In February 2013, GlaxoSmithKline (GSK) announced a … · 2018-11-07 · In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the

In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register.

The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all namedpersons associated with the study

Patient data listings will be completely removed* to protect patient privacy. Anonymized

data from each patient may be made available subject to an approved research

proposal. For further information please see the Patient Level Data section of the GSK

Clinical Study Register. Aggregate data will be included; with any direct reference to individual patients excluded

*Complete removal of patient data listings may mean that page numbers are no longer consecutively

numbered

Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Study Report

Title: A 24-Week Randomized, Double-blind, Double-Dummy, Multicenter Study to Compare the Efficacy of AVANDIA when added to Submaximal Doses of Metformin and to Compare the Tolerability of the Combination to Metformin Monotherapy when Administered to Subjects with Type 2 Diabetes Mellitus

Phase: IV

Compound Number: BRL-049653

Effective Date: 22-March-2005

Description:

Subject: Metabolism, Type II Diabetes Mellitus

Author(s): PhD, MPH, PharmD, MPH, MS, MD, PhD

Indication Studied: Type II Diabetes Mellitus

Initiation Date: 30-June-2001

Completion Date: 13-February-2003

Date of Report: 29-March-2005

Earlier CSRs 4-November-2003

Sponsor Signatory: (and Medical Officer)

Clinical Development and Medical Affairs GlaxoSmithKline

This study was performed in compliance with Good Clinical Practices including the archiving of essential documents.

Copyright 2005 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited

CONFIDENTIAL CM2003/00016/01 BRL049653/284

1

Synopsis

Document Number: CM2003/00016/01 Study Number: BRL-049653/284


Investigator(s): Multicenter study

Study center(s): Sixty-three centers in the United States

Publication(s): N/A as of this report.

Study period: 05-June-2001 to 13-February-2003 Provide the date of the visit/observation for last subject completed reflecting last observation on database.

Phase of Development: IV

Objectives:

Primary objective: To demonstrate the noninferiority of maximal rosiglitazone (RSG, 8mg/day) plus sub-maximal metformin (MET, 1000mg/day) relative to the maximal effective dose of metformin (MET, 2000mg/day) in achieving glycemic control with hemoglobin A1c (HbA1c) as the primary endpoint.

Secondary objectives: To compare HbA1C, FPG, insulin sensitivity, HOMA, DTSQ (Diabetes Treatment Satisfaction Questionnaire) and DHSI (GI questionnaire) change from baseline at week 24 within and between treatment groups.

To compare the proportion of subjects responding (HbA1c and FPG responders) to treatment between groups after 24 weeks of treatment. HbA1c responders were subjects achieving a decrease in HbA1c of ≥0.7% from baseline. FPG responders were defined as subjects with a decrease in FPG of ≥30 mg/dL from baseline. In addition, the proportion of subjects achieving FPG ≤126 mg/dL and ≤140 mg/dL and the proportion of subjects achieving HbA1c ≤ 6.5%, ≤ 7%, ≤ 8% and >8%.

To compare the proportion of subjects who responded (HbA1c responders and FPG responders) to treatment between groups after 24 weeks of treatment in the following ways: subjects without GI side effects, baseline HbA1c (


subjects without GI side effects, baseline HbA1c (


Criteria for evaluation:

Efficacy Parameters

Primary: The primary efficacy variable was the mean change from baseline at week 24 in HbA1c. The primary comparison was between the rosiglitazone plus metformin (RSG+MET) group and the MET escalation group.

Secondary: The secondary efficacy variables included the change from baseline in FPG and fasting plasma insulin at week 24 in the RSG+MET group compared to the MET escalation group.

Additionally, two types of responder rates were compared in each treatment group: one with respect to HbA1c (i.e. the proportion of subjects demonstrating a reduction from baseline of ≥0.7% at week 24), and the other with respect to fasting glucose (i.e. proportion of subjects demonstrating a reduction from baseline of ≥30mg/dL at week 24). In addition, the proportion of subjects achieving an HbA1c ≤6.5%, ≤7.0%, >8.0% and ≤8% and proportion of subjects achieving an FPG ≤110mg/dL, ≤126mg/dL and ≤ 140mg/dL.

Measures of insulin sensitivity were derived from FPG and insulin data using the homeostasis model assessment (HOMA).

The questionnaire, Digestive Health Status Instrument (DHSI) was used to measure change from baseline per visit for IBS-diarrhea, IBS-constipation, and Dysmotility subscores. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was used to measure change from baseline at week 24 on treatment satisfaction (total score), perceived frequency of hyperglycemia (subscore) and perceived frequency of hypoglycemia (subscore).

Safety Parameters

Changes in physical examination, vital signs, body weight and waist to hip ratio, clinical laboratory tests, adverse experiences, and serum lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides) were assessed.

Statistical methods: Using an estimate of standard deviation for change from baseline in HbA1c of 1.4%, one-sided approach (alpha=0.025) and assuming the underlying treatment difference is zero for noninferiority, a sample size of 260 subjects per treatment group was required to give a 90% power to detect that the upper-bound of a 95% confidence interval (two-sided) for a difference (RSG+MET minus MET) in treatment means of less than 0.4 percentage units (noninferiority criterion). Assuming a dropout rate of 30% in the ITT without LOCF subject population, a total of 766 subjects were randomized at 63 centers in order to obtain 520 evaluable subjects.


4


For the assessment of differences between the treatment groups with regard to continuous variables (i.e., HbA1c, FPG, insulin level), an analysis of covariance with a model including effects for treatment, center, baseline measurement and prior therapy was employed.

The treatment-by-covariate interactions were assessed at the 0.1 significance level.

The change from baseline values for HOMA %S was assessed via non-parametric methods. The signed rank test was used to compare week 24 values to baseline values within treatment groups. The Wilcoxon rank sum test was used to compare the change from baseline values between treatment groups.

Analysis of responders (HbA1c responders and FPG responders) was performed using logistic analysis with a model including effects for treatment, baseline measurement and prior therapy.

For the assessment of the markers for cardiovascular disease risk (CV markers), PAI-1, CRP, TNF-α and MMP-9, differences in percent change from baseline between treatment groups were analyzed by an analysis of variance model with a model including an effect for treatment. The analyses were performed on the log-transformed data. The log-transformed data were also used to obtain point estimates and confidence intervals for geometric means and medians at each time point (visits 3, 4 and 6).

For safety variables (e.g., hematocrit, hemoglobin, vital signs and body weight), differences in mean change from baseline between treatment groups at week 24 were analyzed using an analysis of covariance with a model including effects for treatment and prior therapy.

Differences between treatment groups at any visit with regard to number of subjects with gastrointestinal adverse events were analyzed using Fisher’s exact test.


5


Summary:

Efficacy Results

Please refer to the Clinical Study Report Revision History

Data Sets: The intent-to-treat (ITT) population consisted of all subjects who were randomized and had at least one on-therapy value for an efficacy parameter. The ITT population consisted of 709 subjects, 358 subject in the RSG+MET group and 351 subjects in the MET group. Analyses based on two populations were performed. The primary statistical analyses was based on the Intent to Treat (ITT) population without the Last Observation Carried Forward (LOCF). The secondary statistical analyses used the ITT population with LOCF for withdrawn subjects and missing values. A post-hoc statistical analyses used the ITT without LOCF for subjects completing the study according to the investigator.

Primary Efficacy Variables: The adjusted mean difference in HbA1c levels between treatment groups after 24 weeks of treatment showed RSG (8mg/day) plus sub-maximal MET (1000mg/day) was noninferior to the maximal effective dose of MET (2000mg/day) (∆HbA1c= -0.19%, 95% CI: -0.35%, -0.03%). After 24 weeks of treatment, statistically significant reductions in mean HbA1c levels were observed in the RSG+MET combination therapy group (∆HbA1c = -0.82%, 95% CI: -0.95%, -0.69%) and in the MET (∆HbA1c = -0.63%, 95% CI: -0.74%, -0.52%).

Change in HbA1c at Study Endpoint (Week 24) Compared to Baseline and MET Treatment Group ( ITT Population w/o LOCF)

Treatment Group MET (n=313) RSG (n=322) HbA1c%1 Baseline (mean + SD) 7.95 ± 1.207 8.05 ± 1.218 Week 24 (mean + SD) 7.32 ± 1.157 7.23 ± 1.419 Change from Baseline mean + SD -0.63 ± 0.989 -0.82 ± 1.183 95% CI -0.74, -0.52 -0.95, -0.69 Difference from MET adjusted mean difference -0.19 95% CI2 -0.35, -0.03

1. All values calculated are only for those subjects who had a baseline and on-therapy value for week 24. 2. For noninferiority comparision to 0.4%. NOTE: All laboratory values were fasting Analysis on the ITT population without LOCF was based on the model: Change=Baseline + Treatment + Prior Therapy + Center. The p-value for interactions were treatment-by-center= 0.9267, Baseline-by-treatment= 0.4011 and treatment by-prior therapy= 0.1387.



6


• The post-hoc analysis on subjects completing the study showed the RSG+MET group to be noninferior to the MET escalation group (∆= -0.20%, 95% CI: -0.36, -0.04). After 24 treatment weeks, statistically significant reductions in mean HbA1c levels were observed in the RSG+MET combination therapy (∆= -0.93, 95% CI: -1.06%, -0.80%) and the MET monotherapy (∆= -0.71, 95% CI: -0.83%, -0.60%) groups.

Secondary Efficacy Variables:

Please the Clinical Study Report Revision History

Intent to Treat Population w/o LOCF

• The adjusted mean difference in FPG levels for the RSG+MET group compared to the MET escalation group was statistically significant (∆= -15.5mg/dL, p


49.65pmol/L, p


70.0%) by subjects with baseline HbA1c ≥9% was statistically non-significant.

• The difference in total FPG responders observed in the RSG+MET group (137 subjects, 52.9%) compared to the MET escalation group (89 subjects, 32.8%) was statistically significant (∆=20.1%, 95% CI: 11.8%, 28.3%). The odds of being a FPG responder in the RSG+MET group versus the MET group were also statistically significant (OR=2.4, p


%S was observed in the RSG+MET group from baseline at week 24 (∆=46.5%, p


groups was statistically non-significant (∆= -206.3 pmol/L∗h, p=0.1550, 95% CI: -492.99pmol/L∗h, 80.33pmol/L∗h). Statistically non-significant reductions in post-prandial insulin AUC(0-3h) levels were observed at week 24 compared to baseline for the RSG+MET group (∆= -203.5 ± 788.35 pmol/L∗h, p=0.1020, 95%CI: -449.17 pmol/L∗h, 42.16 pmol/L∗h) and the MET escalation group (∆= -60.43 ± 1053.32 pmol/L∗h, p=0.7596, 95% CI: -461.09pmol/L∗h, -340.23 pmol/L∗h).

• The mean difference in insulin Cmax for the RSG+MET group compared to the MET escalation group was statistically significant (∆= -169.5pmol/L, p=0.0503, 95% CI: -339.29pmol/L, 0.21pmol/L). Statistically non-significant reductions in post-prandial insulin Cmax (pmol/L∗h) up to 3 hours at week 24 compared to baseline was observed for the RSG+MET group (∆= -117.9pmol/L, p=0.1049, 95% CI: -261.43pmol/L, 25.68pmol/L) and MET group (∆=9.4, p=0.9324, 95% CI: -215.49pmol/L, 234.30pmol/L).

• Compared to the MET escalation group, a statistically non-significant adjusted mean difference in AUC(0-3h) post-prandial triglyceride values was observed for the RSG+MET group (∆= -1.2864, p=0.8849, 95% CI: -18.99, -16.43). The small reductions in the AUC post-prandial triglyceride values for the RSG+MET (∆= 2.0 ± 34.44, p=0.7012, 95% CI: -8.44, 12.44) and MET (∆= -8.2 ± 41.98, p=0.3014, 95% CI: -24.17, 7.76) treatment groups at week 24 compared to baseline were statistically non-significant.

Subjects by Previous Diet and Exercise Therapy (ITT w/o LOCF)

• The adjusted mean difference in HbA1c % levels between treatment groups from baseline to week 24 showed the RSG+MET combination therapy to be noninferior to the MET monotherapy group (∆= -0.17%, 95% CI: -0.42%, 0.07%). Statistically significant differences in HbA1c % values from baseline to week 24 were observed for the RSG+MET combination therapy group (-0.92%) and the MET monotherapy group (–0.69%).

• The adjusted mean difference in HbA1c levels between treatment groups showed the RSG+MET group to be noninferior to the MET escalation group for subjects evaluable at screen and week 24 (∆= -0.10%, 95% CI: -0.39%, 0.20%). Reductions in HbA1c values from screen to week 24 were observed for both the RSG+MET group (∆= -1.32 ± 1.092, 95% CI: -1.54%, -1.10%) and MET group (∆= -1.26 ± 1.027, 95% CI: -1.48%, -1.04%).

• The mean difference in FPG values in the RSG+MET group compared to the MET group for subjects evaluable at screen and week 24 (∆= -49.9mg/dL, 95% CI: -59.5mg/dL, -40.3mg/dL) was statistically significant. A statistically significant


11


mean difference in FPG values for the RSG+MET group was observed between screening and week 24 (∆= -49.9mg/dL ± 43.78, p30mg/dL) in the RSG+MET group (25 subjects, 42.4%) versus the MET escalation group (17 subjects, 34%) was observed (∆=13%, p


was observed at week 24 compared to baseline (∆= 49%, p


therapy. This latter death, cause unknown, occurred in the RSG+MET group which was considered as being unrelated to study medication by the study investigator. There were 33 subjects with on-therapy serious, non-fatal Aes: 17 in the MET escalation group and 16 in the RSG+MET group. Serious Aes that occurred in more than one subject in any treatment group included cerebrovascular disorder (3 subjects/MET group), chest pain (2 subjects/RSG+MET group), myocardial infarction (2 subjects/RSG+MET group) and diverticulitis (2 subjects/MET group). All on-therapy serious Aes were considered by the investigator to be either unlikely or not related to the study medication.

• The SAE profile for the subjects by prior diet and exercise subgroup was similar to that of All Randomized Subjects. Six subjects in the RSG+MET group versus five subjects in the MET group experienced at least one on-therapy SAE. Two subjects in the RSG+MET subgroup reported GI-related SAEs (“acute diverticulitis” and “constipation due to diverticulitis”).

• Withdrawal Due to Adverse Experiences: The incidence of on-therapy adverse experiences leading to withdrawal was greater in the MET escalation group than in the RSG+MET group: 35 subjects (9.1%) in the MET group compared to 24 subjects (6.3%) in the RSG+MET group. The largest difference in withdrawals between groups occurred with gastrointestinal disturbances (MET 6.8% vs RSG+MET 3.1%)

Summary of Subject Withdrawals Due to On-Therapy Gastrointestinal-related Adverse Events (All Randomized Subjects)

Treatment Group

Aes by Preferred Term, n (%) MET

(n=384) RSG+MET

(n=382) Total

(n=766) No. of subjects with at least one GI-related event

26 (6.8) 12 (3.1) 38 (5.0)

Diarrhea 16 (4.2) 6 (1.6) 22 (2.9) Abdominal Pain 9 (2.3) 4 (1.3) 13 (1.7) Flatulence 1 (0.3) 3 (0.8) 4 (0.5) Constipation 0 2 (0.5) 2 (0.3) Diverticulitis 0 1 (0.3) 1 (0.1) Gastroenteritis 0 1 (0.3) 1 (0.1) Gastrointestinal Disorder NOS1 0 1 (0.3) 1 (0.1) Nausea 4 (1.0) 1 (0.3) 5 (0.7) Dyspepsia 3 (0.8) 0 3 (0.4) Fecal Incontinence 1 (0.3) 0 1 (0.1) Gastroesophageal Reflux 1 (0.3) 0 1 (0.1) Intestinal Obstruction 1 (0.3) 0 1 (0.1) Vomiting 2 (0.5) 0 2 (0.3) 1. NOS = not otherwise specified


14


• Vital Signs, Weight, and BMI: There were no statistically significant differences in SBP, DBP or heart rate between the two treatment groups. The majority of subjects in the RSG+MET group experienced either an increase in weight of 3x ULN at week 24. In the RSG+MET group, one subject had increased AST, two subjects had increased ALT, and two subjects had increased GGT. All of the values were above normal at baseline and remained above normal throughout the subject’s study participation.

• The percentage of subjects in the prior diet and exercise subgroup having laboratory values of potential clinical concern was low and similar to All Randomized


15


Subjects. Three subjects (2 subjects in RSG+MET group versus 1 subject in MET group) had low �avourable and/or hematocrit values; one subject (RSG+MET group) had increased AST, two subjects (RSG+MET group) had increased ALT and four subjects (2 subjects in the RSG+MET group versus 2 subjects in the MET group) had increase GGT.

• Biomarkers: The RSG+MET group showed statistically significant and �avourable effects in the biomarkers of cardiovascular disease risks, CRP, PAI-1 activity and MMP-9. The effects on PAI-1 activity and MMP-9 were found to be superior in the RSG+MET group compared to the MET escalation group. Compared to the MET escalation group, a statistically significant increase in TNF-α was observed with the RSG+MET combination therapy.


16


Percent Change in CV Markers from Baseline to Study End (Week 24) (ITT Population w/o LOCF)

Treatment Group MET RSG+MET MMP-9 (ng/ml) n1 40 48 Baseline: geometric mean 442.0 449.5 Week 24: geometric mean 540.3 385.0 Mean Change from Baseline (%) 22.2 -14.4

95% CI (-3.0, 54.0) (-26.4, -0.3) p-value2 0.0865 0.0462

Comparison with MET adjusted mean difference (%) -29.9 95% CI (-46.2, -8.7) p-value2 0.0090

PAI-1 Activity (IU/ml) n1 39 46 Baseline: geometric mean 16.3 18.3 Week 24: geometric mean 16.2 12.3 Mean Change from Baseline (%) -0.6 -32.8

95% CI (-23.6, 29.4) (-45.6, -16.9) p-value2 0.9661 0.0005

Comparison with MET adjusted mean difference (%) -32.4 95% CI (-51.4, -6.0) p-value2 0.0205

PAI-1 Antigen (ng/ml) n1 34 41 Baseline: geometric mean 39.2 39.0 Week 24: geometric mean 38.6 31.2 Mean Change from Baseline (%) -1.6 -17.9

95% CI (-19.1, 19.8) (-30.9, -2.4) p-value2 0.8718 0.0261

Comparison with MET adjusted mean difference (%) -16.6 95% CI (-35.4, 7.7) p-value2 0.1617

TNF alpha absolute (pg/mL) n1 20 20 Baseline: geometric mean 2.7 2.5 Week 24: geometric mean 2.5 3.2 Mean Change from Baseline (%) -5.6 30.4

95% CI (-22.4, 14.9) (5.5, 61.3) p-value2 0.5481 0.0169

Continued


17

Title: A 24-Week Randomized, Double-blind, Double-Dummy, Multicenter Study to Compare the Efficacy of AVANDIA when added to Submaximal Doses of Metformin and to Compare the Tolerability of the Combination to Metformin Monotherapy when Administered to Subjects with Type 2 Diabetes Mellitus Percent Change in CV Markers from Baseline to Study End (Week 24) (ITT Population w/o

LOCF) Treatment Group MET RSG+MET Comparison with MET

adjusted mean difference (%) 38.1 95% CI (4.4, 82.7) p-value2 0.0247

CRP (g/L) n1 41 49 Baseline: geometric mean 0.014 0.013 Week 24: geometric mean 0.013 0.009 Mean Change from Baseline (%) -9.8 -27.0

95% CI (-38.1, 31.4) (-44.6, -3.8) p-value2 0.5828 0.0264

Comparison with MET adjusted mean difference (%) -19.1 95% CI (-48.4, 27.1) p-value2 0.3544

Change from baseline calculated only for those subjects who had both baseline and week 24 values. Significance level is 0.05. Analysis of variance (with a model including an effect for treatment)

• Quality of Life: As measured by the DTSQ, subjects in the MET escalation group reported more dissatisfaction with their treatment compared to the RSG+MET group. The addition of RSG to sub-maximal MET resulted in a significant decrease in patient perception of hyperglycemia, while there was no differences between groups in perception of hypoglycemia. In addition, subjects in the RSG+MET group reported fewer GI symptoms, in particular diarrhea and abdominal pain, as measured by DHSI.


18


Conclusions:


RSG (8mg/day) when added to a sub-maximal dose of MET (1000mg/day) was noninferior to the maximal effective dose of MET monotherapy (2000mg/day) in improving hyperglycemia in subjects with type 2 DM. However, superior glycemic control was demonstrated by the RSG+MET combination therapy in FPG, HbA1c responders, FPG responders, fasting plasma insulin and HOMA %S. Furthermore, the addition of maximal RSG to sub-maximal MET was associated with greater treatment satisfaction, in particular, with a significant decrease in perception of hyperglycemia. In particular, fewer GI symptoms were reported with the RSG plus sub-maximal MET combination therapy compared to the MET monotherapy. Specifically, although both the RSG (8mg/day) plus sub-maximal MET (2000mg/day) combination therapy were found to be generally safe and well-tolerated, the combination therapy was associated with significantly fewer gastrointestinal side effects than maximal dose of MET (2000mg/day) monotherapy. In the subgroup of total subjects, the addition of RSG (8mg/day) to sub-maximal MET (1000mg/day) had superior effects on the cardiovascular disease risk biomarkers, PAI-1 activity and MMP-9, compared to the maximal dose of MET (2000mg/day).

Although in subjects by prior diet and exercise therapy the RSG (8mg/day) plus MET (1000mg/day) combination therapy was noninferior to the MET monotherapy (2000mg/day) in improving hyperglycemia, superior glycemic control was demonstrated by the RSG+MET combination therapy compared to the MET monotherapy in HbA1c responders, FPG responders, fasting plasma insulin and HOMA %S. In this population subgroup, the RSG (8mg/day) plus sub-maximal MET (2000mg/day) combination therapy was generally safe and well-tolerated with fewer GI symptoms than MET monotherapy.

Date of Report:

March 2005


19

Table of Contents

PageSynopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

List of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

1. ETHICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321.1. Independent Ethics Committee (IEC) or Institutional Review Board

(IRB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321.2. Ethical Conduct of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321.3. Subject Information and Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE . . . . . . 32

3. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

4. STUDY OBJECTIVE(S). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

5. INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385.1. Overall Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

5.1.1. Discussion of Study Design, Including the Choice of ControlGroup(s). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

5.2. Protocol Amendment(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425.3. Selection of Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

5.3.1. Inclusion/Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . 435.3.2. Predetermined Criteria for Subject Withdrawal . . . . . . . . . . . . 44

5.4. Investigational Product(s). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455.4.1. Description of Investigational Product(s) . . . . . . . . . . . . . . . . . 455.4.2. Dosages and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . 465.4.3. Dose Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475.4.4. Blinding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475.4.5. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485.4.6. Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . 485.4.7. Treatment of Investigational Product Overdose . . . . . . . . . . . . 48

5.5. Prior and Concomitant Medications and Non-Drug Therapies . . . . . 485.5.1. Permitted Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485.5.2. Prohibited Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

5.6. Study Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . 50


20

5.6.1. Demographic and Baseline Assessments . . . . . . . . . . . . . . . . 515.6.2. Efficacy Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515.6.3. Safety Assessments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525.6.4. Pharmacodynamic Assessments . . . . . . . . . . . . . . . . . . . . . . . 545.6.5. Biomarker Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555.6.6. Health Outcomes Assessments . . . . . . . . . . . . . . . . . . . . . . . . 55

5.7. Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565.8. Data Analysis Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

5.8.1. Timings of Planned Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . 575.8.2. Sample Size Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . 575.8.3. Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575.8.4. Treatment Comparisons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585.8.5. General Considerations for Data Analyses . . . . . . . . . . . . . . . 585.8.6. Data Handling Conventions . . . . . . . . . . . . . . . . . . . . . . . . . . . 605.8.7. Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615.8.8. Efficacy Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625.8.9. Safety Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645.8.10. Pharmacodynamic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . 655.8.11. Biomarker Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655.8.12. Health Outcomes Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . 65

6. STUDY POPULATION RESULTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666.1. Disposition of Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666.2. Protocol Deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676.3. Populations Analyzed. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676.4. Demographics and Other Baseline Characteristics . . . . . . . . . . . . . . 68

6.4.1. Demographic Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . 686.4.2. Baseline Characteristics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

6.5. Present Conditions and Medical History . . . . . . . . . . . . . . . . . . . . . . 706.6. Previous Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

6.6.1. Prior Non-Anti-Diabetic Medications (All RandomizedSubjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

6.6.2. Prior Anti-Diabetic Medications . . . . . . . . . . . . . . . . . . . . . . . . 726.7. Concomitant Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 736.8. Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

7. EFFICACY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757.1. Primary Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

7.1.1. Data Sets Analysed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75


21

7.2. Secondary Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777.2.1. HbA1c Responder Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . 807.2.2. Change in Fasting Plasma Glucose from Baseline at Week

24 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847.2.3. FPG Responder Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 887.2.4. Fasting Plasma Insulin Analysis. . . . . . . . . . . . . . . . . . . . . . . . 927.2.5. HOMA %S Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

7.3. Efficacy Conclusion(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

8. SAFETY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 978.1. Extent of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 978.2. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

8.2.1. Adverse Events by Relationship to Study Medication . . . . . . . 988.2.2. Adverse Events by Intensity . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

8.3. Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998.3.1. Fatal Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008.3.2. Non-Fatal Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008.3.3. Fatal Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1048.3.4. Non-Fatal Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

8.4. Adverse Events Leading to Premature Discontinuation ofInvestigational Product and/or Study . . . . . . . . . . . . . . . . . . . . . . . . . 108

8.5. Other Relevant Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108.5.1. Cardiac-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . 1108.5.2. Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1168.5.3. Hepatic/Biliary-Related Adverse Events . . . . . . . . . . . . . . . . . 1188.5.4. Anemia Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1198.5.5. Hypoglycemia Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . 1238.5.6. Gastrointestinal Adverse Events . . . . . . . . . . . . . . . . . . . . . . . 124

8.6. Pregnancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1258.7. Clinical Laboratory Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

8.7.1. Assessment of Hemoglobin and Hematocrit Parameters . . . . 1268.7.2. Assessment of Liver Enzyme Parameters . . . . . . . . . . . . . . . . 1288.7.3. Abnormalities of Potential Clinical Concern . . . . . . . . . . . . . . . 128

8.8. Other Safety Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318.8.1 Vital Signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318.8.2 Weight and Waist/Hip Ratio . . . . . . . . . . . . . . . . . . . . . . . . . . . 1338.8.3 Lipid parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

8.9. Safety Conclusion(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136


22

9. BIOMARKER RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1379.1. Biomarker Conclusion(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

10. HEALTH OUTCOMES RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14010.1. Diabetes Treatment Satisfaction Questionnaire . . . . . . . . . . . . . . . 14010.2. Digestive Health Status Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14310.3. Health Outcomes Conclusion(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

11. DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

12. CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

13. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

14. DATA SOURCE TABLES: STUDY POPULATION . . . . . . . . . . . . . . . . . . 158

15. DATA SOURCE TABLES: EFFICACY . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

16. DATA SOURCE TABLES: SAFETY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431

17. OTHER DATA SOURCE TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794

18. CASE NARRATIVES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82918.1. SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83218.2. Adverse Events Leading to Withdrawal . . . . . . . . . . . . . . . . . . . . . . 88218.3. LFTs of Potential Clinical Concern . . . . . . . . . . . . . . . . . . . . . . . . . . 91718.4. Hepatic/Biliary-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . 92418.5. Cardiac Failure Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . 92718.6. Anemia Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929

ATTACHMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935


23

List of Figures

PageFigure 1 BRL-049653.284 Study Design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38Figure 2 Change in HbA1c at Study Endpoint (Week 24) Compared to

baseline and MET Treatment Group (ITT Population w/o LOCF). . . . . . . 77Figure 3 HbA1c Responder Analysis (ITT Population w/o LOCF) . . . . . . . . . 81Figure 4 HbA1c Responder Analysis for Subjects without GI AEs (ITT

Population w/o LOCF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83Figure 5 Change in FPG (mean, SE) Compared to Baseline and MET

Treatment Group (ITT Population w/o LOCF) . . . . . . . . . . . . . . . . . . . . . . 85Figure 6 Mean FPG Over Time (mean, SE) (ITT Population w/o LOCF) . . . . 86Figure 7 Diet and Exercise Subgroup Analysis: Change in FPG (mean, SE)

Compared to baseline and MET Treatment Group (ITT Population w/oLOCF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

Figure 8 Fasting Glucose Responder Analysis (ITT Population w/o LOCF) . . 90Figure 9 Diet and Exercise Subgroup Analysis: Fasting Glucose Response

Analysis (ITT Population w/o LOCF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92


24

List of Tables

PageTable 1 Double-Blind Treatment Dosage Schedule . . . . . . . . . . . . . . . . . . . . 47Table 2 Outline of Study Procedures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50Table 3 Patient Disposition by Phase of Study . . . . . . . . . . . . . . . . . . . . . . . . 66Table 4 Reasons for Withdrawal Prior to Randomization . . . . . . . . . . . . . . . . 66Table 5 Reasons for Withdrawal Post-Randomization (All Randomized

Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67Table 6 Summary of Demographic Characteristics (ITT Population) . . . . . . . 68Table 7 Summary of Prior Therapy (ITT Population) . . . . . . . . . . . . . . . . . . . 69Table 8 Summary of Baseline Characteristics (ITT Population) . . . . . . . . . . . 69Table 9 Presenting Conditions Reported by Greater than or Equal to 5.0%

of Subjects in Either Treatment Group at Baseline (All RandomizedSubjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Table 10 Summary of Prior Lipid Lowering Medications by Treatment Group(All Randomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Table 11 Summary of Prior Gastrointestinal Medication Use in GreaterThan or Equal to 1% of Subjects (All Randomized Subjects) . . . . . . . . . . 72

Table 12 Summary of Prior Anti-Diabetic Medications by Treatment Group(All Randomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Table 13 Concomitant Medications Received by Greater than or Equal to5% of Subjects (All Randomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . 74

Table 14 Concomitant Medications Received by Greater than or Equal to5% of Subjects (All Randomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . 74

Table 15 Summary of HbA1c Change from Baseline, Previously SubmittedAnalysis (ITT with LOCF) and Post-hoc ITT without LOCF/ (Completer)Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

Table 16 Change in HbA1c at Study Endpoint (Week 24) Compared tobaseline and MET Treatment Group (ITT Population w/o LOCF). . . . . . . 77

Table 17 HbA1c (%) at Each Visit by Prior Therapy (ITT Population w/oLOCF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Table 18 Diet and Exercise Subgroup Analysis: Change in HbA1c at StudyEndpoint (Week 24) Compared to baseline and MET Treatment Group(ITT Population w/o LOCF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Table 19 Diet and Exercise Subgroup Analysis: Change in HbA1c at StudyEndpoint (Week 24) Compared to screen and MET Treatment Group(ITT Population w/o LOCF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Table 20 HbA1c Responder Analysis (ITT Population w/o LOCF) . . . . . . . . . 80


25

Table 21 Change in FPG (mg/dL) at Study Endpoint (Week 24) Comparedto baseline and MET Treatment Group (ITT Population w/o LOCF) . . . . 84

Table 22 Diet and Exercise Subgroup Analysis: Change in FPG (mg/dL) atStudy Endpoint (Week 24) Compared to Screen and MET TreatmentGroup (ITT Population w/o LOCF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

Table 23 Fasting Plasma Glucose Responder Analysis (ITT Population w/oLOCF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Table 24 Diet and Exercise Subgroup Analysis: Fasting Plasma GlucoseResponder Analysis (ITT Population w/o LOCF) . . . . . . . . . . . . . . . . . . . 91

Table 25 Change in Fasting Insulin at Study Endpoint (week 24) Comparedto baseline and MET (ITT Population w/o LOCF) . . . . . . . . . . . . . . . . . . . 93

Table 26 Change in HOMA Parameters at Week 24 Compared to baseline(ITT Population w/o LOCF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

Table 27 Diet and Exercise Subgroup Analysis: Change in HOMAParameters at Week 24 Compared to baseline (ITT Population w/oLOCF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Table 28 Duration of Exposure to Study Medication (All RandomizedSubjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Table 29 On-Therapy Adverse Events Reported by Greater Than or Equalto 5% of Subjects in Any Treatment Group (All Randomized Subjects) . . 98

Table 30 On-Therapy Adverse Events Considered to beSuspected/Probably Related to Study Medication in Greater Than orEqual to 2% of Subjects (All Randomized Subjects) . . . . . . . . . . . . . . . . 98

Table 31 Severe On-Therapy Adverse Events Reported by 2 or MoreSubjects in Any Treatment Group (All Randomized Subjects) . . . . . . . . . 99

Table 32 Summary of On-Therapy Serious Non-Fatal Adverse Events (AllRandomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Table 33 Subjects with On-Therapy Serious Non-Fatal Adverse Events (AllRandomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

Table 34 Summary of On-Therapy Serious Non-Fatal Adverse Events (AllRandomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

Table 35 Subjects with On-Therapy Serious Non-Fatal Adverse Events (AllRandomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

Table 36 Summary of Subject Withdrawals Due to On-Therapy AdverseEvents, Excluding Gastrointestinal-related Adverse Events (AllRandomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

Table 37 Summary of Subject Withdrawals Due to On-TherapyGastrointestinal-related Adverse Events (All Randomized Subjects) . . . . 110


26

Table 38 Cardiac Ischemia On-Therapy Adverse Events, Serious Non-FatalAdverse Events and Withdrawals (All Randomized Subjects) . . . . . . . . . 112

Table 39 Subjects with Cardiac Ischemia On-Therapy AEs, SAEs andWithdrawals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Table 40 Cardiac Failure/Pulmonary Edema On-Therapy Adverse Events,Serious Non-Fatal Adverse Events and Withdrawals (All RandomizedSubjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

Table 41 Subjects with Cardiac Failure On-Therapy AEs, SAEs andWithdrawals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

Table 42 Edema On-Therapy Adverse Events, Serious Non-Fatal AdverseEvents and Withdrawals (All Randomized Subjects) . . . . . . . . . . . . . . . . 116

Table 43 Subjects with Edema On-Therapy AEs, SAEs and Withdrawals . . . 117Table 44 Hepatic/Biliary-Related On-Therapy Adverse Events, Serious

Non-Fatal Adverse Events and Withdrawals (All Randomized Subjects) . 118Table 45 Anemia On-Therapy Adverse Events, Serious Non-Fatal Adverse

Events and Withdrawals (All Randomized Subjects) . . . . . . . . . . . . . . . . 120Table 46 Subjects with Anemia On-Therapy AEs, SAEs and Withdrawals. . . 121Table 47 Hemoglobin/Hematocrit Values for Subjects with On-Therapy

Anemia AEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122Table 48 Hypoglycemia On-Therapy Adverse Events, Serious Non-Fatal

Adverse Events and Withdrawals (All Randomized Subjects) . . . . . . . . . 123Table 49 Gastrointestinal On-Therapy Adverse Events, Serious Non-Fatal

Adverse Events and Withdrawals (All Randomized Subjects) . . . . . . . . . 124Table 50 Number of Subjects with GI Adverse Events by Visit (ITT

Population w/o LOCF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125Table 51 Change in Hemoglobin and Hematocrit at Week 24 Compared to

Baseline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127Table 52 Mean Change in Liver Function Parameters over Time (All

Randomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128Table 53 Laboratory Values Considered by the Sponsor to be of Potential

Clinical Concern at Any Time During the Study . . . . . . . . . . . . . . . . . . . . 129Table 54 On-Therapy Laboratory Values of Potential Clinical Concern (All

Randomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130Table 55 Change in Vital Signs at Study End (Week 24) Compared to

Baseline (All Randomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132Table 56 Subjects with On-Therapy Vital Signs of Potential Clinical Concern

(All Randomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132Table 57 Change in Body Weight at Select Timepoints of the Study (All

Randomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133


27

Table 58 Percent Change in Lipid Parameters from Baseline to Study End(Week 24) (All Randomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

Table 59 Summary of Change in Lipid Ratios from Baseline to Study End(Week 24) (All Randomized Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

Table 60 Percent Change in CV Markers from Baseline to Study End (Week24) (ITT Population w/o LOCF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

Table 61 Change from Baseline at Week 24 in the Diabetes TreatmentSatisfaction Questionnaire (Intent-to-Treat Subjects) . . . . . . . . . . . . . . . . 141

Table 62 Change from Baseline at Week 24 in the Diabetes TreatmentSatisfaction Questionnaire (Subjects by Prior Diet and Exercise) . . . . . . 142

Table 63 Change from Baseline at Week 24 in the Digestive Health StatusIndex (Intent-to-Treat Subjects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

Table 64 Change from Baseline at Week 24 in the Digestive Health StatusIndex (Subjects by Prior Diet and Exercise) . . . . . . . . . . . . . . . . . . . . . . . 146


28

Abbreviations

Abbreviation Unabridged Terms ABPM Ambulatory Blood Pressure Monitoring ADA American Diabetes Association ADME Absorption, Distribution, Metabolism and Elimination AE Adverse Experience/Event AGE Advance Glycosylation End Product AP Alkaline Phosphatase ALT Alanine Aminotransferase (SGPT) AM Ante-meridian (from 24.00h to 11.59h) Apo Apolipoprotein AST Aspartate Aminotransferase (SGOT) ATC Anatomical Therapeutic Chemical AUC Area Under the Plasma Concentration Curve AUC (0-∞) Area Under the Plasma Concentration Curve from Time 0 to Infinite Time AUC (0-t) Area Under the Plasma Concentration Curve from Time 0 to Last Measurable

Concentration BD Twice daily B/L Baseline BMI Body Mass Index [weight (kg)/square of height (m2)] BP Blood Pressure bpm Beats Per Minute BUN Blood Urea Nitrogen CFR Code of Federal Regulations CHF Congestive Heart Failure CI Confidence Interval CrCl Creatinine Clearance Cmax Observed Maximum Plasma Concentration CPK Creatinine Phosphokinase CPMP Committee for Proprietary Medicinal Products CRF CRP

Case Report Form C reactive protein

CRT Case Report Data Tabulations CT Clinical Trial CV Curriculum Vitae CVA Cerebral Vascular Accident CXR Chest X-ray DBP Diastolic Blood Pressure dL DHSI

Deciliter Digestive Health Status Instrument

DMPK Drug Metabolism and Pharmacokinetics DM DTSQ

Diabetes Mellitus Diabetes Treatment Satisfaction Questionnaire

ECG Electrocardiogram eCRF Electronic Case Report Form EDTA Ethylenediaminetetraacetic Acid EF Ejection Fraction EMEA European Agency for the Evaluation of Medicinal Products ERC Ethics Review Committee EU European Union F1 Normal range flagging. Denotes all laboratory values above or below the reference

range. F2 Baseline shift flagging. Denotes laboratory values, which have increased or


29

Abbreviation Unabridged Terms decreased from Baseline by more than a sponsor-defined amount.

F3 Clinical concern flagging. Denotes a laboratory value considered by the sponsor to be a potential clinical concern.

FDA Food and Drug Administration FBG Fasting Blood Glucose FPG Fasting Plasma Glucose GCP Good Clinical Practice GDR Glucose Disposal Rate GGT Gamma Glutamyl Transpeptidase GLB Glibenclamide/Glyburide GLIC Glicazide GLIP Glipizide GLUT Glucose Transporter hr/hrs Hour/Hours Hb Hemoglobin HbA1c Glycosylated hemoglobin hCG Human Chorionic Gonadotropin Hct Hematocrit HDL High Density Lipoprotein HGO HOMA

Hepatic Glucose Output Homeostasis Model Assessment

HPF High Powered Field ICH International Conference on Harmonization IDDM Insulin Dependent Diabetes Mellitus (Type 1 Diabetes Mellitus) IGT Impaired Glucose Tolerance INS Insulin IRB Institutional Review Board IU International Units IV Intravenous L Liter LDH Lactate Dehydrogenase LDL Low Density Lipoprotein LLN Lower Limit Normal LLRR Lower Limit of the Reference Range Lp Lipoprotein LV Left Ventricle LVH Left Ventricular Hypertrophy LVMI Left Ventricular Mass Index MCH Mean Corpuscular Hemoglobin MCHC Mean Corpuscular Hemoglobin Concentration McIU Micro International Units MCV Mean Corpuscular Volume MET Metformin mg Milligrams MI Myocardial Infarction min Minute mL Milliliter mmHg Millimeters of Mercury mmol Millimole mol Mole ng Nanograms NIDDM Non-insulin Dependent Diabetes Mellitus (Type 2 Diabetes Mellitus) NOS Not Otherwise Specified od Once daily


30

Abbreviation Unabridged Terms OGTT Oral Glucose Tolerance Test OLE Open Label Extension PAI-1 Type 1 Plasminogen Activator Inhibitor Pbo Placebo PCV Packed Cell Volume PK Pharmacokinetics PM Post-meridian (from 12.00h to 23.59) pmol Picomole PPAR Peroxisomal Proliferator Activated Receptor RBC Red Blood Cell RSG Rosiglitazone SAE Serious Adverse Experience/Event SAS Statistical Analysis System SB SmithKline Beecham SBCL SmithKline Beecham Clinical Laboratories SBP Systolic Blood Pressure SD Standard Deviation SE Standard Error SEM Standard Error of the Mean SGPT Serum Glutamic Oxaloacetic Transaminase (See ALT) SGOT Serum Glutamic Pyruvic Transaminase (See AST) SI International System of Units SmPC Summary of Product Characteristics SOP Standard Operating Procedure SU Sulfonylurea sVCAM Soluble Vascular Cell Adhesion Molecule T ½ Half-life TDD Total Daily Dose TG Triglyceride TGFß Transforming growth factor ß Tmax Time of Observed Maximum Concentration TZD Thiazolidinedione u Micro UK United Kingdom ULN Upper Limit Normal ULRR Upper Limit of the Reference Range umol micromole URI/URTI Upper Respiratory Tract Infection USA United States of America UTI Urinary Tract Infection VLDL Very Low Density Lipoprotein VPC Ventricular Premature Contraction WBC White Blood Cell WHO World Health Organization WRC-GCP Worldwide Regulatory Compliance – Good Clinical Practice

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

AVANDIA Glucophage


31

1. ETHICS

1.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB)

The study protocol, amendments, informed consent, and any other information that required pre-approval were reviewed and approved by a national, regional, or Investigational Center Ethics Committee or Institutional Review Board.

1.2. Ethical Conduct of the Study

This study was conducted in accordance with "Good Clinical Practice" (GCP) and all applicable regulatory requirements, including, where applicable, the Declaration of Helsinki as amended in Somerset West, Republic of South Africa, in October 1996.

1.3. Subject Information and Consent

Written informed consent was obtained from each subject prior to the performance of screening visit procedures. Subjects’ data was recorded in the electronic Case Report Forms (eCRFs).

2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

The study was conducted by investigators at 63 centers in the U.S. and Canada. The investigators were selected based on study interest, study conduct according to GCP standards, and subject enrollment. To ensure that study procedures were consistent across all Investigational centers, GlaxoSmithKline representatives reviewed the protocol, CRF, and study procedures with the investigators and their staff. In addition, a multi-Investigator meeting was held at the Biltmore Hotel, in Coral Gables, Florida.

Contract Research Organizations (CROs) were employed to perform the following functions according to agreed contracts:

CRO Function

Quest Diagnostics, Van Nuys, CA 91405, USA Evaluation of all clinical laboratory parameters.

The authors of this clinical study report are: MPH, PharmD, MPH, PhD, MS, MD, PhD


32

Clinical Study Report Revision History

The BRL-049653/284 clinical study report (GSK Document Number CM2003/00016/00) was amended to include an analysis of the Intent-to-Treat population without Last Observation Carried Forward (ITT without LOCF) for subjects completing the study according to the investigator ("completers") for several efficacy endpoints. This new analysis was necessary due to the data handling convention (‘slotting rule’) used for the on-treatment visit windows. No new data sets were produced to facilitate the analyses and there were no changes made to the original datasets. Analysis of safety parameters was not affected by the slotting rule.

The visit windows defined for HbA1c and FPG were such that the last observation for these parameters was carried forward to the study end. HbA1c (the primary efficacy parameter) was only collected at baseline and at study end (week 24). The primary analysis for the study was defined as the mean change from baseline in HbA1c for ITT without LOCF. ITT without LOCF was defined in the protocol as those subjects who completed the week 24 visit ("completers"). Therefore, for HbA1c, the ITT without LOCF analysis is the same as the ITT with LOCF analysis. Another consequence of the visit window definition was that for some laboratory parameters collected multiple times on-therapy (such as FPG), subjects who withdrew from the study were included in the ITT without LOCF analyses if they withdrew between week 16 and week 24.

The following efficacy endpoints were analyzed as ITT without LOCF for completers: change from baseline at week 24 for HbA1c, FPG, HbA1c responders, FPG responders, HOMA-%S, and insulin. Overall, the results for these endpoints for the ITT without LOCF and the ITT without completer analyses were comparable.

The ITT without LOCF for completers analysis was not performed for the following efficacy endpoints:

• Comparison of the Diabetes Treatment Satisfaction Questionnaire (DTSG) and DHSI (Digestive Health Status Index-GI questionnaire) for change from baseline at week 24, within and between treatment groups.

• The proportion of subjects who were HbA1c responders and FPG responders after 24 weeks of treatment for subjects without GI side-effects, by baseline HbA1c (

3. INTRODUCTION

Diabetes mellitus (DM), the most common endocrine disorder, results in metabolic disturbances of carbohydrate, fat, and protein metabolism. It is a heterogeneous disorder, primarily characterized by chronic hyperglycemia. Diabetes is associated with serious long-term micro- and macrovascular complications leading to a reduced quality of life and heavy burden on healthcare resources. Type 2 DM accounts for approximately 90% of the total number of DM cases [Centers for Disease Control and Prevention, 2000].

Pathophysiologically, type 2 DM results from a combination of insufficient insulin secretion from progressive β-cell dysfunction and target tissue resistance to circulating insulin [Mahler, 1999]. The medical management of type 2 DM encompasses both non-pharmacological and pharmacological approaches targeting insulin resistance and β-cell dysfunction for improving glycemic control and delaying end-organ disease progression. Interventions range from diet, exercise and weight reduction, to the addition of oral antihyperglycemic agents and/or insulin therapy, as appropriate [Nathan, 2002].

Pharmacotherapy for hyperglycemia has greatly expanded, allowing individuals with type 2 DM formerly treated with insulin to be treated solely with oral anti-hyperglycemics, either as monotherapies or as combination agents. However, the United Kingdom Prospective Diabetes Study (UKPDS) has demonstrated that in type 2 diabetics, there is a progressive loss of glucose control regardless of the course of treatment, including metformin monotherapy. That is to approximately 50% of individuals with type 2 DM studied required the addition of a second agent within three years of diagnosis [Turner, 1999]. The loss of glycemic control is likely due to progressive deterioration of β-cell function [U.K. Prospective Diabetes Study Group (UKPDS) UKPDS 16, 1995]. It is of note that diabetic agents used in the UKPDS did not include the thiazolidinediones (TZDs) which have the potential to exert a protective or sparing effect on pancreatic β-cells. When single agent therapies are unable to achieve glycemic targets either an increased dose of monotherapy or beginning combination therapy using agents with complementary modes of action are often employed. The latter strategy has the potential to maximize therapeutic effect while reducing side-effects [Blonde, 2000]. The early utilization of a TZD combination treatment is a logical alternative to non-TZD combinations because of their potential to prevent β-cell deterioration and resultant loss of glycemic control. In addition, the GI AEs observed with metformin monotherapy might be mitigated by early combination therapy with rosiglitazone, rather than maximizing MET monotherapy.

Rosiglitazone (AVANDIA™, rosiglitazone maleate, BRL-049653C, RSG) has been approved by the U.S. Food & Drug Administration for combination therapy with metformin (Glucophage, metformin HCl, MET) in the treatment of type 2 DM. MET, a dimethyl-biguanide, acts primarily on the liver to reduce hepatic glucose production [Inzuchhi, 1998]. On the other hand, RSG, a TZD, exerts its effect by binding to the transcription factor peroxisome proliferator-activated receptor-gamma (PPARγ), targeting the liver, adipose and skeletal muscle tissues to lower insulin resistance, and results primarily in increased peripheral glucose uptake [Inzuchhi, 1998; Jucker, 2002].


34

With different mechanisms of action, these agents, when used in combination, offer a therapeutic advantage by maximizing the therapeutic effect and reducing side-effects [Fonseca, 2000; DiCicco, 2000]. The combination of RSG+MET has shown significant reductions in hemoglobin A1c (HbA1c) levels, improvements in insulin sensitivity and estimates of β-cell function. In two separate clinical studies, RSG in combination with maximal maintenance doses of MET (2500mg/day) demonstrated clinically and statistically significant decreases in HbA1c and FPG when compared to MET monotherapy [GlaxoSmithKline Document Number BRL-049653/RSD-100J23/1, GlaxoSmithKline Document BRL-049653/RSD-100T9SW/1]. Another apparent benefit of RSG+MET combination therapy over MET monotherapy is improvement of β-cell function. Subjects completing at least 30 months of treatment with RSG administered either as 4mg BD or 8mg OD in combination with a maximal dose of MET 2500mg exhibited improvement in both estimates of β-cell function (as measured by HOMA) and HbA1c which appeared to be durable over this period [GlaxoSmithKline Document BRL-049653/RSD-100T9SW/1].

The UKPDS demonstrated no macrovascular benefit of improved glycemic control with any of the hypoglycemic classes under investigation, except biguanides (i.e., MET). Specifically, in overweight subjects with type 2 DM, therapy with MET reduced the risk for any diabetes-related endpoint, diabetes-related death, and all-cause mortality including those associated with macrovascular disease such as stroke and myocardial infarction [U.K. Prospective Diabetes Study Group (UKPDS) UKPDS 34, 1998]. Although the cardiovascular outcomes trials in progress involving RSG have not yet completed, the evolving clinical data have shown RSG treatment to improve numerous biomarkers of cardiovascular risk. RSG improves endothelial-dependent vascular reactivity independent of glycemic control [GlaxoSmithKline Document Number BRL-049653/RSD-101R8S/1], as well as mitigating the incidence of coronary stent restenosis [Choi, 2003], and beneficially alter serum cardiovascular risk and inflammatory markers such as plasminogen activator inhibitor (PAI-1), plasma monocyte chemoattractant protein (MCP-1), C-reactive protein, E-selectin, matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand (sCD40L), adiponectin and lipoprotein particle composition [GlaxoSmithKline Document Number BRL-049653/RSD-101R8S/1; Mohanty, 2002a; Valensi, 2002; Mohanty, 2002b; Natali, 2002; Chu, 2002; Haffner, 2002; Freed, 2002; Combs, 2002; Marx, 2003].

Metformin therapy has been associated with a high percentage of gastrointestinal (GI) disturbances, especially during initiation of treatment. In a clinical trial of MET monotherapy compared to placebo, a 24% increase in digestive disturbances was reported--diarrhea and nausea being the most common [Garber, 1997]. These events resulted in withdrawal of approximately five percent of the subjects from the study. The study also showed no further efficacy of MET with doses beyond 2000mg TDD (1000mg BD).

Despite the lack of clinical trial evidence demonstrating increased GI side-effects with increased dosage of MET, experience in clinical practice suggests that increased MET doses are associated with increased GI side-effects. This is consistent with many physicians not readily prescribing greater than MET 1000mg TDD.


35

This study was conducted to demonstrate that glycemic control achieved by the addition of RSG (8mg/day) to sub-maximal dose MET (1000mg/day) is at least noninferior to up-titration to the maximally effective dose of MET (2000mg/day) and that the GI AEs anticipated by increasing MET from 1000mg to 2000mg TDD are mitigated. Such side-effects were evaluated by examining AEs, and Quality of Life (QOL) questionnaires (i.e., Digestive Health Status Instrument, Diabetes Treatment Satisfaction Questionnaire).

4. STUDY OBJECTIVE(S)

The primary objective of this investigational study was to evaluate the noninferiority of RSG (8mg/day) plus MET (1000mg/day) relative to MET (2000mg/day) monotherapy in reducing hyperglycemia in subjects with type 2 DM. The primary endpoint was the change in HbA1c after 24 weeks of dosing in the RSG+MET combination therapy as compared to the MET monotherapy group.

The secondary objectives of the study were:

To compare HbA1c, FPG, insulin sensitivity, HOMA %S, DTSQ (Diabetes Treatment Satisfaction Questionnaire) and DHSI (GI questionnaire) change from baseline at week 24 within and between treatment groups.

To compare proportion of subjects responding (HbA1c and FPG responders) to treatment between groups after 24 weeks of treatment. HbA1c responders were subjects achieving a decrease in HbA1c of ≥0.7% from baseline. FPG responders were subjects with a decrease in FPG of ≥30mg/dL from baseline. In addition, the proportion of subjects achieving FPG ≤126mg/dL and ≤140mg/dL and proportion of subjects achieving HbA1c ≤6.5%, ≤7% ≤8% and >8%, were summarized.

To compare the proportion of subjects who responded (HbA1c and FPG responders) to treatment between groups after 24 weeks of treatment in the following ways:

• Subjects without GI side-effects

• By baseline HbA1c (

To further compare the proportion of subjects with a prior therapy of diet and exercise, who were HbA1c and FPG responders between treatment groups in the following ways:

• Overall (within the subgroup)

• Subjects without GI side-effects

• By baseline HbA1c (

5. INVESTIGATIONAL PLAN

5.1. Overall Study Design

This was a randomized, double-blind, double dummy, multicenter study to assess the safety, efficacy and tolerability of the addition of RSG to sub-maximal MET combination relative to maximal MET monotherapy in subjects with type 2 DM. The total duration of the study was approximately 20 months.

The study consisted of a two-week washout period, a four to seven-week MET titration period, and a 24-week randomized treatment phase in which subjects, stratified by prior therapy, received either RSG+MET combination therapy or MET monotherapy.

A schematic of the study design is provided in Figure 1.

Figure 1 BRL-049653.284 Study Design

4-7 weeks 24 weeks

Randomization

2 weeks

WASHOUT PERIOD RUN-IN PERIOD TREATMENT PERIOD

Patients receiving currentsulfonylurea, metformin,Acarbose, ormetformin/sulfonylureatreatment will be washedout over a two week period.

Pretherapy visit

InitiateMetformin

Metformin titration to 1000 mg

Week 2titrate metformin

Baseline

Initiate blindedAvandiaor metformin

Blinded Avandia titrationOpen label Metformin (500 mg bd)

Week 8titrate Avandia ormetformin

Blinded Metformin Titration

Open label Metformin (500 mg bd)

PRESCREENASSESSMENT

LFTs,Creatinine,FPG

5.1.1. Discussion of Study Design, Including the Choice of Control Group(s)

The study consisted of:

Visit 1 – Pre-Screen/Washout Period

In order to facilitate screening, subjects underwent a pre-screening assessment. Approximately six to nine weeks prior to baseline, serum creatinine concentrations, liver enzymes (ALT/SGPT, AST/SGOT), and FPG were collected. Subjects fasted for at least eight hours prior to blood sampling. Those subjects with either creatinine concentration or liver enzymes outside protocol limits or FPG >270mg/dL, were immediately excluded from study entry.


38

Procedures:

• Obtain Informed Consent • Review Inclusion/Exclusion criteria. Subjects not meeting eligibility

criteria were excluded • A posterior-anterior chest X-ray. A chest X-ray performed within one year

prior to randomization was accepted • Standard 12-lead electrocardiogram (ECG). A copy of the ECG should be

attached to the subjects source documents • A complete physical examination to include standardized measurements of

blood pressure and heart rate • A complete medical history to include all anti-diabetic medications taken

within the past 12 months and any other prescription medications which have been taken within the last thirty days or those currently being taken

• Record all AE baseline signs and symptoms • Record body weight and height and waist and hip circumference

measurements • Labs: fasting blood and urine specimen, HbA1c, FPG, Serum βhCG for

women of child bearing potential and a partial lipid assessment.

After screening, eligible subjects entered a two-week washout period. During this time, all anti-diabetic treatments were discontinued. Subjects demonstrating a FPG

During week 1, subjects were administered a MET 500mg capsule OD in the p.m., with meals. If no intolerable GI side-effects, all subjects were to take an additional MET 500mg capsule in the a.m. with meals at week 2 (MET 1000mg/day) and remain at this dose level for three weeks, prior to randomization.

However, if subjects were intolerant to the MET 1000mg/day dose, they were back-titrated to MET 500mg/day, for up to a two-week period. At the end of this period, those subjects were administered an additional MET 500mg capsule (MET 1000mg/day) and remained at this dose for three weeks prior to randomization. Subjects who remained intolerant at the end of this period were withdrawn from the study.

At the completion of the MET titration (run-in) period, subjects returned to the clinic (within ± 3 days) in a fasted state and were evaluated for eligibility into the treatment phase of the study.

Visit 3 – Randomization/Baseline (Day 0)

At randomization/baseline (visit 3, day 0), subjects were randomized to receive either RSG+MET combination therapy or MET monotherapy, stratified by prior therapy (diet and exercise, monotherapy and combination therapy). In addition to the open-label MET (1000mg), those subjects randomized to the RSG+MET combination were administered RSG 2mg BD (4 mg/day). For subjects randomized to the MET escalation group, they remained on open-label MET (1000mg/day) and received an additional MET 500mg capsule (MET 1500mg/day). Subjects were administered the initial dose of study medication at the clinic. All medications were administered a.m./p.m., with meals.

All subjects were administered the DHSI and DTSQ (in the protocol). The DHSI and DTSQ were used to assess gastrointestinal symptomatology and subject satisfaction with diabetes treatment, respectively. Subjects were given both questionnaires, in a random manner, prior to study procedures.

At this visit, five subjects per treatment group, at 10 investigational centers, consumed a standardized liquid meal for post-prandial assessments. The standard liquid meal consisted of BOOST HP; a commercially available liquid mixed meal comprised of 55% carbohydrate, 24% protein and 21% fat. Subjects ingested six ml/kg of body weight within 10 minutes. The meal was given in the a.m., prior to dosing with study medication. A blood sample was obtained prior to the a.m. meal (time 0) and five additional samples (0.5, 1, 1.5, 2 and 3 hours) were drawn relative to the start of the meal. Insulin and triglyceride levels were collected at each time interval. On the morning of post-prandial assessments, no study medication was administered prior to obtaining the last post-prandial blood sample.


40

Procedures:

• Standardized methods of measuring BP and heart rate • Interim history, including recording of all concomitant medications as well

as any medication changes and adverse events • Body weight • Labs: fasting blood, partial lipid assessment, HbA1c, FPG, and Insulin. C-

reactive protein (CRP), plasma PAI-1 activity and antigen, TNF-α and MMP-9 assays were performed only in the small subset of subjects involved in the post-prandial study.

Visit 4 and 5 – On-Therapy

At visit 4, subjects randomized to the RSG+MET treatment group were up-titrated to RSG 4mg BD (8mg/day) plus open-label MET (1000mg/day). Those subjects in the MET escalation group remained on open-label MET (1000mg/day) and had their blinded study medication up-titrated to MET 1000mg/day for a TDD of MET 2000mg/day. They remained at this dose for the remainder of the study. Subjects dispensed open-label MET and blinded study medication after visit 4 were instructed to return to the clinic, in a fasted state, within 56 days (± 3 days). Study medications along with similar instructions were dispensed to the subject at visit 5. All medication was administered in the a.m./p.m. with meals.

Procedures:

• Standardized methods of measuring BP and heart rate • Interim history, including recording of all concomitant medications as well as

any medication changes and adverse events • Body weight • Labs: liver enzymes ALT (SGPT), AST (SGOT), FPG, Insulin (visit 4 only)

CRP and plasma PAI-1 activity and antigen, TNF-α and MMP-9 only in subjects involved in post-prandial assessment (visit 4 only)

• Questionnaire: only the DHSI for gastrointestinal symptoms was administered to the subject at visits 4 and 5 (in protocol)

Visit 6 – Treatment End

At visit 6, post-prandial assessments were conducted on the same 100 subjects as at randomization/baseline (visit 3). Again, subjects were administered a standardized liquid meal (a.m.) to be completely consumed (within 10 minutes) prior to dosing with study medication. Blood samples were obtained prior to the a.m. meal (time 0) and five additional samples (0.5, 1, 1.5, 2 and 3 hours) relative to the start of the a.m. meal. Insulin and triglyceride levels were collected at each time interval. Study medication was administered after obtaining the last post-prandial blood sample.

The DHSI and DTSQ were given to all subjects at visit 6, prior to study procedures.


41

Procedures:

• Standardized methods of measuring BP and heart rate • Physical exam, interim history, including recording of all concomitant

medications as well as any medication changes and adverse events • Body weight and waist/hip circumference measurements • Labs: fasting blood, partial lipid assessment, HbA1c, FPG, insulin,

• CRP, and plasma PAI-1 activity and antigen, TNF-α, MMP-9 and serum only in subjects involved in post-prandial assessment.

• βhCG for women of child bearing potential

5.2. Protocol Amendment(s)

The BRL-049653/284 final protocol, dated 01-February-2001, was modified 09-August-2001.

The rationale for changes made in the protocol modification were to expedite subject enrollment as well as to clarify, correct and/or add the following information in the protocol: prior metformin dosing, FPG values at screening and run-in phases, dosing of metformin during the open-label titration phase, numbers of days between visit schedule, number of subjects participating in the post-prandial assessment, analysis of an additional cardiovascular marker, and additional laboratory procedure to the Informed Consent.

On 19-February-2003, the BRL-049653/284 final protocol, dated 9 August 2001; was amended.

In order to investigate the effectiveness of RSG+MET as first line therapy, additional analyses on the subset of patients with a prior therapy of diet and exercise were needed. The additional analyses for subjects with prior therapy of diet and exercise included comparisons within and between treatment groups for HbA1c, FPG, HOMA %S, HOMA %B`, DTSQ and DHSI change from baseline at week 24. Also, for this subgroup, further comparisons to the proportion of subjects who were HbA1c and FPG responders between treatment groups were made in the following ways: overall (within the subgroup), by baseline HbA1c (

5.3. Selection of Study Population

5.3.1. Inclusion/Exclusion Criteria

Inclusion Criteria

Subjects proceeded to the MET titration period (or run-in period if already able to tolerate MET 1000mg/day) if they satisfied the following criteria at the screening visit (visit 1).

1. Subjects with a diagnosis of type 2 DM as defined by the criteria of the American Diabetes Association.

2. Men or women, between the ages of 18 and 75 years of age. However, exceptions were granted to those subjects over the age of 75 on a case-by-case basis and only with the expressed permission of the sponsor. In this instance, a calculation of creatinine clearance from a serum sample and a 24-hour urine collection creatinine clearance test was required to ensure adequate renal function (CrCl ≥ 60ml/min).

3. Females who were post-menopausal (i.e., >6 months without a menstrual period), surgically sterile, or using acceptable contraceptive measures (oral contraceptive, Norplant, Depo-Provera, an IUD, a diaphragm with spermacide or condoms). Women of childbearing potential were to use acceptable contraceptive measures for at least one month prior to screening and for 30 days after study completion.

4. Subjects previously treated by either diet and exercise or oral therapy. Any subjects who were receiving MET or MET plus Sulfonylurea (SU) must have been receiving no more than MET 1000mg/day for at least three months prior to study entry. Subjects must have stopped previous treatment with thiazolidinediones (TZDs) at least three months prior to screening.

5. Subjects with a Body Mass Index (BMI) ≥27 kg/m2. 6. Subjects who signed the Informed Consent. 7. Subjects who received monotherapy treatment within the last three months prior to

study entry or drug-naïves who had HbA1c levels between 7% and 10%, inclusive. Subjects who received prior combination treatment had HbA1c of at least 6.5% to 8.5%, inclusive.

8. Subjects with FPG of

3. Use of TZDs or any investigational drug for glycemic control within three months prior to study entry irregardless of the treatment regimen, or use of any other investigational agent (not related to glycemic management) within 30 days or five half-lives (whichever is longer) preceding study entry.

4. Subjects with FPG ≥270 mg/dL at screening. 5. Subjects with prior history of hepatocellular reaction to or severe edema associated

with troglitazone or any current TZD.

6. History of significant hypersensitivity (e.g., difficulty swallowing, difficulty breathing, tachycardia or skin reaction) to TZDs, biguanides, or compounds with similar chemical structures.

7. Subjects currently using insulin or who discontinued its use for glycemic control within the last three months prior to study entry.

8. History of acute or chronic metabolic acidosis. 9. Presence of clinically significant renal or hepatic disease (i.e., male subjects with

serum creatinine ≥1.5 mg/dL; female subjects with serum creatinine >1.4 mg/dL; ALT, AST, total bilirubin, GGT, or alkaline phosphatase >2.5 times the upper limit of the reference range).

10. Anemia defined by hemoglobin concentration 100mmHg while on anti-hypertensive treatment.

13. Recent history or suspicion of current drug abuse or alcohol abuse (defined as the consumption of more than 35 units of alcohol per week: one unit alcohol = one glass of wine, half a pint of beer, or one measure of spirits).

14. Non-compliance with study medication during MET titration period (run-in). 15. Subjects, who received or anticipated receiving radiocontrast dye during the MET

titration (run-in) or the randomized treatment period of the study.

16. Subjects unwilling or unable to comply with the procedure described in the protocol. 17. Subjects who were unable to read or understand the English language were excluded

from the study due to the administration of the QOL assessments.

5.3.2. Predetermined Criteria for Subject Withdrawal

The investigator was to be proactive with subjects’ retention in the study. However, premature discontinuation from the study may have occurred for the following reasons:

• Adverse Event

• Lack of efficacy (i.e., insufficient therapeutic effect), as defined below:


44

• Subjects with FPG ≥270mg/dL on two consecutive study visits, during the baseline or treatment periods.

• FPG increased to a level deemed by the investigator to represent a safety risk to the subject.

• Subjects were withdrawn if requiring insulin or any additional agent to manage glycemic control.

• Any other metabolic disorder deemed by the investigator to be a safety risk to the subject.

• A protocol violation, including lack of compliance with study medication, visit schedule or treatment with prohibited concomitant medications.

• Subject lost to follow-up.

• The subject requested an early discontinuation.

• ALT levels >3x the upper limit of the reference range on two conse

Documents

In February 2013, GlaxoSmithKline (GSK) announced a … · 2018-11-07 · In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the