| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Degenerative disease of the nervous system |
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| 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 | 16.0 |
| 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 |
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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 assess the effects of rotigotine over placebo on improvement of apathy and motor symptoms in subjects with early-stage and advanced stage idiopathic Parkinson’s disease |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the change in quality of life, anhedonia, depressive symptoms, fatigue, cognitive impairment, apathy rated by the caregiver, safety, and tolerability in subjects with apathy in early-stage and advanced-stage idiopathic Parkinson’s disease |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent form is signed and dated by the subject.
2. Subject is considered reliable and capable of adhering to the protocol, visit schedule or medication application according to the judgment of the investigator.
3. Subject is male or female and ≥ 18 years old at the Screening Visit.
4. Subject has idiopathic Parkinson’s disease, defined by the cardinal sign, bradykinesia, plus the presence of at least 1 of the following: resting tremor, rigidity, or impairment of postural reflexes, and without any other known or suspected cause of Parkinsonism.
5. Subject has unsatisfactory control of Parkinson’s disease motor symptoms under the current treatment, according to the judgment of the investigator.
6. Subject has a Hoehn and Yahr stage score I-IV during the “on” state at the Screening Visit.
7. If subject is taking levodopa, he/she must be on a stable dose of levodopa of at least 200 mg/day (in combination with benserazide or carbidopa) for at least 28 days prior to the Baseline Visit, and the dose is expected to be maintained for the duration of the study.
8. Subject suffers from apathy associated with Parkinson’s disease for at least 3 months, evidenced by a score of ≥ 2 on UPDRS Part I Item 4 at the Screening Visit and an average of at least ≥ 14 on the AS at the Screening and Baseline Visit as rated by the subject.
9. Subject has a Mini-Mental State Examination (MMSE) score ≥ 25 at the Screening Visit.
10. If the subject is receiving an anticholinergic agent, a monoamine oxidase (MAO) B-inhibitor, the Catechol-O-Methyl Transferase (COMT) inhibitor entacapone, or the N Methyl D Aspartate (NMDA) antagonist amantadine, he/she must have been on a stable dose for at least 28 days prior to the Baseline Visit, and the dose is expected to be maintained for the duration of the study.
11. If subject is taking an antidepressant drug, such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), bupropion, or tricyclic antidepressants (TCAs), he/she must have been on a stable dose for at least 28 days prior to the Baseline Visit, and the dose is expected to be maintained for the duration of the study.
12. Female subjects must be either postmenopausal for at least 1 year, surgically incapable of childbearing, or effectively practicing an acceptable method of contraception (either oral/parenteral/implantable hormonal contraceptives, intrauterine device, or barrier and spermicide). Abstinence only is not an acceptable method. Subjects must agree to use adequate contraception during the study and for 4 weeks after their final dose of rotigotine (or longer, if required by local regulations).
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| E.4 | Principal exclusion criteria |
1. Subject has previously participated in this study or subject has previously been assigned to treatment in a study of the medication under investigation in this study.
2. Subject has participated in another study of an investigational medicinal product (IMP) or a medical device within the last 28 days prior to the Screening Visit or is currently participating in another study of an IMP or a medical device.
3. Subject has had prior therapy with a dopamine agonist within 28 days prior to the Baseline Visit.
4. Subject discontinued from previous therapy with a dopamine agonist after an adequate length of treatment, at an adequate dose, due to lack of efficacy as assessed by the investigator.
5. Subject has a history of chronic alcohol or drug abuse within the last 6 months.
6. Subject has any medical or psychiatric condition (ie, bipolar disorder, dementia, hallucinations, or psychosis) that, in the opinion of the investigator, could jeopardize or would compromise the subject’s ability to participate in this study.
7. Subject has received neuroleptics (except clozapine and quetiapine), dopamine releasing substances (eg, methylphenidate or amphetamine), dopamine modulating substances (eg, reserpine), alpha-methyldopa, metoclopramide, MAO-A inhibitors, budipine, or tolcapone within 28 days of the Baseline Visit.
8. Subject has received electroconvulsive therapy within 12 weeks prior to the Screening Visit.
9. Subject is receiving current psychotherapy or behavior therapy while participating in this study.
10. Subject has a history of deep brain stimulation.
11. Subject has a known hypersensitivity to any components of the IMP or comparative drugs as stated in the protocol.
12. Subject has a significant skin disease that would make transdermal drug use inappropriate, including a history of skin sensitivity to adhesives or transdermal medications.
13. Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at the Screening Visit.
14. Subject has an atypical Parkinson’s disease syndrome due to drugs (eg, neuroleptics, metoclopramide, flunarizine), metabolic neurogenetic disorders (eg, Wilson Disease), encephalitis, cerebrovascular disease, or degenerative diseases (progressive supranuclear palsy).
15. Subject has evidence of an impulse control disorder (ICD) according to the modified Minnesota Impulsive Disorders Interview (mMIDI) at the Screening Visit confirmed by a positive structured clinical interview.
16. Subject who is currently lactating or pregnant or planning to become pregnant during the duration of the study.
17. Subject diagnosed with severe depression as evidenced by a BDI-II score of ≥29 at the Screening Visit.
18. Subject has symptomatic orthostatic hypotension at Screening.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Change from Baseline to the end of Maintenance Period in the score of the AS rated by the subject
• Change from Baseline to the end of Maintenance Period in the total score of the UPDRS Parts II (ADL) + III (motor subscale)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Following titration (up to 7 weeks) and maintainance (12 weeks) periods, up to 19 weeks total |
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| E.5.2 | Secondary end point(s) |
• Change from Baseline to the end of Maintenance Period in the score of the AS rated by the caregiver (where available)
• Change from Baseline to the end of Maintenance Period in the sum score of the 8-item Parkinson’s Disease Questionnaire (PDQ-8)
• Change from Baseline to the end of Maintenance Period in the sum score of domain mood/apathy of the NMSS
• Change from Baseline to the end of Maintenance Period in the sum score of the Snaith Hamilton Pleasure Scale (SHAPS)
• Change from Baseline to the end of Maintenance Period in the sum score of the Beck Depression Inventory (BDI-II)
• Change from Baseline to the end of Maintenance Period in the sum score of the UPDRS Part III (motor subscale) in “on” state
• Change from Baseline to the end of Maintenance Period in the score of the Clinical Global Impressions (CGI) Item I (Severity of Illness)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Following titration (up to 7 weeks) and maintainance (12 weeks) periods, up to 19 weeks total |
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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 | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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.8.2.4 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| 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 |
| Austria |
| Bulgaria |
| Hungary |
| Italy |
| Poland |
| Romania |
| Serbia |
| Slovakia |
| Slovenia |
| Spain |
| Turkey |
| Ukraine |
| United States |
| Croatia |
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| 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
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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