Clinical trial NCT03136380: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: healthy Japanese subjects
CXCR2 inhibitor
Danirixin
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-05-02
Enrollment: 34
Sex: MALE
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 1
timeFrame: Up to 32 days in Part 1
measure: Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2
timeFrame: Up to 21 days in Part 2
measure: 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
timeFrame: Baseline and up to 72 hours in Part 1
measure: 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
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Clinical Chemistry Parameters Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Clinical Chemistry Parameter Amylase for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: 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
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Clinical Chemistry Parameters Alkaline Phosphatase, ALT, AST, Creatine Kinase, GGT and Lactate Dehydrogenase for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Clinical Chemistry Parameters Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Clinical Chemistry Parameter Amylase for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes and Total Neutrophils for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Hematology Parameter Hemoglobin for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Hematology Parameter Hematocrit for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Hematology Parameter Mean Corpuscle Volume for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Hematology Parameters Platelet Count and White Blood Cell Count for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Hematology Parameters Red Blood Count and Reticulocyte Count for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes and Total Neutrophils for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Hematology Parameter Hemoglobin for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Hematology Parameter Hematocrit for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Hematology Parameter Mean Corpuscle Volume for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Hematology Parameters Platelet Count and White Blood Cell Count for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Hematology Parameters Red Blood Count and Reticulocyte Count for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Number of Participants With Abnormal Values on Urinalysis by Dipstick Method for Part 1
timeFrame: Up to 72 hours in Part 1
measure: Urine Potential of Hydrogen (pH) Analysis by Dipstick Method for Part 1
timeFrame: Up to 72 hours in Part 1
measure: Urine Specific Gravity Analysis by Dipstick Method for Part 1
timeFrame: Up to 72 hours in Part 1
measure: Number of Participants With Abnormal Values on Urinalysis by Dipstick Method for Part 2
timeFrame: Up to 48 hours in Part 2
measure: Urine pH Analysis by Dipstick Method for Part 2
timeFrame: Up to 48 hours in Part 2
measure: Urine Specific Gravity Analysis by Dipstick Method for Part 2
timeFrame: Up to 72 hours in Part 2
measure: Change From Baseline in Vital Sign Parameters Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Vital Sign Parameter Heart Rate for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Vital Sign Parameter Temperature for Part 1
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Vital Sign Parameters SBP and DBP for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Vital Sign Parameter Heart Rate for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Vital Sign Parameter Temperature for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Change From Baseline in Electrocardiogram (ECG) Parameters PR Interval, QRS Duration, Uncorrected QT Interval and Corrected QT Frederica's Correction) Interval
timeFrame: Baseline and up to 72 hours in Part 1
measure: Change From Baseline in Electrocardiogram Parameters PR Interval, QRS Duration, Uncorrected QT Interval and Corrected QT (Frederica's Correction) Interval for Part 2
timeFrame: Baseline and up to 48 hours in Part 2
measure: Blood Concentration of GSK1325756 in Part 1
timeFrame: 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
measure: Blood Concentration of GSK1325756 in Part 2
timeFrame: 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
measure: Maximum Observed Concentration (Cmax) of GSK1325756H for Part 1
timeFrame: 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
measure: Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of GSK1325756H for Part 1
timeFrame: 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
measure: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of GSK1325756H for Part 1
timeFrame: 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
measure: Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of GSK1325756H for Part 1
timeFrame: 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
measure: Time to Maximum Observed Concentration (Tmax) of GSK1325756H for Part 1
timeFrame: 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
measure: Terminal Half-life (t1/2) of GSK1325756H for Part 1
timeFrame: 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
measure: Lag Time Before Observable Concentration (Tlag) of GSK1325756H for Part 1
timeFrame: 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
measure: Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of GSK1325756H for Part 1
timeFrame: 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
measure: Cmax of GSK1325756H for Part 2
timeFrame: 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
measure: AUC (0-t) of GSK1325756H for Part 2
timeFrame: 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
measure: AUC (0-inf) of GSK1325756H for Part 2
timeFrame: 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
measure: AUC (0-24) of GSK1325756H for Part 2
timeFrame: 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
measure: Tmax of GSK1325756H for Part 2
timeFrame: 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
measure: t1/2 of GSK1325756H for Part 2
timeFrame: 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
measure: Tlag of GSK1325756H for Part 2
timeFrame: 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
measure: Tlast of the Blood Concentration of GSK1325756H for Part 2
timeFrame: 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
Secondary outcomes:
Other outcomes:
Locations:
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
affiliation: GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
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.