Evaluation of Food Effect on the Pharmacokinetics of Sustained Release Metformin in Healthy Indian Volunteers

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01561976
First received: February 16, 2012
Last updated: August 30, 2012
Last verified: August 2012
  Purpose

Metformin hydrochloride in its immediate release (IR) form has been successfully used for decades in the treatment of type 2 diabetes; however the IR formulation may be associated with gastrointestinal side effects (especially nausea, diarrhea) in 20-30% patients, which can limit the tolerated dose, reduce adherence and result in discontinuation of therapy. Metformin hydrochloride extended release formulations have been developed to overcome these problems. In India, extended release formulations of metformin hydrochloride include metformin SR 1000mg tablet and combination of metformin hydrochloride SR 1000mg/glimepiride 2mg tablet. In the combination tablet, only metformin hydrochloride is in the extended release form. In view of the fact that extended release metformin hydrochloride is usually recommended with a meal, that food is known to affect the pharmacokinetic (PK) parameters of metformin and that there is a potential for dose dumping with extended release formulations that may lead to side effects similar to IR formulations, a study to estimate the magnitude of the food effect for these formulations in fed state compared to the fasting state is warranted. This study will be a randomized, single-center, open-label, single-dose, three-period, 6 sequence crossover study in 30 healthy adult volunteers to estimate the bioavailability of metformin from metformin hydrochloride 1000mg SR tablet given in fasting condition relative to metformin hydrochloride 1000mg SR tablet and a fixed dose combination of metformin hydrochloride 1000mg SR /glimepiride 2mg tablet, each given in fed condition. The safety and tolerability profile of metformin SR 1000mg tablet and metformin hydrochloride SR 1000mg/glimepiride 2mg tablet will also be evaluated in this study. The primary PK endpoints will be Cmax and AUC (0-∞). The secondary PK endpoints will include AUC (0-t), Tmax , T lag, Kel and t1/2. Safety endpoints will include vital signs, ECG, physical examination, clinical laboratory tests and adverse event reporting.


Condition Intervention Phase
Diabetes Mellitus, Type 2
Drug: Metformin hydrochloride prolonged release
Drug: metformin hydrochloride prolonged release
Drug: Metformin hydrochloride sustained release/Glimepiride
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Official Title: The Effect of Food on the Pharmacokinetics of Metformin Given Either as Metformin Hydrochloride SR 1000mg Tablet or as a Fixed Dose Combination of Metformin Hydrochloride SR 1000mg/Glimepiride 2mg Tablet in Healthy Indian Volunteers.

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Cmax [ Time Frame: 0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing ] [ Designated as safety issue: No ]
    Cmax of plasma metformin

  • AUC (0-∞) [ Time Frame: 0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing ] [ Designated as safety issue: No ]
    AUC (0-∞) of plasma metformin


Secondary Outcome Measures:
  • AUC (0-t) [ Time Frame: 0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing ] [ Designated as safety issue: No ]
    AUC (0-t) of plasma metformin

  • Tmax [ Time Frame: 0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing ] [ Designated as safety issue: No ]
    Tmax of plasma metformin

  • Tlag [ Time Frame: 0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing ] [ Designated as safety issue: No ]
    Tlag of plasma metformin

  • Kel [ Time Frame: 0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing ] [ Designated as safety issue: No ]
    Kel of plasma metformin

  • t1/2 [ Time Frame: 0.0 (pre-dose) and 0.5, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24 and 30 hours after dosing ] [ Designated as safety issue: No ]
    t1/2 of plasma metformin

  • Adverse events [ Time Frame: Up to 21 days after initiation of study ] [ Designated as safety issue: Yes ]
    Number of participants with adverse events


Enrollment: 30
Study Start Date: January 2012
Study Completion Date: February 2012
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Metformin hydrochloride prolonged release
1000mg in fasting state
Drug: Metformin hydrochloride prolonged release
1000mg in fasting state
Active Comparator: metformin hydrochloride prolonged release
1000mg In fed state
Drug: metformin hydrochloride prolonged release
1000mg in fed state
Active Comparator: Metformin hydrochloride sustained release/Glimepiride
1000/2mg In fed state
Drug: Metformin hydrochloride sustained release/Glimepiride
1000/2mg in fed state

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests, 12 lead ECG and chest-x-ray. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Medical Investigator agrees that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  2. Males between 18 and 50 years of age (both inclusive), who are willing to participate in the study and provide a written signed and dated informed consent.
  3. Body weight more than or equal to 60 kg and BMI within the range 18.5-24.9 kg/m2 (inclusive).
  4. Availability of a study volunteer for the entire study period and willingness to adhere to protocol requirements as evidenced by written informed consent.

Exclusion Criteria:

  1. A positive pre-study urine drug screen.
  2. A positive test for HIV antibody.
  3. Subject has clinically significant abnormal values of laboratory parameters.
  4. Regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits (CTRI, 2010).
  5. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  6. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  7. Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise subject safety.
  8. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator contraindicates their participation.
  9. Where participation in another study would result in donation of blood or blood products in excess of 350 ml within a 90 day period prior to this study.
  10. Unwillingness or inability to follow the procedures outlined in the protocol.
  11. Subject is mentally or legally incapacitated or the subject is incapable of understanding the informed consent.
  12. Subject has any evidence of impaired renal, hepatic, cardiac, lung or gastrointestinal function. Study volunteers with a history of tuberculosis, epilepsy, asthma (during past 5 years), diabetes, psychosis or glaucoma will not be eligible for the study.
  13. History of sensitivity to heparin or heparin-induced thrombocytopenia.
  14. Regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
  15. Subject is intolerant to venipuncture.
  16. Unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice [and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices] from 7 days prior to the first dose of study medication.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01561976

Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01561976     History of Changes
Other Study ID Numbers: 116519
Study First Received: February 16, 2012
Last Updated: August 30, 2012
Health Authority: India: Institutional Review Board

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Glimepiride
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors

ClinicalTrials.gov processed this record on October 16, 2014