E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Autosomal Dominant Polycystic Kidney Disease (ADPKD) |
Poliquistosis renal autosómica dominante (PQRAD) |
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E.1.1.1 | Medical condition in easily understood language |
ADPKD is an inherited condition (passed from ones parents) that causes cysts (fluid filled sacs) to develop on the kidneys. It causes the kidneys to get bigger over time and for the kidneys to fail. |
PQRAD es una afección hereditaria que produce la destrucción progresiva de la estructura normal del riñón y da lugar a una enfermedad renal terminal (ERT). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036046 |
E.1.2 | Term | Polycystic kidney, autosomal dominant |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate and describe the long-term safety of tolvaptan. |
Evaluar y describir la seguridad a largo plazo de tolvaptán |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female subjects aged > 18 years with confirmed diagnosis of ADPKD (during participation in prior tolvaptan trials) who have
- Completed and transferred from the double-blind Trial 156-13-210 (12-month period including post-treatment follow-up, regardless of whether this was on-treatment or off-treatment), or
- Completed Trial 156-08-271 or a prior tolvaptan trial, or
- Interrupted or discontinued treatment in a tolvaptan trial other than Trial 156-13-210. Subjects may be enrolled with the medical monitor approval, and additional close monitoring may be required at the beginning of the trial
- Renal function will be assessed during screening by using historical laboratory values (in the last 30 days) for serum creatinine levels to calculate the estimated glomerular filtration rate (eGFR). The eGFR values will be estimated based on the Chronic Kidney Disease - Epidemiology (CKD-EPI) formula.
2. Estimated glomerular filtration rate > 20 mL/min/1.73 m2 (calculated using the CKD-EPI formula) within 45 days prior to the baseline visit. Subjects who have an eGFR between 15 and 19 mL/min/1.73 m2 may be permitted with documented medical monitor approval prior to enrollment. |
? Sujetos de ambos sexos mayores de 18 años con diagnóstico confirmado de PQRAD (durante su participación en ensayos previos con tolvaptán) que ? han completado y han sido transferidos del ensayo doble ciego 156-13-210 (período de 12 meses, incluido el seguimiento posterior al tratamiento, con independencia de si fue en tratamiento o fuera del mismo), o ? hayan completado el ensayo 156-08-271 o un ensayo previo de PQRAD con tolvaptán, o ? hayan interrumpido o suspendido su participación en un ensayo previo de PQRAD con tolvaptán (distinto del ensayo 156-13-210). Se puede inscribir a los sujetos con la aprobación del supervisor médico y es posible que sea necesaria una atenta supervisión adicional al comienzo del ensayo. ? Filtración glomerular estimada (FGe) ?20 ml/min/1,73 m2 en el plazo de 3 meses desde la visita inicial. Los sujetos que tengan una FGe ?20 ml/min/1,73 m2 pueden inscribirse con la aprobación del supervisor médico y del promotor, y un aumento de la frecuencia de supervisión para garantizar la seguridad de los sujetos. ? La función renal se evaluará durante la selección mediante el uso de valores analíticos históricos (dentro de los 3 meses previos a la visita de selección) para los niveles séricos de creatinina con el fin de calcular la FGe. Los valores de la FGe se calcularán mediante la fórmula Enfermedad Renal Crónica-Epidemiología (Chronic Kidney Disease-Epidemiology, CKD-EPI) |
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E.4 | Principal exclusion criteria |
1. Women of childbearing potential (WOCBP) who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of IMP. If employing birth control, 2 of the following precautions must be used: vasectomy of partner, tubal ligation, vaginal diaphragm, intrauterine device, birth control.
2. Women who are breast-feeding and/or who have a positive pregnancy test result prior to receiving IMP.
3. Need for chronic diuretic use.
4. Hepatic impairment based on liver function abnormalities other than that expected for ADPKD with cystic liver disease during screening.
5. Subjects with contraindications to required trial assessments (contraindications to optional assessments, eg, MRI are not a limitation).
6. Subjects who, in the opinion of the investigator or medical monitor, have a medical history or medical finding inconsistent with safety or trial compliance. This includes prior evidence of significant hepatic injury deemed to be related to tolvaptan use. |
1. MEF que no acepten utilizar 2 métodos anticonceptivos diferentes o no mantener relaciones sexuales durante el ensayo y los 30 días posteriores a la última dosis del PEI. Si emplean un método anticonceptivo, deben utilizarse 2 de las siguientes precauciones: vasectomía del compañero, ligadura de las trompas, diafragma vaginal, dispositivo intrauterino, píldora anticonceptiva, implante anticonceptivo, inyección anticonceptiva depot, preservativo o esponja con espermicida. 2.Mujeres en período de lactancia y/o con resultado positivo en una prueba de embarazo antes de recibir el PEI. 3. Necesidad de uso crónico de diuréticos. 4. Alteración hepática basada en anomalías de la función hepática diferentes a la esperada por una PQRAD, con típica enfermedad hepática quística, durante la selección basada en valores analíticos históricos recientes (en los 3 últimos meses). 5. Los sujetos con contraindicaciones para las evaluaciones obligatorias para el ensayo (las contraindicaciones para las evaluaciones opcionales, p. ej., una RM, no son una limitación). 6. Sujetos que, en opinión del investigador o del supervisor médico, tienen antecedentes médicos o hallazgos médicos contradictorios de seguridad o del cumplimiento del ensayo. Esto incluye evidencia previa de lesión hepática significativa que se considere relacionada con el uso de tolvaptán |
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E.5 End points |
E.5.1 | Primary end point(s) |
This trial will have no formal endpoints. Safety variables will be summarized by descriptive statistics, (eg, proportion, mean, median, standard deviation [SD], minimum, and maximum values). In general, summary statistics, including changes from baseline, will be provided for safety variables based on all available data. Safety endpoints will be as follows:
- Adverse events
- Vital signs
- Clinical laboratory assessments
- Serum transaminase elevations for frequency (2x, 3x, 5x and 10x ULN), time to onset, time to peak levels, time of offset (< 3x, 2x, or 1x ULN), response to de-challenge and re-challenge and frequency of progression to Hy?s laboratory criteria (ALT or AST > 3x ULN and bilirubin, total (BT), > 2x ULN without alkaline phosphatase ? 2x ULN)
- Serum sodium excursions above 145, 150, or 155 mmol/L or below 135, 130, or 125 mmol/L
Pharmacokinetic Endpoints Tolvaptan metabolite DM-4103, tolvaptan, and other tolvaptan metabolite plasma concentrations. |
Las variables de la seguridad se resumirán mediante estadísticas descriptivas, (p. ej., proporción, media, mediana, desviación estándar [DE], valores mínimo y máximo). En general, las estadísticas de resumen, incluidos los cambios con respecto al inicio, se proporcionarán para variables de la seguridad basándose en todos los datos disponibles. Los criterios de valoración de la seguridad serán los siguientes: ? Acontecimientos adversos ? Constantes vitales ? Evaluaciones de laboratorio clínico ? Elevaciones de las transaminasas séricas por frecuencia (2x, 3x, 5x y 10x LSN), tiempo hasta el inicio, tiempo hasta niveles máximos, tiempo hasta la desaparición (<3x, 2x o 1x LSN), respuesta a la retirada y la reintroducción y frecuencia de progresión hasta los criterios analíticos de Hy (ALT o AST >3x LSN y BT >2x LSN sin fosfatasa alcalina ?2x LSN) ? Desviaciones del sodio sérico por encima de 145, 150 o 155 mmol/l o por debajo de 135, 130 o 125 mmol/l |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout Study up to end of treatment and follow up visit. |
A lo largo del tratamiento hasta el final del tratamiento y la visita de seguimiento. |
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E.5.2 | Secondary end point(s) |
Exploratory Endpoints
- Polycystic kidney disease (PKD) outcomes survey
- Medical resource utilization (office/emergency room healthcare visits, hospital admissions, procedures and therapies) and productive days lost due to PKD outcomes will be reported for subjects as part of the ADPKD outcomes survey
(To be analyzed and reported separately from the clinical study report).
- Urine and plasma biomarker concentrations in subjects with liver abnormalities
- DNA (with separate consent) may be assessed in subjects with liver abnormalities |
? Encuesta de resultados de la poliquistosis renal (PQR). ? La utilización de recursos médicos (visitas a la clínica/urgencias, ingresos hospitalarios, procedimientos y tratamientos) y la pérdida de días laborables por PQR de los sujetos se registrarán en el informe de resultados de PQRAD. Seguridad: Estos análisis pueden llevarse a cabo y registrarse de forma independiente del informe del estudio clínico. ? Concentraciones de biomarcadores en orina y plasma en sujetos con alteraciones hepáticas. ? Se puede evaluar el ADN (con un consentimiento separado) en sujetos con alteraciones hepáticas. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout Study up to end of treatment visit. |
A lo largo del estudio y hasta la visita de final del tratamiento |
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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 | No |
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 | 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 | Yes |
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 | 81 |
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 |
Argentina |
Australia |
Belgium |
Brazil |
Canada |
Chile |
Colombia |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Israel |
Italy |
Mexico |
Netherlands |
Norway |
Peru |
Poland |
Romania |
Russian Federation |
South Africa |
Spain |
Sweden |
Switzerland |
United Kingdom |
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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The End of Trial date is defined as the last date of contact or the date of final contact attempt from the post-treatment Follow-up CRF page for the last subject completing or withdrawing from 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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |