A Randomised, Placebo-controlled, Double-blind (Sponsor Open), Segmental LPS Challenge Study to Investigate the Pharmacodynamics of GSK2798745 in Healthy Participants
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 47
- 试验地点
- 1
- 主要终点
- Baseline Adjusted Total Protein Concentration in Broncho-alveolar (BAL) Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose)
研究概览
简要总结
The primary objective of the study is to investigate the effect of GSK2798745 on alveolar-septal barrier permeability following LPS challenge in healthy subjects. The influx of protein-rich fluid into the lung due to damage to the alveolar capillary barrier, with resultant adverse effects on respiratory function, is a fundamental underlying defect in Acute Respiratory Distress Syndrome (ARDS). In this Phase 1, proof-of-mechanism study, a LPS challenge will be used as a surrogate injury model to investigate the effects of Transient receptor potential vanilloid 4 (TRPV4) channel blockade on alveolar-septal barrier permeability in man. This is a randomised, placebo-controlled, parallel group, double-blind (sponsor-open), segmental LPS challenge study of GSK2798745 in healthy subjects. Subjects will be randomised in a ratio of 1:1 to take 2 single doses of either 4.8 milligrams GSK2798745 followed by 2.4 milligrams GSK2798745 after 12 hours or a dose of placebo followed by another dose of placebo after 12 hours. The first dose will be administered on Day 1 at 2 hours before Baseline bronchoalveolar lavage (BAL) sampling from a segment in the left lower lobe of lung. LPS 4 nanogram per kilogram will subsequently be instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose of study treatment will be administered 10 hours after LPS challenge followed by post-dose BAL sampling on Day 2. Each subject will take approximately 5 weeks to complete the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
This will be a double blind study where investigator, sub-investigators, other site staff and the subject will be blinded. Selected sponsor study team members will be unblinded to perform the interim analysis. This may include the medical monitor, study statistician, study programmer (and delegates) and study pharmacokineticist.
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Subjects between 18 and 50 years of age inclusive, at the time of signing the informed consent.
- •Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests (including a normal coagulation profile), ECGs, vital signs and spirometry. In the event of out-of-range results of safety tests, the tests may be repeated once within the screening window. If a retest result is again outside the reference range and considered clinically significant by the investigator and GlaxoSmithKline (GSK) medical monitor, the subject will be considered a screen failure.
- •Normal spirometry (FEV1 >=80% of predicted, FEV1/FVC ratio >=70%) at Screening and before dosing.
- •Body weight >=50 kilogram (kg) and body mass index (BMI) within the range 19 to 29.9 kilogram per square meter (kg/m^2)(inclusive).
- •A male subject must agree to use contraception during the treatment period and for at least 7 days after the last dose of study treatment and refrain from donating sperm during this period.
- •A female is eligible to participate if she is not of childbearing potential.
- •Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.
排除标准
- •Significant history of or current cardiovascular, respiratory (e.g., asthma, chronic obstructive pulmonary disorder (COPD), bronchiectasis, active Tuberculosis [TB]), hepatic, renal, gastrointestinal, endocrine, hematological, autoimmune 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.
- •Subject who, in the investigator/designee's judgement, poses a significant suicide risk. Evidence of serious suicide risk may include any history of suicidal behavior and/or any evidence of suicidal ideation on any questionnaires e.g., Type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) in the last 5 years.
- •Active ulcer disease or gastrointestinal bleeding at the time of Screening (positive FOBT at Screening).
- •Abnormal blood pressure as determined by the investigator.
- •Alanine aminotransferase (ALT) or bilirubin >1.5 times upper limit of normal (ULN) (isolated bilirubin >1.5 times ULN 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 Fridericia's formula (QTcF) >450 milliseconds (msec).
- •At risk of Torsades de pointes (e.g., a personal history or a family history of sudden unexplained death, long QT, familial cardiac syndrome, or cardiomyopathy).
- •Chronic or acute infection within the 4 weeks before dosing, (e.g., upper and lower respiratory infection within the 4 weeks before dosing).
- •Major (as per investigator judgment) surgery within the last 12 weeks prior to randomisation or planned within 3 months of Screening.
- •Use of prescription or non-prescription drugs (except paracetamol), including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days or 5 half-lives (whichever is longer) before 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 and/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 milliliters (mL) within 3 months.
- •The subject has participated in a clinical trial and has received an investigational product within the following time period before the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- •Exposure to more than four new chemical entities within 12 months before the first dosing day.
- •Presence of hepatitis B surface antigen (HBsAg) at Screening.
- •Positive hepatitis C antibody test result at Screening. Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA) test is obtained.
- •Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment. Test is optional and subjects with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing.
- •A positive pre-study drug/alcohol/cotinine screen.
- •A positive test for immunodeficiency virus (HIV) antibody.
- •Regular use of known drugs of abuse.
- •History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
- •Current smoker or a history of smoking within 6 months of screening, or a total pack year history of >5 pack years. [number of pack years = (number of cigarettes per day/20) x number of years smoked].
研究组 & 干预措施
Subjects receiving GSK2798745
Eligible subjects will receive two tablets of 2.4 milligrams GSK2798745 on the morning of Day 1. Subjects will then undergo segmental challenge at 2 hours after first dose wherein LPS will be instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose of a single tablet of 2.4 milligrams of GSK2798745 will be administered 10 hours after LPS and saline challenge.
干预措施: GSK2798745 (Drug)
Subjects receiving GSK2798745
Eligible subjects will receive two tablets of 2.4 milligrams GSK2798745 on the morning of Day 1. Subjects will then undergo segmental challenge at 2 hours after first dose wherein LPS will be instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose of a single tablet of 2.4 milligrams of GSK2798745 will be administered 10 hours after LPS and saline challenge.
干预措施: Lipoplysaccharide from Escherichia Coli (Drug)
Subjects receiving GSK2798745
Eligible subjects will receive two tablets of 2.4 milligrams GSK2798745 on the morning of Day 1. Subjects will then undergo segmental challenge at 2 hours after first dose wherein LPS will be instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose of a single tablet of 2.4 milligrams of GSK2798745 will be administered 10 hours after LPS and saline challenge.
干预措施: Saline (Drug)
Subjects receiving matching Placebo
Eligible subjects will receive two tablets of placebo on the morning of Day 1. Subjects will then undergo segmental challenge at 2 hours after first dose wherein LPS will be instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose placebo will be administered 10 hours after LPS and saline challenge.
干预措施: Placebo (Drug)
Subjects receiving matching Placebo
Eligible subjects will receive two tablets of placebo on the morning of Day 1. Subjects will then undergo segmental challenge at 2 hours after first dose wherein LPS will be instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose placebo will be administered 10 hours after LPS and saline challenge.
干预措施: Lipoplysaccharide from Escherichia Coli (Drug)
Subjects receiving matching Placebo
Eligible subjects will receive two tablets of placebo on the morning of Day 1. Subjects will then undergo segmental challenge at 2 hours after first dose wherein LPS will be instilled into the right middle segment and saline control into the lingula segment of the contralateral side. The second dose placebo will be administered 10 hours after LPS and saline challenge.
干预措施: Saline (Drug)
结局指标
主要结局
Baseline Adjusted Total Protein Concentration in Broncho-alveolar (BAL) Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose)
时间窗: Baseline and at 26 hours post-first dose
Participants underwent segmental challenge to lungs, via bronchoscopy, at 2 hours after first dose of investigational medicinal product. BAL samples were taken, via bronchoscopy and total protein was measured. Baseline (2 hours) samples were taken immediately before the LPS and saline challenges, from a segment in the left lower lobe, and post-challenge samples were taken at 24 hours (26 hours post-first dose) after the LPS and saline challenges, from the challenged segments. Evaluable Population consists of all participants for whom results of the primary analysis can be determined i.e. all randomized participants who received two correct doses of study treatment, received LPS and saline segmental challenge (in contralateral lobes) and for which results of both baseline (2 hours) and LPS lobe (26 hours) BAL samples are evaluable. This population will be based on treatment the participant actually received. Median and 95% credible interval (CrI) has been presented.
次要结局
- Baseline Adjusted Total Cell Count of Neutrophils in BAL Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose)(Baseline and at 26 hours post-first dose)
- Baseline Adjusted Differential Cell Count of Neutrophils in BAL Samples at 24 Hours After Segmental LPS Challenge (26 Hours Post-first Dose)(Baseline and at 26 hours post-first dose)
- Number of Participants Reporting Serious Adverse Events (SAEs) and Non-SAEs(Up to Day 9 (FU/EW))
- Change From Baseline Values for Clinical Chemistry Parameters(Baseline (Day -1) and at Day 2 and Day 9 (FU/EW))
- Change From Baseline Values for Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine(Baseline (Day -1) and at Day 2 and Day 9 (FU/EW))
- Change From Baseline Values for Clinical Chemistry Parameter-C Reactive Protein (CRP)(Baseline (Day -1) and at Day 2 and Day 9 (FU/EW))
- Change From Baseline Values for Clinical Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Urea/Blood Urea Nitrogen (BUN)(Baseline (Day -1) and at Day 2 and Day 9 (FU/EW))
- Change From Baseline Values for Hematology Parameters: Hematocrit and Reticulocytes(Baseline (Day -1) and at Day 2 and Day 9 (FU/EW))
- Change From Baseline Values for Hematology Parameter: Mean Corpuscular Hemogloblin (MCH)(Baseline (Day -1) and at Day 2 and Day 9 (FU/EW))
- Mean Forced Expiratory Volume in 1 Second (FEV1) and Mean Forced Vital Capacity (FVC)(Baseline (Day 1, Pre-dose) pre-bronchodilator and at Day 1 (pre-bronchodilator and 6 Hours), at Day 2 (25.5 and 30 Hours) and Day 9 pre-bronchodilator)
- Maximum Observed Plasma Concentration (Cmax) of GSK2798745(Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 24 and 26 hours post-dose)
- Change From Baseline Values for Clinical Chemistry Parameter-Total Protein(Baseline (Day -1) and at Day 2 and Day 9)
- Change From Baseline in Urine Potential of Hydrogen (pH)(Baseline (Day -1) and at Day 2 and Day 9 (FU/EW))
- Change From Baseline in Temperature(Baseline (Day -1) and at 1, 2, 6, 8, 12, 14, 30 hours and Day 9 (FU/EW))
- Number of Participants With Positive Fecal Occult Blood Test (FOBT) Data(At Day 9)
- Change From Baseline Values for Hematology Parameter: Hemoglobin(Baseline (Day -1) and at Day 2 and Day 9 (FU/EW))
- Change From Baseline Values for Hematology Parameter: Mean Corpuscular Volume (MCV)(Baseline (Day -1) and at Day 2 and Day 9 (FU/EW))
- Change From Baseline Values for Hematology Parameter: Red Blood Cell (RBC) Count(Baseline (Day -1)and at Day 2 and Day 9 (FU/EW))
- Number of Participants With Abnormal Findings During Physical Examinations(Up to Day 9 (FU/EW))
- Area Under the Curve During 26 Hours of GSK2798745(Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 24 and 26 hours post-dose)
- Change From Baseline Values for Hematology Parameters(Baseline (Day -1) and at Day 2 and Day 9 (FU/EW))
- Change From Baseline in Urine Specific Gravity(Baseline (Day -1) and at Day 2 and Day 9 (FU/EW))
- Change From Baseline in Heart Rate(Baseline (Day -1) and at 1, 6, 12, 14, 30 hours and Day 9 (FU/EW))
- Number of Participants With Worst Case Post Baseline Abnormal Electrocardiogram (ECG) Findings(Up to Day 9 (FU/EW))
- Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)(Baseline (Day -1) and at 1, 6, 12, 14, 30 hours and Day 9 (FU/EW))