E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Autosomal Dominant Polycystic Kidney Disease (ADPKD) |
Enfermedad renal poliquística autosómica dominante |
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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), 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 | 17.0 |
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 compare the efficacy of tolvaptan treatment in reducing the change in estimated glomerular filtration rate (eGFR) from pre-treatment baseline to post-treatment followup, as compared with placebo, in subjects with late-stage chronic kidney disease (CKD) due to ADPKD who tolerate tolvaptan during an initial run-in period. |
Comparar la eficacia del tratamiento entre tolvaptán y placebo en la reducción del cambio de la tasa de filtración glomerular estimada (TFGe) entre la línea inicial pretratamiento y el seguimiento postratamiento, en sujetos con enfermedad renal crónica (ERC) avanzada por PQRAD que toleran tolvaptán durante un periodo de preinclusión inicial. |
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E.2.2 | Secondary objectives of the trial |
To compare the efficacy of tolvaptan treatment in reducing the decline of annualized eGFR slope, as compared with placebo, in subjects with late-stage CKD due to ADPKD who tolerate tolvaptan during an initial run-in period. To compare overall and hepatic safety of tolvaptan with placebo and to compare incidence of ADPKD complications (outcomes) during the trial. |
Comparar la eficacia del tratamiento entre tolvaptán y placebo en la reducción del descenso de la pendiente de la TFGe anualizada, en pacientes con ERC avanzada por PQRAD que toleran tolvaptán durante un periodo de preinclusión inicial. Comparar la seguridad global y hepática entre tolvaptán y placebo y comparar la incidencia de complicaciones de la PQRAD (resultados) durante el ensayo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female subjects age 18 to 55 years of age (inclusive) with eGFR between 25 and 65 mL/min/1.73m2 -OR- 2. Male and female subjects age 56 to < 66 years of age with eGFR between 25 and 44 mL/min/1.73m2 (by medical monitor discretion, only). 3. Male and female subjects who are tolvaptan naïve. 4. Diagnosis of ADPKD by modified Pei-Ravine criteria18 19: - with family history: several cysts per kidney (3 if by sonography, 5 if by CT or MRI) - without family history: 10 cysts per kidney (by any radiologic method, above) and exclusion of other cystic kidney diseases. Conditions to be excluded include: multiple simple renal cysts, renal tubular acidosis, cystic dysplasia of the kidney, multicystic kidney, multilocular cysts of the kidney, medullary cystic kidney and acquired cystic disease of the kidney. - Distribution and number of cysts consistent with the observed level of renal function deficit |
1. Varones y mujeres de 18 a 55 años de edad (ambos inclusive) con una TFGe entre 25 y 65 ml/min/1,73 m2 -O- 2. Varones y mujeres de 56 a < 66 años de edad con una TFGe entre 25 y 44 ml/min/1,73 m2 (según el criterio del supervisor médico exclusivamente). 3. Varones y mujeres no tratados anteriormente con tolvaptán. 4. Diagnóstico de PQRAD según los criterios modificados de Pei-Ravine18, 19: ? Con antecedentes familiares: varios quistes en cada riñón (3 si se evalúan mediante ecografía, 5 si se visualizan mediante TC o RM). ? Sin antecedentes familiares: 10 quistes en cada riñón (visualizados mediante cualquiera de los métodos radiológicos mencionados anteriormente) y exclusión de otras enfermedades renales quísticas. Entre los trastornos a excluir se encuentran: múltiples quistes simples del riñón, acidosis tubular renal, displasia renal quística, poliquistosis renal, quistes multiloculares renales, nefropatía quística medular y enfermedad renal quística adquirida. ? Distribución y número de quistes coherentes con el grado observado de déficit de la función renal. |
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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 pill, birth control implant, birth control depot injection, condom, or sponge with spermicide. 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 or liver function abnormalities other than that expected for ADPKD with typical cystic liver disease during the pre-randomization period. 5. Subjects with advanced diabetes (eg, glycosylated hemoglobin [HgbA1c] > 7.5, and/or glycosuria by dipstick, significant proteinuria, retinopathy), evidence of additional significant renal disease(s) (ie, currently active glomerular nephritidies), renal cancer, single kidney, or recent (within last 6 months) renal surgery or acute kidney injury. 6. Subjects with contraindications to required trial assessments. 7. Subjects who, in the opinion of the trial investigator or medical monitor, have a medical history or medical findings inconsistent with safety or compliance with trial assessments. |
1. Mujeres en edad fértil (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 periodo de lactancia y/o con resultado positivo en un test de embarazo antes de recibir el PEI. 3. Necesidad de uso crónico de diuréticos. 4. Alteración hepática o anomalías de la función hepática diferentes a la esperada por una PQRAD, con típica enfermedad hepática quística, durante el periodo previo a la aleatorización. 5. Los sujetos con diabetes avanzada (p. ej., hemoglobina glicosilada [HgbA1c] > 7,5, y/o glucosuria en tira reactiva, proteinuria importante, retinopatía), evidencia de enfermedad o enfermedades renales importantes adicionales (es decir, glomerulonefritis actualmente activa), cáncer renal, riñón único, cirugía renal reciente (en los últimos 6 meses) o lesión renal aguda. 6. Sujetos con contraindicaciones a las evaluaciones necesarias del ensayo. 7. Sujetos que, en opinión del investigador del ensayo o del supervisor médico, tienen un historial médico o hallazgos médicos contradictorios de seguridad o del cumplimiento de las evaluaciones del ensayo. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Treatment difference in the change of eGFR from pre-treatment baseline to posttreatment follow-up, annualized (divided) by each subjects IMP treatment duration. |
La diferencia del tratamiento en el cambio de la TFGe entre condiciones iniciales pretratamiento y el seguimiento postratamiento, anualizado (dividido) según la duración del tratamiento con el PEI en cada sujeto |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout study up to the Follow up period (3 week post treatment end). The eGFR values will be calculated from the central-laboratory serum creatinine concentrations taken at screening and during every trial visit including follow up visit. |
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E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoint Treatment difference in annualized slope of eGFR calculated for individual subjects using an appropriate baseline and available, post-randomization, on-treatment assessments. Safety Endpoints Safety endpoints to be analyzed will include a descriptive summary of: 1)AEs 2)Vital signs 3)Clinical laboratory tests, including serum transaminases, BT, ALP, and serum sodium Pharmacokinetic/Pharmacodynamic Endpoints PK Endpoints: Determination of plasma tolvaptan and metabolite(s), including DM-4103 concentrations. PD Endpoints: Uosm and urine specific gravity |
Criterio de valoración secundario clave de la eficacia: Diferencia del tratamiento en la pendiente de la TFGe anualizada y calculada para los sujetos individuales, usando evaluaciones iniciales apropiadas y las disponibles con tratamiento tras la aleatorización. Criterios de valoración de la seguridad: 1) AA 2) Constantes vitales 3) Pruebas de laboratorio clínico, incluidas transaminasas séricas, bilirrubina total (BT), fosfatasa alcalina (FA) y sodio sérico Criterios de valoración FC: Concentraciones plasmáticas de tolvaptán y metabolito(s), incluidas las concentraciones plasmáticas de DM-4103. Criterios de valoración FD: OsmU y densidad específica de la orina |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy and Safety endpoints will be assessed throughout study up to and including the Follow up period (3 week post treatment end). PK endpoint assessed: End of the tolvaptan run-in period (Day -1) During the double-blind, randomized treatment period at Months 3, 6, 9, 12/EoTx, At the last follow-up visit PD endpoint assessed: second visit of the screening period end of the placebo run-in period (Day -36) end of the tolvaptan titration period (Day -22) end of the tolvaptan run-in period (Day -1) during the double-blind, randomized treatment period at Months 3, 6, 9, and 12/EoTx at the last follow-up visit. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | 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 | 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 | 6 |
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 |
Korea, Republic of |
Malaysia |
Mexico |
Netherlands |
Norway |
Peru |
Poland |
Romania |
Russian Federation |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Turkey |
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 last contact with the subject. |
La fecha de final del ensayo se define como la fecha del último contacto con el sujeto |
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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 | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |