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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01767129
Recruitment Status : Completed
First Posted : January 14, 2013
Results First Posted : April 29, 2022
Last Update Posted : April 29, 2022
Sponsor:
Collaborator:
Michael J. Fox Foundation for Parkinson's Research
Information provided by (Responsible Party):
Avanir Pharmaceuticals

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Dyskinesia Parkinson's Disease Drug: AVP-923-45 Drug: Placebo Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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.
Actual Study Start Date : October 16, 2013
Actual Primary Completion Date : February 5, 2015
Actual Study Completion Date : February 5, 2015


Arm Intervention/treatment
Experimental: AVP-923-45
AVP-923-45 twice daily for 14 days
Drug: AVP-923-45
One capsule twice daily for 14 days
Other Name: dextromethorphan/quinidine

Placebo Comparator: Placebo
Placebo twice a day for 14 days
Drug: Placebo
One capsule twice daily for 14 days




Primary Outcome Measures :
  1. 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 [ Time Frame: Over the 2-hour levodopa infusion period on the last day of each treatment period (Day 14 and Day 42) ]
    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.


Secondary Outcome Measures :
  1. 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 [ Time Frame: Over the 2-hour levodopa infusion period on the last day of each treatment period (Day 14 and Day 42) ]
    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.

  2. 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 [ Time Frame: Over the 2-hour levodopa infusion period on the last day of each treatment period (Day 14 and Day 42) ]
    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.

  3. Least Squares Mean Timed Finger Tapping Area Under the Curve (AUC) Score [ Time Frame: Over the 2-hour levodopa infusion period on the last day of each treatment period (Day 14 and Day 42) ]
    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.

  4. Change From Baseline in MDS-UPDRS Scores for Part I, II, and IV [ Time Frame: Baseline (Day 1); Post-Baseline (Day 14 or 42) ]
    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.

  5. Change From Baseline in MDS-UDysRS Scores for Part 1 and 2 [ Time Frame: Baseline (Day 1); Post-Baseline (Day 14 or 42) ]
    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.

  6. Change From Baseline in PD Motor Diary Ratings Of Duration Of "On-time Without Bothersome Dyskinesia" [ Time Frame: Baseline; Post-Baseline (Days 14 and 42) ]
    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.

  7. Change From Baseline in Parkinson's Disease Questionnaire-39 (PDQ-39) Domain Scores at the End of Each Treatment Period [ Time Frame: Baseline; Post-Baseline (Day 14 or 42) ]
    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.

  8. Change From Baseline in PDQ-39 Single Index (PDQ-39-SI) Scores at the End of Each Treatment Period [ Time Frame: Baseline; Post-Baseline (Day 14 or 42) ]
    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.

  9. Change From Screening in the Montreal Cognitive Assessment (MoCA) Calculated Score at the End of Each Treatment Period [ Time Frame: Screening (Day -28); End of each treatment period (Days 14 or 42) ]
    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.

  10. Change From Baseline in the Dyskinesia and Other PD Symptoms Score As Assessed by Patient Global Impression of Change (PGIC) [ Time Frame: Baseline; Post-Baseline (Days 14 and 42) ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01767129


Locations
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United States, Illinois
Chicago, Illinois, United States, 60612
United States, Oregon
Portland, Oregon, United States, 97239
Canada, Ontario
Toronto, Ontario, Canada, M5T 2S8
Sponsors and Collaborators
Avanir Pharmaceuticals
Michael J. Fox Foundation for Parkinson's Research
Additional Information:
Publications of Results:
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Responsible Party: Avanir Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01767129    
Other Study ID Numbers: 12-AVR-133
First Posted: January 14, 2013    Key Record Dates
Results First Posted: April 29, 2022
Last Update Posted: April 29, 2022
Last Verified: April 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Avanir Pharmaceuticals:
levodopa
dyskinesia
parkinson's disease
AVP-923
dextromethorphan
quinidine
Additional relevant MeSH terms:
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Parkinson Disease
Dyskinesias
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Synucleinopathies
Neurodegenerative Diseases
Neurologic Manifestations
Quinidine
Dextromethorphan
Antitussive Agents
Respiratory System Agents
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Anti-Arrhythmia Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Muscarinic Antagonists