Study to Evaluate the Long-term Efficacy and Safety of Oral Tolvaptan Tablet Regimens in Subjects with Autosomal Dominant Polycystic Kidney Disease

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.

Official Title

Multi-center, Open-label, Extension Study to Evaluate the Long-term Efficacy and Safety of Oral Tolvaptan Tablet Regimens in Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Conditions

Autosomal Dominant Polycystic Kidney Disease

Study Type

Interventional

Study Design

Allocation: Non-Randomised
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

Further Details

Primary Outcome Measures:

• 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 (100×1/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.

 

Secondary Outcome Measures:

• 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 (100×1/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 (100×1/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 (100×1/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.

 

Arm:

Tolvaptan: Experimental

Dose group (blinded or unblinded) from their prior trial, assignment will be based on the subject’s last assigned multiples of either 15 mg or 30 mg tablets. Dose regimen regimens (45/15, 60/30, or 90/30 mg) of tolvaptan using subjects meeting entry criteria and completing baseline assessments will be assigned one of three split-dose

 

Intervention

45/15, 60/30 and 90/30 mg of Tolvaptan

Study Start

June 2010 – August 2014

Eligibility & Criteria

Genders Eligible for Study:               Both
Accepts Healthy Volunteers:             No

Inclusion Criteria:

• Successful completion (protocol defined completer without early termination) of a Phase 1, 2, or 3 tolvaptan ADPKD or renal impairment trial, with a confirmed diagnosis of ADPKD.
• Estimated GFR ≥ 30 mL/min/1.73 meter squared within 30 days prior to enrollment (calculated using the IDMS-traceable modification of diet in renal disease [4 parameter MDRD] equation with correction for gender and race). Subjects with lower estimated GFR (eGFR) may be permitted with documented medical monitor approval prior to enrollment.

 

Exclusion Criteria:

• Inability to provide written informed consent.
• Men or women who will not adhere to the reproductive precautions as outlined in the Informed Consent form.
• Positive urine pregnancy test (women only).
• Subjects who are pregnant or breast-feeding.
• Inability to take oral medications.
• Subjects who have clinically significant allergic reactions to tolvaptan or chemically related structures such as benzazepines (benzazepril, conivaptan, fenoldopam mesylate or mirtazapine).
• Subjects having disorders in thirst recognition or 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 clinically significant 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.
• Subjects taking approved (ie, marketed) therapies, including but not limited to tolvaptan, vasopressin antagonists, anti-sense RNA therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs ( ie, octreotide, sandostatin) for the purpose of affecting PKD cysts.

 

Efficacy Analysis Exclusion Criteria:

• Subjects having contraindications to, or interference with MRI assessments (eg, ferro-magnetic prostheses, aneurysm clips, severe claustrophobia).
• Subjects with a history of taking a vasopressin antagonist, outside of previous participation in a tolvaptan trial.
• Subjects with a history of persistent non-compliance with anti-hypertensive or other important medical therapy.
• Subjects taking medications or having concomitant illnesses likely to confound endpoint assessments.
• Subjects with advanced diabetes (ie, those with poor glycemic control evidenced by a history of severely elevated hemoglobin A1C, or with evidence of advanced retinopathy, nephropathy or peripheral vascular disease due to micro-or-macro vascular disease).

Total Enrolment

1500

Contact Details

Please refer to this study by its ClinicalTrials.gov identifier: NCT01214421