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CompletedNCT03467971Updated Jul 8, 2019Results posted

A Study to Assess the Food Effect on Bioavailability of Metformin/Gliclazide in Healthy Participants

A Phase 1 interventional study of Metformin/Gliclazide Fixed Combination in Healthy, sponsored by Merck KGaA, Darmstadt, Germany. Completed at 1 site in Mexico. Open to participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-07-08.

Sponsored by Merck KGaA, Darmstadt, Germany · Phase 1, Interventional, and Other

Phase
Phase 1
Study type
Interventional
Enrollment
21
Allocation
Randomized
Ages
18 Years to 55 Years
Sex
All
01

Study summary

This study will assess the food effect on bioavailability of Metformin/Gliclazide fixed dose combination tablet in fed and fasted state.

02

Conditions studied

  • Healthy

Keywords

  • Metformin
  • Bioavailability
  • Food effect
  • Pharmacokinetics
03

Who can participate

Ages eligible
18 Years to 55 Years
Sexes eligible
All
Accepts healthy volunteers
Yes

Inclusion criteria

  • Ethnicity: Mexicans
  • Weight between 55 and 95 kilogram (kg)
  • Body mass index between 18 and 27 kilogram per meter square (kg/m\^2)
  • Nonsmokers or participants who do not smoke more than 5 cigarettes or 1 pipe a day
  • Good physical and mental health based on the clinical history and physical examination
  • All results from blood chemistry, hematology, and urinalysis should be within normal ranges or without clinically significant deviations as per Principal Investigator's judgment
  • Hematology complete blood count [CBC]: hematocrit and hemoglobin must be above the lower limit; upper limit may range up to 15 percent (%)
  • Liver Function Test range as defined in the protocol
  • Electrocardiogram (12 leads) without clinically significant pathological signs
  • All women of childbearing potential must have negative tests for pregnancy at screening, and at day -1 for each treatment period and at end of trial (EOT)
  • Vital signs (blood pressure and pulse) in supine position within normal ranges or with clinically significant abnormalities as per the Principal Investigator's judgment
  • All women of childbearing potential who are not pregnant or breastfeeding and who are using a highly effective contraceptive method for at least one month before and following dosing
  • Negative result for alcohol breath test and urine test for drugs of abuse at screening and at each day -1 of the 2 treatment periods
  • Negative serology tests for human immunodeficiency virus (HIV1 and HIV2 antibodies), hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV) and venereal disease research laboratory (VDRL) test screening
  • Other protocol defined inclusion criteria could apply

Exclusion criteria

Exclusion Criteria:

  • Participants who have received any investigational drug within 21 days prior to the study start
  • Participants who have donated or lost 450 milliliter (mL) or more of blood within 21 days prior to the study start
  • Participants with history of cardiovascular, renal, liver, metabolic, gastrointestinal, neurological, endocrine, or hematopoietic (any type of anemia) diseases; mental disease, surgery or other organic abnormalities which might affect the study of the investigational drug pharmacokinetics
  • History of gastrointestinal tract surgery
  • Participants with history of hypersensitivity to the study drug and/or any formulation's ingredient; history of drug induced anaphylaxis
  • Participants who take any other drug 30 days before the study drug dose and for which at least seven elimination half-lives had not elapsed
  • Renal failure or renal impairment assessed by using the Cockcroft-Gault formula
  • Participant's disagreement or lack of capacity to communicate and cooperate with the Investigator, lack of legal capacity or limited legal capacity which prevent him/her from continuing in the study
  • Refusal of the high-fat diet which is necessary to assess the food effect. Considerable deviations to the diet's normal nutritional patterns
  • Participants who have smoked tobacco, having drunk alcohol, or xanthines containing beverages or food above 600 mg of caffeine a day those who have had grilled food within 24 h prior to the drug dosing
  • Intake of grapefruit, orange, cranberries or their juices within 14 days prior to the drug's dosing and throughout the study
  • Legal inability or limited legal capacity
  • Incarcerated participants
  • Participants who have been exposed to agents known as liver enzyme systems' inducers or inhibitors, or who have taken potentially toxic drugs within 30 days prior to the study
  • Other protocol defined exclusion criteria could apply
04

Study design

Phase
Phase 1
Primary purpose
Other
Allocation
Randomized
Intervention model
Crossover assignment
Masking
None (open label)
Enrollment
21 participants (actual)

Study arms

  • Experimental
    Metformin-Gliclazide (fasted), Then Metformin-Gliclazide (fed)

    Participants received single dose of Metformin 1000 milligram (mg) and Gliclazide 30 mg fixed combination tablet in fasting state in treatment period 1 followed by single dose of Metformin 1000 mg and Gliclazide 30 mg fixed combination tablet in fed state in treatment period 2. Each treatment period was separated by a 14-day wash-out period.

    Drug: Metformin/Gliclazide Fixed Combination

  • Experimental
    Metformin-Gliclazide (fed), Then Metformin-Gliclazide (fasted)

    Participants received single dose of Metformin 1000 mg and Gliclazide 30 mg fixed combination tablet in fed state in treatment period 1 followed by single dose of Metformin 1000 mg and Gliclazide 30 mg fixed combination tablet in fasting state in treatment period 2. Each treatment period will be separated by a 14-day wash-out period.

    Drug: Metformin/Gliclazide Fixed Combination

Interventions

  • DrugMetformin/Gliclazide Fixed Combination

    Participants will receive single oral dose of Metformin 1000 mg and Gliclazide 30 mg fixed combination tablet in fasting or fed state.

05

What researchers measure

Primary outcomes

  1. Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin and Gliclazide

    AUC (0-inf) is defined as the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).

    Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose

  2. Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin and Gliclazide

    AUC (0-t) is defined as the area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t)

    Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose

  3. Maximum Observed Plasma Concentration (Cmax) of Metformin and Gliclazide

    Cmax is defined as the maximum observed plasma concentration.

    Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose

Secondary outcomes

  1. Time to Reach Maximum Plasma Concentration (Tmax) of Metformin and Gliclazide

    Tmax is defined as the time to reach maximum plasma concentration.

    Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose

  2. Elimination Half Life (t1/2) of Metformin and Gliclazide

    Elimination Half Life (t1/2) is defined as the time required for the concentration or amount of drug in the body to be reduced by one-half.

    Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose

  3. Apparent Volume of Distribution (Vz/f) of Metformin and Gliclazide

    Vz/f is defined as apparent volume of distribution during terminal phase after non-intravenous administration

    Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose

  4. Apparent Total Body Clearance (CL/f) of Metformin and Gliclazide From Plasma

    CL/f is defined as apparent total clearance of the drug from plasma after oral administration.

    Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose

  5. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

    Adverse event(AE) was defined as any untoward medical occurrence in participants which does not necessarily have causal relationship with treatment. AE was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event(SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs.

    Time frame: Baseline up to Day 39

06

Results

Posted Jul 8, 2019

Participant flow

Treatment Period 1
Participant flow — Treatment Period 1
MilestoneMetformin-Gliclazide (Fasted), Then Metformin-Gliclazide (Fed)Metformin-Gliclazide (Fed), Then Metformin-Gliclazide (Fasted)
Started1011
Completed1011
Not completed00
Treatment Period 2
Participant flow — Treatment Period 2
MilestoneMetformin-Gliclazide (Fasted), Then Metformin-Gliclazide (Fed)Metformin-Gliclazide (Fed), Then Metformin-Gliclazide (Fasted)
Started1011
Completed1010
Not completed01
Withdrew: Withdrawal by subject01

Outcome measures

PrimaryArea Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin and Gliclazide

AUC (0-inf) is defined as the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).

Time frame:
Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Reported as:
Mean · Nanogram*hour per milliliter (ng*h/mL)
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin and Gliclazide
Nanogram*hour per milliliter (ng*h/mL)Metformin-Gliclazide (Fasted)Metformin-Gliclazide (Fed)
Metformin4974.2507 ± 1599.32908556.7752 ± 2544.6658
Gliclazide21192.1682 ± 9220.304421815.4021 ± 8369.0107
Statistical analysis
  • Metformin-Gliclazide (Fasted) vs Metformin-Gliclazide (Fed) · Ratio of mean values: 175.6652 · 90% CI 153.7790 to 200.6664
  • Metformin-Gliclazide (Fasted) vs Metformin-Gliclazide (Fed) · Ratio of mean values: 104.457 · 90% CI 97.7660 to 111.6060
PrimaryArea Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin and Gliclazide

AUC (0-t) is defined as the area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t)

Time frame:
Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Reported as:
Mean · ng*h/mL
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin and Gliclazide
ng*h/mLMetformin-Gliclazide (Fasted)Metformin-Gliclazide (Fed)
Metformin4722.4546 ± 1598.10828298.5628 ± 2422.9059
Gliclazide20348.8381 ± 9154.550920997.1704 ± 8244.2743
Statistical analysis
  • Metformin-Gliclazide (Fasted) vs Metformin-Gliclazide (Fed) · Ratio of mean values: 180.7734 · 90% CI 157.0135 to 208.1287
  • Metformin-Gliclazide (Fasted) vs Metformin-Gliclazide (Fed) · Ratio of mean values: 105.0818 · 90% CI 98.0047 to 112.6699
PrimaryMaximum Observed Plasma Concentration (Cmax) of Metformin and Gliclazide

Cmax is defined as the maximum observed plasma concentration.

Time frame:
Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Reported as:
Mean · ng/mL
Maximum Observed Plasma Concentration (Cmax) of Metformin and Gliclazide
ng/mLMetformin-Gliclazide (Fasted)Metformin-Gliclazide (Fed)
Metformin717.5017 ± 304.8105870.7288 ± 272.6886
Gliclazide968.0305 ± 261.83621013.9753 ± 243.1601
Statistical analysis
  • Metformin-Gliclazide (Fasted) vs Metformin-Gliclazide (Fed) · Ratio of mean values: 127.7779 · 90% CI 110.2732 to 148.0612
  • Metformin-Gliclazide (Fasted) vs Metformin-Gliclazide (Fed) · Ratio of mean values: 105.4183 · 90% CI 94.5723 to 117.5081
SecondaryTime to Reach Maximum Plasma Concentration (Tmax) of Metformin and Gliclazide

Tmax is defined as the time to reach maximum plasma concentration.

Time frame:
Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Reported as:
Mean · Hours
Time to Reach Maximum Plasma Concentration (Tmax) of Metformin and Gliclazide
HoursMetformin-Gliclazide (Fasted)Metformin-Gliclazide (Fed)
Metformin3.6698 ± 0.66007.2389 ± 0.7693
Gliclazide6.5254 ± 1.74748.5238 ± 2.1822
SecondaryElimination Half Life (t1/2) of Metformin and Gliclazide

Elimination Half Life (t1/2) is defined as the time required for the concentration or amount of drug in the body to be reduced by one-half.

Time frame:
Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Reported as:
Mean · Hours
Elimination Half Life (t1/2) of Metformin and Gliclazide
HoursMetformin-Gliclazide (Fasted)Metformin-Gliclazide (Fed)
Metformin6.2547 ± 2.97717.4892 ± 8.7276
Gliclazide16.6222 ± 6.262717.1044 ± 7.5000
SecondaryApparent Volume of Distribution (Vz/f) of Metformin and Gliclazide

Vz/f is defined as apparent volume of distribution during terminal phase after non-intravenous administration

Time frame:
Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Reported as:
Mean · Milliliter (mL)
Apparent Volume of Distribution (Vz/f) of Metformin and Gliclazide
Milliliter (mL)Metformin-Gliclazide (Fasted)Metformin-Gliclazide (Fed)
Metformin2003389.9474 ± 1157828.45471200933.2647 ± 949837.2019
Gliclazide35189.3864 ± 8855.949933813.7843 ± 6970.7706
SecondaryApparent Total Body Clearance (CL/f) of Metformin and Gliclazide From Plasma

CL/f is defined as apparent total clearance of the drug from plasma after oral administration.

Time frame:
Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Reported as:
Mean · Liters
Apparent Total Body Clearance (CL/f) of Metformin and Gliclazide From Plasma
LitersMetformin-Gliclazide (Fasted)Metformin-Gliclazide (Fed)
Metformin226.79 ± 88.58125.93 ± 33.92
Glilclazide1.63 ± 0.571.55 ± 0.52
SecondaryNumber of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Adverse event(AE) was defined as any untoward medical occurrence in participants which does not necessarily have causal relationship with treatment. AE was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event(SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs.

Time frame:
Baseline up to Day 39
Reported as:
Count of participants · Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
ParticipantsMetformin-Gliclazide (Fasted)Metformin-Gliclazide (Fed)
Adverse Events87
Serious Adverse Events (SAEs)00

Adverse events

Collected over Baseline up to Day 39. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Metformin-Gliclazide (Fasted)0/21 (0%)0/21 (0%)8/21 (38.1%)
Metformin-Gliclazide (Fed)0/21 (0%)0/21 (0%)7/21 (33.3%)
Most frequent other events
Most frequent other events
EventMetformin-Gliclazide (Fasted)Metformin-Gliclazide (Fed)
Elevated triglyceridesInvestigations2/213/21
AnemiaBlood and lymphatic system disorders0/213/21
Elevated total bilirubinInvestigations1/210/21
Elevated direct bilirubinInvestigations1/210/21
Elevated indirect bilirubinInvestigations1/210/21
High cholesterolInvestigations1/210/21
HeadacheNervous system disorders1/210/21
VomitingGastrointestinal disorders0/211/21
MyalgiaMusculoskeletal and connective tissue disorders1/210/21

Baseline characteristics

Age, Continuous
Age, Continuous(Years)Metformin-Gliclazide (Fasted), Then Metformin-Gliclazide (Fed)Metformin-Gliclazide (Fed), Then Metformin-Gliclazide (Fasted)Total
Mean37.2 ± 10.932.5 ± 8.034.7 ± 9.6
Sex: Female, Male
Sex: Female, Male(Participants)Metformin-Gliclazide (Fasted), Then Metformin-Gliclazide (Fed)Metformin-Gliclazide (Fed), Then Metformin-Gliclazide (Fasted)Total
Female336
Male7815
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Metformin-Gliclazide (Fasted), Then Metformin-Gliclazide (Fed)Metformin-Gliclazide (Fed), Then Metformin-Gliclazide (Fasted)Total
Hispanic or Latino101121
Not Hispanic or Latino000
Unknown or Not Reported000
07

Study locations

1 site
  • CECYPE
    Mexico City, Mexico
08

References and documents

Study documents

  • Study protocol · Nov 15, 2017
  • Statistical analysis plan · Mar 12, 2018

Documents are hosted by the registry — open the source record to download them.

09

Registry details

Key details

Study ID
NCT03467971
Lead sponsor
Merck KGaA, Darmstadt, Germany
Responsible party
Sponsor
First posted
Mar 16, 2018
Start date
Mar 6, 2018
Primary completion
Apr 22, 2018
Completion
Apr 22, 2018
Results posted
Jul 8, 2019
Last update
Jul 8, 2019

Study contacts

Medical Responsible
study director · Merck KGaA, Darmstadt, Germany

Oversight

FDA-regulated drug
No
FDA-regulated device
No
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