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

NCT01176240 | Completed Phase 3 Results DMC

• 1 other identifier: Droxidopa NOH306 (306A / 306B)
• Study Type: interventional
• Target: 225
• Locations: 1 country
• Sites: 60

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.

Conditions

Orthostatic Hypotension; Parkinson's Disease

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 2 (Visit 5)

  Baseline, Week2

• 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 4 (Visit 6)

  Baseline, Week4

• 306B Efficacy: Change in Systolic Blood Pressure (SBP) Measurements Post Standing From Baseline to Week 1

  Baseline, Week 1

• 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 8 (Visit 7)

  Baseline, Week 8

• 306B Efficacy: Rate of Patient Reported Falls

  up to 10 weeks

Study Arms (2)

Droxidopa

EXPERIMENTAL

droxidopa active drug

Drug: Droxidopa

Placebo

PLACEBO COMPARATOR

Placebo matched control

Other: Placebo

Interventions

Droxidopa DRUG

100 mg and 200 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 8 weeks of treatment

Also known as: Northera, L-DOPS, L-threo-dihydroxyphenylserine, SM-5688

Droxidopa

Placebo OTHER

Placebo

Also known as: Mannitol, Sugar Pill

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years or over
• Clinical diagnosis of Parkinson's disease
• 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

You may not qualify if:

• Score of 23 or lower on the mini-mental state examination (MMSE)
• 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
• Concomitant use of anti-hypertensive medication for the treatment of essential hypertension
• 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)
• Known or suspected alcohol or substance abuse within the past 12 months (DSM-IV definition of alcohol or substance abuse)
• Women who are pregnant or breastfeeding
• Women of child bearing potential (WOCP) who are not using at least one method of contraception with their partner
• Male patients who are sexually active with a woman of child bearing potential (WOCP) and not using at least one method of contraception
• 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
• 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)
• Any significant uncontrolled cardiac arrhythmia
• History of myocardial infarction, within the past 2 years

Sponsors & Collaborators

• Chelsea Therapeutics: lead

Study Sites (60)

Neurology Neurodiagnostic Lab

Alabaster, Alabama, 35007, United States

Location

Neurological Physicians of Arizona

Gilbert, Arizona, 85234, United States

Location

Xenoscience

Phoenix, Arizona, 85004, United States

Location

Barrow Neurology Clinic

Phoenix, Arizona, 85013, United States

Location

Banner Health

Sun City, Arizona, 85351, United States

Location

Center for Neurosciences

Tucson, Arizona, 85718, United States

Location

Northwest Neuro Specialists P.L.L.C.

Tucson, Arizona, 85741, United States

Location

Caring Clinical Research Incorporated

Laguna Hills, California, 92653, United States

Location

Hoag Memorial Hospital, Presbyterian

Newport Beach, California, 92663, United States

Location

Neurosearch - Pasadena

Pasadena, California, 91105, United States

Location

Alliance Clinical Research, LLC

Poway, California, 92064, United States

Location

Neurosearch, Inc.

Reseda, California, 91335, United States

Location

Neurosearch II, Inc.

Ventura, California, 93003, United States

Location

Neurology Consultants Medical Group

Whittier, California, 90606, United States

Location

Associated Neurologist of Southern Connecticut, PC

Fairfield, Connecticut, 06824, United States

Location

Hartford Hospital

Hartford, Connecticut, 06106, United States

Location

Eastern Connecticut Neurology Specialists

Manchester, Connecticut, 06040, United States

Location

Parkinson's Disease & Movement Disorder Disoder

Boca Raton, Florida, 33486, United States

Location

Pharmax Research Clinic, LLC

Miami, Florida, 33126, United States

Location

Neurology Associates of Ormond Beach

Ormond Beach, Florida, 32174, United States

Location

Neurostudies Inc.

Port Charlotte, Florida, 33952, United States

Location

Parkinson's Disease Treatment Center of Southwest Florida

Port Charlotte, Florida, 33980, United States

Location

Lovelace Scientific Research

Sarasota, Florida, 34233, United States

Location

Tampa General University of South Florida

Tampa, Florida, 33606, United States

Location

Vero Neurology

Vero Beach, Florida, 32960, United States

Location

Premiere Research Institute

West Palm Beach, Florida, 33407, United States

Location

Emory University

Atlanta, Georgia, 30329, United States

Location

Neurology Specialists of Decatur Research Center

Decatur, Georgia, 30033, United States

Location

Prism Research Group

Rome, Georgia, 30165, United States

Location

Alexian Brothers Hospital Network

Elk Grove Village, Illinois, 60007, United States

Location

Precise Clinical Research

Topeka, Kansas, 66604, United States

Location

North Oaks Health System

Hammond, Louisiana, 70403, United States

Location

Harvard Vanguard Medical Associates

Boston, Massachusetts, 02215, United States

Location

Detroit Clinical Research Center

Novi, Michigan, 48377, United States

Location

Northern Michigan Neurology

Traverse City, Michigan, 49684, United States

Location

Gulf Coast Neurology Center, PLLC

Ocean Springs, Mississippi, 39564, United States

Location

University of Nevada School of Medicine

Las Vegas, Nevada, 89102, United States

Location

Wellness and Research Center

Belvidere, New Jersey, 07823, United States

Location

AdvanceMed Research

Lawrenceville, New Jersey, 08648, United States

Location

Shore Neurology

Toms River, New Jersey, 08755, United States

Location

Upstate Clinical Research, LLC

Albany, New York, 12205, United States

Location

David L. Kreitzman, M.D., PC

Commack, New York, 11725, United States

Location

Kingston Neurological Associates

Kingston, New York, 12401, United States

Location

Parker Jewish Institute For Health Care and Rehabilitation Foundation

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

Location

Beth Israel Medical Center

New York, New York, 10003, United States

Location

New York University

New York, New York, 10016, United States

Location

Neurological Care of CNY

Syracuse, New York, 13210, United States

Location

Asheville Neurology Specialists, PA

Asheville, North Carolina, 28806, United States

Location

Guilford Neurologic Associates

Greensboro, North Carolina, 27405, United States

Location

Clinical Trials of America Inc

Winston-Salem, North Carolina, 27103, United States

Location

Community Research

Cincinnati, Ohio, 45227, United States

Location

Ohio State University Medical Center

Columbus, Ohio, 43210, United States

Location

University of Toledo

Toledo, Ohio, 43614, United States

Location

Movement Disorder Clinic of Oklahoma PLLC

Tulsa, Oklahoma, 74136, United States

Location

Ilumina Clinical Associates

Johnstown, Pennsylvania, 15904, United States

Location

Clinical Trials Research Services LLC

Pittsburgh, Pennsylvania, 15206, United States

Location

UT Southwestern Medical Center at Dallas

Dallas, Texas, 75390-9063, United States

Location

JM Neuroscience Research

Salt Lake City, Utah, 84108, United States

Location

Neurological Associates, Inc.

Richmond, Virginia, 23226, United States

Location

Sentara Neurology Specialists

Virginia Beach, Virginia, 23456, United States

Location

Related Publications (13)

• 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.

  PMID: 6420517 BACKGROUND

• 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.

  PMID: 12815652 BACKGROUND

• 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.

  PMID: 12835329 BACKGROUND

• 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.

  PMID: 3133573 BACKGROUND

• 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.

  PMID: 12885750 BACKGROUND

• 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.

  PMID: 9513205 BACKGROUND

• 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].

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  PMID: 30003579 DERIVED

• 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.

  PMID: 28494751 DERIVED

• 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.

  PMID: 27538531 DERIVED

• 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.

  PMID: 24326693 DERIVED

MeSH Terms

Conditions

Hypotension, Orthostatic; Parkinson Disease; Dizziness; Asthenia; Fatigue; Neck Pain

Interventions

Droxidopa; Mannitol; Sugars

Condition Hierarchy (Ancestors)

Orthostatic Intolerance; Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Hypotension; Vascular Diseases; Cardiovascular Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Sensation Disorders; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Pain

Intervention Hierarchy (Ancestors)

Norepinephrine; Catecholamines; Amines; Organic Chemicals; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Serine; Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins; Sugar Alcohols; Alcohols; Carbohydrates

Results Point of Contact

• Title: Chief Scientific Officer
• Organization: Chelsea Therapeutics Inc.

hewitt@chelsearx.com

704-973-4202

Study Officials

• Robert Hauser, M.D.

  University of South Florida

  PRINCIPAL INVESTIGATOR

• Lawrence A. Hewitt, Ph.D.

  Chelsea Therapeutics, Inc.

  STUDY CHAIR

• William Schwieterman, M.D.

  Chelsea Therapeutics, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 30, 2010
• First Posted: August 5, 2010
• Study Start: June 1, 2010
• Primary Completion: October 1, 2012
• Study Completion: November 1, 2012
• Last Updated: May 20, 2014
• Results First Posted: May 20, 2014

Record last verified: 2014-04

Locations

US (60)