| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe Parkinson's disease |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061536 |
| E.1.2 | Term | Parkinson's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029205 |
| E.1.2 | Term | Nervous system disorders |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 establish the efficacy of istradefylline 20 and 40 mg/d for reducing the total hours of OFF time per day in moderate to severe PD patients with motor fluctuations and dyskinesia on levodopa combinations levodopa/carbidopa or benserazide/levodopa) therapy |
|
| E.2.2 | Secondary objectives of the trial |
Change from screening/baseline (as appropriate) in:
-total hours of ON time per day without troublesome dyskinesia
-UPDRS Motor Examination Score (Part III), Activities of Daily Living (ADL) score (Part II), and Mentation, Behavior, and Mood (Part I)
-Total UPDRS (Parts I+II+III)
-Patient Global Impression-Improvement (PGI-I) scale
-Sleep time in hours per day based upon 24-hour diaries
-The percentage of awake time per day spent in the OFF state
-The percentage of ON time per day without troublesome dyskinesia
-Total hours of ON time and percentage of ON time per day (without dyskinesia, with dyskinesia, with non-troublesome dyskinesia, and with troublesome dyskinesia)
-Montreal Cognitive Assessment (MOCA)
-Beck Depression Inventory (BDI).
PK objectives include:
-Population PK parameters
-Exploration of the PK exposure-response relationship.
Safety objectives include: AEs, vital signs, laboratory parameters, physical examinations, ECGs, CSSRS, ESS and QUIP-RS. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each subject who meet all of the following inclusion criteris to qualify for entrance into the study:
1) Male or female >/= 30 years of age at enrollment;
2) Subjects diagnosed with idiopathic PD based on the UK Parkinson's Disease Society (UKPDS) Brain Bank Diagnostic Criteria;
3) Subjects with a minimum Modified Hoehn and Yahr Scale stage classification of 2, but no more than 4 when in the ON state;
4) Subjects who have been treated with levodopa therapy for at least 1 year and who continue to have a beneficial clinical response at Baseline visit;
5) Subjects who are currently taking levodopa combinations (carbidopa/levodopa or benserazide/levodopa) with a total daily levodopa dosage of at least 400 mg plus a recommended, clinically effective dose of at least one adjunctive medication approved to treat Parkinson's disease such as a dopamine agonist, MAO-B inhibitor, or COMT inhibitor taken at the recommended dosages listed in the country-approved label for at least 2 weeks prior to randomization. (Note that subjects treated with anticholinergic medications or amantadine alone are not considered adequately treated with adjunctive antiparkinsonian medications and cannot be enrolled);
6) Subjects treated with stable dopaminergic regimen for at least 4 weeks immediately prior to randomization;
7) Subjects who have documented end-of-dose wearing-off and levodopa -induced dyskinesia;
8) Subjects who have successfully completed diary training and a practice diary prior to Week-1 and be confirmed as having passed the training at Week-1;
9) Subjects and site staff who have completed diary concordance testing and have achieved concordance of 80% with respect to both ON and OFF periods at the Week-1 visit;
10) Subjects who have successfully completed 3 valid ON/OFF patient diaries on the 3 consecutive days immediately prior to the Baseline visit;
11) Subjects who are experiencing significant motor fluctuations while receiving levodopa plus adjuvant medication(s) as defined by an average of at least 2 hours OFF time on the three 24-hour ON/OFF patient diaries prior to the Baseline visit;
12) Women of child-bearing potential (WOCBP) must use a reliable method of contraception (e.g., oral contraceptive or long-term injectable or implantable hormonal contraceptive, double barrier methods [such as condom plus diaphragm, condom plus spermicide foam, condom plus sponge], or intra-uterine devices), and must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline
a)WOCBP includes any female who has experienced menarche and who has not undergone successful surgical sterilization or is not postmenopausal (defined as amenorrhea >/= 24 consecutive months or a serum follicle-stimulating hormone [FSH] > 30 IU/L in the absence of hormone replacement therapy [HRT];
13) Subjects who have given written informed consent. |
|
| E.4 | Principal exclusion criteria |
A subject who meets any of the following exclusion criteria will NOT qualify for the study:
1) Subjects currently treated with apomorphine and/or dopamine receptor antagonists or direct gastroinestinal levodopa infusion;
2) Subjects treated with anticholinergic medications or amantadine alone (not considered adequately treated with adjunctive antiparkinsonian medications);
3) Subjects who have been treated within 30 days before Baseline (or 5 half-lives of the compound, if longer) with any investigational agents;
4) Subjects who have a history of psychotic illness;
5) Subjects who are experiencing sleep attacks that would interfere with the integrity of the trial or pose a risk to the subjects in participating in the trial;
6) Subjects who have undergone a neurosurgical operation for PD (e.g., pallidotomy, thalamotomy, or deep brain stimulation);
7) Subjects who have been previously treated with istradefylline;
8) Subjects who are currently receiving another A2a antagonist;
9) Subjects who are taking potent CYP34A inhibitors (systematic antifungals such as ketoconazole);
10) Subjects who are taking potent CYP34A inducers (such as St John's Wort and rifampin);
11) Subjects who have atypical parkinsonism;
12) Subjects who have secondary parkinsonism variants;
13) Subjects who have had a diagnosis of cancer or evidence of continued malignancy within 3 years of study enrollment (with the exception of adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or in situ prostate cancer with a normal prostate-specific antigen [PSA] post resection);
14) Subjects, who, for any reason, are judged by the Investigator to be inappropriate for this study, including a subject who is unable to communicate or to cooperate with the Investigator or who has/had a clinically significant illness or abnormal physical examination that may compromise the safety of the subject during the trial or affect the ability of the subject to adhere to study procedures;
15) Subjects who have clinical laboratory test results that are clinically unaccepatable by the Investigator, or who have an alanine aminotransferase (ALT) and/or an aspartate aminotranserfase (AST) level > 3 times the upper limit of normal (ULN), and serum total bilirubin >2 times the ULN at Screening;
16) Subjects judged to have mild, moderate, or severe hepatic impairment based upon Child-Pugh categorization A, B, or C;
17) Subjects with a MoCA score of </= 25;
18) Subjects with a BDI score of > 20;
19) Subjects with suicidal behavior within the previous month;
20) Subjects who smoke > 5 cigarettes per day;
21) Subjects who have a history of drug abuse or dependence within the last year by the Diagnostic and Statistical Manual of Mental disorders, Revised (DMS-IVR);
22) Subjects must have not known or suspected sensitivity to the investigational study drug or its excipients;
23) Subjects who have untreated major depressive disorder;
24) Subjects who have a history of seizures or seizure disorders;
25) Subjects who have a history of neuroleptic malignant syndrome;
26) Subjects who are pregnant (confirmed by beta human chorionic gonadotrophin [B-HCG]) or breastfeeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is change from Baseline in the total hours per day spent in the OFF state. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy variables include the change from Screening/Baseline (as appropriate) in:
-total hours of ON time per day without troublesome dyskinesia;
-UPDRS Motor Examination (Part III);
-UPDRS ADL score (Part II);
-UPDRS Mentation, Behaviorm and Mood (part I);
-Total UPDRS (Parts I+II+III);
-PGI-I scale;
-Sleep time in hours per day based upon 24-hour diaries;
-Percentage of awake time per day spent in the OFF state; percentage of ON time per day without troublesome dyskinesia;
-Total hours of ON time and percentage of ON time per day (without dyskinesiam with dyskinesia, with non-troublesome dyskinesia and with troublesome dyskinesia);
-MoCA;
-Beck Depression Inventory (BDI). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints are assessed over multiple visits according to the protocol. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 | No |
| 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 |
| Canada |
| Israel |
| Serbia |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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