A Two Part Study (306A/306B) to Assess Droxidopa in Treatment of NOH in Patients With Parkinson's Disease (306A/306B)

• ClinicalTrials.gov Identifier: NCT01176240
• Recruitment Status: Completed
• First Posted: August 5, 2010
• Results First Posted: May 20, 2014
• Last Update Posted: May 20, 2014
• Sponsor: Chelsea Therapeutics
• Information provided by (Responsible Party): Chelsea Therapeutics

Study Description

Brief Summary:

This is a study to evaluate the effects of an investigational drug, Droxidopa, in participants with neurogenic orthostatic hypotension (NOH), associated with Parkinson's disease. Droxidopa is being studied to determine the effects on blood pressure changes upon standing up (orthostatic challenge). Symptoms and activity measurements, including patient reported falls, will be evaluated to determine the effectiveness of the study drug.

Symptoms of NOH may include any of the following:

• Dizziness, light-headedness, feeling faint or feeling like you may blackout
• Problems with vision (blurring, seeing spots, tunnel vision, etc.)
• Weakness
• Fatigue
• Trouble concentrating
• Head & neck discomfort (the coat hanger syndrome)
• Difficulty standing for a short time or a long time
• Trouble walking for a short time or a long time

The study duration is a maximum of approximately 14 weeks including up to 2 weeks for screening, up to 2 weeks for proper dose finding, followed by an 8 week treatment period and a follow-up visit after 2 weeks. A sufficient number of patients will be screened to allow approximately 211 randomized patients. An extension study is also available to continue treatment if determined appropriate by the study doctor. This Study is NCT01132326 sponsored by Chelsea Therapeutics and is enrolling by invitation only.

Condition or disease	Intervention/treatment	Phase
Orthostatic Hypotension; Parkinson's Disease	Drug: Droxidopa; Other: Placebo	Phase 3

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.

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.

Symptomatic OH in patients with Parkinson's disease is thought to be a consequence of norepinephrine depletion leading to low systolic blood pressure (SBP) and cerebral-hypoperfusion (reduced blood flow to the brain). Therapy with droxidopa results in increased levels of norepinephrine which should lead to improved SBP and cerebral perfusion thereby reducing the signs and symptoms of NOH. The present study will evaluate the clinical benefit in NOH patients with PD treated with droxidopa compared to those treated with placebo.

Participation in the study will last a maximum of 14 weeks consisting of a 2 week (maximum) screening/baseline period; a 2 week (maximum) double-blind dose titration; an 8 week double-blind placebo-controlled treatment period; and a 2 week follow-up period. An extension study is also available to continue treatment if determined appropriate by the study doctor. This Study is NCT01132326 sponsored by Chelsea Therapeutics and is enrolling by invitation only.

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. Stereoisomers and enantiomers are compounds that have the same chemical elements; however, they may react differently as the elements are positioned in different locations.

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 225 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Double-blind, Randomized, Parallel-Group, Placebo-Controlled Study to Assess the Clinical Effect of Droxidopa in the Treatment of Symptomatic Neurogenic Orthostatic Hypotension in Patients With Parkinson's Disease
• Study Start Date: June 2010
• Actual Primary Completion Date: October 2012
• Actual Study Completion Date: November 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: Droxidopa; droxidopa active drug	Drug: Droxidopa; 100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment; Other Names: Northera; L-DOPS; L-threo-dihydroxyphenylserine; SM-5688
Placebo Comparator: Placebo; Placebo matched control	Other: Placebo; Placebo; Other Name: Mannitol, Sugar Pill

Outcome Measures

Primary Outcome Measures :

1. 306A Efficacy: Change in Orthostatic Hypotension Questionnaire Score (OHQ) [ Time Frame: Baseline, Week 8 ]

   The primary efficacy endpoint for 306A is the relative mean change in Orthostatic Hypotension Questionnaire (OHQ) composite score from baseline to end of study. The OHQ is the average of two sub-scales, the Orthostatic Hypotension Symptom Assessment Scale (OHSA) and the Orthostatic Hypotension Daily Activities Scale (OHDAS). Each asks the patient to rate their symptoms or disease impact over the past week. The OHSA sub-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. The OHDAS sub-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 item is scored on a Likert scale from 0 to 10, with 10 being the most severe.

   For the change from baseline, negative numbers represent improvement from baseline in OHQ score.

2. 306B Efficacy: Change in Dizziness/Lightheadedness/Feeling Faint/Feeling Like You Might Black Out (OHSA Item 1) [ Time Frame: Baseline, Week1 ]
   OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 1 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.

Secondary Outcome Measures :

1. 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 2 (Visit 5) [ Time Frame: Baseline, Week2 ]
   OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 2 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.
2. 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 4 (Visit 6) [ Time Frame: Baseline, Week4 ]
   OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 4 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.
3. 306B Efficacy: Change in Systolic Blood Pressure (SBP) Measurements Post Standing From Baseline to Week 1 [ Time Frame: Baseline, Week 1 ]
   Measure: Lowest standing systolic blood pressure reading of immediately post standing and 3 minutes post standing. Change: standing systolic blood pressure at Week 1 (Visit 4) minus standing systolic blood pressure at baseline. A positive score indicates an improvement in standing systolic blood pressure during the double-blind randomized phase relative to value at baseline.
4. 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 8 (Visit 7) [ Time Frame: Baseline, Week 8 ]
   OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at Week 8 minus score at baseline. A negative score indicates an improvement in symptoms during the double-blind randomized phase relative to value at baseline.
5. 306B Efficacy: Rate of Patient Reported Falls [ Time Frame: up to 10 weeks ]
   The average number of patient reported falls per week.
6. 306B Efficacy: Change in Orthostatic Hypotension Questionnaire Score (OHQ) [ Time Frame: Baseline, Week 8 ]

   The relative mean change in Orthostatic Hypotension Questionnaire (OHQ) composite score from baseline to end of study. The OHQ is the average of two sub-scales, the Orthostatic Hypotension Symptom Assessment Scale (OHSA) and the Orthostatic Hypotension Daily Activities Scale (OHDAS). Each asks the patient to rate their symptoms or disease impact over the past week. The OHSA sub-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. The OHDAS sub-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 item is scored on a Likert scale from 0 to 10, with 10 being the most severe.

   For the change from baseline, negative numbers represent improvement from baseline in OHQ score.

Eligibility Criteria

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

Criteria

Inclusion criteria:

1. 18 years or over
2. Clinical diagnosis of Parkinson's disease
3. Clinical diagnosis of symptomatic neurogenic orthostatic hypotension

At their baseline visit (Visit 2), patients must demonstrate:

• a score of at least 3 or greater on the OHQ composite
• a score of at least 3 or greater on the clinician CGI-S
• a fall of at least 20 mmHg in their systolic blood pressure, or 10 mmHg in their diastolic blood pressure, within 3 minutes of standing 4. 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:

1. Score of 23 or lower on the mini-mental state examination (MMSE)

2. Concomitant use of vasoconstricting agents for the purpose of increasing blood pressure;

   - Patients taking vasoconstricting agents such as ephedrine, dihydroergotamine, or midodrine must stop taking these drugs at least 2 days or 5 half-lives (whichever is longer) prior to their baseline visit (Visit 2) and throughout the duration of the study

3. Concomitant use of anti-hypertensive medication for the treatment of essential hypertension

4. Have changed dose, frequency or type of prescribed medication, within two weeks of baseline visit (Visit 2) with the following exceptions:

   • Vasoconstricting agents such a ephedrine, dihydroergotamine, or midodrine
   • Short courses (less than 2 weeks) of medications or treatments that do not interfere with, or exacerbate the patient's condition under study (e.g. antibiotics)
5. Known or suspected alcohol or substance abuse within the past 12 months (DSM-IV definition of alcohol or substance abuse)
6. Women who are pregnant or breastfeeding
7. Women of child bearing potential (WOCP) who are not using at least one method of contraception with their partner
8. Male patients who are sexually active with a woman of child bearing potential (WOCP) and not using at least one method of contraception
9. Untreated closed angle glaucoma, or treated closed angle glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk to the patient
10. Sustained severe hypertension (BP ≥ 180 mmHg systolic or ≥ 110 mmHg diastolic in the seated or supine position which is observed in 3 consecutive measurements over an hour)
11. Any significant uncontrolled cardiac arrhythmia
12. History of myocardial infarction, within the past 2 years
13. Current unstable angina
14. Congestive heart failure (NYHA Class 3 or 4)
15. Diabetic autonomic neuropathy
16. 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
17. Gastrointestinal condition, which in the Investigator's judgment, may affect the absorption of study drug (e.g. ulcerative colitis, gastric bypass)
18. Any major surgical procedure within 30 days of the baseline visit (Visit 2)
19. Previously treated with droxidopa
20. Currently receiving any investigational drug or have received an investigational drug within 30 days of the baseline visit (Visit 2)
21. Any condition or laboratory test result, which in the Investigator's judgment, might result in an increased risk to the patient, or would affect their participation in the study. Additionally the Investigator has the ability to exclude a patient if for any reason they feel the subject is not a good candidate for the study or will not be able to follow study procedures.

Contacts and Locations

Locations

United States, Alabama

Neurology Neurodiagnostic Lab

Alabaster, Alabama, United States, 35007

United States, Arizona

Neurological Physicians of Arizona

Gilbert, Arizona, United States, 85234

Xenoscience

Phoenix, Arizona, United States, 85004

Barrow Neurology Clinic

Phoenix, Arizona, United States, 85013

Banner Health

Sun City, Arizona, United States, 85351

Center for Neurosciences

Tucson, Arizona, United States, 85718

Northwest Neuro Specialists P.L.L.C.

Tucson, Arizona, United States, 85741

United States, California

Caring Clinical Research Incorporated

Laguna Hills, California, United States, 92653

Hoag Memorial Hospital, Presbyterian

Newport Beach, California, United States, 92663

Neurosearch - Pasadena

Pasadena, California, United States, 91105

Alliance Clinical Research, LLC

Poway, California, United States, 92064

Neurosearch, Inc.

Reseda, California, United States, 91335

Neurosearch II, Inc.

Ventura, California, United States, 93003

Neurology Consultants Medical Group

Whittier, California, United States, 90606

United States, Connecticut

Associated Neurologist of Southern Connecticut, PC

Fairfield, Connecticut, United States, 06824

Hartford Hospital

Hartford, Connecticut, United States, 06106

Eastern Connecticut Neurology Specialists

Manchester, Connecticut, United States, 06040

United States, Florida

Parkinson's Disease & Movement Disorder Disoder

Boca Raton, Florida, United States, 33486

Pharmax Research Clinic, LLC

Miami, Florida, United States, 33126

Neurology Associates of Ormond Beach

Ormond Beach, Florida, United States, 32174

Neurostudies Inc.

Port Charlotte, Florida, United States, 33952

Parkinson's Disease Treatment Center of Southwest Florida

Port Charlotte, Florida, United States, 33980

Lovelace Scientific Research

Sarasota, Florida, United States, 34233

Tampa General University of South Florida

Tampa, Florida, United States, 33606

Vero Neurology

Vero Beach, Florida, United States, 32960

Premiere Research Institute

West Palm Beach, Florida, United States, 33407

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30329

Neurology Specialists of Decatur Research Center

Decatur, Georgia, United States, 30033

Prism Research Group

Rome, Georgia, United States, 30165

United States, Illinois

Alexian Brothers Hospital Network

Elk Grove Village, Illinois, United States, 60007

United States, Kansas

Precise Clinical Research

Topeka, Kansas, United States, 66604

United States, Louisiana

North Oaks Health System

Hammond, Louisiana, United States, 70403

United States, Massachusetts

Harvard Vanguard Medical Associates

Boston, Massachusetts, United States, 02215

United States, Michigan

Detroit Clinical Research Center

Novi, Michigan, United States, 48377

Northern Michigan Neurology

Traverse City, Michigan, United States, 49684

United States, Mississippi

Gulf Coast Neurology Center, PLLC

Ocean Springs, Mississippi, United States, 39564

United States, Nevada

University of Nevada School of Medicine

Las Vegas, Nevada, United States, 89102

United States, New Jersey

Wellness and Research Center

Belvidere, New Jersey, United States, 07823

AdvanceMed Research

Lawrenceville, New Jersey, United States, 08648

Shore Neurology

Toms River, New Jersey, United States, 08755

United States, New York

Upstate Clinical Research, LLC

Albany, New York, United States, 12205

David L. Kreitzman, M.D., PC

Commack, New York, United States, 11725

Kingston Neurological Associates

Kingston, New York, United States, 12401

Parker Jewish Institute For Health Care and Rehabilitation Foundation

New Hyde Park, New York, United States, 11040-1433

Beth Israel Medical Center

New York, New York, United States, 10003

New York University

New York, New York, United States, 10016

Neurological Care of CNY

Syracuse, New York, United States, 13210

United States, North Carolina

Asheville Neurology Specialists, PA

Asheville, North Carolina, United States, 28806

Guilford Neurologic Associates

Greensboro, North Carolina, United States, 27405

Clinical Trials of America Inc

Winston-Salem, North Carolina, United States, 27103

United States, Ohio

Community Research

Cincinnati, Ohio, United States, 45227

Ohio State University Medical Center

Columbus, Ohio, United States, 43210

University of Toledo

Toledo, Ohio, United States, 43614

United States, Oklahoma

Movement Disorder Clinic of Oklahoma PLLC

Tulsa, Oklahoma, United States, 74136

United States, Pennsylvania

Ilumina Clinical Associates

Johnstown, Pennsylvania, United States, 15904

Clinical Trials Research Services LLC

Pittsburgh, Pennsylvania, United States, 15206

United States, Texas

UT Southwestern Medical Center at Dallas

Dallas, Texas, United States, 75390-9063

United States, Utah

JM Neuroscience Research

Salt Lake City, Utah, United States, 84108

United States, Virginia

Neurological Associates, Inc.

Richmond, Virginia, United States, 23226

Sentara Neurology Specialists

Virginia Beach, Virginia, United States, 23456

Sponsors and Collaborators

Chelsea Therapeutics

Investigators

• Principal Investigator: Robert Hauser, M.D.; University of South Florida
• Study Chair: Lawrence A. Hewitt, Ph.D.; Chelsea Therapeutics, Inc.
• Study Director: William Schwieterman, M.D.; Chelsea Therapeutics, Inc.

More Information

Publications:

Birkmayer W, Birkmayer G, Lechner H, Riederer P. DL-3,4-threo-DOPS in Parkinson's disease: effects on orthostatic hypotension and dizziness. J Neural Transm. 1983;58(3-4):305-13.

Movement Disorder Society Task Force on Rating Scales for Parkinson's Disease. The Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. Mov Disord. 2003 Jul;18(7):738-50. Review.

Goldstein DS, Pechnik S, Holmes C, Eldadah B, Sharabi Y. Association between supine hypertension and orthostatic hypotension in autonomic failure. Hypertension. 2003 Aug;42(2):136-42. Epub 2003 Jun 30. Erratum in: Hypertension. 2003 Oct;43(4):e12.

Kachi T, Iwase S, Mano T, Saito M, Kunimoto M, Sobue I. Effect of L-threo-3,4-dihydroxyphenylserine on muscle sympathetic nerve activities in Shy-Drager syndrome. Neurology. 1988 Jul;38(7):1091-4.

Kaufmann H, Saadia D, Voustianiouk A, Goldstein DS, Holmes C, Yahr MD, Nardin R, Freeman R. Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation. 2003 Aug 12;108(6):724-8. Epub 2003 Jul 28.

Yanagisawa N, Ikeda S, Hashimoto T, Hanyu N, Nakagawa S, Fujimori N, Ushiyama M. [Effects of L-threo-Dops on orthostatic hypotension in Parkinson's disease]. No To Shinkei. 1998 Feb;50(2):157-63. Japanese.

Malamut, R., Freeman, R., Gilden, J., Tulloch, J., Kaufmann, H., 2005. A multi-center, double-blind, randomized, placebo controlled, cross-over study to assess the clinical benefit of midodrine in patients with neurogenic orthostatic hypotension. Clin. Auto. Res. 15 (5) 337[abstract].

Narabayashi, H., Nakanishi, T., Kanazawa, I., Yoshida, M., Mizuno, Y., Yanagisawa, N., Kondo, T. 1987. Clinical effects of L-threo-3,4-dihydroxyphenylserine in Parkinson's disease and Parkinson syndrome: Results of multi-center open study at 45 institutions. Yakuri To Chiryo (Jpn. Pharmacol. Ther.) 15(Suppl. 2):411 to 443.

Sobue, I., Senda, Y., Suzuki, T., Narabayashi, I., Hirayama, K. 1987. Clinical effects of L-threo-3,4-dihydroxyphenylserine on orthostatic hypotension in Shy-Drager Syndrome and its related diseases. Shinkei Naika Chiryo [Neurol. Ther.] 4(2):199-208.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Heller GZ, Couturier DL, Heritier SR. Beyond mean modelling: Bias due to misspecification of dispersion in Poisson-inverse Gaussian regression. Biom J. 2019 Mar;61(2):333-342. doi: 10.1002/bimj.201700218. Epub 2018 Jul 12.

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.

François 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.

Hauser RA, Hewitt LA, Isaacson S. Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson's disease (NOH306A). J Parkinsons Dis. 2014;4(1):57-65. doi: 10.3233/JPD-130259.

• Responsible Party: Chelsea Therapeutics
• ClinicalTrials.gov Identifier: NCT01176240
• Other Study ID Numbers: Droxidopa NOH306 (306A / 306B)
• First Posted: August 5, 2010
• Results First Posted: May 20, 2014
• Last Update Posted: May 20, 2014
• Last Verified: April 2014

Keywords provided by Chelsea Therapeutics:

lightheadedness; unsteadiness; dizziness; weak; fatigue; concentration; head & neck pain; standing/walking for a short time; standing/walking for a long time; Neurogenic Orthostatic Hypotension; falls; NOH; Parkinson's disease; weakness

Additional relevant MeSH terms:

Parkinson Disease; Hypotension, Orthostatic; Hypotension; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Neurodegenerative Diseases; Vascular Diseases; Cardiovascular Diseases; Orthostatic Intolerance; Primary Dysautonomias; Autonomic Nervous System Diseases; Mannitol; Droxidopa; Diuretics, Osmotic; Diuretics; Natriuretic Agents; Physiological Effects of Drugs; Antiparkinson Agents; Anti-Dyskinesia Agents