Open-Label Tolvaptan Study in Subjects With ADPKD (TEMPO 4/4)

• To demonstrate whether tolvaptan modifies ADPKD progression as measured by changes from baseline (from trial 156-04-251) in total kidney volume (TKV). [ Time Frame: 24 months ] [ Designated as safety issue: No ]

  For subjects continuing from protocol 156-04-251 comparing those previously treated with tolvaptan (combining all doses) to those subjects previously treated with placebo, disease modification as measured by:

  • Percent change from 156-04-251 baseline in total kidney volume (TKV) at month 24 in trial 156-08-271 as compared to the percent change in TKV at 156-04-251 Month 36 measured by magnetic resonance imaging (MRI)
• To demonstrate whether tolvaptan modifies ADPKD progression as measured by changes from baseline (from trial 156-04-251) in total Renal Function. [ Time Frame: 24 months ] [ Designated as safety issue: No ]

  For subjects continuing from protocol 156-04-251 comparing those previously treated with tolvaptan (combining all doses) to those subjects previously treated with placebo, disease modification as measured by:

  • Change in renal function (100x1/Serum Creatinine mg/dL) at Month 24 in trial 156-08-271 as compared to change from end of titration in renal function at Month 36 in protocol 156-04-251.

• Change in Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  For subjects randomized to tolvaptan and placebo in 156-04-251 and enrolled and treated in 156-08-271 as early treated and delayed treatment groups: change from 251 baseline eGFR at month 24 of 156-08-271
• Slope of Total Kidney Value (TKV) [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  For subjects randomized to tolvaptan and placebo in 156-04-251 and enrolled and treated in 156-08-271 as early treated and delayed treatment groups
• Slope of eGFR (CKD-EPI) [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  For subjects randomized to tolvaptan and placebo in 156-04-251 and enrolled and treated in 156-08-271 as early treated and delayed treatment groups

• To determine whether, for placebo-treated subjects from trial 156-04-251, the annual rate of change (slope) in TKV. [ Time Frame: 12 Months ] [ Designated as safety issue: No ]

  In prior placebo subjects enrolling from protocol 156-04-251:

  • Change in annual TKV slope when crossing over to tolvaptan treatment
• To determine whether, for placebo-treated subjects from trial 156-04-251, the annual rate of change in Renal Function. [ Time Frame: 12 months ] [ Designated as safety issue: No ]

  In prior placebo subjects enrolling from protocol 156-04-251:

  • Change in annual slope for renal function (100x1/Serum Creatinine mg/dL) when crossing over to tolvaptan treatment
• Change from baseline in TKV by exposure group, for all subjects enrolled in this trial [ Time Frame: 24 Months ] [ Designated as safety issue: No ]

  For all subjects enrolled in this trial:

  • Change from baseline in TKV by exposure group
• Change from end of titration in renal function (100x1/Serum Creatinine mg/dL) by exposure group, for all subjects enrolled in this trial: [ Time Frame: 24 Months ] [ Designated as safety issue: No ]

  For all subjects enrolled in this trial:

  • Change from end of titration in renal function (100x1/Serum Creatinine mg/dL) by exposure group

• Decreases of blood pressure (BP) leading to a sustained reduction in anti-hypertensive therapy compared to Baseline [ Time Frame: Baseline, 12 months and 24 Months ] [ Designated as safety issue: No ]

  For all subjects enrolled in this Trial:

  For subjects who are taking anti-hypertensive therapy at Baseline in this trial, percentage with clinically sustained decreases of blood pressure (BP) leading to a sustained reduction in anti-hypertensive therapy compared to Baseline (while taking investigational product) at visit Months 12 and 24 for hypertensive subjects.

• Pharmacokinetic Endpoint [ Time Frame: Baseline and Months 6, 12, 18 and 24. ] [ Designated as safety issue: No ]
  Sparse samples will be taken for determination of tolvaptan and metabolite (DM-4103 plasma concentration.
• Pharmacodynamic Endpoints [ Time Frame: Baseline until Month 24 ] [ Designated as safety issue: No ]
  Absolute values at each visit and change from last pre-dose value for spot urine osmolality, urine MCP-1 concentrations, and serum Cystatin C.
• Safety Endpoints [ Time Frame: Baseline until Month 24 ] [ Designated as safety issue: Yes ]
  Safety endpoints in all exposed subjects to be analyzed will include a descriptive summary of reported adverse events, vital signs and clinical laboratory tests
• Exploratory Endpoints [ Time Frame: Baseline until Month 24 ] [ Designated as safety issue: No ]

  PKD Outcomes (including onset of end stage renal disease [ESRD]) and resource utilization.

  Change from baseline in EuroQol-5D Summary Index.

  Changes in ADPKD clinical progression events, including progressing hypertension, worsening renal pain, worsening albuminuria, and worsening renal function.

To demonstrate whether tolvaptan modifies ADPKD progression as measured by changes from baseline (from trial 156-04-251) in total kidney volume (TKV) and renal function.

• Experimental: 251 Prior Tolvaptan
  Patients enrolling from protocol 156-04-251 in the tolvaptan-treated group
  Intervention: Drug: Tolvaptan
• Experimental: 251 Prior Placebo
  Patients enrolling from protocol 156-04-251 in the placebo-treated group
  Intervention: Drug: Tolvaptan
• Experimental: Other Prior Study
  Patients enrolling from prior tolvaptan studies other than protocol 156-04-251
  Intervention: Drug: Tolvaptan

Inclusion Criteria:

Subjects who have successfully completed a Phase 1, 2, or 3 tolvaptan ADPKD or renal impairment trial, with a confirmed diagnosis of ADPKD

Exclusion Criteria:

• Subjects unable to provide written informed consent
• Subjects (men or women) who will not adhere to the reproductive precautions as outlined in the Informed Consent Form
• Subjects (women only) with a positive urine pregnancy test
• Subjects who are pregnant or breast-feeding
• Subjects unable to take oral medications
• Subjects who have allergic reactions to tolvaptan or chemically related structures such as benzazepines (benzazepril, conivaptan, fenoldopam mesylate or mirtazapine)
• Subjects who have disorders in thirst recognition or an inability to access fluids
• Subjects with critical electrolyte imbalances, as determined by the investigator
• Subjects with or at risk of significant hypovolemia, as determined by investigator
• Subjects with anemia, as determined by investigator
• Subjects with a history of substance abuse (within the last 3 years)
• Subjects taking other experimental (ie, non-marketed) therapies or current participation in another clinical drug or device trial; current participation in the off-drug follow-up period of another ADPKD trial with tolvaptan is permitted

Efficacy Analysis Exclusion Criteria:

• Subjects unable to complete MRI assessments(eg, subjects with ferro-magnetic prostheses, aneurysm clips, severe claustrophobia)
• Subjects who have taken a vasopressin antagonist (outside of previous participation in a tolvaptan trial)
• Subjects unable to comply with anti-hypertensive or other important medical therapy
• Subjects with advanced diabetes
• Subjects taking medications or having an illness that could confound endpoint assessments (including taking approved therapies for the purpose of affecting PKD cysts)