GXR RM 500 mg Korea BE Study

• ClinicalTrials.gov Identifier: NCT04684420
• Recruitment Status: Recruiting
• First Posted: December 24, 2020
• Last Update Posted: November 18, 2021
• Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Study Description

Brief Summary:

The purpose of this study is to assess bioequivalence (BE) of newly developed Glucophage® XR (GXR) reduced mass (RM) tablet (metformin hydrochloride 500 milligrams (mg) test tablet) and marketed Glucophage ® XR tablet (metformin hydrochloride 500 mg reference tablet) following single oral dose administration under fasted and fed conditions by comparing pharmacokinetics, safety and tolerability between test and reference in healthy participants.

Condition or disease	Intervention/treatment	Phase
Healthy	Drug: Glucophage® XR Test; Drug: Glucophage® XR Reference	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 82 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Randomized Phase I, Open-Label, Active-Controlled Study Assessing The BE Between Single Doses of 500 mg GXR RM Tablets and 500 mg GXR Tablets Under Fasted and Fed State in Two 2-Way Crossover Groups of Healthy Participants
• Actual Study Start Date: December 22, 2020
• Estimated Primary Completion Date: December 24, 2021
• Estimated Study Completion Date: December 24, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: First Test GXR (Fasting), Then Reference GXR (Fasting); Participants will receive a single oral dose of 500 milligrams (mg) of test GXR tablet on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GXR tablet on Day 8 in treatment period 2 under fasting conditions. There will be separate washout period of 7 days between each treatment period.	Drug: Glucophage® XR Test; Participants will receive a single oral dose of 500 mg of test Glucophage® XR tablet under fasting or fed conditions.; Other Name: Metformin hydrochloride; Drug: Glucophage® XR Reference; Participants will receive a single oral dose of 500 mg of reference Glucophage® XR tablet under fasting or fed conditions.; Other Name: Metformin hydrochloride
Experimental: First Reference GXR (Fasting), Then Test GXR (Fasting); Participants will receive a single oral dose of 500 mg of reference GXR tablet on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GXR tablet on Day 8 in treatment period 2 under fasting conditions. There will be separate washout period of 7 days between each treatment period.	Drug: Glucophage® XR Test; Participants will receive a single oral dose of 500 mg of test Glucophage® XR tablet under fasting or fed conditions.; Other Name: Metformin hydrochloride; Drug: Glucophage® XR Reference; Participants will receive a single oral dose of 500 mg of reference Glucophage® XR tablet under fasting or fed conditions.; Other Name: Metformin hydrochloride
Experimental: First Test GXR (Fed), Then Reference GXR (Fed); Participants will receive a single oral dose of 500 mg of test GXR tablet on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GXR tablet on Day 8 in treatment period 2 under fed conditions. There will be separate washout period of 7 days between each treatment period.	Drug: Glucophage® XR Test; Participants will receive a single oral dose of 500 mg of test Glucophage® XR tablet under fasting or fed conditions.; Other Name: Metformin hydrochloride; Drug: Glucophage® XR Reference; Participants will receive a single oral dose of 500 mg of reference Glucophage® XR tablet under fasting or fed conditions.; Other Name: Metformin hydrochloride
Experimental: First Reference GXR (Fed), Then Test GXR (Fed); Participants will receive a single oral dose of 500 mg of reference GXR tablet on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GXR tablet on Day 8 in treatment period 2 under fed conditions. There will be separate washout period of 7 days between each treatment period.	Drug: Glucophage® XR Test; Participants will receive a single oral dose of 500 mg of test Glucophage® XR tablet under fasting or fed conditions.; Other Name: Metformin hydrochloride; Drug: Glucophage® XR Reference; Participants will receive a single oral dose of 500 mg of reference Glucophage® XR tablet under fasting or fed conditions.; Other Name: Metformin hydrochloride

Outcome Measures

Primary Outcome Measures :

1. Area Under the Plasma Concentration-Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of Metformin [ Time Frame: Pre-dose up to 32 hours post-dose ]
2. Maximum Observed Plasma Concentration (Cmax) of Metformin [ Time Frame: Pre-dose up to 32 hours post-dose ]

Secondary Outcome Measures :

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: Day 1 up to Day 21 ]
2. Number of Participants Taking Concomitant Medications [ Time Frame: Day 1 up to Day 21 ]
3. Number of Participants With Clinically Significant Change from Baseline in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-Lead Electrocardiogram (ECG) Findings [ Time Frame: Day 1 up to Day 21 ]
   Number of participants with clinically significant change from baseline in vital signs, laboratory parameters, physical examination findings and 12-lead electrocardiogram findings will be reported.
4. Area Under Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin [ Time Frame: Pre-dose up to 32 hours post-dose ]
5. Ratio of Area Under the Plasma Concentration-Time Curve from Time Zero to the Last Sampling Time (AUC0-tlast) to Area Under the Plasma Concentration-Time Curve from Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin [ Time Frame: Pre-dose up to 32 hours post-dose ]
6. Apparent Terminal Half-life (t½) of Metformin [ Time Frame: Pre-dose up to 32 hours post-dose ]
7. Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin [ Time Frame: Pre-dose up to 32 hours post-dose ]

Eligibility Criteria

• Ages Eligible for Study: 19 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• All values for hematology and biochemistry tests of blood and urinalysis (especially Estimated Glomerular Filtration Rate [eGFR] greater than [>] 80 milliliters per minute per 1.73 square meter [80 ml/min/1.73 m^2] and normal Creatinine) within the normal range or showing no clinically relevant deviation as judged by the Investigator
• Are not having congenital or chronic diseases, nor pathological symptoms based on the screening
• Have no history of gastrointestinal resection that may affect drug absorption
• Have no history of psychiatric disorder within 5 years prior to screening
• Vital signs (body temperature [tympanic], blood pressure [BP], and pulse rate in sitting position) within the normal range or showing no clinically relevant deviation as judged by the Investigator
• Electrocardiogram recording (12-lead) without signs of clinically relevant pathology in particular QTc (Bazett) less than or equal to [<=] 450 millisecond (ms)
• Non-smoker (that is [i.e.] zero cigarettes, pipes, cigars or others) at least three months before study entry
• Negative screen for Hepatitis B surface antigen (HBsAg) and Hepatitis B Virus antibody (anti-HBc), Hepatitis C Virus antibody (anti-HCV) and Human Immunodeficiency Virus antibodies (anti-HIV 1 and 2) and Rapid Plasma Reagin Antibody (RPR Ab)
• Have a body weight within the range 55 to 95 kilograms (kg) and a Body Mass Index (BMI) within the range 18.5 to 29.9 kilograms per square meter (kg/m^2) (inclusive)
• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Participants determined ineligible to participate in this study at the discretion of the Principal Investigator (or delegated investigators)
• Hypersensitivity to venous puncture
• Known hypersensitivity to ingredients of Study Interventions or Biguanides, or having other clinically relevant hypersensitivities
• Type I diabetes mellitus, lactic acidosis, acute or chronic metabolic acidosis including diabetic ketoacidosis, with or without coma; diabetic pre-coma, pre-diabetes
• Participants with renal impairment (eGFR < 80 ml/min/1.73m^2) - calculations according to Modification of Diet in Renal Disease (MDRD) formula). Participants presenting with acute conditions with the potential to alter renal function such as dehydration, severe infection, cardiovascular collapse (shock), acute myocardial infraction, and septicemia
• Participants with acute and unstable heart failure
• Participants with severe infection or severe traumatic general disorder
• Participants who are scheduled to undergo surgical procedures
• Participants with malnutrition, inanition, pituitary dysfunction or adrenal function failure
• Participants with hepatic dysfunction, acute or chronic disease which may cause tissue hypoxia such as respiratory failure, acute myocardial infarction, shock and gastrointestinal (GI) disorder such as excessive alcohol intake, hydration, diarrhea, vomiting etc.
• Participants undergoing intravascular administration of iodinated contrast materials in radio diagnostic examinations (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials etc.)
• Participants who took drugs that significantly induce (e.g., barbiturate) or inhibit drug metabolism enzymes, and those drugs that may alter metformin pharmacokinetic (pK), most importantly organic cation transporter 1/2 [OCT1/2] inhibitors and inducers, within 30 days prior to screening
• Use of a concomitant drug. However, any medications that are considered necessary for participant's welfare and will not interfere with the trial medication may be given at the discretion of the investigator
• Use of any medication that may affect the outcome of the study within 10 days prior to screening and during study conduct
• Participation in another bioequivalence or other clinical studies where the last administration of previous study medication was within 6 months, before the first drug administration in this study
• Other protocol defined exclusion criteria could apply

Contacts and Locations

Contacts

Contact: Communication Center; +49 6151 72 5200; service@emdgroup.com

Locations

Korea, Republic of

Clinical Trials Center, Chungnam National University Hospital; Recruiting

Daejeon, Korea, Republic of, 35015

Sponsors and Collaborators

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible; Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

More Information

Additional Information:

Trial Awareness and Transparency website 

• Responsible Party: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT04684420
• Other Study ID Numbers: MS200084_0028
• First Posted: December 24, 2020
• Last Update Posted: November 18, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany, will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany:

Diabetes Mellitus; Glucophage Extended Release; Bioequivalence Study

Additional relevant MeSH terms:

Metformin; Hypoglycemic Agents; Physiological Effects of Drugs