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 de la respuesta motriz (fenómeno OFF) |
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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 inmovilidad o bloqueo |
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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 | 19.0 |
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 |
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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 characterize the effects of CVT-301 on pulmonary safety, as assessed by spirometry (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and FEV1/FVC ratio) over a 12-month period. |
? Caracterizar los efectos de CVT-301 sobre la seguridad pulmonar, evaluada mediante espirometría (volumen espiratorio forzado en 1 segundo [VEF1], la capacidad vital forzada [CVF] y el cociente VEF1/CVF), durante un período de 12 meses. |
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E.2.2 | Secondary objectives of the trial |
? 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 examiner?s subjective assessment) Patient-reported total daily OFF time, total daily ON time without dyskinesia, total daily ON time with non-troublesome dyskinesia, and total daily ON time with troublesome dyskinesia, assessed by the patient and recorded in the patient diary ? Change from baseline visit 39-Item PD Questionnaire (PDQ-39) ? Proportion of patients who improved based on the Patient Global Impression of Change (PGI-C) rating scale measured pre-dose ? Change from baseline visit Schwab and England (S&E) Activities of Daily Living (ADL) score ? Change from baseline visit 9-Item Patient Health Questionnaire (PHQ-9) ? Change from baseline visit Impact of Parkinson?s OFF Episodes Patient Survey ? Change from baseline visit UPDRS Part 2 score |
?Proporción de pacientes que logran la resolución de un estado OFF al estado ON en los 60 min después de la administración del medicamento del estudio en la clínica y que mantienen el estado ON a los 60 minutos de la administración del medicamento del estudio (según la evaluación subjetiva del examinador). ?Cambio con respecto a los valores iniciales en el cuestionario para la enfermedad de Parkinson de 39 preguntas (PDQ-39) ?Proporción de pacientes que mejoran, de acuerdo con la puntuación de la escala de Impresión global de cambio del paciente (PGI-C) ?Cambio con respecto a los valores iniciales de la puntuación de las actividades de la vida diaria (AVD) según Schwab y England (S&E) ?Cambio con respecto a los valores iniciales en el cuestionario (PHQ-9) ?Cambio con respecto a los valores iniciales en la encuesta de influencia de los episodios OFF de la enfermedad de Parkinson ?Cambio con respecto a los valores iniciales en la puntuación de la Parte 2 de la UPDRS. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria (not assessed for the CVT-301-004 study patients): ? Has signed and dated an IRB/IEC-approved informed consent form before any protocol-specific screening procedures are performed. ? Is a male or female aged 30 to 86 years, inclusive. Women of child-bearing potential must use protocol-defined contraceptive measures 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. ? 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. ? 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. ? 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. ? 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/dopamine decarboxylase inhibitor (DDI)-containing regimen. ? 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 ? 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 ? Patients should be stable on other PD medications for at least 4 weeks prior to SV1. ? Patients must have a ?25% difference between UPDRS Part 3 scores recorded in their ON and OFF states at screening. ? Patients must have normal cognition as confirmed by a score of ?25 on the MMSE (in the ON state). ? 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. (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.) |
Criterios de inclusión (no se evalúan para los pacientes del estudio CVT-301-004): ?Ha firmado y fechado un formulario de consentimiento informado aprobado por el IRB/CEIC antes de que se lleve a cabo cualquier procedimiento de selección específico del protocolo. ?Es hombre o mujer de 30 a 86 años de edad, inclusive. Las mujeres con capacidad para procrear deben tomar medidas anticonceptivas definidas n 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 cumplimiento de los pasos 1 y 2 de los criterios del Banco de Cerebros del Reino Unido (RU), 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 autoinformes y confirmadas por el diario de la EP (durante 3 días consecutivos) durante el período de selección. ?Los pacientes que estén recibiendo un tratamiento con LD, excepto Rytary (o equivalente), deben estar estabilizados en un tratamiento con LD por vía oral durante al menos 2 semanas antes de la VS1 con un régimen con LD/un inhibidor de la dopamina descarboxilasa (DDI). ?Los pacientes que estén recibiendo un tratamiento con LD, si incluye Rytary (o equivalente), deben estar recibiendo una dosis estable durante al menos 6 semanas antes de la VS1. ?La frecuencia de las administraciones de L-dopa debe ser de al menos 3 veces durante la vigilia, con una dosis diaria total 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 presentar cognición normal, confirmada por una puntuación ? 25 en el MMSE (en estado ON). ?Los pacientes deben tener la capacidad de efectuar una maniobra de espirometría en los estados ON y OFF, y presentar un valor VEF1 en 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/la morfología de la espirometría de todos los pacientes con un valor VEF1 que esté entre ? 50 y < 60 % de lo previsto o un cociente VEF1/CVF entre > 60 % y < 70 % para determinar su posible 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.) |
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E.4 | Principal exclusion criteria |
? Patients who have dyskinesia of a severity that would significantly interfere with their ability to participate or perform study procedures. ? Pregnant or lactating females or females wishing to become pregnant. ? Patients who have any known contraindication to the use of LD, including a history of malignant melanoma or a history of narrow-angle glaucoma. ? Patients who have had previous surgery for PD (including but not limited to cell transplantation) or plan to have stereotactic surgery during the study period. Patients who have had deep brain stimulation [DBS] will also be excluded unless the procedure was performed more than 6 months prior to study enrollment. ? Patients with a history of psychotic symptoms requiring treatment, or suicidal ideation or attempt within the prior 12 months. ? 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. ? Patients taking certain prohibited medications. ? Patients with a history of drug or alcohol abuse within the prior 12 months. ? Patients with chronic obstructive pulmonary disease (COPD), asthma, or other chronic respiratory disease within the last 5 years ? Patients with any contraindication to performing routine spirometry or who are unable to perform a spirometry maneuver. ? Patients with a current history of symptomatic orthostatic hypotension despite adequate treatment. ? Patients with any condition that in the investigator?s opinion would make patients unable to comply with study procedures or make them unsuitable for their participation in the study. ? 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. ? For new CVT-301 naïve patients, patients who have been treated with an investigational drug within 4 weeks or 5 halflives (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 hayan tenido intervenciones quirúrgicas anteriores para la EP (entre ellas, trasplante de células) o planeen someterse a cirugía estereotáctica durante el período del estudio. Los pacientes que hayan tenido estimulación cerebral profunda [ECP] también serán excluidos, a menos que el procedimiento se haya efectuado más de 6 meses antes de la inscripción en el estudio. ?Pacientes con antecedentes de síntomas sicóticos que requieran tratamiento o ideas o intentos de suicidio en los 12 meses anteriores. ?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 Appendix 15 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 que haga que sean inadecuados para su participación 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. ?En el caso de los pacientes que no han recibido anteriormente CVT-301, 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). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoints related to the primary objective of the study are the pulmonary safety measures, FEV1, FVC and FEV1/ FVC ratio, assessed over a 12 month period. FEV1, FVC and FEV1/FVC ratio will be recorded from the single ?best test? (based on effort with highest summed FEV1 and FVC). Variables will include the absolute FEV1, FVC, and FEV1/FVC ratio and FEV1 and FVC expressed as % of predicted value. Percent Predicted = 100 * (Observed) / Predicted, where predicted is calculated and provided to INC by Biomedical Systems (BMS). |
?Caracterizar los efectos de CVT-301 sobre la seguridad pulmonar, evaluada mediante espirometría (volumen espiratorio forzado en 1 segundo [VEF1], la capacidad vital forzada [CVF] y el cociente VEF1/CVF), durante un período de 12 meses. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Changes from baseline (TV1) for each variable will be calculated at each subsequent visit. |
Cambios desde el inicio (VT1) para cada variable se calculará en cada visita subsiguiente |
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E.5.2 | Secondary end point(s) |
?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. 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. ?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 in-clinic visits (or in case of missing data, the last 3 recorded days before the visit). 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. Change from baseline in total daily ON time without dyskinesia, total daily ON time with non-troublesome dyskinesia, and total daily ON time with troublesome dyskinesia will be calculated similarly. ?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. ?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.
Off Time / (Total time recorded ? Asleep Time ? missing time interval) x 16 ?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. ?Change from TV1 in PDQ-39 sub-scores and summary index score. The questionnaire provides scores on eight dimensions: mobility, activities of daily living, emotional well-being, stigma, social support, cognitions, communication, bodily discomfort. ?Change from TV1 (pre-dose) to TV6 (pre-dose) in 9-Item PHQ-9 sum score. The sum score will be calculated as the sum of the 9 individual questions. In case of 1 or more missing questions, the sum score will be set as missing. ?Change from baseline to TV6 in Impact of Parkinson?s OFF Episodes Patient Survey. The Impact of Parkinson?s OFF episodes patient survey score will be calculated as the sum of the individual items of the Impact of Parkinson?s OFF Episodes Patient Survey questionnaire. Missing individual items will not be imputed and the sum score will be missing in case of 1 or more missing items. ?The PGI-C score. 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). ?Change from TV1 (baseline) Schwab and England (S&E) Activities of Daily Living (ADL). No further derivation will be done for the S&E scores. ?Change from TV1 (pre-dose) to TV6 (pre-dose) in the UPDRS Part 2 score. The UPDRS Part 2 score will be calculated as the sum of the individual items of the UPDRS Part 2 questionnaire (UPDRS items 5-17). Missing individual items will not be imputed and the sum score will be missing in case of 1 or more missing items. |
? Proporción de pacientes que logran la resolución de un estado OFF al estado ON en los 60 minutos después de la administración del medicamento del estudio en la clínica y que mantienen el estado ON a los 60 minutos de la administración del medicamento del estudio (según la evaluación subjetiva del examinador). Tiempo diario total OFF informado por el paciente, tiempo diario total ON sin discinesia, tiempo diario total ON con discinesia no problemática y tiempo diario total ON con discinesia problemática, evaluados por el paciente y registrados en el diario del paciente. ? Cambio con respecto a los valores iniciales en el cuestionario para la enfermedad de Parkinson de 39 preguntas (PDQ-39) ? Proporción de pacientes que mejoran, de acuerdo con la puntuación de la escala de Impresión global de cambio del paciente (PGI-C) ? Cambio con respecto a los valores iniciales de la puntuación de las actividades de la vida diaria (AVD) según Schwab y England (S&E) ?Cambio con respecto a los valores iniciales en el cuestionario de salud del paciente de 9 preguntas (PHQ-9) ?Cambio con respecto a los valores iniciales en la encuesta de influencia de los episodios OFF de la enfermedad de Parkinson ?Cambio con respecto a los valores iniciales en la puntuación de la Parte 2 de la UPDRS. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Changes from baseline (TV1) for each variable will be calculated at each subsequent visit. |
Cambios desde el inicio (VT1) para cada variable se calculará en cada visita subsiguiente |
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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 | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | No |
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 | 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 |
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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
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LVLS |
Ultima visita del último centro |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
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 |