Clinical trial NCT01176240: A Two Part Study (306A/306B) to Assess Droxidopa in Treatment of NOH in Patients With Parkinson's Disease
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: Chelsea Therapeutics
Sponsor class: INDUSTRY
First posted: 2010-08-05
Enrollment: 225
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: 306A Efficacy: Change in Orthostatic Hypotension Questionnaire Score (OHQ)
timeFrame: Baseline, Week 8
measure: 306B Efficacy: Change in Dizziness/Lightheadedness/Feeling Faint/Feeling Like You Might Black Out (OHSA Item 1)
timeFrame: Baseline, Week1
Secondary outcomes:
measure: 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 2 (Visit 5)
timeFrame: Baseline, Week2
measure: 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 4 (Visit 6)
timeFrame: Baseline, Week4
measure: 306B Efficacy: Change in Systolic Blood Pressure (SBP) Measurements Post Standing From Baseline to Week 1
timeFrame: Baseline, Week 1
measure: 306B Efficacy: Change in OHSA Item 1 From Baseline to Week 8 (Visit 7)
timeFrame: Baseline, Week 8
measure: 306B Efficacy: Rate of Patient Reported Falls
timeFrame: up to 10 weeks
measure: 306B Efficacy: Change in Orthostatic Hypotension Questionnaire Score (OHQ)
timeFrame: Baseline, Week 8
Other outcomes:
Locations:
city: Alabaster
country: United States
facility: Neurology Neurodiagnostic Lab
state: Alabama
city: Gilbert
country: United States
facility: Neurological Physicians of Arizona
state: Arizona
city: Phoenix
country: United States
facility: Xenoscience
state: Arizona
city: Phoenix
country: United States
facility: Barrow Neurology Clinic
state: Arizona
city: Sun City
country: United States
facility: Banner Health
state: Arizona
city: Tucson
country: United States
facility: Center for Neurosciences
state: Arizona
city: Tucson
country: United States
facility: Northwest Neuro Specialists P.L.L.C.
state: Arizona
city: Laguna Hills
country: United States
facility: Caring Clinical Research Incorporated
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital, Presbyterian
state: California
city: Pasadena
country: United States
facility: Neurosearch - Pasadena
state: California
city: Poway
country: United States
facility: Alliance Clinical Research, LLC
state: California
city: Reseda
country: United States
facility: Neurosearch, Inc.
state: California
city: Ventura
country: United States
facility: Neurosearch II, Inc.
state: California
city: Whittier
country: United States
facility: Neurology Consultants Medical Group
state: California
city: Fairfield
country: United States
facility: Associated Neurologist of Southern Connecticut, PC
state: Connecticut
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Manchester
country: United States
facility: Eastern Connecticut Neurology Specialists
state: Connecticut
city: Boca Raton
country: United States
facility: Parkinson's Disease & Movement Disorder Disoder
state: Florida
city: Miami
country: United States
facility: Pharmax Research Clinic, LLC
state: Florida
city: Ormond Beach
country: United States
facility: Neurology Associates of Ormond Beach
state: Florida
city: Port Charlotte
country: United States
facility: Neurostudies Inc.
state: Florida
city: Port Charlotte
country: United States
facility: Parkinson's Disease Treatment Center of Southwest Florida
state: Florida
city: Sarasota
country: United States
facility: Lovelace Scientific Research
state: Florida
city: Tampa
country: United States
facility: Tampa General University of South Florida
state: Florida
city: Vero Beach
country: United States
facility: Vero Neurology
state: Florida
city: West Palm Beach
country: United States
facility: Premiere Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Decatur
country: United States
facility: Neurology Specialists of Decatur Research Center
state: Georgia
city: Rome
country: United States
facility: Prism Research Group
state: Georgia
city: Elk Grove Village
country: United States
facility: Alexian Brothers Hospital Network
state: Illinois
city: Topeka
country: United States
facility: Precise Clinical Research
state: Kansas
city: Hammond
country: United States
facility: North Oaks Health System
state: Louisiana
city: Boston
country: United States
facility: Harvard Vanguard Medical Associates
state: Massachusetts
city: Novi
country: United States
facility: Detroit Clinical Research Center
state: Michigan
city: Traverse City
country: United States
facility: Northern Michigan Neurology
state: Michigan
city: Ocean Springs
country: United States
facility: Gulf Coast Neurology Center, PLLC
state: Mississippi
city: Las Vegas
country: United States
facility: University of Nevada School of Medicine
state: Nevada
city: Belvidere
country: United States
facility: Wellness and Research Center
state: New Jersey
city: Lawrenceville
country: United States
facility: AdvanceMed Research
state: New Jersey
city: Toms River
country: United States
facility: Shore Neurology
state: New Jersey
city: Albany
country: United States
facility: Upstate Clinical Research, LLC
state: New York
city: Commack
country: United States
facility: David L. Kreitzman, M.D., PC
state: New York
city: Kingston
country: United States
facility: Kingston Neurological Associates
state: New York
city: New Hyde Park
country: United States
facility: Parker Jewish Institute For Health Care and Rehabilitation Foundation
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: New York University
state: New York
city: Syracuse
country: United States
facility: Neurological Care of CNY
state: New York
city: Asheville
country: United States
facility: Asheville Neurology Specialists, PA
state: North Carolina
city: Greensboro
country: United States
facility: Guilford Neurologic Associates
state: North Carolina
city: Winston-Salem
country: United States
facility: Clinical Trials of America Inc
state: North Carolina
city: Cincinnati
country: United States
facility: Community Research
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Toledo
country: United States
facility: University of Toledo
state: Ohio
city: Tulsa
country: United States
facility: Movement Disorder Clinic of Oklahoma PLLC
state: Oklahoma
city: Johnstown
country: United States
facility: Ilumina Clinical Associates
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Clinical Trials Research Services LLC
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center at Dallas
state: Texas
city: Salt Lake City
country: United States
facility: JM Neuroscience Research
state: Utah
city: Richmond
country: United States
facility: Neurological Associates, Inc.
state: Virginia
city: Virginia Beach
country: United States
facility: Sentara Neurology Specialists
state: Virginia
Study officials:
affiliation: University of South Florida
name: Robert Hauser, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Chelsea Therapeutics, Inc.
name: Lawrence A. Hewitt, Ph.D.
role: STUDY_CHAIR
affiliation: Chelsea Therapeutics, Inc.
name: William Schwieterman, M.D.
role: STUDY_DIRECTOR
References:
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citation: 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.
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. doi: 10.1161/01.HYP.0000081216.11623.C3. Epub 2003 Jun 30.
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. doi: 10.1212/wnl.38.7.1091.
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. doi: 10.1161/01.CIR.0000083721.49847.D7. Epub 2003 Jul 28.
citation: 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.
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].
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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.