Type 2 Diabetes Mellitus
Conditions
Brief summary
The purpose of this study is to investigate the effect of the baseline body mass index (BMI) on the response to Glucophage XR monotherapy in glycemic control in Chinese patients with newly diagnosed type 2 diabetes
Interventions
DRUGMetformin XR
Tablets, Oral, 500mg tid, 1500 mg/day, 16 weeks
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
17 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Signed Written Informed Consent * Age≥ 17 and \<80 years, * Newly diagnosed T2DM (defined as T2DM diagnosed within 6 months prior to enrollment) * Oral antidiabetic agents naïve (defined as without receiving any anti-diabetic medication therapy before, or having received anti-diabetic medication ≤ 14 days but not received any antidiabetic medication within the last 1 month prior to enrollment) * HbA1c ≥ 7.0% and ≤10.0%
Exclusion criteria
* Women of child bearing potential * body mass index (BMI)≥35 Kg/m2 or BMI \<18.5 Kg/m2 * Hemoglobin A1c (HbA1c)\>10.0% or \<7.0% * Active liver disease and/or significant abnormal liver function * Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma * Congestive heart failure defined as New York Heart Association (NYHA) class III or IV and /or left ventricular ejection fraction ≤40% * Significant cardiovascular history with the past 6 months * Severe retinopathy, persistent uncontrolled hypertension (SBP≥180mmHg, or DBP≥105mmHg) * Severe chronic gastrointestinal disease * History of alcohol abuse or illegal drug abuse within the past 12 months * Diagnosed anemia * Creatine kinase ≥3 X ULN * Serum creatinine ≥1.5 mg/dL(133μmol/L) \[males\], ≥1.4 mg/dL(124 μmol/L)\[females\] * Alanine amino transferase (ALT) and/or aspartate amino transferase (AST)\> 1.5 X ULN and/or total bilirubin \> 2 X ULN * Hemoglobin \<12g/dL \[males\], \<11g/dL \[females\] * Allergies and Adverse Drug Reactions * Prohibited Treatments and/or Therapies * Prisoners or subjects who are involuntarily incarcerated * Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness * Subjects decline to participate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline at Week 16 (95% Confidence Interval) in Glycosated Hemoglobin A1c (HbA1c) (Last Observation Carried Forward) - Full Analysis Set (FAS) | Baseline to Week 16 | Baseline for HbA1c is defined as that value obtained at screening visit. HbA1c was measured as a percent (%) of hemoglobin; normal range was 4.7 to 6.4% and values were obtained through a central laboratory. The Last Observation Carried Forward (LOCF) data set includes data recorded at a given visit or, if no observation is recorded at that visit, data carried forward from the previous visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Total Cholesterol (TC) - Full Analysis Set | Baseline to Week 16 | For fasting total cholesterol (TC), baseline is defined as Day 1 (first day of treatment). Total cholesterol was measured in millimoles per liter (mmol/L) and obtained through local laboratories. |
| Mean Change From Baseline at Week 16 (95% Confidence Interval) of Fasting Plasma Glucose (FPG) - Full Analysis Set | Baseline to Week 16 | Baseline was defined as the value obtained at the screening visit. FPG was measured in millimoles/Liter (mmol/L) and obtained through local laboratories. |
| Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Low-density Lipoprotein Cholesterol (LDL-C) - Full Analysis Set | Baseline to Week 16 | Baseline was defined as values obtained on Day 1. Low-density lipoprotein cholesterol (LDL-C) was measured in millimoles per liter (mmol/L) and obtained through local laboratories. |
| Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting High-density Lipoprotein Cholesterol (HDL-C) - Full Analysis Set | Baseline to Week 16 | Baseline was defined as value obtained on Day 1 (first day of treatment). High-density lipoprotein cholesterol (HDL-C) was measured in millimoles per liter (mmol/L) and obtained through local laboratories. |
| Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Triglycerides (TG) - Full Analysis Set | Baseline to Week 16 | Baseline was defined as value obtained on Day 1 (first day of treatment). Triglycerides (TG) were measured in millimoles per liter (mmol/L)and values obtained through local laboratories. |
| Mean Change From Baseline at Week 16 (95% Confidence Interval) in C-Reactive Protein (CRP) - Full Analysis Set | Baseline to Week 16 | Baseline was defined as value obtained on Day 1 (first day of treatment). C-Reactive Protein (CRP) was measured in milligrams/liter (mg/L) and values were obtained through a central laboratory; normal was less than 5.0 mg/L. |
| Mean Change From Baseline at Week 16 (95% Confidence Interval) in Plasminogen Activator Inhibitor-1 (PAI-1) - Full Analysis Set | Baseline to Week 16 | Baseline was defined as value obtained on Day 1 (first day of treatment). PAI-1 (activity) was measured in units/milliliter (U/mL)and values obtained through a central laboratory; normal was less than 25.00 U/mL. |
| Mean Change From Baseline at Week 16 (95% Confidence Interval) in Adiponectin - Full Analysis Set | Baseline to Week 16 | Baseline was defined as value obtained on Day 1 (first day of treatment). Adiponectin was measured in milligrams/liter (mg/L) and values obtained through a central laboratory; normal range was 1.20 to 20.00 mg/L. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Baseline to Week 16 | Baseline defined as value obtained either in screening visit or last value obtained before glucophage XR treatment given on Day 1. Serum chemistries evaluating kidney or liver function: blood urea nitrogen(BUN), serum creatinine (SCr), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), total bilirubin (BR), uric acid (UA). Abnormal increase in kidney and liver function tests defined as 1.25 - less than, equal to (\<=)2.6 times (x) upper limit of normal (ULN)in ALT, AST, total BR, UA; abnormal increase defined as 1.25 to \<= 5.1 x ULN in BUN. Safety population included participants who enrolled in the study and took at least 1 dose of Glucophage XR. |
| Number of Participants With Clinically Significant Changes From Baseline at Week 16 in Urinalysis - Safety Population | Baseline to Week 16 | Urinalysis included pH and specific gravity. Baseline defined as values obtained at screening visit. Clinically significant: outside the reference range (low/high)and judged to be significant by the investigator: Specific gravity 1.003 - 1.035; ph 5 - 8. Safety population included participants who enrolled in the study and took at least 1 dose of Glucophage XR. |
| Mean Change From Baseline at Week at Week 16 in ECG Parameter Heart Rate (HR) - Safety Population | Baseline to Week 16 | Baseline was defined as ECG obtained at the screening visit. ECG was 12-lead. Heart rate (HR) was measured in beats per minute (beats/min). Safety population included participants who enrolled in the study and took at least 1 dose of Glucophage XR. |
| Mean Change From Baseline at Week 16 in Diastolic and Systolic Blood Pressure - Safety Population | Baseline to Week 16 | Baseline was defined as the value obtained at screening or value obtained on Day 1 before treatment. Diastolic and systolic blood pressure was measured in millimeters of mercury (mm Hg). Safety population included participants who enrolled in the study and took at least 1 dose of Glucophage XR. |
| Number of Participants Who Had a Normal Electrocardiogram (ECG) at Baseline and an ECG at Week 16 (or Termination Visit) Which Was Considered to be Abnormal With Clinical Significance - Safety Population | Baseline to Week 16 | Baseline was defined as ECG obtained at the screening visit. A judgment of clinical significance was at the discretion of the investigator. Safety population included participants who enrolled in the study and took at least 1 dose of Glucophage XR. |
| Number of Participants With Clinically Significant Changes From Baseline at Week 16 in the Hematology Laboratory Test Profile - Safety Population | Baseline to Week 16 | Hematology profile = hematocrit, hemoglobin, red blood cell count (RBC), white blood cell count(WBC), lymphocytes, monocytes, basophils, eosinophils, neutrophils, platelet count. Baseline: value obtained at screening or last value obtained before treatment. LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Hemoglobin (g/dL): \>3 g/dL decrease from preRX; hematocrit (%): \<0.75\*preRX; RBC (\*10\^6 c/uL): \<0.75\*preRX; platelet count (\*10\^9 c/uL): \<0.67\*LLN or \>1.5\*ULN, of if preRX\<LLN, use 0.5\*preRX and \<100,000/mm\^3; WBC (\*10\^3 c/uL): \<0.75\*LLN or \>1.25\*ULN, or if preRX \<LLN, use \<0.8\*preRX or \>ULN, or if preRX\>ULN, use \>1.2\*preRX or \<LLN; neutrophils+bands (\*10\^3 c/uL): if value \<1.0\*10\^3 c/uL; eosinophils (\*10\^3 c/uL): if value \>0.750\*10\^3 c/uL; basophils (\*10\^3 c/uL): if value \>400/mm\^3; monocytes (\*10\^3 c/uL): if value \>2000/mm\^3; lymphocytes (\*10\^3 c/uL): if value \<0.750\*10\^3 c/uL or if value \>7.50\*10\^3 c/uL. |
| Number of Participants With Episodes of Lactic Acidosis or Hypoglycemia From Day 1 to Week 16 - Safety Population | Day 1 to Week 16 | Day 1 was first day of treatment. Lactic acidosis defined as elevated blood lactate levels (\>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and increased lactate/pyruvate ratio. Hypoglycemia (low levels of blood glucose) was reported as an adverse event. Safety population included participants who had enrolled in the study and took at least 1 dose of glucophage extended release (glucophage XR). If a subject experienced more than one adverse event, the subject was counted once at the highest severity. |
Countries
China
Participant flow
Recruitment details
Started November 2009, Completed March 2011 at Peking University People's Hospital. Participants diagnosed with Type 2 diabetes mellitus 6 months prior to enrollment; were oral antidiabetic agent naive (either having received no antidiabetic agents or received agents 14 days or less, or received none within a month of enrollment in the study.
Pre-assignment details
Participants had glycosated hemoglobin A1c (HbA1c) screening values greater than, equal to 7.0% and less than, equal to 10.0%. Participants were between the ages of 17 and 80 years of age and Chinese Asian. Screening visit was up to 7 days prior to Day 1 (treatment).
Participants by arm
| Arm | Count |
|---|---|
| Glucophage XR in Normal Weight Participants Normal weight was defined as body mass index (BMI) greater than, equal to 18.5 kg/m\^2 and \< 24 kg/m\^2 ). Glucophage XR titrated from Day 1 to Week 4 in increments of 500 mg up to maximum dose of 2000 mg. Participants were dosed for a total of 16 weeks. | 125 |
| Glucophage XR in Overweight Participants Overweight was defined as body mass index (BMI) greater than, equal to 24 kg/m\^2 and less than 28 kg/m\^2. Glucophage XR titrated from Day 1 to Week 4 in increments of 500 mg up to maximum dose of 2000 mg. Participants were dosed for a total of 16 weeks. | 122 |
| Glucophage XR in Obese Participants Obese was defined as body mass index (BMI) greater than, equal to 28 kg/m\^2. Glucophage XR titrated from Day 1 to Week 4 in increments of 500 mg up to maximum dose of 2000 mg. Participants were dosed for a total of 16 weeks. | 124 |
| Total | 371 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 4 | 7 |
| Overall Study | immigration | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 2 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 3 | 2 |
| Overall Study | Other | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 5 | 5 |
Baseline characteristics
| Characteristic | Glucophage XR in Normal Weight Participants | Glucophage XR in Overweight Participants | Glucophage XR in Obese Participants | Total |
|---|---|---|---|---|
| Age Continuous | 53.0 years FULL_RANGE 10.32 | 51.0 years FULL_RANGE 9.21 | 52.5 years FULL_RANGE 10.97 | 52.0 years FULL_RANGE 10.17 |
| Region of Enrollment China | 125 participants | 122 participants | 124 participants | 371 participants |
| Sex: Female, Male Female | 64 Participants | 45 Participants | 52 Participants | 161 Participants |
| Sex: Female, Male Male | 61 Participants | 77 Participants | 72 Participants | 210 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 43 / 125 | 47 / 122 | 46 / 124 |
| serious Total, serious adverse events | 1 / 125 | 0 / 122 | 1 / 124 |
Outcome results
Primary
Mean Change From Baseline at Week 16 (95% Confidence Interval) in Glycosated Hemoglobin A1c (HbA1c) (Last Observation Carried Forward) - Full Analysis Set (FAS)
Baseline for HbA1c is defined as that value obtained at screening visit. HbA1c was measured as a percent (%) of hemoglobin; normal range was 4.7 to 6.4% and values were obtained through a central laboratory. The Last Observation Carried Forward (LOCF) data set includes data recorded at a given visit or, if no observation is recorded at that visit, data carried forward from the previous visit.
Time frame: Baseline to Week 16
Population: Full Analysis Set included participants who were enrolled, took at least 1 study medication and had at least 1 post baseline HbA1c assessment. Baseline data was not carried forward or averaged with on-treatment data to impute missing values for the LOCF data set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Glycosated Hemoglobin A1c (HbA1c) (Last Observation Carried Forward) - Full Analysis Set (FAS) | -1.95 percentage of hemoglobin | 95% Confidence Interval 0.922 |
| Glucophage XR in Overweight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Glycosated Hemoglobin A1c (HbA1c) (Last Observation Carried Forward) - Full Analysis Set (FAS) | -1.79 percentage of hemoglobin | 95% Confidence Interval 0.941 |
| Glucophage XR in Obese Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Glycosated Hemoglobin A1c (HbA1c) (Last Observation Carried Forward) - Full Analysis Set (FAS) | -1.68 percentage of hemoglobin | 95% Confidence Interval 0.854 |
Comparison: Standard deviation assumed for changes from baseline in HbA1c maximally was 1.0 across the baseline BMI subgroups. 97 participants in a single subgroup would be sufficient to estimate mean change in HbA1c with precision of 0.20% within the subgroup. Given number of baseline BMI subgroups and no correction for reason of multiplicity was made to the 95% CI within each BMI subgroup, total sample size calculated as 291. Sample size used the method CI for mean for one group in nQuery Advisor v6.0.p-value: 0.0806ANCOVA
p-value: 0.1984t-test, 2 sided
p-value: 0.0232t-test, 2 sided
p-value: 0.3589t-test, 2 sided
Secondary
Mean Change From Baseline at Week 16 (95% Confidence Interval) in Adiponectin - Full Analysis Set
Baseline was defined as value obtained on Day 1 (first day of treatment). Adiponectin was measured in milligrams/liter (mg/L) and values obtained through a central laboratory; normal range was 1.20 to 20.00 mg/L.
Time frame: Baseline to Week 16
Population: Full Analysis Set (FAS) included participants who were enrolled, took at least 1 study medication and had at least 1 post baseline HbA1c assessment. For this outcome measure, 78, 70, and 72 normal, overweight, obese participants, respectively, were missing and were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Adiponectin - Full Analysis Set | 1.742 mg/L | 95% Confidence Interval 8.6503 |
| Glucophage XR in Overweight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Adiponectin - Full Analysis Set | 1.102 mg/L | 95% Confidence Interval 2.2116 |
| Glucophage XR in Obese Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Adiponectin - Full Analysis Set | 0.050 mg/L | 95% Confidence Interval 3.5516 |
Secondary
Mean Change From Baseline at Week 16 (95% Confidence Interval) in C-Reactive Protein (CRP) - Full Analysis Set
Baseline was defined as value obtained on Day 1 (first day of treatment). C-Reactive Protein (CRP) was measured in milligrams/liter (mg/L) and values were obtained through a central laboratory; normal was less than 5.0 mg/L.
Time frame: Baseline to Week 16
Population: Full Analysis Set (FAS) consisted of participants who were enrolled, took at least 1 study medication and had at least 1 post baseline HbA1c assessment. For this outcome measure, 102, 95, and 85 normal, overweight, obese participants, respectively, were missing and were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in C-Reactive Protein (CRP) - Full Analysis Set | -0.589 mg/L | 95% Confidence Interval 1.0914 |
| Glucophage XR in Overweight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in C-Reactive Protein (CRP) - Full Analysis Set | 3.144 mg/L | 95% Confidence Interval 16.4019 |
| Glucophage XR in Obese Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in C-Reactive Protein (CRP) - Full Analysis Set | 1.633 mg/L | 95% Confidence Interval 8.0706 |
Secondary
Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting High-density Lipoprotein Cholesterol (HDL-C) - Full Analysis Set
Baseline was defined as value obtained on Day 1 (first day of treatment). High-density lipoprotein cholesterol (HDL-C) was measured in millimoles per liter (mmol/L) and obtained through local laboratories.
Time frame: Baseline to Week 16
Population: Full Analysis Set (FAS) consisted of participants who were enrolled, took at least 1 study medication and had at least 1 post baseline HbA1c assessment. For this outcome measure, 2, 3, and 8 normal, overweight, obese participants, respectively, were missing and were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting High-density Lipoprotein Cholesterol (HDL-C) - Full Analysis Set | 0.056 mmol/L | 95% Confidence Interval 0.2016 |
| Glucophage XR in Overweight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting High-density Lipoprotein Cholesterol (HDL-C) - Full Analysis Set | 0.024 mmol/L | 95% Confidence Interval 0.3428 |
| Glucophage XR in Obese Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting High-density Lipoprotein Cholesterol (HDL-C) - Full Analysis Set | 0.032 mmol/L | 95% Confidence Interval 0.2042 |
p-value: 0.1431ANCOVA
p-value: 0.4066t-test, 2 sided
p-value: 0.4071t-test, 2 sided
Secondary
Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Low-density Lipoprotein Cholesterol (LDL-C) - Full Analysis Set
Baseline was defined as values obtained on Day 1. Low-density lipoprotein cholesterol (LDL-C) was measured in millimoles per liter (mmol/L) and obtained through local laboratories.
Time frame: Baseline to Week 16
Population: Full Analysis Set (FAS) consisted of participants who were enrolled, took at least 1 study medication and had at least 1 post baseline HbA1c assessment. For this outcome measure, 1, 3, and 9 normal, overweight, obese participants, respectively, were missing and were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Low-density Lipoprotein Cholesterol (LDL-C) - Full Analysis Set | -0.306 mmol/L | 95% Confidence Interval 0.5746 |
| Glucophage XR in Overweight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Low-density Lipoprotein Cholesterol (LDL-C) - Full Analysis Set | -0.143 mmol/L | 95% Confidence Interval 0.6605 |
| Glucophage XR in Obese Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Low-density Lipoprotein Cholesterol (LDL-C) - Full Analysis Set | -0.181 mmol/L | 95% Confidence Interval 0.6258 |
p-value: 0.4508ANCOVA
p-value: 0.0526t-test, 2 sided
p-value: 0.1295t-test, 2 sided
Secondary
Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Total Cholesterol (TC) - Full Analysis Set
For fasting total cholesterol (TC), baseline is defined as Day 1 (first day of treatment). Total cholesterol was measured in millimoles per liter (mmol/L) and obtained through local laboratories.
Time frame: Baseline to Week 16
Population: Full Analysis Set (FAS) consisted of participants who were enrolled, took at least 1 study medication and had at least 1 post baseline HbA1c assessment. For this outcome measure, 1, 3, and 8 normal, overweight, obese participants, respectively, were missing and were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Total Cholesterol (TC) - Full Analysis Set | -0.388 mmol/L | 95% Confidence Interval 0.9164 |
| Glucophage XR in Overweight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Total Cholesterol (TC) - Full Analysis Set | -0.048 mmol/L | 95% Confidence Interval 0.956 |
| Glucophage XR in Obese Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Total Cholesterol (TC) - Full Analysis Set | -0.144 mmol/L | 95% Confidence Interval 0.8188 |
p-value: 0.0305ANCOVA
p-value: 0.008t-test, 2 sided
p-value: 0.0422t-test, 2 sided
Secondary
Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Triglycerides (TG) - Full Analysis Set
Baseline was defined as value obtained on Day 1 (first day of treatment). Triglycerides (TG) were measured in millimoles per liter (mmol/L)and values obtained through local laboratories.
Time frame: Baseline to Week 16
Population: Full Analysis Set (FAS) consisted of participants who were enrolled, took at least 1 study medication and had at least 1 post baseline HbA1c assessment. For this outcome measure, 1, 4, and 8 normal, overweight, obese participants, respectively, were missing and were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Triglycerides (TG) - Full Analysis Set | -0.172 mmol/L | 95% Confidence Interval 2.0678 |
| Glucophage XR in Overweight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Triglycerides (TG) - Full Analysis Set | 0.262 mmol/L | 95% Confidence Interval 3.3195 |
| Glucophage XR in Obese Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Fasting Triglycerides (TG) - Full Analysis Set | -0.041 mmol/L | 95% Confidence Interval 2.2018 |
p-value: 0.021ANCOVA
p-value: 0.2507t-test, 2 sided
p-value: 0.6546t-test, 2 sided
Secondary
Mean Change From Baseline at Week 16 (95% Confidence Interval) in Plasminogen Activator Inhibitor-1 (PAI-1) - Full Analysis Set
Baseline was defined as value obtained on Day 1 (first day of treatment). PAI-1 (activity) was measured in units/milliliter (U/mL)and values obtained through a central laboratory; normal was less than 25.00 U/mL.
Time frame: Baseline to Week 16
Population: Full Analysis Set (FAS) population = 111, 111, 112 in normal, overweight, obese participants respectively. For this outcome measure, 84, 79, and 75 normal, overweight, obese participants, respectively, were missing and were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Plasminogen Activator Inhibitor-1 (PAI-1) - Full Analysis Set | 0.465 U/mL | 95% Confidence Interval 8.5233 |
| Glucophage XR in Overweight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Plasminogen Activator Inhibitor-1 (PAI-1) - Full Analysis Set | 1.177 U/mL | 95% Confidence Interval 8.9405 |
| Glucophage XR in Obese Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) in Plasminogen Activator Inhibitor-1 (PAI-1) - Full Analysis Set | -1.792 U/mL | 95% Confidence Interval 7.9231 |
Secondary
Mean Change From Baseline at Week 16 (95% Confidence Interval) of Fasting Plasma Glucose (FPG) - Full Analysis Set
Baseline was defined as the value obtained at the screening visit. FPG was measured in millimoles/Liter (mmol/L) and obtained through local laboratories.
Time frame: Baseline to Week 16
Population: Full Analysis Set (FAS) included enrolled participants,who took at least 1 dose of drug and had at least 1 post baseline HbA1c assessment. For this outcome measure, 1, 1, and 1 normal, overweight, obese participants, respectively, were missing and were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) of Fasting Plasma Glucose (FPG) - Full Analysis Set | -1.979 mmol/L | 95% Confidence Interval 1.7877 |
| Glucophage XR in Overweight Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) of Fasting Plasma Glucose (FPG) - Full Analysis Set | -2.171 mmol/L | 95% Confidence Interval 2.1222 |
| Glucophage XR in Obese Participants | Mean Change From Baseline at Week 16 (95% Confidence Interval) of Fasting Plasma Glucose (FPG) - Full Analysis Set | -2.141 mmol/L | 95% Confidence Interval 2.0287 |
p-value: 0.4614ANCOVA
p-value: 0.4696t-test, 2 sided
p-value: 0.5305t-test, 2 sided
p-value: 0.9145t-test, 2 sided
Other Pre-specified
Mean Change From Baseline at Week 16 in Diastolic and Systolic Blood Pressure - Safety Population
Baseline was defined as the value obtained at screening or value obtained on Day 1 before treatment. Diastolic and systolic blood pressure was measured in millimeters of mercury (mm Hg). Safety population included participants who enrolled in the study and took at least 1 dose of Glucophage XR.
Time frame: Baseline to Week 16
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Mean Change From Baseline at Week 16 in Diastolic and Systolic Blood Pressure - Safety Population | Week 16 change in diastolic blood pressure | -2.2 mm Hg | Standard Deviation 8.63 |
| Glucophage XR in Normal Weight Participants | Mean Change From Baseline at Week 16 in Diastolic and Systolic Blood Pressure - Safety Population | Week 16 change in systolic blood pressure | -4.6 mm Hg | Standard Deviation 14.21 |
| Glucophage XR in Overweight Participants | Mean Change From Baseline at Week 16 in Diastolic and Systolic Blood Pressure - Safety Population | Week 16 change in diastolic blood pressure | -4.1 mm Hg | Standard Deviation 9.31 |
| Glucophage XR in Overweight Participants | Mean Change From Baseline at Week 16 in Diastolic and Systolic Blood Pressure - Safety Population | Week 16 change in systolic blood pressure | -5.5 mm Hg | Standard Deviation 12.14 |
| Glucophage XR in Obese Participants | Mean Change From Baseline at Week 16 in Diastolic and Systolic Blood Pressure - Safety Population | Week 16 change in diastolic blood pressure | -1.4 mm Hg | Standard Deviation 9.37 |
| Glucophage XR in Obese Participants | Mean Change From Baseline at Week 16 in Diastolic and Systolic Blood Pressure - Safety Population | Week 16 change in systolic blood pressure | -1.7 mm Hg | Standard Deviation 14.55 |
Other Pre-specified
Mean Change From Baseline at Week at Week 16 in ECG Parameter Heart Rate (HR) - Safety Population
Baseline was defined as ECG obtained at the screening visit. ECG was 12-lead. Heart rate (HR) was measured in beats per minute (beats/min). Safety population included participants who enrolled in the study and took at least 1 dose of Glucophage XR.
Time frame: Baseline to Week 16
Population: Safety population included 125, 122, 124 participants in each arm, respectively. Participants missing from analysis for change at Week 16 for Heart Rate were 17, 18, 20 participants in the normal, overweight, obese arms, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Mean Change From Baseline at Week at Week 16 in ECG Parameter Heart Rate (HR) - Safety Population | 0.4 beats/min | Standard Deviation 8.91 |
| Glucophage XR in Overweight Participants | Mean Change From Baseline at Week at Week 16 in ECG Parameter Heart Rate (HR) - Safety Population | 1.2 beats/min | Standard Deviation 9.56 |
| Glucophage XR in Obese Participants | Mean Change From Baseline at Week at Week 16 in ECG Parameter Heart Rate (HR) - Safety Population | 1.1 beats/min | Standard Deviation 12.36 |
Other Pre-specified
Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population
Baseline defined as value obtained either in screening visit or last value obtained before glucophage XR treatment given on Day 1. Serum chemistries evaluating kidney or liver function: blood urea nitrogen(BUN), serum creatinine (SCr), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), total bilirubin (BR), uric acid (UA). Abnormal increase in kidney and liver function tests defined as 1.25 - less than, equal to (\<=)2.6 times (x) upper limit of normal (ULN)in ALT, AST, total BR, UA; abnormal increase defined as 1.25 to \<= 5.1 x ULN in BUN. Safety population included participants who enrolled in the study and took at least 1 dose of Glucophage XR.
Time frame: Baseline to Week 16
Population: Number of participants (normal, overweight, obese, respectively) who were missing values and were not included in the Week 16 analysis for the following serum chemistry tests: ALT = 14, 11, 13; AST = 14, 11, 13; total BR = 14, 11, 13; creatinine = 14, 12, 13; BUN = 14, 12, 13; UA = 14, 12, 13.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 UA 1.25 to <=2.6xULN | 3 participants |
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 ALT 1.25 to <= 2.6xULN | 2 participants |
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 UA > 2.6 x ULN | 0 participants |
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 AST > 2.6 x ULN | 0 participants |
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 SCr 1.25 to <=2.6xULN | 0 participants |
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 SCr > 1.25 x ULN | 0 participants |
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 ALT > 2.6 x ULN | 0 participants |
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 Total BR 1.25 to <=2.6xULN | 3 participants |
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 Total BR > 2.6 x ULN | 0 participants |
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 AST 1.25 to <= 2.6xULN | 0 participants |
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 BUN1.25 to <=5.1xULN | 0 participants |
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 BUN > 5.1 x ULN | 0 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 AST 1.25 to <= 2.6xULN | 5 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 UA 1.25 to <=2.6xULN | 5 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 BUN > 5.1 x ULN | 0 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 Total BR 1.25 to <=2.6xULN | 2 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 UA > 2.6 x ULN | 0 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 ALT 1.25 to <= 2.6xULN | 11 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 BUN1.25 to <=5.1xULN | 1 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 SCr 1.25 to <=2.6xULN | 0 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 AST > 2.6 x ULN | 0 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 Total BR > 2.6 x ULN | 0 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 SCr > 1.25 x ULN | 0 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 ALT > 2.6 x ULN | 0 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 SCr > 1.25 x ULN | 0 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 BUN1.25 to <=5.1xULN | 0 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 ALT 1.25 to <= 2.6xULN | 9 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 ALT > 2.6 x ULN | 0 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 AST 1.25 to <= 2.6xULN | 4 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 AST > 2.6 x ULN | 0 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 Total BR 1.25 to <=2.6xULN | 1 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 Total BR > 2.6 x ULN | 0 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 BUN > 5.1 x ULN | 0 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 UA 1.25 to <=2.6xULN | 7 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 UA > 2.6 x ULN | 0 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had Abnormal Increase From Baseline at Week 16 in Kidney or Liver Function Serum Chemistry Values - Safety Population | Number with Week 16 SCr 1.25 to <=2.6xULN | 0 participants |
Other Pre-specified
Number of Participants Who Had a Normal Electrocardiogram (ECG) at Baseline and an ECG at Week 16 (or Termination Visit) Which Was Considered to be Abnormal With Clinical Significance - Safety Population
Baseline was defined as ECG obtained at the screening visit. A judgment of clinical significance was at the discretion of the investigator. Safety population included participants who enrolled in the study and took at least 1 dose of Glucophage XR.
Time frame: Baseline to Week 16
Population: number of participants with a normal ECG at baseline for normal weight, overweight, and obese arms were 71, 62, 65, respectively.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Glucophage XR in Normal Weight Participants | Number of Participants Who Had a Normal Electrocardiogram (ECG) at Baseline and an ECG at Week 16 (or Termination Visit) Which Was Considered to be Abnormal With Clinical Significance - Safety Population | 0 participants |
| Glucophage XR in Overweight Participants | Number of Participants Who Had a Normal Electrocardiogram (ECG) at Baseline and an ECG at Week 16 (or Termination Visit) Which Was Considered to be Abnormal With Clinical Significance - Safety Population | 1 participants |
| Glucophage XR in Obese Participants | Number of Participants Who Had a Normal Electrocardiogram (ECG) at Baseline and an ECG at Week 16 (or Termination Visit) Which Was Considered to be Abnormal With Clinical Significance - Safety Population | 3 participants |
Other Pre-specified
Number of Participants With Clinically Significant Changes From Baseline at Week 16 in the Hematology Laboratory Test Profile - Safety Population
Hematology profile = hematocrit, hemoglobin, red blood cell count (RBC), white blood cell count(WBC), lymphocytes, monocytes, basophils, eosinophils, neutrophils, platelet count. Baseline: value obtained at screening or last value obtained before treatment. LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Hemoglobin (g/dL): \>3 g/dL decrease from preRX; hematocrit (%): \<0.75\*preRX; RBC (\*10\^6 c/uL): \<0.75\*preRX; platelet count (\*10\^9 c/uL): \<0.67\*LLN or \>1.5\*ULN, of if preRX\<LLN, use 0.5\*preRX and \<100,000/mm\^3; WBC (\*10\^3 c/uL): \<0.75\*LLN or \>1.25\*ULN, or if preRX \<LLN, use \<0.8\*preRX or \>ULN, or if preRX\>ULN, use \>1.2\*preRX or \<LLN; neutrophils+bands (\*10\^3 c/uL): if value \<1.0\*10\^3 c/uL; eosinophils (\*10\^3 c/uL): if value \>0.750\*10\^3 c/uL; basophils (\*10\^3 c/uL): if value \>400/mm\^3; monocytes (\*10\^3 c/uL): if value \>2000/mm\^3; lymphocytes (\*10\^3 c/uL): if value \<0.750\*10\^3 c/uL or if value \>7.50\*10\^3 c/uL.
Time frame: Baseline to Week 16
Population: Safety population included participants who enrolled in the study and took at least 1 dose of Glucophage XR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Glucophage XR in Normal Weight Participants | Number of Participants With Clinically Significant Changes From Baseline at Week 16 in the Hematology Laboratory Test Profile - Safety Population | 0 participants |
| Glucophage XR in Overweight Participants | Number of Participants With Clinically Significant Changes From Baseline at Week 16 in the Hematology Laboratory Test Profile - Safety Population | 0 participants |
| Glucophage XR in Obese Participants | Number of Participants With Clinically Significant Changes From Baseline at Week 16 in the Hematology Laboratory Test Profile - Safety Population | 0 participants |
Other Pre-specified
Number of Participants With Clinically Significant Changes From Baseline at Week 16 in Urinalysis - Safety Population
Urinalysis included pH and specific gravity. Baseline defined as values obtained at screening visit. Clinically significant: outside the reference range (low/high)and judged to be significant by the investigator: Specific gravity 1.003 - 1.035; ph 5 - 8. Safety population included participants who enrolled in the study and took at least 1 dose of Glucophage XR.
Time frame: Baseline to Week 16
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Glucophage XR in Normal Weight Participants | Number of Participants With Clinically Significant Changes From Baseline at Week 16 in Urinalysis - Safety Population | 0 participants |
| Glucophage XR in Overweight Participants | Number of Participants With Clinically Significant Changes From Baseline at Week 16 in Urinalysis - Safety Population | 0 participants |
| Glucophage XR in Obese Participants | Number of Participants With Clinically Significant Changes From Baseline at Week 16 in Urinalysis - Safety Population | 0 participants |
Other Pre-specified
Number of Participants With Episodes of Lactic Acidosis or Hypoglycemia From Day 1 to Week 16 - Safety Population
Day 1 was first day of treatment. Lactic acidosis defined as elevated blood lactate levels (\>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and increased lactate/pyruvate ratio. Hypoglycemia (low levels of blood glucose) was reported as an adverse event. Safety population included participants who had enrolled in the study and took at least 1 dose of glucophage extended release (glucophage XR). If a subject experienced more than one adverse event, the subject was counted once at the highest severity.
Time frame: Day 1 to Week 16
Population: All participants enrolled in the study and who received at least 1 dose of Glucophage XR.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Glucophage XR in Normal Weight Participants | Number of Participants With Episodes of Lactic Acidosis or Hypoglycemia From Day 1 to Week 16 - Safety Population | Lactic Acidosis | 0 participants |
| Glucophage XR in Normal Weight Participants | Number of Participants With Episodes of Lactic Acidosis or Hypoglycemia From Day 1 to Week 16 - Safety Population | Hypoglycemia | 1 participants |
| Glucophage XR in Overweight Participants | Number of Participants With Episodes of Lactic Acidosis or Hypoglycemia From Day 1 to Week 16 - Safety Population | Lactic Acidosis | 0 participants |
| Glucophage XR in Overweight Participants | Number of Participants With Episodes of Lactic Acidosis or Hypoglycemia From Day 1 to Week 16 - Safety Population | Hypoglycemia | 0 participants |
| Glucophage XR in Obese Participants | Number of Participants With Episodes of Lactic Acidosis or Hypoglycemia From Day 1 to Week 16 - Safety Population | Lactic Acidosis | 0 participants |
| Glucophage XR in Obese Participants | Number of Participants With Episodes of Lactic Acidosis or Hypoglycemia From Day 1 to Week 16 - Safety Population | Hypoglycemia | 0 participants |