Study to Investigate the Effect of Balovaptan on the QTC Interval in Healthy Subjects

A Single-Center, Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study to Investigate the Effect of Balovaptan on the QTC Interval in Healthy Subjects

This was a single-center, multiple-dose, randomized, double-blind, placebo-controlled, positive-controlled, twelve sequence, 3-period cross-over study to investigate the effect of balovaptan on the QTc interval in healthy subjects.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Balovaptan therapeutic dose Treatment A; Drug: Balovaptan supra-therapeutic dose Treatment B; Drug: Active control [moxifloxacin] on Day 2 Treatment C; Drug: Placebo for Balovaptan Treatment C; Drug: Placebo for Moxifloxacin Treatment A; Drug: Placebo for Moxifloxacin Treatment B; Drug: Moxifloxacin Treatment C; Drug: Placebo for Moxifloxacin Treatment C; Drug: Active control [Moxifloxacin] on Day 15 Treatment D; Drug: Placebo for Balovaptan Treatment D; Drug: Placebo for Moxifloxacin Treatment D; Drug: Moxifloxacin Treatment D

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Lenexa, Kansas, United States, 66219
      • PRA International Clinical Pharmacology Center (EDS US Clinic)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 1 acceptable form of contraception during the entire study and for 90 days following last dose of study drug.
• For men: vasectomized, agreement to remain abstinent or use of a condom during intercourse. Must also agree to refrain from donating sperm.
• Fluent in English.

Exclusion Criteria:

• If female, a positive pregnancy test at screening or prior to Day 1 of any Treatment Period.
• Lactating women.
• 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 or designee.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Sequence 1: A, B, C	Drug: Balovaptan therapeutic dose Treatment A; Days 1-14: A single once daily dose at dose level A of balovaptan for 14 days; Drug: Balovaptan supra-therapeutic dose Treatment B; Days 1-14: A single once daily oral dose at dose level B of balovaptan for 14 days.; Drug: Active control [moxifloxacin] on Day 2 Treatment C; Day 2: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Balovaptan Treatment C; Days 1-14: Matching placebo for balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment A; Day 2 and 15: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Placebo for Moxifloxacin Treatment B; Days 2 and 15: Single oral dose of a matching placebo capsule of moxifloxacin.; Drug: Moxifloxacin Treatment C; Day 2: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Moxifloxacin Treatment C; Day 15: A single oral dose of a matching placebo capsule for moxifloxacin.
Experimental: Treatment Sequence 2: A, C, B	Drug: Balovaptan therapeutic dose Treatment A; Days 1-14: A single once daily dose at dose level A of balovaptan for 14 days; Drug: Balovaptan supra-therapeutic dose Treatment B; Days 1-14: A single once daily oral dose at dose level B of balovaptan for 14 days.; Drug: Active control [moxifloxacin] on Day 2 Treatment C; Day 2: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Balovaptan Treatment C; Days 1-14: Matching placebo for balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment A; Day 2 and 15: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Placebo for Moxifloxacin Treatment B; Days 2 and 15: Single oral dose of a matching placebo capsule of moxifloxacin.; Drug: Moxifloxacin Treatment C; Day 2: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Moxifloxacin Treatment C; Day 15: A single oral dose of a matching placebo capsule for moxifloxacin.
Experimental: Treatment Sequence 3: B, A, C	Drug: Balovaptan therapeutic dose Treatment A; Days 1-14: A single once daily dose at dose level A of balovaptan for 14 days; Drug: Balovaptan supra-therapeutic dose Treatment B; Days 1-14: A single once daily oral dose at dose level B of balovaptan for 14 days.; Drug: Active control [moxifloxacin] on Day 2 Treatment C; Day 2: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Balovaptan Treatment C; Days 1-14: Matching placebo for balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment A; Day 2 and 15: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Placebo for Moxifloxacin Treatment B; Days 2 and 15: Single oral dose of a matching placebo capsule of moxifloxacin.; Drug: Moxifloxacin Treatment C; Day 2: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Moxifloxacin Treatment C; Day 15: A single oral dose of a matching placebo capsule for moxifloxacin.
Experimental: Treatment Sequence 4: B, C, A	Drug: Balovaptan therapeutic dose Treatment A; Days 1-14: A single once daily dose at dose level A of balovaptan for 14 days; Drug: Balovaptan supra-therapeutic dose Treatment B; Days 1-14: A single once daily oral dose at dose level B of balovaptan for 14 days.; Drug: Active control [moxifloxacin] on Day 2 Treatment C; Day 2: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Balovaptan Treatment C; Days 1-14: Matching placebo for balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment A; Day 2 and 15: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Placebo for Moxifloxacin Treatment B; Days 2 and 15: Single oral dose of a matching placebo capsule of moxifloxacin.; Drug: Moxifloxacin Treatment C; Day 2: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Moxifloxacin Treatment C; Day 15: A single oral dose of a matching placebo capsule for moxifloxacin.
Experimental: Treatment Sequence 5: C, A, B	Drug: Balovaptan therapeutic dose Treatment A; Days 1-14: A single once daily dose at dose level A of balovaptan for 14 days; Drug: Balovaptan supra-therapeutic dose Treatment B; Days 1-14: A single once daily oral dose at dose level B of balovaptan for 14 days.; Drug: Active control [moxifloxacin] on Day 2 Treatment C; Day 2: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Balovaptan Treatment C; Days 1-14: Matching placebo for balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment A; Day 2 and 15: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Placebo for Moxifloxacin Treatment B; Days 2 and 15: Single oral dose of a matching placebo capsule of moxifloxacin.; Drug: Moxifloxacin Treatment C; Day 2: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Moxifloxacin Treatment C; Day 15: A single oral dose of a matching placebo capsule for moxifloxacin.
Experimental: Treatment Sequence 6: C, B, A	Drug: Balovaptan therapeutic dose Treatment A; Days 1-14: A single once daily dose at dose level A of balovaptan for 14 days; Drug: Balovaptan supra-therapeutic dose Treatment B; Days 1-14: A single once daily oral dose at dose level B of balovaptan for 14 days.; Drug: Active control [moxifloxacin] on Day 2 Treatment C; Day 2: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Balovaptan Treatment C; Days 1-14: Matching placebo for balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment A; Day 2 and 15: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Placebo for Moxifloxacin Treatment B; Days 2 and 15: Single oral dose of a matching placebo capsule of moxifloxacin.; Drug: Moxifloxacin Treatment C; Day 2: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Moxifloxacin Treatment C; Day 15: A single oral dose of a matching placebo capsule for moxifloxacin.
Experimental: Treatment Sequence 7: A, B, D	Drug: Balovaptan therapeutic dose Treatment A; Days 1-14: A single once daily dose at dose level A of balovaptan for 14 days; Drug: Balovaptan supra-therapeutic dose Treatment B; Days 1-14: A single once daily oral dose at dose level B of balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment A; Day 2 and 15: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Placebo for Moxifloxacin Treatment B; Days 2 and 15: Single oral dose of a matching placebo capsule of moxifloxacin.; Drug: Active control [Moxifloxacin] on Day 15 Treatment D; Day 15: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Balovaptan Treatment D; Days 1-14: Matching placebo for balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment D; Day 2: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Moxifloxacin Treatment D; Day 15: A single oral dose of 400 mg moxifloxacin capsule.
Experimental: Treatment Sequence 8: A, D, B	Drug: Balovaptan therapeutic dose Treatment A; Days 1-14: A single once daily dose at dose level A of balovaptan for 14 days; Drug: Balovaptan supra-therapeutic dose Treatment B; Days 1-14: A single once daily oral dose at dose level B of balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment A; Day 2 and 15: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Placebo for Moxifloxacin Treatment B; Days 2 and 15: Single oral dose of a matching placebo capsule of moxifloxacin.; Drug: Active control [Moxifloxacin] on Day 15 Treatment D; Day 15: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Balovaptan Treatment D; Days 1-14: Matching placebo for balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment D; Day 2: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Moxifloxacin Treatment D; Day 15: A single oral dose of 400 mg moxifloxacin capsule.
Experimental: Treatment Sequence 9: B, A, D	Drug: Balovaptan therapeutic dose Treatment A; Days 1-14: A single once daily dose at dose level A of balovaptan for 14 days; Drug: Balovaptan supra-therapeutic dose Treatment B; Days 1-14: A single once daily oral dose at dose level B of balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment A; Day 2 and 15: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Placebo for Moxifloxacin Treatment B; Days 2 and 15: Single oral dose of a matching placebo capsule of moxifloxacin.; Drug: Active control [Moxifloxacin] on Day 15 Treatment D; Day 15: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Balovaptan Treatment D; Days 1-14: Matching placebo for balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment D; Day 2: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Moxifloxacin Treatment D; Day 15: A single oral dose of 400 mg moxifloxacin capsule.
Experimental: Treatment Sequence 10: B, D, A	Drug: Balovaptan therapeutic dose Treatment A; Days 1-14: A single once daily dose at dose level A of balovaptan for 14 days; Drug: Balovaptan supra-therapeutic dose Treatment B; Days 1-14: A single once daily oral dose at dose level B of balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment A; Day 2 and 15: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Placebo for Moxifloxacin Treatment B; Days 2 and 15: Single oral dose of a matching placebo capsule of moxifloxacin.; Drug: Active control [Moxifloxacin] on Day 15 Treatment D; Day 15: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Balovaptan Treatment D; Days 1-14: Matching placebo for balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment D; Day 2: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Moxifloxacin Treatment D; Day 15: A single oral dose of 400 mg moxifloxacin capsule.
Experimental: Treatment Sequence 11: D, A, B	Drug: Balovaptan therapeutic dose Treatment A; Days 1-14: A single once daily dose at dose level A of balovaptan for 14 days; Drug: Balovaptan supra-therapeutic dose Treatment B; Days 1-14: A single once daily oral dose at dose level B of balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment A; Day 2 and 15: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Placebo for Moxifloxacin Treatment B; Days 2 and 15: Single oral dose of a matching placebo capsule of moxifloxacin.; Drug: Active control [Moxifloxacin] on Day 15 Treatment D; Day 15: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Balovaptan Treatment D; Days 1-14: Matching placebo for balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment D; Day 2: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Moxifloxacin Treatment D; Day 15: A single oral dose of 400 mg moxifloxacin capsule.
Experimental: Treatment Sequence 12: D, B, A	Drug: Balovaptan therapeutic dose Treatment A; Days 1-14: A single once daily dose at dose level A of balovaptan for 14 days; Drug: Balovaptan supra-therapeutic dose Treatment B; Days 1-14: A single once daily oral dose at dose level B of balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment A; Day 2 and 15: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Placebo for Moxifloxacin Treatment B; Days 2 and 15: Single oral dose of a matching placebo capsule of moxifloxacin.; Drug: Active control [Moxifloxacin] on Day 15 Treatment D; Day 15: A single oral dose of 400 mg moxifloxacin capsule.; Drug: Placebo for Balovaptan Treatment D; Days 1-14: Matching placebo for balovaptan for 14 days.; Drug: Placebo for Moxifloxacin Treatment D; Day 2: A single oral dose of a matching placebo capsule for moxifloxacin.; Drug: Moxifloxacin Treatment D; Day 15: A single oral dose of 400 mg moxifloxacin capsule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change-From-Baseline QTcF at Dose Level B Measured on 12-Lead ECGs Extracted From Continuous Recordings	Change-from-baseline QTcF (ΔΔQTcF) at dose level B of balovaptan measured on 12-lead ECGs extracted from continuous recordings at the specified time points on Day 14.	Baseline (Predose Day 1), Day 14. (Each treatment period is 15 days.)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change-From-Baseline QTcF at Dose Level B Measured on 12-Lead ECGs Extracted From Continuous Recordings	Change-from-baseline QTcF (ΔΔQTcF) at dose level B of balovaptan measured on 12-lead ECGs extracted from continuous recordings at the specified time points on Day 1.	Baseline (Predose Day 1), Day 1. (Each treatment period is 15 days.)
Change-From-Baseline QTcF of Balovaptan at Dose Level A Measurred on 12-Lead ECGs Extracted From Continuous Recordings	Change-from-baseline QTcF (ΔΔQTcF) at dose level A of balovaptan measured on 12-lead ECGs extracted from continuous recordings at the specified time points on Days 1 and 14.	Baseline (Predose Day 1), Day 1 and Day 14. (Each treatment period is 15 days.)
Change-From-Baseline Heart Rate Measured on 12-Lead ECGs Extracted From Continuous Recordings	Change-from-baseline heart rate at dose level A and dose level B of balovaptan measured on 12-Lead ECGs extracted from continuous recordings on Days 1 and 14.	Baseline (Predose Day 1), Day 1 and Day 14. (Each treatment period is 15 days.)
Change-From-Baseline PR Interval Measured on 12-Lead ECGs Extracted From Continuous Recordings	Change-from-baseline PR interval at dose level A and dose level B of balovaptan measured on 12-Lead ECGs extracted from continuous recordings on Day 1 and 14.	Baseline (Predose Day 1), Day 1 and Day 14. (Each treatment period is 15 days.)
Change-From-Baseline QRS Interval Measured on 12-Lead ECGs Extracted From Continuous Recordings	Change-from-baseline QRS interval at dose level A and dose level B of balovapton measured on 12-Lead ECGs extracted from continuous recordings on Days 1 and 14.	Baseline (Predose Day 1), Day 1 and Day 14. (Each treatment period is 15 days.)
Number of Categorical Outliers for QTcF	The number (percentage) of categorical outliers were participants who had increases in absolute QTcF values > 450 and ≤ 480 ms, > 480 and ≤ 500 ms, or > 500 ms.	Up to approximately 20 weeks
Number of Categorical Outliers for HR	Number (percentage) of categorical outliers were participants with a decrease in HR from pre-dose baseline > 25% to a HR < 50 bpm; and increase in HR from pre-dose baseline > 25% to a HR > 100 bpm.	Up to approximately 20 weeks
Number of Categorical Outliers for PR	PR outliers criteria is as an increase of PR from baseline >25% resulting in PR >200 ms.	Up to approximately 20 weeks
Number of Categorical Outliers for QRS	QRS outlier criteria is an increase of QRS from baseline >25% resulting in QRS >120 ms.	Up to approximately 20 weeks
Number of Treatment Emergent Changes of T-Wave Morphology	Number (%) of participants falling into each of the T-wave categories: Normal (+), Flat, Notched (+), Biphasic, Normal (-), Notched (-).	Up to approximately 20 weeks
Number of Treatment Emergent Changes of U-Wave Presence	Number (percentage) of participants with treatment emergent changes of U-wave presence.	Up to approximately 20 weeks
Tmax of Balovaptan		Day 1 and Day 14. (Each treatment period is 15 days.)
Tmax of M2 Metabolite		Day 1 and Day 14. (Each treatment period is 15 days.)
Tmax M3 Metabolite		Day 1 and Day 14. (Each treatment period is 15 days.)
Cmax of Balovaptan		Day 1 and Day 14. (Each treatment period is 15 days.)
Cmax of M2 Metabolite		Day 1 and Day 14. (Each treatment period is 15 days.)
Cmax of M3 Metabolite		Day 1 and Day 14. (Each treatment period is 15 days.)
AUC0-24 of Balovaptan		Day 1 and Day 14 (Each treatment period is 15 days.)
AUC0-24 of M2 Metabolite		Day 1 and Day 14 (Each treatment period is 15 days.)
AUC0-24 of M3 Metabolite		Day 1 and Day 14 (Each treatment period is 15 days.)
Tmax of Moxifloxacin		Days 2 (Treatment C) or 15 (Treatment D). (Each treatment period is 15 days.)
Cmax of Moxifloxacin		Days 2 (Treatment C) or 15 (Treatment D) (Each treatment period is 15 days.)
AUC0-24 of Moxifloxacin		Days 2 (Treatment C) or 15 (Treatment D) (Each treatment period is 15 days.)
Predicted ΔΔQTcF Interval at Geometric Mean Peak Concentrations at Tmax of Balovaptan From Concentration-QTc Analysis		Baseline, Day 14. (Each treatment period is 15 days.)
Predicted ΔΔQTcF Interval at Geometric Mean Peak Concentrations at Tmax of M2 From Concentration-QTc Analysis		Baseline, Day 14. (Each treatment period is 15 days.)
Predicted ΔΔQTcF Interval at Geometric Mean Peak Concentration for M3 From Concentration-QTc Analysis		Baseline, Day 14. (Each treatment period is 15 days.)
Change-From-Baseline QTcF Measured on 12 Lead ECGs Extracted From Continuous Records		Baseline, Day 15. (Each treatment period is 15 days.)
Percentage of Participants With Treatment Emergent Adverse Events		Up to approximately 20 weeks.

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2019
• Primary Completion (Actual): June 14, 2019
• Study Completion (Actual): July 13, 2019

Study Registration Dates

• First Submitted: January 7, 2019
• First Submitted That Met QC Criteria: January 15, 2019
• First Posted (Actual): January 17, 2019

Study Record Updates

• Last Update Posted (Actual): July 24, 2020
• Last Update Submitted That Met QC Criteria: July 8, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral, Combined; Contraceptives, Oral; Contraceptive Agents, Female; Moxifloxacin; Norgestimate, ethinyl estradiol drug combination
• Other Study ID Numbers: WP40734

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No