Sustained Effect of Droxidopa in Symptomatic Neurogenic Orthostatic Hypotension

Symptomatic Neurogenic Orthostatic Hypotension Clinical Trial

— RESTORE  

Official title:

RESTORE: A Clinical Study of Patients With Symptomatic Neurogenic Orthostatic Hypotension to Assess Sustained Effects of Droxidopa Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02586623
• Other study ID #: 16306A
• Secondary ID: NOH402
• Status: Completed
• Phase: Phase 4
• Start date: February 11, 2016
• Est. completion date: September 9, 2022

Study information

• Verified date: August 2023
• Source: H. Lundbeck A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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 information / eligibility

• Status: Completed
• Enrollment: 453
• Est. completion date: September 9, 2022
• Est. primary completion date: July 21, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hypotension
• Hypotension, Orthostatic
• Symptomatic Neurogenic Orthostatic Hypotension

Intervention

Drug:
• Droxidopa capsules
100, 200 or 300 mg
• Placebo capsules

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
H. Lundbeck A/S

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time To Intervention	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.	Randomization (Day 0) up to Week 12
Secondary	Number of Participants Who Needed Intervention During the 12-week Double-Blind Treatment Period	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.	Randomization (Day 0) up to Week 12
Secondary	Time To All-cause Discontinuation	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.	Randomization (Day 0) up to Week 12
Secondary	Change From Randomization To All Post-randomization Visits in Orthostatic Hypotension Symptom Assessment (OHSA) Item #1 Score	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.	Randomization (Day 0); Weeks 2 to 12
Secondary	Change From Randomization To All Post-randomization Visits in Orthostatic Hypotension Questionnaire (OHQ) Composite Score	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.	Randomization (Day 0); Weeks 2 to 12
Secondary	Clinician-rated Clinical Global Impressions - Severity (CGI-S)	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).	Weeks 2 to 12
Secondary	Participant-rated CGI-S	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).	Weeks 2 to 12