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 (ADPKD) |
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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. |
ADPKD è una patologia ereditaria che provoca la formazione di cisti nei reni con conseguente 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 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. |
Confrontare l’efficacia, rispetto al placebo, di tolvaptan nella riduzione delle variazioni del tasso di filtrazione glomerulare stimato (estimated glomerular filtration rate, eGFR) dal basale prima del trattamento al follow-up dopo il trattamento, in soggetti affetti da malattia renale cronica (chronic kidney disease, CKD) in fase avanzata dovuta ad ADPKD, che tollerano tolvaptan durante un periodo di run-in iniziale. |
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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. |
Confrontare l’efficacia, rispetto al placebo, di tolvaptan nella pendenza della riduzione dell’eGFR annualizzato, in soggetti affetti da CKD in fase avanzata dovuta ad ADPKD, che tollerano tolvaptan durante un periodo iniziale di run-in.
Confrontare la sicurezza generale ed epatica di tolvaptan con placebo e confrontare l’incidenza delle complicazioni dell’ADPKD (esiti) durante la sperimentazione.
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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 |
• eGFR compreso fra 25 e 65 ml/min/1.73m2 (da 18 a 55 anni) o eGFR compreso fra 25 e 44 ml/min/1.73m2 (da 56 a < 66 anni, solo a discrezione del medical monitor).
• Naïve a tolvaptan.
• Diagnosi di ADPKD in base a criteri modificati di Pei-Ravine
• Con anamnesi familiare: diverse cisti per rene (3 se valutate tramite sonografia, 5 se tramite tomografia computerizzata o risonanza magnetica).
• Senza anamnesi familiare: 10 cisti per rene (tramite uno dei metodi radiologici indicati sopra) ed esclusione di altre malattie cistiche renali. Le condizioni di esclusione includono: cisti renali semplici multiple, acidosi tubolare renale, displasia cistica del rene, rene multicistico, cisti multiloculari del rene, rene cistico midollare e malattia cistica renale acquisita.
• Distribuzione e numero di cisti coerente con il livello osservato di deficit della funzionalità renale.
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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. |
• Bisogno di trattamento cronico con diuretici.
• Deficit epatico o anomalie della funzionalità epatica, diverse da quelle previste per l’ADPKD, malattia cistica del fegato durante il periodo di pre-randomizzazione.
• Soggetti con diabete in fase avanzata (ad esempio emoglobina glicosilata [HgbA1c] > 7,5, e/o glicosuria tramite dipstick, proteinuria importante, retinopatia), ecidenza di malattie renali supplementari importanti (come nefrite glomerulae attiva in corso), tumore ai reni, rene singolo o intervento chirurgico renale recente (negli ultimi 6 mesi) o insufficienza renale acuta.
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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 subject’s IMP treatment duration. |
Differenza di trattamento nella variazione dell’eGFR dal basale pre-trattamento al follow-up post-trattamento, annualizzato (diviso) per ogni durata di trattamento con l’IMP per ogni soggetto. |
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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. |
nel corso dello studio fino al periodo di follow up (3 settimane dopo la fine del trattamento). I valori di eGFR saranno calcolati dal laboratorio centralizzato sulla concentrazione di creatinina nel siero prelevato allo screening e durante tutte le visite di studio, incluse le visite di follow up. |
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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
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Principale endpoint secondario di efficacia:
Differenza di trattamento nella riduzione dell’eGFR annualizzato, calcolata per singoli soggetti utilizzando un’appropriata valutazione sul trattamento disponibile al basale e post-randomizzazione.
Endpoint di sicurezza:
1) EA
2) Segni vitali
3) Test clinici di laboratorio, inclusa transaminasi sierica, bilirubina totale (BT), fosfatasi alcalina (alkaline phosphatase, ALP) e sodio sierico.
Endpoint PK: Metaboliti e tolvaptan nel plasma, incluse concentrazioni nel plasma di DM-4103.
Endpoint PD: Uosm e gravità specifica delle urine.
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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. |
Gli endpoint di efficacia e sicurezza saranno valutati durante il corso dello studio incluso il periodo di follow up (3 settimane dopo la fine del trattamento).
Gli endpoint PK saranno valutati:
- Alla fine del periodo di run-in con tolvaptan (day -1)
- Durante il periodo di randomizzazione al trattamento in doppio cieco, al Mese 3, 6, 9, 12 / EoTx
- All’ultima visita di follow up
Gli endpoint di PD saranno valutati:
- Alla seconda visita del periodo di screening
- al termine del periodo di run-in con placebo (day -36)
- al termine del periodo di titolazione con tolvaptan (day -22)
- al termine del periodo di run-in con tolvaptan (day -1) - durante il periodo di randomizzazione al trattamento in doppio cieco al Mese 3, 6, 9 e 12 /EoTx - all’ultima visita di follow up |
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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 | 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 |
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 data dell’ultimo contatto con il soggetto |
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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 |