BE Study of Metformin GSK 500mg

Overview[ - collapse ][ - ]

Purpose A randomized, balanced, open label, crossover, two period, two treatment, two sequence, single dose, oral bioequivalence study under fasting condition. It is a pivotal study. To demonstrate the bioequivalence of Metformin 500 mg tablets manufactured by Savipharm J.S.C, Vietnam and Glucophage® 500 mg tablets of MERCK SANTE in healthy adult human male subjects under fasting condition and to monitor the safety of the study subjects.
ConditionDiabetic Foot
InterventionDrug: Metformin 500mg
Drug: Glucophage 500mg
PhasePhase 2
SponsorGlaxoSmithKline
Responsible PartyGlaxoSmithKline
ClinicalTrials.gov IdentifierNCT01710527
First ReceivedSeptember 27, 2012
Last UpdatedOctober 17, 2012
Last verifiedOctober 2012

Tracking Information[ + expand ][ + ]

First Received DateSeptember 27, 2012
Last Updated DateOctober 17, 2012
Start DateMay 2012
Estimated Primary Completion DateMay 2012
Current Primary Outcome MeasuresCmax, Tmax, AUC0-t, AUC0-¥, t1/2, Kel and AUC% Extrapolated (Residual area) [Time Frame: 7 days] [Designated as safety issue: No]Cmax, Tmax, AUC0-t, AUC0-¥, t1/2, Kel and AUC% Extrapolated (Residual area). These pharmacokinetic parameters were estimated by employing non-compartmental model of WinNonlin® Enterprise Version 5.3 software. The calculated 90% confidence interval (CI) for the test to reference ratio of Metformin should fall within the range of 80%-125% for log-transformed Cmax, AUC0-t and AUC0-∞ for the conclusion of bioequivalence.
Current Secondary Outcome MeasuresSafety profile [Time Frame: 14 days] [Designated as safety issue: Yes]The safety assessments included monitoring of adverse events (AEs), periodic physical examination, vital signs monitoring and subject well-being questionnaire at pre-determined intervals and whenever appropriate

Descriptive Information[ + expand ][ + ]

Brief TitleBE Study of Metformin GSK 500mg
Official TitleAN OPEN LABEL, BALANCED, RANDOMIZED, TWO-TREATMENT, TWO-PERIOD, TWO-SEQUENCE, CROSSOVER, SINGLE ORAL DOSE, BIOEQUIVALENCE STUDY OF METFORMIN 500 MG TABLETS MANUFACTURED BY SAVIPHARM J.S.C, VIETNAM AND GLUCOPHAGE® 500 MG TABLETS MANUFACTURED BY MERCK SANTE S.A.S.2, RUE DU PRESSOIR VERT-45400 SEMOY-FRANCE AND BE REGISTERED IN VIETNAM IN HEALTHY, ADULT, HUMAN MALE SUBJECTS UNDER FASTING CONDITION
Brief Summary
A randomized, balanced, open label, crossover, two period, two treatment, two sequence,
single dose, oral bioequivalence study under fasting condition. It is a pivotal study.

To demonstrate the bioequivalence of Metformin 500 mg tablets manufactured by Savipharm
J.S.C, Vietnam and Glucophage® 500 mg tablets of MERCK SANTE in healthy adult human male
subjects under fasting condition and to monitor the safety of the study subjects.
Detailed Description
Sample Size Estimation Assuming the formulation ratio (T/R) 95-105% and with the maximum
observable intra subject variability for Metformin is 22% (based on literature), a sample
size of 29 subjects would be sufficient to prove bioequivalence between the two formulations
with power of at least 90%. Hence, total 32 subjects will be enrolled in the study
considering withdrawal and dropouts.

Hence, 32 healthy adult human male subjects will be enrolled. Adverse Events The
investigator or site staff is responsible for detecting, documenting and reporting events
that meet the definition of an AE or SAE.

AEs will be collected from the start of Study Treatment and until the follow-up contact.
Medical occurrences that begin prior to the start of study treatment but after obtaining
informed consent may be recorded on the Medical History/Current Medical Conditions CRF.

SAEs will be collected over the same time period as stated above for AEs. However, any SAEs
assessed as related to study participation (e.g. study treatment, protocol-mandated
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant
medication will be recorded from the time a subject consents to participate in the study up
to and including any follow-up contact. All SAEs will be recorded and reported to the
sponsor within 24 hours.

Investigators are not obligated to actively seek AEs or SAEs in former study participants.
However, if the investigator learns of any SAE, including a death, at any time after a
subject has been discharged from the study, and he considers the event reasonably related to
the study treatment or study participation, the investigator would promptly notify the
sponsor.

All serious adverse events will be informed to the sponsor within 24 hrs and to the IEC
within 7 working days. Any unexpected serious adverse event (SAE) occurring during a
clinical trial should be communicated promptly (within 14 calendar days) by the Sponsor/CRO
to the Licensing Authority.

Any follow-up information on a previously reported SAE will also be reported to the sponsor
within 24 hours.

If the investigator does not have all information regarding an SAE, he/she will not wait to
receive additional information before notifying the sponsor of the event and completing the
appropriate data collection tool. The investigator will always provide an assessment of
causality at the time of the initial report.

Screening procedures: Demographic data, medical and medication histories, complete physical
examination, height, weight and BMI as well as 12 lead ECG, chest X-ray [PA view], vital
signs [blood pressure, pulse rate, respiratory rate and oral temperature], hematology,
biochemistry, HIV 1 & 2, Hepatitis B and C, RPR test for Syphilis and urine analysis will
be done at screening.

Urine drug screen, Liver chemistry test and breath alcohol test to be done prior to each
check-in.

Breath alcohol test to be done prior to each ambulatory visit blood collection. Liver
chemistry test to be done at the end of each period. Housing: The study subjects will be
housed at least 11 h prior to drug administration until after the 24 h blood sampling in
each study period. The housing will be followed by one ambulatory visits [36.0 hr post dose]
for each period.

Washout: At least 7 days, but not exceeding 14 days between two dosing days. Treatment arms:
Test: A single dose of Metformin 500 mg tablet manufactured by Savipharm J.S.C, Vietnam.

Reference: A single dose of Glucophage® 500 mg tablet of Merck Sante, France Drug
administration: As per the randomization schedule, one tablet of either test or reference
product will be orally administered to each subject in each period in sitting posture, after
an overnight fast of at least 10 h.

To avoid hypoglycemic episodes, the investigational products will be administered with 240
mL of a 20% glucose solution in water, followed by 60 mL of the glucose solution
administered every 15 min for up to 4 h after dosing.

Subjects will be instructed not to chew or crush the tablet but should be swallowed.
Compliance for dosing will be assessed by identification of subjects with subject ID card,
identification of label on investigational product to confirm correct allocation of
treatment and checking the oral cavity immediately after dosing.

Restrictions: Subjects will remain in upright position [sitting or ambulatory] for two hours
after dosing in each period except when clinically indicated to change the posture. The
subjects will fast for at least 10 h prior to dosing and 4 h post-dose. Water will be
permitted ad libitum except for 1 h before and until 1 h after post dose. During 1 hr post
dose water restriction a, 60 mL of 20% glucose solution will be administered every 15 min to
the study subjects.

In each period of the study, 18 blood samples of 6 mL each will be collected in K2EDTA
vacutainers via an indwelling catheter placed in one of the forearm veins. Heparin-lock
technique will be used to prevent clotting of blood in the indwelling catheter. Before each
in-house blood sample is drawn through catheter, 0.5 mL of blood will be discarded so as to
purge the heparin containing blood sample in the catheter. Blood can also be collected by
direct venipuncture in case of cannula blockage, during ambulatory visits or for any other
practical reasons. The two pre-dose blood samples will be collected within a period of 1 h
before the drug administration. The post-dose blood samples will be collected at 0.5, 1.0,
1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0 and 36.0 h. The 36.0 h
post dose blood samples will be collected during ambulatory visits by direct venipuncture.
Immediately after collection of blood, the sample will be kept in ice bath. After collecting
the blood samples from all the subjects at each sampling time point, samples will be
centrifuged at 4oC with 3500 rpm for 10 minutes. The plasma samples will be separated and
stored in pre-labeled polypropylene tubes at -70 ± 10°C pending assay. The time interval
between sample collection and the start of centrifugation should not exceed more than 45
minutes. The blood sample collection, processing and analysis will be done under sodium
monochromatic light.

The total volume of blood drawn including the volume necessary for the laboratory tests, PK
sample analysis and the volume of blood discarded before each in house blood draw will be
about 250 mL per subject for the entire study.

Subjects monitoring: Brief physical examination and vital signs [blood pressure, pulse rate
and oral temperature] will be carried out and recorded at each check-in and at check-out.
Vital signs [blood pressure and pulse rate] will also be recorded before dosing of
investigational products, between 2 - 3, 9 - 10 and 36.0 h post dose. Vital signs should be
done in sitting position after rest of at least 5 minutes. Physical examination and
measurement of vital signs can also be carried out at any time during the conduct of the
study if the Investigator/Doctor feels it necessary. In case of abnormality in pre-dose
vital signs, Investigator based on his medical judgement will take the decision whether to
dose the subject or not. During vitals recording each subject will be asked about his
well-being. Also subject well-being questionnaire will be performed at 1.0 and 5.0 h post
dose.

Post-study Procedures: Safety evaluation [complete physical examination, vital signs,
hematology [except blood grouping & Rh typing] and biochemistry] will be done at the end of
the clinical part of the study. In case of any withdrawals during the study safety
assessment will be done at the time of withdrawal. In case of dropouts subjects will be
asked to visit the facility to undergo safety assessments.

Pharmacokinetic Parameters: Cmax, Tmax, AUC0-t, AUC0-∞, AUC%_Extrap, Kel and t1/2 Analytical
Methods: Metformin in plasma will be estimated using validated LC-MS/MS method.

Statistical Methods: Statistical analyses will be done using SAS® version 9.2 or higher.
Analysis of variance [ANOVA] for log-transformed pharmacokinetic parameters [Cmax, AUC0-t
and AUC0-∞], two one-sided tests [Schuirmann] for bioequivalence, power, ratio and 90%
confidence interval for log-transformed pharmacokinetic parameters - Cmax, AUC0-t and AUC0-∞
will be performed.

Standards for Bioequivalence: The calculated 90% Confidence Interval for the test to
reference ratio of Metformin should fall within the range of 80%-125% for log transformed
Cmax, AUC0-t and AUC0-∞ for the conclusion of bioequivalence.
Study TypeInterventional
Study PhasePhase 2
Study DesignAllocation: Randomized, Endpoint Classification: Bio-equivalence Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Basic Science
ConditionDiabetic Foot
InterventionDrug: Metformin 500mg
EVALUATE BIOEQUIVALENCE BETWEEN METFORMIN 500 MG TABLETS MANUFACTURED BY SAVIPHARM J.S.C, VIETNAM AND GLUCOPHAGE® 500 MG TABLETS MANUFACTURED BY MERCK SANTE S.A.S.2, RUE DU PRESSOIR VERT-45400 SEMOY-FRANCE AND BE REGISTERED IN VIETNAM IN HEALTHY, ADULT, HUMAN MALE SUBJECTS UNDER FASTING CONDITION
Drug: Glucophage 500mg
EVALUATE BIOEQUIVALENCE BETWEEN METFORMIN 500 MG TABLETS MANUFACTURED BY SAVIPHARM J.S.C, VIETNAM AND GLUCOPHAGE® 500 MG TABLETS MANUFACTURED BY MERCK SANTE S.A.S.2, RUE DU PRESSOIR VERT-45400 SEMOY-FRANCE AND BE REGISTERED IN VIETNAM IN HEALTHY, ADULT, HUMAN MALE SUBJECTS UNDER FASTING CONDITION
Study Arm (s)
  • Other: Metformin 500mg
    Cross over, two treatment, two period, two sequence, cross over, single dose
  • Other: Glucophage 500mg
    Cross over, two treatment, two period, two sequence, sigle dose

Recruitment Information[ + expand ][ + ]

Recruitment StatusCompleted
Estimated Enrollment32
Estimated Completion DateMay 2012
Estimated Primary Completion DateMay 2012
Eligibility Criteria
Inclusion Criteria

- Healthy adult male human subjects within the age range of 18 to 45 years inclusive.

- Weight not less than 50 kg.

- Normal BMI [18.5 to 24.99 kg/m2 inclusive].

- Willingness and capability to provide written informed consent to participate in the
study.

- Free of significant diseases or clinically significant abnormal findings based on
medical history, physical examination, laboratory evaluations, 12-lead ECG, Chest
X-ray [PA view].

- Absence of disease markers of HIV 1 and 2, Hepatitis B and C and Syphilis.

- AST, ALT, alkaline phosphatase and bilirubin 1.5xULN
is acceptable if bilirubin is fractionated and direct bilirubin <35%).

- ECG normal for morphology and measurements. QTcB or QTcF < 450 msec or QTc < 480 msec
in subjects with Bundle Branch Block, based on an average from three ECGs obtained
over a brief recording period.

- Male subjects with female partners of child-bearing potential must agree to use one
of the contraception methods listed below. This criterion must be followed from the
time of the first dose of study medication until one week of last dose
administration.

- Condom plus partner use of a highly effective contraceptive such as occlusive
cap (diaphragm or cervical/vault cap) plus spermicidal agent
(foam/gel/film/cream/suppository), oral contraceptive, injectable progesterone,
implant of etonogestrel or levonorgestrel, estrogenic vaginal ring, percutaneous
contraceptive patches, or intrauterine device.

OR

- Abstinence, defined as sexual inactivity consistent with the preferred and usual
lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
contraception.

Exclusion Criteria

- History or presence of significant: Cardiovascular, pulmonary, hepatic, renal,
hematological, gastro-intestinal, endocrine, immunologic, dermatologic, neurological,
psychiatric disease.

- History or presence of significant:

- Alcohol dependence, alcohol abuse during past one year.

- Drug abuse [Marijuana [THC], Cocaine, Morphine, Benzodiazepines, Barbiturates
and Amphetamine] for the last 6 months.

- Smoking of more than 5 cigarettes per day or consumption of other forms of
tobacco containing products.

- Asthma, urticaria or other allergic type reactions after taking aspirin or any
other drug.

- Ulceration or history of gastric and / or duodenal ulcer.

- Jaundice in the past 6 months.

- Bleeding disorder.

- Allergy to the test drug or any drug chemically similar to the drug or to the
excipients of the products under investigation.

- Donation of 500 mL or more blood within 8 weeks prior to receiving the first dose of
study drug.

- Subjects who have participated in another clinical study in the past 3 months prior
to commencement of this study.

- Any difficulty in accessibility of forearm veins for cannulation or blood sampling.

- Refusal to abstain from food for at least 10 h prior to drug administration and for
at least 4 h post dose in each period.

- Refusal to abstain from fluid for at least 1 h prior to and 1 h post each dose except
20 % glucose solution given after dosing.

- Positive breath alcohol test result found on the day of check-in.

- Positive urine test result for drug of abuse found on the day of check-in.

- History of difficulty in swallowing tablet.

- Use of any concomitant medication [including over-the-counter products, vitamins
etc.] for 14 days preceding the study drug administration.

- Use of drugs which induce or inhibit metabolizing enzymes within 30 days prior to
receiving the first dose of study medication.

Other Eligibility Criteria Considerations To assess any potential impact on subject
eligibility with regard to safety, the investigator must refer to the product data sheet
for detailed information regarding warnings, precautions, contraindications, adverse
events, and other significant data pertaining to the product being used in this study.
GenderMale
Ages18 Years
Accepts Healthy VolunteersAccepts Healthy Volunteers
ContactsNot Provided
Location CountriesNot Provided

Administrative Information[ + expand ][ + ]

NCT Number NCT01710527
Other Study ID Numbers116723
Has Data Monitoring CommitteeNo
Information Provided ByGlaxoSmithKline
Study SponsorGlaxoSmithKline
CollaboratorsNot Provided
Investigators Study Director: GSK Clinical Trials GlaxoSmithKline
Verification DateOctober 2012