A Multicenter, Double-Blind, Randomized Placebo-Controlled Phase II Study to Evaluate the Pharmacodynamics, Safety, Tolerability, and PK of Single Doses of the Oral Motilin Receptor Agonist GSK962040, in Type 1 Diabetic Male and Female Patients With Gastroparesis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- Pharmacokinetic parameters of GSK962040: Cmax, Tmax, AUC(0-t), AUC(0-inf) for single-dose, CL/F, V/F, and, if possible, half-life
研究概览
简要总结
The purpose of this study is to assess the pharmacodynamic effects (gastric emptying), safety, tolerability, and pharmacokinetics of single doses of GSK962040 in Type 1 diabetic patients with gastroparesis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Controlled Type 1 Diabetes Mellitus (glucose < 250 mg/dL) with onset < 30 years of age.
- •Male or female between 18 and 70 years of age, inclusive.
- •Patient has documented diagnosis of moderate to severe gastroparesis (> 30% at 2 h as determined by scintigraphy; or t1/2b > 109 min as determined by 13C-octanoic acid breath test). All of the following apply:
- •Confirmed delayed gastric emptying (properly conducted gastric emptying assessments within last 6 months acceptable) AND a minimum 3 month history of relevant symptoms for gastroparesis (e.g., chronic postprandial fullness, postprandial nausea, vomiting)
- •A female patient is eligible to participate if she is of:
- •Non-childbearing potential
- •Child-bearing potential and agrees to use contraception for at least 4 days following the last dose of study medication.
- •Male patients must agree to use contraception from the time of the first dose of study medication through at least 4 days after the last dose of study medication.
- •Body weight ≤110 kg and BMI < 32.0 kg/m2 (inclusive).
- •Patient has never had a gastrectomy, nor major gastric surgical procedure or any evidence of bowel obstruction 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
- •HbA1c level is ≤ 10.0%
- •Calculated creatinine clearance > or equal to 50 ml/min
- •QTcB or QTcF < 450 msec or QTc<480msec in patients with Bundle Branch Block based on single or average QTc value of triplicate values obtained over a brief recording period.
- •AST, ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
排除标准
- •Patient has acute severe gastroenteritis
- •Patient has a gastric pacemaker
- •Patient is on chronic parenteral feeding
- •Patient has daily persistent severe vomiting
- •Patient has pronounced dehydration
- •Patient has had clinical diabetic ketoacidosis in last 4 weeks
- •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))
- •Patient is taking opiates.
- •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 known to interfere with the absorption, distribution, metabolism or excretion of drugs.
- •Presence of thyroid dysfunction (NOTE: patients with abnormal TSH at screening/baseline are not eligible. Patients with a history of hypothyroidism on a stable dose of thyroid replacement therapy are eligible to participate in the 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 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 or pregnant females.
- •Unwillingness or inability to follow the procedures outlined in the protocol.
- •Patients deemed unable to comply with the procedures outlined in the protocol may be excluded at the Investigator's discretion.
- •For male volunteers: An unwillingness of the male patient to comply with the contraception requirements listed in Section 8.1, from the time of the first dose of study medication until at least 4 days following administration of the last dose of study medication.
- •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
Cohort 1 Period 1
All patients will receive placebo and 2 of the 3 possible doses of GSK962040 in a randomized, double blind, placebo controlled, incomplete block, three period crossover design.
干预措施: GSK962040 25 mg (Drug)
Cohort 1 Period 1
All patients will receive placebo and 2 of the 3 possible doses of GSK962040 in a randomized, double blind, placebo controlled, incomplete block, three period crossover design.
干预措施: Placebo (Drug)
Cohort 1 Period 1
All patients will receive placebo and 2 of the 3 possible doses of GSK962040 in a randomized, double blind, placebo controlled, incomplete block, three period crossover design.
干预措施: GSK962040 50 mg (Drug)
Cohort 1 Period 1
All patients will receive placebo and 2 of the 3 possible doses of GSK962040 in a randomized, double blind, placebo controlled, incomplete block, three period crossover design.
干预措施: GSK962040 1250 mg (Drug)
Cohort 1 Period 2
All patients will receive placebo and 2 of the 3 possible doses of GSK962040 in a randomized, double blind, placebo controlled, incomplete block, three period crossover design.
干预措施: GSK962040 25 mg (Drug)
Cohort 1 Period 2
All patients will receive placebo and 2 of the 3 possible doses of GSK962040 in a randomized, double blind, placebo controlled, incomplete block, three period crossover design.
干预措施: Placebo (Drug)
Cohort 1 Period 2
All patients will receive placebo and 2 of the 3 possible doses of GSK962040 in a randomized, double blind, placebo controlled, incomplete block, three period crossover design.
干预措施: GSK962040 50 mg (Drug)
Cohort 1 Period 2
All patients will receive placebo and 2 of the 3 possible doses of GSK962040 in a randomized, double blind, placebo controlled, incomplete block, three period crossover design.
干预措施: GSK962040 1250 mg (Drug)
Cohort 1 Period 3
All patients will receive placebo and 2 of the 3 possible doses of GSK962040 in a randomized, double blind, placebo controlled, incomplete block, three period crossover design.
干预措施: GSK962040 25 mg (Drug)
Cohort 1 Period 3
All patients will receive placebo and 2 of the 3 possible doses of GSK962040 in a randomized, double blind, placebo controlled, incomplete block, three period crossover design.
干预措施: Placebo (Drug)
Cohort 1 Period 3
All patients will receive placebo and 2 of the 3 possible doses of GSK962040 in a randomized, double blind, placebo controlled, incomplete block, three period crossover design.
干预措施: GSK962040 50 mg (Drug)
Cohort 1 Period 3
All patients will receive placebo and 2 of the 3 possible doses of GSK962040 in a randomized, double blind, placebo controlled, incomplete block, three period crossover design.
干预措施: GSK962040 1250 mg (Drug)
结局指标
主要结局
Pharmacokinetic parameters of GSK962040: Cmax, Tmax, AUC(0-t), AUC(0-inf) for single-dose, CL/F, V/F, and, if possible, half-life
时间窗: 24 h post dose
Safety and tolerability of GSK962040 (Change from baseline in clinical chemistry and hematology parameters)
时间窗: 24 h post dose
Gastric emptying, as measured by the 13C octanoic acid breath test (Gastric half emptying time (t1/2b), Duration of the lag time (tlag), Gastric evacuation coefficient (GEC))
时间窗: 1.5 h post dose to 5.5 h post dose
Safety and tolerability of GSK962040 (Change from baseline and number of patients outside the normal range for blood pressure, heart rate, 12-lead ECG parameters)
时间窗: 2 h post dose
Safety and tolerability of GSK962040 (Adverse events)
时间窗: 6 weeks
次要结局
- Bowel movement parameters (Time to first bowel movement after first dose, Bowel movement count, Stool consistency (Bristol Stool Form scale))(24 h post dose)
- PK/PD relationship of PP, plasma glucagon, GLP-1, and ghrelin after a single dose of GSK962040.(0-6 h post dose)
- Food intake(24 h post dose)
- Plasma glucose(24 h post dose)