Safety and Efficacy of AVP-923 in the Treatment of Levodopa-induced Dyskinesia in Parkinson's Disease Patients

Study Overview
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Brief Summary
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To evaluate the efficacy, safety, and tolerability of AVP-923 capsules containing 45 mg dextromethorphan and 10 mg quinidine (AVP-923-45) compared to placebo for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD).

Detailed Description
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Proof-of-concept phase 2a, double-blind, randomized, placebo-controlled, crossover study.

Official Title
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A Phase 2a, Double-blind, Randomized, Placebo-controlled, Crossover Study to Evaluate the Safety and Efficacy of AVP-923 (Dextromethorphan/Quinidine) in the Treatment of Levodopa-induced Dyskinesia in Parkinson's Disease Patients.

Conditions
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Dyskinesia, Parkinson's Disease

Intervention / Treatment
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* Drug: AVP-923-45
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females 30 to 80 years of age, inclusive. Diagnosis of idiopathic PD meeting the United Kingdom Parkinson's disease Society Brain Bank criteria. Levodopa-induced dyskinesia present greater than 25% of the day as per MDS-UPDRS. Dyskinesia of at least moderate severity as per MDS-UPDRS Amantadine and Monoamine Oxidase (MAO) inhibitors must be discontinued at least three weeks prior to randomization. Subjects currently receiving anti-parkinsonian medications, including all Levodopa preparations are eligible provided they have been on a stable dose of these medications for at least 1 month prior to randomization. Concomitant use of antidepressants such as selective serotonin reuptake inhibitors are allowed, provided the dose has been stable for at least 1 month prior to randomization. Exclusion Criteria: Subject had a prior surgery for PD except Deep Brain Stimulation (Deep Brain Stimulation must not have been performed within one year of screening) Hoehn and Yahr score of 5 when off. Subject with Cognitive impairment and/or history of psychiatric manifestations or active hallucinations. Subjects with any history of complete heart block, QTc prolongation, or torsades de pointes. Subjects with any family history of congenital QT interval prolongation syndrome. Subjects with history of postural syncope, or any history of unexplained syncope within the last 12 months. Subjects with a history of substance and/or alcohol abuse within the past 2 years.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AVP-923-45<br>AVP-923-45 twice daily for 14 days | Drug: AVP-923-45<br>* One capsule twice daily for 14 days<br>* Other names: dextromethorphan/quinidine;|
| Placebo Comparator: Placebo<br>Placebo twice a day for 14 days | Drug: Placebo<br>* One capsule twice daily for 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Squares Mean Dyskinesia Severity Area Under the Curve (AUC) Score As Assessed By Modified Movement Disorder Society-Unified Dyskinesia Rating Scale (MDS-UDysRS) Part 3 | The MDS-UDysRS was developed to evaluate involuntary movements often associated with treated Parkinson's disease (PD). Levodopa-Induced Dyskinesia severity was assessed via video analysis by unbiased blinded central raters, and was calculated using the Intensity Scale from Part 3 of the MDS-UDysRS. The Intensity Scale was made up of seven body parts: face, neck, right arm/shoulder, left arm/shoulder, trunk, right leg/hip, and left leg/hip. Each body part was scored on a variety of disability items (communication, drinking, and ambulation [walking]) on a scale of 0 (normal) to 4 (incapacitating dyskinesia) with a maximum total score of 28. For each body part, the highest disability score was summed to calculate the intensity score. A score of '0' was assigned to questions associated with the dressing task which were not performed due to the placement of the treatment infusion (IV) line. A higher score indicated more severe symptoms. | Over the 2-hour levodopa infusion period on the last day of each treatment period (Day 14 and Day 42) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Squares Mean Disability Area Under the Curve (AUC) Score As Assessed By Modified Movement Disorder Society-Unified Dyskinesia Rating Scale (MDS-UDysRS) Part 4 | The MDS-UDysRS was developed to evaluate involuntary movements often associated with treated PD. Part 4 of the MDS-UDysRS objectively measures the disability associated with levodopa-induced dyskinesia. Disability was assessed via video analysis by unbiased blinded central raters. Disability was evaluated for communication, drinking from a cup, and ambulation items. Each item was rated from 0 (no dyskinesia) to 4 (most severe disability), with a sum range of 0 to 12. A score of '0' was assigned to questions associated with the dressing task because it was not performed due to placement of the IV line. A higher score indicated more severe symptoms. | Over the 2-hour levodopa infusion period on the last day of each treatment period (Day 14 and Day 42) | 
| Least Squares Mean Motor Movement Area Under the Curve Score As Assessed by Modified Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part III | The Modified MDS-UPDRS (4 parts) was used to assess the severity of parkinsonian disability. Part III of the MDS-UPDRS was used as an objective measure of the severity of parkinsonian disability per motor examination with focus on the treated side tremor and motor fluctuations. The motor examination were videotaped using a standardized protocol for review by an expert central rater blinded to the treatment schedule. A total of 11 items were scored as follows: 0 (normal), 1 (slight), 2 (mild), 3 (moderate), 4 (severe), with a maximum total score of 44. For each part, a higher score indicated more severe symptoms. Due to placement of the IV line, a score of '0' was assigned to rigidity questions. | Over the 2-hour levodopa infusion period on the last day of each treatment period (Day 14 and Day 42) | 
| Least Squares Mean Timed Finger Tapping Area Under the Curve (AUC) Score | Timed finger tapping test was used to quantify the upper extremity impairment in participants with idiopathic PD. Timed finger tapping was assessed using the Objective Parkinson's Disease Measurement (OPDM) System. Participants were instructed to tap for 60 seconds while speed and accuracy were assessed across 4 tests; right and left two finger test (m,n keystrokes) and one finger test (p,q keystrokes). The mean peak finger tapping score was calculated using the individual peak values. A higher score signifies improvement (faster typing, more accuracy), while a lower score signifies increased symptom severity. | Over the 2-hour levodopa infusion period on the last day of each treatment period (Day 14 and Day 42) | 
| Change From Baseline in MDS-UPDRS Scores for Part I, II, and IV | The MDS-UPDRS was used to assess the status of PD. Parts I and II (completed by the participant) and Part IV (completed by a rater) of the MDS-UPDRS provided a subjective measure of parkinsonian disability. Part I measured non-motor experiences of daily living, Part II measured motor experiences of daily living, and Part IV measures motor complications associated with PD. Each part was comprised of a series of questions, and each question was scored from 0 (normal) to 4 (severe). Part I and Part II were each comprised of 13 items; the total score ranges from 0 (normal) to 52 (severe). Part III was comprised of 33 items; the total score ranges from 0 (normal) to 132 (severe). Part IV was comprised of 6 items; the total score ranged from 0 (normal) to 24 (severe). For each part, a higher score indicated more severe symptoms. Post-Baseline was Visit 2 (Day 14) or Visit 4 (Day 42). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline (Day 1); Post-Baseline (Day 14 or 42) | 
| Change From Baseline in MDS-UDysRS Scores for Part 1 and 2 | The MDS-UDysRS was developed to evaluate involuntary movements often associated with treated PD. Part 1 (On-Dyskinesia ['jerking or twisting movements that occur when your medicine is working']) and Part 2 (Off-Dyskinesia [spasms or cramps that can be painful and occur when your PD medications are not taken or are not working]) of the MDS-UDysRS were assessed by a blinded rater. Parts 1B and 2B (participant questionnaires) were completed at home by the participant. Part 1 comprised of 11 items, and Part 2 comprised of 4 items. All items were assigned a score of: 0, normal; 1, slight; 2, mild; 3, moderate; 4, severe. The total score for Parts 1 and 2 ranged from 0 to 44 and from 0 to 16, respectively. Higher scores indicate increased symptom severity. Post-Baseline was Visit 2 (Day 14) or Visit 4 (Day 42). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline (Day 1); Post-Baseline (Day 14 or 42) | 
| Change From Baseline in PD Motor Diary Ratings Of Duration Of On-time Without Bothersome Dyskinesia | The PD motor diary is a home diary used to assess functional status in participants with PD with motor fluctuations and dyskinesia. Participants were instructed to complete the PD motor diary at home for a minimum of 3 consecutive days within the 7 days prior to Visits 2 and 4 (Days 14 and 42). Baseline is Visit 1 (Day 1) or Visit 3 (Day 29); Post-Baseline is Visit 2 (Day 14) or Visit 4 (Day 42). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Post-Baseline (Days 14 and 42) | 
| Change From Baseline in Parkinson's Disease Questionnaire-39 (PDQ-39) Domain Scores at the End of Each Treatment Period | The PDQ-39 was a self-reported questionnaire consisting of 39 questions assessing Parkinson's disease-specific health quality of life covering 8 aspects of quality of life: mobility; activities of daily living; emotional wellbeing; stigma; social support; cognitive impairment (cognitions); communication; bodily discomfort. Each item was scored on 5-point scale: 0 = Never (better in outcome), 1 = Occasionally, 2 = Sometimes, 3 = Often, 4 = Always (worse in outcome). Total scores ranged between 0 to 156. Higher scores indicated poor quality of life. Baseline was Visit 1 (Day 1) or Visit 3 (Day 29); Post-Baseline was Visit 2 (Day 14) or Visit 4 (Day 42). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Post-Baseline (Day 14 or 42) | 
| Change From Baseline in PDQ-39 Single Index (PDQ-39-SI) Scores at the End of Each Treatment Period | The PDQ-39 was the most widely used PD-specific measure of health status. It consists of 39 questions, covering 8 aspects of quality of life: mobility; activities of daily living; emotional wellbeing; stigma; social support; cognitive impairment (cognitions); communication; bodily discomfort. The instrument was developed on the basis of interviews with people diagnosed with PD. The PDQ-39-SI) score was calculated as the weighted addition of scores on all 8 dimensions of the PDQ-39. The total score ranged from 0 (no disease impact) to 100 (severe disease impact). Baseline was Visit 1 (Day 1) or Visit 3 (Day 29); Post-Baseline was Visit 2 (Day 14) or Visit 4 (Day 42). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Post-Baseline (Day 14 or 42) | 
| Change From Screening in the Montreal Cognitive Assessment (MoCA) Calculated Score at the End of Each Treatment Period | The MoCA was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. The total score is calculated by summing the items from each domain. Total scores can range from 0 to 30; lower scores indicate cognitive dysfunction. A final total score of 26 and above is considered normal. Change from Screening was calculated as the post-Screening value minus the Screening value. | Screening (Day -28); End of each treatment period (Days 14 or 42) | 
| Change From Baseline in the Dyskinesia and Other PD Symptoms Score As Assessed by Patient Global Impression of Change (PGIC) | The PGIC was a 7-point scale used to assess treatment response as judged by the participant. The participant was asked to assess change in dyskinesia symptoms and change in overall PD symptoms (e.g., slowness, stiffness, balance) on a score range of 1, much improved; 2, improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, worse; 7, much worse. The average PGIC score was calculated at each visit by treatment group. Baseline is Visit 1 (Day 1) or Visit 3 (Day 29); Post-Baseline is Visit 2 (Day 14) or Visit 4 (Day 42). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Post-Baseline (Days 14 and 42) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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levodopa, dyskinesia, parkinson's disease, AVP-923, dextromethorphan, quinidine