<?xml version="1.0" encoding="UTF-8"?><section ID="S14">
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<title>14 CLINICAL STUDIES</title>
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<title>14.1 Overview of Clinical Studies </title>
<text>
<paragraph>BYDUREON BCISE has been studied in adult patients with type 2 diabetes mellitus as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione <content styleCode="italics">[see <linkHtml href="#ID_254802ec-f194-4fc0-af08-8efbd0d8a9a3">Clinical Studies (14.2)</linkHtml>]</content>.</paragraph>
<paragraph>The effectiveness of BYDUREON BCISE as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus was also supported by adequate and well-controlled studies of BYDUREON, another extended-release exenatide product, in adult and pediatric patients aged 10 years and older with type 2 diabetes mellitus <content styleCode="italics">[see <linkHtml href="#ID_2badd56a-87d8-44d0-952f-f7ed8c6e28cf">Clinical Studies (14.3</linkHtml>, <linkHtml href="#ID_a793b932-6c1c-4858-ad00-2b93b0230034">14.4</linkHtml>, <linkHtml href="#ID_2badd56a-87d8-44d0-952f-f7ed8c6e28cf">14.6)</linkHtml>]</content>. </paragraph>
<paragraph>Cardiovascular (CV) outcomes were studied in the EXSCEL trial that enrolled adult patients with type 2 diabetes mellitus and multiple risk factors for CV disease or established CV disease <content styleCode="italics">[see <linkHtml href="#ID_ceaadace-3720-4e70-923a-1364f7a2bcb9">Clinical Studies (14.5)</linkHtml>]</content>.</paragraph>
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<title>14.2 BYDUREON BCISE Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus </title>
<text>
<paragraph>
<content styleCode="underline">BYDUREON BCISE versus BYETTA, Both as Monotherapy or as Add-on to Metformin, a Sulfonylurea, a Thiazolidinedione, or Combination of Oral Agents</content>
</paragraph>
<paragraph>A 28-week, randomized, open-label comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON BCISE to BYETTA in adult patients with type 2 diabetes and inadequate glycemic control with diet and exercise alone or with oral antidiabetic therapy, including metformin, a sulfonylurea, a thiazolidinedione, or a combination of any two of these therapies (Trial 1 - NCT01652716). Patients were randomly assigned to receive BYDUREON BCISE 2 mg given subcutaneously once every 7 days (weekly) (n=229) or BYETTA (10 mcg twice daily) (n=146), in addition to existing oral antidiabetic agents. Patients assigned to BYETTA initiated treatment with 5 mcg twice daily then increased the dosage to 10 mcg twice daily after 4 weeks.</paragraph>
<paragraph>A total of 375 adult patients were studied: 278 (74%) were Caucasian, 61 (16%) Black or African American, 25 (7%) Asian, 5 (1%) listed as other, 5 (1%) American Indian or Alaska Native, and 1 (<1%) Native Hawaiian or Other Pacific Islander. Patients were treated with diet and exercise alone (13%), a single oral antidiabetic agent (49%), or combination therapy of oral antidiabetic agents (38%). The mean baseline HbA1c was 8.5%.</paragraph>
<paragraph>The primary endpoint was change in HbA<sub>1c</sub> from baseline to Week 28. </paragraph>
<paragraph>
<content styleCode="italics">Efficacy Results:</content>
</paragraph>
<paragraph>The results for the primary endpoint at Week 28 are summarized in Table 4. Treatment with BYDUREON BCISE 2 mg once weekly (QW) resulted in a statistically significantly greater reduction in HbA1c compared to BYETTA 10 mcg twice daily. The mean reduction in HbA1c was non-inferior compared with BYETTA 10 mcg twice daily at the pre-specified non-inferiority margin +0.4% in this study. BYDUREON BCISE 2 mg QW was statistically superior to BYETTA 10 mcg twice daily (ANCOVA p-value=0.0032).</paragraph>
<paragraph>The proportions of subjects achieving HbA1c <7.0% at Week 28 were 40% in BYDUREON BCISE group compared to 38% in BYETTA group. Subjects with missing values at Week 28 counted as non-responders. The mean changes from baseline to Week 28 for fasting plasma glucose were -36 mg/dL and -27 mg/dL for BYDUREON BCISE and BYETTA, respectively, and for body weight were -1.4 kg and -1.9 kg for BYDUREON BCISE and BYETTA, respectively.</paragraph>
<table width="100%">
<caption>Table 4: Results of 28-Week Trial of BYDUREON BCISE versus BYETTA, Both as Monotherapy or as Add-On to Metformin, a Sulfonylurea, a Thiazolidinedione, or Combination of Oral Agents in Patients with Type 2 Diabetes Mellitus (Trial 1)</caption>
<col width="56%"/>
<col width="23%"/>
<col width="21%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYDUREON BCISE</content>
<br/>
<content styleCode="bold">2 mg QW</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYETTA<br/>10 mcg twice daily</content>
<footnote ID="_Ref137196252">Least squares means were obtained using an Analysis of Covariance (ANCOVA) model with treatment, baseline HbA<sub>1c</sub>, baseline HbA<sub>1c</sub> stratum (<9% or ≥9%), diabetes management method at screening (diet/exercise alone, SU use, or non-SU use), and renal function (normal, mild, or moderate renal impairment) in the population included subjects discontinued treatment before 28 weeks regardless of initiation of rescue medicine.</footnote>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Intent-to-Treat Population (N)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>229</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>146</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Mean Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Mean Change at Week 28</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>‑1.39</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>‑1.03</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from BYETTA<footnoteRef IDREF="_Ref137196252"/>[95% CI]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>‑0.36<footnote ID="_Ref137193213">p-value <0.01</footnote>
</paragraph>
<paragraph>(‑0.66, ‑0.14)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td colspan="3" valign="top">
<paragraph>N = number of patients in each treatment group, CI = unadjusted confidence interval, QW = once weekly.</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="underline">BYDUREON BCISE versus Sitagliptin and Placebo, All as Add-on to Metformin Therapy</content>
</paragraph>
<paragraph>A 28-week open-label (oral medication blinded), comparator- and placebo-controlled trial was conducted to compare the safety and efficacy of BYDUREON BCISE to sitagliptin and placebo in adult patients with type 2 diabetes whose glycemic control was inadequate with metformin therapy (Trial 2 - NCT01652729). Patients were randomly assigned to receive BYDUREON BCISE 2 mg given subcutaneously once every 7 days (weekly) (n=181), sitagliptin 100 mg/day (n=122) or placebo (n=61), in addition to their existing metformin therapy.</paragraph>
<paragraph>A total of 364 adult patients were studied, 296 (81%) were Caucasian, 49 (14%) Black or African American, 14 (4%) Asian and 3 (<1%) American Indian or Alaska Native, 1 (<1%) Native Hawaiian or Other Pacific Islander, and 1 (<1%) was classified otherwise. The mean baseline HbA1c was 8.5%. </paragraph>
<paragraph>The primary endpoint was change in HbA<sub>1c</sub> from baseline to Week 28. </paragraph>
<paragraph>
<content styleCode="italics">Efficacy Results:</content>
</paragraph>
<paragraph>Results for the primary endpoint at 28 weeks are summarized in Table 5. In this study, treatment with BYDUREON BCISE 2 mg once weekly resulted in a statistically significant mean reduction in HbA1c compared to placebo. BYDUREON BCISE 2 mg was statistically superior to placebo (ANCOVA p-value=0.02). </paragraph>
<paragraph>The proportions of subjects who achieved an HbA1c <7.0% at Week 28 were 41%, 31%, and 26% in BYDUREON BCISE, Sitagliptin and Placebo groups, respectively. Subjects with missing values at Week 28 counted as non-responders. The mean changes from baseline to Week 28 for fasting plasma glucose were -24 mg/dL, -19 mg/dL and -1 mg/dL for BYDUREON BCISE, Sitagliptin and Placebo, respectively, and for body weight were -1.4 kg, -1.2 kg, and 0.4 kg for BYDUREON BCISE, Sitagliptin and Placebo, respectively. </paragraph>
<table width="100%">
<caption>Table 5: Results of 28-Week Trial of BYDUREON BCISE versus Sitagliptin and Placebo, All as Add-On to Metformin Therapy in Adult Patients with Type 2 Diabetes Mellitus (Trial 2)</caption>
<col width="40%"/>
<col width="28%"/>
<col width="17%"/>
<col width="15%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYDUREON BCISE </content>
<br/>
<content styleCode="bold">2 mg QW</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Sitagliptin<br/>100 mg/day</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Placebo<br/>once daily</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Intent-to-Treat Population (N)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>181</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>122</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>61</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Mean Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Mean Change at Week 28</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>‑1.07</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>‑0.79</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>‑0.59 </paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from sitagliptin<footnote ID="_Ref120886312">Least squares means were obtained using an Analysis of Covariance (ANCOVA) model with treatment, baseline HbA<sub>1c</sub> and baseline HbA<sub>1c</sub> stratum (<9% or ≥ 9%) in the population included subjects discontinued treatment before 28 weeks regardless of initiation of rescue medicine.</footnote>
<footnote ID="_Ref120886328">Sitagliptin 100 mg/day did not show the superiority to placebo in this study.</footnote>
<br/> [95% CI]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>‑0.28</paragraph>
<paragraph>(‑0.62, 0.02)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref120886312"/>
<br/> [95% CI]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>‑0.49</paragraph>
<paragraph>(‑0.91, ‑0.07)<footnote ID="_Ref120886375">p-value <0.05</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td colspan="4" valign="top">
<paragraph>N = number of patients in each treatment group, CI = unadjusted confidence interval, QW = once weekly.</paragraph>
</td>
</tr>
</tbody>
</table>
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<title>14.3 BYDUREON Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus - Monotherapy </title>
<text>
<paragraph>BYDUREON, another exenatide extended-release product, has been studied as monotherapy in adult patients with type 2 diabetes mellitus.</paragraph>
<paragraph>
<content styleCode="underline">BYDUREON Monotherapy versus Metformin, Sitagliptin, and Pioglitazone </content>
</paragraph>
<paragraph>A 26-week, randomized, comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to metformin, sitagliptin, and pioglitazone in patients with type 2 diabetes whose glycemic control was inadequate with diet and exercise (Trial 3 - NCT00676338). Patients were randomly assigned to receive BYDUREON 2 mg given subcutaneously once every seven days (weekly), titrated metformin from 1000 to 2500 mg/day, sitagliptin 100 mg/day or titrated pioglitazone from 30 to 45 mg/day, all dosed according to approved labeling.</paragraph>
<paragraph>A total of 820 patients were studied: 552 (67%) were Caucasian, 102 (12%) were East Asian, 71 (9%) were West Asian, 65 (8%) were Hispanic, 25 (3.0%) were Black, 4 (0.5%) were Native American, and 1 was classified otherwise. The mean baseline HbA<sub>1c</sub> was 8.5%. </paragraph>
<paragraph>The primary endpoint was change in HbA<sub>1c</sub> from baseline to Week 26 (or the last value at time of early discontinuation). </paragraph>
<paragraph>
<content styleCode="italics">Efficacy Results:</content>
</paragraph>
<paragraph>Treatment with BYDUREON 2 mg once weekly (QW) resulted in mean HbA1c reduction that was statistically significantly greater compared to sitagliptin 100 mg/day. The mean reduction in HbA1c was non-inferior compared with metformin 1000-2500 mg/day (mean dose 2077 mg/day at study endpoint). Non-inferiority of BYDUREON 2 mg QW to pioglitazone 30-45 mg/day (mean dose 40 mg/day at study endpoint) in reducing HbA<sub>1c</sub> after 26 weeks of treatment was not demonstrated (the mean change from baseline in HbA<sub>1c</sub> after 26 weeks was -1.6% with BYDUREON and -1.7% with pioglitazone). The non-inferiority margin was set at +0.3% in this study. The results for the primary endpoint at 26 weeks are summarized in Table 6. </paragraph>
<paragraph>The proportion of patients with a Week 26 value achieving HbA<sub>1c</sub> of less than 7% at Week 26 were 56%, 52%, 40%, and 55% for BYDUREON, metformin, sitagliptin, and pioglitazone, respectively. Patients who did achieve HbA<sub>1c</sub> goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose were -41 mg/dL, -36 mg/dL, -20 mg/dL and -46 mg/dL, and for body weight were -2.0 kg, -2.0 kg, -0.8 kg and +1.5 kg for BYDUREON, metformin, sitagliptin, and pioglitazone, respectively.</paragraph>
<table width="101.38%">
<caption>Table 6: Results of 26-Week Trial of BYDUREON Monotherapy versus Metformin, Sitagliptin, and Pioglitazone in Patients with Type 2 Diabetes Mellitus (Trial 3)</caption>
<col width="33%"/>
<col width="18%"/>
<col width="18%"/>
<col width="15%"/>
<col width="16%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYDUREON</content>
<br/>
<content styleCode="bold">2 mg QW</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Metformin<br/>1000-2500<br/>(mean dose<br/>2077) mg/day</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Sitagliptin<br/>100 mg/day</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Pioglitazone<br/>30-45 (mean<br/>dose 40)<br/>mg/day</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Intent-to-Treat Population (N)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>248</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>246</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>163</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>163</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Mean Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Mean Change at Week 26<footnote ID="_Ref121996846">Least squares means were obtained using a mixed model repeated measure analysis with treatment, pooled country, visit, baseline HbA1c value, and treatment by visit interaction as fixed effects, and subject as a random effect.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from metformin<footnoteRef IDREF="_Ref121996846"/>
<br/> [Bonferroni-adjusted 98.3% CI]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.05<br/>[−0.26, 0.17]</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from sitagliptin<footnoteRef IDREF="_Ref121996846"/>
<br/> [Bonferroni-adjusted 98.3% CI]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.39<footnote ID="_Ref121996922">p<0.001, treatment vs comparator.</footnote>
<br/>[−0.63, −0.16]</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from pioglitazone<footnoteRef IDREF="_Ref121996846"/>
<br/> [Bonferroni-adjusted 98.3% CI]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.16<br/>[−0.08, 0.41]</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td colspan="5" styleCode="Toprule " valign="top">
<paragraph>N = number of patients in each treatment group; mean change is least squares mean change; QW = once weekly.</paragraph>
<paragraph>The primary efficacy analysis was adjusted for multiple comparisons and a two-sided 98.3% confidence interval was utilized to assess difference between treatments.</paragraph>
<paragraph>HbA<sub>1c</sub> change data at 26 weeks were available from 86%, 87%, 85%, and 82% of the randomized subjects in the BYDUREON, metformin, sitagliptin, and pioglitazone groups, respectively.</paragraph>
</td>
</tr>
</tbody>
</table>
</text>
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<title>14.4 BYDUREON Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus - Combination Therapy </title>
<text>
<paragraph>BYDUREON, another exenatide extended-release product, has been studied in combination with metformin, sulfonylurea, thiazolidinedione, SGLT2 inhibitor and basal insulin in adult patients with type 2 diabetes mellitus.</paragraph>
<paragraph>
<content styleCode="underline">BYDUREON versus Sitagliptin and Pioglitazone, All as Add-on to Metformin Therapy </content>
</paragraph>
<paragraph>A 26-week double-blind comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to sitagliptin and pioglitazone in patients with type 2 diabetes whose glycemic control was inadequate with metformin therapy (Trial 4 - NCT00637273). Patients were randomly assigned to receive BYDUREON 2 mg given subcutaneously once every 7 days (weekly), sitagliptin 100 mg/day or pioglitazone 45 mg/day, in addition to their existing metformin therapy.</paragraph>
<paragraph>A total of 491 patients were studied 168 (34.2%) were Caucasian, 143 (29.1%) were Hispanic, 119 (24.2%) were Asian, 52 (10.6%) were Black, 3 (0.6%) were Native American, and 6 (1.2%) were classified otherwise. The mean baseline HbA<sub>1c</sub> was 8.5%. </paragraph>
<paragraph>The primary endpoint was change in HbA<sub>1c</sub> from baseline to Week 26 (or the last value at time of early discontinuation). </paragraph>
<paragraph>
<content styleCode="italics">Efficacy Results:</content>
</paragraph>
<paragraph>In this study, treatment with BYDUREON 2 mg QW resulted in a statistically significant mean HbA<sub>1c</sub> reduction compared to sitagliptin 100 mg/day. There was a numerically greater reduction in HbA<sub>1c</sub> with BYDUREON compared to pioglitazone, but there was not sufficient evidence to conclude superiority of BYDUREON 2 mg QW to pioglitazone 45 mg/day in reducing HbA<sub>1c</sub> after 26 Weeks of treatment. Results for the primary endpoint at 26 Weeks are summarized in Table 7. </paragraph>
<paragraph>The proportion of patients with a Week 26 value achieving HbA<sub>1c</sub> of less than 7% at Week 26 were 46%, 30%, and 39% for BYDUREON, sitagliptin, and pioglitazone, respectively. Patients who did achieve an HbA<sub>1c</sub> goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose were -32 mg/dL, -16 mg/dL and -27 mg/dL, and for body weight were -2.3 kg, -0.8 kg and +2.8 kg for BYDUREON, sitagliptin, and pioglitazone, respectively.</paragraph>
<table width="100%">
<caption>Table 7: Results of 26-Week Trial of BYDUREON versus Sitagliptin and Pioglitazone, All as Add-On to Metformin Therapy in Patients with Type 2 Diabetes Mellitus (Trial 4)</caption>
<col width="17%"/>
<col width="27%"/>
<col width="21%"/>
<col width="17%"/>
<col width="17%"/>
<thead>
<tr>
<th align="left" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYDUREON</content>
<br/>
<content styleCode="bold">2 mg QW</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Sitagliptin</content>
<br/>
<content styleCode="bold">100 mg/day</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Pioglitazone</content>
<br/>
<content styleCode="bold">45 mg/day</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="2" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Intent-to-Treat Population (N)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>160</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>166</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>165</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td colspan="4" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="2" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Mean Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.5</paragraph>
</td>
</tr>
<tr>
<td colspan="2" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Mean Change at Week 26<footnote ID="_Ref137194534">Least squares means were obtained using an ANCOVA model with treatment, baseline HbA<sub>1c</sub> stratum, and country as fixed effects. Missing Week 26 data (28%, 18%, and 24% for the BYDUREON, sitagliptin, and pioglitazone groups, respectively) were imputed by the LOCF technique.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.2</paragraph>
</td>
</tr>
<tr>
<td colspan="2" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from sitagliptin<footnoteRef IDREF="_Ref137194534"/> [95% CI]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.63 </paragraph>
<paragraph>[−0.89, −0.37]</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td colspan="2" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from pioglitazone<footnoteRef IDREF="_Ref137194534"/>
</paragraph>
<paragraph> [95% CI]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.32 </paragraph>
<paragraph>[−0.57, −0.06]</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td colspan="5" styleCode="Toprule " valign="top">
<paragraph>N = number of patients in each treatment group; mean change is least squares mean change; QW = once weekly. QW = once weekly.</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="underline">BYDUREON versus Insulin Glargine, Both as Add-on to Metformin or Metformin + Sulfonylurea Therapy </content>
</paragraph>
<paragraph>A 26-week open-label comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to titrated insulin glargine in patients with type 2 diabetes whose glycemic control was inadequate with metformin or metformin plus sulfonylurea therapy (Trial 5 - NCT00641056). Patients were randomly assigned to receive BYDUREON 2 mg given subcutaneously once every 7 days (weekly) or insulin glargine once daily in addition to their existing oral antidiabetic therapy. Insulin glargine was dosed to a target fasting glucose concentration of 72 to 100 mg/dL. </paragraph>
<paragraph>The mean dose of insulin glargine was 10 units/day at baseline and 31 units/day at endpoint. At Week 26, 21% of insulin glargine-treated patients were at fasting glucose goal.</paragraph>
<paragraph>A total of 456 patients were studied: 379 (83.1%) were Caucasian, 47 (10.3%) were Hispanic, 25 (5.5%) were East Asian, 3 (0.7%) were Black, and 2 (0.4%) were West Asian. Background therapy was either metformin (70%) or metformin plus sulfonylurea (30%). The mean baseline HbA<sub>1c</sub> was 8.3%.</paragraph>
<paragraph>The primary endpoint was change in HbA<sub>1c</sub> from baseline to Week 26 (or the last value at time of early discontinuation). </paragraph>
<paragraph>
<content styleCode="italics">Efficacy Results:</content>
</paragraph>
<paragraph>Treatment with BYDUREON once weekly resulted in a mean reduction in HbA<sub>1c</sub> from baseline at 26 weeks of -1.5%. The mean reduction in HbA1c seen in insulin glargine arm at 26 weeks was -1.3%. The difference in observed effect size between BYDUREON and glargine in this trial excluded the pre-specified non-inferiority margin of +0.3%.</paragraph>
<paragraph>The proportion of patients with a Week 26 value achieving HbA<sub>1c</sub> of less than 7% at Week 26 were 57% and 48% for BYDUREON and insulin glargine, respectively. Patients who did achieve an HbA<sub>1c</sub> goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose in this study were -38 mg/dL and -50 mg/dL, and for body weight were -2.6 kg and +1.4 kg for BYDUREON and insulin glargine, respectively.</paragraph>
<paragraph>
<content styleCode="underline">BYDUREON versus Liraglutide, Both as Add-on to Metformin, a Sulfonylurea, Metformin + Sulfonylurea, or Metformin + Pioglitazone Therapy </content>
</paragraph>
<paragraph>A 26-week open-label comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to liraglutide in patients with type 2 diabetes whose glycemic control was inadequate with metformin, a sulfonylurea, metformin plus sulfonylurea, or metformin plus pioglitazone therapy (Trial 6 - NCT01029886). Patients were randomly assigned to receive BYDUREON 2 mg given subcutaneously once every 7 days (weekly) or liraglutide uptitrated from 0.6 mg/day to 1.2 mg/day, then 1.8 mg/day in addition to their existing oral antidiabetic therapy. Each titration was to be completed after at least one week, but could be delayed if the patient had severe nausea or vomiting as established by the investigator. Patients not tolerating the 1.8 mg/day dose of liraglutide by Week 4 were discontinued from the study.</paragraph>
<paragraph>A total of 911 patients were studied: 753 (82.7%) were Caucasian, 111 (12.2%) were Asian, 32 (3.5%) were American Indian or Alaska Native, 8 (0.9%) were Black, 6 (0.7%) were multiple races, and 1 (0.1%) was Pacific Islander. Background therapy was either a single oral antidiabetic agent (35%) or a combination of oral antidiabetic agents (65%). The mean baseline HbA<sub>1c</sub> was 8.4%.</paragraph>
<paragraph>The primary endpoint was change in HbA<sub>1c</sub> from baseline to Week 26 (or the last value at time of early discontinuation). </paragraph>
<paragraph>
<content styleCode="italics">Efficacy Results:</content>
</paragraph>
<paragraph>Treatment with BYDUREON once weekly resulted in a mean reduction in HbA<sub>1c</sub> from baseline at 26 weeks of -1.3%. The mean reduction in HbA<sub>1c</sub> seen in the liraglutide arm at 26 weeks was -1.5%. The HbA<sub>1c</sub> reduction with BYDUREON did not meet predefined non-inferiority criteria compared to liraglutide 1.8 mg/day. The non-inferiority margin was set at +0.25% in this study. Results for the primary endpoint at 26 weeks are summarized in Table 8. </paragraph>
<paragraph>The proportion of patients with a Week 26 value achieving HbA<sub>1c </sub>of less than 7% at Week 26 were 48% and 56% for BYDUREON and liraglutide, respectively. Patients who did achieve an HbA<sub>1c</sub> goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose were -32 mg/dL and -38 mg/dL, and for body weight were -2.7 kg and -3.6 kg for BYDUREON and liraglutide, respectively.</paragraph>
<table width="100%">
<caption>Table 8: Results of 26-Week Trial of BYDUREON versus Liraglutide, Both as Add-On to Metformin, a Sulfonylurea, Metformin + Sulfonylurea, or Metformin + Pioglitazone Therapy in Patients with Type 2 Diabetes Mellitus (Trial 6)</caption>
<col width="49%"/>
<col width="28%"/>
<col width="23%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYDUREON</content>
<br/>
<content styleCode="bold">2 mg QW</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Liraglutide<br/>1.8 mg/day</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Intent-to-Treat Population (N)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>461</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>450</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Mean Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Mean Change at Week 26<footnote ID="_Ref121998700">Least squares means were obtained using a mixed model repeated measure analysis with treatment, country, OAD stratum, baseline HbA<sub>1c</sub> stratum, visit, baseline HbA<sub>1c</sub> and treatment by visit interaction as fixed effects, and subject as a random effect.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from liraglutide<footnoteRef IDREF="_Ref121998700"/> [95% CI]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.2 [0.08, 0.33]</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td colspan="3" valign="top">
<paragraph>N = number of patients in each treatment group; mean change is least squares mean change; QW = once weekly.</paragraph>
<paragraph>HbA<sub>1c</sub> change data at 26 weeks were available from 85% and 86% of the randomized subjects in the BYDUREON and liraglutide groups, respectively.</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="underline">BYDUREON in Combination with Dapagliflozin versus BYDUREON Alone and Dapagliflozin Alone, All as Add-On to Metformin </content>
</paragraph>
<paragraph>A 28-week double-blind comparator-controlled trial was conducted to compare the efficacy of BYDUREON and dapagliflozin (an SGLT2 inhibitor) to BYDUREON alone and dapagliflozin alone in patients with type 2 diabetes with inadequate glycemic control with metformin therapy (Trial 7 - NCT02229396). All patients entered a 1- week placebo lead–in period. Patients with HbA<sub>1c</sub> ≥8.0% and ≤12% and on metformin at a dose of at least 1,500 mg per day were randomly assigned to receive either BYDUREON 2 mg given subcutaneously once every 7 days (weekly) plus dapagliflozin 10 mg once daily, BYDUREON 2 mg given subcutaneously once weekly, or dapagliflozin 10 mg once daily.</paragraph>
<paragraph>A total of 694 patients were studied; 580 (83.6%) were Caucasian, 96 (13.8%) were Black, 5 (0.7%) were Asian, 2 (0.3%) were American Indian or Alaska Native, and 11 (1.6%) were classified otherwise. The mean baseline HbA<sub>1c</sub> was 9.3%.</paragraph>
<paragraph>The primary endpoint was change in HbA1c from baseline to Week 28. </paragraph>
<paragraph>
<content styleCode="italics">Efficacy Results:</content>
</paragraph>
<paragraph>At Week 28, BYDUREON in combination with dapagliflozin provided statistically significantly greater reductions in HbA<sub>1c</sub> (-1.77%) compared to BYDUREON alone (-1.42%, p=0.012) and dapagliflozin alone (-1.32%, p=0.001). BYDUREON in combination with dapagliflozin provided statistically significantly greater reductions in FPG (-57.35 mg/dL) compared to BYDUREON alone (-40.53, p <0.001) and dapagliflozin alone (-44.72 mg/dL, p=0.006).</paragraph>
<paragraph>
<content styleCode="underline">BYDUREON versus Placebo, Both as Add-On to Basal Insulin or Basal Insulin + Metformin Therapy </content>
</paragraph>
<paragraph>A 28-week, double-blind, placebo-controlled trial was conducted to compare the safety and efficacy of BYDUREON to placebo when added to basal insulin glargine, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control (Trial 8 - NCT02229383). Patients on sulfonylurea therapy discontinued sulfonylurea. Patients on metformin continued the same dose of metformin. All patients initially entered an 8-week insulin dose-titration phase. Insulin glargine was to be titrated every 3 days with an aim of achieving a target fasting plasma glucose concentration of 72 to 99 mg/dL. Following the titration period, patients with HbA<sub>1c</sub> ≥7.0% and ≤10.5% were then randomly assigned to receive either BYDUREON 2 mg given subcutaneously once every 7 days (weekly) or placebo once every 7 days (weekly).</paragraph>
<paragraph>A total of 460 patients were studied: 400 (87.0%) were White, 47 (10.2%) were Black or African American, 6 (1.3%) were Asian, 1 (0.2%) was American Indian or Alaska Native, 1 (0.2%) was Pacific Islander, and 5 (1.1%) were classified otherwise.</paragraph>
<paragraph>The primary endpoint was the change in HbA1c from baseline to Week 28. </paragraph>
<paragraph>
<content styleCode="italics">Efficacy Results:</content>
</paragraph>
<paragraph>Compared to placebo, treatment with BYDUREON resulted in a statistically significant reduction in mean HbA<sub>1c</sub> from baseline to Week 28 (Table 9). </paragraph>
<paragraph>The mean change in fasting plasma glucose from baseline to Week 28 was -12.50 mg/dL for BYDUREON and -2.26 mg/dL for placebo. The mean change from baseline to Week 28 in body weight was -0.92 kg for BYDUREON and +0.38 kg for placebo.</paragraph>
<table width="100%">
<caption>Table 9: Results of 28-Week Trial of BYDUREON versus Placebo, Both as Add-On to Insulin Glargine or Insulin Glargine + Metformin (Trial 8)</caption>
<col width="41%"/>
<col width="29%"/>
<col width="30%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Lrule Toprule " valign="middle"/>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">BYDUREON </content>
<br/>
<content styleCode="bold">2 mg QW</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">Placebo</content>
<br/>
<content styleCode="bold">QW</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Intent-to-Treat Population (N)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>231</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>229</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">Mean HbA<sub>1c</sub> (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>Mean Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>8.53</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>8.53</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="bottom">
<paragraph>Mean Change at Week 28<footnote ID="_Ref121999863">Adjusted LS means and treatment group difference(s) in the change from baseline values at Week 28 using a multiple imputation method that models a “wash-out” for patients having missing data who discontinued treatment. ANCOVA was used with treatment, region, baseline HbA<sub>1c</sub> stratum (<9.0% or ≥9.0%), and baseline SU-use stratum (yes vs. no) as fixed factors, and baseline value as a covariate.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="bottom">
<paragraph>-0.88 (0.070)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="bottom">
<paragraph>-0.24 (0.069)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="bottom">
<paragraph>Difference from Placebo [95% CI]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="bottom">
<paragraph>-0.64<footnote ID="_Ref122001153">p-value <0.001 (adjusted for multiplicity).</footnote>
<sup/>
</paragraph>
<paragraph>[-0.83, -0.45]</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule " valign="bottom"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">Percentage Achieving HbA<sub>1c</sub> <7.0% at Week 28 (%)</content>
<footnote ID="_Ref122001172">Categories are derived from continuous measurements. All patients with missing endpoint data are imputed as non-responders. Treatment comparison is based on Cochran-Mantel-Haenszel (CMH) test stratified by baseline HbA1c (<9.0% or ≥9.0%), and baseline SU use stratum (yes vs. no). P values are from the general association statistics.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>32.5<sup>†</sup>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>7.0</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Toprule " valign="bottom">
<paragraph>N = number of patients in each treatment group, CI = confidence interval, QW = once weekly.<br/>Note: mean change is least squares mean change.</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Analyses include measurements post rescue therapy and post premature discontinuation of study medication.</paragraph>
</text>
<effectiveTime value="20230504"/>
</section>
</component>
<component>
<section ID="ID_ceaadace-3720-4e70-923a-1364f7a2bcb9">
<id root="a3c54e4e-1f49-462a-8aee-172b60db3b82"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.5 EXSCEL Cardiovascular Outcomes Trial in Adult Patients with Type 2 Diabetes </title>
<text>
<paragraph>EXSCEL was a multinational, placebo-controlled, double-blind, randomized, parallel group pragmatic study that evaluated cardiovascular (CV) outcomes during treatment with BYDUREON (exenatide) for extended-release injectable suspension in adult patients with type 2 diabetes and any level of CV risk when added to the current usual care (NCT01144338).</paragraph>
<paragraph>A total of 14,752 adult patients were randomized 1:1 to either BYDUREON 2 mg given subcutaneously once weekly or placebo and followed as in routine clinical practice for a median of 38.7 months with a median treatment duration of 27.8 months. </paragraph>
<paragraph>Ninety six percent of the patients in both treatment groups completed the study in accordance with the protocol, and the vital status was known at the end of the study for 98.9% and 98.8% of the patients in the BYDUREON and placebo group, respectively. The mean age at study entry was 62 years (21 to 92 years with 8.5% of the patients ≥75 years). Approximately 62.0% of the patients were male, 75.8% were Caucasian, 9.8% were Asian, 6.0% were Black, and 20.5% were Hispanic or Latino. The mean BMI was 32.7 kg/m<sup>2</sup> and the mean duration of diabetes was 13.1 years. Approximately 49.3% had mild renal impairment (estimated glomerular filtration rate [eGFR] ≥60 to ≤89 mL/min/1.73 m<sup>2</sup>) and 21.6% had moderate renal impairment (eGFR ≥30 to ≤59 mL/min/1.73 m<sup>2</sup>).</paragraph>
<paragraph>The mean HbA<sub>1c</sub> was 8.1%. At baseline, 1.5% of patients were not treated with either oral antidiabetic medications or insulin, 42.3% were treated with one oral antidiabetic medication and 42.4% were treated with two or more oral antidiabetic medications. Usage of oral antidiabetic medications included metformin (76.6%), sulfonylurea (36.6%), DPP-4 inhibitors (14.9%), thiazolidinediones (3.9%), and SGLT2 inhibitors (0.9%). Overall insulin usage was 46.3% (13.8% with insulin alone and 32.6% with insulin and one or more oral antidiabetic medications).</paragraph>
<paragraph>Overall, at baseline, 26.9% of patients did not have established cardiovascular (CV) disease, while 73.1% had established CV disease. The concomitant use of CV medications (e.g., ACE inhibitors, angiotensin receptor blockers, diuretics, beta blockers, calcium channel blockers, antithrombotic and anticoagulants, and lipid-lowering agents) was similar in the BYDUREON and placebo groups. At baseline, the mean systolic blood pressure was 135.5 mmHg, the mean diastolic blood pressure was 78.1 mmHg, the mean LDL was 95.0 mg/dL, and the mean HDL was 44.0 mg/dL.</paragraph>
<paragraph>The primary endpoint in EXSCEL was the time to first confirmed Major Adverse Cardiac Event (MACE) from randomization. MACE was defined as occurrence of either a cardiovascular (CV)-related death, or a nonfatal myocardial infarction (MI) or a nonfatal stroke. All-cause mortality, CV-related death, and fatal or nonfatal MI or stroke, hospitalization for acute coronary syndrome, and hospitalization for heart failure were also assessed as secondary endpoints.</paragraph>
<paragraph>A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated. Type-1 error was controlled across multiple tests using a hierarchical testing strategy.</paragraph>
<paragraph>
<content styleCode="italics">MACE Results:</content>
</paragraph>
<paragraph>BYDUREON did not increase the risk of MACE in adult patients with type 2 diabetes mellitus (HR: 0.91; 95% CI: 0.832, 1.004; P<0.001 for non-inferiority; P=0.06 for superiority). See results in Table 10 and Figure 2. The incidence of MACE in patients with and without established CV disease was 13.4% in the BYDUREON group versus 14.6% in the placebo group and 6.0% (BYDUREON) versus 5.9% (placebo), respectively. Five hundred and seven (507) patients (6.9%) died in the BYDUREON group versus 584 (7.9%) in the placebo group.</paragraph>
<table width="100%">
<caption>Table 10: Analysis of Primary Composite Endpoint MACE and Its Components in Adult Patients with Type 2 Diabetes (EXSCEL)</caption>
<col width="41%"/>
<col width="19%"/>
<col width="20%"/>
<col width="21%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYDUREON</content>
<br/>
<content styleCode="bold">N=7356</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Placebo</content>
<br/>
<content styleCode="bold">N=7396</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">HR</content>
<footnote ID="_Ref122000143">HR (active/placebo) and CI are based on Cox proportional hazards regression model, stratified by established CV disease, with treatment group only as explanatory variable.</footnote>
<br/>
<content styleCode="bold">(95% CI)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>MACE Composite of CV death, nonfatal MI or nonfatal stroke (time to first confirmed event)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>839 (11.4%)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>905 (12.2%)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.91</paragraph>
<paragraph>(0.832, 1.004)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Cardiovascular Death</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>340 (4.6%)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>383 (5.2%)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.88</paragraph>
<paragraph>(0.76, 1.02)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Nonfatal Myocardial Infarction</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>466 (6.3%)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>480 (6.5%)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.96</paragraph>
<paragraph>(0.85, 1.09)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Nonfatal Stroke</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>169 (2.3%)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>193 (2.6%)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.86</paragraph>
<paragraph>(0.70, 1.06)</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Toprule " valign="top">
<paragraph>N=number of patients in each treatment group, HR=hazard ratio, CI=confidence interval, CV=cardiovascular, MI=myocardial infarction.</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="bold">Figure 2: Time to First Adjudicated MACE in Adult Patients with Type 2 Diabetes (EXSCEL)</content>
</paragraph>
<renderMultiMedia ID="id1216928514" referencedObject="FC152859-6F5D-4B2A-8194-0C53205FA51E"/>
<paragraph>HR=hazard ratio, CI=confidence interval.</paragraph>
</text>
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<text>P:\01_SPL\02_SPL_PREVIEW_SUBMISSION_FOR_PROOFING-TEMPORARY_HOLDING\BYDUREON BCISE\Harmonisation for Proofing\Figure 2.JPG</text>
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<section ID="ID_2badd56a-87d8-44d0-952f-f7ed8c6e28cf">
<id root="0869e018-32ca-42bd-824e-f3f144ffa8cb"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.6 Glycemic Control Trial in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus </title>
<text>
<paragraph>The efficacy and safety of BYDUREON 2 mg given subcutaneously once weekly or placebo was evaluated in a 24-week randomized, double-blind, placebo-controlled, parallel-group study (Trial 9 - NCT01554618) in 82 patients aged 10 to 17 years with type 2 diabetes treated with diet and exercise alone or in combination with a stable dose of oral antidiabetic agents and/or insulin. This study included a 28-week open-label long-term extension in which patients in both treatment groups received BYDUREON 2 mg given subcutaneously once weekly after the 24-week controlled period.</paragraph>
<paragraph>In this trial, 88% of patients completed the assessment period. The mean age at study entry was 15.1 years (13% were 11 to 12 years old, 59% were 13 to 16 years old and 28% were older than 16 years). Approximately 42% of the patients were male, 43% were White, 4% were Asian, 31% were Black or African American, 6% were American Indian or Alaska Native, and 44% were Hispanic or Latino. The mean body weight was 100.6 kg (67% were in ≥97 weight percentile group, 26% in ≥85 to <97 and 6% in ≥3 to <85), mean BMI was 36.4 kg/m2 and the mean duration of diabetes was 2.3 years.</paragraph>
<paragraph>At baseline, mean HbA1c was 8.17%, 12.2% of patients were not treated with either oral antidiabetic medications or insulin, 40.2% were treated with one oral antidiabetic medication and 1.2% were treated with two oral antidiabetic medications. 79.3% of patients were receiving metformin and 1.2% were receiving sulfonylurea. Overall insulin usage was 46.3% (8.5% with insulin alone and 37.8% with insulin and one other oral antidiabetic medication).</paragraph>
<paragraph>The primary endpoint of the study was the change in HbA<sub>1c</sub> from baseline to Week 24.</paragraph>
<paragraph>
<content styleCode="italics">Efficacy Results:</content>
</paragraph>
<paragraph>BYDUREON was superior to placebo in reducing HbA<sub>1c</sub> (Table 11). </paragraph>
<paragraph>The mean changes from baseline to Week 24 for body weight were -0.17 kg with (SE 0.7) and +0.88 kg (SE 1.0) for BYDUREON and placebo, respectively.</paragraph>
<table width="100%">
<caption>Table 11: Results of 24-Week Trial of BYDUREON versus Placebo, Both alone or in Combination with Oral Antidiabetic Agents and/or Insulin in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus (Trial 9)</caption>
<col width="52%"/>
<col width="30%"/>
<col width="18%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYDUREON 2 mg</content>
<br/>
<content styleCode="bold">QW</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Placebo<br/>QW</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Intent-to-Treat Population (N)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>58</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>24</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>Mean Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>8.13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>8.28</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>Mean Change at Week 24 (SE)<footnote ID="_Ref122000486">Adjusted LS means and treatment group difference(s) in the change from baseline values at Week 24 using a multiple imputation method that models a “wash-out” for patients having missing data who discontinued treatment. ANCOVA was used with treatment, region as fixed factors, and baseline HbA1c value as a covariate. SE – standard error.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>-0.25 (0.21)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>0.45 (0.29)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>Difference from Placebo (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>-0.71<footnote ID="_Ref122000523">p<0.05</footnote> (-1.42, 0)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="bottom"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub><7%</content>
</paragraph>
</td>
<td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>Percentage achieved goal at Week 24</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>31.0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>8.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</paragraph>
</td>
<td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>Mean Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>165.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>170.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>Mean Change at Week 24 (SE)<footnote ID="_Ref122000543">Adjusted LS means in the change from baseline values at Week 24 using a multiple imputation method that models a “wash-out” for patients having missing data who discontinued treatment. ANCOVA was used with treatment, region, as fixed factors, and baseline FPG value as a covariate.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>-1.3 (8.1)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>16.2 (11.9)</paragraph>
</td>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20230504"/>
</section>
</component>
</section>
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