A Randomized Double-blind, Placebo-controlled, Crossover, Dose Escalation Study to Examine the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Single Inhaled Doses of GSK1160724 and Tiotropium Bromide
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Number of subjects with adverse events (AEs)
研究概览
简要总结
GSK1160724 is a potent mAChR antagonist, which is being developed for treatment of chronic obstructive pulmonary disease (COPD)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy male and female subjects. Female subjects must be of non-child bearing potential.
- •Aged between 18-55 years inclusive
- •Non-smokers
- •Normal spirometry
- •A signed and dated written informed consent is obtained from the subject
- •The subject is capable of giving informed consent, which includes compliance with the requirements and restrictions listed in the consent form
- •Available to complete the study
- •The subject is greater than or equal to 50kg with a body mass index within the range 19.0 to 29.9 kg/m2 inclusive
- •Response to ipratropium bromide
排除标准
- •Any clinically relevant and important abnormality identified at the screening medical assessment (physical examination/medical history), clinical laboratory tests, or ECG (12-lead or Holter)
- •A history of breathing problems
- •A mean QTc(B) value > 450ms, the QTc(B) of the 3 screening ECGs are not within 10% of the mean, a PR interval outside the range 90-210ms or an ECG that is not suitable for QT measurements at screening
- •A history of elevated resting blood pressure or a mean blood pressure higher than 140/90 mmHg at screening
- •A mean heart rate outside the range 40-90 bpm inclusive at screening
- •History of use of tobacco- or nicotine-containing products within 6 months of screening, and/or positive urine cotinine test results at screening
- •Where participation in the study would result in donation of blood in excess of 500mL within a 56 day period at screening
- •The subject is currently taking regular (or a course of) medication, whether prescribed or not, including herbal remedies such as St John's Wort etc.
- •The subject has taken:
- •prescription medications for 14 days prior to first dose of study drug, or
- •Over-the-counter (OTC) medications/preparations (including herbal remedies, etc.) excluding simple analgesics for 48 hours prior to first dose of study drug,unless it is judged by the Investigator not to compromise the subject's safety or influence the outcome of the study.
- •The subject has participated in a study with a new molecular entity or any other trial within a period of 3 months prior first dose of study drug
- •The subject has tested positive for hepatitis C antibody (third generation enzyme immunoassay), hepatitis B surface antigen or HIV antibodies (if tested according to site SOP's) at screening.
- •The subject has tested positive for drugs-of-abuse at screening
- •The subject has tested positive for urine alcohol (including ethanol) at screening The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study
- •The subject is unable to use the DISKUS™ and/or HandiHaler inhaler devices correctly at screening
- •The subject has a suspected history of alcohol abuse within the six months previous to the screening visit
- •The subject has a known allergy or hypersensitivity to magnesium stearate, milk protein or the excipient lactose monohydrate, iodine, ipratropium bromide, tiotropium bromide, atropine and/or any of its derivatives
- •The subject has a significant clinical history of prostatic hypertrophy or narrow angle glaucoma
- •The subject has received an allogeneic bone marrow transplant
- •The subject has claustrophobia that may be aggravated by entering the whole body plethysmography cabinet
研究组 & 干预措施
All subjects
Eligible subjects will receive one of the following treatment in cohort I and cohort II in five different treatment periods; Placebo, GSK1160724 (10 micrograms, 50 micrograms or 125 micrograms) and tiotropium bromide
干预措施: GSK1160724 (Drug)
All subjects
Eligible subjects will receive one of the following treatment in cohort I and cohort II in five different treatment periods; Placebo, GSK1160724 (10 micrograms, 50 micrograms or 125 micrograms) and tiotropium bromide
干预措施: Tiotropium bromide (Drug)
All subjects
Eligible subjects will receive one of the following treatment in cohort I and cohort II in five different treatment periods; Placebo, GSK1160724 (10 micrograms, 50 micrograms or 125 micrograms) and tiotropium bromide
干预措施: Placebo (Drug)
结局指标
主要结局
Number of subjects with adverse events (AEs)
时间窗: Up to Week 24
An AE is any untoward medical occurrence in a clinical study subjects, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.
Forced vital capacity (FVC)
时间窗: Up to Week 24
Lung function will be measured by FVC, defined as the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible.
Number of subjects with abnormal values for urinalysis
时间窗: Up to Week 24
Urinalysis will be performed as a measure of safety.
Number of subjects with abnormal values for blood pressure
时间窗: Up to Week 24
Systolic and diastolic blood pressure will be measured in a semi-recumbent position after 5 minutes rest.
Number of subjects with abnormal electrocardiogram (ECG) findings
时间窗: Up to Week 24
Triplicate 12-lead ECGs will be measured in a semi-recumbent position after 5 minutes rest at each time point using ECG machine.
Number of subjects with abnormal findings after holter monitoring
时间窗: Up to 24 hour
Holter monitoring will be conducted at 24 hour.
Maximum value for resting ECG over 0-4 hour
时间窗: Up to 4 hours
Maximum value for resting ECG over 0-4 hour will be determined.
Forced expiratory volume in 1 second (FEV1)
时间窗: Up to Week 24
Lung function will be measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second.
Number of subjects with abnormal clinical chemistry parameters
时间窗: Up to Week 24
Clinical parameters will be assessed as a measure of safety.
Maximum value for resting heart rate over 0-4 hour
时间窗: Up to 4 hours
Maximum value for heart rate over 0-4 hour will be determined.
Number of subjects with abnormal values for heart rate
时间窗: Up to Week 24
Heart rate will be measured in a semi-recumbent position after 5 minutes rest.
Weighted mean of resting blood pressure over 0-4 hour
时间窗: Up to 4 hours
Weighted mean for resting systolic and diastolic blood pressure over 0-4 hour will be determined.
Number of subjects having abnormal hematology laboratory parameters
时间窗: Up to Week 24
Hematology parameters will be assessed as a measure of safety.
Maximum value for resting blood pressure over 0-4 hour
时间窗: Up to 4 hours
Maximum value for resting systolic and diastolic blood pressure over 0-4 hour will be determined.
Weighted mean of resting heart rate over 0-4 hour
时间窗: Up to 4 hours
Weighted mean for resting heart rate over 0-4 hour will be determined.
Weighted mean of resting ECG over 0-4 hour
时间窗: Up to 4 hours
Weighted mean for resting resting ECG over 0-4 hour will be determined.
次要结局
- Plasma concentrations of GSK1762245(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- Plasma concentrations of GSK1160724(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- Urine concentrations of GSK1160724(0-2 hours, 2-8 hours, 8-12 hours and 12-24 hours)
- Maximum observed concentration (Cmax) of GSK1160724(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- Time to Cmax (Tmax) of GSK1160724(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- Lambda z of GSK1762245(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- Cmax of GSK1762245(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- Tmax of GSK1762245(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- Time to last observed plasma concentration (Tlast) of GSK1160724(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- Urine concentrations of GSK1762245(0-2 hours, 2-8 hours, 8-12 hours and 12-24 hours)
- Area under the plasma concentration time curve from time 0 to last time of quantifiable concentration (AUC [0-T]) of GSK1160724(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- Tlast of GSK1762245(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- AUC (0-T) of GSK1762245(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- Area under the plasma concentration time curve from time 0 to infinity (AUC [0-infinity]) of GSK1160724(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- The terminal phase elimination rate constant (Lambda z) of GSK1160724(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- The Terminal phase half life (T1/2) of GSK1160724(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- FVC over 24 hours post-dose of GSK1160724 and tiotropium bromide(Up to 24 hours)
- AUC (0-infinity) of GSK1762245(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- T1/2 of GSK1762245(Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose)
- Serial specific airway conductance (sGaw) response over 24 hours post-dose of GSK1160724 and tiotropium bromide(Up to 24 hours)
- FEV1 over 24 hours post-dose of GSK1160724 and tiotropium bromide(Up to 24 hours)
- Serial sGaw measurements over 48 hours of GSK1160724 and tiotropium bromide(Up to 48 hours)