| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Parkinson's disease |
| Enfermedad de Parkinson |
|
| E.1.1.1 | Medical condition in easily understood language |
| Parkinson's disease |
| Enfermedad de Parkinson |
|
| 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 | 20.0 |
| 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 |
|
| 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 |
| The primary objective of the study is to determine the effect of ND0612 on daily “ON” time without troublesome dyskinesia (defined as the sum of "ON" time without dyskinesia and “ON” time with non-troublesome dyskinesia) using subject-completed “ON/OFF” diary assessments of motor function in subjects with Parkinson’s disease (PD) experiencing motor fluctuations. |
| El objetivo principal del estudio es determinar el efecto de ND0612 en el período diario “ON” sin discinesia molesta (definida como la suma del período ”ON” sin discinesia y período de “ON” con discinesia no molesta) a través de evaluaciones diarias ”ON/OFF) cumplimentadas por el paciente en relación con la función motora en pacientes con enfermedad de Parkinson (EP) que experimentan fluctuaciones motoras. |
|
| E.2.2 | Secondary objectives of the trial |
| Key secondary objective of the study is to determine the effect of ND0612 on daily “OFF” time in subjects with PD experiencing motor fluctuations using subject-completed “ON/OFF” diary assessments of motor function. |
| El objetivo secundario clave del estudio es determinar el efecto de ND0612 en el período diario OFF en los pacientes con EP que experimentan fluctuaciones motoras utilizando evaluaciones en el diario “ON/OFF” cumplimentadas por los pacientes en relación con la función motora. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| There is an optional pharmacogenetics sub study |
| Hay un studio opcional pharmacogenétcio |
|
| E.3 | Principal inclusion criteria |
1. Male and female subjects with PD of any race at least 30 years of age who sign an Institutional Review Board/Ethics Committee–approved informed consent form (ICF).
2. Parkinson’s disease diagnosis consistent with the UK Brain Bank Criteria.
3. Modified Hoehn and Yahr scale in “ON” stage ≤ 3.
4. Subjects must experience motor fluctuations and experience an average of at least 2.5 hours daily (with a minimum of 2 hours every day) in the “OFF” state during the waking hours as confirmed by an adequately completed “ON/OFF” diary over 3 days.
5. Subject treatment should be at least 4 doses/day of LD/ Dopa Decarboxylase Inhibition (DDI) (or at least 3 doses/day of Rytary) and at least 400 mg/day of LD, or equivalent according to the conversion table, and, according to the Investigator’s judgement, the subject experiences motor fluctuations that cannot be further improved by adjusting anti-PD medications.
6. Subjects and/or study partners have no impediment that may prevent them from operating the pump system.
7. Subjects and/or study partners must demonstrate ability to keep accurate diary entries of PD symptoms (“ON/OFF” diaries) with at least 75% concordance with the blinded study rater by the end of the diary training session during the Screening Period, including at least 1 "OFF" assessment.
8. Mini Mental State Examination (MMSE) score ≥ 24.
9. Female subjects must be surgically sterile (hysterectomy, bilateral oophorectomy, or tubal ligation); postmenopausal (defined as cessation of menses for at least 1 year); or willing to practice a highly effective method of contraception. All female subjects must be non-lactating and not pregnant and have a negative urine pregnancy test at Screening and at Enrollment (IR1 D1). Female subjects of childbearing potential must practice a highly effective method of contraception (e.g., hormonal methods of birth control such as oral contraceptive, contraceptive patch, long-acting injectable contraceptive, intrauterine devices, or a partner with vasectomy) from 1 month before Enrollment (IR1 D1) until 1 month after the last dose of study treatment. Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred and usual lifestyle. If a subject is usually not sexually active but becomes active, the subject and sexual partner must comply with the contraceptive requirements detailed above.
10. Willingness and ability to comply with study requirements.
11. Subjects must have a named study partner that signed the ICF.
12. Approval for entry into the study by an independent EAC. |
1. Pacientes varones y mujeres con EP de cualquier raza de al menos 30 años de edad que firmen un formulario de consentimiento informado (FCI) aprobado por el Comité de Revisión Institucional/Comité de Ética.
2. Diagnóstico de enfermedad de Parkinson de acuerdo con los criterios de Brain Bank del Reino Unido.
3. Escala de Hoehn y Yahr modificada en el período ”ON” ≤3.
4. Los pacientes deben experimentar fluctuaciones motoras y un promedio de al menos 2,5 horas al día (con un mínimo de 2 horas cada día) en el período “OFF” durante las horas de vigilia según lo confirmado por el diario “ON/OFF” cumplimentado adecuadamente durante 3 días.
5. El tratamiento del paciente debe ser de al menos 4 dosis/día de LD/ inhibición de dopa decarboxilasa (IDD) (o al menos 3 dosis/día de Rytary) y, al menos, 400 mg/día de LD, o equivalente, de acuerdo con la tabla de conversión, y, de acuerdo con el criterio del Investigador, el paciente experimenta fluctuaciones motoras que no se pueden mejorar más mediante el ajuste de los medicamentos para la EP.
6. Los pacientes y/o las parejas del estudio no tienen ningún impedimento que les impide utilizar el sistema de la bomba.
7. Los pacientes o las parejas del estudio deben demostrar la capacidad para mantener la exactitud de las entradas del diario de síntomas de la EP (diario ”ON/OFF”) con al menos un 75 % de concordancia con el evaluador del estudio enmascarado al final de la sesión de entrenamiento sobre el diario durante el período de selección, incluida al menos 1 evaluación del período d”OFF”.
8. Puntuación del miniexamen del estado mental (MMSE) ≥24.
9. Las mujeres deben ser quirúrgicamente estériles (histerectomía, ovariectomía bilateral o ligadura de trompas); posmenopáusicas (definido como el cese de |
|
| E.4 | Principal exclusion criteria |
1. Atypical or secondary Parkinsonism.
2. Acute psychosis or troublesome hallucinations in the past 6 months.
3. Subjects with clinically significant or unstable medical, surgical, or psychiatric condition or laboratory abnormalities which, in the opinion of the Investigator or the EAC, represents a safety risk, makes the subject unsuitable for study entry, or potentially unable to complete all aspects of the study.
4. Clinically significant ECG abnormalities.
5. Renal or liver dysfunction that may alter drug metabolism including Screening Visit serum levels of creatinine > 1.5 mg/dL, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 × upper limit of normal, and total bilirubin > 2.5 mg/dL.
6. Any malignancy in the 5 years before enrollment, excluding basal cell carcinoma of the skin or cervical carcinoma in situ that have been successfully treated.
7. Use of subcutaneous (SC) apomorphine injections, sublingual apomorphine, or inhaled LD within 4 weeks before the enrollment.
8. Concomitant therapy or within 28 days before enrollment with: metoclopramide, reserpine, methylphenidate, or amphetamines, well as neuroleptics; exception in case of Quetiapine and Pimavanserin use: (1) allowed only in case it had been used for a period of at least 3 months before enrollment, (2) subject is on stable therapy for at least 3 months (3) underlying psychosis to be under control and anticipating no changes to the dosage of the medication throughout the study.
9. Subjects with a history of alcohol or substance abuse within the past 12 months.
10. Subjects who have taken experimental medications within 30 days before enrollment.
11. Subjects who have previously participated in studies ND0612H-006 and/or ND0612H-012.
12. Subjects who have previously undergone treatment for PD with a surgical intervention (e.g., pallidotomy, thalamotomy, transplantation, deep brain stimulation procedures), Duodopa®/Duopa®, or continuous dopaminergic or apomorphine infusion. Subjects who have discontinued Duodopa®/Duopa® treatment at least 6 months before enrollment and have undergone stoma closure surgery at least 6 months before enrollment, may be included in this study. Subjects who are planning to undergo treatment for PD with a surgical intervention will be enrolled at the Investigator’s discretion.
13. Subjects with severe disabling dyskinesias.
14. History of significant skin conditions or disorders (e.g., psoriasis, atopic dermatitis, etc.) or evidence of different lesions (e.g., sunburn, acne, scar tissue, tattoo, open wound, branding, or pigmentation) that, in the Investigator's opinion, would interfere with the infusion of the study drug or could interfere with study assessments.
15. Subjects who do not have sufficient SC tissue for SC infusion treatment.
16. Use of non-selective monoamine oxidase inhibitors (e.g., phenelzine, isocarboxazid, tranylcypromine) within 4 weeks before enrollment.
17. Use of monoamine-depleting agents (e.g., reserpine, tetrabenazine, deutetrabenazine, valbenazine, xenazine) within 4 weeks before enrollment.
18. Current or previous diagnosis of Dopamine Dysregulation Syndrome or Impulse Control Disorder.
19. Subjects who answered “yes” to questions 4 or 5 of the C-SSRS within the last 5 years.
20. Known allergy to the study drug or placebo or any of their excipients. |
1. Parkinsonismo atípico o secundario.
2. Psicosis aguda o alucinaciones problemáticas en los últimos 6 meses.
3. Los pacientes con afecciones médicas, quirúrgicas o psiquiátricas inestables o clínicamente significativas o anomalías analíticas que, en opinión del investigador o del CAA, representen un riesgo de seguridad, hagan que el paciente no sea apto para la inclusión en el estudio, o posiblemente no puedan completar todos los aspectos del estudio.
4. Anomalías del ECG clínicamente significativas.
5. Disfunción renal o hepática que puede alterar el metabolismo del fármaco, incluidos niveles séricos de creatinina >1,5 mg/dl, aspartato aminotransferasa (AST) alanina aminotransferasa (ALT) >2 × límite superior de la normalidad y bilirrubina total >2,5 mg/dl en la visita de selección.
6. Cualquier neoplasia maligna en los 5 años previos a la inscripción, excepto carcinoma basocelular de la piel o carcinoma cervicouterino in situ que hayan sido tratados de forma satisfactoria.
7. Uso de inyecciones subcutáneas (s.c.) de apomorfina, apomorfina sublingual, o LD inhalado dentro de las 4 semanas previas a la inscripción.
8. Tratamiento concomitante o en el plazo de 28 días antes de la inscripción con: metoclopramida, reserpina, metilfenidato o anfetaminas, así como neurolépticos; con excepción en el caso de uso de quetiapina y pimavanserina: (1) solo se permite en caso de que se hubiera utilizado durante un período de al menos 3 meses antes de la inscripción, (2) el paciente está en tratamiento estable durante al menos 3 meses (3) psicosis subyacente bajo control y que no se prevean cambios en la dosis de la medicación a lo largo de todo el estudio.
9. Pacientes con antecedentes de consumo de alcohol o drogas en los últimos 12 meses.
10. Pacientes que hayan tomado medicamentos experimentales en el plazo de 30 días antes de la inscripción.
11. Pacientes que hayan participado previamente en los estudios ND0612H-006 y/o ND0612H-012.
12. Pacientes que previamente han recibido tratamiento para la EP con una intervención quirúrgica (p. ej., intervenciones de palidotomía, talamotomía, trasplante, estimulación cerebral profunda); Duodopa®/Duopa®; o infusión continua dopaminérgica o con apomorfina. Se pueden incluir en este estudio pacientes que hayan interrumpido el tratamiento con Duodopa/Duopa al menos 6 meses antes de la inscripción y se hayan sometido a una cirugía de cierre del estoma al menos 6 meses antes de la inscripción. Los pacientes que tienen previsto someterse a tratamiento para la EP con una intervención quirúrgica se inscribirán según el criterio del investigador.
13. Pacientes con discinesias discapacitantes graves.
14. Antecedentes de afecciones o trastornos de la piel significativos (p. ej., psoriasis, dermatitis atópica, etc.) o evidencia de diferentes lesiones (p. ej., quemaduras solares, acné, tejido cicatricial, tatuajes, herida abierta, marcas o pigmentación) que, en opinión del investigador, interferirían con la infusión del fármaco del estudio o podrían interferir en las evaluaciones del estudio.
15. Pacientes que no tengan suficiente tejido s.c. para el tratamiento de infusión s.c..
16. Uso de inhibidores no selectivos de la monoaminooxidasa (p. ej., fenelzina, isocarboxazida, tranilcipromina) en las 4 semanas antes de la inscripción.
17. Uso de agentes reductores de monoamina (p. ej., reserpina, tetrabenazina, deutetrabenazina, valbenazina, xenazina) en las 4 semanas antes de la inscripción.
18. Diagnóstico actual o previo del síndrome de desregulación de la dopamina o trastorno del control de impulsos.
19. Pacientes que hayan respondido “sí” a las preguntas 4 o 5 de la C-SSRS en los últimos 5 años.
20. Alergia conocida al fármaco del estudio o placebo, o a cualquiera de sus excipients. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the change from Baseline to the end of the DBDD Maintenance Period (DB W12) in the mean duration of “ON” time without troublesome dyskinesia adjusted to subject’s waking hours and normalized to 16 waking hours, based on subject's “ON/OFF” diary assessments on the 3 consecutive days before the visit. “ON” time without troublesome dyskinesia is defined as the sum of “ON” time without dyskinesia and “ON” time with non-troublesome dyskinesia. |
| Es el cambio desde el inicio hasta el final del período de mantenimiento con doble ciego y doble simulación (DC S12) en el período ”ON” sin discinesia molesta (horas) ajustado a las horas de vigilia del paciente y normalizado a 16 horas de vigilia basado en la evaluación del diario "ON/OFF" de tres días consecutivos nates de la visita. El periodo "ON" sin disquinesia es definido como la suma de periodos "ON"sin disquinesia y períodos "ON" con disquinesia sin disquinesia problemática. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of the DBDD Maintenance Period (DB W12) |
| Fin del período de mantenimiento con doble ciego y doble simulación (DC S12) |
|
| E.5.2 | Secondary end point(s) |
| The key secondary efficacy endpoint is the change from Baseline to the end of the DBDD Maintenance Period (DB W12) in the mean duration (hours) of “OFF” time adjusted to subject’s waking hours and normalized to 16 waking hours, based on subject's “ON/OFF” diary assessments on the 3 consecutive days before the visits. |
| Cambio desde el inicio hasta el final del período de mantenimiento con doble ciego y doble simulación (DC S12) en la media de la duración (horas) del período “OFF” ajustado a las horas de vigilia del paciente y normalizado a 16 horas de vigilia, en función de las evaluaciones del diario “On/OFF” de los pacientes en los 3 días consecutivos previos a las visitas. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of the DBDD Maintenance Period (DB W12) |
| Fin del período de mantenimiento con doble ciego y doble simulación (DC S12) |
|
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Portugal |
| Russian Federation |
| Serbia |
| Slovakia |
| Spain |
| Sweden |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| LVLS |
| Última visita del ultimo paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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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