E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Autosomal Dominant Polycystic Kidney Disease (ADPKD) |
rene policistico autosomico 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. |
il rene policistico è una malattia ereditaria che causa la formazione di cisti nel rene con conseguente ingrossamento del rene e danno renale. |
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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 evaluate and describe the long-term safety of tolvaptan. |
valutare e descrivere la sicurezza a lungo termine di tolvaptan. |
|
E.2.2 | Secondary objectives of the trial |
Not Applicable |
non applicabile |
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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. |
• Soggetti di sesso maschile e femminile di età 18 anni con diagnosi confermata di ADPKD (durante la partecipazione a precedenti sperimentazioni su tolvaptan) che
• provengano da e abbiano completato la sperimentazione in doppio cieco 156-13-210 (periodo di 12 mesi comprendente il follow-up post-trattamento, indipendentemente dal fatto che abbiano ricevuto il trattamento) oppure
• abbiano completato la sperimentazione 156-08-271 o una precedente sperimentazione per la cura dell'ADPKD a base di tolvaptan oppure
• abbiano interrotto o sospeso il trattamento in una precedente sperimentazione per la cura dell'ADPKD tramite tolvaptan, diversa dalla sperimentazione 156-13-210. I soggetti potranno essere arruolati previa approvazione di un responsabile del monitoraggio medico, e all'inizio della sperimentazione potrebbe essere richiesto un ulteriore e più rigoroso monitoraggio.
• Tasso di filtrazione glomerulare stimato (estimated Glomerular Filtration Rate, eGFR) 20 ml/min/1,73 m2 entro 45 giorni dalla visita basale. I soggetti con eGFR tra 15 e 19 ml/min/1,73 m2 potranno essere arruolati previa approvazione di un responsabile del monitoraggio medico.
• La funzionalità renale verrà valutata durante lo screening sulla base dei precedenti valori degli esami di laboratorio (relativi agli ultimi 30 giorni) con riferimento ai livelli di creatinina sierica per il calcolo dell'eGFR. I valori dell’eGFR saranno calcolati secondo la formula dell’epidemiologia della malattia renale cronica (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. |
• Necessità di impiego cronico di diuretici
• Insufficienza epatica calcolata sulla base di esami di laboratorio (alanina aminotransferasi [alanine aminotransferase, ALT], aspartato aminotransferasi [aspartate aminotransferase, AST], bilirubina totale [bilirubin total, BT]) con valori discrepanti da quelli previsti per l'ADPKD con malattia epatica cistica.
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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. |
lo studio non avrà endpoint formali. Le variabili di sicurezza saranno riassunte con metodi di statistica descrittiva (ad es. proporzione, media, mediana, deviazione standard, valori minimo e massimo). In generale, il riassunto delle statistiche, incluse le variazioni dal basale, saranno fornite per le variabili di di sicurezza sulla base di tutti i dati disponibili . Gli endpoint di sicurezza saranno i seguenti:
- eventi avversi
- segni vitali
- valutazioni cliniche di laboratorio
- aumento delle transaminasi seriche per frequenza (2x, 3x, 5x, e 10x ULN), tempo di comparsa, tempo per il raggiungimento del picco, tempo di spostamento (<3x, 2x, o 1x ULN), risposta alla sospensione del farmaco e alla ripresa e frequenza di progressione secondo i criteri di laboratorio di Hy (ALT o AST >3x ULN e bilirubina, totale (BT), >2x ULN senza fosfatasi alcalina ≥2x ULN).
- variazioni di sodio nel siero al di sopra di 145, 150 o 155 mmol/L o sotto 135, 130 o 125 mmol/L.
Endpoint di farmacocinetica: concentrazioni plasmatiche del metabolita DM-4103 di tolvaptan, di tolvaptan e altri metaboliti.
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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. |
nel corso dello studio fino al termine del trattamento e visita di follow up. |
|
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 |
Endpoint esplorativi:
- esiti della valutazione della malattia del rene policistico
- ricorso al pronto soccorso, ricoveri, procedure e terapie) e perdita di giornate produttive a causa della patologia come parte della survey sulla malattia
(da analizzare e riportare separatamente dal clinical study report)
- concentrazione del biomarcatore nel plasma e nelle urinenei soggetti con anomalie epatiche
- DNA potrà essere valutato nei soggetti con anomalie epatiche
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout Study up to end of treatment visit. |
nel corso dello studio fino alla visita di fine trattamento. |
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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 | 10 |
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. |
la data dell’ultimo contatto o la data dell’ultimo tentativo di contatto estrapolata dalla pagina di CRF relativa al follow up post trattamento per l’ultimo soggetto che ha completato il trattamento o che si è ritirato dallo studio. |
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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 |