Phase I Study of GW856553 (Losmapimod)

July 24, 2017 updated by: GlaxoSmithKline

A Phase I, Randomized, Single-Blind, Three-Period Cross-Over, Placebo-Controlled, Single Oral Dose, Dose-Escalation (Part 1), Fixed Sequence, and Repeat Dose (Part 2) Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Losmapimod in Healthy Japanese Subjects.

This study is the first study of losmapimod in Japanese subjects. This study will be a single-center, single blind, phase I and two part study to characterize the safety, tolerability, pharmacokinetic and pharmacodynamic profiles in healthy Japanese volunteers (male and female of non-childbearing potential). Part1 will be a single dose, randomized, three-period, placebo-controlled and dose escalation part. Each subject will participate in 3 dosing sessions, and receive, on separate days, three of four treatments of losmapimod 2.5, 7.5 and 20 mg, and the matching placebo in the fasted state after overnight fast (at least 10 hours). The design incorporates sufficient washout between treatments (at least 7 days after the previous administration), and is an efficient design for the study objectives. Part 2 will be a fixed dose and placebo-controlled part. Each subject will participate in one dosing session, and receive losmapimod 7.5 mg or the matching placebo twice daily in the fasted state for 14 days. Only subjects will be blind to the sequence and dose studied. The study will include the placebo treatment to allow a valid evaluation of adverse events attributable to treatment versus those independent of treatment. Approximately 18 subjects in each part will receive treatments of losmapimod and/or placebo in the design. The primary objective of the study is to characterize the safety and tolerability of single doses and repeat doses of losmapimod in healthy Japanese subjects. Serial pharmacokinetic samples will be collected and safety assessments will be performed following each dose.

Study Overview

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • New South Wales
      • Randwick, New South Wales, Australia, 2031
        • GSK Investigational Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 55 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  • Male or female between 20 and 55 years of age inclusive, at the time of signing the informed consent.
  • A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females.
  • Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication until follow-up visit.
  • Body weight >= 45 kg and BMI within the range 18.5 - 29.0 kg/m2 (inclusive).
  • Japanese defined as being born in Japan, having four ethnic Japanese grandparents, holding a Japanese passport or identity papers and being able to speak Japanese. Japanese subjects must not have lived outside of Japan for more than 10 years.
  • ALT, alkaline phosphatase and bilirubin <= 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Single QTc, QTcB or QTcF < 450 msec.

Exclusion Criteria:

  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • A positive pre-study drug/alcohol screen.
  • A positive test for HIV antibody.
  • History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of greater than 21 units for men and 14 for women or an average daily intake of greater than 3 units. One unit is equivalent to a 285 mL glass of full strength beer or 425 mL schooner of light beer or 1 (30 mL) measure of spirits or 1 glass (100 mL) of wine (NHMRC Guidelines [NHMRC, 2009])
  • The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  • Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
  • Pregnant females as determined by positive urine hCG test at screening or prior to dosing.
  • Lactating females.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Subject is mentally or legally incapacitated.
  • History or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Film coated white tablet
Experimental: 2.5 mg
Losmapimod for single dose
Film coated white tablet
Experimental: 7.5 mg
Losmapimod for single dose
Film coated white tablet
Experimental: 20 mg
Losmapimod for single dose
Film coated white tablet
Experimental: 7.5 mg BID
Losmapimod for repeat dose (14 days)
Film coated white tablet
Placebo Comparator: Placebo BID
Placebo
Film coated white tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adverse events
Time Frame: Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
Number of participants with adverse events as a measure of safety and tolerability (evaluated by the result of Clinical safety laboratory tests, vital signs and 12-lead ECG).
Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
AUC(0-t)
Time Frame: up to 96h post dose.
Area under the concentration-time curve from pre-dose to last time of quantifiable concentration of losmapimod and GSK198602 (inactive metabolite) (Single dose only).
up to 96h post dose.
AUC(0-inf)
Time Frame: up to 96h post dose.
Area under the concentration-time curve from time pre-dose extrapolated to infinite time of losmapimod and GSK198602 (Single dose only).
up to 96h post dose.
AUC(0-tau)
Time Frame: up to 17 days post dose.
Area under the concentration-time curve over the dosing interval of losmapimod and GSK198602 (Repeat dose only).
up to 17 days post dose.
Cmax
Time Frame: Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
Maximum observed concentration of losmapimod and GSK198602.
Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
tmax
Time Frame: Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
Time of occurrence of Cmax of losmapimod and GSK198602.
Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
t1/2
Time Frame: Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
Terminal phase half-life of losmapimod and GSK198602
Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
accumulation ratios
Time Frame: up to 17 days post dose.
accumulation ratios of losmapimod and GSK198602 (Repeat dose only).
up to 17 days post dose.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
hsCRP
Time Frame: Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
Change from baseline in hsCRP after the oral dose of losmapimod.
Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
phosphorylated HSP27
Time Frame: Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
Change from baseline in phosphorylated HSP27 assayed following ex vivo stimulation of cells in wholeblood.
Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
%AUCex
Time Frame: Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
Percentage of AUC(0-inf) obtained by extrapolation of losmapimod and GSK198602.
Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
tlast
Time Frame: Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
Time of last quantifiable concentration of losmapimod and GSK198602.
Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
λz
Time Frame: Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
Terminal phase rate constant of losmapimod and GSK198602.
Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
CL/F
Time Frame: Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
Apparent clearance following oral dosing of losmapimod.
Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
Vz/F
Time Frame: Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
Apparent volume of distribution following oral dosing of losmapimod.
Single dose: up to 96h post dose. Repeat dose: up to 17 days post dose.
AUC(0-inf)
Time Frame: up to 17 days post dose.
Area under the concentration-time curve from time pre-dose extrapolated to infinite time of losmapimod and GSK198602 (Repeat dose only).
up to 17 days post dose.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 24, 2012

Primary Completion (Actual)

October 26, 2012

Study Completion (Actual)

October 26, 2012

Study Registration Dates

First Submitted

July 12, 2012

First Submitted That Met QC Criteria

July 19, 2012

First Posted (Estimate)

July 24, 2012

Study Record Updates

Last Update Posted (Actual)

July 26, 2017

Last Update Submitted That Met QC Criteria

July 24, 2017

Last Verified

July 1, 2017

More Information

Terms related to this study

Other Study ID Numbers

  • 116681

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

  1. Informed Consent Form
    Information identifier: 116681
    Information comments: For additional information about this study please refer to the GSK Clinical Study Register
  2. Dataset Specification
    Information identifier: 116681
    Information comments: For additional information about this study please refer to the GSK Clinical Study Register
  3. Individual Participant Data Set
    Information identifier: 116681
    Information comments: For additional information about this study please refer to the GSK Clinical Study Register
  4. Clinical Study Report
    Information identifier: 116681
    Information comments: For additional information about this study please refer to the GSK Clinical Study Register
  5. Annotated Case Report Form
    Information identifier: 116681
    Information comments: For additional information about this study please refer to the GSK Clinical Study Register
  6. Statistical Analysis Plan
    Information identifier: 116681
    Information comments: For additional information about this study please refer to the GSK Clinical Study Register
  7. Study Protocol
    Information identifier: 116681
    Information comments: For additional information about this study please refer to the GSK Clinical Study Register

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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