Glucophage® Extended Release (XR) 750 Milligram (mg) Indonesia Bioequivalence (BE) Study

• ClinicalTrials.gov Identifier: NCT03583385
• Recruitment Status: Completed
• First Posted: July 11, 2018
• Results First Posted: November 25, 2019
• Last Update Posted: November 25, 2019
• Sponsor: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): Merck KGaA, Darmstadt, Germany

Study Description

Brief Summary:

The purpose of this study is to assess bioequivalence between metformin hydrochloride (Glucophage® XR) manufactured in PT Merck Tbk, Indonesia (test drug) and metformin hydrochloride (Glucophage® XR) manufactured in Merck Santé, France (comparator drug) following single oral dose administration under fasting condition.

Condition or disease	Intervention/treatment	Phase
Healthy	Drug: Glucophage XR (Test drug); Drug: Glucophage XR (Comparator drug)	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Other
• Official Title: A Randomized, Open-label, Two-way Crossover Study Assessing the Bioequivalence (BE) Between Single Dose of 750 mg Glucophage® XR Tablets (PT Merck Tbk, Jakarta, Indonesia-Manufactured) and 750 mg Glucophage® XR Tablets (Merck Santé, Semoy, France-Manufactured) Under Fasted State in Healthy Subjects
• Actual Study Start Date: August 16, 2018
• Actual Primary Completion Date: October 5, 2018
• Actual Study Completion Date: October 5, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: First Glucophage XR (Test), Then Glucophage XR (Comparator); Participants received single oral dose of 750 milligram (mg) Glucophage® XR tablet manufactured by PT Merck Tbk, Jakarta, Indonesia (Test Drug) in treatment period 1 followed by single oral dose of 750 mg Glucophage® XR tablet manufactured by Merck Santé, Semoy, France (Comparator Drug) in treatment period 2 under fasting conditions. The two periods were separated by a 7-day wash-out period.	Drug: Glucophage XR (Test drug); Participants received single oral dose of Glucophage® XR tablet manufactured by PT Merck Tbk, Jakarta, Indonesia (Test Drug) under fasted conditions.; Other Name: Metformin hydrochloride; Drug: Glucophage XR (Comparator drug); Participants received single oral dose of Glucophage® XR tablet manufactured by Merck Santé, Semoy, France (Comparator Drug) under fasted conditions.; Other Name: Metformin hydrochloride
Experimental: First Glucophage XR (Comparator), Then Glucophage XR (Test); Participants received single oral dose of 750 milligram (mg) Glucophage® XR tablet manufactured by Merck Santé, Semoy, France (Comparator Drug) in treatment period 1 followed by single oral dose of 750 mg Glucophage® XR tablet manufactured by PT Merck Tbk, Jakarta, Indonesia (Test Drug) in treatment period 2 under fasting conditions. The two periods were separated by a 7-day wash-out period.	Drug: Glucophage XR (Test drug); Participants received single oral dose of Glucophage® XR tablet manufactured by PT Merck Tbk, Jakarta, Indonesia (Test Drug) under fasted conditions.; Other Name: Metformin hydrochloride; Drug: Glucophage XR (Comparator drug); Participants received single oral dose of Glucophage® XR tablet manufactured by Merck Santé, Semoy, France (Comparator Drug) under fasted conditions.; Other Name: Metformin hydrochloride

Outcome Measures

Primary Outcome Measures :

1. Maximum Observed Plasma Concentration (Cmax) of Metformin [ Time Frame: Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1 ]
   The maximum plasma concentration of Metformin.
2. Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin [ Time Frame: Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1 ]
   Area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration.

Secondary Outcome Measures :

1. Area Under Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin [ Time Frame: Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1 ]
   AUC (0-inf) is defined as the area under the plasma concentration versus time curve (AUC) from time zero (predose) to extrapolated infinite time (0-inf).
2. Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin [ Time Frame: Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1 ]
   Time of the maximum drug concentration.
3. Terminal Elimination Half-life in Plasma (t½) of Metformin [ Time Frame: Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1 ]
   Elimination Half Life (t1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half.
4. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: Up to Day 51 ]
   An adverse event (AE) was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. Number of participants with TEAEs included participants with both non serious and serious TEAEs.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Participants has provided written informed consent prior to the conduct of any study-related activities
• Body mass index of 18 to 25 kilogram per square meter (kg/m^2)
• Good physical and mental health status, determined on the basis of medical history and physical examination
• Vital signs (blood pressure, pulse rate, respiratory rate and body temperature) in sitting position within the normal range or showing no clinically relevant deviation per the Investigator's opinion
• All values for laboratory assessments (hematology, clinical chemistry and urinalysis) within the normal range or showing no clinically relevant deviation per the Investigator's opinion
• No clinically significant abnormality on 12-lead electrocardiogram (ECG) recording as judged by the Investigator; corrected QT interval (QTc) (Bazett) should be less than equals to (<=) 450 milliseconds (ms)
• Non-smoker or smoker less than 10 cigarettes per day
• Women of childbearing potential (WOCBP) who are not nursing, are not pregnant, and are using highly effective methods of birth control. Female participants may also be enrolled if they are postmenopausal or surgically sterilized/ hysterectomized at least 6 months prior to study participation
• WOCBP must have a negative urine pregnancy test at Screening and on each admission (Day 1 of each dosing period)
• Negative screen for alcohol and drugs abuse (opiate class, barbiturates, cocaine and metabolites, amphetamines, cannabinoids and benzodiazepines) at Screening and on each Study Check-In (Day -1 of each dosing period)
• Negative screen for Hepatitis B surface antigen (HBsAg), Hepatitis C Virus (HCV) antibodies and/or Human Immunodeficiency Virus (HIV) antibodies.

Exclusion Criteria:

• Participation in a clinical trial/study within 90 days prior to Screening
• Blood donation (equal or more than 300 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 prestudy 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 malignant diseases, except in-situ basal cell skin tumors treated with curative intent
• History of surgery of the gastrointestinal tract which could influence the gastrointestinal absorption and/or motility per the Investigator's opinion
• History or presence of relevant liver diseases or hepatic dysfunction (laboratory result for liver function test greater than equals to (>=) 1.5 upper limit of normal (ULN)
• History or presence of renal failure or renal dysfunction based on clinical symptoms and finding (serum creatinine concentration >1.4 milligram per milliliter (mg/mL)
• 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 14 days before the first drug administration, except for hormonal contraceptives in female, and including multivitamins and herbal products (e.g. St John's Wort)
• Consumption of large quantities of methylxanthine-containing beverages (> 5 cups of coffee/day or equivalent)
• Consumption of grapefruit, orange, cranberry or juices of these three fruits, 24 hours prior to drug administration
• Known lack of participant compliance or inability to communicate or cooperate with the Investigator (e.g., language problem, poor mental status)

Contacts and Locations

Locations

Indonesia

PT Equilab International

Jakarta, Indonesia, 12430

Sponsors and Collaborators

Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible; PT Merck Tbk, Indonesia, and affiliate of Merck KGaA, Darmstadt, Germany

  Study Documents (Full-Text)

Documents provided by Merck KGaA, Darmstadt, Germany:

Statistical Analysis Plan  [PDF] September 6, 2018

Study Protocol  [PDF] May 22, 2018

More Information

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT03583385
• Other Study ID Numbers: MS200084_0015
• First Posted: July 11, 2018
• Results First Posted: November 25, 2019
• Last Update Posted: November 25, 2019
• Last Verified: November 2019

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

Additional relevant MeSH terms:

Metformin; Hypoglycemic Agents; Physiological Effects of Drugs