A Phase 1 Placebo-controlled Trial To Assess The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Multiple Escalating Oral Doses Of Pf-04937319 In Adult Patients With Type 2 Diabetes Mellitus (t2dm)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 61
- 试验地点
- 4
- 主要终点
- Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
The purpose of this study is to characterize the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-04937319 following multiple (14 days) escalating oral doses in patients with type 2 diabetes.
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
- Double (Participant, Investigator)
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
- •Patients with type 2 diabetes mellitus who are taking metformin only.
- •Treatment should be stable, where this is defined as no change in the treatment, including dose, over the past 2 months. Regimens may include once daily and twice daily dosing only.
- •Male and/or female patients (females will be women of non childbearing potential)
- •Body Mass Index (BMI) of 18.5 to 45.0 kg/m2; and a total body weight >50 kg (110 lbs).
- •HbA1c between 7.0% and 10.0%.
排除标准
- •Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). Patients who have chronic conditions other than T2DM (for example, hypercholesterolemia or hypertension) but are controlled by either diet or stable (for the last 2 months) doses of medications may be included as well (for example, a subject with hypercholesterolemia on appropriate treatment is eligible).
- •Evidence or history of diabetic complications with significant end organ damage, eg, proliferative retinopathy and/or macular edema, creatinine clearance less than 60 mL/min
- •Any condition possibly affecting drug absorption (eg, gastrectomy)
- •History of stroke or transient ischemic attack or myocardial infarction within the past 6 months
- •History of coronary artery bypass graft or stent implantation.
- •Clinically significant peripheral vascular disease (eg, manifested by claudication).
- •Any history or clinical evidence of congestive heart failure, NYHA Classes II to IV.
- •One or more self reported significant/severe/requiring treatment episodes of hypoglycemia within the last 3 months, or two or more self reported significant/severe/requiring treatment episodes of hypoglycaemia within the last 6 months.
- •Current history of angina/unstable angina.
- •Milk or soy allergy
研究组 & 干预措施
PF-04937319
干预措施: PF-04937319 (Drug)
Placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: Baseline (Day 1) up to 14 days after last dose of study treatment (up to 28 days)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 14 days after last dose that were absent before treatment or that worsened relative to pre-treatment state.
Plasma Decay Half-Life (t1/2) on Day 14
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8, 12, 16, 24, 36, 48 hours post morning dose on Day 14 (fasted condition)
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Observed Accumulation Ratio for AUCtau (Rac)
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8, 12, 16, 24 hours post morning dose on Day 1 and Day 14 (fasted condition)
Accumulation ratio for AUCtau (Rac) was calculated as area under the curve from time zero to end of dosing interval (AUCtau) on Day 14 divided by area under the curve from time zero to end of dosing interval (AUCtau) on Day 1. Dosing interval = 24 hours.
Percent Change From Baseline in Glucose Area Under the Curve From Time 2 to 6 Hours (AUC [2-6]) After a Mixed Meal Tolerance Test (MMTT) at Day 1
时间窗: -46, -45.75, -45.5, -45, -44.5, -44, -43, -42 hrs pre-dose on Day -1; 2, 2.25, 2.5, 3, 3.5, 4, 5, 6 hrs post-dose on Day 1 (fasted condition)
Percent change from baseline in area under the plasma glucose concentration-time curve as determined by standardized MMTT. Linear trapezoidal method was used to compute AUC. Baseline value was the AUC (2-6) calculated on Day -1.
Percent Change From Baseline in Glucose Area Under the Curve From Time 2 to 6 Hours (AUC [2-6]) After a Mixed Meal Tolerance Test (MMTT) at Day 14
时间窗: -46, -45.75, -45.5, -45, -44.5, -44, -43, -42 hrs pre-dose on Day -1; 2, 2.25, 2.5, 3, 3.5, 4, 5, 6 hrs post-dose on Day 14 (fasted condition)
Percent change from baseline in area under the plasma glucose concentration-time curve as determined by standardized MMTT. Linear trapezoidal method was used to compute AUC. Baseline value was the AUC (2-6) calculated on Day -1.
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) on Day 1
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8, 12, 16, 24 hours post morning dose on Day 1 (fasted condition)
AUCtau is the area under the plasma concentration versus time curve from time zero (pre-dose) to the end of the dosing interval (tau), here dosing interval is 24 hours.
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 6
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8 hours post-dose on Day 6 (fed condition)
Maximum Observed Plasma Concentration at Steady State (Cmax, ss) On Day 14
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8, 12, 16, 24 hours post morning dose on Day 14 (fasted condition)
Area Under the Curve From Time Zero to End of Dosing Interval at Steady State (AUCtau, ss) on Day 14
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8, 12, 16, 24 hours post morning dose on Day 14 (fasted condition)
AUCtau, ss = Area under the plasma concentration versus time curve from time zero (pre-dose) to the end of the dosing interval (tau) at steady state, here dosing interval is 24 hours.
Apparent Oral Clearance (CL/F) on Day 14
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8, 12, 16, 24 hours post morning dose on Day 14 (fasted condition)
Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Apparent Volume of Distribution (Vz/F) on Day 14
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8, 12, 16, 24 hours post morning dose on Day 14 (fasted condition)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Maximum Observed Plasma Concentration (Cmax) On Day 1
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8, 12, 16, 24 hours (hrs) post morning dose on Day 1 (fasted condition)
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8, 12, 16, 24 hours post morning dose on Day 1 (fasted condition)
Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax, ss) on Day 14
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8, 12, 16, 24 hours post morning dose on Day 14 (fasted condition)
Minimum Observed Plasma Trough Concentration at Steady State (Cmin, ss) on Day 14
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8, 12, 16 hours post morning dose on Day 14 (fasted condition)
Percentage of Unchanged Drug Excreted in the Urine Over Dosing Interval (Ae[%]) on Day 14
时间窗: 0 hour (pre-dose) through 24 hours post-dose on Day 14
Percentage of drug excreted unchanged in urine calculated as overall amount of unchanged drug excreted in the urine over the dosing interval (24 hours) divided by total daily dose multiplied by 100.
Maximum Observed Plasma Concentration (Cmax) On Day 6
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8 hours post-dose on Day 6 (fed condition)
Observed Accumulation Ratio for Cmax (Rac, Cmax)
时间窗: 0 (pre-dose), 0.5, 1.5, 3, 5, 8, 12, 16, 24 hours post morning dose on Day 1 and Day 14 (fasted condition)
Accumulation ratio for Cmax (Rac, Cmax) was calculated as maximum observed plasma concentration (Cmax) on Day 14 divided by maximum observed plasma concentration (Cmax) on Day 1.
次要结局
- Percent Change From Baseline in C-peptide Area Under the Curve From Time 2 to 6 Hours (AUC [2-6]) After a Mixed Meal Tolerance Test (MMTT) at Day 1 and 14(-46, -45.75, -45.5, -45, -44.5, -44, -43, -42 hrs pre-dose on Day -1; 2, 2.25, 2.5, 3, 3.5, 4, 5, 6 hrs post-dose on Day 1 and 14 (fasted condition))
- Change From Baseline in Total Cholesterol (TC) Level at Day 3, 6, 10, 14, 16 and Follow-up(Baseline (Day -2), Day 3, 6, 10, 14, 16 and Follow-up (7 to 14 days after last dose of study medication))
- Change From Baseline in Low Density Lipoprotein-Cholesterol (LDL-C) Level at Day 3, 6, 10, 14, 16 and Follow-up(Baseline (Day -2), Day 3, 6, 10, 14, 16 and Follow-up (7 to 14 days after last dose of study medication))
- Change From Baseline in Lactate Level at Day 6 and 14(Baseline (Day 1), Day 6 and 14)
- Percent Change From Baseline in Insulin Area Under the Curve From Time 2 to 6 Hours (AUC [2-6]) After a Mixed Meal Tolerance Test (MMTT) at Day 1 and 14(-46, -45.75, -45.5, -45, -44.5, -44, -43, -42 hrs pre-dose on Day -1; 2, 2.25, 2.5, 3, 3.5, 4, 5, 6 hrs post-dose on Day 1 and 14 (fasted condition))
- Change From Baseline in High Density Lipoprotein-Cholesterol (HDL-C) Level at Day 3, 6, 10, 14, 16 and Follow-up(Baseline (Day -2), Day 3, 6, 10, 14, 16 and Follow-up (7 to 14 days after last dose of study medication))
- Change From Baseline in Average Plasma Glucose at Day 1, 6, 14(-46, -44, -42, -40, -38, -36, -30, -27 hrs pre-dose on Day -1; 2, 6, 8, 10, 12,18,21 hrs post-dose on Day 1, 6 and 14; additional 0 hr (pre-dose) on Day 6 and 4 hr post-dose on Day 1 and 14)
- Change From Baseline in Fasting Plasma Glucose at Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15(Baseline (Pre-dose on Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
- Change From Baseline in Triglyceride (TG) Level at Day 3, 6, 10, 14, 16 and Follow-up(Baseline (Day -2), Day 3, 6, 10, 14, 16 and Follow-up (7 to 14 days after last dose of study medication))