This study's purpose is to evaluate the long-term safety and efficacy of tolvaptan versus placebo in patients with ADPKD.
This study evaluated whether or not tolvaptan is potentially beneficial, while maintaining an adequate safety profile, by reducing the rate of total kidney volume increase, while impacting the onset, severity, and progression of other important consequences of ADPKD. During the 3-week titration phase, tolvaptan or placebo was titrated in weekly intervals from lowest to highest tolerated levels given in split-dose regimens of 45/15 mg, 60/30 mg and 90/30 mg orally upon awakening and approximately 9 hours later. As soon as a subject could not tolerate a given dose, the titration phase was over and the maintenance phase began at the dose level tolerated. The maintenance phase lasted to Month 36. Subjects were able to titrate down at any point during the study. Subjects were able to titrate up during the maintenance phase with Medical Monitor approval.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
1,445
Percentage Change Per Year in Total Kidney Volume From Baseline to Month 36
Kidney volume was assessed in T1-weighted magnetic resonance images collected at each study site and sent to a central reviewing facility. At the central reviewing facility, blinded radiologists used proprietary software to measure the volume of both kidneys.
Time frame: Baseline to Month 36
Number of ADPKD Clinical Progression Events Per 100 Follow-up Years From Baseline to Month 36
These ADPKD events in the key secondary Outcome Measure were selected on the basis of their potential relationship to progressing cystogenesis. Reducing the rate of cyst development and expansion would likely slow the progression of ADPKD. The 4 events were: (1) Onset or progression of hypertension (someone is hypertensive if they have \> 139 mmHg systolic blood pressure \[BP\], \> 89 mmHg diastolic BP, or if they are taking antihypertensive medication at any BP level); (2) severe renal pain requiring medical intervention; (3) worsening albuminuria (by category, see below); and (4) worsening renal function, defined as a 25% decrease in 1/serum creatinine from Baseline. Albuminuria was assessed using spot urine albumin/creatinine ratio measurements (all measurements in mg/mmol). Categories included normal (\< 2.8 female or \< 2.0 male), microalbuminuria (2.8-28 female or 2.0-20 male), and overt proteinuria (\> 28 female or \> 20 male.
Time frame: Baseline to Month 36
Change in Renal Function Per Year From Week 3 to Month 36
Renal function was assessed using serum creatinine measurements and was estimated using 1/serum creatinine. The formula for 1/serum creatinine is: 1/Pcr, where Pcr = serum creatinine concentration (mg/dL). The change in renal function per year was based on the slope of change, obtained by regressing renal function data against time by subject.
Time frame: Week 3 to Month 36
Change in Mean Arterial Blood Pressure Per Year in Non-hypertensive Participants From Baseline to Month 36
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Coastal Clinical Research
Mobile, Alabama, United States
University of South Alabama
Mobile, Alabama, United States
Apex Research of Riverside
Riverside, California, United States
Stanford University Medical Center
Stanford, California, United States
University of Colorado Health Sciences Center
Denver, Colorado, United States
Yale University School of Medicine
New Haven, Connecticut, United States
Jacksonville Center for Clinical Research
Jacksonville, Florida, United States
Coastal Nephrology Associates Research Center, LLC
Port Charlotte, Florida, United States
Emory University School of Medicine
Atlanta, Georgia, United States
Northwestern University
Chicago, Illinois, United States
...and 123 more locations
For participants who were non-hypertensive (systolic BP ≤ 139 mmHg and diastolic BP ≤ 89 mmHg without taking antihypertensive medications) at baseline, mean arterial blood pressure was measured at scheduled clinic visits up to the point of exposure to antihypertensive therapy for any reason. The change in mean arterial blood pressure per year was based on the slope of blood pressure, obtained by regressing blood pressure against time by subject.
Time frame: Baseline to Month 36
Area Under the Concentration-time Curve of Change in Renal Pain From Baseline to Month 36
Change from baseline in renal pain was assessed by a 0 to 10 pain scale as average area under the concentration-time curve (AUC) between baseline and the last trial visit or the last visit prior to initiating medical (eg, narcotic or anti-nociceptives \[eg, tricyclic antidepressants\]) or surgical therapy for pain. In the pain scale, score 0 represented no pain at all and score 10 represented the worst pain. A negative change score indicates less pain. AUC of renal pain was derived from renal pain scores within treatment period and was calculated using the trapezoidal rule, by dividing the number of days between the first and last assessment.
Time frame: At screening, Baseline, Day 1, every 4 months up to month 36/early tremination (ET), follow-up visit 1 and 2
Number of Hypertensive Events Per 100 Follow-up Years in Non-hypertensive Participants From Baseline to Month 36
A hypertensive event was defined as a change from non-hypertensive (systolic BP ≤ 139 mmHg and diastolic BP ≤ 89 mmHg without taking antihypertensive medications) status to 1 of 3 conditions: (1) High pre-hypertensive (systolic BP \[sBP\] \> 129 mmHg and/or diastolic BP \[dBP\] \> 84 mmHg), (2) hypertensive (sBP \> 139 mmHg and/or dBP \> 89 mmHg), or (3) requiring antihypertensive therapy.
Time frame: Baseline to Month 36
Percentage of Participants With a Clinically Sustained Decrease of Blood Pressure Leading to a Sustained Reduction in Antihypertensive Therapy From Baseline to Month 36
Time frame: Baseline to Month 36