<?xml version="1.0" encoding="UTF-8"?><section ID="ID_00eafa89-0751-4a85-a506-88a98705f88c">
<id root="e99d149b-a316-4c11-a051-37d0b2f99743"/>
<code code="34092-7" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL STUDIES SECTION"/>
<title>14 CLINICAL STUDIES </title>
<text>
<paragraph>BYETTA has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, a combination of metformin and a thiazolidinedione, or in combination with insulin glargine with or without metformin and/or thiazolidinedione.</paragraph>
</text>
<effectiveTime value="20241101"/>
<component>
<section ID="ID_3a055f68-81f4-4d3d-8746-3d869f5b06b5">
<id root="e10c8548-19a7-401f-9321-c78732a99842"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.1 Monotherapy </title>
<text>
<paragraph>In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, BYETTA 5 mcg BID (n=77), BYETTA 10 mcg BID (n=78), or placebo BID (n=77) was used as monotherapy in patients with entry HbA<sub>1c</sub> ranging from 6.5% to 10%. All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. BYETTA or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were Caucasian, 26% West Asian, 3% Hispanic, 3% Black, and 0.4% East Asian.</paragraph>
<paragraph>The primary endpoint was the change in HbA<sub>1c</sub> from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, BYETTA 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA<sub>1c</sub> from baseline at Week 24 (Table 6).</paragraph>
<table width="100%">
<caption>Table 6: Results of 24-Week Placebo-Controlled Trial of BYETTA used as Monotherapy</caption>
<col width="41%"/>
<col width="11%"/>
<col width="26%"/>
<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">Placebo</content>
<br/>
<content styleCode="bold">BID</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYETTA 5 mcg BID</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYETTA 10 mcg</content>
<footnote ID="_Ref516121117">BYETTA 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 5 months before the morning and evening meals.</footnote>
<br/>
<content styleCode="bold">BID</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule 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>77</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>77</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>78</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%), Mean </content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7.8</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Change at Week 24<footnote ID="_Ref516121221">Least squares means are adjusted for screening HbA1c strata and baseline value of the dependent variable.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121221"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.5 [−0.9, −0.2]<footnote ID="_Ref516121239">p <0.01, treatment vs. placebo.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.7 [−1.0, −0.3]</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Proportion Achieving HbA<sub>1c</sub> <7%</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>38%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>48%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>53%</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Body Weight (kg), Mean </content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>86.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>85.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>86.2</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Change at Week 24<footnoteRef IDREF="_Ref516121221"/>
</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>−2.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−2.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121221"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.3 [−2.3, −0.2]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.5 [−2.5, −0.4]</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Serum Glucose</content>
<footnote ID="_Ref516121303">Measured using the hexokinase-based glucose method.</footnote>
<content styleCode="bold"> (mg/dL), Mean </content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>159</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>155</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Change at Week 24<footnoteRef IDREF="_Ref516121221"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−19</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121221"/> (95% CI) </paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−12 [−23.2, −1.3]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−14 [−24.5, −2.5]</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Toprule " valign="top">
<paragraph>BID = twice daily.</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>On average, there were no adverse effects of exenatide on blood pressure or lipids.</paragraph>
</text>
<effectiveTime value="20241101"/>
</section>
</component>
<component>
<section ID="ID_559c16df-38e7-4bc0-a6f7-d6a946b54d67">
<id root="6c57ba33-90da-4e97-9a0b-94b68e591eaf"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.2 Combination Therapy with Oral Antihyperglycemic Medicines </title>
<text>
<paragraph>Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of BYETTA in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea. In addition, a 16-week, placebo-controlled trial was conducted where BYETTA was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control.</paragraph>
<paragraph>In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive BYETTA 5 mcg BID, BYETTA 10 mcg BID, or placebo BID before the morning and evening meals, in addition to their existing oral antidiabetic agent. All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the study. A total of 1446 patients were randomized in the three 30-week trials: 991 (69%) were Caucasian, 224 (16%) Hispanic, and 174 (12%) Black. Mean HbA<sub>1c</sub> values at baseline for the trials ranged from 8.2% to 8.7%.</paragraph>
<paragraph>In the placebo-controlled trial of 16 weeks duration, BYETTA (n=121) or placebo (n=112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin. Randomization to BYETTA or placebo was stratified based on whether the patients were receiving metformin. BYETTA treatment was initiated at a dose of 5 mcg BID for 4 weeks then increased to 10 mcg BID for 12 more weeks. Patients assigned to placebo received placebo BID throughout the study. BYETTA or placebo was injected subcutaneously before the morning and evening meals. In this trial, 79% of patients were taking a thiazolidinedione and metformin and 21% were taking a thiazolidinedione alone. The majority of patients (84%) were Caucasian, 8% Hispanic, and 3% Black. The mean baseline HbA<sub>1c</sub> values were 7.9% for BYETTA and placebo.</paragraph>
<paragraph>The primary endpoint in each study was the mean change in HbA<sub>1c</sub> from baseline to study end (or early discontinuation). Table 7 summarizes the study results for the 30- and 16-week clinical trials.</paragraph>
<table width="100%">
<caption>Table 7: Results of 30-Week and 16-Week Placebo-Controlled Trials of BYETTA used in Combination with Oral Antidiabetic Agents</caption>
<col width="32%"/>
<col width="14%"/>
<col width="27%"/>
<col width="28%"/>
<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">Placebo</content>
<br/>
<content styleCode="bold">BID</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYETTA 5 mcg</content>
<br/>
<content styleCode="bold">BID</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYETTA 10 mcg</content>
<footnote ID="_Ref516121817">BYETTA 5 mcg twice daily for 1 month followed by 10 mcg BID for 6 months for the 30-week trials or 10 mcg BID for 3 months in the 16-week trial before the morning and evening meals.</footnote>
<br/>
<content styleCode="bold">BID</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td align="center" colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">In Combination with Metformin (30 Weeks)</content>
</paragraph>
</td>
</tr>
<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>113</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>110</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>113</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.2</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 30<footnote ID="_Ref516121884">Least squares means are adjusted for baseline HbA<sub>1c</sub> strata or value, investigator site, baseline value of the dependent variable (if applicable), and background antihyperglycemic therapy (if applicable).</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121884"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.5 [−0.7, −0.2]<footnote ID="_Ref516122025">p <0.01, treatment vs. placebo.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.9 [−1.1, −0.6]<footnoteRef IDREF="_Ref516122025"/>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Proportion Achieving HbA<sub>1c</sub> <7%</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>12%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>32%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>40%</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Body Weight (kg), Mean </content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>99.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>100.0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>100.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 30<footnoteRef IDREF="_Ref516121884"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.2</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>−2.6</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121884"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.1 [−2.2, −0.0]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−2.4 [−3.5, −1.3]</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Plasma Glucose</content>
<footnote ID="_Ref516122108">Measured using the hexokinase-based glucose method.</footnote>
<content styleCode="bold">
<content styleCode="italics"/> (mg/dL), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>169</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>176</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>168</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 30<footnoteRef IDREF="_Ref516121884"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>+14</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−10</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121884"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−20 [−32, −7]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−24 [−37, −12]</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td align="center" colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">In Combination with a Sulfonylurea (30 Weeks)</content>
</paragraph>
</td>
</tr>
<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>123</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>125</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>129</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.7</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>8.6</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 30<footnoteRef IDREF="_Ref516121884"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>+0.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121884"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.6 [−0.9, −0.3]<footnoteRef IDREF="_Ref516122025"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.0 [−1.3, −0.7]<footnoteRef IDREF="_Ref516122025"/>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Proportion Achieving HbA<sub>1c</sub> <7%</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>25%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>36%</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Body Weight (kg), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>99.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>94.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>95.2</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 30<footnoteRef IDREF="_Ref516121884"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.6</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121884"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.3 [−1.1, 0.6]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.9 [−1.7, −0.0]</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Plasma Glucose</content>
<footnoteRef IDREF="_Ref516122108"/>
<content styleCode="bold"> (mg/dL), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>194</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>180</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>178</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 30<footnoteRef IDREF="_Ref516121884"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>+6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−11</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121884"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−11 [−25, 3]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−17 [−30, −3]</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td align="center" colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">In Combination with Metformin and a Sulfonylurea (30 Weeks)</content>
</paragraph>
</td>
</tr>
<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>247</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>245</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>241</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%), Mean</content>
</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> 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>
<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> Change at Week 30<footnoteRef IDREF="_Ref516121884"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>+0.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121884"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.8 [−1.0, −0.6]<footnoteRef IDREF="_Ref516122025"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.0 [−1.2, −0.8]<footnoteRef IDREF="_Ref516122025"/>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Proportion Achieving HbA<sub>1c</sub> <7%</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>25%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>31%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Body Weight (kg), Mean</content>
</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> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>99.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>96.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>98.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 30<footnoteRef IDREF="_Ref516121884"/>
</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>−1.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.6</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121884"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.7 [−1.2, −0.2]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.7 [−1.3, −0.2]</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Plasma Glucose</content>
<footnoteRef IDREF="_Ref516122108"/>
<content styleCode="bold"> (mg/dL), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline</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>182</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>178</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 30<footnoteRef IDREF="_Ref516121884"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>+13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−11</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−12</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121884"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−24 [−33, −15]</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−25 [−34, −16]</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td align="center" colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">In Combination with a Thiazolidinedione or a Thiazolidinedione plus Metformin (16 Weeks)</content>
</paragraph>
</td>
</tr>
<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>112</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Dose not studied</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>121</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Dose not studied</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>7.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 16<footnoteRef IDREF="_Ref516121884"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>+0.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Dose not studied</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121884"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Dose not studied</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.9 [−1.1, −0.7]<footnoteRef IDREF="_Ref516122025"/>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Proportion Achieving HbA<sub>1c</sub> <7%</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>15%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Dose not studied</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>51%</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Body Weight (kg), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>96.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Dose not studied</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>97.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 16<footnoteRef IDREF="_Ref516121884"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Dose not studied</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 placebo<footnoteRef IDREF="_Ref516121884"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Dose not studied</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.5 [−2.2, −0.7]</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Serum Glucose</content>
<footnoteRef IDREF="_Ref516122108"/>
<content styleCode="bold"> (mg/dL), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>159</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Dose not studied</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>164</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 16<footnoteRef IDREF="_Ref516121884"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>+4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Dose not studied</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−21</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516121884"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Dose not studied</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−25 [−33, −16]</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Toprule " valign="top">
<paragraph>BID = twice daily.</paragraph>
</td>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20241101"/>
<component>
<section ID="ID_7f92207b-5642-41f7-b643-12d68a8c9c52">
<id root="7f92207b-5642-41f7-b643-12d68a8c9c52"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">HbA<sub>1c </sub>
</content>
</title>
<text>
<paragraph>The addition of BYETTA to a regimen of metformin, a sulfonylurea, or both, resulted in statistically significant reductions from baseline in HbA<sub>1c</sub> compared with patients receiving placebo added to these agents in the three controlled trials (Table 7).</paragraph>
<paragraph>In the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin, BYETTA resulted in statistically significant reductions from baseline in HbA<sub>1c</sub> compared with patients receiving placebo (Table 7).</paragraph>
</text>
<effectiveTime value="20141211"/>
</section>
</component>
<component>
<section ID="ID_8d96c95d-eb99-4b64-80db-c1e9eb5512b7">
<id root="8d96c95d-eb99-4b64-80db-c1e9eb5512b7"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">Postprandial Glucose</content>
</title>
<text>
<paragraph>Postprandial glucose was measured after a mixed meal tolerance test in 9.5% of patients participating in the 30-week add-on to metformin, add-on to sulfonylurea, and add-on to metformin in combination with sulfonylurea clinical trials. In this pooled subset of patients, BYETTA reduced postprandial plasma glucose concentrations in a dose-dependent manner. The mean (SD) change in 2-hour postprandial glucose concentration following administration of BYETTA at Week 30 relative to baseline was <content styleCode="bold">−</content>63 (65) mg/dL for 5 mcg BID (n=42), <content styleCode="bold">−</content>71 (73) mg/dL for 10 mcg BID (n=52), and +11 (69) mg/dL for placebo BID (n=44).</paragraph>
</text>
<effectiveTime value="20141211"/>
</section>
</component>
</section>
</component>
<component>
<section ID="ID_4fa1ede4-f411-40ea-b0ea-4cba47777d40">
<id root="9c1a43c8-b946-4557-a533-98fb3b54b94c"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.3 Combination with Insulin Glargine </title>
<effectiveTime value="20241101"/>
<component>
<section ID="ID_a9cf4c2c-1c93-4d87-b9f9-06ffa1d8d37b">
<id root="3924d3bc-530f-4108-8062-afc90fd5259c"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">30-Week Placebo-Controlled Trial</content>
</title>
<text>
<paragraph>A 30-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of BYETTA (n=137) versus placebo (n=122) when added to titrated insulin glargine, with or without metformin and/or thiazolidinedione, in patients with type 2 diabetes with inadequate glycemic control.</paragraph>
<paragraph>All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients assigned to BYETTA had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. BYETTA or placebo was injected subcutaneously before the morning and evening meals. Patients with an HbA<sub>1c</sub> ≤8.0% decreased their prestudy dose of insulin glargine by 20% and patients with an HbA<sub>1c</sub> ≥8.1% maintained their current dose of insulin glargine. Five weeks after initiating randomized treatment, insulin doses were titrated with guidance from the investigator toward predefined fasting glucose targets according to the dose titration algorithm provided in Table 9. The majority of patients (78%) were Caucasian, 10% American Indian or Alaska Native, 9% Black, 3% Asian, and 0.8% of multiple origins.</paragraph>
<paragraph>The primary endpoint was the change in HbA<sub>1c</sub> from baseline to Week 30. Compared to placebo, BYETTA 10 mcg BID resulted in statistically significant reductions in HbA<sub>1c</sub> from baseline at Week 30 (Table 8) in patients receiving titrated insulin glargine.</paragraph>
<table width="100%">
<caption>Table 8: 30-Week Placebo-Controlled Trial of BYETTA Used in Combination with Insulin Glargine with or without Metformin and/or Thiazolidinediones</caption>
<col width="40%"/>
<col width="30%"/>
<col width="30%"/>
<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">Placebo BID</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">Titrated Insulin Glargine</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">BYETTA 10 mcg</content>
<footnote ID="_Ref516122889">BYETTA 5 mcg twice daily for 1 month followed by 10 mcg BID for 5 months for the 30-week trial.</footnote>
<content styleCode="bold">
<content styleCode="italics"/> BID</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">Titrated Insulin Glargine</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>122</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>137</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%), Mean </content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> 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>8.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 30<footnote ID="_Ref516122935">Least squares means are based on a mixed model adjusting for treatment, pooled investigator, visit, baseline HbA<sub>1c</sub> value, and treatment by visit, where subject is treated as a random effect.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.0</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 placebo<footnoteRef IDREF="_Ref516122935"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.7 [−1.0, −0.5]<footnote ID="_Ref516122981">p <0.01, treatment vs. placebo.</footnote>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Proportion Achieving HbA<sub>1c</sub> <7%</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>29%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>56%</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Body Weight (kg), Mean </content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>93.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>95.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 30<footnote ID="_Ref516123017">Least squares means are based on a mixed model adjusting for treatment, pooled investigator, visit, baseline HbA<sub>1c</sub> stratum, baseline value of the dependent variable (where applicable), and treatment by visit, where subject is treated as a random effect.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.8</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516123017"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−2.7 [−3.7, −1.7]<footnoteRef IDREF="_Ref516122981"/>
</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Serum Glucose</content>
<footnote ID="_Ref516123168">Patients in both groups titrated insulin glargine dose to achieve optimal fasting glucose concentrations.</footnote>
<content styleCode="bold"> (mg/dL), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>133</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>132</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change at Week 30<footnoteRef IDREF="_Ref516123017"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−16</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−23</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo<footnoteRef IDREF="_Ref516123017"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−7 [−18, 3]</paragraph>
</td>
</tr>
<tr>
<td colspan="3" valign="top">
<paragraph>BID = twice daily.</paragraph>
</td>
</tr>
</tbody>
</table>
<table width="100%">
<caption>Table 9: Dosing Algorithm for Titration of Insulin Glargine<footnote ID="_Ref72924364">Adapted from Riddle et al. 2003.</footnote>
</caption>
<col width="69%"/>
<col width="31%"/>
<tbody>
<tr>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Plasma Glucose Values</content>
<br/>
<content styleCode="bold">(mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Dose Change</content>
<br/>
<content styleCode="bold">(U)</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph><56<footnote ID="_Ref516123333">Value for at least 1 fasting plasma glucose measurement since the last assessment.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">−</content>4</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>56 to 72<footnoteRef IDREF="_Ref516123333"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">−</content>2</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>73 to 99<footnote ID="_Ref516123353">Based on the average of fasting plasma glucose measurements taken over the prior 3 to 7 days. The increase in the total daily dose should not have exceeded more than 10 units per day or 10% of the current total daily dose, whichever was greater.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>100 to 119<footnoteRef IDREF="_Ref516123353"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>+2</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>120 to 139<footnoteRef IDREF="_Ref516123353"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>+4</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>140 to 179<footnoteRef IDREF="_Ref516123353"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>+6</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>≥180<footnoteRef IDREF="_Ref516123353"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>+8</paragraph>
</td>
</tr>
<tr>
<td colspan="2" valign="top">
<paragraph>Abbreviations: U = units.</paragraph>
</td>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20241101"/>
</section>
</component>
<component>
<section ID="ID_a197e426-632f-4d8c-967b-762fe2f79517">
<id root="3215fb36-8263-4f89-a65e-c55723a5ec60"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>
<content styleCode="bold">30-Week Comparator-Controlled Noninferiority Trial</content>
</title>
<text>
<paragraph>A 30 week, open-label, active comparator-controlled, noninferiority study was conducted to evaluate the safety and efficacy of BYETTA (n=315) versus titrated insulin lispro (n=312) on a background of optimized basal insulin glargine and metformin in patients with type 2 diabetes with inadequate glycemic control.</paragraph>
<paragraph>Following a 12-week basal insulin optimization (BIO) phase, subjects with an HbA<sub>1c</sub> >7.0% entered a 30-week intervention phase and were randomized to add either BYETTA or insulin lispro to their existing regimen of insulin glargine and metformin. Insulin glargine was titrated to a target fasting plasma glucose of 72 to 100 mg/dL.</paragraph>
<paragraph>All patients assigned to BYETTA initially received 5 mcg BID for four weeks. After four weeks, their dose was increased to 10 mcg BID. Patients in the BYETTA-treated arm with an HbA<sub>1c</sub> ≤8.0% at the end of the BIO phase decreased their insulin glargine dose by at least 10%.</paragraph>
<paragraph>All patients assigned to insulin lispro three times daily (TID) maintained their prior total daily insulin dose at baseline; however, the initial insulin lispro dose was ⅓ to ½ of the total daily insulin dose with the insulin glargine dose reduced accordingly. The insulin lispro dose was titrated based on preprandial glucose values.</paragraph>
<paragraph>The majority of patients (87%) were Caucasian, 7% American Indian or Alaska Native, 5% Asian, and <1% African American.</paragraph>
<paragraph>The primary endpoint was the change in HbA<sub>1c</sub> from baseline to Week 30. Both BYETTA 10 mcg BID and titrated lispro provided a mean reduction in HbA<sub>1c</sub> at Week 30 that met the pre-specified non-inferiority margin of 0.4%.</paragraph>
<table width="100%">
<caption>Table 10: 30-Week Comparator-Controlled Trial of BYETTA used in Combination with Insulin Glargine and Metformin</caption>
<col width="38%"/>
<col width="29%"/>
<col width="33%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Titrated Insulin Lispro TID</content>
</paragraph>
<paragraph>
<content styleCode="bold">+</content>
</paragraph>
<paragraph>
<content styleCode="bold">Titrated Insulin Glargine</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">BYETTA 10 mcg<footnote ID="_Ref516123408">BYETTA 5 mcg BID for 1 month followed by 10 mcg BID for 5 months for the 30-week trial.</footnote> BID</content>
</paragraph>
<paragraph>
<content styleCode="bold">+</content>
</paragraph>
<paragraph>
<content styleCode="bold">Titrated Insulin Glargine</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule 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>312</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>315</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA<sub>1c</sub> (%), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Change at Week 30<footnote ID="_Ref516123458">Least squares means are based on a mixed model adjusting for treatment, country, prior use of sulfonylurea (yes/no), visit, corresponding baseline, and treatment by visit interaction, where subject is treated as a random effect.</footnote>
<footnote ID="_Ref516123523">Data at 30 weeks are available from 88% and 84% of the intent-to-treat subjects in the Lispro and BYETTA groups, respectively.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−1.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Difference from Insulin Lispro<footnoteRef IDREF="_Ref516123458"/>
<footnoteRef IDREF="_Ref516123523"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.0 [−0.2, 0.1]</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Body Weight (kg), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>89.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>89.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Change at Week 30<footnoteRef IDREF="_Ref516123458"/>
<footnoteRef IDREF="_Ref516123523"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−2.6</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Difference from Insulin Lispro<footnoteRef IDREF="_Ref516123458"/>
<footnoteRef IDREF="_Ref516123523"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−4.5 [−5.2, −3.9]</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Serum Glucose</content>
<footnote ID="_Ref516123575">Patients titrated insulin glargine or insulin lispro dose to achieve prespecified target fasting and preprandial glucose concentrations.</footnote>
<content styleCode="bold">
<content styleCode="italics"/>(mg/dL), Mean</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>126</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>130</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Change at Week 30<footnoteRef IDREF="_Ref516123458"/>
<footnoteRef IDREF="_Ref516123523"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph> Difference from Insulin Lispro<footnoteRef IDREF="_Ref516123458"/>
<footnoteRef IDREF="_Ref516123523"/> (95% CI)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−12 [−19, −4]</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Toprule " valign="top">
<paragraph>BID = twice daily.</paragraph>
<paragraph>TID = three times daily.</paragraph>
</td>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20241101"/>
</section>
</component>
</section>
</component>
</section>
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