PK Study of IV Formulation of GW856553

Evaluation of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Intravenous Dose(s) and a Single Oral Dose of GW856553 in Healthy Volunteers

The purpose of this study is to evaluate the safety of an IV infusion of GW856553 in healthy volunteers.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Disease
• Intervention / Treatment: Drug: losmapimod 1 mg; Drug: losmapimod; Drug: losmapimod 15 mg

Detailed Description

The aims of this study are to evaluate the safety and tolerability of single intravenous (IV) doses of GW856553 in healthy adult subjects and to investigate the relationship between PK and PD markers within the first few hours following administration of study drug to support progression of this formulation into a patient population.

Subjects in Cohort 1 (n=4) will receive a single 1mg IV dose (given as a 15 minute infusion) of GW856553. Safety, tolerability and PK exposures will be reviewed, and in an optional cohort (Cohort 2) (n=4), the dose may be adjusted upward or downward based on data from Cohort 1. Based on the results from Cohort 1 (and Cohort 2 if required), Cohort 3 (n=12) will be dosed appropriately to receive a single IV 15 minute infusion of GW856553.

After a one week washout, Cohort 3 subjects will receive a single oral dose of 15mg GW856553. Access to both IV and oral PK in the same individuals will permit calculation of absolute bioavailability for the oral dose. Subjects will be resident in the research unit from the morning prior to dosing until after the last PK blood sample is collected at 24 hours after the dose of study drug (excluding any washout period).

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB2 2GG
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• AST, ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
• Male or female between 18 and 75 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 with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhoea
• Male subjects must agree to use contraception from the time of the first dose of study medication until seven days following the last dose.
• Body weight >50kg (110 pounds) and body mass index (BMI) within the range >19 and <30kg/m2.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• 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 >21 units for males or >14 units for females. One unit is equivalent to 8g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125ml) of wine or 1 (25ml) measure of spirits.
• Treatment with an investigational product within 90 days or 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) prior to dosing in this study.
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
• Where participation in the study would result in donation of blood or blood products in excess of 500mL within a 56 day period.
• Pregnant females as determined by positive serum or 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.
• Taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), 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 until completion of the follow-up visit, unless in the opinion of the Investigator and Sponsor the medication will not interfere with the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1 mg IV; Unit Dose Strength: 0.4 mg/mL	Drug: losmapimod 1 mg; IV infusion
Experimental: ?mg IV; dose to be determined based on PK of first IV dose	Drug: losmapimod; IV infusion (dose to be determined based on PK from first dose)
Experimental: 15 mg (oral); two 7.5 mg tablets	Drug: losmapimod 15 mg; oral, two 7.5 mg tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
General safety and tolerability endpoints include changes in clinical laboratory assessments, spontaneous AE reporting, ECGs, vital signs and nursing/physician observations.	Up to 15 days post IV infusion.

Secondary Outcome Measures

Outcome Measure	Time Frame
pHSP27 measurements	Up to 24 hours post dose.
hsCRP measurements	Up to 24 hours post dose.
Maximum Plasma Concentration [Cmax]	Up to 24 hours post dose
Area Under the Curve [AUC]	Up to 24 hours post dose
Time of maximum plasma concentation [Tmax]	Up to 24 hours post dose
Half life [T1/2]	Up to 24 hours post dose

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Barbour AM, Sarov-Blat L, Cai G, Fossler MJ, Sprecher DL, Graggaber J, McGeoch AT, Maison J, Cheriyan J. Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers. Br J Clin Pharmacol. 2013 Jul;76(1):99-106. doi: 10.1111/bcp.12063.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2010
• Primary Completion (Actual): April 15, 2010
• Study Completion (Actual): April 15, 2010

Study Registration Dates

• First Submitted: December 23, 2009
• First Submitted That Met QC Criteria: December 23, 2009
• First Posted (Estimate): December 25, 2009

Study Record Updates

• Last Update Posted (Actual): June 14, 2017
• Last Update Submitted That Met QC Criteria: June 13, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: healthy volunteers; IV formulation study
• Additional Relevant MeSH Terms: Cardiovascular Diseases
• Other Study ID Numbers: 113022

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. Annotated Case Report Form
   Information identifier: 113022
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Statistical Analysis Plan
   Information identifier: 113022
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Dataset Specification
   Information identifier: 113022
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Informed Consent Form
   Information identifier: 113022
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Clinical Study Report
   Information identifier: 113022
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Individual Participant Data Set
   Information identifier: 113022
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Study Protocol
   Information identifier: 113022
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register