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

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

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.

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease; Orthostatic Hypotension
• Intervention / Treatment: Other: Placebo; Drug: Droxidopa

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 Type: Interventional
• Enrollment (Actual): 225
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Alabaster, Alabama, United States, 35007
      • Neurology Neurodiagnostic Lab
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Neurological Physicians of Arizona
    • Phoenix, Arizona, United States, 85004
      • Xenoscience
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurology Clinic
    • Sun City, Arizona, United States, 85351
      • Banner Health
    • Tucson, Arizona, United States, 85718
      • Center for Neurosciences
    • Tucson, Arizona, United States, 85741
      • Northwest Neuro Specialists P.L.L.C.
  • California
    • Laguna Hills, California, United States, 92653
      • Caring Clinical Research Incorporated
    • Newport Beach, California, United States, 92663
      • Hoag Memorial Hospital, Presbyterian
    • Pasadena, California, United States, 91105
      • Neurosearch - Pasadena
    • Poway, California, United States, 92064
      • Alliance Clinical Research, LLC
    • Reseda, California, United States, 91335
      • Neurosearch, Inc.
    • Ventura, California, United States, 93003
      • Neurosearch II, Inc.
    • Whittier, California, United States, 90606
      • Neurology Consultants Medical Group
  • Connecticut
    • Fairfield, Connecticut, United States, 06824
      • Associated Neurologist of Southern Connecticut, PC
    • Hartford, Connecticut, United States, 06106
      • Hartford Hospital
    • Manchester, Connecticut, United States, 06040
      • Eastern Connecticut Neurology Specialists
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Parkinson's Disease & Movement Disorder Disoder
    • Miami, Florida, United States, 33126
      • Pharmax Research Clinic, LLC
    • Ormond Beach, Florida, United States, 32174
      • Neurology Associates of Ormond Beach
    • Port Charlotte, Florida, United States, 33952
      • Neurostudies Inc.
    • Port Charlotte, Florida, United States, 33980
      • Parkinson's Disease Treatment Center of Southwest Florida
    • Sarasota, Florida, United States, 34233
      • Lovelace Scientific Research
    • Tampa, Florida, United States, 33606
      • Tampa General University of South Florida
    • Vero Beach, Florida, United States, 32960
      • Vero Neurology
    • West Palm Beach, Florida, United States, 33407
      • Premiere Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University
    • Decatur, Georgia, United States, 30033
      • Neurology Specialists of Decatur Research Center
    • Rome, Georgia, United States, 30165
      • Prism Research Group
  • Illinois
    • Elk Grove Village, Illinois, United States, 60007
      • Alexian Brothers Hospital Network
  • Kansas
    • Topeka, Kansas, United States, 66604
      • Precise Clinical Research
  • Louisiana
    • Hammond, Louisiana, United States, 70403
      • North Oaks Health System
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Harvard Vanguard Medical Associates
  • Michigan
    • Novi, Michigan, United States, 48377
      • Detroit Clinical Research Center
    • Traverse City, Michigan, United States, 49684
      • Northern Michigan Neurology
  • Mississippi
    • Ocean Springs, Mississippi, United States, 39564
      • Gulf Coast Neurology Center, PLLC
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • University of Nevada School of Medicine
  • New Jersey
    • Belvidere, New Jersey, United States, 07823
      • Wellness and Research Center
    • Lawrenceville, New Jersey, United States, 08648
      • AdvanceMed Research
    • Toms River, New Jersey, United States, 08755
      • Shore Neurology
  • New York
    • Albany, New York, United States, 12205
      • Upstate Clinical Research, LLC
    • Commack, New York, United States, 11725
      • David L. Kreitzman, M.D., PC
    • Kingston, New York, United States, 12401
      • Kingston Neurological Associates
    • New Hyde Park, New York, United States, 11040-1433
      • Parker Jewish Institute For Health Care and Rehabilitation Foundation
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
    • New York, New York, United States, 10016
      • New York University
    • Syracuse, New York, United States, 13210
      • Neurological Care of CNY
  • North Carolina
    • Asheville, North Carolina, United States, 28806
      • Asheville Neurology Specialists, PA
    • Greensboro, North Carolina, United States, 27405
      • Guilford Neurologic Associates
    • Winston-Salem, North Carolina, United States, 27103
      • Clinical Trials of America Inc
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Community Research
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center
    • Toledo, Ohio, United States, 43614
      • University of Toledo
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • Movement Disorder Clinic of Oklahoma PLLC
  • Pennsylvania
    • Johnstown, Pennsylvania, United States, 15904
      • Ilumina Clinical Associates
    • Pittsburgh, Pennsylvania, United States, 15206
      • Clinical Trials Research Services LLC
  • Texas
    • Dallas, Texas, United States, 75390-9063
      • UT Southwestern Medical Center at Dallas
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • JM Neuroscience Research
  • Virginia
    • Richmond, Virginia, United States, 23226
      • Neurological Associates, Inc.
    • Virginia Beach, Virginia, United States, 23456
      • Sentara Neurology Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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; 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: L-DOPS; Northera; L-threo-dihydroxyphenylserine; SM-5688
Placebo Comparator: Placebo; Placebo matched control	Other: Placebo; Placebo; Other Names: Mannitol, Sugar Pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
306A Efficacy: Change in Orthostatic Hypotension Questionnaire Score (OHQ)	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.	Baseline, Week 8
306B Efficacy: Change in Dizziness/Lightheadedness/Feeling Faint/Feeling Like You Might Black Out (OHSA Item 1)	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.	Baseline, Week1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
306B Efficacy: Change in OHSA Item 1 From Baseline to Week 2 (Visit 5)	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.	Baseline, Week2
306B Efficacy: Change in OHSA Item 1 From Baseline to Week 4 (Visit 6)	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.	Baseline, Week4
306B Efficacy: Change in Systolic Blood Pressure (SBP) Measurements Post Standing From Baseline to 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.	Baseline, Week 1
306B Efficacy: Change in OHSA Item 1 From Baseline to Week 8 (Visit 7)	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.	Baseline, Week 8
306B Efficacy: Rate of Patient Reported Falls	The average number of patient reported falls per week.	up to 10 weeks
306B Efficacy: Change in Orthostatic Hypotension Questionnaire Score (OHQ)	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.	Baseline, Week 8

Collaborators and Investigators

• Sponsor: 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.

Publications and helpful links

General Publications

• 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. doi: 10.1002/mds.10473.
• 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.
• 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. doi: 10.1007/BF01252816.
• 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. doi: 10.1161/01.HYP.0000081216.11623.C3. 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. doi: 10.1212/wnl.38.7.1091.
• 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. doi: 10.1161/01.CIR.0000083721.49847.D7. 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: July 30, 2010
• First Submitted That Met QC Criteria: August 4, 2010
• First Posted (Estimate): August 5, 2010

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: fatigue; falls; NOH; Parkinson's disease; dizziness; concentration; weakness; lightheadedness; Neurogenic Orthostatic Hypotension; unsteadiness; weak; head & neck pain; standing/walking for a short time; standing/walking for a long time
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Autonomic Nervous System Diseases; Primary Dysautonomias; Orthostatic Intolerance; Parkinson Disease; Hypotension; Hypotension, Orthostatic; Physiological Effects of Drugs; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Antiparkinson Agents; Anti-Dyskinesia Agents; Mannitol; Droxidopa
• Other Study ID Numbers: Droxidopa NOH306 (306A / 306B)