Trial Outcomes & Findings for A Study to Investigate the Effect of Itraconazole on the PK of Multiple Doses of Balovaptan in Healthy Volunteers (NCT NCT03579719)

NCT ID: NCT03579719

Last Updated: 2019-11-04

Results Overview

Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 15 participants
• Primary outcome timeframe: Day 10 of Period 1, Day 10 and Day 15 of Period 2
• Results posted on: 2019-11-04

Participant Flow

The study was conducted at 1 site in the Netherlands.

Participants in this study included healthy volunteers.

Participant milestones

Measure	Balovaptan + Itraconzole Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Overall Study STARTED	15
Overall Study COMPLETED	14
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Measure	Balovaptan + Itraconzole Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Overall Study Protocol deviation, pre-existent disease	1

Baseline Characteristics

A Study to Investigate the Effect of Itraconazole on the PK of Multiple Doses of Balovaptan in Healthy Volunteers

Baseline characteristics by cohort

Measure	Balovaptan + Itraconzole n=15 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Age, Continuous	43 Years STANDARD_DEVIATION 13 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	15 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	12 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 10 of Period 1, Day 10 and Day 15 of Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Maximum Plasma Concentration (Cmax) for Balovaptan Balovaptan Day 10 of Period 1	31.5 ng/mL Geometric Coefficient of Variation 25.3
Maximum Plasma Concentration (Cmax) for Balovaptan Balovaptan + itraconazole Day 10 of Period 2	125 ng/mL Geometric Coefficient of Variation 27.7
Maximum Plasma Concentration (Cmax) for Balovaptan Balovaptan + itraconazole Day 15 of Period 2	140 ng/mL Geometric Coefficient of Variation 31.7

PRIMARY outcome

Timeframe: Day 10 of Period 1, Day 10 and Day 15 of Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Maximum Plasma Concentration (Cmax) for M2 Metabolite (as Applicable) Balovaptan Day 10 of Period 1	11.0 ng/mL Geometric Coefficient of Variation 26.5
Maximum Plasma Concentration (Cmax) for M2 Metabolite (as Applicable) Balovaptan + itraconazole Day 10 of Period 2	6.34 ng/mL Geometric Coefficient of Variation 45.3
Maximum Plasma Concentration (Cmax) for M2 Metabolite (as Applicable) Balovaptan + itraconazole Day 15 of Period 2	7.60 ng/mL Geometric Coefficient of Variation 44.9

PRIMARY outcome

Timeframe: Day 10 of Period 1, Day 10 and Day 15 of Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Maximum Plasma Concentration (Cmax) for M3 Metabolite Balovaptan Day 10 of Period 1	19.9 ng/mL Geometric Coefficient of Variation 16.5
Maximum Plasma Concentration (Cmax) for M3 Metabolite Balovaptan + itraconazole Day 10 of Period 2	21.3 ng/mL Geometric Coefficient of Variation 20.0
Maximum Plasma Concentration (Cmax) for M3 Metabolite Balovaptan + itraconazole Day 15 of Period 2	28.6 ng/mL Geometric Coefficient of Variation 19.7

PRIMARY outcome

Timeframe: Day 10 of Period 1, Day 10 and Day 15 of Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for Balovaptan Balovaptan Day 10 of Period 1	464 ng.h/mL Geometric Coefficient of Variation 29.7
Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for Balovaptan Balovaptan + itraconazole Day 10 of Period 2	2304 ng.h/mL Geometric Coefficient of Variation 31.8
Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for Balovaptan Balovaptan + itraconazole Day 15 of Period 2	2587 ng.h/mL Geometric Coefficient of Variation 35.1

PRIMARY outcome

Timeframe: Day 10 of Period 1, Day 10 and Day 15 of Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M2 Metabolite (as Applicable) Balovaptan Day 10 of Period 1	230 ng.h/mL Geometric Coefficient of Variation 26.9
Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M2 Metabolite (as Applicable) Balovaptan + itraconazole Day 10 of Period 2	129 ng.h/mL Geometric Coefficient of Variation 46.9
Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M2 Metabolite (as Applicable) Balovaptan + itraconazole Day 15 of Period 2	156 ng.h/mL Geometric Coefficient of Variation 48.5

PRIMARY outcome

Timeframe: Day 10 of Period 1, Day 10 and Day 15 of Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M3 Metabolite Balovaptan Day 10 of Period 1	402 ng.h/mL Geometric Coefficient of Variation 17.8
Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M3 Metabolite Balovaptan + itraconazole Day 10 of Period 2	449 ng.h/mL Geometric Coefficient of Variation 21.3
Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M3 Metabolite Balovaptan + itraconazole Day 15 of Period 2	570 ng.h/mL Geometric Coefficient of Variation 20.9

PRIMARY outcome

Timeframe: Day 10 of Period 1; Day 10 and Day 15 of Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan Balovaptan Day 10 of Period 1	3.00 Hour(s) Interval 1.0 to 6.0
Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan Balovaptan + itraconazole Day 10 of Period 2	4.00 Hour(s) Interval 2.0 to 10.0
Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan Balovaptan + itraconazole Day 15 of Period 2	4.00 Hour(s) Interval 2.0 to 24.0

PRIMARY outcome

Timeframe: Day 10 of Period 1; Day 10 and Day 15 of Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Time to Maximum Observed Plasma Concentration (Tmax) for M2 Metabolite (as Applicable) Balovaptan Day 10 of Period 1	5.00 Hour(s) Interval 0.0 to 12.0
Time to Maximum Observed Plasma Concentration (Tmax) for M2 Metabolite (as Applicable) Balovaptan + itraconazole Day 10 of Period 2	6.00 Hour(s) Interval 0.0 to 24.0
Time to Maximum Observed Plasma Concentration (Tmax) for M2 Metabolite (as Applicable) Balovaptan + itraconazole Day 15 of Period 2	6.00 Hour(s) Interval 0.0 to 24.0

PRIMARY outcome

Timeframe: Day 10 of Period 1; Day 10 and Day 15 of Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Time to Maximum Observed Plasma Concentration (Tmax) for M3 Metabolite Balovaptan Day 10 of Period 1	4.00 Hour(s) Interval 1.0 to 24.0
Time to Maximum Observed Plasma Concentration (Tmax) for M3 Metabolite Balovaptan + itraconazole Day 10 of Period 2	9.00 Hour(s) Interval 2.0 to 24.0
Time to Maximum Observed Plasma Concentration (Tmax) for M3 Metabolite Balovaptan + itraconazole Day 15 of Period 2	3.50 Hour(s) Interval 1.0 to 8.0

SECONDARY outcome

Timeframe: Day 10 of Period 1; Day 10 and Day 15 of Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Trough Plasma Concentration (Ctrough) for Balovaptan Balovaptan Day 10 of Period 1	13.3 ng/mL Standard Deviation 4.7
Trough Plasma Concentration (Ctrough) for Balovaptan Balovaptan + itraconazole Day 10 of Period 2	91.9 ng/mL Standard Deviation 26.6
Trough Plasma Concentration (Ctrough) for Balovaptan Balovaptan + itraconazole Day 15 of Period 2	102 ng/mL Standard Deviation 36.0

SECONDARY outcome

Timeframe: Day 10 of Period 1; Day 10 and Day 15 of Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Trough Plasma Concentration (Ctrough) for M2 Metabolite (as Applicable) Balovaptan Day 10 of Period 1	9.93 ng/mL Standard Deviation 2.62
Trough Plasma Concentration (Ctrough) for M2 Metabolite (as Applicable) Balovaptan + itraconazole Day 10 of Period 2	5.82 ng/mL Standard Deviation 2.99
Trough Plasma Concentration (Ctrough) for M2 Metabolite (as Applicable) Balovaptan + itraconazole Day 15 of Period 2	6.88 ng/mL Standard Deviation 3.05

SECONDARY outcome

Timeframe: Day 10 of Period 1; Day 10 and Day 15 of Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Trough Plasma Concentration (Ctrough) for M3 Metabolite Balovaptan Day 10 of Period 1	15.1 ng/mL Standard Deviation 2.5
Trough Plasma Concentration (Ctrough) for M3 Metabolite Balovaptan + itraconazole Day 10 of Period 2	18.9 ng/mL Standard Deviation 4.7
Trough Plasma Concentration (Ctrough) for M3 Metabolite Balovaptan + itraconazole Day 15 of Period 2	23.9 ng/mL Standard Deviation 6.1

SECONDARY outcome

Timeframe: Days 1, 3, 5, 8, 9, 10 in Period 1 and Days 1, 3, 5, 8, 9, 10, 13, 14, 15 in Period 2

Population: The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least 1 dose of balovaptan. Subjects were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete.

Outcome measures

Measure	Balovaptan + Itraconzole n=14 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Time to Steady State for Balovaptan Balovaptan + itraconazole	13 Day
Time to Steady State for Balovaptan Balovaptan	4 Day

SECONDARY outcome

Timeframe: Up to 21 days postdose

Population: The safety analysis population consisted of subjects who received at least one dose of balovaptan.

Outcome measures

Measure	Balovaptan + Itraconzole n=15 Participants Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Percentage of Participants With Adverse Events	73 Percentage

Adverse Events

Balovaptan + Itraconzole

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Balovaptan + Itraconzole n=15 participants at risk Dosing in Period 1 was separated by at least a 7 day washout period before dosing started in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.
Nervous system disorders Headache	20.0% 3/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Nervous system disorders Head discomfort	13.3% 2/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Nervous system disorders Presyncope	13.3% 2/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Nervous system disorders Dizziness	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Nervous system disorders Somnolence	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
General disorders Medical device site pruritus	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
General disorders Asthenia	13.3% 2/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
General disorders Catheter site pain	13.3% 2/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
General disorders Catheter site haematoma	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Musculoskeletal and connective tissue disorders Myalgia	20.0% 3/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Musculoskeletal and connective tissue disorders Back pain	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Musculoskeletal and connective tissue disorders Muscle spasms	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Musculoskeletal and connective tissue disorders Musculoskeletal discomfort	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Gastrointestinal disorders Abdominal discomfort	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Gastrointestinal disorders Abdominal pain	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Gastrointestinal disorders Anal pruritus	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Gastrointestinal disorders Diarrhoea	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Gastrointestinal disorders Nausea	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Psychiatric disorders Insomnia	13.3% 2/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Skin and subcutaneous tissue disorders Hyperhidrosis	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Skin and subcutaneous tissue disorders Pruritus	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Investigations Blood creatine phosphokinase increased	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Metabolism and nutrition disorders Decreased appetite	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Renal and urinary disorders Pollakiuria	6.7% 1/15 • From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: genentech@druginfo.com

Results disclosure agreements

• Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
• Publication restrictions are in place

Restriction type: OTHER