A Study to Assess the Relative Bioavailability of Different Formulations of GSK2018682, a Sphingosine-1-phosphate Receptor Subtype 1 Agonist, in Healthy Volunteers.

NCT01466322 | Completed Phase 1

• 1 other identifier: 114919
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

GSK2018682 is a potent and selective agonist for the sphingosine-1- phosphate receptor subtype 1 (S1P1) with the potential to be an effective treatment for multiple sclerosis (MS). The immunomodulatory properties of GSK2018682 are related to functional antagonism of S1P1 on lymphocytes, resulting in sequestration of lymphocytes within the lymphoid organs, rendering them incapable of migrating to sites of inflammation and leading to lymphopenia. Orally administered GSK2018682 is very effective in murine experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. This study will assess the relative bioavailability of different oral formulations of GSK2018682 in healthy volunteers. A tablet formulation is desired for progression into future clinical safety and efficacy studies as the current capsule formulation is not suited to large scale manufacture. The information obtained in this study will help to establish the optimal dosing form for future studies, and also determine the effect of food on the pharmacokinetics of GSK2018682.

Conditions

Multiple Sclerosis, Relapsing-Remitting

Keywords

Healthy volunteers; GSK2018682; Pharmacokinetics; Relapsing Remitting Multiple Sclerosis; Pharmacodynamics

Outcome Measures

Primary Outcomes (1)

• To assess the pharmacokinetics of different oral formulations of GSK2018682 in healthy volunteers

  -Peak blood concentration (Cmax); -Time of peak blood concentration (tmax); - Area under the blood concentration-time curve up to the last quantifiable time point (AUC(0-t)) and extrapolated to infinite time (AUC (0-∞)); -Terminal half-life (T½ ); -Apparent oral clearance (CL/F)

  PK sampling at dosing and at 1, 2, 3, 4, 6, 8, 10, 16, 24, 36, 48, 72, 96, 120, and 144 hr post-dose

Secondary Outcomes (3)

• To investigate the effect of food on the pharmacokinetic parameters of the CD3 tablet formulation of GSK2018682

  High fat breakfast to be provided within 30 mins prior to dosing

• Evaluate the effect of different oral formulations of GSK2018682 on lymphocytes in healthy volunteers

  Sampling for absolute lymphocyte count at dosing and at 6 and 24 hr post-dose.

• To investigate the safety and tolerability of different oral formulations of GSK2018682 in healthy volunteers (males and females of non childbearing potential)

  AE review: from dosing to follow-up; safety lab parameters: at 48 hr post-dose; Telemetry ECG: dosing to 6 hr post-dose; vital signs: pre-dose,1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 hr post-dose.

Study Arms (1)

Oral formulations of GSK2018682

EXPERIMENTAL

Three oral formulations of GSK2018682. A: CD2 Capsule; B: CD3 non-micronised Tablet; C: CD3 micronised Tablet; D: CD3 non-micronised Tablet in fed state

Drug: GSK2018682 CD2 Capsule; GSK2018682 CD3 non-micronised Tablet; GSK2018682 CD3 micronised Tablet; GSK2018682 CD3 non-micronised Tablet in fed state

Interventions

GSK2018682 CD2 Capsule; GSK2018682 CD3 non-micronised Tablet; GSK2018682 CD3 micronised Tablet; GSK2018682 CD3 non-micronised Tablet in fed state DRUG

Four single dosing sessions where each regimen A,B C or D will be administered orally in a randomised, cross-over manner. At each dosing session, pharmacokinetic sampling time-points will be the same.

Oral formulations of GSK2018682

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• AST, ALT, alkaline phosphatase and bilirubin less than or equal to 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. A subject with a clinical abnormality or laboratory parameters significantly 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. Subjects with lymphocyte counts outside the normal range should always be excluded from enrollment.
• Male or female between 18 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 with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MIU/ml and estradiol \< 40 pg/ml (\<140 pmol/L) is confirmatory\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
• Male subjects must agree to use one of the protocol-approved contraception methods. This criterion must be followed from the time of the first dose of study medication until the study follow up visit.
• BMI within the range 19 - 29 kg/m2 (inclusive).
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• QTcB or QTcF \< 450 msec.

You may not qualify if:

• 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 285 ml glass of full strength beer or 425 schooner of light beer or 1 glass (100 ml) of wine or 1 (30 ml) measure of spirits.
• 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.
• 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 serum or urine hCG test at screening or prior to dosing.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• Subject is mentally or legally incapacitated.
• Subjects who have asthma.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Herston, Queensland, 4006, Australia

Location

Related Publications (5)

• Bronnum-Hansen H, Stenager E, Hansen T, Koch-Henriksen H. Survival and mortality rates among Danes with MS. Int MS J. 2006 May;13(2):66-71.

  PMID: 16635423 BACKGROUND

• Chun J, Goetzl EJ, Hla T, Igarashi Y, Lynch KR, Moolenaar W, Pyne S, Tigyi G. International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol Rev. 2002 Jun;54(2):265-9. doi: 10.1124/pr.54.2.265.

  PMID: 12037142 BACKGROUND

• Compston A, Coles A. Multiple sclerosis. Lancet. 2008 Oct 25;372(9648):1502-17. doi: 10.1016/S0140-6736(08)61620-7.

  PMID: 18970977 BACKGROUND

• Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000 Nov 16;343(20):1430-8. doi: 10.1056/NEJM200011163432001.

  PMID: 11078767 BACKGROUND

• GlaxoSmithKline Document Number JH2009/00002/01. GSK2018682 Investigator's Brochure.

  BACKGROUND

Related 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.
• Results for study 114919 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 3, 2011
• First Posted: November 7, 2011
• Study Start: December 22, 2010
• Primary Completion: February 15, 2011
• Study Completion: February 15, 2011
• Last Updated: July 7, 2017

Record last verified: 2017-07

Data Sharing

• IPD Sharing: Will share

Locations

AU (1)