Evaluation of the Efficacy and Safety of Modified Release AFQ056 in Parkinson's Patients With L-dopa Induced Dyskinesias

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01491529
First received: December 12, 2011
Last updated: January 17, 2014
Last verified: January 2014
  Purpose

This study will assess the efficacy and safety of modified release AFQ056 in patients that have Parkinson's Disease L-dopa Induced Dyskinesias (PD-LID)


Condition Intervention Phase
Dyskinesias
Parkinson Disease
Movement Disorders
Parkinsonian Disorders
Anti-Dyskinesia Agents
Drug: AFQ056
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 13-week, Double-blind, Placebo-controlled, Fixed-dose, Multicenter Study to Evaluate the Efficacy and Safety of Modified Release AFQ056 in Reducing Moderate to Severe L-dopa Induced Dyskinesias in Patients With Parkinson's Disease

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Change in modified AIMS (Abnormal Involuntary Movement Scale) total score from baseline to Week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

    The modified AIMS is a scale used to assess dyskinesia. It focuses on six different parts of the body and rates abnormal movements from 0 (absence of dyskinesia to 4 (severe) (maximal score, 24).

    Change from baseline to Week 12 will be analyzed using the mixed effect repeated measures model (MMRM) including treatment, pooled center, week, treatment by week interaction as fixed effects and baseline total score as covariate with an unstructured covariance structure.


  • The incidence rate of adverse events [ Time Frame: Monitored for the duration of the study which is 13 weeks ] [ Designated as safety issue: Yes ]

    The occurrence of adverse events would be sought by non-directive questioning of the patient. Adverse events may also be detected when they are volunteered by the patient or through physical examination, laboratory test, or other assessments.

    AEs will be summarized by presenting, for each treatment group the number and percentage of patients having any adverse event, having an adverse event in each system organ class and having each individual adverse event by system organ class and preferred term.


  • Time to onset of adverse events [ Time Frame: Monitored for the duration of the study which is 13 weeks ] [ Designated as safety issue: Yes ]

    The occurrence of adverse events (AEs) would be sought by non-directive questioning of the patient. Adverse events may also be detected when they are volunteered by the patient or through physical examination, laboratory test, or other assessments.

    AEs will be summarized by presenting, for each treatment group the number and percentage of patients having any adverse event, having an adverse event in each system organ class and having each individual adverse event by system organ class and preferred term.


  • The percentage of patients reaching and maintaining the target dose during the fixed dose treatment period [ Time Frame: Assessed during the fixed dose treatment period of 6 weeks ] [ Designated as safety issue: Yes ]

    Randomized patients will be up titrated to the target dose and remain on the target dose for the duration of the fixed dose treatment period.

    AEs will be summarized by presenting, for each treatment group the number and percentage of patients having any adverse event, having an adverse event in each system organ class and having each individual adverse event by system organ class and preferred term.


  • The percentage of patients discontinued during the up titration period due to AE [ Time Frame: Assessed during the up titration period of 6 weeks ] [ Designated as safety issue: Yes ]

    Patients randomized will be up titrated to the target doses at regular intervals during the up titration period.

    AEs will be summarized by presenting, for each treatment group the number and percentage of patients having any adverse event, having an adverse event in each system organ class and having each individual adverse event by system organ class and preferred term.



Secondary Outcome Measures:
  • The change in total score and sub-score of UDysRS Parts I, II, III, and IV from baseline to Week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

    The UDysRS captures dyskinesia and has 4 parts: I: Historical Disability of On-Dyskinesia impact (max 44 pts); II: Historical Disability of Off-Dystonia impact (max 16 pts); III: Objective Impairment dyskinesia (max 28 pts); IV: Objective Disability based on Part III activities (max 16 pts). Higher scores mean greater severity.

    Change from baseline to Week 12 will be analyzed using mixed-effect repeated measure model (MMRM) including treatment, pooled center, week, treatment by week interaction as fixed effects and baseline total score as covariate with an unstructured covariance structure.


  • Change in Lang-Fahn Activities of Daily Living Dyskinesia Scale (LFADLDS) total score from baseline to Week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

    The LFADLDS assesses the degree of dyskinesia interfering with activities of daily living. Specific definitions for severity rating codes (range, 0-4 for each task) will be provided for reproducibility of results. A higher score indicates more severe impairment. A patient and caregiver version of the revised LFADLDS will be used in this study.

    Change from baseline to Week 12 will be analyzed using MMRM including treatment, pooled center, week, treatment by week interaction as fixed effects and baseline total score as covariate with an unstructured covariance structure.


  • Change in clinician-rated global impression of change (CGIC) score from baseline to Week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

    The CGIC provides investigator-rated assessment of change from baseline to assess disability due to dyskinesia. Change from baseline will be rated on a 7-point, Likert-type scale where 1 = markedly improved, 2 = moderately improved, 3 = minimally improved, 4 = unchanged, 5 = minimally worse, 6 = moderately worse, and 7 = markedly worse.

    The CGIC score at week 12 last observation carried forward (LOCF) will be analyzed using analysis of covariance (ANCOVA) model with treatment group, pooled center, and baseline CGIS (Clinical Global Impression of Severity) score as factors.


  • Change from baseline Total ON- and OFF-times and ON-time with dyskinesia and with troublesome dyskinesias (patient diary) to Week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

    A patient home diary developed and validated for use in PD patients will be used to record whether the patient is asleep, OFF, ON without dyskinesia, ON with troublesome dyskinesias, and ON with non-troublesome dyskinesia.

    Change from baseline to Week 12 will be analyzed using MMRM including treatment, pooled center, week, treatment by week interaction as fixed effects and baseline total score as covariate with an unstructured covariance structure.


  • Change in score for items 32, 33 and 34 of Part IV of the Unified Parkinson's Disease Rating Scale (UPDRS ) from baseline to Week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

    UPDRS assesses the disease state of PD. Question 32 assesses length of dyskinesias in percentage of the day. Question 33 assesses disability during the previous week (not disabling, mildly disabling, moderately disabling, severely disabling, completely disabling). Question 34 assesses painfulness of dyskinesias from 0 (no painful dyskinesias) to 4 (marked).

    The change will be analyzed using MMRM including treatment, pooled center, week, treatment by week interaction as fixed effects and baseline total score as covariate with an unstructured covariance structure.


  • Changes in vital signs from baseline to each post-baseline visit [ Time Frame: Monitored at regular visits throughout duration of the study which is 13 weeks ] [ Designated as safety issue: Yes ]
    Pulse and blood pressures are taken at each visit. Vital sign data will be summarized by presenting summary statistics for change from baseline values. The incidence rates of clinically notable vital sign abnormalities will be summarized.

  • Changes in hematology/blood chemistry and urinalysis laboratory evaluations from baseline to each post-baseline visit where hematology/blood chemistry and urinalysis are collected [ Time Frame: Monitored at regular visits throughout duration of the study which is 13 weeks ] [ Designated as safety issue: Yes ]
    Standard hematology with differential; measures of coagulability: aPTT, PT/INR; standard clinical chemistry; FSH, LH, oxytocin, prolactin, TBG, TSH, and T4; urinalysis (specific gravity, protein, glucose and blood) Laboratory data will be summarized by presenting shift tables, by presenting summary statistics, change from baseline values, and incidence rates of clinically notable abnormalities summarized.

  • Changes in electrocardiogram (ECG) from baseline to each post-baseline visit where ECGs are performed [ Time Frame: Monitored at regular visits throughout duration of the study which is 13 weeks ] [ Designated as safety issue: Yes ]

    A standard 12-lead ECG will be performed. A central facility will be used for interpretation and analysis of the ECGs.

    ECG intervals will be summarized by summary statistics for change from baseline values and incidence rates of clinically notable abnormalities summarized.


  • Percentage of adverse events including treatment emergent adverse events and serious adverse events [ Time Frame: Monitored for the duration of the study which is 13 weeks ] [ Designated as safety issue: Yes ]

    The occurrence of adverse events would be sought by non-directive questioning of the patient. Adverse events may be detected when they are volunteered by the patient or through physical examination, laboratory test, or other assessments.

    Treatment-emergent adverse events (TEAEs) will be summarized by presenting, for each treatment group, the number and percentage of patients having an AE, having an AE in each system organ class and having each AE by system organ class and preferred term.


  • Change in Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) scores from baseline to Week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]

    Part III of the UPDRS (items 18-31; score 0-56), measures speech, facial expression, tremor, action or postural tremor, rigidity, finger taps, hand movement, alternating movement, leg agility, arising from a chair, posture, gait, postural stability, and bradykinesia. A higher score means worsening of symptoms.

    Changes from baseline to Week 12 will be analyzed using MMRM including treatment, pooled center, week, treatment by week interaction as fixed effects and baseline total score as covariate with an unstructured covariance structure.


  • Change in Mini Mental State Exam (MMSE) total scores from baseline to Week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]

    The MMSE is a test of cognitive dysfunction consisting of orientation, registration, attention-calculation, recall, and language administered by a health care professional. The MMSE results in total possible score of 30, with higher scores meaning better function.

    The change from baseline to endpoint at Week 12 in MMSE total score will be analyzed using LOCF ANCOVA with treatment group and pooled center as factors and the baseline score as a covariate. Treatment differences in the change from baseline for scores with 90% CI will be reported as descriptive statistics.


  • Change in cognitive test battery (CogState) scores form baseline to Week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]

    This test consists of: Detection Task, Identification Task, One Card Learning Task, One Back Task, and International Shopping List Task. Speed times and working memory will be measured by the number of correct responses.

    The change from baseline to endpoint at Week 12 for cognitive function will be analyzed using LOCF ANCOVA with treatment group and pooled center as factors and the baseline score as a covariate. Treatment differences in the change from baseline for cognitive function with 90% CI will be reported as descriptive statistics


  • Total scores of the Scales for Outcomes in Parkinson's disease - Psychiatric Complications (SCOPA-PC) [ Time Frame: Assessed for 12 weeks ] [ Designated as safety issue: Yes ]

    The SCOPA-PC is an easily administered semi-structured, questionnaire developed for the assessment of psychiatric symptoms in Parkinson's disease patients administered by a clinician with input provided by patient and caregiver. The total SCOPA score ranges from 0-21, with higher scores reflecting more psychiatric complications.

    The SCOPA-PC total score and each of the item scores will be summarized.


  • Proportion of patients who have suicidal ideation and behavior as mapped to Columbia Classification Algorithm for Suicide assessment (C-CASA) using data from Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: This will be assessed for the duration of the study which is 13 weeks ] [ Designated as safety issue: Yes ]

    The C-SSRS assesses suicidal ideation/behavior using a patient interview. The data is mapped to Columbia Classification Algorithm for Suicide assessment. The code and categories are: completed suicide, suicide attempt, preparatory actions toward imminent suicide behavior, suicidal ideation, self-injurious behavior without suicidal intent.

    The proportion of patients who are coded in the categories above, the proportion of patients with any suicidal behavior engaged in during the study, and the proportion of patients with suicidality will be summarized.


  • Plasma Pharmacokinetics of AFQ056 in patients with Parkinson's disease with moderate to severe dyskinesias [ Time Frame: At Week 12 or earlier if the patient discontinues the study before Week 12 ] [ Designated as safety issue: No ]

    Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. The first blood sample will be collected 1-3 hours after morning study medication dose. The second sample will be collected 3-5 hours after the morning study medication dose. The third blood sample will be collected 5-7 hours after the morning study medication dose.

    Summary statistics for concentrations per sampling window will be provided and average plasma levels will be calculated.


  • Pharmacokinetics of AFQ056 in patients with Parkinson's disease with moderate to severe dyskinesias [ Time Frame: Monitored at regular visits throughout duration of the study which is 13 weeks ] [ Designated as safety issue: No ]

    Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. An alternative sampling method will also be explored. At all visits, the sample will be collected 1-3 hours after morning study medication dose. At Week 12, the second sample will be collected 3-5 hours after the morning study medication dose and the third sample will be collected 5-7 hours after the morning study medication dose.

    Summary statistics for concentrations per sampling window will be provided and average plasma levels will be calculated.


  • Investigate the safety of concomitant administration of AFQ056 with amantadine [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
    Investigation of the safety of AFQ056 with concomitant amantadine is being studied to gather drug-drug interaction data of amantadine and AFQ056 in this patient population.


Enrollment: 154
Study Start Date: April 2012
Study Completion Date: April 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AFQ056 150 mg
Patients randomized to the AFQ056 150 mg arm will receive AFQ056 oral tablets to be titrated until reaching the target dose of 150 mg twice daily.
Drug: AFQ056

AFQ056 will be supplied as oral modified release tablets in 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg.

Patients will be randomized in two groups by amantadine status.

  • Group 1: Patients are not permitted to take amantadine within 2 weeks prior to the BL1 visit.
  • Group 2: Patients must be on a stable and well tolerated dose of amantadine for at least 4 weeks prior to BL1 and must maintain the stable dose of amantadine during the remainder of the study.)
Experimental: AFQ056 200 mg

Patients randomized to the AFQ056 200 mg arm will receive AFQ056 oral tablets to be titrated until reaching the target dose of 200 mg twice daily.

Patients will be randomized in two groups by amantadine status.

  • Group 1: Patients are not permitted to take amantadine within 2 weeks prior to the BL1 visit.
  • Group 2: Patients must be on a stable and well tolerated dose of amantadine for at least 4 weeks prior to BL1 and must maintain the stable dose of amantadine during the remainder of the study.)
Drug: AFQ056

AFQ056 will be supplied as oral modified release tablets in 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg.

Patients will be randomized in two groups by amantadine status.

  • Group 1: Patients are not permitted to take amantadine within 2 weeks prior to the BL1 visit.
  • Group 2: Patients must be on a stable and well tolerated dose of amantadine for at least 4 weeks prior to BL1 and must maintain the stable dose of amantadine during the remainder of the study.)
Placebo Comparator: Placebo
Patients randomized to the Placebo arm will receive oral AFQ056 Placebo twice daily
Drug: Placebo
Placebo for AFQ056 will be supplied as oral tablets.

  Eligibility

Ages Eligible for Study:   30 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males and Females 30-80 years old
  • Use of highly effective methods of contraception during study in women of childbearing potential
  • Outpatients
  • Clinical diagnosis of Parkinson's Disease according to UK Parkinson's Disease Society Brain Bank Clinical Diagnosis criteria
  • Score of >/= 2 on UPDRS items 32 and 33
  • Dyskinesias for at least 3 months before baseline
  • On stable treatment regimen with L-dopa and other anti-parkinsonian treatment for 4 weeks prior to baseline
  • Demonstrate capacity to complete accurate diary ratings
  • Patients who have a primary caregiver willing to assess the condition of the patient throughout the study in accordance with protocol requirements
  • Group 2 only: Patients must be on a stable and well tolerated dose of amantadine for at least 4 weeks prior to BL1 and must maintain the stable dose of amantadine during the remainder of the study

Exclusion Criteria:

  • Atypical/secondary form of Parkinson's disease
  • History of surgical treatment of PD, including deep brain stimulation
  • A score of 5 in the "ON"- state on the Modified Hoehn and Yahr scale
  • Advanced, severe, or unstable disease other than PD
  • Evidence of dementia
  • Treatment with certain prohibited medications
  • Amantadine within 2 weeks prior to BL1 visit (applies to Group 1 only)

Other protocol-defined inclusion/exclusion criteria may apply.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01491529

  Show 39 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01491529     History of Changes
Other Study ID Numbers: CAFQ056A2223, 2011-002074-23
Study First Received: December 12, 2011
Last Updated: January 17, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
Germany: Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Italy: Agenzia Italiana del Farmaco (AIFA)
Hungary: National Institute of Pharmacy
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Austria: Bundesamt für Sicherheit im Gesundheitswesen/AGES
Slovakia: State Institute for Drug Control
Switzerland: Swissmedic

Keywords provided by Novartis:
Parkinson Disease
L-dopa
Levodopa
Dyskinesia
Amantadine

Additional relevant MeSH terms:
Parkinsonian Disorders
Dyskinesias
Movement Disorders
Parkinson Disease
Central Nervous System Diseases
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Basal Ganglia Diseases
Brain Diseases
Neurodegenerative Diseases
Amantadine
Levodopa
Antiparkinson Agents
Anti-Dyskinesia Agents
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Antiviral Agents
Anti-Infective Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on August 26, 2014