A Randomized, Open-label, 2-Way-Crossover Study Assessing the Bioequivalence Between Single Doses of 500 mg Glucophage Extended Release (GXR) Tablets (Merck/China Nantong-Manufactured) and 500 mg GXR Tablets (Merck/Germany Darmstadt-Manufactured) Under Fed and Fasted State in Two Groups of Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 54
- 试验地点
- 1
- 主要终点
- Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin
研究概览
简要总结
The study will assess the bioequivalence between single doses of GXR manufactured in Merck Nantong China (test drug) and GXR manufactured in Merck Darmstadt Germany (reference drug) under fed and fasted state in healthy participants.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 盲法
- None
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
- •Overtly healthy as determined by medical evaluation, including medical history and a physical examination
- •Have a body weight within 50 to 90 kilogram (kg) and Body mass index (BMI) within the range 18 to 30 kg per meter square (kg/m^2) (inclusive)
- •Chinese male and female (at least 1/4 of each gender per study group)
- •A male participant must agree to use and to have their female partners use a highly effective contraception (that is, methods with a failure rate of less than 1 percent per year) for a period of at least 1 month before and after dosing
- •A female is eligible if she is not pregnant (that is, after a confirmed menstrual period and a negative serum pregnancy test), not breastfeeding, and at least one of the following conditions applies
- •Is not a woman of childbearing potential (WOCBP) OR
- •Is a WOCBP who agrees to use a highly effective contraceptive method (that is, has a failure rate of less than 1 percent per year) for a period of at least 1 month before and after dosing
- •Can give signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol
- •Non-smoker (0 cigarettes, pipes, cigars, or others) since at least 3 months
- •All values for biochemistry and hematology tests of blood and urine within the normal range or showing no clinically relevant deviation as judged by the Investigator
- •Electrocardiogram recording (12 lead ECG) without signs of clinically relevant pathology as judged by the Investigator.
- •Pulse, body temperature, and respiration in sitting position within the normal range or showing no clinically relevant deviation as judged by the Investigator. Blood pressure in sitting position within normal range: greater than or equals to (>=) 90 millimeter of mercury (mmHg) and less than or equal to (=<) 139 mmHg for systolic blood pressure; >= 60 mmHg and =< 90 mmHg for diastolic blood pressure
- •Negative screen for alcohol and drugs of abuse (cannabis, benzodiazepines, barbiturates, opiates, cocaine, and methyl amphetamine) at screening and on admission
- •Negative screen for hepatitis A virus (HAV) antibodies, hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies, human immunodeficiency virus (HIV) antibodies, and Treponema pallidum (TP) antibodies
排除标准
- •Participation in a clinical trial within 90 days prior to first drug administration
- •Blood donation (equal or more than 500 milliliter [mL]) or significant blood loss within 90 days prior to first drug administration
- •Any surgical or medical condition, including findings in the medical history or in the pre-study assessments, or any other significant disease, that in the opinion of the Investigator, constitutes a risk or a contraindication for the participation of the participant in the study or that could interfere with the study objectives, conduct or evaluation
- •History of surgery of the gastrointestinal tract which could influence the gastrointestinal absorption and/or motility according to the Investigator's opinion
- •History or presence of relevant liver diseases or hepatic dysfunction.
- •Allergy: ascertained or presumptive hypersensitivity to the active drug substance and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the Investigator considers may affect the outcome of the study
- •Receipt of any prescription or non-prescription medication within 2 weeks before the first Investigational medicinal product (IMP) administration, including multivitamins and herbal products (that is St John's Wort, or traditional Chinese medicines), except for the permitted medications
- •Renal failure or renal dysfunction (creatinine clearance [Ccr] < 80 mL/minute) as assessed by using the estimated measure with the Cockcroft-Gault equation.
- •Known lack of participant compliance or inability to communicate or cooperate with the Investigator (example, language problem, poor mental status)
- •Non-acceptance of study high-fat breakfast (example, vegetarians, vegans and participants who follow special diets)
- •Consumption of large quantities of methylxanthine-containing beverages (>5 cups of coffee/day or equivalent)
- •Consumption of grapefruit, cranberry, or juices of these fruits, from 14 days prior to drug administration until collection of the last Pharmacokinetics sample in Period 2
- •Any contraindication to Glucophage
- •Abnormal and clinically significant chest X-ray finding at screening
研究组 & 干预措施
First Test GXR (Fasting), Then Reference GXR (Fasting)
Participants received a single oral dose of 500 milligrams (mg) of test GXR tablet (Merck Nantong/China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GXR (Merck Darmstadt/Germany) on Day 8 in treatment period 2 under fasting conditions. There was a wash-out period of 7 days between each treatment period.
干预措施: Test GXR (Drug)
First Test GXR (Fasting), Then Reference GXR (Fasting)
Participants received a single oral dose of 500 milligrams (mg) of test GXR tablet (Merck Nantong/China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GXR (Merck Darmstadt/Germany) on Day 8 in treatment period 2 under fasting conditions. There was a wash-out period of 7 days between each treatment period.
干预措施: Reference GXR (Drug)
First Reference GXR (Fasting), Then Test GXR (Fasting)
Participants received a single oral dose of 500 mg of reference GXR tablet (Merck Darmstadt/Germany) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GXR (Merck Nantong/China) on Day 8 in treatment period 2 under fasting conditions. There was a wash-out period of 7 days between each treatment period.
干预措施: Test GXR (Drug)
First Reference GXR (Fasting), Then Test GXR (Fasting)
Participants received a single oral dose of 500 mg of reference GXR tablet (Merck Darmstadt/Germany) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GXR (Merck Nantong/China) on Day 8 in treatment period 2 under fasting conditions. There was a wash-out period of 7 days between each treatment period.
干预措施: Reference GXR (Drug)
First Test GXR (Fed), Then Reference GXR (Fed)
Participants received a single oral dose of 500 mg of test GXR tablet (Merck Nantong/China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GXR (Merck Darmstadt/Germany) on Day 8 in treatment period 2 under fed conditions. There was a wash-out period of 7 days between each treatment period.
干预措施: Test GXR (Drug)
First Test GXR (Fed), Then Reference GXR (Fed)
Participants received a single oral dose of 500 mg of test GXR tablet (Merck Nantong/China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GXR (Merck Darmstadt/Germany) on Day 8 in treatment period 2 under fed conditions. There was a wash-out period of 7 days between each treatment period.
干预措施: Reference GXR (Drug)
First Reference GXR (Fed), Then Test GXR (Fed)
Participants received a single oral dose of 500 mg of reference GXR tablet (Merck Darmstadt/Germany) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GXR (Merck Nantong/China) on Day 8 in treatment period 2 under fed conditions. There was a wash-out period of 7 days between each treatment period.
干预措施: Test GXR (Drug)
First Reference GXR (Fed), Then Test GXR (Fed)
Participants received a single oral dose of 500 mg of reference GXR tablet (Merck Darmstadt/Germany) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GXR (Merck Nantong/China) on Day 8 in treatment period 2 under fed conditions. There was a wash-out period of 7 days between each treatment period.
干预措施: Reference GXR (Drug)
结局指标
主要结局
Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin
时间窗: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.
Maximum Observed Plasma Concentration (Cmax) of Metformin
时间窗: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10
Pharmacokinetic (PK) parameter Cmax was obtained directly from the concentration versus time curve.
次要结局
- Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Metformin(Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10)
- Elimination Rate Constant (Lambda z) of Metformin(Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10)
- Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUCextra) of Metformin(Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10)
- Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin(Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs(Time from informed consent up to end of study (Day 15))
- Total Body Clearance (CL/f) of Metformin(Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10)
- Number of Participants With Clinically Significant Abnormalities in Vital Signs(Time from informed consent up to end of study (Day 15))
- Number of Participants With Clinically Significant Abnormalities in Laboratory Values(Time from informed consent up to end of study (Day 15))
- Number of Participants With Clinically Significant Abnormalities in Physical Examination Findings(Time from informed consent up to end of study (Day 15))
- Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings(Time from informed consent up to end of study (Day 15))
- Time to Reach Maximum Plasma Concentration of Metformin(Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10)
- Apparent Terminal Half-Life (t1/2) of Metformin(Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10)