Clinical trial NCT03566810: Glucophage Extended Release (GXR) China Bioequivalence Study (Nantong - Darmstadt)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Diabetes Mellitus
Glucophage Extended Release (GXR)
Bioequivalence Study
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2018-06-25
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Metformin
timeFrame: 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
Secondary outcomes:
measure: Time to Reach Maximum Plasma Concentration of Metformin
timeFrame: 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
measure: Apparent Terminal Half-Life (t1/2) of Metformin
timeFrame: 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
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Metformin
timeFrame: 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
measure: Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUCextra) of Metformin
timeFrame: 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
measure: Elimination Rate Constant (Lambda z) of Metformin
timeFrame: 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
measure: Total Body Clearance (CL/f) of Metformin
timeFrame: 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
measure: Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin
timeFrame: 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
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Time from informed consent up to end of study (Day 15)
measure: Number of Participants With Clinically Significant Abnormalities in Vital Signs
timeFrame: Time from informed consent up to end of study (Day 15)
measure: Number of Participants With Clinically Significant Abnormalities in Laboratory Values
timeFrame: Time from informed consent up to end of study (Day 15)
measure: Number of Participants With Clinically Significant Abnormalities in Physical Examination Findings
timeFrame: Time from informed consent up to end of study (Day 15)
measure: Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings
timeFrame: Time from informed consent up to end of study (Day 15)
Other outcomes:
Locations:
city: Beijing
country: China
facility: Xuanwu Hospital Capital Medical University
Study officials:
affiliation: Merck Pharmaceutical Manufacturing (Jiangsu) Co., Ltd., an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: