NCT01262898已完成2 期
A Randomized, Double-Blind, Placebo-Controlled Multicenter Phase II Study to Evaluate the Safety and Efficacy and Dose Response of 28 Days of Once-Daily Dosing of the Oral Motilin Receptor Agonist GSK962040, in Type I and II Diabetic Male and Female Subjects With Gastroparesis
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 79
- 试验地点
- 1
- 主要终点
- Gastric Half Emptying Time (GEt1/2)
研究概览
简要总结
GSK962040 is a novel small molecule motilin agonist. The Phase I studies (MOT107043 and MOT109681) demonstrated that single doses of GSK962040 up to 150 mg and repeat dosing of up to 125 mg/day for 14 days were well tolerated with adverse events not occurring in greater prevalence than placebo, and no significant abnormal vital sign, ECG, or clinical laboratory findings. Pharmacokinetic parameters were linear and approximately dose proportional over the range of doses administered. Single doses of 50 mg - 150 mg GSK962040 significantly increased the rate of gastric emptying up to 40% as measured by the 13C octanoic acid stable isotope breath test. A similar effect of 50 mg and 125 mg on gastric emptying was observed throughout repeated dosing to healthy volunteers for 14-days.
The aims of the present investigation (MOT114479) are to assess the pharmacodynamic effects (gastric emptying and symptoms), safety, tolerability, and pharmacokinetics of GSK962040 after 28 days of once-daily dosing in Type I and Type II diabetic subjects with gastroparesis. An additional aim is to characterize the dose/exposure - pharmacodynamic effect relationship.
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, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Type I or II Diabetes Mellitus (HbA1C < 10%)
- •Male or female between 18 and 80 years of age, inclusive.
- •Patient has gastroparesis at screening (gastric half-time of emptying > upper limit of normal as determined by 13C-oral breath test)
- •Patient must have a > or = 3 month history of relevant symptoms of gastroparesis (e.g., chronic post-prandial fullness, early satiety, postprandial nausea), patients will have a mean of the daily scores over a minimum of 7 days indicating > or = mild (2) and < or = severe (4) post-prandial fullness assessed using the GCSI-DD during the screening period prior to randomization.
- •A female patient 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, or a value consistent with the local laboratory standard value, is confirmatory. OR Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 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 patients must agree to use contraception for at least 5 days following the last dose of study medication.
- •Male patients must agree to use one of the contraception methods listed in Section 8.
- •This criterion must be followed from the time of the first dose of study medication through at least 5 days after the last dose of study medication.
- •BMI >18 and < or = 35.0 kg/m2 (inclusive).
- •Patient has never had a gastrectomy, nor major gastric surgical procedure or any evidence of bowel obstruction or strictures within the previous 12 months
- •Dosage of any concomitant medications has been stable for at least 3 weeks, except for routine adjustments in daily insulin treatments.
- •Estimated (or measured) glomerular filtration rate > or = 30 mL/min.
- •QTcB or QTcF < 450 msec or QTc < 480 msec in patients with Bundle Branch Block based on single or average QTc value of triplicate values obtained over a brief recording period.
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- •AST and ALT < 2xULN; alkaline phosphatase and bilirubin < or = 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
排除标准
- •Patient has acute severe gastroenteritis
- •Patient has a gastric pacemaker
- •Patient is on chronic parenteral feeding
- •Patient has pronounced dehydration
- •Recent (last 6 weeks) history of poor control of diabetes e.g. hypoglycaemia requiring medical intervention, diabetic ketoacidosis, admission for control diabetes or complications of diabetes
- •Patient has evidence of severe cardiovascular autonomic neuropathy (e.g. history of recurrent syncope in the last 6 months)
- •Patient has a history of eating disorders (anorexia nervosa, binge eating, bulimia)
- •Use of medications potentially influencing upper gastrointestinal motility or appetite within one week of the study (e.g., prokinetic drugs, macrolide antibiotics (erythromycin), GLP-1 mimetics)
- •Regular opiate use
- •Use of prohibited medications listed in Section 9.2 within the restricted timeframe relative to the first dose of study medication.
- •History or presence of clinically significant gastro-intestinal, hepatic or renal disease or other condition that would in the opinion of the investigator or medical monitor make the subject unsuitable for inclusion in this clinical study.
- •The patient 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: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- •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 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 mL within a 56 day time-period.
- •Pregnant females as determined by positive serum or urine hCG test (from the first urine of the day) at screening or prior to dosing.
- •Lactating females.
- •Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
研究组 & 干预措施
GSK962040 (10 mg)
Experimental
GSK962040 10 mg
干预措施: GSK962040 (5 mg tablet) (Drug)
GSK962040 (50 mg)
Experimental
GSK962040 50 mg
干预措施: GSK962040 (25 mg tablet) (Drug)
GSK962040 (125 mg)
Experimental
GSK962040 125 mg
干预措施: GSK962040 (125 mg tablet) (Drug)
Placebo
Experimental
Placebo
干预措施: GSK962040 (5 mg tablet) (Drug)
Placebo
Experimental
Placebo
干预措施: GSK962040 (25 mg tablet) (Drug)
Placebo
Experimental
Placebo
干预措施: GSK962040 (125 mg tablet) (Drug)
Placebo
Experimental
Placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Gastric Half Emptying Time (GEt1/2)
时间窗: Screening2/Baseline (Day -30 to -1) , Day 1, and Day 28
Gastric half emptying time is the time taken for half the contents of the stomach to empty. Gastric emptying was measured using the 13C-oral breath test, which is a tracer method that utilizes 13C, a non-radioactive isotope. Basal breath samples were obtained after an overnight fast or otherwise after 4 hours of fasting following a light meal. On Day 1 and Day 28, participants were then dosed with GSK962040 and additional breath test samples were taken prior to administration of a 13C-labelled test meal. The test meal was consumed approximately 80 minutes(min) later. After consumption of the test meal, breath samples were collected at pre-specified time points over an approximately 4 hour period following the test meal. For the duration of the breath test, no food or drink were allowed. The 13C breath content was determined by isotope ratio mass spectrometry. GE t1/2 was determined by using the cumulative percentage of the administered dose of 13C excreted in breath over 4 hours.
次要结局
- Number of Participants With On-treatment Adverse Events (AES) and Serious Adverse Events(SAEs)(Up to follow-up (5-10 days post last dose))
- Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure(DBP) at Specified Time Points in Semi-supine Position(Baseline, Day 1, and Day 8)
- Change From Baseline in Heart Rate at Specified Time Points in Semi-supine Position(Baseline, Day 1, and Day 8)
- Change From Baseline in Electrocardiography Parameters (12-lead ECG)(Baseline, Day 1 and Day 28)
- Number of Participants Outside the Normal Range for SBP and DBP(Screening2/Baseline (Day -30 to -1), Day 1 and 28)
- Number of Participants Outside the Normal Range for Heart Rate(Screening2/Baseline (Day -30 to -1), Day 1 and 28)
- Number of Participants Outside the Normal Range for 12-lead ECG(Baseline (Day 1 pre-dose), Day 1, Day 14 and Day 28)
- Mean Change From Baseline in Clinical Chemistry: Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Gamma Glutamyl Transferase, Creatine Kinase, Lactate Dehydrogenase(Baseline (Day 1 pre-dose), Day 5, 10, 14, 21 and 28)
- Mean Change From Baseline in Clinical Chemistry: Direct Bilirubin, Total Bilirubin, Creatinine, Uric Acid(Baseline (Day 1 pre-dose), Day 5, 10, 14, 21 and 28)
- Mean Change From Baseline in Clinical Chemistry : Albumin, Total Protein(Baseline (Day 1 pre-dose) and Day 28)
- Mean Change From Baseline in Clinical Chemistry : Calcium, Chloride, Glucose, Potassium, Sodium, Urea/BUN, Carbon Dioxide Content/Bicarbonate(Baseline (Day 1 pre-dose) and Day 28)
- Mean Change From Baseline in Hematology Parameters : Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Total ANC - Total Absolute Neutrophil Count), Platelet Count, White Blood Cell Count(Baseline (Day 1 pre-dose) and Day 28)
- Mean Change From Baseline in Hematology Parameters : Hematocrit(Baseline (Day 1 pre-dose) and Day 28)
- Mean Change From Baseline in Hematology Parameters : Mean Corpuscle Hemoglobin(Baseline (Day 1 pre-dose) and Day 28)
- Mean Change From Baseline in Hematology Parameters : Hemoglobin, Mean Corpuscle Hemoglobin Concentration(Baseline (Day 1 pre-dose) and Day 28)
- Mean Change From Baseline in Hematology Parameters : Mean Corpuscle Volume(Baseline (Day 1 pre-dose) and Day 28)
- Mean Change From Baseline in Hematology Parameters : Red Blood Cell Count, Reticulocytes(Baseline (Day 1 pre-dose) and Day 28)
- Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration AUC(0-t) at Specified Time Points(Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28)
- Maximum Observed Concentration (Cmax) at Specified Time Points(Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28)
- Time of Occurrence of Cmax (Tmax) at Specified Time Points(Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28)
- Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ct) at Specified Time Points(Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28)
- Apparent Clearance Following Oral Dosing (CL/F) at Specified Time Points(Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28)
- Apparent Volume of Distribution (V/F) at Specified Time Points(Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28)
- Apparent Terminal Elimination Half-life (t1/2) at Specified Time Points(The parameter was planned to be analyzed using samples collected at Pre-dose and 1.5, 2.5, 3.5, 4.5, and 5.5 hours post dose on Day 1 and 28, however, the data for this outcome measure was not collected.)
- Time to First Bowel Movement After First Dose(Up to Day 28)
- Daily Bowel Movement Frequency(Up to Week 4 (Day 28))
- Daily Average Stool Consistency(Up to Week 4 (Day 28))
- Change From Baseline in Upper Gastrointestinal (GI) Symptoms as Assessed by Total Gastrointestinal Cardinal Symptom Index - Daily Diary (GCSI-DD)(Up to 14 days post last dose (Day 28))
- Change From Baseline in Whole Bowel Transit Time, 100 % Gastric Emptying Time (Truncated at 240 Minutes), Small Bowel Transit Time, Colonic Transit Time as Determined by Wireless Motility Capsule (WMC)(Baseline(Screening i.e., Day -30 to -1), Day 1 and 28)
研究者
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