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

NCT ID: NCT01176240

Last Updated: 2014-05-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 225 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-06-30
• Study Completion Date: 2012-11-30

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.

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.

Conditions

Orthostatic Hypotension; Parkinson's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Droxidopa

droxidopa active drug

Group Type: EXPERIMENTAL

Droxidopa

Intervention Type: DRUG

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

Placebo

Placebo matched control

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo

Interventions

Droxidopa

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

Intervention Type: DRUG

Placebo

Placebo

Intervention Type: OTHER

Other Intervention Names

Northera; L-DOPS; L-threo-dihydroxyphenylserine; SM-5688; Mannitol, Sugar Pill

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chelsea Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Robert Hauser, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of South Florida

Lawrence A. Hewitt, Ph.D.

Role: STUDY_CHAIR

Chelsea Therapeutics, Inc.

William Schwieterman, M.D.

Role: STUDY_DIRECTOR

Chelsea Therapeutics, Inc.

Locations

Neurology Neurodiagnostic Lab

Alabaster, Alabama, United States

Neurological Physicians of Arizona

Gilbert, Arizona, United States

Xenoscience

Phoenix, Arizona, United States

Barrow Neurology Clinic

Phoenix, Arizona, United States

Banner Health

Sun City, Arizona, United States

Center for Neurosciences

Tucson, Arizona, United States

Northwest Neuro Specialists P.L.L.C.

Tucson, Arizona, United States

Caring Clinical Research Incorporated

Laguna Hills, California, United States

Hoag Memorial Hospital, Presbyterian

Newport Beach, California, United States

Neurosearch - Pasadena

Pasadena, California, United States

Alliance Clinical Research, LLC

Poway, California, United States

Neurosearch, Inc.

Reseda, California, United States

Neurosearch II, Inc.

Ventura, California, United States

Neurology Consultants Medical Group

Whittier, California, United States

Associated Neurologist of Southern Connecticut, PC

Fairfield, Connecticut, United States

Hartford Hospital

Hartford, Connecticut, United States

Eastern Connecticut Neurology Specialists

Manchester, Connecticut, United States

Parkinson's Disease & Movement Disorder Disoder

Boca Raton, Florida, United States

Pharmax Research Clinic, LLC

Miami, Florida, United States

Neurology Associates of Ormond Beach

Ormond Beach, Florida, United States

Neurostudies Inc.

Port Charlotte, Florida, United States

Parkinson's Disease Treatment Center of Southwest Florida

Port Charlotte, Florida, United States

Lovelace Scientific Research

Sarasota, Florida, United States

Tampa General University of South Florida

Tampa, Florida, United States

Vero Neurology

Vero Beach, Florida, United States

Premiere Research Institute

West Palm Beach, Florida, United States

Emory University

Atlanta, Georgia, United States

Neurology Specialists of Decatur Research Center

Decatur, Georgia, United States

Prism Research Group

Rome, Georgia, United States

Alexian Brothers Hospital Network

Elk Grove Village, Illinois, United States

Precise Clinical Research

Topeka, Kansas, United States

North Oaks Health System

Hammond, Louisiana, United States

Harvard Vanguard Medical Associates

Boston, Massachusetts, United States

Detroit Clinical Research Center

Novi, Michigan, United States

Northern Michigan Neurology

Traverse City, Michigan, United States

Gulf Coast Neurology Center, PLLC

Ocean Springs, Mississippi, United States

University of Nevada School of Medicine

Las Vegas, Nevada, United States

Wellness and Research Center

Belvidere, New Jersey, United States

AdvanceMed Research

Lawrenceville, New Jersey, United States

Shore Neurology

Toms River, New Jersey, United States

Upstate Clinical Research, LLC

Albany, New York, United States

David L. Kreitzman, M.D., PC

Commack, New York, United States

Kingston Neurological Associates

Kingston, New York, United States

Parker Jewish Institute For Health Care and Rehabilitation Foundation

New Hyde Park, New York, United States

Beth Israel Medical Center

New York, New York, United States

New York University

New York, New York, United States

Neurological Care of CNY

Syracuse, New York, United States

Asheville Neurology Specialists, PA

Asheville, North Carolina, United States

Guilford Neurologic Associates

Greensboro, North Carolina, United States

Clinical Trials of America Inc

Winston-Salem, North Carolina, United States

Community Research

Cincinnati, Ohio, United States

Ohio State University Medical Center

Columbus, Ohio, United States

University of Toledo

Toledo, Ohio, United States

Movement Disorder Clinic of Oklahoma PLLC

Tulsa, Oklahoma, United States

Ilumina Clinical Associates

Johnstown, Pennsylvania, United States

Clinical Trials Research Services LLC

Pittsburgh, Pennsylvania, United States

UT Southwestern Medical Center at Dallas

Dallas, Texas, United States

JM Neuroscience Research

Salt Lake City, Utah, United States

Neurological Associates, Inc.

Richmond, Virginia, United States

Sentara Neurology Specialists

Virginia Beach, Virginia, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 6420517 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12815652 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12835329 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 3133573 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12885750 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 9513205 (View on PubMed)

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].

Reference Type: 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.

Reference Type: 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.

Reference Type: 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.

Reference Type: DERIVED

PMID: 30003579 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28494751 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27538531 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24326693 (View on PubMed)

Other Identifiers

Droxidopa NOH306 (306A / 306B)

Identifier Type: -

Identifier Source: org_study_id