| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Parkinson’s Disease Patients With Moderate to Severe Dyskinesia |
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| E.1.1.1 | Medical condition in easily understood language |
| Parkinson’s Disease Patients With Moderate to Severe Abnormal Movements |
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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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10013113 |
| E.1.2 | Term | Disease Parkinson's |
| E.1.2 | System Organ Class | 100000004852 |
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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 compare the efficacy of JM-010 (administered as 2 different dose combinations of JM-010) to that of placebo therapy in reducing dyskinesia severity in PD by evaluating the mean change from Baseline to Week 12 on the Unified Dyskinesia Rating Scale (UDysRS). |
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| E.2.2 | Secondary objectives of the trial |
To compare the efficacy of JM-010 (administered as 2 different dose combinations of JM-010) to that of placebo therapy in relation to:
• Change in parkinsonian disability/disease progression as measured by the MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts I to IV
• Improvement in clinician-reported PD symptoms as measured by the Clinician Global Impression of Change (CGI-C)
• Change in ON time with troublesome dyskinesia, ON time with non-troublesome dyskinesia, ON time without dyskinesia, and OFF time as measured by Hauser diaries
To determine the safety and tolerability of JM-010 (administered as 2 different dose combinations of JM-010) to that of placebo therapy. Safety and tolerability will be assessed in relation to:
• Incidence of treatment-emergent adverse events (TEAEs)
• Clinical laboratory evaluations
• 12-lead electrocardiogram (ECG) assessments
• Vital signs
• Columbia Suicide Severity Rating Scale (C-SSRS) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Is able to read, understand, and provide written, dated informed consent prior to Screening Visit. Subjects will be deemed likely to comply with study protocol and communicate with study personnel about AEs and other clinically important information.
2. Is male or female, between 18 and 80 years of age at Screening Visit.
3. Is diagnosed with idiopathic PD that meets UK Parkinson’s Disease Society (UKPDS) Brain Bank Clinical Diagnostic Criteria and requires treatment with and shows responsiveness to levodopa.
4. Has experienced dyskinesia over a period of at least 3 months prior to Screening Visit
5. Has stable peak-effect dyskinesia; the dyskinesia should be moderately to completely disabling (MDS-UPDRS, Part IV, item 4.2, rating ≥ 3).
6. Has more than one hour of “ON” time with troublesome dyskinesia (i.e., at least three 30-minute periods of “ON” time with troublesome dyskinesia) during daily waking hours on a 24-hour Hauser diary on each of 2 consecutive days just prior to Visit 2, Week 0 (Baseline Visit).
7. Is on a stable levodopa dosing regimen requiring at least 3 dose administrations but no more than 6 dose administrations per day with at least 2 to 3 hour intervals between 2 successive doses of levodopa for at least 30 days prior to Screening Visit, and is expected to continue this levodopa regimen with no changes for the duration of study participation.
8. Must be on a stable dosing regimen if taking other anti-parkinsonian medication(s) and is expected to continue this regimen with no changes for the duration of study participation.
9. Is willing and able to stop using;
• Amantadine ER: from at least 4 weeks prior to Visit 2, Week 0 (Baseline Visit) and for the duration of study participation and/or
• Amantadine IR: from at least 2 weeks prior to Visit 2, Week 0 (Baseline Visit) and for the duration of study participation and/or.
• Monoamine oxidase inhibitors (MAOi): from at least 4 weeks prior to Visit 2, Week 0 (Baseline Visit) and for the duration of study participation. |
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| E.4 | Principal exclusion criteria |
A potential subject will not be eligible for participation in this study if any of the following criteria are met:
Parkinson’s Disease-Specific Criteria:
1. Has undergone surgery for the treatment of PD (e.g., pallidotomy, deep brain stimulation, fetal tissue transplantation) or has undergone any other major brain surgery.
Criteria related to psychiatric and other neurological disorders:
2. Has current diagnosis of Substance Use (including alcohol) Disorder (Abuse or Dependence, as defined by Diagnostic and Statistical Manual, Fifth Edition[DSM-5], with the exception of caffeine and nicotine dependence, at Screening Visit or within 12 months prior to Screening Visit (e.g., acute intoxication with alcohol, hypnotics, analgesics, or antipsychotic drugs).
3. Has psychiatric diagnosis of acute psychotic disorder or other psychiatric diagnoses such as bipolar disorder or major depressive disorder, or generalized anxiety disorder that are clinically predominant to their PD or have been predominant to their PD at any time within 6 months prior to Screening Visit.
4. Has other psychiatric (not including hallucinations due to side effects of dopamine therapy), neurological or behavioral disorders that in the opinion of the investigator may interfere with the conduct or interpretation of the study, including dementia, or subject who is considered violent.
5. Has a significant risk for suicidal behavior in the opinion of the investigator during the course of their participation in the study or
• At Screening Visit: the subject scores “yes” on items 4 or 5 in the Suicidal Ideation section of the C-SSRS with reference to a 6-month period prior to Screening Visit; or
• At Screening Visit: the subject has had one or more suicidal attempts with reference to a 2-year period prior to Screening Visit; or
• At Baseline Visit: the subject scores “yes” on items 4 or 5 in the Suicidal Ideation section of the C SSRS with reference to Screening Visit; or
6. Has current seizure disorders (other than febrile seizures in childhood) requiring treatment with anti convulsants.
7. Has known serious ongoing symptomatic cerebral disease or cerebrovascular disease or any acute brain trauma requiring treatment with anti-convulsant therapy (if they are not potent/moderate CYP3A4 inhibitors/inducers, they are prohibited only if given for epilepsy/seizures) within 5 years prior to Visit 2, Week 0 (Baseline Visit).
8. Has history of exclusively diphasic, OFF state, myoclonic, dystonic, or akathetic dyskinesia without peak dose dyskinesia.
Criteria related to other medical conditions:
9. Has current evidence of clinically significant hematological, autoimmune, endocrine, cardiovascular, peripheral vascular, renal (e.g., severe kidney failure[creatinine clearance≤20mL/min]), severe liver failure, or gastrointestinal disorder(intestinal ischemia, galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption) or other known condition (e.g. porphyria, unstable diabetes mellitus, acute closed-angle glaucoma, myasthenia gravis) that would possibly interfere with the subject’s participation in the study and/or assessments.
10. Has any malignant disease or a history of neoplasms treated within the 3 years prior to the Screening Visit, other than carcinoma in situ of the cervix or basal cell carcinoma of the skin.
11. Has orthostatic or symptomatic hypotension: a decrease of > 20 mm Hg in SBP and/or > 10 mm Hg in DBP after at least 3 minutes standing compared to the previous supine BP in 2 separate measurements and/or history or current episode of repeated hypotensive or vasovagal syncope.
12. Has known history or current episode of:
• History of stroke or transient ischemic attack.
• History of ischemic heart disease (e.g., myocardial infarction), coronary vasospasm (Prinzmetal’s angina), peripheral artery disease, or symptoms of ischemic heart disease or signs compatible with ischemic heart disease or New York Heart Association Functional Classification of Heart Failure Class 3 or 4 within 2 years prior to screening.
• Uncontrolled hypertension.
• Any clinically significant ECG abnormalities, including any findings of abnormal ventricular conduction or rhythm other than isolated premature ventricular contractions or first degree atrioventricular block (e.g., Wolff-Parkinson-White syndrome or known rhythm disorders associated with an accessory conduction pathway).
• Current treatment with medications that prolong the QT interval and have a known risk of torsades de pointes (e.g., haloperidol).
13. Has known hypersensitivity or contraindication to the use of serotonergic agents including buspirone and zolmitriptan, or to any of the excipients used in the study medication tablets.
14. Has Mini Mental State Examination-2 (MMSE-2) score of <24 at Screening Visit.
15. Has body mass index (BMI) ≤17.5 or ≥40.0 kg/m2, and total body weight < 45 kg.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the UDysRS total score change from Baseline to Week 12. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints include the following:
1. UDysRS total score changes from Baseline to Weeks 2, 4, 8
2. MDS-UPDRS Part III score changes from Baseline to Week 2, 4, 8, 12
3. CGI-C score at Week 12
4. ON time without troublesome dyskinesia (ON time without dyskinesia plus ON time with non-troublesome dyskinesia) changes from Baseline to Week 2, 4, 8, 12
5. OFF time changes from Baseline to Week 2, 4, 8, 12
6. ON time with troublesome dyskinesia changes from Baseline to Week 2, 4, 8, 12
7. Total time with dyskinesia (non-troublesome and troublesome) changes from Baseline to Week 2, 4, 8, 12
8. UDysRS Total Objective Score (Parts III and IV) changes from Baseline to Week 2, 4, 8, 12
9. MDS-UPDRS, individual (Parts I, II, III, and IV) and combined scores (Parts I, II, and III) changes from Baseline to Week 2, 4, 8, 12 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Korea, Republic of |
| France |
| Germany |
| Italy |
| Slovakia |
| Spain |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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