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Study of Danirixin in Japanese Healthy Elderly Male Subjects

Primary Purpose

Pulmonary Disease, Chronic Obstructive

Status

Completed

Phase

Phase 1

Locations

Japan

Study Type

Interventional

Intervention

GSK1325756H

Placebo

About this trial

This is an interventional treatment trial for Pulmonary Disease, Chronic Obstructive focused on measuring healthy Japanese subjects, CXCR2 inhibitor, Danirixin

Eligibility Criteria

65 Years - undefined (Older Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria

Participant must be over 65 years of age inclusive, at the time of signing the informed consent.
Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and ECG. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator in consultation with the Medical Monitor if required agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
Participants whose peripheral blood neutrophil counts and hematocrit values are within normal range at screening visit.
Body weight >=50 kilogram (Kg) and body mass index (BMI) within the range 18.5-24.9 kg/square meter (m^2) (inclusive).
Japanese Male: A male participant must agree to use contraception during the treatment period and until follow up visit.
Capable of giving signed informed consent.

Exclusion Criteria

History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
Abnormal blood pressure as determined by the investigator.
Alanine Aminotransferase (ALT)>1.5x upper limit of normal (ULN).
Bilirubin>1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%).
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
QT interval corrected for heart rate according to Fridericia's formula (QTcF)> 450 millisecond (msec).
Past or intended use of over-the-counter or prescription medication including herbal medications and proton pump inhibitor (PPI) within 14 days prior to dosing.
History of donation of blood or blood products >=400 milliliter (mL) within 3 months or >=200 mL within 1 month prior to screening.
Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
Current enrolment or past participation within the last 30 days before signing of consent in this clinical study involving an investigational study treatment or any other type of medical research.
The subject with positive Serological test for syphilis (Rapid Plasma Reagin [RPR] and Treponema pallidum hemagglutination test [TPHA]), Human immunodeficiency virus (HIV) Antigen/Antibody, Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV) antibody, or Human T-cell lymphotropic virus type 1 (HTLV-1) antibody at screening.
Positive pre-study drug screen.
Regular alcohol consumption within 6 months prior to the study defined as: an average weekly intake of > 14 units for males. One unit is equivalent to 350 mL of beer, 150 mL of wine or 45 mL of 80 proof distilled spirits.
Smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.

Sites / Locations

GSK Investigational Site
GSK Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Part 1: Group A

Part 1: Group B

Part 1: Group C

Part 2: Group D

Part 2: Group E

Arm Description

Subjects will receive GSK1325756H 10 mg in P-1, GSK1325756H 50 mg in P-2 and placebo in P-3 after a high fat meal. There will be a washout period of at least 7 days between each treatment period.

Subjects will receive GSK1325756H 10 mg in P-1, placebo in P-2 and GSK1325756H 100 mg in P-3 after a high fat meal. There will be a washout period of at least 7 days between each treatment period.

Subjects will receive placebo in P-1, GSK1325756H 50 mg in P-2 and GSK1325756H 100 mg in P-3 after a high fat meal. There will be a washout period of at least 7 days between each treatment period.

Subjects will receive GSK1325756H 50 mg after a low fat meal and fasted state respectively. There will be a washout period of at least 7 days between each treatment period.

Subjects will receive GSK1325756H 50 mg after a fasted state and a low fat meal respectively. There will be a washout period of at least 7 days between each treatment period.

Outcomes

Primary Outcome Measures

Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 1

AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. Safety population comprised of all participants who took at least one dose of study treatment.

Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2

Change From Baseline in Clinical Laboratory Parameters Calcium, Cholesterol, Chloride, Glucose, High Density Lipids (HDL) Cholesterol, Potassium, Low Density Lipids (LDL) Cholesterol,Sodium,Phosphorus,Triglycerides,Urea/Blood Urea Nitrogen (BUN) in Part 1

Blood samples were collected for the assessment of chemistry parameters namely calcium, cholesterol, chloride, glucose, HDL cholesterol, potassium, LDL cholesterol, sodium, phosphorus, triglycerides, and urea/BUN results for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Clinical Chemistry Parameters Alkaline Phosphatase, Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Creatine Kinase, Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase for Part 1

Blood samples were collected for the assessment of chemistry parameters namely alkaline phosphatase, ALT, AST, creatine kinase, GGT and lactate dehydrogenase for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein for Part 1

Blood samples were collected for the assessment of chemistry parameters namely albumin and total protein for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Clinical Chemistry Parameters Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid for Part 1

Blood samples were collected for the assessment of chemistry parameters namely direct bilirubin, total bilirubin, creatinine and uric acid for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Clinical Chemistry Parameter Amylase for Part 1

Blood samples were collected for the assessment of chemistry parameters namely amylase for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Clinical Laboratory Parameters Calcium, Cholesterol, Chloride, Glucose, HDL Cholesterol, Potassium, LDL Cholesterol, Sodium, Phosphorus Inorganic, Triglycerides, Urea/BUN for Part 2

Blood samples were collected for the assessment of chemistry parameters namely calcium, cholesterol, chloride, glucose, HDL cholesterol, potassium, LDL cholesterol, sodium, phosphorus, triglycerides, urea/BUN results for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Clinical Chemistry Parameters Alkaline Phosphatase, ALT, AST, Creatine Kinase, GGT and Lactate Dehydrogenase for Part 2

Blood samples were collected for the assessment of chemistry parameters namely alkaline phosphatase, ALT, AST, creatine kinase, GGT and lactate dehydrogenase for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein for Part 2

Blood samples were collected for the assessment of chemistry parameters namely albumin and total protein for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Clinical Chemistry Parameters Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid for Part 2

Blood samples were collected for the assessment of chemistry parameters namely direct bilirubin, total bilirubin, creatinine and uric acid for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Clinical Chemistry Parameter Amylase for Part 2

Blood samples were collected for the assessment of chemistry parameter namely amylase for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes and Total Neutrophils for Part 1

Blood samples were collected for the assessment of hematology parameters namely basophils, eosinophils, leukocytes, lymphocytes, monocytes, total neutrophils and platelets for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Hematology Parameter Hemoglobin for Part 1

Blood samples were collected for the assessment of hematology parameter namely hemoglobin for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Hematology Parameter Hematocrit for Part 1

Blood samples were collected for the assessment of hematology parameter namely hematocrit for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin for Part 1

Blood samples were collected for the assessment of hematology parameter namely mean corpuscle hemoglobin for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Hematology Parameter Mean Corpuscle Volume for Part 1

Blood samples were collected for the assessment of hematology parameter namely mean corpuscle volume for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Hematology Parameters Platelet Count and White Blood Cell Count for Part 1

Blood samples were collected for the assessment of hematology parameters namely platelet count and white blood cell count for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Hematology Parameters Red Blood Count and Reticulocyte Count for Part 1

Blood samples were collected for the assessment of hematology parameters namely red blood count and reticulocyte count for Part 1. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes and Total Neutrophils for Part 2

Blood samples were collected for the assessment of hematology parameters namely basophils, eosinophils, leukocytes, lymphocytes, monocytes, total neutrophils and platelets for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Hematology Parameter Hemoglobin for Part 2

Blood samples were collected for the assessment of hematology parameter namely hemoglobin for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Hematology Parameter Hematocrit for Part 2

Blood samples were collected for the assessment of hematology parameter namely hematocrit for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin for Part 2

Blood samples were collected for the assessment of hematology parameter namely mean corpuscle hemoglobin for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Hematology Parameter Mean Corpuscle Volume for Part 2

Blood samples were collected for the assessment of hematology parameter namely mean corpuscle volume for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Hematology Parameters Platelet Count and White Blood Cell Count for Part 2

Blood samples were collected for the assessment of hematology parameters namely platelet count and white blood cell count for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Hematology Parameters Red Blood Count and Reticulocyte Count for Part 2

Blood samples were collected for the assessment of hematology parameters namely red blood count and reticulocyte count for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Number of Participants With Abnormal Values on Urinalysis by Dipstick Method for Part 1

Urinalysis parameters assessed were urine bilirubin, urine occult blood, urine glucose, urine ketones, urine protein and urine urobilinogen. In this dipstick test, the level of bilirubin, occult blood, glucose, ketones, urine protein and urobilinogen in urine samples was recorded as negative, trace and +. Urine samples were collected for the measurement of urinalysis parameters by dipstick method up to 72 hours in Part 1. Only categories with significant values have been presented.

Urine Potential of Hydrogen (pH) Analysis by Dipstick Method for Part 1

Urinary pH measurement is a routine part of urinalysis. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Urine samples were collected for the measurement of urine pH by method up to 72 hours in Part 1. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Urine Specific Gravity Analysis by Dipstick Method for Part 1

Urinary specific gravity measurement is a routine part of urinalysis. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Urine samples were collected for the measurement of urine specific gravity by dipstick method up to 72 hours in Part 1. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles). Density is the mass per unit volume and has units (such as g/cm^3), however, the specific gravity is a ratio so it has no unit.

Number of Participants With Abnormal Values on Urinalysis by Dipstick Method for Part 2

Urinalysis parameters assessed were urine bilirubin, urine occult blood, urine glucose, urine ketones, urine protein and urine urobilinogen. In this dipstick test, the level of bilirubin, occult blood, glucose, ketones, urine protein and urobilinogen in urine samples was recorded as negative, trace and +. Urine samples were collected for the measurement of urinalysis parameters by dipstick method up to 48 hours in Part 2. Only categories with significant values have been presented.

Urine pH Analysis by Dipstick Method for Part 2

Urine Specific Gravity Analysis by Dipstick Method for Part 2

Urinary specific gravity measurement is a routine part of urinalysis. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Urine samples were collected for the measurement of urine specific gravity by dipstick method up to 48 hours in Part 2. Density is the mass per unit volume and has units (such as g/cm^3), however, the specific gravity is a ratio so it has no unit.

Change From Baseline in Vital Sign Parameters Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) for Part 1

Vital sign measurements included SBP and DBP at Baseline and up to 72 hours in Part 1. SBP and DBP measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions and were measured in a supine position after 5 minutes rest. Baseline was defined as pre-dose assessments performed on Day 1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Vital Sign Parameter Heart Rate for Part 1

Vital sign measurements included heart rate at Baseline and up to 72 hours in Part 1. Heart rate measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions and were measured in a supine position after 5 minutes rest. Baseline was defined as pre-dose assessments performed on Day 1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Vital Sign Parameter Temperature for Part 1

Vital sign measurements included temperature at Baseline and up to 72 hours in Part 1. Temperature measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions and were measured in a supine position after 5 minutes rest. Baseline was defined as pre-dose assessments performed on Day 1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Vital Sign Parameters SBP and DBP for Part 2

Vital sign measurements included SBP and DBP at Baseline and up to 72 hours in Part 2. SBP and DBP measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions and were measured in a supine position after 5 minutes rest. Baseline was defined as pre-dose assessments performed on Day 1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Vital Sign Parameter Heart Rate for Part 2

Vital sign measurements included heart rate at Baseline and up to 72 hours in Part 2. Heart rate measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions and were measured in a supine position after 5 minutes rest. Baseline was defined as pre-dose assessments performed on Day 1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Vital Sign Parameter Temperature for Part 2

Vital sign measurements included temperature at Baseline and up to 72 hours in Part 2. Temperature measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions and were measured in a supine position after 5 minutes rest. Baseline was defined as pre-dose assessments performed on Day 1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Change From Baseline in Electrocardiogram (ECG) Parameters PR Interval, QRS Duration, Uncorrected QT Interval and Corrected QT Frederica's Correction) Interval

Single 12-lead ECG's were obtained from Baseline and up to 72 hours in Part 1 using an ECG machine that automatically calculated the heart rate and measured PR Interval, QRS Duration, Uncorrected QT interval and Corrected QT (Fridericia's correction) interval. Baseline was defined as pre-dose assessments performed on Day 1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value. Only those participants with data available at the specified time were analyzed (represented by n=x in the category titles).

Change From Baseline in Electrocardiogram Parameters PR Interval, QRS Duration, Uncorrected QT Interval and Corrected QT (Frederica's Correction) Interval for Part 2

Single 12-lead ECG's were obtained from Baseline and up to 72 hours in Part 2 using an ECG machine that automatically calculated the heart rate and measured PR Interval, QRS Duration, Uncorrected QT interval and Corrected QT (Frederica's correction) interval. Baseline was defined as pre-dose assessments performed on Day 1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Blood Concentration of GSK1325756 in Part 1

Whole blood samples of approximately 1 milliliters were collected for measurement of blood concentrations of GSK1325756 at pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in all 3 periods; 60 and 72 hours post-dose in period-3 of part 1. Data has been presented for blood concentrations of GSK1325756 in fed state. Pharmacokinetic (PK) population was defined as participants who were administered at least one dose of study treatment and who had PK sample taken and analyzed. NA indicates standard deviation could not be calculated due to high proportion of non-quantifiable [NQ] values (more than 30% of values were imputed i.e., NQ assigned zero concentration) which affected the standard deviation and no sample was obtained per protocol for 60 and 72 hours.

Blood Concentration of GSK1325756 in Part 2

Whole blood samples of approximately 1 milliliters were collected for measurement of blood concentrations of GSK1325756 at Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours post-dose in part 1. Data has been presented for blood concentrations of GSK1325756 in fasted and fed state. NA indicates standard deviation could not be calculated due to high proportion of NQ values (more than 30% of values were imputed i.e., NQ assigned zero concentration) which affected the standard deviation.

Maximum Observed Concentration (Cmax) of GSK1325756H for Part 1

Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of GSK1325756H in fasted state. PK parameters were calculated by standard non-compartmental analysis using Phoenix WinNonlin Version 6.4 or higher based on actual sampling times.

Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of GSK1325756H for Part 1

Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of GSK1325756H for Part 1

Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of GSK1325756H for Part 1

Time to Maximum Observed Concentration (Tmax) of GSK1325756H for Part 1

Terminal Half-life (t1/2) of GSK1325756H for Part 1

Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of GSK1325756 in fasted state. PK parameters were calculated by standard non-compartmental analysis using Phoenix WinNonlin Version 6.4 or higher based on actual sampling times.

Lag Time Before Observable Concentration (Tlag) of GSK1325756H for Part 1

Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of GSK1325756H for Part 1

Cmax of GSK1325756H for Part 2

AUC (0-t) of GSK1325756H for Part 2

AUC (0-inf) of GSK1325756H for Part 2

AUC (0-24) of GSK1325756H for Part 2

Tmax of GSK1325756H for Part 2

t1/2 of GSK1325756H for Part 2

Tlag of GSK1325756H for Part 2

Tlast of the Blood Concentration of GSK1325756H for Part 2

Secondary Outcome Measures

Full Information

NCT ID

NCT03136380

First Posted

April 17, 2017

Last Updated

January 14, 2019

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT03136380

Brief Title

Study of Danirixin in Japanese Healthy Elderly Male Subjects

Official Title

A Single Centre, Double Blind (Sponsor Open), Placebo Controlled, 3-Period Crossover, Ascending Dose Study in Japanese Healthy Elderly Male Subjects to Evaluate the Safety, Tolerability and Pharmacokinetics of Danirixin in the Fed State (Part1) and an Open Label, 2-way Crossover to Evaluate Food Effect on the Pharmacokinetics of Danirixin (Part2)

Study Type

Interventional

2. Study Status

Record Verification Date

January 2019

Overall Recruitment Status

Completed

Study Start Date

May 10, 2017 (Actual)

Primary Completion Date

July 31, 2017 (Actual)

Study Completion Date

July 31, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Danirixin is a selective chemokine receptor antagonist being developed as a potential anti-inflammatory agent for the treatment of chronic obstructive pulmonary disease (COPD). The aim of the study is to assess the safety, tolerability and pharmacokinetics (PK) in healthy Japanese subjects over the age of 65 years (inclusive). The study will be conducted in two parts: Part 1 will be a double blind, placebo-controlled, 3-period crossover, ascending single oral dose administration of GSK1325756H (Hydrobromide Salt Tablet Formulations of Danirixin) 10, 50 and 100 milligram (mg) in the fed condition. Part 2 will be an open label, 2-period crossover, single oral dose of GSK1325756H 50 mg in fed and fasted state. This study will provide an understanding of PK of hydrobromide salt of GSK1325756 in population of healthy elderly subjects and also contribute to the selection of appropriate dosing for Phase IIa study in Japan.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pulmonary Disease, Chronic Obstructive

Keywords

healthy Japanese subjects, CXCR2 inhibitor, Danirixin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

34 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1: Group A

Arm Type

Experimental

Arm Description

Subjects will receive GSK1325756H 10 mg in P-1, GSK1325756H 50 mg in P-2 and placebo in P-3 after a high fat meal. There will be a washout period of at least 7 days between each treatment period.

Arm Title

Part 1: Group B

Arm Type

Experimental

Arm Description

Subjects will receive GSK1325756H 10 mg in P-1, placebo in P-2 and GSK1325756H 100 mg in P-3 after a high fat meal. There will be a washout period of at least 7 days between each treatment period.

Arm Title

Part 1: Group C

Arm Type

Experimental

Arm Description

Subjects will receive placebo in P-1, GSK1325756H 50 mg in P-2 and GSK1325756H 100 mg in P-3 after a high fat meal. There will be a washout period of at least 7 days between each treatment period.

Arm Title

Part 2: Group D

Arm Type

Experimental

Arm Description

Subjects will receive GSK1325756H 50 mg after a low fat meal and fasted state respectively. There will be a washout period of at least 7 days between each treatment period.

Arm Title

Part 2: Group E

Arm Type

Experimental

Arm Description

Subjects will receive GSK1325756H 50 mg after a fasted state and a low fat meal respectively. There will be a washout period of at least 7 days between each treatment period.

Intervention Type

Drug

Intervention Name(s)

GSK1325756H

Intervention Description

Danirixin will be available as 10 and 50 milligram (mg) white film coated, round and oval tablets intended for oral administration. It will be administered with 240 mL of water.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Subjects will receive visually matching danirixin placebo tablets. It will be administered with 240 mL of water.

Primary Outcome Measure Information:

Title

Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 1

Description

Time Frame

Up to 32 days in Part 1

Title

Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2

Description

Time Frame

Up to 21 days in Part 2

Title

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Clinical Chemistry Parameters Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Clinical Chemistry Parameter Amylase for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Description

Blood samples were collected for the assessment of chemistry parameters namely calcium, cholesterol, chloride, glucose, HDL cholesterol, potassium, LDL cholesterol, sodium, phosphorus, triglycerides, urea/BUN results for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Clinical Chemistry Parameters Alkaline Phosphatase, ALT, AST, Creatine Kinase, GGT and Lactate Dehydrogenase for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Clinical Chemistry Parameters Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Clinical Chemistry Parameter Amylase for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes and Total Neutrophils for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Hematology Parameter Hemoglobin for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Hematology Parameter Hematocrit for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Hematology Parameter Mean Corpuscle Volume for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Hematology Parameters Platelet Count and White Blood Cell Count for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Hematology Parameters Red Blood Count and Reticulocyte Count for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes and Total Neutrophils for Part 2

Description

Blood samples were collected for the assessment of hematology parameters namely basophils, eosinophils, leukocytes, lymphocytes, monocytes, total neutrophils and platelets for Part 2. Baseline was defined as assessments performed on Day -1. Change from Baseline was calculated by subtracting the post-dose-visit value from the Baseline value.

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Hematology Parameter Hemoglobin for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Hematology Parameter Hematocrit for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Hematology Parameter Mean Corpuscle Volume for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Hematology Parameters Platelet Count and White Blood Cell Count for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Hematology Parameters Red Blood Count and Reticulocyte Count for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Number of Participants With Abnormal Values on Urinalysis by Dipstick Method for Part 1

Description

Time Frame

Up to 72 hours in Part 1

Title

Urine Potential of Hydrogen (pH) Analysis by Dipstick Method for Part 1

Description

Time Frame

Up to 72 hours in Part 1

Title

Urine Specific Gravity Analysis by Dipstick Method for Part 1

Description

Time Frame

Up to 72 hours in Part 1

Title

Number of Participants With Abnormal Values on Urinalysis by Dipstick Method for Part 2

Description

Urinalysis parameters assessed were urine bilirubin, urine occult blood, urine glucose, urine ketones, urine protein and urine urobilinogen. In this dipstick test, the level of bilirubin, occult blood, glucose, ketones, urine protein and urobilinogen in urine samples was recorded as negative, trace and +. Urine samples were collected for the measurement of urinalysis parameters by dipstick method up to 48 hours in Part 2. Only categories with significant values have been presented.

Time Frame

Up to 48 hours in Part 2

Title

Urine pH Analysis by Dipstick Method for Part 2

Description

Time Frame

Up to 48 hours in Part 2

Title

Urine Specific Gravity Analysis by Dipstick Method for Part 2

Description

Urinary specific gravity measurement is a routine part of urinalysis. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Urine samples were collected for the measurement of urine specific gravity by dipstick method up to 48 hours in Part 2. Density is the mass per unit volume and has units (such as g/cm^3), however, the specific gravity is a ratio so it has no unit.

Time Frame

Up to 72 hours in Part 2

Title

Change From Baseline in Vital Sign Parameters Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Vital Sign Parameter Heart Rate for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Vital Sign Parameter Temperature for Part 1

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Vital Sign Parameters SBP and DBP for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Vital Sign Parameter Heart Rate for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Vital Sign Parameter Temperature for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Change From Baseline in Electrocardiogram (ECG) Parameters PR Interval, QRS Duration, Uncorrected QT Interval and Corrected QT Frederica's Correction) Interval

Description

Time Frame

Baseline and up to 72 hours in Part 1

Title

Change From Baseline in Electrocardiogram Parameters PR Interval, QRS Duration, Uncorrected QT Interval and Corrected QT (Frederica's Correction) Interval for Part 2

Description

Time Frame

Baseline and up to 48 hours in Part 2

Title

Blood Concentration of GSK1325756 in Part 1

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in all 3 periods; 60 and 72 hours post-dose in period-3 of Part 1

Title

Blood Concentration of GSK1325756 in Part 2

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours post-dose in Part 2

Title

Maximum Observed Concentration (Cmax) of GSK1325756H for Part 1

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in all 3 periods; 60 and 72 hours post-dose in period-3 of Part 1

Title

Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of GSK1325756H for Part 1

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in all 3 periods; 60 and 72 hours post-dose in period-3 of Part 1

Title

Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of GSK1325756H for Part 1

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in all 3 periods; 60 and 72 hours post-dose in period-3 of Part 1

Title

Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of GSK1325756H for Part 1

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in all 3 periods; 60 and 72 hours post-dose in period-3 of Part 1

Title

Time to Maximum Observed Concentration (Tmax) of GSK1325756H for Part 1

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in all 3 periods; 60 and 72 hours post-dose in period-3 of Part 1

Title

Terminal Half-life (t1/2) of GSK1325756H for Part 1

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in all 3 periods; 60 and 72 hours post-dose in period-3 of Part 1

Title

Lag Time Before Observable Concentration (Tlag) of GSK1325756H for Part 1

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in all 3 periods; 60 and 72 hours post-dose in period-3 of Part 1

Title

Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of GSK1325756H for Part 1

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in all 3 periods; 60 and 72 hours post-dose in period-3 of Part 1

Title

Cmax of GSK1325756H for Part 2

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours post-dose in Part 2

Title

AUC (0-t) of GSK1325756H for Part 2

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours post-dose in Part 2

Title

AUC (0-inf) of GSK1325756H for Part 2

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours post-dose in Part 2

Title

AUC (0-24) of GSK1325756H for Part 2

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours post-dose in Part 2

Title

Tmax of GSK1325756H for Part 2

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours post-dose in Part 2

Title

t1/2 of GSK1325756H for Part 2

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours post-dose in Part 2

Title

Tlag of GSK1325756H for Part 2

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours post-dose in Part 2

Title

Tlast of the Blood Concentration of GSK1325756H for Part 2

Description

Time Frame

Pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 post-dose in Part 2

10. Eligibility

Sex

Male

Gender Based

Yes

Gender Eligibility Description

Japanese Healthy Elderly Male Subjects

Minimum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria Participant must be over 65 years of age inclusive, at the time of signing the informed consent. Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and ECG. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator in consultation with the Medical Monitor if required agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Participants whose peripheral blood neutrophil counts and hematocrit values are within normal range at screening visit. Body weight >=50 kilogram (Kg) and body mass index (BMI) within the range 18.5-24.9 kg/square meter (m^2) (inclusive). Japanese Male: A male participant must agree to use contraception during the treatment period and until follow up visit. Capable of giving signed informed consent. Exclusion Criteria History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data. Abnormal blood pressure as determined by the investigator. Alanine Aminotransferase (ALT)>1.5x upper limit of normal (ULN). Bilirubin>1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%). Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). QT interval corrected for heart rate according to Fridericia's formula (QTcF)> 450 millisecond (msec). Past or intended use of over-the-counter or prescription medication including herbal medications and proton pump inhibitor (PPI) within 14 days prior to dosing. History of donation of blood or blood products >=400 milliliter (mL) within 3 months or >=200 mL within 1 month prior to screening. Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day. Current enrolment or past participation within the last 30 days before signing of consent in this clinical study involving an investigational study treatment or any other type of medical research. The subject with positive Serological test for syphilis (Rapid Plasma Reagin [RPR] and Treponema pallidum hemagglutination test [TPHA]), Human immunodeficiency virus (HIV) Antigen/Antibody, Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV) antibody, or Human T-cell lymphotropic virus type 1 (HTLV-1) antibody at screening. Positive pre-study drug screen. Regular alcohol consumption within 6 months prior to the study defined as: an average weekly intake of > 14 units for males. One unit is equivalent to 350 mL of beer, 150 mL of wine or 45 mL of 80 proof distilled spirits. Smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening. Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

Official's Role

Study Director

Facility Information:

Facility Name

GSK Investigational Site

City

Tokyo

ZIP/Postal Code

162-0053

Country

Japan

Facility Name

GSK Investigational Site

City

Tokyo

ZIP/Postal Code

162-00

Country

Japan

12. IPD Sharing Statement

Citations:

PubMed Identifier

31056840

Citation

Iida T, Matsuzawa Y, Ogura H, Nagakubo T, Wakamatsu A, Ambery C, Miller BE, Lazaar AL, Numachi Y. Evaluation of the Safety, Tolerability, Pharmacokinetics, and Food Effect of Danirixin Hydrobromide Tablets in Japanese Healthy Elderly Participants. Clin Pharmacol Drug Dev. 2019 Nov;8(8):1081-1087. doi: 10.1002/cpdd.693. Epub 2019 May 6.

Results Reference

derived

Learn more about this trial

Study of Danirixin in Japanese Healthy Elderly Male Subjects

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