A Study To Assess The Effect Of Linezolid On QTc Interval

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Primary Purpose

Status

Completed

Phase

Phase 1

Locations

Singapore

Study Type

Interventional

Intervention

Placebo

Linezolid 900 mg

Linezolid 1200 mg

Placebo

Linezolid 600 mg

Linezolid 1200 mg

Moxifloxacin 400 mg

About this trial

This is an interventional basic science trial for Bacterial Infections focused on measuring Linezolid, QTc interval, pharmacokinetics, therapeutic dose, supra-therapeutic dose

Eligibility Criteria

21 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Healthy male and female subjects between the ages of 21 and 55 years.
Body mass Index (BMI) of 18 to 30 kg/m2; and a total body weight > 45 kg (99 lbs).
An informed consent document signed and dated.

Exclusion Criteria:

Evidence or history of clinically significant abnormality.
12-lead ECG demonstrating QTc >450 msec at Screening.
Receiving selective serotonin reuptake inhibitors (SSRIs) and/or sympathomimetic agents.
Abnormal liver function tests.
A positive urine drug screen, history of excessive alcohol and tobacco use.

Sites / Locations

Pfizer Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Active Comparator

Arm Label

Cohort 1: Placebo

Cohort 1: 900 mg linezolid

Cohort 1: 1200 mg linezolid

Cohort 2: Placebo

Cohort 2: 600 mg linezolid

Cohort 2: 1200 mg linezolid

Cohort 2: 400 mg Moxifloxacin

Arm Description

Outcomes

Primary Outcome Measures

Cohort 1: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

All observed or volunteered AEs and SAEs regardless of treatment group or suspected causal relationship to the investigational product(s) were reported.

Cohort 2: Mean Time-Matched Difference in Time Corresponding to Beginning of Depolarization to Repolarization of the Ventricles, Corrected for Heart Rate Using Fridericia's Formula (QTcF Interval) Between Linezolid 600 mg and 1200 mg Compared to Placebo

The time corresponding to the beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for ventricular rate (VR) using the QT and VR from each electrocardiogram by Fridericia's formula (QTcF = QT divided by cube root of VR in seconds). A measure of dispersion is not available.

Secondary Outcome Measures

Cohort 1: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC Inf) and Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC Last)

AUC inf = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. AUC last = Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).

Cohort 1: Maximum Observed Plasma Concentration (Cmax)

Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) and Plasma Decay Half-Life (t1/2)

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

Cohort 1: Clearance of Linezolid (CL)

Drug clearance = Dose / AUC inf

Cohort 1: Steady-State Volume of Distribution (Vss)

Vss = (mean residence time [The average total time molecules of a given dose spend in the body] extrapolated to infinity) multiplied by CL

Cohort 2: Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin and Placebo

A measure of dispersion is not available.

Cohort 2: Mean Time-Matched Difference in Uncorrected QT Intervals Between Linezolid 600 mg and 1200 mg Compared to Placebo

A measure of dispersion is not available.

Cohort 2: AUC Inf and AUC Last

AUC inf = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. AUC last = Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).

Cohort 2: Cmax

Cohort 2: Tmax and t1/2

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Tmax is the time to reach Cmax.

Cohort 2: CL

Drug clearance = Dose / AUC inf

Cohort 2: Vss

Vss = (mean residence time [The average total time molecules of a given dose spend in the body] extrapolated to infinity) multiplied by CL

Cohort 2: Number of Subjects With AEs and SAEs

All observed or volunteered AEs and SAEs regardless of treatment group or suspected causal relationship to the investigational product(s) were reported.

Full Information

NCT ID

NCT00795145

First Posted

November 20, 2008

Last Updated

May 17, 2010

Sponsor

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT00795145

Brief Title

A Study To Assess The Effect Of Linezolid On QTc Interval

Official Title

Single Dose Safety, Tolerability And Pharmacokinetics Of Escalating Intravenous Doses Of Linezolid Followed By Evaluation Of The Effect Of Single Intravenous Doses Of Linezolid On QTc Interval In Healthy Subjects

Study Type

Interventional

2. Study Status

Record Verification Date

May 2010

Overall Recruitment Status

Completed

Study Start Date

December 2008 (undefined)

Primary Completion Date

March 2009 (Actual)

Study Completion Date

March 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

Pfizer

4. Oversight

Data Monitoring Committee

No

5. Study Description

Brief Summary

The FDA has asked Pfizer to assess the risk of linezolid on QT interval (obtained from ECG readings) which could predispose patients to ventricular arrhythmias. This study is conducted to satisfy this requirement.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Bacterial Infections

Keywords

Linezolid, QTc interval, pharmacokinetics, therapeutic dose, supra-therapeutic dose

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

49 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1: Placebo

Arm Type

Placebo Comparator

Arm Title

Cohort 1: 900 mg linezolid

Arm Type

Experimental

Arm Title

Cohort 1: 1200 mg linezolid

Arm Type

Experimental

Arm Title

Cohort 2: Placebo

Arm Type

Placebo Comparator

Arm Title

Cohort 2: 600 mg linezolid

Arm Type

Experimental

Arm Title

Cohort 2: 1200 mg linezolid

Arm Type

Experimental

Arm Title

Cohort 2: 400 mg Moxifloxacin

Arm Type

Active Comparator

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Intravenous, Placebo control for blinding, Normal Saline, Single dose

Intervention Type

Drug

Intervention Name(s)

Linezolid 900 mg

Other Intervention Name(s)

Zyvox

Intervention Description

Intravenous, 900 mg linezolid, single dose

Intervention Type

Drug

Intervention Name(s)

Linezolid 1200 mg

Other Intervention Name(s)

Zyvox

Intervention Description

Intravenous, 1200 mg linezolid, single dose

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Intravenous, Placebo control for blinding, Normal Saline, Single dose

Intervention Type

Drug

Intervention Name(s)

Linezolid 600 mg

Other Intervention Name(s)

Zyvox

Intervention Description

Intravenous, 600 mg linezolid, single dose

Intervention Type

Drug

Intervention Name(s)

Linezolid 1200 mg

Other Intervention Name(s)

Zyvox

Intervention Description

Intravenous, 1200 mg linezolid, single dose

Intervention Type

Drug

Intervention Name(s)

Moxifloxacin 400 mg

Other Intervention Name(s)

Avelox

Intervention Description

Oral, 400 mg moxifloxacin, single dose

Primary Outcome Measure Information:

Title

Cohort 1: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Description

All observed or volunteered AEs and SAEs regardless of treatment group or suspected causal relationship to the investigational product(s) were reported.

Time Frame

From the time the subject had taken at least one dose of study treatment up to 5 weeks

Title

Cohort 2: Mean Time-Matched Difference in Time Corresponding to Beginning of Depolarization to Repolarization of the Ventricles, Corrected for Heart Rate Using Fridericia's Formula (QTcF Interval) Between Linezolid 600 mg and 1200 mg Compared to Placebo

Description

The time corresponding to the beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for ventricular rate (VR) using the QT and VR from each electrocardiogram by Fridericia's formula (QTcF = QT divided by cube root of VR in seconds). A measure of dispersion is not available.

Time Frame

0.5, 1, 2, 4, 8, 12, 24 hours post-dose

Secondary Outcome Measure Information:

Title

Cohort 1: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC Inf) and Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC Last)

Description

AUC inf = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. AUC last = Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).

Time Frame