Efficacy of Orally Disintegrating Selegiline in Parkinson's Patients Experiencing Adverse Effects With Dopamine Agonists (AtoZ)

Adding Orally Disintegrating Selegiline (Zelapar) to Patients Taking Dopamine Agonists and Experiencing Complications

The purpose of the study is to determine if reducing or eliminating a dopamine agonist (DA) causing one of the side effects of daytime sleepiness, swelling of the lower legs or feet, hallucinations or impulsive behaviors while adding orally disintegrating selegiline can eliminate the adverse effect and maintain control of Parkinson's disease (PD) symptoms.

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease
• Intervention / Treatment: Drug: orally disintegrating selegiline (Zelapar)

Detailed Description

Parkinson's disease (PD) is a progressive neurodegenerative disease. Symptomatic therapy is primarily aimed at restoring dopamine function in the brain. Levodopa is the most effective symptomatic treatment; however, long term use is associated with motor fluctuations (periods of return of PD symptoms when medication effect wears off) and dyskinesia (drug induced involuntary movements including chorea and dystonia). Once patients develop motor fluctuations treatment options include increasing the frequency of levodopa dosing, switching to sustained-release levodopa, adding other therapies including monoamine oxidase type B (MAO-B) inhibitors, dopamine agonists, catechol-o-methyltransferase (COMT) inhibitors and in patients with severe motor fluctuations deep brain stimulation surgery. There are no good evidence based studies indicating whether the use of one of these class of drugs is superior to the other nor are there treatment algorithms that recommend which class of drug should be initiated when the patients initially develop motor fluctuations. It is believed that the efficacy of the different drug classes is similar. However, the frequency of adverse effects may differ between drug classes, but such studies are lacking. In clinical practice when patients develop adverse effects to a drug from one class, a drug from another class is substituted in an attempt to maintain efficacy with reduced adverse effects.

Dopamine agonists often have a higher risk of adverse effects compared to MAO B inhibitors. Therefore, the rationale for this study is that the addition of orally disintegrating selegiline after the reduction or discontinuation of the offending dopamine agonist will result in comparable efficacy with reduced adverse events. This study will assess the safety and efficacy of the addition of orally disintegrating selegiline in PD patients who are having adverse effects to dopamine agonists for which a dose reduction of the dopamine agonist is being considered. All patients in the study will receive orally disintegrating selegiline 1.25 mg once a day and the dose will be increased to 2.5 mg once a day if tolerated.

Comparisons: The status of the adverse event at the end of the study while on orally disintegrating selegiline will be compared to the adverse event at the start of the study. In addition, efficacy will be compared at the start of the study while on the dopamine agonist to the end of the study with orally disintegrating selegiline.

• Study Type: Interventional
• Enrollment (Actual): 77
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Irvine, California, United States, 92697
      • University of California - Irvine
    • La Jolla, California, United States, 92037
      • Coastal Neurological Medical Group, Inc
    • Los Angeles, California, United States, 90093
      • University of Southern California
    • Sunnyvale, California, United States, 94085
      • The Parkinson's Institute
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Parkinson's Disease And Movement Disorder Center Of Boca Raton
    • Tampa, Florida, United States, 33606
      • University of South Florida
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Methodist Plaza Speciality Clinic
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Harvard Vanguard Medical Associates
  • Michigan
    • Southfield, Michigan, United States, 48034
      • Henry Ford Health Center - Franklin Pointe
  • Minnesota
    • Golden Valley, Minnesota, United States, 55427
      • Struthers Parkinson's Center
  • Ohio
    • Toledo, Ohio, United States, 43614
      • University of Toledo
  • Rhode Island
    • Warwick, Rhode Island, United States, 02886
      • NeuroHealth Parkinson Disease and Movement Disorder Center
  • Texas
    • Dallas, Texas, United States, 75231
      • Neurology Specialists Dallas
    • Tyler, Texas, United States, 75701
      • ETMC Neurological Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 26 years to 86 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Idiopathic Parkinson's disease (PD) confirmed by at least two of the following signs: resting tremor, bradykinesia,rigidity
• Male or female outpatients
• Age 30-90 years
• Current use of levodopa (stable for at least 1 month) and a dopamine agonist (pramipexole or ropinirole)
• Treatment response to current anti-parkinsonian medications in the opinion of the investigator
• Dopamine agonist adverse effect that in the opinion of the investigator requires a reduction or discontinuation of the dopamine agonist. The adverse effects must be in one of the following four categories and should not be so severe as to require immediate discontinuation of the dopamine agonist (i.e., hallucinations without insight, serious impulsive behavior resulting in significant loss or danger to the patient).

Daytime sleepiness - must score >10 on Epworth Sleepiness Scale (ESS) at Baseline; Pedal edema - bothersome/concerning to patient; Hallucinations - insight should be maintained; Impulsive behavior - not including behaviors that are harmful to the patient requiring immediate discontinuation of the agonist.

• Daily off time
• Acceptable contraception for females of child bearing potential
• Willing and able to comply with study procedures.
• Willing and able to give written informed consent prior to beginning any study procedures.

Exclusion Criteria:

• Atypical parkinsonism due to drugs, metabolic disorders, encephalitis, trauma, or other neurodegenerative diseases.
• Significant cognitive or psychiatric impairment which, in the opinion of the investigator, would interfere with the ability to complete all the tests required in the protocol.
• Participation in another clinical drug trial within the previous four weeks.
• Patients currently on monoamine oxidase type A or B (MAO-A or B) inhibitors, meperidine, tramadol, methadone, propoxyphene, dextromethorphan, and mirtazapine.
• History of hypersensitivity or adverse reaction to selegiline or previous exposure to orally disintegrating selegiline
• History of melanoma
• Unstable/uncontrolled medical problems
• History of drug/alcohol abuse

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: orally disintegrating selegiline; This is a one arm open label study of patients who are experiencing a dopamine agonist (DA) related adverse effects (AE) of either one or more of the following: excessive daytime sleepiness, hallucinations, pedal edema, impulse control disorder. All subjects received orally disintegrating selegiline.	Drug: orally disintegrating selegiline (Zelapar); 1.25 mg once daily orally disintegrating selegiline for 6 weeks with an increase to 2.5 mg once daily orally disintegrating selegiline for remaining 6 weeks if tolerated

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Reduction in Adverse Events	The primary outcome measure was the reduction of daytime sleepiness, hallucinations, pedal edema, and impulse control disorders after a reduction of dopamine agonist dose with the addition of an monoamine oxidase (MAO)-B inhibitor (orally disintegrating selegiline). Percentages of participants with reduction in individual adverse events as well as reduction in any adverse events are reported.	3 Months
Epworth Sleepiness Scale Score for Those With Daytime Sleepiness	This is a measure of daytime sleepiness. The test is a list of eight situations in which one rates their tendency to become sleepy on a scale of 0, no change of dozing to 3, high chance of dozing. The total score ranges fro 0-24, with higher values representing excessive sleepiness. A score of greater than 10 represents clinically significant sleepiness.	Baseline and 3 months
Neuropsychiatric Inventory (NPI) Hallucinations Scale Score for Those With Hallucinations	Report of hallucinations with insight maintained based on the hallucinations questions of the Neuropsychiatric Inventory (NPI). The participant and their caregiver are asked a series of questions to determine if hallucinations are present. If present they rate the frequency of hallucinations on a scale of 1 (rarely, less than once a week) to 4, very often (once or more daily). They also rate the severity of the hallucinations, as mild (1 - present but harmless and cause little distress), moderate (2 - distressing and disruptive) or severe (3 - very disruptive, major source of behavioral disturbance, may need meds). The frequency and severity scores are multiplied (maximum score 12, with higher scores representing more distress/disability) for the total score.	Baseline and 3 months
Circumference of Lower Leg/Foot at Greatest Point of Swelling for Pedal Edema	The circumference of the lower leg/ankle with the greatest swelling was measured using a standard tape measure at baseline and 12 weeks for both the right and left ankles.	Baseline and 3 months
Barratt Impulsiveness Scale Score for Those With Impulsive Behavior	This is a measure of impulsiveness. There are 30 questions regarding the presence of impulsive and non-impulsive behaviors each scored from 1 (rarely/never) to 4 (almost always/always). The total score reflects the sum of the 30 items. A higher score represents more impulsiveness.	Baseline and 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Unified Parkinson's Disease Rating Scale (UPDRS) Scores	The UPDRS activities of daily living sub scale has 14 questions regarding the ability to perform daily activities like dressing, eating, etc. These questions are completed by the patient and each question has 5 responses ranging from 0 (no problems) to 4 (severe disability/cannot do). The total score for this sub scale is the sum of the scores for the 14 questions (higher scores represent greater disability), maximum score is 56. The motor assessment is completed by the investigator. There are 14 questions evaluating motor function in various body parts, representing 27 individual items (i.e., some questions, such as rigidity, are rated for 5 different body parts, other questions, such as finger tapping, are rated on both the right and left sides, and other questions are rated individually). Each item has 5 responses, 0 being none/no disability and 4 being the most severe disability. The 27 items are summed (higher scores represent greater disability); maximum score is 108.	Baseline and 3 months
PDQ-39 Quality of Life Assessment Total Scores	The PDQ-39 is a measure of quality of life, it has 8 sub scales and a total score. For this study only the total score was examined. There are a total of 39 questions related to the following 8 sub scales: ability/difficulty to perform motor activities, ability to perform daily activities, cognition, emotional well being, stigma, social support, communication, bodily discomfort; each question with 5 responses (0, no/never, 4 always). The total score is calculated by adding the scores for each of the 39 items, dividing by 39 x 4 (maximum score for all 39 items) and then multiplying by 100 to get a percentage score ranging from 0-100 with 100 representing the most disability and greatest impact on quality of life.	Baseline and 3 months
Beck Depression Inventory for All Subjects	The Beck Depression Inventory is a general measure of depression. There are 21 questions each with responses ranging from 0 (no issue or problem) to 3 (maximum issue/distress), all questions are related to emotions, mood, feelings, etc. The total possible score is 63 (higher scores represent more depression). The total score is calculated by adding the scores of the 21 items.	Baseline and 3 months
Beck Anxiety Inventory Scores for All Subjects	The Beck Anxiety Inventory is a general measure of anxiety. There are 21 questions each with responses ranging from 0 (no issue or problem) to 3 (severe - I could barely stand it), all questions are related to the presence of signs or symptoms of anxiety. The total possible score is 63 and a higher score represents greater anxiety. The total score is calculated by adding the responses for each of the 21 items.	Baseline and 3 months
Mini Mental State Examination (MMSE) Scores for All Subjects	The MMSE is a general measure of cognition (i.e., measures attention, memory, visuospatial construction, etc). It has 30 items, each item representing 1 point. The total score ranges from 0-30 with 30 being a perfect score (no cognitive impairment) and 0 being the lowest score (greatest possible level of impairment). The total score is calculated by adding the scores of each item.	Baseline and 3 months

Collaborators and Investigators

• Sponsor: Parkinson's Disease and Movement Disorder Center of Boca Raton
• Collaborators: Bausch Health Americas, Inc.
• Investigators: Principal Investigator: Rajesh Pahwa, MD, University of Kansas Medical Center

Publications and helpful links

General Publications

• Lyons KE, Friedman JH, Hermanowicz N, Isaacson SH, Hauser RA, Hersh BP, Silver DE, Tetrud JW, Elmer LW, Parashos SA, Struck LK, Lew MF, Pahwa R. Orally disintegrating selegiline in Parkinson patients with dopamine agonist-related adverse effects. Clin Neuropharmacol. 2010 Jan-Feb;33(1):5-10. doi: 10.1097/WNF.0b013e3181b7926f.

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: March 3, 2007
• First Submitted That Met QC Criteria: March 3, 2007
• First Posted (Estimate): March 6, 2007

Study Record Updates

• Last Update Posted (Estimate): October 31, 2014
• Last Update Submitted That Met QC Criteria: October 30, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: Parkinson's disease; MAO-B inhibitor; Dopamine agonist adverse effects; orally disintegrating selegiline; Zelapar
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Neuroprotective Agents; Protective Agents; Psychotropic Drugs; Antidepressive Agents; Monoamine Oxidase Inhibitors; Antiparkinson Agents; Anti-Dyskinesia Agents; Selegiline
• Other Study ID Numbers: VAL-1.0-IV