Clinical Trial: A PK Study of 3 Dosages of Tolvaptan in Patients With Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Phase 1b, Multicenter, Pilot, Randomized, Double-blind Trial to Determine the Pharmacokinetics and Pharmacodynamics of Orally Administered Tolvaptan 3.75, 7.5, and 15 mg Tablets in Subjects With

Brief Summary: This is a study to evaluate how the body handles and metabolizes (PK) the various doses of the drug Tolvaptan, and what the effect (PD) of the various doses of Tolvaptan are on the content of "salt" in blood and urine

Detailed Summary:
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Current Primary Outcome:

• Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration. [ Time Frame: Baseline to Day 2 ]
  Maximal increase in serum sodium is summarized below by tolvaptan dose. Blood samples for determination of plasma concentrations of tolvaptan were collected predose and at 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose on Day 1 or at Early Termination (ET).
• Time of Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration. [ Time Frame: Baseline to Day 2 ]
  Time of maximal increase in serum sodium is summarized in the table below by tolvaptan dose. Samples were taken on Day 0 (baseline) at the corresponding Day 1 predose time and 12 hours postdose time; and on Day 1 at predose and at 2, 4, 6, 8, 12, and 24 hours postdose.

Original Primary Outcome: Pharmacodynamics: Maximal change from baseline and time of maximal change from baseline in serum sodium concentration following tolvaptan administration. [ Time Frame: 2 days ]

Current Secondary Outcome:

• Cmax (Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma. [ Time Frame: Baseline to Day 2 ]
  Blood samples for determination of plasma concentrations of tolvaptan were collected predose and 1, 2, 3, 4, 8, 12, 16, and 24 hours postdose on Day 1 or at ET. PK parameters in participants with SIADH following tolvaptan administration for three different doses are presented below.
• Tmax (Time to Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma [ Time Frame: Baseline to Day 2 ]
  Blood samples for determination of plasma concentrations of tolvaptan were collected predose and 1, 2, 3, 4, 8, 12, 16, and 24 hours postdose on Day 1 or at ET. PK parameters in participants with SIADH following tolvaptan administration for three different doses are presented below.
• AUC Infinity (Area Under the Concentration-time Curve From Time Zero to Infinity) for Tolvaptan in Plasma [ Time Frame: Baseline to Day 2 ]
  Blood samples for determination of plasma concentrations of tolvaptan were collected predose and 1, 2, 3, 4, 8, 12, 16, and 24 hours postdose on Day 1 or at ET. If an indwelling catheter was utilized, saline flushes were used. PK parameters in participants with SIADH following tolvaptan administration for three different doses are presented below.
• Change From Baseline in Serum Sodium Concentrations [ Time Frame: Baseline and Day 2 ]
  Samples were taken on Day 0 (baseline) at the corresponding Day 1 predose time and 12 hours postdose time; and on Day 1 at predose and at 2, 4, 6, 8, 12, and 24 hours postdose.
• Change From Baseline in Fluid Intake From 0-6 Hours, 0-12 Hours and 0-24 Hours [ Time Frame: Baseline and Day 2 ]
  Fluid intake was monitored on Day 0 (times relative to Day 1 dosing), and Day 1 at intervals of 0 to 6, 6 to 12, and 12 to 24 hours postdose. Fluid intake included fluid used for dosing (study medication and any concomitant medication); food items that included any significant amounts of water (e.g., Jello [including Gelatin and Jelly dessert] and soup) was added to the total fluid intake. Samples were taken on Day 0 (baseline) at the corresponding Day 1 predose time and 12 hours postdose time; and on Day 1 at predose and at 2, 4, 6, 8, 12, and 24 hours postdose.
• Change From Baseline in Fluid Balance (Fluid Intake Minus Urine Output) From 0-6 Hours, 0-12 Hours and 0-24 Hours. [ Time Frame: 2 days ]
  Fluid intake was monitored on Day 0 (times relative to Day 1 dosing), and Day 1 at intervals of 0 to 6, 6 to 12, and 12 to 24 hours postdose. Fluid intake included fluid used for dosing (study medication and any concomitant medication); food items that included any significant amounts of water (e.g., Jello [including Gelatin and Jelly dessert] and soup) was added to the total fluid intake. Urine was collected for baseline comparison on Day 0 for the 24 hour prior to Day 1 dosing at intervals of 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12 hours, and 12 to 24 hours relative to the Day 1 dosing time. Fluid balance was determined as fluid intake minus urine output.
• Change From Baseline in Cumulative Urine Volume at 0-6 Hours, 0-12 Hours and 0-24 Hours. [ Time Frame: 2 days ]
  Urine was collected for baseline comparison on Day 0 for the 24 hour prior to Day 1 dosing at intervals of 0 to 2, 2 to 4, 4, to 6, 6, to 8, 8, to 12, and 12 to 24 hours relative to Day 1 dosing time. Urine was collected on Day 1 at intervals of 0 to 2,2 to 4, 4 to 6, 6 to 8, 8 to 12, and 12 to 24 hours postdose. For the start of the urine collection on Day 0, a window of 15 to 40 minutes prior to the assigned dosing time was acceptable, with the 0 to 24 hour collection period on Day 1 starting 24 hours after the start time on Day 0. Participants were asked to void immediately prior to the end of the collection interval. The volume of individual voids were measured and recorded prior to refrigerating. All voids in a collection interval were pooled at the end of the collection interval, at which time the volume was determined, recorded and an aliquot taken for osmolality, sodium, potassium, and creatinine assessments.

Original Secondary Outcome:

• PK: The secondary PK endpoints for this trial are: Cmax, time to maximum (peak) plasma concentration (tmax), and AUC(infinity) for tolvaptan in plasma. [ Time Frame: 2 days ]
• PD: The secondary PD endpoints for this trial are: Sodium serum concentrations and change from baseline (time 0 of each day) by timepoint; [ Time Frame: 2 days ]
• 0 to 6, 0 to 12, and 0 to 24 hour fluid intake and fluid balance (intake-urine output) and change from baseline (corresponding intervals on Day 0); [ Time Frame: 2 days ]
• 0 to 6, 0 to 12, and 0 to 24 hour urine output from baseline (corresponding intervals on Day 0). [ Time Frame: 2 days ]

Dates:
Date Received: December 9, 2013
Date Started: November 2013
Date Completion:
Last Updated: April 8, 2016
Last Verified: April 2016