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

Parkinson's Disease Clinical Trial

— 306A/306B  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01176240
• Other study ID #: Droxidopa NOH306 (306A / 306B)
• Status: Completed
• Phase: Phase 3
• First received: July 30, 2010
• Last updated: April 22, 2014
• Start date: June 2010
• Est. completion date: November 2012

Study information

• Verified date: April 2014
• Source: Chelsea Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 225
• Est. completion date: November 2012
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypotension
• Hypotension, Orthostatic
• Orthostatic Hypotension
• Parkinson Disease
• Parkinson's Disease

Intervention

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

Other:
• Placebo
Placebo

Locations

Country	Name	City	State
United States	Neurology Neurodiagnostic Lab	Alabaster	Alabama
United States	Upstate Clinical Research, LLC	Albany	New York
United States	Asheville Neurology Specialists, PA	Asheville	North Carolina
United States	Emory University	Atlanta	Georgia
United States	Wellness and Research Center	Belvidere	New Jersey
United States	Parkinson's Disease & Movement Disorder Disoder	Boca Raton	Florida
United States	Harvard Vanguard Medical Associates	Boston	Massachusetts
United States	Community Research	Cincinnati	Ohio
United States	Ohio State University Medical Center	Columbus	Ohio
United States	David L. Kreitzman, M.D., PC	Commack	New York
United States	UT Southwestern Medical Center at Dallas	Dallas	Texas
United States	Neurology Specialists of Decatur Research Center	Decatur	Georgia
United States	Alexian Brothers Hospital Network	Elk Grove Village	Illinois
United States	Associated Neurologist of Southern Connecticut, PC	Fairfield	Connecticut
United States	Neurological Physicians of Arizona	Gilbert	Arizona
United States	Guilford Neurologic Associates	Greensboro	North Carolina
United States	North Oaks Health System	Hammond	Louisiana
United States	Hartford Hospital	Hartford	Connecticut
United States	Ilumina Clinical Associates	Johnstown	Pennsylvania
United States	Kingston Neurological Associates	Kingston	New York
United States	Caring Clinical Research Incorporated	Laguna Hills	California
United States	University of Nevada School of Medicine	Las Vegas	Nevada
United States	AdvanceMed Research	Lawrenceville	New Jersey
United States	Eastern Connecticut Neurology Specialists	Manchester	Connecticut
United States	Pharmax Research Clinic, LLC	Miami	Florida
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	Hoag Memorial Hospital, Presbyterian	Newport Beach	California
United States	Detroit Clinical Research Center	Novi	Michigan
United States	Gulf Coast Neurology Center, PLLC	Ocean Springs	Mississippi
United States	Neurology Associates of Ormond Beach	Ormond Beach	Florida
United States	Neurosearch - Pasadena	Pasadena	California
United States	Barrow Neurology Clinic	Phoenix	Arizona
United States	Xenoscience	Phoenix	Arizona
United States	Clinical Trials Research Services LLC	Pittsburgh	Pennsylvania
United States	Neurostudies Inc.	Port Charlotte	Florida
United States	Parkinson's Disease Treatment Center of Southwest Florida	Port Charlotte	Florida
United States	Alliance Clinical Research, LLC	Poway	California
United States	Neurosearch, Inc.	Reseda	California
United States	Neurological Associates, Inc.	Richmond	Virginia
United States	Prism Research Group	Rome	Georgia
United States	JM Neuroscience Research	Salt Lake City	Utah
United States	Lovelace Scientific Research	Sarasota	Florida
United States	Banner Health	Sun City	Arizona
United States	Neurological Care of CNY	Syracuse	New York
United States	Tampa General University of South Florida	Tampa	Florida
United States	University of Toledo	Toledo	Ohio
United States	Shore Neurology	Toms River	New Jersey
United States	Precise Clinical Research	Topeka	Kansas
United States	Northern Michigan Neurology	Traverse City	Michigan
United States	Center for Neurosciences	Tucson	Arizona
United States	Northwest Neuro Specialists P.L.L.C.	Tucson	Arizona
United States	Movement Disorder Clinic of Oklahoma PLLC	Tulsa	Oklahoma
United States	Neurosearch II, Inc.	Ventura	California
United States	Vero Neurology	Vero Beach	Florida
United States	Sentara Neurology Specialists	Virginia Beach	Virginia
United States	Premiere Research Institute	West Palm Beach	Florida
United States	Neurology Consultants Medical Group	Whittier	California
United States	Clinical Trials of America Inc	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Chelsea Therapeutics

Country where clinical trial is conducted

United States, 

References & Publications (9)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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].

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. — View Citation

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.

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	306B Efficacy: Rate of Patient Reported Falls	The average number of patient reported falls per week.	up to 10 weeks	Yes
Secondary	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	No