Tolvaptan Open-Label Pilot Efficacy, Tolerability and Safety Study in ADPKD (TEMPO 2/4)

• The evaluation of long-term safety of tolvaptan in patients with ADPKD with various dosing regimens:
• Safety:Adverse events,vital signs,clinical laboratory tests,12- lead electrocardiograms.

• Trough Urine Osmolality at steady state [ Time Frame: 36 Months ] [ Designated as safety issue: No ]
  Change from baseline at each study visit.
• Change in Total Kidney Volume (TKV) [ Time Frame: 36 Months ] [ Designated as safety issue: No ]
• Renal function by estimated GFR [ Time Frame: 36 Months ] [ Designated as safety issue: No ]
• Trough Urine Osmolality at Steady State [ Time Frame: Extension Day 1, Extension Year 1 ] [ Designated as safety issue: No ]
• Change in Total Kidney Volume [ Time Frame: Extension Day 1, Extension Year 1 ] [ Designated as safety issue: No ]
• Renal function by estimated GFR [ Time Frame: Extension Day 1, Extension Year 1 ] [ Designated as safety issue: No ]

This study's purpose is to evaluate the long-term safety of open-label tolvaptan regimens to determine the maximally-tolerated dose and acquire pilot efficacy data in patients with ADPKD.

Autosomal Dominant Polycystic Kidney Disease is a genetic disease classified by the formation of fluid-filled cysts in the kidneys. The accumulation of these cysts causes the kidneys to enlarge several times the normal size and leads to the eventual loss of renal function and ultimately results in renal failure in end-stage patients. This is a disease with life-threatening implications to those who have it and their family members who may also be affected. Aside from early antihypertensive control and dietary protein restriction, which are presumed to offer a modest degree of protection, most surviving patients require renal replacement therapy (dialysis and transplant) and suffer from high morbidity and mortality.

A rationale for use of tolvaptan in these genetic disorders has been proven, in principle, through use of a variety of animal models. In these models, tolvaptan is effective in halting or reversing the progression of this renal disease.

The current study is being undertaken in order to evaluate whether tolvaptan, an oral AVP inhibitor, will maintain an adequate safety profile and show a potential clinical benefit by reducing total renal volume in the hopes of making an impact upon disease progression.

• Drug: tolvaptan
  45 mg tablet in the morning, 15 mg tablet 8 hours later for up to 4 years
  Other Name: OPC-41061
• Drug: tolvaptan
  60 mg tablet in the morning, 30 mg tablet 8 hours later for up to 4 years
  Other Name: OPC-41061
• Drug: tolvaptan
  30mg/15mg, 45mg/15mg, 60mg/30mg, 90mg/30mg tablets with the higher strength taken in the morning and the second dose 8 hours later. Split-dose regimens titrated weekly to maximally tolerated dose group. Maximum tolerated dose maintained up to 2 months.
  Other Name: OPC-41061

• Experimental: Fixed Low Dose
  Intervention: Drug: tolvaptan
• Experimental: Fixed High Dose
  Intervention: Drug: tolvaptan
• Experimental: Titration
  Intervention: Drug: tolvaptan

• 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.
• Higashihara E, Torres VE, Chapman AB, Grantham JJ, Bae K, Watnick TJ, Horie S, Nutahara K, Ouyang J, Krasa HB, Czerwiec FS; TEMPOFormula and 156-05-002 Study Investigators. Tolvaptan in autosomal dominant polycystic kidney disease: three years' experience. Clin J Am Soc Nephrol. 2011 Oct;6(10):2499-507. Epub 2011 Sep 8.

Inclusion Criteria:

• Prior participation in designated tolvaptan ADPKD studies (156-04-248, 156-04-249)
• Able to give Informed Consent

Exclusion Criteria:

• 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
• Patients who are unlikely to adequately comply with study procedures
• Patients who at Day 1 have an estimated GFR below 30 mL/min or who anticipate renal-replacement therapy within one year of study entry.
• Patients having contraindications to MRI or gadolinium contrast will be eligible but will not be able to participate in MRI
• Patients taking within 1 week of enrollment, or likely to need diuretic therapy, prior to Month 2