A 12-week Randomized Study to Evaluate Oral Istradefylline in Subjects With Moderate to Severe Parkinson's Disease

Study Overview
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Brief Summary
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This is a study to assess the efficacy and safety of oral Istradefylline (KW-6002) in patients with moderate to severe Parkinson's Disease. While on this study, participants will continue to take their usual, prescribed, stable regimen of Levodopa/Carbidopa or Levodopa/Benserazide therapy plus adjunct Parkinson's medications. Patients will be randomized 1:1:1 to receive either Istradefylline 20 mg per day, or Istradefylline 40 mg per day or an equivalent placebo. Patients will be treated for a 12 week period to demonstrate the effectiveness of Istradefylline in improving Parkinson's disease symptoms (referred to as improvement in patient OFF time) and that Istradefylline has an acceptable safety profile in this group.

Official Title
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A Phase 3, 12-week, Double-Blind, Placebo-Controlled, Randomized, Multicenter Study to Evaluate the Efficacy of Oral Istradefylline 20 and 40 mg/Day as Treatment for Subjects With Moderate to Severe Parkinson's Disease

Conditions
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Idiopathic Parkinson's Disease

Intervention / Treatment
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* Drug: Istradefylline 40 mg
* Drug: Istradefylline 20 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 30 years of age or older. UK Parkinson's Disease Society (UKPDS) brain bank criteria (Step 1 and 2) for PD PD Stages 2-4 in the ON state for Modified Hoehn and Yahr Scale. On levodopa therapy for at least 1 year with beneficial clinical response at the baseline visit Taking at least 400mg levodopa combination daily and on stable regimen of any other anti-Parkinsonian drugs (MAO-B, COMT, DA) for at least 2 weeks prior to randomization Stable dopaminergic regimen for at least 4 weeks immediately prior to randomization Documented end-of-dose wearing-off and levodopa-induced dyskinesia Have an average of two hours of OFF time per day Exclusion Criteria: Subjects on apomorphine and/or dopamine receptor antagonists or direct gastrointestinal levodopa infusion. Subject who have had neurosurgical operation for PD Subjects taking A2a antagonist, potent CYP3A4 inhibitors, potent CYP34A inducers Subjects who smoke > 5 cigarettes/day

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Istradefylline 20 mg/day<br>Istradefylline 20 mg and placebo to match istradefylline 40 mg: A daily, oral, double-blind treatment dose of both tablets will be taken in the morning for 12 weeks. | Drug: Istradefylline 20 mg<br>* Istradefylline 20 mg and placebo<br>* Other names: KW-6002;Drug: Placebo<br>* Placebo<br>|
| Experimental: Istradefylline 40 mg/day<br>Istradefylline 40 mg and placebo to match istradefylline 20 mg: A daily, oral, double-blind treatment dose of both tablets will be taken in the morning for 12 weeks. | Drug: Istradefylline 40 mg<br>* Istradefylline 40 mg and placebo<br>* Other names: KW-6002;Drug: Placebo<br>* Placebo<br>|
| Placebo Comparator: Placebo<br>Placebo to match istradefylline 20 mg and placebo to match istradefylline 40 mg: A daily, oral, double-blind treatment dose of both tablets will be taken in the morning for 12 weeks. | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Total Hours of Awake Time/Day Spent in the OFF State at Week 12 | Based on the 24-hour ON/OFF patient diary data. | Baseline, Week 2, Week 6, Week 10 and Week 12. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Hours of ON Time Per Day Without Troublesome Dyskinesia | Based on Patient's ON/OFF Diary | Baseline, Week 2, Week 6, Week 10 and Week 12. | 
| Unified Parkinson's Disease Rating Scale (UPDRS) Motor Examination Score (Part III); | The Unified Parkinson's Disease Rating Scale (UPDRS) evaluates various aspects of Parkinson's disease including non-motor and motor experiences of daily living and motor complications. Part III assesses the motor signs of Parkinson's Disease with a rating from 0 to 4, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The possible score range of Part III is 0 to 68. The lower the score, the more favorable the response. | Baseline, Week 2, Week 6, Week 10 and Week 12. | 
| Unified Parkinson's Disease Rating Scale (UPDRS) Activities of Daily Living (ADL) Score (Part II) | The Unified Parkinson's Disease Rating Scale (UPDRS) evaluates various aspects of Parkinson's disease including non-motor and motor experiences of daily living and motor complications. Part II is a self-evaluation of the activities of daily life (ADL) including speech, swallowing, handwriting, dressing, hygiene, falling, salivating, turning in bed, walking, and cutting food with a rating from 0 to 4, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The possible score range of Part II is 0 to 52. The lower the score, the more favorable the response. | Baseline, Week 2, Week 6, Week 10 and Week 12. | 
| Unified Parkinson's Disease Rating Scale (UPDRS Mentation, Behaviour) and Mood (Part I) | The Unified Parkinson's Disease Rating Scale (UPDRS) evaluates various aspects of Parkinson's disease including non-motor and motor experiences of daily living and motor complications. Part I is the evaluation of mentation, behavior, and mood with a rating from 0 to 4, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The possible score range of Part I is 0 to 16. The lower the score, the more favorable the response. | Baseline, Week 2, Week 6, Week 10 and Week 12. | 
| Total UPDRS (Parts I + II + III); | The Unified Parkinson's Disease Rating Scale (UPDRS) evaluates various aspects of Parkinson's disease including non-motor and motor experiences of daily living and motor complications with a rating from 0 to 4, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The total possible score range for all parts combined is 0 to 136. The lower the score, the more favorable the response. | Baseline, Week 2, Week 6, Week 10 and Week 12. | 
| Patient Global Impression - Improvement (PGI-I) Scale | The key symptom on the PGI-I was evaluated at baseline and subsequent post-baseline visits for the subject's overall condition and the symptoms of fatigue, sleep, motivation to get things done, and each subject's key symptom. Subjects rated each on a scale of 1 to 5 for change from baseline utilizing the following scale: 1 = Moderate improvement (or greater) 2 = Mild improvement 3 = No change from baseline 4 = Mild deterioration 5 = Moderate deterioration (or greater) A lower number is a better outcome. Overall condition is presented below. | Baseline, Week 2, Week 6, Week 10, Week 12 and 30-day FU visit | 
| Sleep Time in Hours Per Day Based Upon 24-hour Diaries. |  | Baseline, Week 2, Week 6, Week 10 and Week 12. | 
| Percentage of Awake Time Per Day Spent in the OFF State |  | Baseline, Week 2, Week 6, Week 10 and Week 12. | 
| Percentage of ON Time Per Day Without Troublesome Dyskinesia. |  | Baseline, Week 2, Week 6, Week 10 and Week 12. | 
| Montreal Cognitive Assessment (MoCA) | The Montreal Cognitive Assessment (MoCA) assesses different cognitive domains, broken down as follows: Visuospatial and executive functioning: 5 points Animal Naming: 3 points Attention: 6 points Language: 3 points Abstraction: 2 points Delayed recall (short-term memory): 5 points Orientation: 6 points Scores can range from 0 to 30. A score of 26 or above is considered normal. | Baseline and Week 12. | 
| Beck Depression Inventory (BDI) | The Beck Depression Inventory is a 21-question test that measures the severity of depression. Subjects rated each on a scale of 0 to 3 for change from baseline utilizing the following scale: 0 = I do not feel sad 1 = I feel sad 2 = I am sad all the time and I can't snap out of it 3 = I am so sad or unhappy that I can't stand it The test is scored for each question using the above scale to determine the severity of depression. Scoring is as shown below: 0 to 9: minimal depression 10 to 18: mild depression 19 to 29: moderate depression 30 to 63: severe depression | Baseline and Week 12. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's disease, Moderate to Severe Parkinson's Disease