Trial Outcomes & Findings for A PK Study of 3 Dosages of Tolvaptan in Patients With Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (NCT NCT02009878)

NCT ID: NCT02009878

Last Updated: 2016-05-16

Results Overview

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).

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 30 participants
• Primary outcome timeframe: Baseline to Day 2
• Results posted on: 2016-05-16

Participant Flow

The study was conducted in 30 participants (29 received treatment) at 14 trial sites in 7 countries.

Participants with syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a serum sodium concentration between 120 and 133 mmol/L were randomized to single doses of 3.75, 7.5, or 15 mg tolvaptan. Baseline pharmacodynamics (PD) was assessed for 24 hours predose. Pharmacokinetic (PK) and PD assessments were obtained 24 hours postdose.

Participant milestones

Measure	Tolvaptan 3.75 mg Participants had received a single dose of 3.75 mg oral tolvaptan.	Tolvaptan 7.5 mg Participants had received a single dose of 7.5 mg oral tolvaptan.	Tolvaptan 15 mg Participants had received a single dose of 15 mg oral tolvaptan.
Overall Study STARTED	10	11	9
Overall Study COMPLETED	10	10	9
Overall Study NOT COMPLETED	0	1	0

Reasons for withdrawal

Measure	Tolvaptan 3.75 mg Participants had received a single dose of 3.75 mg oral tolvaptan.	Tolvaptan 7.5 mg Participants had received a single dose of 7.5 mg oral tolvaptan.	Tolvaptan 15 mg Participants had received a single dose of 15 mg oral tolvaptan.
Overall Study Participant Met Withdrawal Criteria	0	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Tolvaptan 3.75 mg n=10 Participants Participants had received a single dose of 3.75 mg oral tolvaptan.	Tolvaptan 7.5 mg n=10 Participants Participants had received a single dose of 7.5 mg oral tolvaptan.	Tolvaptan 15 mg n=9 Participants Participants had received a single dose of 15 mg oral tolvaptan.	Total n=29 Participants Total of all reporting groups
Age, Continuous	68.50 years STANDARD_DEVIATION 8.66 • n=93 Participants	70.20 years STANDARD_DEVIATION 9.90 • n=4 Participants	59.67 years STANDARD_DEVIATION 15.43 • n=27 Participants	66.34 years STANDARD_DEVIATION 12.04 • n=483 Participants
Sex: Female, Male Female	6 Participants n=93 Participants	8 Participants n=4 Participants	5 Participants n=27 Participants	19 Participants n=483 Participants
Sex: Female, Male Male	4 Participants n=93 Participants	2 Participants n=4 Participants	4 Participants n=27 Participants	10 Participants n=483 Participants

PRIMARY outcome

Timeframe: Baseline to Day 2

Population: PD dataset comprised of all participants who had taken 1 dose of study medication and had all observed measurements.

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).

Outcome measures

Measure	Tolvaptan 3.75 mg n=10 Participants Participants had received a single dose of 3.75 mg oral tolvaptan.	Tolvaptan 7.5 mg n=10 Participants Participants had received a single dose of 7.5 mg oral tolvaptan.	Tolvaptan 15 mg n=8 Participants Participants had received a single dose of 15 mg oral tolvaptan.
Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration.	3.6 mmol/L Standard Deviation 3.3	5.3 mmol/L Standard Deviation 2.5	7.9 mmol/L Standard Deviation 5.3

PRIMARY outcome

Timeframe: Baseline to Day 2

Population: PD dataset comprised of all participants who had taken 1 dose of study medication and had all observed measurements.

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.

Outcome measures

Measure	Tolvaptan 3.75 mg n=10 Participants Participants had received a single dose of 3.75 mg oral tolvaptan.	Tolvaptan 7.5 mg n=10 Participants Participants had received a single dose of 7.5 mg oral tolvaptan.	Tolvaptan 15 mg n=7 Participants Participants had received a single dose of 15 mg oral tolvaptan.
Time of Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration.	24.13 hours Interval 2.03 to 24.25	6.38 hours Interval 2.05 to 24.28	24.02 hours Interval 6.25 to 24.3

SECONDARY outcome

Timeframe: Baseline to Day 2

Population: PK parameter dataset comprised of all participants who had taken 1 dose of study medication and had evaluable PK data.

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.

Outcome measures

Measure	Tolvaptan 3.75 mg n=10 Participants Participants had received a single dose of 3.75 mg oral tolvaptan.	Tolvaptan 7.5 mg n=10 Participants Participants had received a single dose of 7.5 mg oral tolvaptan.	Tolvaptan 15 mg n=8 Participants Participants had received a single dose of 15 mg oral tolvaptan.
Cmax (Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma.	37.7 ng/mL Standard Deviation 12.6	107 ng/mL Standard Deviation 48.9	157 ng/mL Standard Deviation 68.1

SECONDARY outcome

Timeframe: Baseline to Day 2

Population: PK parameter dataset comprised of all participants who had taken 1 dose of study medication and had evaluable PK data.

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.

Outcome measures

Measure	Tolvaptan 3.75 mg n=10 Participants Participants had received a single dose of 3.75 mg oral tolvaptan.	Tolvaptan 7.5 mg n=10 Participants Participants had received a single dose of 7.5 mg oral tolvaptan.	Tolvaptan 15 mg n=8 Participants Participants had received a single dose of 15 mg oral tolvaptan.
Tmax (Time to Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma	1.50 hours Interval 0.95 to 4.0	2.00 hours Interval 1.0 to 4.0	2.00 hours Interval 0.97 to 3.0

SECONDARY outcome

Timeframe: Baseline to Day 2

Population: PK parameter dataset comprised of all participants who had taken 1 dose of study medication and had evaluable PK data.

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.

Outcome measures

Measure	Tolvaptan 3.75 mg n=10 Participants Participants had received a single dose of 3.75 mg oral tolvaptan.	Tolvaptan 7.5 mg n=10 Participants Participants had received a single dose of 7.5 mg oral tolvaptan.	Tolvaptan 15 mg n=8 Participants Participants had received a single dose of 15 mg oral tolvaptan.
AUC Infinity (Area Under the Concentration-time Curve From Time Zero to Infinity) for Tolvaptan in Plasma	244 ng·h/mL Standard Deviation 90.7	655 ng·h/mL Standard Deviation 373	1000 ng·h/mL Standard Deviation 361

SECONDARY outcome

Timeframe: Baseline and Day 2

Population: PD dataset comprised of all participants who had taken 1 dose of study medication and had all observed measurements.

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.

Outcome measures

Measure	Tolvaptan 3.75 mg n=10 Participants Participants had received a single dose of 3.75 mg oral tolvaptan.	Tolvaptan 7.5 mg n=10 Participants Participants had received a single dose of 7.5 mg oral tolvaptan.	Tolvaptan 15 mg n=9 Participants Participants had received a single dose of 15 mg oral tolvaptan.
Change From Baseline in Serum Sodium Concentrations (Day 0) 12 hour (N= 10, 9, 9)	-2.5 mmol/L Standard Deviation 1.3	-2.3 mmol/L Standard Deviation 3.0	-2.6 mmol/L Standard Deviation 2.2
Change From Baseline in Serum Sodium Concentrations (Day 1) 2 hour (N= 10, 10, 8)	-2.0 mmol/L Standard Deviation 4.4	2.4 mmol/L Standard Deviation 1.3	1.7 mmol/L Standard Deviation 1.8
Change From Baseline in Serum Sodium Concentrations (Day 1) 4 hour (N= 10, 10, 8)	-1.7 mmol/L Standard Deviation 4.7	3.5 mmol/L Standard Deviation 3.0	3.0 mmol/L Standard Deviation 2.3
Change From Baseline in Serum Sodium Concentrations (Day 1) 6 hour (N= 10, 10, 8)	-0.1 mmol/L Standard Deviation 4.7	3.1 mmol/L Standard Deviation 3.1	5.3 mmol/L Standard Deviation 4.2
Change From Baseline in Serum Sodium Concentrations (Day 1) 8 hour (N= 10, 10, 8)	0.0 mmol/L Standard Deviation 4.8	3.2 mmol/L Standard Deviation 1.9	5.4 mmol/L Standard Deviation 4.6
Change From Baseline in Serum Sodium Concentrations (Day 1) 12 hour (N= 9, 10, 9)	-0.6 mmol/L Standard Deviation 4.5	3.6 mmol/L Standard Deviation 1.8	5.9 mmol/L Standard Deviation 4.7
Change From Baseline in Serum Sodium Concentrations (Day 1) 24 hour (N= 10, 10, 9)	2.9 mmol/L Standard Deviation 3.8	4.6 mmol/L Standard Deviation 1.9	7.4 mmol/L Standard Deviation 4.8

SECONDARY outcome

Timeframe: Baseline and Day 2

Population: PD dataset comprised of all participants who had taken 1 dose of study medication and had all observed measurements.

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.

Outcome measures

Measure	Tolvaptan 3.75 mg n=10 Participants Participants had received a single dose of 3.75 mg oral tolvaptan.	Tolvaptan 7.5 mg n=10 Participants Participants had received a single dose of 7.5 mg oral tolvaptan.	Tolvaptan 15 mg n=9 Participants Participants had received a single dose of 15 mg oral tolvaptan.
Change From Baseline in Fluid Intake From 0-6 Hours, 0-12 Hours and 0-24 Hours Day 1 (0 to 6 hour)	97.5 mL Standard Deviation 461.9	-255.0 mL Standard Deviation 257.3	-103.0 mL Standard Deviation 693.2
Change From Baseline in Fluid Intake From 0-6 Hours, 0-12 Hours and 0-24 Hours Day 1 (0 to 12 hour)	210.0 mL Standard Deviation 558.1	-65.0 mL Standard Deviation 566.4	118.8 mL Standard Deviation 1019.6
Change From Baseline in Fluid Intake From 0-6 Hours, 0-12 Hours and 0-24 Hours Day 1 (0 to 24 hour)	361.0 mL Standard Deviation 647.0	129.0 mL Standard Deviation 632.1	525.6 mL Standard Deviation 1265.3

SECONDARY outcome

Timeframe: 2 days

Population: PD dataset comprised of all participants who had taken 1 dose of study medication and had all observed measurements.

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.

Outcome measures

Measure	Tolvaptan 3.75 mg n=10 Participants Participants had received a single dose of 3.75 mg oral tolvaptan.	Tolvaptan 7.5 mg n=10 Participants Participants had received a single dose of 7.5 mg oral tolvaptan.	Tolvaptan 15 mg n=9 Participants Participants had received a single dose of 15 mg oral tolvaptan.
Change From Baseline in Fluid Balance (Fluid Intake Minus Urine Output) From 0-6 Hours, 0-12 Hours and 0-24 Hours. Day 1 (0 to 6 hour)	-403.7 mL Standard Deviation 783.2	-856.8 mL Standard Deviation 528.1	-1478.8 mL Standard Deviation 958.6
Change From Baseline in Fluid Balance (Fluid Intake Minus Urine Output) From 0-6 Hours, 0-12 Hours and 0-24 Hours. Day 1 (0 to 12 hour)	-588.8 mL Standard Deviation 1078.8	-839.8 mL Standard Deviation 553.7	-1897.5 mL Standard Deviation 1072.7
Change From Baseline in Fluid Balance (Fluid Intake Minus Urine Output) From 0-6 Hours, 0-12 Hours and 0-24 Hours. Day 1 (0 to 24 hour)	-278.3 mL Standard Deviation 1171.7	-537.8 mL Standard Deviation 831.1	-1700.6 mL Standard Deviation 1301.3

SECONDARY outcome

Timeframe: 2 days

Population: PD dataset comprised of all participants who had taken 1 dose of study medication and had all observed measurements.

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.

Outcome measures

Measure	Tolvaptan 3.75 mg n=10 Participants Participants had received a single dose of 3.75 mg oral tolvaptan.	Tolvaptan 7.5 mg n=10 Participants Participants had received a single dose of 7.5 mg oral tolvaptan.	Tolvaptan 15 mg n=9 Participants Participants had received a single dose of 15 mg oral tolvaptan.
Change From Baseline in Cumulative Urine Volume at 0-6 Hours, 0-12 Hours and 0-24 Hours. Day 1 (0 to 6 hour)	501.2 mL Standard Deviation 584.4	601.8 mL Standard Deviation 486.6	1375.6 mL Standard Deviation 911.6
Change From Baseline in Cumulative Urine Volume at 0-6 Hours, 0-12 Hours and 0-24 Hours. Day 1 (0 to 12 hour)	798.8 mL Standard Deviation 1024.4	774.8 mL Standard Deviation 596.2	2016.3 mL Standard Deviation 1668
Change From Baseline in Cumulative Urine Volume at 0-6 Hours, 0-12 Hours and 0-24 Hours. Day 1 (0 to 24 hour)	639.3 mL Standard Deviation 1223.8	666.8 mL Standard Deviation 732.3	2226.3 mL Standard Deviation 2151.5

Adverse Events

Tolvaptan 3.75 mg

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Tolvaptan 7.5 mg

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Tolvaptan 15 mg

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Measure	Tolvaptan 3.75 mg n=10 participants at risk Subjects will receive a single dose of 3.75, 7.5 or 15 mg of tolvaptan on study Day 1	Tolvaptan 7.5 mg n=10 participants at risk Subjects will receive a single dose of 3.75, 7.5 or 15 mg of tolvaptan on study Day 1	Tolvaptan 15 mg n=9 participants at risk Subjects will receive a single dose of 3.75, 7.5 or 15 mg of tolvaptan on study Day 1
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer	0.00% 0/10 • Adverse events were reported from the signing of the informed consent throughout the study and were followed for 7 (+2) days post last dose of study medication.	0.00% 0/10 • Adverse events were reported from the signing of the informed consent throughout the study and were followed for 7 (+2) days post last dose of study medication.	11.1% 1/9 • Adverse events were reported from the signing of the informed consent throughout the study and were followed for 7 (+2) days post last dose of study medication.

Other adverse events

Measure	Tolvaptan 3.75 mg n=10 participants at risk Subjects will receive a single dose of 3.75, 7.5 or 15 mg of tolvaptan on study Day 1	Tolvaptan 7.5 mg n=10 participants at risk Subjects will receive a single dose of 3.75, 7.5 or 15 mg of tolvaptan on study Day 1	Tolvaptan 15 mg n=9 participants at risk Subjects will receive a single dose of 3.75, 7.5 or 15 mg of tolvaptan on study Day 1
Nervous system disorders Dizziness	0.00% 0/10 • Adverse events were reported from the signing of the informed consent throughout the study and were followed for 7 (+2) days post last dose of study medication.	10.0% 1/10 • Adverse events were reported from the signing of the informed consent throughout the study and were followed for 7 (+2) days post last dose of study medication.	11.1% 1/9 • Adverse events were reported from the signing of the informed consent throughout the study and were followed for 7 (+2) days post last dose of study medication.
Psychiatric disorders Insomnia	0.00% 0/10 • Adverse events were reported from the signing of the informed consent throughout the study and were followed for 7 (+2) days post last dose of study medication.	0.00% 0/10 • Adverse events were reported from the signing of the informed consent throughout the study and were followed for 7 (+2) days post last dose of study medication.	11.1% 1/9 • Adverse events were reported from the signing of the informed consent throughout the study and were followed for 7 (+2) days post last dose of study medication.
Renal and urinary disorders Polyuria	0.00% 0/10 • Adverse events were reported from the signing of the informed consent throughout the study and were followed for 7 (+2) days post last dose of study medication.	0.00% 0/10 • Adverse events were reported from the signing of the informed consent throughout the study and were followed for 7 (+2) days post last dose of study medication.	11.1% 1/9 • Adverse events were reported from the signing of the informed consent throughout the study and were followed for 7 (+2) days post last dose of study medication.

Additional Information

Global Medical Affairs

Otsuka Pharmaceutical Development and Commercialization, Inc.

Phone: 800 562-3974

Results disclosure agreements

• Principal investigator is a sponsor employee Center may publish study results but ≥ 60 days prior to any public presentation, a copy is sent to Sponsor for review and Center can delay publication for 60 days to permit Sponsor to protect its intellectual property rights or confidential information contained within the publication. The first publication is a joint publication, if Center is part of a multi-center study. Center is free to publish, if there is no multi-center publication within 18 months of completion/ termination of study.
• Publication restrictions are in place

Restriction type: OTHER