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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Balovaptan therapeutic dose Treatment A
* Drug: Balovaptan supra-therapeutic dose Treatment B
* Drug: Active control [moxifloxacin] on Day 2 Treatment C
* Drug: Active control [Moxifloxacin] on Day 15 Treatment D
* Drug: Placebo for Balovaptan Treatment C
* Drug: Placebo for Balovaptan Treatment D
* Drug: Placebo for Moxifloxacin Treatment A
* Drug: Placebo for Moxifloxacin Treatment B
* Drug: Moxifloxacin Treatment C
* Drug: Placebo for Moxifloxacin Treatment C
* Drug: Placebo for Moxifloxacin Treatment D
* Drug: Moxifloxacin Treatment D


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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. |