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					Metformin HCl/Glyburide                                                                        CV138056
BMS-207150                                                                          Clinical Study Report

Name of Sponsor/Company:       Individual Study Table Referring            (For National Authority Use
                               to the Dossier                              Only)
Bristol-Myers Squibb
Name of Finished Product:


Name of Active Ingredient:


                                            SYNOPSIS
TITLE OF STUDY: A Multicenter, Randomized, Double-Blind, Parallel Group Trial Comparing the
                Safety and Efficacy of Metformin/Glyburide to Pioglitazone as First Line Therapy
                in Patients with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control
                with Diet and Exercise
INVESTIGATORS: 73
STUDY CENTERS: 73
PUBLICATIONS:          None
STUDY PERIOD:          Date first subject enrolled: 16-Jun-2000
                       Date last subject completed: 04-Jan-2002
CLINICAL PHASE: IIIB
RATIONALE:
The purpose of this study was to determine the effect of metformin HCl/glyburide (Met/Gly) compared to
pioglitazone on glycemic control in subjects with type 2 diabetes mellitus who had inadequate glycemic
control with diet and exercise. Glycemic control was assessed using multiple glycemic parameters
including hemoglobin A1c (HbA1c), fructosamine, fasting plasma glucose (FPG), and post-prandial plasma
glucose (PPPG).
RESEARCH HYPOTHESIS:

Metformin HCl/glyburide would result in a greater reduction in HbA1c than pioglitazone when used as first
line therapy in subjects with type 2 diabetes.
OBJECTIVES:
Primary Objective:
The primary objective was to compare, after 48 weeks of oral administration of double-blind treatment, the
change from baseline in HbA1c level achieved with metformin HCl/glyburide therapy to the change from
baseline in HbA1c level achieved with pioglitazone monotherapy in subjects with type 2 diabetes mellitus
who had inadequate glycemic control with diet and exercise.




                              Approved v1.0 930003062 1.0
Metformin HCl/Glyburide                                                                            CV138056
BMS-207150                                                                              Clinical Study Report
Secondary Objectives:
•   Compare, after 12 and 24 weeks of oral administration of double-blind treatment, the change from
    baseline in HbA1c level achieved with metformin HCl/glyburide therapy to the change from baseline
    in HbA1c level achieved with pioglitazone monotherapy.
•   Assess at all measurement timepoints, and compare after 24 and 48 weeks of oral administration of
    double-blind treatment, the change from baseline in FPG, insulin, C-peptide, fructosamine, fasting free
    fatty acids, and 30-minute, 60-minute, and 120-minute post-prandial plasma glucose and insulin, and
    120-minute post-prandial C-peptide and free fatty acid levels achieved with metformin HCl/glyburide
    therapy to the change from baseline achieved with pioglitazone monotherapy.
•   Assess, after 24 and 48 weeks of oral administration of double-blind treatment, the change from
    baseline in glucose and insulin excursion profiles (difference between 30-minute, 60-minute, and
    120-minute post-prandial profiles and fasting measurements) achieved with metformin HCl/glyburide
    therapy to the change from baseline achieved with pioglitazone monotherapy.
•   Assess, after 24 and 48 weeks of oral administration of double-blind treatment, the change from
    baseline in 120-minute post-prandial C-peptide and free fatty acid excursion profiles (difference
    between 120-minute post-prandial profiles and fasting measurements) achieved with metformin
    HCl/glyburide therapy to the change from baseline achieved with pioglitazone monotherapy.
•   Compare, after 24 and 48 weeks of oral administration of double-blind treatment, the body weight
    change from baseline with metformin HCl/glyburide therapy to the body weight change from baseline
    with pioglitazone monotherapy.
•   Ascertain the safety and tolerability of the study medications when administered for 48 weeks.
•   Assess, the proportion of subjects achieving a therapeutic glycemic response (defined as a fasting
    plasma glucose < 126 mg/dL and an HbA1c < 7.0%) following 24 and 48 weeks of oral administration
    of metformin HCl/glyburide therapy.


STUDY DESIGN AND METHODOLOGY:
This was a multicenter, randomized, two-arm, parallel group, double-blind trial of the antihyperglycemic
activity of metformin HCl/glyburide as first line therapy in subjects with type 2 diabetes mellitus who had
inadequate glycemic control (HbA1c ≥ 7.0%) with diet and exercise. Subjects were either drug naive or
should not have taken antihyperglycemic therapy during the eight weeks prior to screening.
The design included the following treatment phases:
The Lead-In Phase was a one-week instructional and dietary phase. At the enrollment visit, subjects were
instructed on maintaining a eucaloric weight-maintaining diet for the duration of the study. Dietary
guidelines established by the American Diabetes Association for patients with diabetes were recommended
for standardization purposes.
Glucose meters were dispensed with instructions provided to subjects on their use. Self blood glucose
monitoring (SBGM) requirements (subjects performed SBGM four times daily during the three to five days
prior to each titration visit) and procedures were explained to the subjects.
The Double-Blind Treatment Phase was a 48-week, randomized, double-blind, double-dummy treatment
phase. Eligible subjects were randomized to one of two treatment arms that included metformin
HCl/glyburide 250/1.25 mg or pioglitazone 15 mg. Subjects began on a once-daily dosing regimen prior to
the morning meal. Study medication was titrated to achieve a therapeutic glycemic target during
randomized therapy, based on the mean daily glucose (MDG). A MDG was calculated from fingerstick
glucose values (four times daily) performed during the three to five days prior to the titration visits. If the




                              Approved v1.0 930003062 1.0
Metformin HCl/Glyburide                                                                           CV138056
BMS-207150                                                                             Clinical Study Report
MDG ≥ 126 mg/dL then the study medication was titrated to the next Titration Level. For this study, the
maximum allowable total daily doses were metformin HCl/glyburide 1500/7.5 mg and pioglitazone 45 mg.
NUMBER OF SUBJECTS:
Of the 373 subjects enrolled in the lead-in phase, 361 were randomized, 214 completed and
147 prematurely discontinued.
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION:
•   Males and females, 18-78 years of age
•   Established type 2 diabetes mellitus of at least 3 months but less than 10 years duration
•   Failure to achieve adequate glycemic control with diet and exercise
•   HbA1c ≥ 7.0% at the Screening Visit
                                           2
•   Body Mass Index (BMI) 23 - 45 kg/m


TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS:

                                                                                              Duration of
Product     Tablet                     Dose          Product Code         Lot Number        Treatment (oral)
            Metformin
Test                                 250 mg/                                 9127,
            HCl/Glyburide film                     207150-K999-017                               48 weeks
Product                              1.25 mg                              020006NCC1
            coated
Reference                                                                00C052, 00J132,
            Pioglitazone              15 mg       207150-RXXX-095                               48 Weeks
Therapy                                                                      00J133
            Placebo Matching
Reference   Metformin                                                         9132,
                                     ----------    207150-K000-018                              48 Weeks
Therapy     HCl/Glyburide film                                             030002NCC
            coated
Reference   Placebo Matching                                               00C049,
                                     ----------    000000-R000-021                              48 Weeks
Therapy     Pioglitazone                                                00C050, N00210


DURATION OF TREATMENT:
48 weeks of double-blind treatment with metformin HCl/glyburide therapy or pioglitazone monotherapy.
CRITERIA FOR EVALUATION:
Primary Efficacy Outcome Measure:

•   Change in HbA1c level from baseline to Week 48 or the last prior visit.


Secondary Efficacy Outcome Measures:
•   Change from baseline to Weeks 24 (or the last prior visit) and 48 (or the last prior visit) in
    fructosamine, fasting, 30-minute, 60-minute, and 120-minute post-prandial plasma glucose and insulin.
•   Change from baseline to Weeks 24 (or the last prior visit) and 48 (or the last prior visit) in fasting and
    120-minute post-prandial C-peptide and FFA levels.




                             Approved v1.0 930003062 1.0
Metformin HCl/Glyburide                                                                           CV138056
BMS-207150                                                                             Clinical Study Report

•   Change in HbA1c from baseline to Weeks 12 (or the last prior visit) and 24 (or the last prior visit).
•   Change in body weight from baseline to Weeks 24 (or the last prior visit) and 48 (or the last prior
    visit).
•   Change from baseline to Weeks 24 (or the last prior visit) and 48 (or the last prior visit) in glucose and
    insulin excursion profiles (difference between 30-minute, 60-minute, and 120-minute post prandial and
    fasting measurements).
•   Change from baseline to Weeks 24 (or the last prior visit) and 48 (or the last prior visit) in C-peptide
    and FFA excursion profiles (difference between 120-minute post prandial and fasting measurements).
•   Proportion of subjects achieving HbA1c < 7.0% at Weeks 24 (or the last prior visit) and 48 (or the last
    prior visit).
•   Proportion of subjects achieving fasting plasma glucose < 126 mg/dL at Weeks 24 (or the last prior
    visit) and 48 (or the last prior visit).


Primary Safety Outcome Measure:
Adverse events and laboratory measurements.
STATISTICAL METHODS:
With 150 subjects per group, there was 90% power to show a difference between metformin HCl/glyburide
therapy and pioglitazone if the true mean difference between treatment groups in reduction in HbA1c was
0.35%, assuming a standard deviation of 0.9%.
Statistical analyses for efficacy outcome measures were performed within the framework of an analysis of
covariance (ANCOVA) with a term for treatment and the baseline value as the covariate. All tests were
2-sided with a significance level of 0.05.
EFFICACY RESULTS:

Mean Change in HbA1c (Percent) from Baseline to Week 48 or the Last Prior Visit

                                                            Met/Gly                      Pioglitazone
                                                            N = 163                        N = 174
Baseline Mean (SD)                                        9.72 (1.94)                     9.70 (2.11)
Week 48/Last Mean (SD)                                    6.87 (1.36)                     7.63 (2.29)
                                            a
Adjusted Mean Change from Baseline (SE)                   -2.84 (0.12)                   -2.07 (0.11)
Difference between Metformin HCl/
                                 b                        -0.78 (0.16)
Glyburide and Pioglitazone (SE)
95% CI                                                    -1.10, -0.46
          a
p-value                                                     < 0.001

Source:    Appendix 10.0A1
Reference: Supplemental Table S.10.1.1A1
Dataset:   Randomized Subjects
N = number of subjects with available data at both baseline and Week 48 or the last prior visit.




                             Approved v1.0 930003062 1.0
Metformin HCl/Glyburide                                                                              CV138056
BMS-207150                                                                                Clinical Study Report
a
    Mean changes are adjusted mean changes obtained from the ANCOVA model with terms for baseline
    and treatment. Standard errors and p-value are also obtained from this model.
b
    Difference = (adjusted mean change for Metformin HCl/Glyburide group) - (adjusted mean change for
    Pioglitazone group).


There was significant improvement in HbA1c equal to a difference of -0.78% in the metformin
HCl/glyburide treated group versus the pioglitazone treated group. (change in HbA1c from baseline in
metformin HCl/glyburide group was -2.84%, change in HbA1c from baseline in pioglitazone group was
-2.07%, p-value < 0.001).


The following figure displays the mean HbA1c from baseline through Week 48.


                           M e a n (S E ) H b A 1 c (P e r c e n t) O v e r T im e

                 10
                9 .5
                   9
                8 .5
     HbA1c(%)




                   8
                7 .5
                   7
                6 .5
                   6
                5 .5
                   5
                       0       8        12       16          20          24         32    40       48
                                                            W eek


                                               M e t/G ly           P io g lita z o n e

Last observation carried forward


There was a rapid early improvement in HbA1c for the metformin HCl/glyburide treated group relative to
the pioglitazone treated group. Subjects in the metformin HCl/glyburide group achieved the HbA1c level
below 7.0% on the average as early as week 12 while subjects in the pioglitazone group achieved the mean
HbA1c level of 7.6% at Week 48. At the end of 48 weeks of double-blind therapy, 65% of metformin
HCl/glyburide subjects achieved a final HbA1c < 7% relative to 55.2% of pioglitazone subjects.




                                Approved v1.0 930003062 1.0
Metformin HCl/Glyburide                                                                         CV138056
BMS-207150                                                                           Clinical Study Report
Mean Change in Fasting Plasma Glucose (mg/dL) from Baseline to Week 48 or the Last Prior Visit
                                                           Met/Gly                    Pioglitazone
                                                            N = 168                     N = 184
Baseline Mean (SD)                                        221.0 (69.8)                221.1 (71.1)
Week 48/Last Mean (SD)                                    145.4 (53.3)                170.0 (81.0)
                                               a
Adjusted Mean Change from Baseline (SE)                   -75.7 (4.5)                     -51.1 (4.3)
Difference between Metformin HCl/
                                   b                      -24.6 (6.2)
Glyburide and Pioglitazone (SE)
95% CI                                                    -36.8, -12.3
            a
p-value                                                     < 0.001
Source:      Appendices 10.0A1 and 10.0A2
Reference: Supplemental Table S.10.2.1A2
Dataset:     Randomized Subjects
N = number of subjects with available data at both baseline and Week 48 or the last prior visit.
a
  Mean changes are adjusted mean changes obtained from the ANCOVA model with terms for baseline
  and treatment. Standard errors and p-value are also obtained from this model.
b
  Difference = (adjusted mean change for metformin HCl/glyburide group) - (adjusted mean change for
  pioglitazone group).

There was also significant improvement in FPG equal to a difference of -24.6 mg/dL in the metformin
HCl/glyburide treated group versus the pioglitazone treated group. (Change in FPG from baseline in
metformin HCl/glyburide group was -75.7 mg/dL, change in FPG from baseline in pioglitazone group was
-51.1 mg/dL, p-value < 0.001).
The following figure displays the mean FPG from baseline through Week 48.


                             M ea n (S E ) F P G (m g /d L ) O ve r T im e
                  24 0
                  22 0
     FPG(mg/dL)




                  20 0
                  18 0
                  16 0
                  14 0
                  12 0
                         0   2         4   8       12    16      20      24     32   40       48
                                                        W e ek

                                           M et/G ly          P io glitazo ne

Last observation carried forward




                                 Approved v1.0 930003062 1.0
Metformin HCl/Glyburide                                                                      CV138056
BMS-207150                                                                        Clinical Study Report
After 12 weeks of therapy, the mean FPG decreased from 221 mg/dL to 137 mg/dL (mean decrease of
84 mg/dL) in the metformin HCl/glyburide group and from 221 mg/dL to 175 mg/dL (mean decrease of
46 mg/dL) in the pioglitazone group. At the end of 48 weeks of double-blind therapy, 42.9% of metformin
HCl/glyburide subjects achieved a final fasting plasma glucose < 126 mg/dL relative to 36.4% of
pioglitazone subjects.


 Proportion of Subjects Achieving a Therapeutic Glycemic Response at Week 48 or the Last Prior
 Visit
                                                            Number (%) of Subjects
 Characteristic                                      Met/Gly                      Pioglitazone
 Subjects Reaching HbA1c Goal                        (N = 163)                      (N = 174)
 < 7.0% by Week 48                                  106 (65.0%)                    96 (55.2%)
 Subjects Reaching Targeted FPG Goal                 (N = 168)                      (N = 184)
 < 126 mg/dL by Week 48                             72 (42.9%)                     67 (36.4%)

Source:    Appendices 10.0A1 and 10.0A2
Reference: Supplemental Tables S.10.1.1A2 and 10.2.2A2
Dataset:   Randomized Subjects

SAFETY RESULTS:
Adverse events (AEs) were reported by 148 subjects (86.0%) in the metformin HCl/glyburide group, and
163 subjects (86.7%) in the pioglitazone group. Sixteen subjects (9.3%) in the metformin HCl/glyburide
group discontinued due to AEs, relative to 20 subjects (10.6%) in the pioglitazone group. SAEs were
reported by 14 subjects (8.1%) in the metformin HCl/glyburide group, and by 16 subjects (8.5%) in the
pioglitazone group. One death (0.6%) occurred in the metformin HCl/glyburide group and three deaths
(1.6%) occurred in the pioglitazone group.




                           Approved v1.0 930003062 1.0
Metformin HCl/Glyburide                                                                            CV138056
BMS-207150                                                                              Clinical Study Report
Safety Summary
                                                                     Number (%) of Subjects
                                                           Met/Gly                      Pioglitazone
Event                                                     (N = 172)                      (N = 188)
                                                            n (%)                             n (%)
     a,b,c
AE            total subjects (% of subjects)              148 (86.0)                     163 (86.7)
       a,b,c
ADE                                                       58 (33.7)                      68 (36.2)
      c                                                                                       d
SAE                                                        14 (8.1)                       16 (8.5)
          c
Death                                                      1 (0.6)                         3 (1.6)
Discontinuations due to AE
(Includes clinical and lab AEs)                            16 (9.3)                      20 (10.6)

Dataset: Treated Subjects
Note: Subjects may be represented in more than one category.
N = Number of treated subjects, n = Number of subjects with events
a
    Treatment-emergent Clinical AEs
b
    Excludes symptoms of hypoglycemia.
c
    During and up to 14 days post double-blind therapy.
d
    Includes laboratory SAE of “serum glucose increase” for Subject 020/011.

                     a
Hypoglycemia

                                                                 Number (%) of Subjects
                                                           Met/Gly                      Pioglitazone
Characteristic
                                                          (N = 172)                      (N = 188)
Total                                                     19 (11.0)                        2 (1.1)
> 169 Days on Double-Blind Treatment                        7 (4.1)                        1 (0.5)
                                                                                                      b
Medical Assistance Required                                    0                          1 (0.5)
                                                                     c
Discontinued                                               1 (0.6)                                0
Dataset: Treated Subjects
Note: Subjects are counted once in each row where at least one event occurred. A subject may be in
         more than one row.
N = Number of treated subjects, n = Number of subjects with events
a
    Hypoglycemia is any event with symptoms consistent with hypoglycemia and fingerstick value
    ≤ 50 mg/dL.
b
    The subject asked a coworker to bring him food to alleviate hypoglycemic symptoms. This third party
    assistance was recorded as medical assistance by the investigator
c
    Discontinue due to Investigator identified hypoglycemia with no reported fingerstick value ≤ 50 mg/dL.




                                   Approved v1.0 930003062 1.0
Metformin HCl/Glyburide                                                                          CV138056
BMS-207150                                                                            Clinical Study Report
Subjects with Edema Reported as AEs and Subjects with Laboratory Values Meeting the Predefined
Limits of Change: LFTs and Hemoglobin/Hematocrit During the Double-Blind Phase

                                                     Number (%) of Subjects
                                     Met/Gly                                     Pioglitazone
                                a                       b                   a                           b
                            N                   n (%)                   N                       n (%)
AST                        165                  6 (3.6)                 182                      3 (1.6)
ALT                        165                  5 (3.0)                 182                      2 (1.1)
Hemoglobin                 148                  1 (0.7)                 151                      2 (1.3)
Hematocrit                 148                  1 (0.7)                 151                      1 (0.7)
                                 c                                           c
Edema                      172                  11 (6.4)               188                      34 (18.1)

Dataset:    Treated Subjects
Predefined limits of change: ALT and AST: > 3X baseline and > ULN, Hemoglobin: > 3g/dL decrease
from baseline, Hematocrit < 0.75X baseline.
a
    Number of treated subjects with available data
b
    Number of subjects with a finding
c
    Number of treated subjects




                                Approved v1.0 930003062 1.0
Metformin HCl/Glyburide                                                                          CV138056
BMS-207150                                                                            Clinical Study Report
CONCLUSIONS:
EFFICACY:

•   There was a significant difference in improvement in HbA1c (-0.78%) in the metformin HCl/glyburide
    treated group versus the pioglitazone treated group at Week 48 or the last prior visit. (change in HbA1c
    from baseline in metformin HCl/glyburide group was -2.84%, change in HbA1c from baseline in
    pioglitazone group was -2.07%, p-value < 0.001)
•   There was a significant difference in improvement in FPG (-24.6 mg/dL) in the metformin
    HCl/glyburide treated group versus the pioglitazone treated group at Week 48 or the last prior visit
    (change in FPG from baseline in metformin HCl/glyburide group was -75.7 mg/dL, change in FPG
    from baseline in pioglitazone group was -51.1 mg/dL, p-value < 0.001)
•   Time course curves for changes in both HbA1c and FPG show more rapid early improvement in these
    glycemic parameters for the metformin HCl/glyburide treated group than for the pioglitazone treated
    group. Subjects in the metformin HCl/glyburide group achieved a mean HbA1c level below 7.0% as
    early as Week 12 while subjects in the pioglitazone group achieved their lowest mean HbA1c level of
    7.6% at Week 48.
•   Target rate assessment demonstrated that 65.0% of metformin HCl/glyburide treated subjects attained
    the ADA goal of HbA1c < 7.0% relative to 55.2% of pioglitazone treated subjects.


SAFETY & TOLERABILITY:
•   Symptoms of hypoglycemia with a confirmatory fingerstick ≤ 50 mg/dL were reported in 11.0% of
    subjects in the metformin HCl/glyburide treated group relative to 1.1% of subjects in the pioglitazone
    treated group.
•   One subject in the metformin HCl/glyburide treated group discontinued due to symptoms of
    hypoglycemia (no reported fingerstick value ≤ 50 mg/dL) versus no subjects in the pioglitazone treated
    group.
•   Edema was reported by 6.4% of subjects in the metformin HCl/glyburide group relative to 18.1% of
    subjects treated with pioglitazone. No subjects were discontinued due to edema in the metformin
    HCl/glyburide group relative to five subjects in the pioglitazone group
•   Gastrointestinal adverse events were reported by 24.4% of subjects in the metformin HCl/glyburide
    group relative to 13.8% of subjects in the pioglitazone group.


DATE OF REPORT: 20-Nov-2002




                            Approved v1.0 930003062 1.0

				
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