Clinical trial NCT03155893: A Study to Evaluate the Cardiac Safety of a Single Dose of AL-335 Administered on a Background of Simeprevir and Odalasvir and of Repeated Doses of Odalasvir Administered Alone in Healthy Participants
Official title: A Randomized, Double-blind, Double-dummy, Placebo- and Positive-controlled Study to Evaluate the Cardiac Safety of a Single Dose of AL-335 Administered on a Background of Simeprevir and Odalasvir and of Repeated Doses of Odalasvir Administered Alone in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2017-05-16
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The main purpose of this study is to assess the effect of a single supratherapeutic dose of AL-335 administered on top of multiple doses of odalasvir (ODV) and simeprevir (SMV) versus placebo on QT/QT interval corrected for heart rate (QTc) interval changes, using intersection-union test (IUT) analysis (Panel 1); to assess the effect of ODV on QT/QTc and PR interval changes after multiple supratherapeutic doses of ODV using an exposure-response (ER) approach (Panel 2); and to assess the effect of multiple supratherapeutic doses of ODV on echocardiographic left ventricular ejection fraction (LVEF) (Panel 2) in healthy participants.


Eligibility criteria: Inclusion Criteria:

* Participants must sign and date an informed consent form (ICF) indicating that he or she understands the purpose of, and the procedures required for, the study and is willing to participate in the study
* Participant must be healthy on the basis of physical examination, medical history, vital signs, and laboratory tests performed at screening
* Participant must have a blood pressure (supine after at least 5 minutes rest) between 90 and 140 millimeters of mercury (mmHg) systolic, inclusive, and no higher than 90 mmHg diastolic
* Participant must have a 12-lead electrocardiogram (ECG) (based on the mean value of triplicate ECG parameters) consistent with normal cardiac conduction and function at screening
* Participant must have an echocardiogram at screening with left ventricular ejection fraction (LVEF) greater than or equal to (\>=)55 percent (%). Participant should not have any other echocardiogram finding suggestive of clinically relevant cardiomyopathy
* Female participant must have a negative highly sensitive urine pregnancy test at Day -2 (Panel 1) or Day -4 (Panel 2)

Exclusion Criteria:

* Participant has a history of liver or renal insufficiency, significant cardiac, vascular, pulmonary, gastrointestinal (such as significant diarrhea, gastric stasis, constipation, or gastrointestinal surgery that in the investigator's opinion could influence drug absorption or bioavailability), endocrine, neurologic, hematologic, rheumatologic, psychiatric, neoplastic, or metabolic disturbances
* Participant with a history of clinically relevant heart rhythm disturbances including atrial, junctional, re-entry, and ventricular tachycardia, and heart blocks
* Participant with unusual T-wave morphology (such as bifid T-wave) likely to interfere with corrected QT (QTc) measurements
* Participant with a past history of sick sinus syndrome, heart arrhythmias (example, extrasystolic rhythms or tachycardia at rest). Isolated extrasystolic beats are not exclusionary; risk factors associated with Torsade de Pointes (TdP) such as hypokalemia; family history of short/long QT syndrome; sudden unexplained death (including sudden infant death syndrome in a first-degree relative \[that is, sibling, offspring, or biological parent\])
* Participant with any skin condition likely to interfere with electrocardiogram (ECG) electrode placement or adhesion
* Participant with a breast implant or a history of thoracic surgery likely to cause abnormality of the electrical conduction through thoracic tissues

Primary outcomes:
measure: Panel 1:Effect of AL-335 Single Supratherapeutic Dose on QT/QTc Interval Change on top of Multiple Doses of ODV and SMV Vs. Placebo Using IUT Analysis at Day 16
timeFrame: Baseline (Day 1), Day 15
measure: Panel 2: Effect of ODV on QT/QTc Interval Change From Baseline After Multiple Supratherapeutic Doses of ODV Using ER Approach at Day 14
timeFrame: Baseline (Day -3), Day 14
measure: Panel 2: Effect of ODV on QT/QTc Interval Change From Baseline After Multiple Supratherapeutic Doses of ODV Using ER Approach at Day 15
timeFrame: Baseline (Day -3), Day 15
measure: Panel 2: Effect of ODV on QT/QTc Interval Change From Baseline After Multiple Supratherapeutic Doses of ODV Using ER Approach at Day 16
timeFrame: Baseline (Day -3), Day 16
measure: Panel 2: Effect of ODV on PR Interval Change From Baseline After Multiple Supratherapeutic Doses of ODV Using ER Approach at Day 14
timeFrame: Baseline (Day -3), Day 14
measure: Panel 2: Effect of ODV on PR Interval Change From Baseline After Multiple Supratherapeutic Doses of ODV Using ER Approach at Day 15
timeFrame: Baseline (Day -3), Day 15
measure: Panel 2: Effect of ODV on PR Interval Change From Baseline After Multiple Supratherapeutic Doses of ODV Using ER Approach at Day 16
timeFrame: Baseline (Day -3), Day 16
measure: Panel 2: Effect of Multiple Supratherapeutic Doses of ODV on Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Day 10
timeFrame: Baseline (Day -2 and -1), Day 10
measure: Panel 2: Effect of Multiple Supratherapeutic Doses of ODV on Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Day 14
timeFrame: Baseline (Day -2 and -1), Day 14
measure: Panel 2: Effect of Multiple Supratherapeutic Doses of ODV on Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Day 28
timeFrame: Baseline (Day -2 and -1), Day 28
Secondary outcomes:
measure: Panel 1: Maximum Observed Analyte Concentration (Cmax) of AL-335 and its 2 metabolites ALS-022399 and ALS-022227
timeFrame: Panel 1, Day 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose
measure: Panel 1: Time to Reach the Maximum Observed Analyte Concentration (Tmax) of AL-335 and its 2 metabolites ALS-022399 and ALS-022227
timeFrame: Panel 1, Day 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose
measure: Panel 1: Area Under the Analyte Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC24) of AL-335 and its 2 metabolites ALS-022399 and ALS-022227
timeFrame: Panel 1, Day 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose
measure: Panel 1: Area Under the Analyte Concentration-time Curve from Time 0 to the Time of the Last Measurable Concentration (AUClast) of AL-335 and its 2 metabolites ALS-022399 and ALS-022227
timeFrame: Panel 1, Day 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose
measure: Panel 1: Apparent Terminal Elimination Half-life (t1/2term) of AL-335 and its 2 metabolites ALS-022399 and ALS-022227
timeFrame: Panel 1, Day 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose
measure: Panel 1: Apparent Terminal Elimination Rate Constant (Lambda[z]) of AL-335 and its 2 metabolites ALS-022399 and ALS-022227
timeFrame: Panel 1, Day 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose
measure: Panel 1: Area Under the Analyte Concentration-time Curve From Time 0 to Infinite Time (AUC[0-infinity]) of AL-335 and its 2 metabolites ALS-022399 and ALS-022227
timeFrame: Panel 1, Day 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose
measure: Panel 1 and 2: Maximum Observed Analyte Concentration (Cmax) of ODV
timeFrame: Panel 1, Days 14 and 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose; Panel 2, Day 14: predose, 1, 3, 4, 5, 6, 7, 8, 10, 12, 24, 28, 32, 36, 48, 52, 56, 60, and 72 hours postdose
measure: Panel 1 and 2: Time to Reach the Maximum Observed Analyte Concentration (Tmax) of ODV
timeFrame: Panel 1, Days 14 and 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose; Panel 2, Day 14: predose, 1, 3, 4, 5, 6, 7, 8, 10, 12, 24, 28, 32, 36, 48, 52, 56, 60, and 72 hours postdose
measure: Panel 1 and 2: Minimum Observed Analyte Concentration (Cmin) of ODV
timeFrame: Panel 1, Days 14 and 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose; Panel 2, Day 14: predose, 1, 3, 4, 5, 6, 7, 8, 10, 12, 24, 28, 32, 36, 48, 52, 56, 60, and 72 hours postdose
measure: Panel 1 and 2: Observed Analyte Concentration Just Prior to the Beginning of a Dosing Interval (Ctrough) of ODV
timeFrame: Panel 1: Predose on Days 14 and 15; Panel 2: Predose on Day 14
measure: Panel 1 and 2: Area Under the Analyte Concentration-time Curve From Time 0 to 24 hours Postdose (AUC24) of ODV
timeFrame: Panel 1, Days 14 and 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose; Panel 2, Day 14: predose, 1, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours postdose
measure: Panel 2: Observed Analyte Concentration of ODV
timeFrame: Panel 2, Days 10 and 14: 6 and 8 hours postdose; Day 28: 6 and 8 hours
measure: Panel 1: Maximum Observed Analyte Concentration (Cmax) of SMV
timeFrame: Panel 1, Days 14 and 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose
measure: Panel 1: Time to Reach the Maximum Observed Analyte Concentration (Tmax) of SMV
timeFrame: Panel 1, Days 14 and 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose
measure: Panel 1: Minimum Observed Analyte Concentration (Cmin) of SMV
timeFrame: Panel 1, Days 14 and 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose
measure: Panel 1: Observed Analyte Concentration Just Prior to the Beginning of a Dosing Interval (Ctrough) of SMV
timeFrame: Panel 1: Predose on Days 14 and 15
measure: Panel 1: Area Under the Analyte Concentration-time Curve From Time 0 to 24 hours Postdose (AUC24) of SMV
timeFrame: Panel 1, Days 14 and 15: Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose
measure: Panel 1 and 2: Number of Participants With Adverse Events as a Measure of Safety and Tolerability
timeFrame: Up to Day 49 (Panel 1) and Day 66 (Panel 2)
measure: Panel 1: Effect of Moxifloxacin on the QT/QTc Interval Change From Baseline at Day 2 and 16
timeFrame: Baseline (Day 1), Days 2 and 16
Other outcomes:
Locations:
city: Tempe
country: United States
facility: Celerion
state: Arizona
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References: