A Study to Investigate the Effect of Rifampicin on the PK of Multiple Doses of Balovaptin In Healthy Volunteers

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03586726
• Collaborator: (none)
• Enrollment: 16
• Location: 1
• Arm: 1
• Actual Duration (Months): 3.7
• Patients Per Site Per Month: 4.3

Study Details

Study Description

Brief Summary

This study was a single-center, non-randomized, open-label, one-sequence, two-period, within-subject study to investigate the effects of multiple doses of rifampicin on the PK and safety of multiple doses of balovaptan in healthy subjects. The study was conducted at 1 site in the Netherlands.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 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 Rifampicin on the Pharmacokinetics of Multiple Doses of Balovaptin In Healthy Volunteers
• Actual Study Start Date: Jul 24, 2018
• Actual Primary Completion Date: Nov 2, 2018
• Actual Study Completion Date: Nov 15, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Balovaptan + Rifampicin Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.	Drug: Balovaptan; In Period 1, balovaptan was administered alone as a once daily (qd) dose on Days 1 to 10. In Period 2, balovaptan was administered as a qd dose on Days 7 to 16.; Drug: Rifampicin; In Period 2, 600 mg of rifampicin will be administered alone as a qd dose from Day 1 to Day 6, and as a qd dose on Days 7 to 16.

Outcome Measures

Primary Outcome Measures

1. Maximum Plasma Concentration (Cmax) for Balovaptan [Day 10 of Period 1 and Day 16 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 [Day 10 of Period 1 and Day 16 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 and Day 16 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 Plasma Concentration Curve From Time 0 to 24 Hours (AUC0-24) for Balovaptan [Day 10 and 11 of Period 1; Day 16 and 17 of Period 2]

   AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post dose.

5. Area Under the Plasma Concentration Curve From Time 0 to 24 Hours for M2 Metabolite [Day 10 and 11 of Period 1; Day 16 and 17 of Period 2]

   AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post dose.

6. Area Under the Plasma Concentration Curve From Time 0 to 24 Hours for M3 Metabolite [Day 10 and 11 of Period 1; Day 16 and 17 of Period 2]

   AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post dose.

Secondary Outcome Measures

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

2. Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan [Day 10 of Period 1 and Day 16 of Period 2]

   Tmax is the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units.

3. Time to Maximum Observed Plasma Concentration for M2 Metabolite [Day 10 of Period 1 and Day 16 of Period 2]

   Tmax is the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units.

4. Time to Maximum Observed Plasma Concentration for M3 Metabolite [Day 10 of Period 1 and Day 16 of Period 2]

   Tmax is the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units.

5. Metabolite to Parent Ratio for M2 Metabolite Based on AUC0-24 [Day 10 and 11 of Period 1; Day 16 and 17 of Period 2]

6. Metabolite to Parent Ratio for M2 Metabolite Based on Cmax [Day 10 of Period 1 and Day 16 of Period 2]

7. Metabolite to Parent Ratio for M3 Metabolite Based on AUC0-24 [Day 10 and 11 of Period 1; Day 16 and 17 of Period 2]

8. Metabolite to Parent Ratio for M3 Metabolite Based on Cmax [Day 10 of Period 1 and Day 16 of Period 2]

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.

Rifampicin-related Exclusion Criteria:

• Subjects diagnosed, or suspected of having porphyria, and subjects with first-degree relatives diagnosed, or suspected of having porphyria.

• Known hypersensitivity to rifampicin

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 - Jun 3, 2018
• Statistical Analysis Plan - Oct 9, 2018

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03586726
• Other Study ID Numbers: WP40608; 2018-001783-40
• First Posted: Jul 16, 2018
• Last Update Posted: Nov 7, 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: Rifampin

Study Results

Participant Flow

Arm/Group Title	Balovaptan + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Period Title: Overall Study
STARTED	16
COMPLETED	15
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Balovaptan + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Overall Participants	16
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	39.0 (14.7)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	16 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	16 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	16 100%
More than one race	0 0%
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 and Day 16 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	94.2 (33.4)
Balovaptan + rifampicin (Period 2)	12.9 (22.8)

2. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) for M2 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 and Day 16 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	22.0 (22.7)
Balovaptan + rifampicin (Period 2)	8.09 (20.5)

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 and Day 16 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	49.6 (26.4)
Balovaptan + rifampicin (Period 2)	10.9 (23.2)

4. Primary Outcome

Title	Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC0-24) for Balovaptan
Description	AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post dose.
Time Frame	Day 10 and 11 of Period 1; Day 16 and 17 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	1000 (29.6)
Balovaptan + rifampicin (Period 2)	67.0 (16.3)

5. Primary Outcome

Title	Area Under the Plasma Concentration Curve From Time 0 to 24 Hours for M2 Metabolite
Description	AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post dose.
Time Frame	Day 10 and 11 of Period 1; Day 16 and 17 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	448 (22.7)
Balovaptan + rifampicin (Period 2)	149 (21.9)

6. Primary Outcome

Title	Area Under the Plasma Concentration Curve From Time 0 to 24 Hours for M3 Metabolite
Description	AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post dose.
Time Frame	Day 10 and 11 of Period 1; Day 16 and 17 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	844 (20.8)
Balovaptan + rifampicin (Period 2)	110 (13.3)

7. 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Number [Percentage]	94

8. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) for Balovaptan
Description	Tmax is the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units.
Time Frame	Day 10 of Period 1 and Day 16 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	1.00
Balovaptan + rifampicin (Period 2)	1.00

9. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration for M2 Metabolite
Description	Tmax is the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units.
Time Frame	Day 10 of Period 1 and Day 16 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	2.50
Balovaptan + rifampicin (Period 2)	3.00

10. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration for M3 Metabolite
Description	Tmax is the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units.
Time Frame	Day 10 of Period 1 and Day 16 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	1.00
Balovaptan + rifampicin (Period 2)	1.00

11. Secondary Outcome

Title	Metabolite to Parent Ratio for M2 Metabolite Based on AUC0-24
Time Frame	Day 10 and 11 of Period 1; Day 16 and 17 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	0.430 (32.3)
Balovaptan + rifampicin (Period 2)	2.14 (14.8)

12. Secondary Outcome

Title	Metabolite to Parent Ratio for M2 Metabolite Based on Cmax
Time Frame	Day 10 of Period 1 and Day 16 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	0.225 (30.9)
Balovaptan + rifampicin (Period 2)	0.606 (20.7)

13. Secondary Outcome

Title	Metabolite to Parent Ratio for M3 Metabolite Based on AUC0-24
Time Frame	Day 10 and 11 of Period 1; Day 16 and 17 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	0.872 (16.6)
Balovaptan + rifampicin (Period 2)	1.70 (6.9)

14. Secondary Outcome

Title	Metabolite to Parent Ratio for M3 Metabolite Based on Cmax
Time Frame	Day 10 of Period 1 and Day 16 of Period 2

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis population consisted of all subjects who received at least one dose of balovaptan. Participants 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 + Rifampicin
Arm/Group Description	Participants received the study drugs in 2 periods. There was a minimum of a 14-day to a maximum of a 21-day washout between the last dose in Period 1 and the first dose in Period 2.
Measure Participants	16
Balovaptan (Period 1)	0.545 (16.5)
Balovaptan + rifampicin (Period 2)	0.873 (9.0)

Adverse Events

Time Frame	Up to 21 days postdose (15 November 2018).
Arm/Group Title	BALOVAPTAN+RIFAMPICIN
Arm/Group Description	In Period 1, balovaptan was administered alone as a once daily (qd) dose on Days 1 to 10. In Period 2, balovaptan was administered as a qd dose on Days 7 to 16. In Period 2, 600 mg of rifampicin was administered alone as a qd dose on Days 7 to 16.
All Cause Mortality
	BALOVAPTAN+RIFAMPICIN
	Affected / at Risk (%)	# Events
Total	0/16 (0%)
Serious Adverse Events
	BALOVAPTAN+RIFAMPICIN
	Affected / at Risk (%)	# Events
Total	0/16 (0%)
Other (Not Including Serious) Adverse Events
	BALOVAPTAN+RIFAMPICIN
	Affected / at Risk (%)	# Events
Total	15/16 (93.8%)
Ear and labyrinth disorders
Vertigo	1/16 (6.3%)	1
Eye disorders
Eye irritation	1/16 (6.3%)	1
Gastrointestinal disorders
Abdominal pain	4/16 (25%)	4
Diarrhoea	2/16 (12.5%)	3
Nausea	2/16 (12.5%)	3
Frequent bowel movements	2/16 (12.5%)	2
Abdominal distension	1/16 (6.3%)	1
Anorectal discomfort	1/16 (6.3%)	1
Eructation	1/16 (6.3%)	1
Flatulence	1/16 (6.3%)	1
Glossodynia	1/16 (6.3%)	1
Lip pain	1/16 (6.3%)	1
General disorders
Fatigue	3/16 (18.8%)	3
Catheter site pain	1/16 (6.3%)	1
Musculoskeletal and connective tissue disorders
Myalgia	2/16 (12.5%)	4
Back pain	2/16 (12.5%)	2
Arthralgia	1/16 (6.3%)	1
Muscular weakness	1/16 (6.3%)	1
Musculoskeletal stifness	1/16 (6.3%)	1
Nervous system disorders
Headache	6/16 (37.5%)	11
Dizziness	4/16 (25%)	5
Head discomfort	1/16 (6.3%)	3
Paraesthesia	1/16 (6.3%)	1
Somnolence	1/16 (6.3%)	2
Psychiatric disorders
Insomnia	5/16 (31.3%)	7
Nightmare	1/16 (6.3%)	1
Panic attack	1/16 (6.3%)	1
Persistent depressive disorder	1/16 (6.3%)	1
Restlessness	1/16 (6.3%)	1
Stress	1/16 (6.3%)	1
Renal and urinary disorders
Chromaturia	12/16 (75%)	14
Respiratory, thoracic and mediastinal disorders
Cough	2/16 (12.5%)	2
Dry throat	1/16 (6.3%)	1
Oropharyngeal pain	1/16 (6.3%)	1
Rhinorrhoea	1/16 (6.3%)	1
Vascular disorders
Hot flush	1/16 (6.3%)	1

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.