Assessment of Repeat Ascending Doses of GSK2018682 in Healthy Volunteers (P1A114347)

A Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Repeat Ascending Doses of GSK2018682 (S1P1 Agonist) in Healthy Volunteers

The study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat ascending doses of GSK2018682. The study will also provide further evidence of the potential therapeutic dose-range by measuring the inhibitory effect of GSK2018682 on Absolute Lymphocyte Counts (ALC).

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis, Relapsing-Remitting
• Intervention / Treatment: Drug: Placebo; Drug: GSK2018682

Detailed Description

The study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat ascending doses of GSK2018682. The study will also provide further evidence of the potential therapeutic dose-range by measuring the inhibitory effect of GSK2018682 on Absolute Lymphocyte Counts (ALC).

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • GSK Investigational Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • GSK Investigational Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• 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.
• Females must be of non-childbearing potential.
• BMI within the range 19 - 29 kg/m2 (inclusive).

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.
• 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.
• 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.
• Were 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 serum or urine hCG test at screening or prior to dosing.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• Other exclusion criteria to be detailed at the time of physical screening by the Investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GSK2018682; Active Drug	Drug: GSK2018682; Active Drug
Placebo Comparator: Placebo Control; Placebo	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To investigate the safety and tolerability of repeat oral doses of GSK2018682 in healthy volunteers (males and females of non-childbearing potential)	Adverse event monitoring, Laboratory parameters (haematology, clinical chemistry, urinalysis), Ophthalmic examination	Participants will be followed and monitored for the duration of their hospital stay. The longest duration of participation in the study will be approximately 13 weeks
To investigate effects of repeat oral doses of GSK2018682 on heart rate and blood pressure in healthy volunteers	12-lead ECG, Telemetry ECG, Holter ECG, Vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, body temperature), Ambulatory blood pressure monitoring	Participants will be followed and monitored for the duration of their hospital stay. The longest duration of participation in the study will be approximately 13 weeks
To investigate effects of repeat oral doses of GSK2018682 on lung function in healthy volunteers	FEV1 obtained via spirometry	Participants will be followed and monitored for the duration of their hospital stay. The longest duration of participation in the study will be approximately 13 weeks
To investigate the pharmacokinetics of repeat oral doses of GSK2018682 in healthy volunteers	Peak blood concentration, Time of peak blood concentration, Area under the blood concentration-time curve over the 24-hour dose interval and area under the blood concentration-time curve from time-zero extrapolated to infinite time, Accumulation ratio, Terminal half-life, Apparent oral clearance, Through concentration	Participants will be followed and monitored for the duration of their hospital stay. The longest duration of participation in the study will be approximately 13 weeks
To characterize the metabolism of GSK2018682	GSK2018682 bile metabolites, GSK2018682 whole blood metabolites	Participants will be followed and monitored for the duration of their hospital stay. The longest duration of participation in the study will be approximately 13 weeks
Evaluate the effect of repeat oral doses of GSK2018682 on lymphocytes in healthy volunteers	% Change from baseline in absolute lymphocyte counts (ALC), % Change from baseline in subsets CD3+ [CD4+ and CD8+], CD19+, CD16+/CD56+ counts, % Change from baseline in further defined functional T cell subsets (naïve, central memory, effector memory and regulatory T cells)	Participants will be followed and monitored for the duration of their hospital stay. The longest duration of participation in the study will be approximately 13 weeks
To explore the PK/PD relationship between blood concentrations and changes in vital signs and ECG parameters	PK/PD model with parameters of the models will be determined that best describe the relationship between blood concentrations of GSK2018682 and vital signs and ECG parameters	Participants will be followed and monitored for the duration of their hospital stay. The longest duration of participation in the study will be approximately 13 weeks
To explore the PK/PD relationship between blood concentrations of GSK2018682 and reduction in lymphocyte counts	PK/PD model with parameters of the models will be determined that best describe the relationship between blood concentrations of GSK2018682 and reduction ALC and subset counts CD3+ [CD4+ and CD8+], CD19+, CD16+/CD56+ and further defined functional T cell subsets (naïve, central memory, effector memory and regulatory T cells)	Participants will be followed and monitored for the duration of their hospital stay. The longest duration of participation in the study will be approximately 13 weeks

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

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): October 10, 2010
• Primary Completion (Actual): March 29, 2011
• Study Completion (Actual): March 29, 2011

Study Registration Dates

• First Submitted: August 11, 2011
• First Submitted That Met QC Criteria: September 8, 2011
• First Posted (Estimate): September 12, 2011

Study Record Updates

• Last Update Posted (Actual): July 7, 2017
• Last Update Submitted That Met QC Criteria: July 5, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Pharmacodynamics
• Additional Relevant MeSH Terms: Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
• Other Study ID Numbers: 114347

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. Individual Participant Data Set
   Information identifier: 114347
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Annotated Case Report Form
   Information identifier: 114347
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Informed Consent Form
   Information identifier: 114347
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Study Protocol
   Information identifier: 114347
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Statistical Analysis Plan
   Information identifier: 114347
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Clinical Study Report
   Information identifier: 114347
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Dataset Specification
   Information identifier: 114347
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register