Tolvaptan Phase 3 Efficacy and Safety Study in ADPKD (TEMPO3/4)

• Time to onset of multiple ADPKD outcomes [ Time Frame: 36 months ] [ Designated as safety issue: No ]
  ADPKD outcomes include new onset hypertension, worsening hypertension, renal pain, worsening albuminuria and worsening renal function
• Evaluate long-term efficacy of tolvaptan in ADPKD using single clinical 4-markers of ADPKD progression [ Time Frame: 36 months ] [ Designated as safety issue: No ]
• Evaluate long-term safety of tolvaptan through standard clinical measures. [ Time Frame: 36 months ] [ Designated as safety issue: Yes ]
• Evaluate pharmacokinetic (PK), pharmacodynamic (PD) and exploratory parameters for tolvaptan in ADPKD. [ Time Frame: 36 months ] [ Designated as safety issue: No ]

• Evaluate long-term efficacy of tolvaptan in ADPKD through a composite of ADPKD progression clinical markers (ie, hypertension, renal pain, albuminuria and renal function).
• Evaluate long-term efficacy of tolvaptan in ADPKD using single clinical 4-markers of ADPKD progression
• Evaluate long-term safety of tolvaptan through standard clinical measures.
• Evaluate pharmacokinetic (PK), pharmacodynamic (PD) and exploratory parameters for tolvaptan in ADPKD.

This study's purpose is to evaluate the long-term safety and efficacy of tolvaptan versus placebo in patients with ADPKD.

The current study will evaluate whether tolvaptan will be potentially beneficial, while maintaining an adequate safety profile, by reducing the rate of total renal volume increase, while impacting the onset, severity and progression of other important consequences of ADPKD.

• Drug: tolvaptan
  oral tablet split-dose regimens (45/15mg, 60/30 mg or 90/30 mg) by mouth twice a day on awakening and approximately 9 hours later for 36 months. Daily dose regimen based on maximally tolerated dose.
  Other Name: OPC-41061 or OPC-156
• Drug: Placebo
  oral tablet split-dose regimens (45/15mg Placebo, 60/30 mg Placebo or 90/30 mg Placebo) by mouth twice a day on awakening and approximately 9 hours later for 36 months. Daily dose regimen based on maximally tolerated dose.

• Experimental: Tolvaptan
  Intervention: Drug: tolvaptan
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

• Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med. 2003 Oct;9(10):1323-6. Epub 2003 Sep 21.
• Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH 2nd. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med. 2004 Apr;10(4):363-4. Epub 2004 Feb 29.
• Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012 Dec 20;367(25):2407-18. doi: 10.1056/NEJMoa1205511. Epub 2012 Nov 3.

Inclusion Criteria:

• GFR estimated at ≥60 mL/ min
• Diagnosis of ADPKD and rapidly progressive kidney growth (total volume ≥750 cc) by Magnetic Resonance Imaging (MRI) at randomization
• Legal adult age and able to give Informed Consent
• Willingness to comply with reproductive precautions if female

Exclusion Criteria:

• Prior exposure to tolvaptan or other experimental PKD therapies
• Currently taking medication for purpose of affecting PKD cysts
• Women who are breast feeding and females of childbearing potential who are not using acceptable contraceptive methods
• In the opinion of the study investigator or sponsor may present a safety risk or confound study objectives
• Patients who are unlikely to adequately comply with study procedures
• Patients having contraindications to MRI
• Patients taking medications or having any illnesses likely to affect ADPKD outcomes.