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CompletedNCT03467945Updated Jul 16, 2019Results posted

Bioequivalence and Drug - Drug Interaction Study of Metformin/Gliclazide in Healthy Participants

A Phase 1 interventional study of Metformin/Gliclazide Fixed Combination and Metformin in Healthy, sponsored by Merck KGaA, Darmstadt, Germany. Completed at 1 site in Germany. Open to participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-07-16.

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

Phase
Phase 1
Study type
Interventional
Enrollment
40
Allocation
Randomized
Ages
18 Years to 55 Years
Sex
All
01

Study summary

This study investigated the bioequivalence and drug-drug interaction of Metformin/Gliclazide fixed combination tablet compared to co-administration of individual tablets of Metformin and Gliclazide.

02

Conditions studied

  • Healthy

Keywords

  • Metformin
  • Gliclazide
  • Bioequivalence
  • Drug-drug Interaction
  • Pharmacokinetics
03

Who can participate

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

Inclusion criteria

  • Participants has given written informed consent before any study-related activities were carried out
  • Ethnic origin: Mexicans
  • Weight between 55 and 95 kilogram (kg)
  • Body mass index between 18.5 and 27 kilogram per meter square (kg/m\^2)
  • Not smoking more than 5 cigarettes or 1 cigar or 1 pipe per day (or non smokers)
  • Good physical and mental health status
  • Vital signs (blood pressure and pulse) in supine 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) \<450 milliseconds (ms)
  • All values for biochemistry and hematology tests of blood and urine within the normal range or showing no clinically relevant deviation as judged by the Investigator
  • All women of childbearing potential (WOCBP) were not nursing, were not pregnant, and were using highly effective methods of birth control for a period of at least one month before and after dosing
  • 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)
  • Negative screen for alcohol and drugs of abuse at Screening and on each admission
  • Negative screen for Hepatitis B surface (HBs) antigens, Hepatitis C Virus (HCV) antibodies, Hepatitis A Virus (HAV) antibodies and Human Immunodeficiency Virus (HIV) 1 and 2 antibodies
  • Other protocol defined inclusion criteria could apply

Exclusion criteria

Exclusion Criteria:

  • Participation in a clinical trial within 90 days prior to first drug administration
  • Participants who have donated more than 500 milliliter (mL) of blood or who have lost significantly (more than 450 mL) blood within 90 days prior to first drug of administration
  • Any surgical or medical condition, 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 surgery of the gastrointestinal tract
  • Allergy
  • Receipt of any prescription or non-prescription medication within 2 weeks before the first study drug administration
  • Renal failure or renal dysfunction (creatinine clearance less than [\<] 80 mL/minute) as assessed by using the estimated measure with the Cockcroft-Gault formula
  • Known lack of participant compliance or inability to communicate or cooperate with the Investigator
  • Considerable diet deviations from normal nutritional patterns
  • Consumption of large quantities of methylxanthine-containing beverages (more than 600 milligram [mg] caffeine / day: one cup [240 mL] of coffee contains approx. 100 mg of caffeine, one cup of tea approximately 30 mg and one glass of cola approximately 20 mg caffeine)
  • Consumption of grapefruit, orange, cranberry or juices of these fruits, 14 days prior to drug administration and during the study
  • Legal incapacity or limited legal capacity
  • Participants kept in detention
  • 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
40 participants (actual)

Study arms

  • Experimental
    Treatment Sequence 1

    Participants received single oral dose of metformin 1000 milligram (mg) and gliclazide 30 mg fixed combination tablet in treatment period 1 followed by concomitant oral dosing of metformin 1000 mg and gliclazide 30 mg in treatment period 2 followed by single oral dose of metformin 1000 mg in treatment period 3 and then a single oral dose of gliclazide 30 mg in treatment period 4. Each treatment period was separated by a 14-day wash-out period.

    Drug: Metformin/Gliclazide Fixed Combination · Drug: Metformin · Drug: Gliclazide

  • Experimental
    Treatment Sequence 2

    Participants received concomitant oral dosing of metformin 1000 mg and gliclazide 30 mg in treatment period 1 followed by single oral dose of gliclazide 30 mg in treatment period 2 followed by single oral dose of metformin 1000 mg and gliclazide 30 mg fixed combination tablet in treatment period 3 and then single oral dose of metformin 1000 mg in treatment period 4. Each treatment period was separated by a 14-day wash-out period.

    Drug: Metformin/Gliclazide Fixed Combination · Drug: Metformin · Drug: Gliclazide

  • Experimental
    Treatment Sequence 3

    Participants received single oral dose of metformin 1000 mg in treatment period 1 followed by single oral dose of metformin 1000 mg and gliclazide 30 mg fixed combination tablet in treatment period 2 followed by single oral dose of gliclazide 30 mg in treatment period 3 and then concomitant oral dosing of metformin 1000 mg and gliclazide 30 mg in treatment period 4. Each treatment period was separated by a 14-day wash-out period.

    Drug: Metformin/Gliclazide Fixed Combination · Drug: Metformin · Drug: Gliclazide

  • Experimental
    Treatment Sequence 4

    Participants received single oral dose of gliclazide 30 mg in treatment period 1 followed by single oral dose of metformin 1000 mg in treatment period 2 followed by concomitant oral dosing of metformin 1000 mg and gliclazide 30 mg in treatment period 3 and then single oral dose of metformin 1000 mg and gliclazide 30 mg fixed combination tablet in treatment period 4. Each treatment period was separated by a 14-day wash-out period.

    Drug: Metformin/Gliclazide Fixed Combination · Drug: Metformin · Drug: Gliclazide

Interventions

  • DrugMetformin/Gliclazide Fixed Combination

    Participants received single oral dose of Metformin and Gliclazide fixed combination tablet in treatment period 1, 2, 3 or 4.

  • DrugMetformin

    Participants received single oral dose of Metformin tablet in treatment period 1, 2, 3 or 4.

  • DrugGliclazide

    Participants received single oral dose of Gliclazide tablet in treatment period 1, 2, 3 or 4.

05

What researchers measure

Primary outcomes

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

    Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

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

    Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

  3. Maximum Observed Plasma Concentration (Cmax) of Metformin

    Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

  4. Maximum Observed Plasma Concentration (Cmax) of Gliclazide

    Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

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

    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, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

  6. Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of 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, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

Secondary outcomes

  1. Apparent Volume of Distribution (Vz/f) of Metformin

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

    Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

  2. Apparent Volume of Distribution (Vz/f) of Gliclazide

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

    Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

  3. Elimination Half Life (t1/2) of Metformin

    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.

    Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

  4. Elimination Half Life (t1/2) of Gliclazide

    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.

    Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

  5. Apparent Total Body Clearance (CL/f) of Metformin

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

    Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

  6. Apparent Total Body Clearance (CL/f) of Gliclazide

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

    Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

  7. Median Residence Time (MRT) for Metformin

    MRT is the average time that the molecules introduced into the body stays in the body.

    Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

  8. Median Residence Time (MRT) for Gliclazide

    MRT is the average time that the molecules introduced into the body stays in the body.

    Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose

  9. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

    An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. 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. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. TEAEs included both Serious TEAEs and non-serious TEAEs.

    Time frame: Baseline up to Day 72

06

Results

Posted Jul 16, 2019

Participant flow

Treatment Period 1
Participant flow — Treatment Period 1
MilestoneTreatment Sequence 1Treatment Sequence 2Treatment Sequence 3Treatment Sequence 4
Started10101010
Completed10101010
Not completed0000
Treatment Period 2
Participant flow — Treatment Period 2
MilestoneTreatment Sequence 1Treatment Sequence 2Treatment Sequence 3Treatment Sequence 4
Started10101010
Completed1091010
Not completed0100
Withdrew: Withdrawal by subject0100
Treatment Period 3
Participant flow — Treatment Period 3
MilestoneTreatment Sequence 1Treatment Sequence 2Treatment Sequence 3Treatment Sequence 4
Started1091010
Completed9989
Not completed1021
Withdrew: Withdrawal by subject1021
Treatment Period 4
Participant flow — Treatment Period 4
MilestoneTreatment Sequence 1Treatment Sequence 2Treatment Sequence 3Treatment Sequence 4
Started9989
Completed9989
Not completed0000

Outcome measures

PrimaryArea Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin
Time frame:
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · nanogram*hour per milliliter (ng*h/ml)
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin
nanogram*hour per milliliter (ng*h/ml)Metformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyMetformin
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin5033.8718 ± 1475.34186142.2821 ± 1848.48576090.7932 ± 1543.6463
Statistical analysis
  • Metformin-Gliclazide Combination vs Metformin and Gliclazide Separately · Geometric least squares mean ratio: 81.4421 · 90% CI 75.2805 to 88.1079
  • Metformin and Gliclazide Separately vs Metformin · Geometric least squares mean ratio: 102.2930 · 90% CI 97.8819 to 106.9028
  • Metformin-Gliclazide Combination vs Metformin · Geometric least squares mean ratio: 81.0112 · 90% CI 74.8823 to 87.6417
PrimaryArea Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Gliclazide
Time frame:
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours 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 Gliclazide
ng.h/mlMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyGliclazide
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Gliclazide20707.7394 ± 8267.065320280.3103 ± 8219.152021205.2514 ± 7638.0877
Statistical analysis
  • Metformin-Gliclazide Combination vs Metformin and Gliclazide Separately · Geometric least squares mean ratio: 102.2930 · 90% CI 97.8819 to 106.9028
  • Metformin and Gliclazide Separately vs Gliclazide · Geometric least squares mean ratio: 105.7255 · 90% CI 101.1665 to 110.4900
  • Metformin-Gliclazide Combination vs Gliclazide · Geometric least squares mean ratio: 96.7533 · 90% CI 92.5812 to 101.1135
PrimaryMaximum Observed Plasma Concentration (Cmax) of Metformin
Time frame:
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · nanogram per milliliter (ng/ml)
Maximum Observed Plasma Concentration (Cmax) of Metformin
nanogram per milliliter (ng/ml)Metformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyMetformin
Maximum Observed Plasma Concentration (Cmax) of Metformin806.3895 ± 279.50631011.3941 ± 309.8136977.2693 ± 262.4312
Statistical analysis
  • Metformin-Gliclazide Combination vs Metformin and Gliclazide Separately · Geometric least squares mean ratio: 77.6923 · 90% CI 70.3830 to 85.7606
  • Metformin and Gliclazide Separately vs Metformin · Geometric least squares mean ratio: 108.0819 · 90% CI 102.2370 to 114.2609
  • Metformin-Gliclazide Combination vs Metformin · Geometric least squares mean ratio: 79.4367 · 90% CI 71.9633 to 87.6861
PrimaryMaximum Observed Plasma Concentration (Cmax) of Gliclazide
Time frame:
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · ng/ml
Maximum Observed Plasma Concentration (Cmax) of Gliclazide
ng/mlMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyGliclazide
Maximum Observed Plasma Concentration (Cmax) of Gliclazide972.168 ± 312.7305892.6201 ± 259.7459836.7239 ± 251.6451
Statistical analysis
  • Metformin-Gliclazide Combination vs Metformin and Gliclazide Separately · Geometric least squares mean ratio: 108.0819 · 90% CI 102.2370 to 114.2609
  • Metformin and Gliclazide Separately vs Gliclazide · Geometric least squares mean ratio: 93.6828 · 90% CI 88.6166 to 99.0386
  • Metformin-Gliclazide Combination vs Gliclazide · Geometric least squares mean ratio: 115.3700 · 90% CI 109.1310 to 121.9658
PrimaryArea Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin

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, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · ng*h/ml
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin
ng*h/mlMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyMetformin
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin5313.3897 ± 1549.26886388.9849 ± 1857.62056341.5658 ± 1560.7170
Statistical analysis
  • Metformin-Gliclazide Combination vs Metformin and Gliclazide Separately · Geometric least squares mean ratio: 82.6022 · 90% CI 76.5513 to 89.1314
  • Metformin and Gliclazide Separately vs Metformin · Geometric least squares mean ratio: 101.8499 · 90% CI 97.8819 to 106.9028
  • Metformin-Gliclazide Combination vs Metformin · Geometric least squares mean ratio: 81.0112 · 90% CI 74.8823 to 87.6417
PrimaryArea Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of 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, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · ng*h/ml
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Gliclazide
ng*h/mlMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyGliclazide
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Gliclazide21495.2343 ± 8358.337321120.6761 ± 8270.509222136.9988 ± 7687.4829
Statistical analysis
  • Metformin-Gliclazide Combination vs Metformin and Gliclazide Separately · Geometric least squares mean ratio: 101.8499 · 90% CI 97.5947 to 106.2906
  • Metformin and Gliclazide Separately vs Gliclazide · Geometric least squares mean ratio: 105.9150 · 90% CI 101.4900 to 110.5330
  • Metformin-Gliclazide Combination vs Gliclazide · Geometric least squares mean ratio: 96.1619 · 90% CI 92.1443 to 100.3546
SecondaryApparent Volume of Distribution (Vz/f) of Metformin

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

Time frame:
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · Milliliter
Apparent Volume of Distribution (Vz/f) of Metformin
MilliliterMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyMetformin
Apparent Volume of Distribution (Vz/f) of Metformin1893618.4672 ± 1346880.11981414424.1926 ± 643556.20881489164.0229 ± 818767.0681
SecondaryApparent Volume of Distribution (Vz/f) of Gliclazide

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

Time frame:
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · Milliliter
Apparent Volume of Distribution (Vz/f) of Gliclazide
MilliliterMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyGliclazide
Apparent Volume of Distribution (Vz/f) of Gliclazide31636.8920 ± 7584.165132601.0115 ± 7057.805031413.9679 ± 6422.4920
SecondaryElimination Half Life (t1/2) of Metformin

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.

Time frame:
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · Hours
Elimination Half Life (t1/2) of Metformin
HoursMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyMetformin
Elimination Half Life (t1/2) of Metformin6.7151 ± 5.13725.9796 ± 2.84426.3048 ± 3.7114
SecondaryElimination Half Life (t1/2) of Gliclazide

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.

Time frame:
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · Hours
Elimination Half Life (t1/2) of Gliclazide
HoursMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyGliclazide
Elimination Half Life (t1/2) of Gliclazide15.3086 ± 6.023115.4587 ± 5.600715.6222 ± 5.2904
SecondaryApparent Total Body Clearance (CL/f) of Metformin

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

Time frame:
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · Milliliter per Hour (mL/ h)
Apparent Total Body Clearance (CL/f) of Metformin
Milliliter per Hour (mL/ h)Metformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyMetformin
Apparent Total Body Clearance (CL/f) of Metformin207132.8293 ± 70959.4296170273.4024 ± 51108.0288167260.5841 ± 39170.7306
SecondaryApparent Total Body Clearance (CL/f) of Gliclazide

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

Time frame:
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · mL/h
Apparent Total Body Clearance (CL/f) of Gliclazide
mL/hMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyGliclazide
Apparent Total Body Clearance (CL/f) of Gliclazide1572.5246 ± 516.37241606.8952 ± 569.48111498.9932 ± 463.2158
SecondaryMedian Residence Time (MRT) for Metformin

MRT is the average time that the molecules introduced into the body stays in the body.

Time frame:
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · Hours
Median Residence Time (MRT) for Metformin
HoursMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyMetformin
Median Residence Time (MRT) for Metformin8.3952 ± 3.07587.5836 ± 1.68077.7636 ± 2.0658
SecondaryMedian Residence Time (MRT) for Gliclazide

MRT is the average time that the molecules introduced into the body stays in the body.

Time frame:
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose
Reported as:
Mean · Hours
Median Residence Time (MRT) for Gliclazide
HoursMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyGliclazide
Median Residence Time (MRT) for Gliclazide23.0593 ± 7.801024.4927 ± 7.748425.8590 ± 7.5834
SecondaryNumber of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. 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. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. TEAEs included both Serious TEAEs and non-serious TEAEs.

Time frame:
Baseline up to Day 72
Reported as:
Count of participants · Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
ParticipantsMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyMetforminGliclazide
TEAEs9678
SAEs0000

Adverse events

Collected over Baseline up to Day 72. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Metformin-Gliclazide Combination0/35 (0%)0/35 (0%)9/35 (25.7%)
Metformin and Gliclazide Separately0/35 (0%)0/35 (0%)6/35 (17.1%)
Metformin0/35 (0%)0/35 (0%)7/35 (20%)
Gliclazide0/35 (0%)0/35 (0%)8/35 (22.9%)
Most frequent other events
Showing 10 of 17
Most frequent other events
EventMetformin-Gliclazide CombinationMetformin and Gliclazide SeparatelyMetforminGliclazide
AnemiaBlood and lymphatic system disorders5/352/355/357/35
Elevated aspartate aminotrasferaseInvestigations1/350/355/351/35
Elevated alanine aminostrasferaseInvestigations1/350/354/351/35
Elevated triglyceridesInvestigations1/353/352/350/35
UrethritisInfections and infestations1/352/350/350/35
High cholesterolInvestigations0/350/351/350/35
Vasovagal reactionNervous system disorders0/351/350/350/35
HeadacheNervous system disorders1/350/350/351/35
DizzinessNervous system disorders0/350/350/351/35
OdynophagiaGastrointestinal disorders0/351/350/351/35

Baseline characteristics

All participants who were randomized into the study.

Age, Continuous
Age, Continuous(Years)Treatment Sequence 1Treatment Sequence 2Treatment Sequence 3Treatment Sequence 4Total
Mean22.8 ± 9.823.9 ± 3.731.5 ± 8.325.7 ± 5.227.3 ± 7.5
Sex: Female, Male
Sex: Female, Male(Participants)Treatment Sequence 1Treatment Sequence 2Treatment Sequence 3Treatment Sequence 4Total
Female633517
Male477523
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Treatment Sequence 1Treatment Sequence 2Treatment Sequence 3Treatment Sequence 4Total
Hispanic or Latino1010101040
Not Hispanic or Latino00000
Unknown or Not Reported00000
07

Study locations

1 site
  • Please Contact the Merck KGaA Communication Center
    Darmstadt, 64293, Germany
08

References and documents

Study documents

  • Statistical analysis plan · Aug 31, 2018
  • Study protocol · May 18, 2017

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

09

Registry details

Key details

Study ID
NCT03467945
Lead sponsor
Merck KGaA, Darmstadt, Germany
Responsible party
Sponsor
First posted
Mar 16, 2018
Start date
Feb 16, 2018
Primary completion
Apr 29, 2018
Completion
Apr 29, 2018
Results posted
Jul 16, 2019
Last update
Jul 16, 2019

Study contacts

Medical Responsible
study director · Merck KGaA, Darmstadt, Germany

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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