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Completed

NCT Number: 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

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.

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Key information

Conditions

Healthy

Age range

18 year–55 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Celerion

Tempe, Arizona, 85283, United States

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

ODV Placebo (Matching 25 mg ODV)

Drug

Participants will receive ODV placebo (matching 25 [mg] ODV [1*25 mg tablet]) once daily in Treatment A and B from Day 1 to 16 and Treatment C on Day 1.

ODV Placebo (Matching 200 mg ODV)

Drug

Participants will receive ODV placebo (matching 200 mg ODV [4*50 mg tablets]) on Days 1 and 2 in Treatment E.

ODV Placebo (Matching 125 mg ODV)

Drug

Participants will receive ODV placebo (matching 125 mg ODV [2*50 mg tablets + 1*25 mg tablets]) orally once daily on Days 3 to 7 in Treatment E.

ODV Placebo (Matching 100 mg ODV)

Drug

Participants will receive ODV placebo (matching 100 mg ODV [2*50 mg tablets] orally once daily on Days 8 to 14 in Treatment E.

SMV Placebo (Matching 150 mg SMV)

Drug

Participants will receive SMV Placebo (matching 150 mg SMV [2*75 mg capsules]) orally once daily administered from Day 1 to 16 in Treatment A, B and on Day 1 in Treatment C.

AL-335 Placebo (matching 1200 mg AL-335)

Drug

Participants will receive a single dose of AL-335 placebo (matching 1200 mg AL-335 [3*400 mg tablets]) administered orally on Day 15 in Treatment A and B.

Moxifloxacin Placebo (matching 400 mg moxifloxacin)

Drug

Participants will receive a single dose of moxifloxacin placebo (matching 400 mg moxifloxacin [1*400 mg capsule]) administered orally on Day 1, 15 and 16 in Treatment A, on Day 1, 2 and 15 in Treatment B and on Day 1, 2, 15 and 16 in Treatment C.

ODV 25 mg

Drug

Participants will receive ODV 25 mg orally once daily administered on Days 2 to 16 in Treatment C.

ODV 200 mg

Drug

Participants will receive ODV 200 mg (4*50 mg tablets) orally once daily will be administered on Days 1 and 2 in Treatment F.

ODV 125 mg

Drug

Participants will receive ODV 125 mg (2*50 mg tablets + 1*25 mg tablets) once daily administered on Days 3 to 7 in Treatment F.

ODV 100 mg

Drug

Participants will receive ODV 100 mg (2*50 mg tablets) orally once daily administered on Days 8 to 14 in Treatment F.

SMV 150 mg

Drug

Participants will receive SMV 150 mg (2*75 mg capsules) orally once daily administered on Days 2 to 16 in Treatment C.

AL-335 1200 mg

Drug

Participants will receive a single oral dose of AL-335 1200 mg (3*400 mg tablets) administered on Day 15 in Treatment C.

Primary outcomes

  1. 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

    Time frame: Baseline (Day 1), Day 15

    Intersection-union test (IUT) analysis will be performed to evaluate the effect of AL-335 on QT/QTc interval changes after a single supratherapeutic dose of AL-335 on top of multiple doses of odalasvir (ODV) and simeprevir (SMV) versus placebo.

  2. Panel 2: Effect of ODV on QT/QTc Interval Change From Baseline After Multiple Supratherapeutic Doses of ODV Using ER Approach at Day 14

    Time frame: Baseline (Day -3), Day 14

    Exposure-response (ER) analysis will be performed to evaluate the effect of ODV on QT/QTc interval changes after multiple supratherapeutic doses of ODV.

  3. Panel 2: Effect of ODV on QT/QTc Interval Change From Baseline After Multiple Supratherapeutic Doses of ODV Using ER Approach at Day 15

    Time frame: Baseline (Day -3), Day 15

    ER analysis will be performed to evaluate the effect of ODV on QT/QTc interval changes after multiple supratherapeutic doses of ODV.

  4. Panel 2: Effect of ODV on QT/QTc Interval Change From Baseline After Multiple Supratherapeutic Doses of ODV Using ER Approach at Day 16

    Time frame: Baseline (Day -3), Day 16

    ER analysis will be performed to evaluate the effect of ODV on QT/QTc interval changes after multiple supratherapeutic doses of ODV.

  5. Panel 2: Effect of ODV on PR Interval Change From Baseline After Multiple Supratherapeutic Doses of ODV Using ER Approach at Day 14

    Time frame: Baseline (Day -3), Day 14

    ER analysis will be performed to evaluate the effect of ODV on PR interval changes after multiple supratherapeutic doses of ODV.

  6. Panel 2: Effect of ODV on PR Interval Change From Baseline After Multiple Supratherapeutic Doses of ODV Using ER Approach at Day 15

    Time frame: Baseline (Day -3), Day 15

    ER analysis will be performed to evaluate the effect of ODV on PR interval changes after multiple supratherapeutic doses of ODV.

  7. Panel 2: Effect of ODV on PR Interval Change From Baseline After Multiple Supratherapeutic Doses of ODV Using ER Approach at Day 16

    Time frame: Baseline (Day -3), Day 16

    ER analysis will be performed to evaluate the effect of ODV on PR interval changes after multiple supratherapeutic doses of ODV.

  8. Panel 2: Effect of Multiple Supratherapeutic Doses of ODV on Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Day 10

    Time frame: Baseline (Day -2 and -1), Day 10

    Echocardiogram measurements will be performed to evaluate the effect of multiple supratherapeutic doses of ODV on change in echocardiographic LVEF. The baseline for echocardiographic LVEF will be the average of Days -2 and -1.

  9. Panel 2: Effect of Multiple Supratherapeutic Doses of ODV on Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Day 14

    Time frame: Baseline (Day -2 and -1), Day 14

    Echocardiogram measurements will be performed to evaluate the effect of multiple supratherapeutic doses of ODV on change in echocardiographic LVEF. The baseline for echocardiographic LVEF will be the average of Days -2 and -1.

  10. Panel 2: Effect of Multiple Supratherapeutic Doses of ODV on Change From Baseline in Echocardiographic Left Ventricular Ejection Fraction (LVEF) at Day 28

    Time frame: Baseline (Day -2 and -1), Day 28

    Echocardiogram measurements will be performed to evaluate the effect of multiple supratherapeutic doses of ODV on change in echocardiographic LVEF. The baseline for echocardiographic LVEF will be the average of Days -2 and -1.

Secondary outcomes

  1. Panel 1: Maximum Observed Analyte Concentration (Cmax) of AL-335 and its 2 metabolites ALS-022399 and ALS-022227

    Time frame: 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

    The Cmax is the maximum observed analyte concentration.

  2. Panel 1: Time to Reach the Maximum Observed Analyte Concentration (Tmax) of AL-335 and its 2 metabolites ALS-022399 and ALS-022227

    Time frame: 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

    The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.

  3. 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

    Time frame: 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

    AUC24 is defined as area under the analyte concentration-time curve from time 0 to 24 hours postdose.

  4. 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

    Time frame: 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

    AUClast is defined as area under the analyte concentration-time curve from time 0 to the time of the last measurable (non-below quantification limit [BQL]) concentration.

  5. Panel 1: Apparent Terminal Elimination Half-life (t1/2term) of AL-335 and its 2 metabolites ALS-022399 and ALS-022227

    Time frame: 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

    Apparent terminal elimination half-life is defined as 0.693/lambda(z).

  6. Panel 1: Apparent Terminal Elimination Rate Constant (Lambda[z]) of AL-335 and its 2 metabolites ALS-022399 and ALS-022227

    Time frame: 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

    Lambda(z) is defined as apparent terminal elimination rate constant, determined by linear regression using the terminal log-linear phase of the log transformed concentration versus time curve.

  7. 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

    Time frame: 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

    The AUC (0-infinity) is the area under the analyte concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.

  8. Panel 1 and 2: Maximum Observed Analyte Concentration (Cmax) of ODV

    Time frame: 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

    The Cmax is the maximum observed analyte concentration.

  9. Panel 1 and 2: Time to Reach the Maximum Observed Analyte Concentration (Tmax) of ODV

    Time frame: 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

    The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.

  10. Panel 1 and 2: Minimum Observed Analyte Concentration (Cmin) of ODV

    Time frame: 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

    The Cmin is a minimum observed analyte concentration.

  11. Panel 1 and 2: Observed Analyte Concentration Just Prior to the Beginning of a Dosing Interval (Ctrough) of ODV

    Time frame: Panel 1: Predose on Days 14 and 15; Panel 2: Predose on Day 14

    The Ctrough is the observed analyte concentration just prior to the beginning of a dosing interval.

  12. Panel 1 and 2: Area Under the Analyte Concentration-time Curve From Time 0 to 24 hours Postdose (AUC24) of ODV

    Time frame: 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

    AUC24 is defined as area under the analyte concentration-time curve from time 0 to 24 hours postdose.

  13. Panel 2: Observed Analyte Concentration of ODV

    Time frame: Panel 2, Days 10 and 14: 6 and 8 hours postdose; Day 28: 6 and 8 hours

    Observed analyte concentration of ODV will be assessed on Days 10, 14 and 28.

  14. Panel 1: Maximum Observed Analyte Concentration (Cmax) of SMV

    Time frame: 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

    The Cmax is the maximum observed analyte concentration.

  15. Panel 1: Time to Reach the Maximum Observed Analyte Concentration (Tmax) of SMV

    Time frame: 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

    The tmax is defined as actual sampling time to reach maximum observed analyte concentration.

  16. Panel 1: Minimum Observed Analyte Concentration (Cmin) of SMV

    Time frame: 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

    The Cmin is the minimum observed analyte concentration.

  17. Panel 1: Observed Analyte Concentration Just Prior to the Beginning of a Dosing Interval (Ctrough) of SMV

    Time frame: Panel 1: Predose on Days 14 and 15

    The Ctrough is the observed analyte concentration just prior to the beginning of a dosing interval.

  18. Panel 1: Area Under the Analyte Concentration-time Curve From Time 0 to 24 hours Postdose (AUC24) of SMV

    Time frame: 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

    AUC24 is defined as area under the analyte concentration-time curve from time 0 to 24 hours postdose.

  19. Panel 1 and 2: Number of Participants With Adverse Events as a Measure of Safety and Tolerability

    Time frame: Up to Day 49 (Panel 1) and Day 66 (Panel 2)

    An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.

  20. Panel 1: Effect of Moxifloxacin on the QT/QTc Interval Change From Baseline at Day 2 and 16

    Time frame: Baseline (Day 1), Days 2 and 16

    The effect of moxifloxacin on the QT/QTc Interval changes will be assessed for assay sensitivity.

Sponsors and collaborators

Lead sponsor

Janssen Research & Development, LLC

Industry

Registry information

Official study 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

Important dates

Study start
2017
Primary completion
2017
Study completion
2017
First posted
May 16, 2017
Registry last updated
Nov 14, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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