GSK1325756 Relative Bioavailability Study in Healthy Elderly Subjects

Study Overview
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Brief Summary
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This 2-part study will be carried out on healthy elderly subjects to evaluate relative bioavailability of danirixin formulations. Part A will support the selection of the formulation and Part B will assess food effect, bioavailability and pharmacokinetic (PK) profile of selected formulation from Part A. Danirixin is currently administered with food, therefore the investigation of food effect for the selected formulation could potentially enable dosing without food. Approximately 16 subjects will be included in Part A and approximately 24 subjects will be included in Part B. Both parts will include a screening phase, treatment phase with in-between washout period and a follow-up phase.

Official Title
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A Two Part, Randomized, Open-label, Cross Over Study in Healthy Elderly Participants to Evaluate the Relative Bioavailability of Hydrobromide Salt Tablet Formulations of Danirixin in the Fed and Fasted States, and to Evaluate the Effect of Food and Gastric Acid Secretion Suppression on Danirixin Pharmacokinetics Following Administration of Hydrobromide Salt Tablets

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Danirixin
* Drug: Omeprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be 65 to 80 years of age inclusive, at the Screening Visit. Subjects who are healthy, as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring or a subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included if the investigator and the GlaxoSmithKline (GSK) Medical Monitor agree that the finding is unlikely to introduce risk factors and will not interfere with the study procedures and objectives. Additionally, laboratory assessments that are specifically listed in the inclusion or exclusion criteria and are outside of the reference range can be repeated once during the screening period. Body weight >=50 kilograms (kg) and body mass index (BMI) within the range 19 - 34 kg per meter square (kg/m^2) (inclusive). Male or female subjects will be included. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 60 hours after the last dose of study treatment. Capable of giving signed informed consent. AST, ALT, alkaline phosphatase and bilirubin <= 1.5 × upper limit of normal (ULN) (isolated bilirubin > 1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35 percent). Resting BP of <= 160/90 millimeters of mercury (mmHg), irrespective of anti-hypertensive medication status for the subject. Able to consume the Food and Drug Administration (FDA) defined high fat meal within 30 minutes in each of the four treatment periods where study treatment is administered in a fed state. Exclusion Criteria: Significant history of or current 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. Evidence of active or latent tuberculosis (TB) as documented by medical history and examination, chest x-rays (posterior anterior and lateral), and TB testing: either a positive tuberculin skin test [TST; defined as a skin induration <5 millimeter (mm) at 48 to 72 hours, regardless of Bacillus Calmette-Guerin (BCG) or other vaccination history] or a positive (not indeterminate) QuantiFERON®-TB Gold test. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years. Breast cancer within the past 10 years. ALT >1.5x ULN Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent). Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Corrected QT interval (QTc) >450 milliseconds (msec). Use of prescription or non-prescription drugs, including proton pump inhibitors, histamine receptor 2 antagonists, systemic antacid medications (unless these can be held during the study), 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 treatment until completion of the last study assessment , unless in the opinion of the investigator and GSK Medical Monitor, the medication will not interfere with the study procedures or compromise subject safety. Some examples of exceptions (permitted medications) are: Stable dose of anti-hypertensive medication for at least 3 months prior to the screening visit; Stable dose of lipid-lowering medications (statins or fibrates) for at least 3 months prior to the screening visit; Antacids up to 24 hours prior to dosing. Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 3 months. 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, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day. Participation in a previous clinical trial with danirixin within 1 year prior to the first dosing day in the current study. Female Subjects: Positive urine beta-human chorionic gonadotropin (beta-hCG) test at screening. Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C antibody test result at screening. Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment. For potent immunosuppressive agents, presence of the Hepatitis B core antibody (HBcAb) should also lead to exclusion from the study even if HBsAg is negative. Positive pre-study drug/alcohol screen. Positive human immunodeficiency virus (HIV) antibody test. Regular use of known drugs of abuse. Regular alcohol consumption within 6 months prior to the study defined as: an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 grams of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. Consumption of red wine, Seville oranges, grapefruit or grapefruit juice and/or pummelos, citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study treatment until collection of the final blood sample. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 90 days prior to screening. Sensitivity to heparin or heparin-induced thrombocytopenia. 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.

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Subjects will receive danirixin reference and test formulations in a cross-over manner.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subjects receiving danirixin: Part A<br>Subjects will receive a single oral dose of 50 mg danirixin reference and test formulations with food and 240 mL of water in a cross-over manner. | Drug: Danirixin<br>* Danirixin is being developed as a potential anti-inflammatory agent for the treatment of chronic obstructive pulmonary disorder (COPD) and other inflammatory diseases and influenza. Danirixin reference (600 mg) or test formulation (475 or 600 mg or 600 mg with 5 percent HPMC) immediate release tablets will be administered by oral route in a cross-over manner.<br>|
| Experimental: Subjects receiving danirixin without omeprazole: Part B<br>Subjects will receive a single oral dose of 50 mg danirixin formulation (selected in Part A) in fasted or fed state in a cross-over manner. | Drug: Danirixin<br>* Danirixin is being developed as a potential anti-inflammatory agent for the treatment of chronic obstructive pulmonary disorder (COPD) and other inflammatory diseases and influenza. Danirixin reference (600 mg) or test formulation (475 or 600 mg or 600 mg with 5 percent HPMC) immediate release tablets will be administered by oral route in a cross-over manner.<br>|
| Experimental: Subjects receiving danirixin with omeprazole: Part B<br>Subjects will receive a single oral dose of 50 mg danirixin formulation (selected in Part A) along with once daily 40 mg OMP capsule in fasted or fed state in a cross-over manner. | Drug: Danirixin<br>* Danirixin is being developed as a potential anti-inflammatory agent for the treatment of chronic obstructive pulmonary disorder (COPD) and other inflammatory diseases and influenza. Danirixin reference (600 mg) or test formulation (475 or 600 mg or 600 mg with 5 percent HPMC) immediate release tablets will be administered by oral route in a cross-over manner.<br>Drug: Omeprazole<br>* Omeprazole is used as an antacid. OMP 40 mg delayed-release capsule will be administered by oral route to randomized subjects.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the pharmacokinetic (PK) profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | 
| Maximum Observed Concentration (Cmax) of Danirixin for Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | 
| Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. 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. | Up to 29 days in Part 1 | 
| Number of Participants With Vital Signs of Potential Clinical Concern in Part 1 | Vital signs included systolic and diastolic blood pressure, temperature, respiratory rate and pulse rate were measured with participants in semi-supine position after 5 minutes rest. | Up to 29 days in Part 1 | 
| Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 1 | Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals, and QT interval corrected by Fridericia's formula (QTcF). Number of participants with 12-lead ECG values of potential clinical concern in Part 1 are presented. | Up to 29 days in Part 1 | 
| Number of Participants With Laboratory Values of Potential Clinical Concern in Part 1 | Hematology parameters included platelet count, RBC Count, hemoglobin, hematocrit, MCV, MCH, %Reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils. Clinical chemistry parameters included potassium aspartate aminotransferase(AST)/Serum Glutamic-Oxaloacetic Transaminase (SGOT), total and direct bilirubin, creatinine, sodium alanine, aminotransferase, (ALT)/ Serum Glutamic-Pyruvic, Transaminase (SGPT), total protein, fasting glucose, calcium, alkaline phosphatase and albumin. Urinalysis included specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick and microscopic examination of urine. | Up to 29 days in Part 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | 
| Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC [0-24]) of Danirixin for Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | 
| Time to Occurrence of Cmax (Tmax) of Danirixin for Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | 
| Terminal Half-life (t1/2) of Danirixin for Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | 
| Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | 
| Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Danirixin for Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | 
| Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | 
| Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | 
| Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of Danirixin for Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | 
| Maximum Observed Concentration (Cmax) of Danirixin for Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | 
| Time to Maximum Observed Concentration (Tmax) of Danirixin for Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | 
| Terminal Half-life (t1/2) of Danirixin for Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | 
| Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | 
| Lag Time Before Observable Concentration (Tlag) of Danirixin for Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | 
| Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. 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. | Up to 52 days in Part 2 | 
| Number of Participants With Vital Signs of Potential Clinical Concern in Part 2 | Vital signs included systolic and diastolic blood pressure, temperature, respiratory rate and pulse rate were measured with participants in semi-supine position after 5 minutes rest. | Up to 52 days in Part 2 | 
| Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 2 | Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals, and QT interval corrected by Fridericia's formula (QTcF). Number of participants with 12-lead ECG values of potential clinical concern in Part 2 are presented. | Up to 52 days in Part 2 | 
| Number of Participants With Laboratory Values of Potential Clinical Concern in Part 2 | Hematology parameters included platelet count, RBC Count, hemoglobin, hematocrit, MCV, MCH, %Reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils. Clinical chemistry parameters included potassium aspartate, Aminotransferase(AST)/Serum Glutamic-Oxaloacetic Transaminase (SGOT), total and direct, bilirubin, creatinine sodium alanine, Aminotransferase, (ALT)/ Serum Glutamic-Pyruvic, Transaminase (SGPT), total protein, fasting glucose, calcium, alkaline phosphatase and albumin. Urinalysis included specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick and microscopic examination of urine. | Up to 52 days in Part 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Danirixin, Healthy, Food effect, Relative Bioavailability, Hydrobromide Salt