A Study To Assess The Effect Of Linezolid On QTc Interval - Full Text View

Sponsor:	Pfizer
Information provided by:	Pfizer
ClinicalTrials.gov Identifier:	NCT00795145

Purpose

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.

Condition	Intervention	Phase
Bacterial Infections	Drug: Placebo Drug: Linezolid 900 mg Drug: Linezolid 1200 mg Drug: Linezolid 600 mg Drug: Moxifloxacin 400 mg	Phase I

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator, Outcomes Assessor) Primary Purpose: Basic Science
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

Resource links provided by NLM:

MedlinePlus related topics: Bacterial Infections

Drug Information available for: Moxifloxacin Linezolid Moxifloxacin hydrochloride

U.S. FDA Resources

Further study details as provided by Pfizer:

Primary Outcome Measures:

Cohort 1: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From the time the subject had taken at least one dose of study treatment up to 5 weeks ] [ Designated as safety issue: Yes ]
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 [ Time Frame: 0.5, 1, 2, 4, 8, 12, 24 hours post-dose ] [ Designated as safety issue: No ]
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) [ Time Frame: predose, 30 minutes, and at 1 (end of infusion), 1.5, 2, 3, 4, 6, 8, 12, 24, and 46 hours after start of infusion ] [ Designated as safety issue: No ]
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) [ Time Frame: predose, 30 minutes, and at 1 (end of infusion), 1.5, 2, 3, 4, 6, 8, 12, 24, and 46 hours after start of infusion ] [ Designated as safety issue: No ]
Cohort 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) and Plasma Decay Half-Life (t1/2) [ Time Frame: predose, 30 minutes, and at 1 (end of infusion), 1.5, 2, 3, 4, 6, 8, 12, 24, and 46 hours after start of infusion ] [ Designated as safety issue: No ]
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Cohort 1: Clearance of Linezolid (CL) [ Time Frame: predose, 30 minutes, and at 1 (end of infusion), 1.5, 2, 3, 4, 6, 8, 12, 24, and 46 hours after start of infusion ] [ Designated as safety issue: No ]
Drug clearance = Dose / AUC inf
Cohort 1: Steady-State Volume of Distribution (Vss) [ Time Frame: predose, 30 minutes, and at 1 (end of infusion), 1.5, 2, 3, 4, 6, 8, 12, 24, and 46 hours after start of infusion ] [ Designated as safety issue: No ]
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 [ Time Frame: 0.5, 1, 2, 4, 8, 12, 24 hours post-dose ] [ Designated as safety issue: No ]
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 [ Time Frame: 0.5, 1, 2, 4, 8, 12, 24 hours post-dose ] [ Designated as safety issue: No ]
A measure of dispersion is not available.
Cohort 2: AUC Inf and AUC Last [ Time Frame: Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
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 [ Time Frame: Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
Cohort 2: Tmax and t1/2 [ Time Frame: Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
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 [ Time Frame: Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
Drug clearance = Dose / AUC inf
Cohort 2: Vss [ Time Frame: Predose, 30 minutes, 1, 2, 4, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
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 [ Time Frame: From the time the subject had taken at least one dose of study treatment up to 5 weeks ] [ Designated as safety issue: Yes ]
All observed or volunteered AEs and SAEs regardless of treatment group or suspected causal relationship to the investigational product(s) were reported.

Enrollment:	49
Study Start Date:	December 2008
Study Completion Date:	March 2009
Primary Completion Date:	March 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: Cohort 1: Placebo	Drug: Placebo Intravenous, Placebo control for blinding, Normal Saline, Single dose
Experimental: Cohort 1: 900 mg linezolid	Drug: Linezolid 900 mg Intravenous, 900 mg linezolid, single dose Other Name: Zyvox
Experimental: Cohort 1: 1200 mg linezolid	Drug: Linezolid 1200 mg Intravenous, 1200 mg linezolid, single dose Other Name: Zyvox
Placebo Comparator: Cohort 2: Placebo	Drug: Placebo Intravenous, Placebo control for blinding, Normal Saline, Single dose
Experimental: Cohort 2: 600 mg linezolid	Drug: Linezolid 600 mg Intravenous, 600 mg linezolid, single dose Other Name: Zyvox
Experimental: Cohort 2: 1200 mg linezolid	Drug: Linezolid 1200 mg Intravenous, 1200 mg linezolid, single dose Other Name: Zyvox
Active Comparator: Cohort 2: 400 mg Moxifloxacin	Drug: Moxifloxacin 400 mg Oral, 400 mg moxifloxacin, single dose Other Name: Avelox

Eligibility

Ages Eligible for Study:	21 Years to 55 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00795145

Locations

Singapore
Pfizer Investigational Site
Singapore, Singapore, 188770

Sponsors and Collaborators

Pfizer

Investigators

Study Director:

Pfizer CT.gov Call Center

Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Director, Clinical Trial Disclosure Group, Pfizer, Inc.
ClinicalTrials.gov Identifier:	NCT00795145 History of Changes
Other Study ID Numbers:	A5951151
Study First Received:	November 20, 2008
Results First Received:	March 2, 2010
Last Updated:	May 17, 2010
Health Authority:	United States: Food and Drug Administration

Keywords provided by Pfizer:

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

Additional relevant MeSH terms:

Bacterial Infections
Linezolid
Moxifloxacin
Norgestimate, ethinyl estradiol drug combination
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Protein Synthesis Inhibitors

Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on February 09, 2012