|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Autosomal Dominant Polycystic Kidney Disease (ADPKD)
|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.
|Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
|E.1.2 Medical condition or disease under investigation
|Polycystic kidney, autosomal dominant
|System Organ Class
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To evaluate and describe the long-term safety of tolvaptan.
|Secondary objectives of the trial
|Trial contains a sub-study
|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.
|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.
|E.5 End points
|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
- 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
Tolvaptan metabolite DM-4103, tolvaptan, and other tolvaptan metabolite plasma concentrations.
|Timepoint(s) of evaluation of this end point
|Throughout Study up to end of treatment and follow up visit.
|Secondary end point(s)
- 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
|Timepoint(s) of evaluation of this end point
|Throughout Study up to end of treatment visit.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|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.
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months