Efficacy and Safety of Tolvaptan in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease

The protocol will extend the understanding of the efficacy and safety of tolvaptan treatment
in ADPKD patients with late stage 2 to early stage 4 CKD (chronic kidney disease).

This trial will compare the efficacy of tolvaptan treatment in reducing the annualized change
in estimated glomerular filtration rate (eGFR) from pre-treatment baseline to post-treatment
follow-up, as compared with placebo, in subjects who tolerate tolvaptan during an initial
run-in period. The change in eGFR, calculated by the Chronic Kidney Disease-Epidemiology
(CKD-EPI) formula, will provide kidney function data that are complementary to the data
demonstrating the benefits previously observed primarily in ADPKD subjects with earlier
stages of disease.

Also, it will compare the efficacy of tolvaptan treatment in reducing the decline of
annualized eGFR slope, as compared with placebo, in this type of subjects. Finally, it will
compare the overall and hepatic safety profile of tolvaptan with placebo and to compare
incidence of ADPKD complications (outcomes) during the trial

Inclusion Criteria:

- Male and female subjects with eGFR between 25-65 mL/min/1.73m2 (if aged 18 to55) or
eGFR between 25-44 mL/min/1.73m2 (if aged 56 to <66)

- Tolvaptan naïve

- Diagnosis of ADPKD by modified pei-Ravine criteria 1) 3 cysts per kidney by sonography
or 5 cysts by CT or MRI with family history of ADPKD or 2) 10 cysts per kidney by any
radiologic method and exclusion of other cystic kidney diseases if without family
history

Exclusion Criteria:

- Women of childbearing potential 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 Investigational medicinal product (IMP)

- Women who are breast-feeding and/or who have a positive pregnancy test prior to
receiving IMP

- Need for chronic diuretic use

- Hepatic impairment or liver function abnormalities other than that expected for ADPKD
with typical cystic liver disease

- Advanced diabetes, evidence of additional significant renal disease, renal cancer,
single kidney, recent renal surgery or acute kidney injury

- Contraindications to required trial assessments

- Medical history or medical findings inconsistent with safety or compliance with trial
assessments