| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderate to severe levodopa induced dyskinesias in patients with Parkinson's disease |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10013916 |
| E.1.2 | Term | Dyskinesia |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To demonstrate the anti-dyskinetic efficacy, as measured by change from baseline to endpoint at week 12 in the modified AIMS (Abnormal Involuntary Movement Scale) total score, of five fixed doses of AFQ056 versus placebo in patients with moderate to severe PD-LID
To estimate the dose-response relationship among five fixed doses of AFQ056 and placebo after 12 weeks of treatment, as measured by the changes from baseline in modified AIMS total score.
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| E.2.2 | Secondary objectives of the trial |
| To evaluate any effect of AFQ056 on psychiatric and compulsive behaviors, as measured by the SCOPA-PC (SCales for Outcomes in PArkinson’s disease – Psychiatric Complications) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 30-80 years of age (inclusive)
2.males and females
Females must be surgically sterile or one year postmenopausal or, if of childbearing potential they must be using two birth control methods
“Childbearing potential” is defined as all women physiologically capable of becoming pregnant including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means. The two methods of birth control can be a double barrier method or a barrier method plus a hormonal method. Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent.
Male patients must be using double-barrier local contraception for the entire duration of the study, and must refrain from fathering a child in the three months following the last study drug treatment.
3.outpatients, residing in the community (nursing home patients are not allowed)
4.have a clinical diagnosis of Parkinson’s disease according to the UK Parkinson's Disease Society Brain Bank Clinical Diagnosis criteria
5.score of ≥ 2 on UPDRS item 32 (i.e. dyskinesia present for greater than 25% of the time) and score of ≥ 2 on UPDRS item 33 (i.e. moderate to severely disabling)
6.onset of dyskinesias at least 3 months before randomization
7.have been on L-dopa for at least 3 years prior to randomization or, if duration of treatment is ≤ 3 years, then must have shown clear responsiveness (UPDRS, part III) to L-dopa treatment
8.be on a stable treatment regimen with L-dopa and other anti-parkinsonian treatment for at least 4 weeks prior to the first baseline visit (BL1) with optimized dosing as determined by the enrolling clinician. In addition to this stable treatment, up to three doses per week of soluble L-dopa or subcutaneous apomorphine are allowed to optimize the treatment regimen to alleviate fluctuations (OFF-periods).
9.demonstrate capacity to complete, in an office-based training session and during the baseline period prior to randomization, accurate diary ratings of ON/OFF and dyskinesia, with at least 66% concordance between patient and investigator/coordinator on a day in which the patient experienced ON without dyskinesia, ON with dyskinesia, and OFF time
10.be cooperative and willing to complete all aspects of the study and capable of doing so, according to the judgment of the investigator
11.must provide written informed consent before any study-related procedure is performed.
12.have a caregiver/family informant, unless the investigator considers support not to be necessary
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| E.4 | Principal exclusion criteria |
1.clinical evidence suggestive of an atypical or secondary form of Parkinson’s disease (e.g. Progressive Supranuclear Palsy, Multi Systemic Atrophy)
2.a history of surgical treatment for PD, including deep brain stimulation
3.a score of 5 in the “ON”-state on the Modified Hoehn and Yahr Staging (UPDRS Part V) assessment at screening
4.unable (in the opinion of the Principal Investigator) to maintain current stable dosing of their anti-parkinsonian medications during trial
5.any advanced, severe or unstable disease (other than PD) that may interfere with the primary and secondary study outcome evaluations
6.history of malignancy of any organ system (other than localized basal cell carcinoma of the skin or non-invasive, non-metastatic prostate cancer that has been effectively treated), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
7.evidence of dementia (or MMSE ≤ 26 at Screening); untreated or ineffectively treated major depressive disorder; currently experiencing hallucinations/psychosis requiring antipsychotic treatment, and/or confusional states (DSM-IVR, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, revised)
8.treatment with any of the following
•previous treatment with AFQ056
•treatment with concomitant medications that are strong or moderate inhibitors of CYP3A4 (see Appendix 2) within 1 week prior to BL2 visit
•treatment with concomitant medications that are strong or moderate inducers of CYP3A4 (see Appendix 2) within 1 week prior to BL2 visit
•warfarin and digixine within 1 week priorto BL2 visit
•centrally acting anti-cholinergic medication within 1 week prior to BL1 visit
•amantadine within 3 weeks prior to BL1 visit
•metoclopramide within 4 weeks prior to BL1 visit
•unstable treatment with domperidone, antidepressants, and anxiolytics in the 6 weeks prior to BL1 visit. Patients with stable treatment (≥ 6 weeks) with domperidone (not exceeding 30 mg/day), antidepressants, and anxiolytics are allowed in the study
•typical or atypical neuroleptic agents within 3 months prior to BL1 visit
•other investigational drugs within 30 days or 5 half-lives of the BL1 visit, whichever is longer
9.lab screening values that include AST, ALT, total bilirubin or creatinine ≥ 1.5 X ULN (upper limit of normal) for the central laboratory
10.long QT syndrome or QTc > 450 msec for males and > 470 msec for females at screening or baseline.
11.pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL)
12.participated in an antidyskinetic study in the 4 weeks prior to BL 1 visit
13.any patient unable or unwilling to participate in all study-related activities
No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The AIMS is a widely used, reliable scale for assessing dyskinesia (Guy 1976). It was originally developed as a 12-item scale to assess patients with tardive dyskinesia and thus has an emphasis on orofacial dyskinesias. The modified version of the scale used in this study focuses on six different parts of the body (face/neck, trunk, and four limbs) and rates the abnormal movements from 0 (none) to 4 (severe with markedly impaired function) in (maximal score, 24).
Where possible, the modified AIMS should be done by the same clinician for individual patients.
Assessed at screening, baseline, weeks 1,2,3,6,9,12 and 13 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| assess validity and reliability of dyskinesia scales |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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