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

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03579719
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arm: 1
• Actual Duration (Months): 4
• Patients Per Site Per Month: 3.7

Study Details

Study Description

Brief Summary

This study was a non-randomized, open-label, one-sequence, two-period within-subject study to investigate the effect of CYP3A inhibition on the PK of balovaptan in healthy male and female volunteers using itraconazole as a CYP3A inhibitor. The study was conducted at 1 site in the Netherlands.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Balovaptan; Drug: Itraconazole	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Single-Center, Non-Randomized, Open-Label, One-Sequence, Two-Period Within-Subject Study to Investigate the Effect of Itraconazole on the Pharmacokinetics of Multiple Doses of Balovaptan in Healthy Volunteers
• Actual Study Start Date: Jul 10, 2018
• Actual Primary Completion Date: Nov 9, 2018
• Actual Study Completion Date: Nov 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Balovaptan + Itraconzole Dosing in Period 1 was separated by at least a 7 day washout period before dosing starts in Period 2. Participants received the study drugs in 2 periods over a total of 37 days.	Drug: Balovaptan; In Period 1, balovaptan was administered orally once daily (qd) on Days 1 to 10. In Period 2, balovaptan was administered qd on Days 6 to 20.; Drug: Itraconazole; In Period 2, 200 mg itraconzole was administered bid for 4 days and qd on Days 5-20, approximately 12 hours apart. On Days 6-20, 200 mg itraconazole was administered qd.

Outcome Measures

Primary Outcome Measures

1. Maximum Plasma Concentration (Cmax) for Balovaptan [Day 10 of Period 1, Day 10 and Day 15 of Period 2]

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

2. Maximum Plasma Concentration (Cmax) for M2 Metabolite (as Applicable) [Day 10 of Period 1, Day 10 and Day 15 of Period 2]

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

3. Maximum Plasma Concentration (Cmax) for M3 Metabolite [Day 10 of Period 1, Day 10 and Day 15 of Period 2]

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

4. Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for Balovaptan [Day 10 of Period 1, Day 10 and Day 15 of Period 2]

5. Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M2 Metabolite (as Applicable) [Day 10 of Period 1, Day 10 and Day 15 of Period 2]

6. Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M3 Metabolite [Day 10 of Period 1, Day 10 and Day 15 of Period 2]

7. Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan [Day 10 of Period 1; Day 10 and Day 15 of Period 2]

8. Time to Maximum Observed Plasma Concentration (Tmax) for M2 Metabolite (as Applicable) [Day 10 of Period 1; Day 10 and Day 15 of Period 2]

9. Time to Maximum Observed Plasma Concentration (Tmax) for M3 Metabolite [Day 10 of Period 1; Day 10 and Day 15 of Period 2]

Secondary Outcome Measures

1. Trough Plasma Concentration (Ctrough) for Balovaptan [Day 10 of Period 1; Day 10 and Day 15 of Period 2]

2. Trough Plasma Concentration (Ctrough) for M2 Metabolite (as Applicable) [Day 10 of Period 1; Day 10 and Day 15 of Period 2]

3. Trough Plasma Concentration (Ctrough) for M3 Metabolite [Day 10 of Period 1; Day 10 and Day 15 of Period 2]

4. Time to Steady State for Balovaptan [Days 1, 3, 5, 8, 9, 10 in Period 1 and Days 1, 3, 5, 8, 9, 10, 13, 14, 15 in Period 2]

5. Percentage of Participants With Adverse Events [Up to 21 days postdose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy male and female subjects. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, hematology, blood chemistry, urinalysis, and serology.

• Body Mass Index of 18 to 30 kg/m2, inclusive.

• For women of childbearing potential: agreement to use at least 2 acceptable contraceptive methods during the treatment period and for 90 days after the last dose of study drug.

• For men: agreement to use contraceptive measures, and agreement to refrain from donating sperm until 90 days after the last dose of study drug.

Exclusion Criteria:

• Female subjects who are pregnant or lactating.

• Any condition or disease detected during the medical interview/physical examination that would render the subject unsuitable for the study, place the subject at undue risk or interfere with the ability of the subject to complete the study in the opinion of the Investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pra International Group B.V	Groningen		Netherlands	9728 NZ

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 18, 2018
• Statistical Analysis Plan - Nov 20, 2018

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03579719
• Other Study ID Numbers: WP40609; 2018-001454-10
• First Posted: Jul 9, 2018
• Last Update Posted: Nov 4, 2019
• Last Verified: Oct 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Itraconazole

Study Results

Participant Flow

Recruitment Details	The study was conducted at 1 site in the Netherlands.
Pre-assignment Detail	Participants in this study included healthy volunteers.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Period Title: Overall Study
STARTED	15
COMPLETED	14
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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 Participants	15
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	43 (13)
Sex: Female, Male (Count of Participants)
Female	3 20%
Male	12 80%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	15 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 6.7%
Asian	1 6.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	12 80%
More than one race	1 6.7%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) for Balovaptan
Description	Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units.
Time Frame	Day 10 of Period 1, Day 10 and Day 15 of Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan Day 10 of Period 1	31.5 (25.3)
Balovaptan + itraconazole Day 10 of Period 2	125 (27.7)
Balovaptan + itraconazole Day 15 of Period 2	140 (31.7)

2. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) for M2 Metabolite (as Applicable)
Description	Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units.
Time Frame	Day 10 of Period 1, Day 10 and Day 15 of Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan Day 10 of Period 1	11.0 (26.5)
Balovaptan + itraconazole Day 10 of Period 2	6.34 (45.3)
Balovaptan + itraconazole Day 15 of Period 2	7.60 (44.9)

3. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) for M3 Metabolite
Description	Cmax is the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units.
Time Frame	Day 10 of Period 1, Day 10 and Day 15 of Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan Day 10 of Period 1	19.9 (16.5)
Balovaptan + itraconazole Day 10 of Period 2	21.3 (20.0)
Balovaptan + itraconazole Day 15 of Period 2	28.6 (19.7)

4. Primary Outcome

Title	Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for Balovaptan
Time Frame	Day 10 of Period 1, Day 10 and Day 15 of Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan Day 10 of Period 1	464 (29.7)
Balovaptan + itraconazole Day 10 of Period 2	2304 (31.8)
Balovaptan + itraconazole Day 15 of Period 2	2587 (35.1)

5. Primary Outcome

Title	Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M2 Metabolite (as Applicable)
Time Frame	Day 10 of Period 1, Day 10 and Day 15 of Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan Day 10 of Period 1	230 (26.9)
Balovaptan + itraconazole Day 10 of Period 2	129 (46.9)
Balovaptan + itraconazole Day 15 of Period 2	156 (48.5)

6. Primary Outcome

Title	Area Under the Concentration Vs Time Curve Over the Dosing Interval (AUC0-tau) for M3 Metabolite
Time Frame	Day 10 of Period 1, Day 10 and Day 15 of Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan Day 10 of Period 1	402 (17.8)
Balovaptan + itraconazole Day 10 of Period 2	449 (21.3)
Balovaptan + itraconazole Day 15 of Period 2	570 (20.9)

7. Secondary Outcome

Title	Trough Plasma Concentration (Ctrough) for Balovaptan
Time Frame	Day 10 of Period 1; Day 10 and Day 15 of Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan Day 10 of Period 1	13.3 (4.7)
Balovaptan + itraconazole Day 10 of Period 2	91.9 (26.6)
Balovaptan + itraconazole Day 15 of Period 2	102 (36.0)

8. Secondary Outcome

Title	Trough Plasma Concentration (Ctrough) for M2 Metabolite (as Applicable)
Time Frame	Day 10 of Period 1; Day 10 and Day 15 of Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan Day 10 of Period 1	9.93 (2.62)
Balovaptan + itraconazole Day 10 of Period 2	5.82 (2.99)
Balovaptan + itraconazole Day 15 of Period 2	6.88 (3.05)

9. Secondary Outcome

Title	Trough Plasma Concentration (Ctrough) for M3 Metabolite
Time Frame	Day 10 of Period 1; Day 10 and Day 15 of Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan Day 10 of Period 1	15.1 (2.5)
Balovaptan + itraconazole Day 10 of Period 2	18.9 (4.7)
Balovaptan + itraconazole Day 15 of Period 2	23.9 (6.1)

10. Secondary Outcome

Title	Time to Steady State for Balovaptan
Time Frame	Days 1, 3, 5, 8, 9, 10 in Period 1 and Days 1, 3, 5, 8, 9, 10, 13, 14, 15 in Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan	4
Balovaptan + itraconazole	13

11. Secondary Outcome

Title	Percentage of Participants With Adverse Events
Time Frame	Up to 21 days postdose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	15
Number [Percentage]	73

12. Primary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan
Time Frame	Day 10 of Period 1; Day 10 and Day 15 of Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan Day 10 of Period 1	3.00
Balovaptan + itraconazole Day 10 of Period 2	4.00
Balovaptan + itraconazole Day 15 of Period 2	4.00

13. Primary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) for M2 Metabolite (as Applicable)
Time Frame	Day 10 of Period 1; Day 10 and Day 15 of Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan Day 10 of Period 1	5.00
Balovaptan + itraconazole Day 10 of Period 2	6.00
Balovaptan + itraconazole Day 15 of Period 2	6.00

14. Primary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) for M3 Metabolite
Time Frame	Day 10 of Period 1; Day 10 and Day 15 of Period 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
Measure Participants	14
Balovaptan Day 10 of Period 1	4.00
Balovaptan + itraconazole Day 10 of Period 2	9.00
Balovaptan + itraconazole Day 15 of Period 2	3.50

Adverse Events

Time Frame	From the first study drug to the data cutoff date: 9 Nov 2018 (up to 21 days postdose)
Arm/Group Title	Balovaptan + Itraconzole
Arm/Group Description	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.
All Cause Mortality
	Balovaptan + Itraconzole
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Serious Adverse Events
	Balovaptan + Itraconzole
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Other (Not Including Serious) Adverse Events
	Balovaptan + Itraconzole
	Affected / at Risk (%)	# Events
Total	11/15 (73.3%)
Gastrointestinal disorders
Abdominal discomfort	1/15 (6.7%)
Abdominal pain	1/15 (6.7%)
Anal pruritus	1/15 (6.7%)
Diarrhoea	1/15 (6.7%)
Nausea	1/15 (6.7%)
General disorders
Medical device site pruritus	1/15 (6.7%)
Asthenia	2/15 (13.3%)
Catheter site pain	2/15 (13.3%)
Catheter site haematoma	1/15 (6.7%)
Investigations
Blood creatine phosphokinase increased	1/15 (6.7%)
Metabolism and nutrition disorders
Decreased appetite	1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Myalgia	3/15 (20%)
Back pain	1/15 (6.7%)
Muscle spasms	1/15 (6.7%)
Musculoskeletal discomfort	1/15 (6.7%)
Nervous system disorders
Headache	3/15 (20%)
Head discomfort	2/15 (13.3%)
Presyncope	2/15 (13.3%)
Dizziness	1/15 (6.7%)
Somnolence	1/15 (6.7%)
Psychiatric disorders
Insomnia	2/15 (13.3%)
Renal and urinary disorders
Pollakiuria	1/15 (6.7%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/15 (6.7%)
Pruritus	1/15 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.