| 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 |
| Pacientes con Enfermedad de Parkinson con disquinesia de moderada a severa |
|
| E.1.1.1 | Medical condition in easily understood language |
| Parkinson’s Disease Patients With Moderate to Severe Abnormal Movements |
| Pacientes con Enfermedad de Parkinson con movimientos anormales de moderados a severos |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| 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). |
| Comparar la eficacia de JM-010 (administrado en forma de dos combinaciones diferentes de dosis de buspirona y zolmitriptán) con una terapia con placebo en la reducción de la intensidad de la disquinesia en pacientes con EP mediante la evaluación de un cambio significativo desde la visita basal a la semana 12 sobre la Escala unificada de valoración de la disquinesia (Unified Dyskinesia Rating Scale, UDysRS). |
|
| 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) |
Comparar la eficacia de JM-010 (administrado en dos combinaciones de dosis de JM-010) con placebo:
• Cambio de discapacidad/progresión de enfermedad parkinsoniana determinada mediante partes I a IV de la MDS-Escala unificada de valoración de la enfermedad de Parkinson (Unified Parkinson’s Disease Rating Scale, MDS-UPDRS).
•Mejoría clinica de síntomas de EP medidos por la Impresión clinica global del cambio (CGI-C)
•Cambio del tiempo en fase "ON" con disquinesia problemática, disquinesia no problemática y sin disquinesia, y el tiempo en fase "OFF" determinado con diarios de Hauser.
Determinar seguridad y tolerabilidad de JM-010 (admin en dos combinaciones de dosis de JM-010) con placebo:
•Incidencia de acontecimientos adversos aparecidos con tratamiento (AAAT)
•Análisis clínicos
•Electrocardiograma (ECG) de 12 derivaciones
•Constantes vitales
•Escala de valoración de riesgo de suicidio de Columbia (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. Participants will be deemed likely to comply with study protocol and communicate with study personnel about adverse events (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 (as reported by the subjects); 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 during daily waking hours on a 24-hour PD subject 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 and/or monoamine oxidase inhibitors (MAOi), where applicable, from at least 4 weeks prior to Visit 2, Week 0 (Baseline Visit) and for the duration of study participation. |
1.Es capaz de leer, entender y dar su consentimiento informado escrito y fechado antes de la visita de selección. Se considerará que es probable que los participantes cumplan el protocolo del estudio y se comuniquen con el personal del estudio en relación con acontecimientos adversos (AA) y otra información de importancia clínica.
2.Es un varón o una mujer de entre ≥ 18 y 80 años en la visita de selección.
3.Se le ha diagnosticado EP idiopática que cumple los criterios para diagnóstico clínico del UK Parkinson's Disease Society (UKPDS) Brain Bank y precisa tratamiento con levodopa y responde a ella.
4.Ha sufrido disquinesia durante un período de al menos tres meses antes de la visita de selección.
5.Tiene disquinesia con el efecto máximo estable (notificada por los sujetos); la disquinesia debe ser entre moderada y completamente discapacitante (MDS-UPDRS, Parte IV, apartado 4.2, puntuación >=3).
6.Tiene más de una hora de tiempo "ON" con disquinesia problemática durante las horas de vigilia diarias en un diario de EP de 24 horas en cada uno de dos días consecutivos antes de la visita 2, semana 0 (visita basal).
7.Está en un régimen posológico estable de levodopa que exige al menos tres administraciones de dosis pero no más de seis administraciones al día con intervalos de al menos 2-3 horas entre dos dosis sucesivas de levodopa durante al menos 30 días antes de la visita de selección, y se espera que siga recibiendo este régimen de levodopa sin cambio alguno durante toda la participación en el estudio.
8.Deberá seguir una pauta posológica estable si está tomando otra medicación antiparkinsoniana, y se espera que siga con este régimen sin cambio alguno durante toda la participación en el estudio.
9.Está dispuesto a (y es capaz de) dejar de usar amantadina, inhibidores de la monoaminooxidasa (IMAO) o ambos, cuando proceda, desde al menos cuatro semanas antes de la visita 2, semana 0 (visita basal) y durante toda la participación en el estudio. |
|
| 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:
PD-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 DSM 5th Edition), with the exception of caffeine and nicotine dependence, at Screening Visit or within 12 months prior to Screening Visit.
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 within 5 years prior to Screening 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 or gastrointestinal disorder or other known condition (eg. porphyria, unstable diabetes mellitus) 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 5 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 within 2 years prior to screening
• History of myocardial infarction, or New York Heart Association Functional Classification of Heart Failure Class 3 or 4 within 2 years prior to screening.
• 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.
• Current treatment with medications that prolong the QT interval and have a known risk of torsades de pointes.
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. |
Un sujeto no será elegible si cumple los siguientes criterios:
Específicos de EP:
1.Cirugía para el tto de EP (ej., palidotomía, estimulación cerebral profunda, trasplante tejido fetal) o otra cirugía cerebral importante.
Relacionados con trastornos psiquiátricos y neurológicos:
2.Diagnostico actual de trastorno por consumo de sustancias (incluido el alcohol), excep dependencia de cafeína y nicotina, en selección o 12 meses previos.
3.Diagnostico psiquiátrico de trastornos psicótico agudo u otros diagnostico psiquiátricos como trastorno bipolar o trastorno depresivo mayor, o trastorno de ansiedad generalizada que predomina sobre la EP o ha predominado sobre EP en otro momento en 6 meses antes de selección.
4.Otros trastornos psiquiátricos, neurológicos o conductuales que puedan interferir en desarrollo o interpretación del estudio, incluida la demencia, o se considera violento al sujeto.
5.Riesgo importante de conducta suicida durante el curso del estudio o
•En visita selección: el paciente contesta "sí" en los apartados 4 ó 5 de la CSSRS con referencia al período de 6 meses previo a selección; o
•En visita selección: el paciente ha intentado suicidarse una o más veces en período de 2 años previo a selección; o
•En visita basal: el paciente contesta "sí" en los apartados 4 ó 5 de la C-SSRS con referencia a selección; o
6.Trastornos convulsivos que exigen tto antiepilépticos.
7.Enfermedad cerebral o cerebrovascular sintomática grave conocida o cualquier traumatismo cerebral agudo que haya precisado tto antiepiléptico en 5 años previos a selección.
8.Disquinesia exclusiva bifásica, en fase "OFF", mioclonica, distónica o acatísica sin disquinesia de pico de dosis.
Otros procesos médicos:
9.Signos de trastorno hematológico, autoinmune, endocrino, cardiovascular, vascular periférico, renal o digestivo de importancia clínica u otro proceso conocido que dificulta participación y valoraciones o ambas.
10.Enfermedad maligna o antecedentes de neoplasias tratadas en 5 años previos a selección distintas de carcinoma cervical in situ o carcinoma basocelular de piel.
11.Hipotensión ortostática o sintomática: descenso de > 20 mm Hg de la presión arterial sistólica y/o de > 10 mm Hg de la presión arterial diastólica después de al menos tres minutos en bipedestación en comparación con la presión arterial en decúbito supino previa en dos determinaciones separadas, o antecedentes de un episodio actual de síncope hipotensivo o vasovagal repetido.
12.Antecedentes conocidos o episodio actual:
•Ictus o accidente isquémico transitorio en 2 años previo a selección.
•Infarto de miocardio, o clase 3 ó 4 de clasificación funcional de insuficiencia cardíaca de New York Heart Association en los 2 años previo a selección.
•Anomalía de importancia clínica en el ECG, incluidos los hallazgos de anomalías de la conducción o el ritmo ventriculares distintos de extrasístoles ventriculares aisladas o bloqueo auriculoventricular de primer grado.
•Tratamiento actual en curso con medicacion que prolongue intervalo QT y existencia de riesgo conocido de taquicardia helicoidal.
13.Hipersensibilidad o contraindicación al uso de serotoninérgicos, buspirona y zolmitriptán, o excipientes de comprimidos de medicación del estudio. |
|
| 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. |
| El criterio de valoración principal de eficacia es el cambio de puntuación total la Escala de disquinesia unificada (Unified Dyskinesia Scale, DysRS) desde la visita basal hasta la semana 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 0, 2, 4, 8, 12 |
| Semana 0, 2,4, 8 y 12 |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints include the following:
1. UDysRS total score changes from Baseline
2. MDS-UPDRS Part III score changes from Baseline
3. CGI-C score
4. ON time without troublesome dyskinesia (ON time without dyskinesia plus ON time with non-troublesome dyskinesia) changes from Baseline
5. OFF time changes from Baseline
6. ON time with troublesome dyskinesia changes from Baseline
7. Total time with dyskinesia (non-troublesome and troublesome) changes from Baseline
8. UDysRS Total Objective Score (Parts III and IV) changes from Baseline
9. MDS-UPDRS, individual (Parts I, II, III, and IV) and combined scores (Parts I, II, and III) changes from Baseline |
Los criterios de valoración secundarios de eficacia incluye los siguientes:
1. Cambios en el puntaje total de UDysRS desde la visita basal
2. Cambios en la puntuación de MDS-UPDRS Parte III desde la visita basal
3. Puntuación CGI-C
4. Cambios de tiempo ON sin disquinesia problemática (tiempo ON sin disquinesia más tiempo ON con disquinesia no molesta) desde la visita basal
5. Cambios de tiempo OFF desde la visita basal
6. Cambios de tiempo ON con problemas de disquinesia desde la visita basal
7. Tiempo total con disquinesia (no problemático y problemático) desde la visita basal
8. Cambios en la puntuación total del objetivo UDysRS (partes III y IV) desde la visita basal
9. Cambios en las puntuaciones de MDS-UPDRS, individual (Partes I, II, III y IV) y combinadas (Partes I, II y III) desde la visita basal |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 0, 2, 4, 8, 12 |
| Semana 0, 2,4, 8 y 12 |
|
| 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 | 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) | 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.8.2.4 | 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 | 1 |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| LVLS |
| Ultima visita último paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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