A Randomised, Double-blind, Placebo-controlled, Dose Ascending, 2-cohort, Parallel Group Study to Examine the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Twice-daily Inhaled Doses of GSK233705B Formulated With the Excipient Magnesium Stearate in COPD Subjects for 7-days.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 23
- 试验地点
- 5
- 主要终点
- Summary of Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
研究概览
简要总结
GSK233705 is a high-affinity specific muscarinic receptor (mAChR) antagonist which is being developed for the treatment of chronic obstructive pulmonary disease. This is a randomised, double-blind, placebo-controlled, dose ascending, parallel group study to examine the safety, tolerability, pharmacokinetics and pharmacodynamics of twice daily inhaled doses of GSK233705B for 7 days, in COPD subjects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
入排标准
- 年龄范围
- 40 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men or women who are between 40 and 75 years of age
- •Female subjects must be of non-childbearing
- •Subject diagnosed with COPD
- •Body Mass Index 18.0 - 32.0 kg/m2 (inclusive)
- •Subject is a smoker or an ex-smoker
- •Subject has post-bronchodilator (200µg salbutamol) FEV1 of = 40% to = 80% of predicted normal.
- •Subject has FEV1/FVC < 0.7 post-bronchodilator (200µg salbutamol).
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- •Subject is available to complete all study measurements and procedures.
- •Subjects have a 24hour holter recording that is within normal limits and does not demonstrate any clinically important abnormality that, in the opinion of the investigator, would make the subject unsuitable for participation in the study.
排除标准
- •Subjects who have a past or present disease, which as judged by the Investigator and the Medical Monitor, may affect the outcome of this study.
- •The subject has a positive pre-study alcohol screen.
- •The subject has a positive pre-study drug screen.
- •History of alcohol/drug abuse or dependence within 12 months of the study: Abuse
- •The subject has a positive pregnancy test.
- •A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
- •Subject has tested positive for HIV
- •The subject has participated in a clinical trial and has received a drug or a new chemical entity within 60 days or 5 half-lives
- •Exposure to more than three new chemical entities (NCE) within 10 months prior to the first dosing day or one NCE within 3 months prior to the first dosing day.
- •The subject has donated a unit (400ml) of blood within 60 days of screening, or, intends to donate during the study.
- •The subject has a known allergy or hypersensitivity to ipratropium bromide, atropine and any of its derivatives or milk protein/lactose.
- •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 physician responsible, contraindicates their participation
- •Subject has prostate hypertrophy or narrow angle glaucoma
结局指标
主要结局
Summary of Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
时间窗: Up to Day 7 (24 hours post-dose)
Blood pressure was measured subsequent to 12 lead electrocardiogram (ECG). Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on Baseline (triplicate), 15, 30 minutes, 1.5, 4, 8 and 24 hours on Day 1 and 7.
Maximum Value of Heart Rate (0-4 Hour) for the Morning Dose
时间窗: Up to Day 7 (0-4 hour)
Heart rate was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
时间窗: Up to follow-up (approximately 45 days)
An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.
Number of Participants With Abnormalities in Hematology Data of Clinical Concern
时间窗: Up to Day 7
Hematology parameters included platelet count, red blood cell (RBC) count, mean corpuscular volume (MCV), total neutrophils, white blood cell (WBC) count (absolute), mean corpuscular hemoglobin (MCH), lymphocytes, mean corpuscular hemoglobin concentration (MCHC), monocytes, hemoglobin, eosinophils, hematocrit and basophils. It was assessed on Day 1 (pre-dose, 24 hours) and Day 7 (pre-dose, 24 hours). Data for parameters with above and below the PCI is provided.
Summary of Mean (0-24 Hour) and Maximum (0-24 Hour) Heart Rate Measured Using 24 Hour Using Holter ECG Data
时间窗: Up to Day 7
Holter monitors were switched on immediately prior to dosing (up to 15mins pre-dose) so as to capture Holter ECG data from the 24 hour period following dosing. It was assessed on Day 1 and 7.
Maximum Value of SBP and DBP (0-4 Hour) for the Morning Dose
时间窗: Up to Day 7 (0-4 hour)
Blood pressure was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.
Number of Participants With Abnormalities in Chemistry Data of Clinical Concern
时间窗: Up to Day 7
Clinical chemistry parameters included urea, potassium, aspartate aminotransferase (AST), total bilirubin, creatinine, creatine kinase, chloride, alanine aminotransferase (ALT), uric acid, glucose, gamma glutamyltransferase (GGT), albumin, sodium, phosphorus inorganic, calcium, alkaline phosphatase (ALP) and total protein. It was assessed on Day 1 (pre-dose, 24 hours) and Day 7 (pre-dose, 24 hours). Data for parameters with above and below the potential clinical concern (PCI) is provided.
Summary of Microscopy Data for Participants With Abnormal Urinalysis Dipstick Results
时间窗: Up to Day 7 (pre dose)
Urinalysis parameters included protein, blood, ketones, glucose, bilirubin, urobilinogen, leukocyte esterase, specific gravity, nitrites and pH. Sediment microscopy was performed only on urine samples showing an abnormality on the dipstick. Microscopy was performed for: WBC, RBC, hyaline casts, granular casts and cellular casts. It was assessed on Day 1 (pre-dose, 24 hours) and Day 7 (pre-dose, 24 hours).
Summary of Mean Heart Rate
时间窗: Up to Day 7 (24 hour post dose)
Heart rate was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on Baseline (triplicate), 15, 30 minutes, 1.5, 4, 8 and 24 hours on Day 1 and 7.
Weighted Mean of SBP and DBP (0-4 Hour) for the Morning Dose
时间窗: Up to Day 7 (0-4 hour)
Blood pressure was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.
Weighted Mean of Heart Rate (0-4 Hour) for the Morning Dose
时间窗: Up to Day 7 (0-4 hour)
Heart rate was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.
Number of Participants With Abnormal 12-lead ECG Findings
时间窗: Up to Day 7 (24 hour post dose)
Single measurements were taken at all time points. The pre-dose values were classed as Baseline. Data for number of participants with normal, abnormal not clinically significant and abnormal clinically significant is presented. It was assessed on Baseline (triplicate), 15, 30 minutes, 1.5, 4, 8 and 24 hours on Day 1 and 7.
Weighted Mean (0-4 h) for the Morning Dose of ECG Parameters QTcF and QTc B
时间窗: Up to Day 7 (0-4 hour)
Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.
Summary of Mean Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC)
时间窗: Up to Day 7 (24-hour post dose)
It was assessed on 1, 2, 4, 9, 12 and 24 hours on Days 1 and 7. Also on Day 7, it was measured on 0 hour (Baseline). At all time points 3 measurements were taken and formal statistical analysis was carried out on the derived maximum readings. Data for adjusted mean is presented as least square mean.
Maximum Value (0-4 Hour) for the Morning Dose of ECG Parameters Corrected According to Fredericia's Formula (QTcF) and Corrected According to Bazett's Formula (QTc B)
时间窗: Up to Day 7 (0-4 hour)
Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.
Number of Participants Who Used Rescue Medication
时间窗: Up to Day 7
Inhaled salbutamol was used as a rescue medication. Participants were required to keep a diary of their rescue medication (total number of salbutamol doses taken) over the entire 7-day treatment period. Diaries were reviewed by the Investigator when participants were admitted to the unit on Days 1, 2, 7 and 8.
次要结局
- Derived Plasma PK Parameters-area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC0-tau)(Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose)
- Derived Urine Pharmacokinetic (PK) Parameters-area Under the Plasma Concentration-amount of Drug Excreted Unchanged in Urine (Ae)(Day 1 and 7 throughout 24 hours)
- Urine Concentrations of GSK233705(Day 1 and 7 throughout 24 hours)
- Plasma Concentrations of GSK233705(Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose)
- Derived Plasma PK Parameters-area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-t)(Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose)
- Derived PK Plasma Parameters-area Under Concentration-time of Maximum Observed Plasma Concentration (T-max), Half-life (T-half) and Last Time Point Where the Concentration is Above the Limit of Quantification (T-last)(Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose)
- Derived Urine PK Parameters-area Under Concentration-fraction of Dose Excreted Unchanged in Urine (Fe)(Day 1 and 7 throughout 24 hours)
- Derived Urine PK Parameters-area Under Concentration-renal Clearance (Clr)(Day 1 and 7 throughout 24 hours)
- Derived PK Plasma Parameters-area Under Concentration-maximum Observed Plasma Concentration (Cmax)(Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose)