| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Parkinson's Disease With Motor Response Fluctuations (OFF Phenomena) |
| Enfermedad de Parkinson con fluctuaciones a la respuesta motriz (fenómeno OFF) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Parkinson's Disease With Periods of Prolonged Immobility or Freezing |
| Enfermedad de parkinson con periodos prolongados de inmobilidad |
|
| 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 | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10034007 |
| E.1.2 | Term | Parkinson's disease NOS |
| E.1.2 | System Organ Class | 100000004852 |
|
| 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 effects of CVT-301 versus placebo on the change from pre-dose in Unified Parkinson?s Disease Rating Scale (UPDRS) Part 3 motor score at 30 minutes following treatment of patients experiencing an OFF episode at Treatment Visit 4 (TV4) (Week 12). |
| Comparar los efectos del CVT-301 frente al placebo en el cambio desde antes de la administración en la puntuación motriz de la parte 3 de la Escala de valoración unificada de la enfermedad de Parkinson (UPDRS) a los 30 minutos después del tratamiento de pacientes con un episodio OFF en la visita de tratamiento 4 (VT4) (semana 12) |
|
| E.2.2 | Secondary objectives of the trial |
1. Proportion of patients achieving resolution of an OFF to an ON state within 60 minutes after study drug is administered in the clinic, maintaining the ON state at 60 minutes after study drug administration (per the examiner?s subjective assessment).
2. Change from pre-dose in UPDRS Part 3 motor score at 20 minutes following treatment of patients experiencing an OFF episode.
3. Proportion of patients who improved based on the Patient Global Impression of Change (PGI-C) rating scale measured pre-dose.
4. Change from pre-dose in total daily OFF time assessed by the patient and recorded in the PD Diary for 3 consecutive days prior to TV4.
5. Change from pre-dose in UPDRS Part 3 motor score at 10 minutes following treatment of patients experiencing an OFF episode. |
1. La proporción de pacientes que logran pasar de un estado OFF a un estado ON en un plazo de 60 minutos después de administrarse el medicamento del estudio en la clínica y que mantengan el estado ON a los 60 minutos después de la administración del medicamento del estudio (según la evaluación subjetiva del examinador).2. El cambio desde el momento previo a la administración en la puntuación motriz de la parte 3 de la UPDRS a los 20 min después del tratamiento de pacientes que hayan tenido un episodio OFF.
3. La proporción de pacientes que mejoraron de acuerdo con la PGI-C, medido antes de la administración.4. El cambio desde el momento previo a la administración en el tiempo OFF/día total evaluado por el paciente y registrado en el diario de la EP durante 3 días consecutivos antes de la VT4.5. El cambio desde el momento previo a la administración en la puntuación motriz de la parte 3 de la UPDRS a los 10 minutos después del tratamiento de pacientes que hayan tenido un episodio OFF. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has signed and dated an IRB/IEC-approved informed consent form before any protocol-specific screening procedures are performed.
2. Is a male or female aged 30 to 85 years, inclusive.Women of child-bearing potential must use protocol-defined contraceptive measures (see Section 11.1.5) and must have a negative serum human chorionic gonadotropin (hCG) test at screening. These patients must be willing to remain on their current form of contraception for the duration of the study.
3. Patients who have idiopathic PD (i.e., not induced by drugs or other diseases) as defined by fulfilling Steps 1 and 2 of the United Kingdom (UK) Brain Bank criteria, diagnosed after the age of 30 years.
4. Patients who are classified as Stage 1 to 3 (in the ON state) on the modified Hoehn and Yahr scale for staging of PD severity.
5. Patients who have experienced motor fluctuations for a minimum of 2 hours of average daily OFF time per waking day (excluding early morning OFF time) by self-report and confirmed by the PD Diary (on 3 consecutive days) during the screening period.
6a. Patients who are on a LD-containing therapy, not including Rytary (or equivalent), must be stable on oral LD-containing therapy for at least 2 weeks prior to SV1 with a LD/DDI-containing regimen
6b. Patients who are on a LD-containing therapy, when including Rytary (or equivalent), should be on a stable dose for at least 6 weeks prior to SV1.
6c. The frequency of L-dopa administrations must be at least 3 times during the waking day and a total daily LD dose of ? 1600 mg.
7. Patients should be stable on other PD medications for at least 4 weeks prior to SV1.
8. Patients must have a ? 25% difference between UPDRS Part 3 scores recorded in their ON and OFF states at screening.
9. Patients must understand (with or without caregiver assistance) their daily medication regimen and must agree that they will not change their daily medication doses during the study.
10. Patients must have normal cognition as confirmed by a score of ? 25 on the Mini Mental State Examination (MMSE), performed in the ON state.
11. Patients must be able to perform a spirometry maneuver in the ON and OFF states and must have a screening FEV1 ? 50% of predicted, and an FEV1/FVC ratio >60% in the ON state at screening.
12. (A pulmonologist will review the spirometry tracings/morphology of any patients with an FEV1 that is ? 50% to <60% of predicted or an FEV1/FVC ratio that is >60% to <70% in order to determine eligibility. Patients with an FEV1/FVC ratio that is >60% to <70% will complete spirometry before and after the administration of a bronchodilator in a pulmonary function laboratory. Testing will be performed in accordance with the 2005 ATS/European Respiratory Society (ERS) criteria prior to randomization. The results of the bronchodilator challenge will be reviewed by a pulmonologist prior to potential randomization.) |
Ha firmado y fechado un formulario de consentimiento informado aprobado por el Comité de Revisión Institucional (IRB)/Comité Ético de Investigación Clínica (CEIC) antes de que se lleve a cabo cualquier procedimiento de selección específico del protocolo.
? Es hombre o mujer de 30 a 85 años de edad, inclusive. Las mujeres
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con capacidad para procrear deben tomar medidas anticonceptivas definidas en el protocolo (véase la Sección 11.1.5) y tener un resultado negativo en una prueba de gonadotropina coriónica humana (hCG) en suero en el momento de la selección. Estas pacientes deben estar dispuestas a seguir usando su método anticonceptivo actual durante todo el estudio.
Pacientes con EP idiopática (es decir, no inducida por medicamentos u otras enfermedades), como se define por el cumplimiento de los pasos 1 y 2 de los criterios del Banco de cerebros del Reino Unido, diagnosticada después de los 30 años de edad.
? Pacientes clasificados como estadios 1 a 3 (en estado ON) según la escala de Hoehn y Yahr modificada para estadificación de la gravedad de la EP.
? Pacientes que hayan presentado fluctuaciones motrices durante al menos 2 horas al día, en promedio, en estado OFF, durante la vigilia diurna (excluido el tiempo OFF por la mañana temprano) según los informes del propio paciente y confirmadas por el diario de la EP (durante 3 días consecutivos) durante el período de selección.
? Los pacientes bajo tratamiento con LD, excluyendo Rytary (o equivalente) deben estar estables en su tratamiento con LD durante 2 semanas como mínimo antes de la VS1 con una pauta posológica que contenga LD/inhibidor de la dopamina descarboxilasa (DDI).
? Los pacientes bajo tratamiento con LD, excluyendo Rytary (o equivalente) deben estar estables en su tratamiento con LD durante 6 semanas como mínimo antes de la VS1.
? La frecuencia de las administraciones de L-dopa debe ser de al menos 3 veces durante la vigilia diurna y una dosis total diaria de LD de ? 1600 mg.
? Los pacientes deben haber recibido dosis estables de otros medicamentos para la EP durante al menos 4 semanas antes de la VS1.
? Los pacientes deben tener una diferencia ? 25 % entre las puntuaciones de la parte 3 de la UPDRS registradas en los estados ON y OFF en el momento de la selección.
? Los pacientes deben comprender (con sin ayuda de su cuidador) su pauta posológica diaria y deben aceptar no modificar sus dosis de medicación diaria durante el estudio.
? Los pacientes deben presentar cognición normal, confirmada por una puntuación ? 25 en el MMSE.Los pacientes deben tener la capacidad de efectuar una maniobra de espirometría en los estados ON y OFF, y presentar un valor VEF1 en
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la selección ? 50 % del valor previsto y un cociente VEF1/CVF > 60 % en estado ON en el momento de la selección. Un neumólogo revisará los trazados y la morfología de la espirometría de cualquier paciente con un valor VEF1 que esté entre ? 50 % y < 60 % del valor previsto o un cociente VEF1/CVF entre > 60 % y < 70 % para determinar su idoneidad. Los pacientes con un cociente VEF1/CVF entre > 60 % y < 70 % efectuarán la espirometría antes y después de la administración de un broncodilatador en un laboratorio de función pulmonar. Las pruebas se efectuarán de acuerdo con los criterios de la ATS/Sociedad Respiratoria Europea (European Respiratory Society, ERS) del año 2005, antes de la aleatorización. Los resultados de la prueba de provocación con el broncodilatador serán revisados por un neumólogo antes de la posible aleatorización.) |
|
| E.4 | Principal exclusion criteria |
1. Patients who have dyskinesia of a severity that would significantly interfere with their ability to participate or perform study procedures.
2. Pregnant or lactating females or females wishing to become pregnant.
3. Patients who have any known contraindication to the use of LD, including a history of malignant melanoma or a history of narrow-angle glaucoma.
4. Patients who have had previous surgery for PD (including but not limited to deep brain stimulation or cell transplantation) or plan to have stereotactic surgery during the study period.
5. Patients with a history of psychotic symptoms requiring treatment, or suicidal ideation or attempt within the prior 12 months (stable regimens [for at least 4 weeks prior to SV1] of anti-depressant medications and certain low-dose atypical antipsychotic medications are permitted in case they are indicated to treat symptoms other than psychotic symptoms).
6. Patients who have cancer with the exception of the following: basal cell carcinoma or successfully treated squamous cell carcinoma of the skin; cervical carcinoma in situ; prostatic carcinoma in situ; or other malignancies curatively treated and with no evidence of disease recurrence for at least 3 years.
7. Patients taking certain prohibited medications (see Section 9.4.2).
8. Patients with a history of drug or alcohol abuse within the prior 12 months.
9. Patients with chronic obstructive pulmonary disease (COPD), asthma, or other chronic respiratory disease within the last 5 years.
10. Patients with any contraindication to performing routine spirometry or who are unable to perform a spirometry maneuver (see Appendix 14 for a list of contraindications).
11. Patients with a current history of symptomatic orthostatic hypotension despite adequate treatment.
12. Patients with any condition that in the investigator?s opinion would make patients unable to comply with study procedures or make them unsuitable for participation in the study.
13. Patients who have any clinically significant abnormality or finding from examination, tests, or history that may compromise patient safety. Potential issues of concern should be raised to the medical monitor during eligibility review.
14. Patients who have participated in any prior CVT-301 study, regardless of treatment group assignment.
15. Patients who have been treated with an investigational drug within 4 weeks or 5 half-lives (whichever is longer) prior to the beginning of the screening period (this includes investigational formulations of marketed products). |
Pacientes con discinesia de una intensidad tal que interferiría significativamente con su capacidad de participar o de llevar a cabo los procedimientos del estudio.
? Mujeres embarazadas o en período de lactancia, o mujeres que desean concebir.
? Pacientes con cualquier contraindicación conocida para el uso de LD, incluidos los antecedentes de melanoma maligno o de glaucoma de ángulo estrecho.
? Pacientes que se hayan sometido a una cirugía anterior para la EP (incluida, entre otras, estimulación cerebral o trasplante de células) o tengan pensado someterse a una cirugía estereotáctica durante el período del estudio.
? Pacientes con antecedentes de síntomas psicóticos que requieran tratamiento, o ideas o intentos de suicidio en los 12 meses anteriores (se permiten tratamientos estables [durante al menos las 4 semanas anteriores a la VS1] de antidepresivos y de ciertos medicamentos antipsicóticos atípicos en bajas dosis en caso de que se les haya indicado un tratamiento para sus síntomas que no sean síntomas psicóticos).
?Pacientes con cáncer, excepto los siguientes: carcinoma basocelular o carcinoma espinocelular tratado satisfactoriamente, carcinoma in situ del cuello uterino, carcinoma de próstata in situ u otros tumores malignos tratados curativamente sin pruebas de recidiva de la enfermedad durante al menos 3 años.
? Pacientes que usan ciertos medicamentos prohibidos (véase la Sección 9.4.2).
? Pacientes con antecedentes de drogadicción o alcoholismo en los 12 meses anteriores.
Pacientes con enfermedad pulmonar obstructiva crónica (EPOC), asma u otra enfermedad respiratoria crónica en los últimos 5 años.
? Pacientes con cualquier contraindicación para efectuar las espirometrías de rutina o que no puedan efectuar una maniobra de espirometría (véase en el Anexo 14 una lista de las contraindicaciones).
? Pacientes con historia actual de hipotensión ortostática sintomática a pesar de recibir el tratamiento adecuado.
? Pacientes con cualquier problema médico que, según la opinión del investigador, haga que los pacientes no puedan cumplir los procedimientos del estudio o los hagan no aptos para participar en el estudio.
Pacientes que tienen cualquier anomalía o hallazgo en la exploración o en las pruebas clínicamente importantes, o antecedentes que pueden comprometer la seguridad del paciente. Los posibles temas de preocupación deben comunicarse al monitor médico durante la revisión de la idoneidad.
? Pacientes que hayan participado en cualquier estudio anterior al CVT-301, independientemente del grupo de tratamiento al que se le haya asignado
Pacientes que hayan recibido tratamiento con un medicamento en fase de investigación en las 4 semanas o 5 semividas (lo que sea más prolongado) previas al comienzo del período de selección (esto incluye las formulaciones en fase de investigación de productos comercializados). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The change from pre-dose in the UPDRS Part 3 score at 30 minutes post-dose. |
| El cambio delsdel el momento previo a la administraciion UPDRS parte 3 a los 30 minutos después del tratamiento |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Treatment Visit 4 (week 12). |
| Tratamiento Visita 4 (Semana 12) |
|
| E.5.2 | Secondary end point(s) |
The following endpoints related to the key secondary objectives will be calculated.
? Endpoint related to secondary objective #1: Proportion of patients achieving resolution of an OFF to an ON state within 60 minutes after study drug is administered in the clinic and maintaining the ON at 60 minutes after study drug administration (per the examiner?s subjective assessment). This endpoint will be based on the examiner?s subjective assessment at TV4. In case the assessment of turning on within 60 minutes is missing but the assessment of maintaining the ON at 60 minutes has been done, the patient will be classified based on the available assessment. In case the assessment of maintenance of ON at 60 minutes is missing, the patient will be classified as having missing data.
? Endpoint related to secondary objective #2: Change from pre-dose in UPDRS Part 3 motor score at 20 minutes following treatment of patients experiencing an OFF episode in the clinic at TV4. The missing assessment will be managed similarly as for the primary endpoint.
? Endpoint related to secondary objective #3: The PGI-C rating scale measured pre-dose at TV4. The non-missing values will be categorized as improvements (much improved, improved, a little improved) or non-improvements (no change, a little worse, worse, much worse).
? Endpoint related to secondary objective #4: Change from baseline (3 consecutive days prior to TV1, or in case of missing data, the last 3 recorded days before TV1) in patient-recorded total daily OFF time, assessed by the patient and recorded in the PD Diary for 3 consecutive days prior to TV4 (or in case of missing data, the last 3 recorded days before TV4). The validity of the PD diary entries will be checked prior to including a diary day in the summary calculations. Only valid diary days will be included in the diary summarizations.
o A day will be considered as being valid if at least 80% of the entries during the day have been completed per instructions. That is, for each half hour period, only one entry among the responses (Asleep, OFF, ON without dyskinesia, ON with non-troublesome dyskinesia, or ON with troublesome dyskinesia) has been checked. The entry will not be used if no responses are checked or more than one response is checked. However, if the proportion of entries rejected due to multiple checked responses is large, sensitivity analysis will be performed by using the worst case out of the entries that had been checked. The worst case will be defined in the following order: OFF, ON with troublesome dyskinesia, ON with non-troublesome dyskinesia, ON without dyskinesia, Asleep. In case there are duplicate entries (i.e., multiple entries recorded with same date and time interval), the worst entry will be used for the date and time interval in question. The worst entry will be selected in the order defined above.
o All diary data will be normalized to 16 awake hours per day. The daily OFF time will be extrapolated to a 16 hour period by determining the percentage of OFF time among accurately recorded entries, excluding Asleep time and missing/non-valid recordings, and by multiplying this percentage by 16 hours.
o The mean daily OFF time prior to each visit will be calculated as mean value of the valid days documented in the patient?s diary prior to that visit. In case there are gaps within the 3 days preceding the visit, the last 3 recorded days before the visit will be used regardless of the gaps. If there are more than 3 valid days, only the last 3 days will be used. If there are only 1 or 2 valid days, the average of these days will be used.
? Endpoint related to secondary objective #5: Change from pre-dose in UPDRS Part 3 motor score at 10 minutes following treatment of patients experiencing an OFF episode in the clinic at TV4. The missing assessment will be managed similarly as for the primary endpoint. |
La proporción de pacientes que logran pasar de un estado OFF a un estado ON en un plazo de 60 minutos después de administrarse el medicamento del estudio en la clínica y que mantengan el estado ON a los 60 minutos después de la administración del medicamento del estudio (según la evaluación subjetiva del examinador).
2. El cambio desde el momento previo a la administración en la puntuación motriz de la parte 3 de la UPDRS a los 20 minutos después del tratamiento de pacientes que hayan tenido un episodio OFF.
3. La proporción de pacientes que mejoraron de acuerdo con la escala de puntuación Impresión global de cambio del paciente (PGI-C), medido antes de la administración.
4. El cambio desde el momento previo a la administración en el tiempo OFF/día total evaluado por el paciente y registrado en el diario de la EP durante 3 días consecutivos antes de la VT4.
5. El cambio desde el momento previo a la administración en la puntuación motriz de la parte 3 de la UPDRS a los 10 minutos después del tratamiento de pacientes que hayan tenido un episodio OFF. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| These will be repeated throughout the study where necessary as indicated above. |
| Estos se repetiran durante el estudio donde se necesite como se indica arriba. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Czech Republic |
| Poland |
| Spain |
| 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 |
| Ultima visita Ultimo centro |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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