disease & Movement Disorder of Silicon Valley
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Palo Alto, California, United States
Neurosearch, Inc. - Ventura
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Pasadena, California, United States
SC3 Research Group
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Pasadena, California, United States
Neurosearch, Inc. - Reseda
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Reseda, California, United States
The Parkinson's Institute and Clinical Center
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Sunnyvale, California, United States
Associated Neurologists of Southern Connecticut, P.C.
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Fairfield, Connecticut, United States
Neurosearch Inc. - Torrance
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Torrance, California, United States
Associated Neurologists, P.C.
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Danbury, Connecticut, United States
Eastern Connecticut Neurology Specialists, LLC
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Manchester, Connecticut, United States
MedStar Georgetown-MedStar Georgetown Transplant Institute University Hospital (MGUH)
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Washington, District of Columbia, United States
Parkinson's Disease And Movement Disorders Center of Boca Raton
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Boca Raton, Florida, United States
South Florida Neurology Associates, P.A.
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Boca Raton, Florida, United States
SIH Research
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Kissimmee, Florida, United States
Galiz Research
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Hialeah, Florida, United States
Future Clinical Research
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Miami, Florida, United States
Pro-Care Research Center, Corporation
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Miami Gardens, Florida, United States
Premium Medical Research, Corp
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Miami, Florida, United States
Neurological Center of North Georgia
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Gainesville, Georgia, United States
Vero Neurology
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Vero Beach, Florida, United States
Emory University
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Atlanta, Georgia, United States
The Neurological Center of North Georgia
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Gainesville, Georgia, United States
Northwestern Medical Group
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Chicago, Illinois, United States
Rush University Medical Center - Department Of Cardiology
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Chicago, Illinois, United States
Cardio Specialists Group, Ltd., Rush University Medical Center
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Chicago, Illinois, United States
Rush University Medical Center, Department of Neurology
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Chicago, Illinois, United States
NorthShore Neurological Institute
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Glenview, Illinois, United States
Central Dupage Hospital
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Winfield, Illinois, United States
Franciscan Physician Network Indiana Heart Physicians
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Indianapolis, Indiana, United States
Massachusetts General Hospital - Movement Disorders Clinic
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Boston, Massachusetts, United States
JFK Neuroscience Institution
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Edison, New Jersey, United States
Neuroscience Research Institute, LLC
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Toms River, New Jersey, United States
SUNY Downstate Medical Center
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Brooklyn, New York, United States
David L. Kreitzman MD, PC
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Commack, New York, United States
Office of David L. Kreitzman, M.D., P.C.
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Commack, New York, United States
Neurology Associates of West Chester
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Hawthorne, New York, United States
Parker Jewish Institute for Health Care & Rehabilitation
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New Hyde Park, New York, United States
Weill Cornell Medical College, Dept. of Neurology
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New York, New York, United States
The Bendheim Parkinson and Movement Disorders Center
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New York, New York, United States
Project 4 Research, Inc., The Neurological Institute at Columbia University Medical Center
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New York, New York, United States
Parker Jewish Institute For Healthcare And Rehabilitation
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New York, New York, United States
The Neurological Institute at Columbia University Medical Center
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New York, New York, United States
Columbia University Medical Center
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New York, New York, United States
Island Neurological Associates
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Plainview, New York, United States
UBMD Neurology
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Williamsville, New York, United States
Helen Hayes Hospital
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West Haverstraw, New York, United States
Peak Clinical Trials
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Apex, North Carolina, United States
Neurosciences Institute
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Charlotte, North Carolina, United States
Carolinas HealthCare System Neurosciences Institute
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Charlotte, North Carolina, United States
Insight Neuroscience, LLC
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Bellevue, Ohio, United States
Ohio Health Research Institute
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Columbus, Ohio, United States
Dayton Center for Neurological Disorders
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Centerville, Ohio, United States
Ohio State University, Department of Neurology
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Columbus, Ohio, United States
Baha Abu-Esheh, MD
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Ardmore, Oklahoma, United States
Gardner-McMaster Parkinson Center - The University of Toledo
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Toledo, Ohio, United States
CardioVoyage, LLC
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Ardmore, Oklahoma, United States
Medical College of Ohio, Department of Neurology
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Toledo, Ohio, United States
St. Luke's Neurology Associates
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Bethlehem, Pennsylvania, United States
Penn State Hershey Children's Hospital
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Hershey, Pennsylvania, United States
Penn State Milton S. Hershey Medical Center
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Hershey, Pennsylvania, United States
University of Pennsylvania, Parkinson's Disease & Movement Disorders Center
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Philadelphia, Pennsylvania, United States
Dr. Umer Akbar MD, Office of
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Providence, Rhode Island, United States
Sunbeam Clinical Research
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Greenville, Texas, United States
iMD Medical Center
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Carrollton, Texas, United States
UT Southwestern Medical Center
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Dallas, Texas, United States
Elite Primary Care
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Greenville, Texas, United States
University of Texas Health Science Center at Houston
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Houston, Texas, United States
Texas Institute of Cardiology, The Heartbeat Clinic
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McKinney, Texas, United States
Central Texas Neurology Consultants
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Round Rock, Texas, United States
Sunbeam Clinical Research, LLC.
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Prosper, Texas, United States
The Heartbeat Clinic
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McKinney, Texas, United States
Christus Research Institute
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Tyler, Texas, United States
Clear Lake Specialties
🇺🇸
Webster, Texas, United States
Integrated Neurology Services, PLLC
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Falls Church, Virginia, United States
Inova Health Systems
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Alexandria, Virginia, United States
Sentara Neurology Specialists
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Norfolk, Virginia, United States
Northwest Neurology, Premier Clinical Research
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Spokane, Washington, United States
Health Research of Hampton Roads-Norfolk, Inc
🇺🇸
Norfolk, Virginia, United States
Premeir Clinical Research
🇺🇸
Spokane, Washington, United States
Booth Gardner Parkinson's Care Center
🇺🇸
Kirkland, Washington, United States
Loma Linda University Medical Center
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Loma Linda, California, United States
Fort Wayne Neurological Center
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Fort Wayne, Indiana, United States
Colorado Springs Neurological Associates
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Colorado Springs, Colorado, United States
Christiana Care Neurology Specialists
🇺🇸
Newark, Delaware, United States
Georgia Regents University
🇺🇸
Augusta, Georgia, United States
UF Center for Movement Disorders and Neurorestoration
🇺🇸
Gainesville, Florida, United States
Yale-New Haven Hospital
🇺🇸
New Haven, Connecticut, United States
Yale Neurology / Hypertension Program
🇺🇸
New Haven, Connecticut, United States
Hawaii Pacific Neuroscience
🇺🇸
Honolulu, Hawaii, United States
Radiological Associates of Sacramento
🇺🇸
Sacramento, California, United States
Sutter Neuroscience
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Sacramento, California, United States
Yale University School Of Medicine
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New Haven, Connecticut, United States
Henrico Doctors Neurology Associates, LLC
🇺🇸
Richmond, Virginia, United States
University of Kansas Medical Center
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Kansas City, Kansas, United States
Rhode Island Hospital
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Providence, Rhode Island, United States