A Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Compare GW766944 (an Oral CCR3 Receptor Antagonist) Versus Placebo in Patients With Asthma and Sputum Eosinophilia.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Number of eosinophils (absolute cell count) in induced sputum
研究概览
简要总结
GW766994 is a selective, competitive antagonist of the human CC chemokine receptor-3 (CCR3). It is proposed that the inhibition of the CCR3 receptor may provide a treatment for airway inflammation such as in asthma. This will be a double-blind, placebo controlled, parallel group study being conducted to evaluate the effects of GW766994 in subjects with mild-moderate asthma who have high sputum eosinophilia. The primary objective is to compare the effects of GW766994 to placebo on sputum eosinophils.
详细描述
This will be a multi-centre study. This is a randomized, double-blind, placebo-controlled, parallel-group study, in patients with asthma and eosinophilic bronchitis. Subjects with asthma will be atopic and not on oral prednisone. Inhaled corticosteroids are allowed if on stable dose. All subjects will receive a 5 day course of 30mg daily of oral prednisone after one week stopping study drug.
All subjects will attend screening (Visit 1) at which their eligibility for inclusion will be assessed. Eligible subjects will be randomized to receive either 300 mg of GW766994 twice daily or matching placebo at Day 1 (Visit 2) and will be stratified according to the subject's sputum eosinophil count at Visit 1. Treatment will be 10 days of oral dosing, and subjects will participate in a Day 7 or 8 visit (Visit 3), Day 10 visit (Visit 4 - End of Treatment), followed by a 1 week wash out period (Visit 5 -Follow Up Visit). At Visit 5, all subjects will be given 30 mg oral daily prednisone for 5 days and subjects to return to clinic at a Post Oral Prednisone Visit (Visit 6) at Day 22.
Pharmacodynamic assessments will include both sputum and blood biomarkers and spirometry.
Safety will be assessed by vital sign measurement, electrocardiogram, clinical laboratory tests (hematology, chemistry & urinalysis), clinical monitoring and adverse event reporting. Pharmacokinetic samples will be collected from each subject according to the sample schedule in the timing and events table.
Study will involved sputum biology (progenitors, cell counts). Study will be conducted in Canada only.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Physician diagnosis of asthma (>12% improvement in FEV1 with a bronchodilator or PC20 methacholine less than 8 mg/ml) documented within the past 2 years.
- •Males and females aged ≥18-75 years inclusive.
- •A female subject is eligible to participate if she is of:
- •Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory].
- •Child-bearing potential and agrees to use one of the contraception methods listed in Section 9.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until 2 days after the last dose of GW
- •Non smoker. Current smokers with a with a pack history of less than 10 years may be enrolled into the study. Subjects who only use chewing tobacco products may be enrolled at the discretion of the Investigator and after consultation with the GSK medical monitor.
- •Sputum eosinophils >4.9%.
- •AST, ALT, alkaline phosphatase and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
- •QTcB or QTcF < 450 msec assessed within 6 months of the screening visit.
- •To be eligible, female patients must have a negative urine pregnancy test.
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- •The subject is able to understand and comply with protocol requirements, instructions and protocol- stated restrictions.
排除标准
- •Any clinically relevant abnormality identified on the screening medical assessment, laboratory examination, or ECG.
- •Current smokers.
- •Subjects unable to produce a technically acceptable sputum sample.
- •Sputum TCC >25 million cells/g.
- •Clinically significant hepatic impairment or current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
- •Positive HIV, Hepatitis B surface antigen or Hepatitis C antibody within 3 months of screening.
- •The subject regularly drinks more than 28 units of alcohol in a week, if male or 21 units per week, if female. One unit of alcohol is defined as a medium (125ml) glass of wine, half a pint (250ml) of beer, or one measure (25ml) of spirits.
- •Pregnant and lactating women.
- •Asthma considered unstable within 2 months prioir to screening.
- •Respiratory Infection: Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within the 4 weeks before screening and led to a change in asthma management, or in the opinion of the Investigator is expected to affect the subjects asthma status or the subjects ability to participate in the study.
- •Baseline post-bronchodilator FEV1 <50% predicted (spirometry to be done at screening visit).
- •Regular oral prednisone use.
- •Subjects who have received therapy with monoclonal antibodies within the proceeding 3 months prior to screening visit.
- •Co-morbidities that, in the investigator's opinion may interfere with study including systemic inflammatory conditions such as rheumatoid arthritis.
- •Donation of blood in excess of 500 mL within a 56-day period prior to dosing
- •Participation in a trial with any drug within 30 days or 5 half-lives (whichever is longer), or participation in a trial with a new chemical entity within 2 months prior to first dose of current study medication, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety.
- •The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened but not limited to amphetamines, barbiturates, cocaine, opiates, and cannabinoids.
- •Subjects who use benzodiazepines or other anxiolytic on a regular basis can be included at the discretion of the investigator and in consultation with the GSK medical monitor.
- •Cytochrome P450 3A4 inhibitors including but not limited to antiretrovirals (protease inhibitors) (e.g.indinavir, nelfinavir, ritonavir, saquinavir); imidazole and triazole anti-fungals (e.g.
- •ketaconazole, itraconazole); macrolide antibiotics (e.g. clarithromycin, erytrhomycin and; telithromycin); calcium channel blockers (diltiazem and verapamil) and nefazodone, 6 weeks before.
- •Consumption of seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication.
- •Unwillingness or inability to follow the procedures outlined in the protocol.
研究组 & 干预措施
GW766944
This is the active drug (GW766944)
干预措施: GW766944 (Drug)
Placebo
Placebo Arm.
干预措施: Placebo (Other)
结局指标
主要结局
Number of eosinophils (absolute cell count) in induced sputum
时间窗: Day 10
Sputum was collected according to the Hargreave/Nair Sputum Induction procedures.Each site performed their sputum analysis locally. Sputum induction for eosinophils was carried out at screening and Day 10. The absolute cell count of eosinophils in induced sputum has been presented.
Number of eosinophils (absolute cell count) in induced sputum following predisone
时间窗: Day 22
Sputum was collected according to the Hargreave/Nair Sputum Induction procedures. Each site performed their sputum analysis locally. At Visit 5 (Day 17), all participants were given 30 mg oral daily prednisone for 5 days and participants returned to clinic at a Post Oral Prednisone Visit (Visit 6) at Day 22. Sputum induction for eosinophils was carried out at screening and Post Oral Prednisone Visit (Day 22). The absolute cell count of eosinophils in induced sputum has been presented.
Number of eosinophils (percentage count) in induced sputum
时间窗: Day 10
Sputum was collected according to the Hargreave/Nair Sputum Induction procedures. Each site performed their sputum analysis locally. Sputum induction for eosinophils was carried out at screening and Day 10. Percentage count of eosinophils in induced sputum has been presented.
Number of eosinophils (percentage count) in induced sputum following prednisone
时间窗: Day 22
Sputum was collected according to the Hargreave/Nair Sputum Induction procedures. Each site performed their sputum analysis locally. At Visit 5, all participants were given 30 mg oral daily prednisone for 5 days and participants returned to clinic at a Post Oral Prednisone Visit (Visit 6) at Day 22. Sputum induction for eosinophils was carried out at screening and Post Oral Prednisone Visit (Day 22). Percentage count of eosinophils in induced sputum has been presented.
次要结局
- Number of eosinophils (absolute cell count) in blood(Day 10)
- Number of eosinophils (absolute cell count) in blood following prednisone(Day 22)
- Eosinophil progenitors in sputum and blood(Day 1, Day 10)
- Chemotactic effect of sputum supernatant on eosinophils(Day 10)
- Provocative concentration of methacholine resulting in a 20 percent reduction (PC 20) in forced expiratory volume in 1 second (FEV1).(Day 10)
- Change from baseline in forced expiratory volume in 1 second (FEV1)(From Baseline (Day 1) to Day 10 and Day 17)
- Change from baseline in FEV1 following prednisone(Baseline (Day 1) to Day 22)
- Assessment of asthma stability using Asthma Control Questionnaire (ACQ)(Day 1 and Day 10)
- Number of participants with adverse events (AEs) and serious adverse events (SAEs)(From start of first dose of study drug, Day 1 to upto Day 17)
- Number of participants with AEs and SAEs following prednisone(From start of first dose of study drug Day 1 up to follow-up Day 22)
- Assessment of vital sign systolic blood pressure (SBP) and diastolic blood pressure (DBP)(Upto Day 22)
- Assessment of vital sign heart rate(Upto Day 22)
- Number of participants with abnormal electrocardiogram (ECG) findings(Day 1 and Day 10)
- Assessment of clinical chemistry parameters albumin and Total protein(Day 10)
- Assessment of clinical chemistry parameters albumin and Total protein following prednisone(Day 22)
- Assessment of clinical chemistry parameters creatinine and uric acid(Day 10)
- Assessment of clinical chemistry parameters creatinine and uric acid following prednisone(Day 22)
- Assessment of hematology parameters basophils, eosinophils, lymphocytes, monocytes, total absolute neutrophil count (TANC),platelet count (PC),white blood cell count (WBC)(Day 10)
- Assessment of hematology parameters basophils, eosinophils, lymphocytes, monocytes, TANC, PC, WBC following prednisone(Day 22)
- Assessment of clinical chemistry parameters calcium, chloride ,carbon dioxide content/bicarbonate, glucose, potassium, sodium ,Urea /Blood urea nitrogen (BUN)(Day 10)
- Assessment of clinical chemistry parameters calcium, chloride ,carbon dioxide content/bicarbonate, glucose, potassium, sodium ,Urea / BUN following prednisone(Day 22)
- Assessment of hematology parameters hemoglobin and mean corpuscle hemoglobin concentration (MCHC)(Day 10)
- Assessment of hematology parameters hemoglobin and MCHC following prednisone(Day 22)
- Assessment of hematology parameter hematocrit(Day 10)
- Assessment of hematology parameter hematocrit following prednisone(Day 22)
- Assessment of hematology parameter mean corpuscle hemoglobin (MCH)(Day 10)
- Assessment of hematology parameter MCH following prednisone(Day 22)
- Assessment of hematology parameter mean corpuscle volume (MCV)(Day 10)
- Assessment of hematology parameter MCV following prednisone(Day 22)
- Assessment of hematology parameter red blood cell count (RBC)(Day 10)
- Assessment of hematology parameter RBC following prednisone(Day 22)
- Assessment of liver function tests (LFTs) alkaline phosphatase, alanine amino transferase (ALT), aspartate amino transferase (AST) and gamma glutamyl transferase (GGT) as a measure of monitoring liver toxicity(Upto Day 17)
- Assessment of LFTs alkaline phosphatase, ALT, AST and GGT as a measure of monitoring liver toxicity following prednisone(Day 22)
- Assessment of LFTs direct bilirubin and total bilirubin as a measure of monitoring liver toxicity.(Upto Day 17)
- Assessment of LFTs direct bilirubin and total bilirubin as a measure of monitoring liver toxicity following prednisone(Day 22)
- Assessment of plasma concentrations of GW766994 Pre-dose Day 7 (Visit 3) and Day 10 (Visit 4)(Pre-dose Day 7 (Visit 3) and Day 10 (Visit 4))
- Assessment of plasma concentrations of GW766994 1 hours post-dose on Day 1 (Visit 2), Day 7 (Visit 3) and Day 10 (Visit 4)(Day 1 (Visit 2), Day 7 (Visit 3) and Day 10 (Visit 4))