GSK2190915A - Bioavailability Study

NCT02224521 | Completed Phase 1

• 1 other identifier: 112071
• Study Type: interventional
• Target: 67
• Locations: 1 country
• Sites: 1

Brief Summary

GSK2190915 is a high affinity 5-lipoxygenase-activating protein (FLAP) inhibitor that reduces inflammation in cells. This study will evaluate three capsule and two tablet formulations to select the optimal formulation for further development. Safety will be assessed through clinical laboratory testing, 12-lead electrocardiogram (ECG), vital signs and Adverse Event/ Serious Adverse Event (AE/ SAE) recording.

Conditions

Asthma

Keywords

FLAP inhibitor; Chronic Obstructive Pulmonary Disease (COPD); COPD; Bioavailability

Outcome Measures

Primary Outcomes (3)

• Composite of plasma pharmacokinetic (PK) parameters of GSK2190915 in Cohort 1, 2 and 3

  PK parameters including area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC \[0-∞\]), Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments (AUC\[0-t\]), concentrations at 24h post dose (C24), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), terminal half-life (t1/2) and oral clearance (CL/F) for Cohort 1, 2, 3 will be measured.

  PK samples will be collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post dose in each period up to 36 days

• Composite of PK parameters in Cohort 4

  PK parameters including area under the plasma concentration-time curve over the dosing interval (AUC \[0-tau\]), trough C24, Cmax, Tmax, and accumulation for Cohort 4 will be measured.

  Up to 12 days

• Composite of PK parameters in Cohort 5 and 6

  PK parameters including AUC (0-∞), AUC (0-t), C24, Cmax, Tmax, t1/2 and CL/F for Cohort 5 and 6 will be measured.

  PK samples will be collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post dose in each period up to 36 days

Secondary Outcomes (16)

• Blood pressure measurement for Cohorts 1, 2, and 3 after GSK2190915 administration

  Up to 36 days

• Blood pressure measurement for Cohorts 4 after GSK2190915 administration

  Up to 12 days

• Blood pressure measurement for Cohorts 5 and 6 after GSK2190915 administration

  Up to 36 days

• Pulse rate measurement for Cohorts 1, 2, and 3 after GSK2190915 administration

  Up to 36 days

• Pulse rate measurement for Cohort 4 after GSK2190915 administration

  Up to 12 days

Study Arms (6)

Cohort 1

EXPERIMENTAL

Subjects will be assigned to any of the 4 dosage regimen (A, B, C, D) in four periods. A= GSK2190915 Solution, 50mg single dose, fasted; B = GSK2190915 Capsule Formulation A, 50mg single dose (1 x 50mg capsule), fasted; C= GSK2190915 Capsule Formulation B, 50mg single dose (1 x 50mg capsule), fasted; D= GSK2190915 Capsule Formulation C, 50mg single dose (1 x 50mg capsule), fasted.

Drug: GSK2190915 Solution.; Drug: GSK2190915 Granule Capsule (A); Drug: GSK2190915 Semi-solid Lipid Capsule (B); Drug: GSK2190915 Liquid Lipid Capsule (C)

Cohort 2

EXPERIMENTAL

The selected formulation will be dosed with GSK2190915 capsule formulation at 20mg (fasted), 100mg (fasted), 100mg (fed) and 200mg (fasted).

Drug: GSK2190915 Solution.; Drug: GSK2190915 Granule Capsule (A); Drug: GSK2190915 Semi-solid Lipid Capsule (B); Drug: GSK2190915 Liquid Lipid Capsule (C)

Cohort 3

EXPERIMENTAL

Cohort 3 will be a 4-way complete crossover study with single doses of 20mg and 200mg of up to two capsule formulations taken forward from cohort 2 in 10 healthy adult subjects in the fasted state.

Drug: GSK2190915 Solution.; Drug: GSK2190915 Granule Capsule (A); Drug: GSK2190915 Semi-solid Lipid Capsule (B); Drug: GSK2190915 Liquid Lipid Capsule (C)

Cohort 4

EXPERIMENTAL

The regimen for Cohort 4 will be either the highest dose (200mg) of the capsule formulation (A, B or C) taken forward from the previous cohorts or the solution formulation (200mg).

Drug: GSK2190915 Solution.; Drug: GSK2190915 Granule Capsule (A); Drug: GSK2190915 Semi-solid Lipid Capsule (B); Drug: GSK2190915 Liquid Lipid Capsule (C)

Cohort 5

EXPERIMENTAL

Subjects will take milled and micronised tablet formulations of GSK2190915 in the fasted state in periods 1 and 2, and will take milled and micronised tablet formulations of GS2190915 in the fed state in periods 3 and 4.

Drug: GSK2190915 Milled Tablet; Drug: GSK2190915 Micronised Tablet

Cohort 6

EXPERIMENTAL

Tablet formulations (milled and micronised, different to the Cohort 5 formulations) of GSK2190915 will be dosed in the fasted and fed (after a light breakfast) states.

Drug: GSK2190915 Milled Tablet; Drug: GSK2190915 Micronised Tablet

Interventions

GSK2190915 Solution. DRUG

Aqueous Solution, 10mg/mL.

Cohort 1; Cohort 2; Cohort 3; Cohort 4

GSK2190915 Granule Capsule (A) DRUG

GSK2190915A granule filled in to Gelatin capsules

Cohort 1; Cohort 2; Cohort 3; Cohort 4

GSK2190915 Semi-solid Lipid Capsule (B) DRUG

GSK2190915A dispersed in a lipid vehicle and filled in to HPMC capsules

Cohort 1; Cohort 2; Cohort 3; Cohort 4

GSK2190915 Liquid Lipid Capsule (C) DRUG

GSK2190915A dissolved in lipid vehicle milled and filled in to Gelatin capsules

Cohort 1; Cohort 2; Cohort 3; Cohort 4

GSK2190915 Milled Tablet DRUG

GSK2190915A granule is blended, compressed into tablets and aqueous film coated

Cohort 5; Cohort 6

GSK2190915 Micronised Tablet DRUG

GSK2190915A granule is blended, compressed into tablets and aqueous film coated

Cohort 5; Cohort 6

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase and bilirubin less than or equal to 1.5 times Upper Limit of Normal, ULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35 percent).
• Healthy as determined by the Investigator, based on a medical evaluation including medical history, physical examination, laboratory tests and Electrocardiogram (ECG). 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 objectives.
• Male or female (of non child-bearing potential) between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• A female subject is eligible to participate only if she is of:
• Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation (in which case the male partner should use an acceptable form of contraception as specified in section 8.1) or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 million international units, MlU/ml and estradiol less than 40 picogrammes per millilitre (less than 140 picomoles per litre) is confirmatory\]. \[Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.\]
• Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until 5 terminal half-lives post-last dose.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• lead ECG without any clinically significant abnormality as judged by the Investigator, and QTc intervals corrected for Bazett ror Fredericia (QTcB and QTcF) less than450 milliseconds (msec)
• Body weight greater than or equal to 50 kilogrammes (kg) (110 pounds, lbs) for men and greater than or equal to 45 kg (99 lbs) for women and Body Mass Index, BMI within the range 18-30 kilogrammes per squared metre (kg/m2) inclusive.
• Non-smokers only- Negative urine cotinine test at screening, no history of smoking within 6 months of the start of the study, and with a total pack year history of less than or equal to 1 pack years.
• Healthy as determined by the Investigator, based on a medical evaluation including medical history, physical examination, laboratory tests, ECG and Holter assessment at screening. A subject with a clinical abnormality or laboratory parameter 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 objectives. A subject with a well controlled or mild medical condition (eg controlled hypertension, hypothyroidism adequately treated with replacement therapy, mild chronic obstructive pulmonary disease (COPD) requiring short acting bronchodilators only) may be included only if the Investigator and the GSK Medical Monitor agree that the condition is unlikely to introduce additional risk factors and will not interfere with the study objectives.
• Male or female (of non child-bearing potential) over 65 years of age inclusive, at the time of signing the informed consent.
• A female subject is eligible to participate only if she is of:
• Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation (in which case the male partner should use an acceptable form of contraception as specified in section 8.1) or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 million international units, MlU/ml and estradiol less than 40 picogrammes per millilitre (less than 140 picomoles per litre) is confirmatory\]. \[Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.\]
• Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until 5 terminal half-lives post-last dose.

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).
• Significant cardiac, pulmonary, metabolic, renal, gastrointestinal or other conditions that in the opinion of the investigator and/or GSK medical monitor, places the subject at an unacceptable risk as participant in this trial.
• A positive pre-study drug/alcohol screen.
• A positive test for human immunodeficiency virus (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 males or less than14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (\~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 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: 3 months or 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 human Chorionic Gonadotrophin (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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

London, NW10 7EW, United Kingdom

Location

Related Links

• Results for study 112071 can be found on the GSK Clinical Study Register.
• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Asthma; Pulmonary Disease, Chronic Obstructive

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: June 23, 2011
• First Posted: August 25, 2014
• Study Start: April 20, 2009
• Primary Completion: June 8, 2010
• Study Completion: June 8, 2010
• Last Updated: June 14, 2017

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will share

Locations

GB (1)