Table 3.
Endpoints of the study
| Co-primary endpoints (phase A) | |
| • Change from baseline in spot urine osmolality (premorning dose) after 1 week of daily dosing | |
| • Change from baseline in specific gravity (premorning dose) after 1 week of daily dosing | |
| Key secondary endpoint | |
| • Percent change in htTKV from phase A baseline to month 12, as measured by MRI | |
| Other secondary endpoints | |
| • 24-h fluid balance prior to week 1 in phase A | |
| • Change from baseline in renal function (eGFR by Schwartz formula [15]) at each clinic visit (week 1, month 1, month 6, and month 12 in phase A) | |
| • Change from baseline in renal function (eGFR by Schwartz formula) at each clinic visit (week 1, month 1, month 6, month 12, month 18, and month 24 in phase B) | |
| • Percent change in htTKV as measured by MRI from phase B baseline to phase B month 12 | |
| • Percent change in htTKV as measured by MRI from phase B baseline to phase B month 24 | |
| • Pharmacodynamic endpoints of urine volume (including 24-h fluid volume), fluid intake and fluid balance, sodium, creatinine, and free water clearance during dense PK sampling (after at least 1 month on study drug) | |
| • Proportions of each Tanner stage by gender and age compared to normative populations at baseline, month 6, and month 12 during the placebo-controlled phase (phase A), and every 6 months during the open-label extension phase (phase B) | |
| • Description of changes from baseline percentiles for height and weight by gender and age at baseline, month 6, and month 12 during the placebo-controlled phase (phase A), and every 6 months during the open-label extension phase (phase B) | |
| • Safety variables (changes from baseline in creatinine, vital signs, laboratory values including liver function tests, rate of aquaretic adverse events) in placebo and tolvaptan | |
| Exploratory endpoints | |
| • Percent change in htTKV as measured by MRI from phase A baseline to phase B month 24 | |
| • Change from phase A baseline in spot urine osmolality (premorning dose) and specific gravity (premorning dose) after 1 month (phase A only) | |
| • Time to discontinuation due to any reasons in phase A and phase B | |
| • Tolvaptan maximum (peak) plasma concentration (Cmax), minimum plasma concentration (Cmin), time to Cmax (tmax), and area under the concentration-time curve from time zero to 24 h (AUC0–24 h) following dense PK sampling | |
| • PK sampling for separate population analysis | |
| • Tolvaptan metabolite concentrations from dense sampling | |
| • Generic pediatric quality of life assessments | |
| • Daytime and nighttime void collection | |
| Endpoints for subjects < 12 years who have ultrasound assessments | |
| • Percent change in htTKV as measured by ultrasound from phase A baseline to phase A month 12 | |
| • Percent change in htTKV as measured by ultrasound from phase A baseline to phase B month 24 | |
| • Percent change in htTKV as measured by ultrasound from phase B baseline to phase B month 24 | |
| • Percent change in htTKV as measured by ultrasound from phase B baseline to phase B month 12 |
eGFR estimated glomerular filtration rate, htTKV height-adjusted total kidney volume, MRI magnetic resonance imaging, PK pharmacokinetic