<?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 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus </title>
<text>
<paragraph>ONGLYZA has been studied as monotherapy and in combination with metformin HCl, glyburide, and thiazolidinedione (pioglitazone and rosiglitazone) therapy.</paragraph>
<paragraph>A total of 4148 patients with type 2 diabetes mellitus were randomized in six, double-blind, controlled clinical trials conducted to evaluate the safety and glycemic efficacy of ONGLYZA administered orally. A total of 3021 patients in these trials were treated with ONGLYZA. In these trials, the mean age was 54 years, and 71% of patients were White, 16% were Asian, 4% were Black or African American, and 9% were of other racial groups. An additional 423 patients, including 315 who received ONGLYZA, participated in a placebo-controlled, dose-ranging trial of 6 to 12 weeks in duration.</paragraph>
<paragraph>In these six, double-blind trials, ONGLYZA was evaluated at doses of 2.5 mg and 5 mg once daily. Three of these trials also evaluated an ONGLYZA dose of 10 mg daily. The 10 mg daily dose of ONGLYZA did not provide greater efficacy than the 5 mg daily dose. The 10 mg dosage is not an approved dosage. Treatment with ONGLYZA 5 mg and 2.5 mg doses produced statistically significant improvements in A1C, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) following a standard oral glucose tolerance test (OGTT), compared to control. Reductions in A1C were seen across subgroups including gender, age, race, and baseline BMI.</paragraph>
<paragraph>ONGLYZA was not associated with significant changes from baseline in body weight or fasting serum lipids compared to placebo.</paragraph>
<paragraph>ONGLYZA has also been evaluated in five additional trials in patients with type 2 diabetes mellitus: an active-controlled trial comparing add-on therapy with ONGLYZA to glipizide in 858 patients inadequately controlled on metformin HCl alone, a trial comparing ONGLYZA to placebo in 455 patients inadequately controlled on insulin alone or on insulin in combination with metformin HCl, a trial comparing ONGLYZA to placebo in 257 patients inadequately controlled on metformin HCl plus a sulfonylurea, a trial comparing ONGLYZA to placebo in 315 patients inadequately controlled on dapagliflozin and metformin HCl, and a trial comparing ONGLYZA to placebo in 170 patients with type 2 diabetes mellitus and moderate or severe renal impairment or ESRD.</paragraph>
</text>
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<title>
<content styleCode="underline">Monotherapy</content>
</title>
<text>
<paragraph>A total of 766 patients with type 2 diabetes mellitus inadequately controlled on diet and exercise (A1C ≥7% to ≤10%) participated in two 24-week, double-blind, placebo-controlled trials evaluating the efficacy and safety of ONGLYZA monotherapy.</paragraph>
<paragraph>In the first trial, following a 2-week single-blind diet, exercise, and placebo lead-in period, 401 patients were randomized to 2.5 mg, 5 mg, or 10 mg of ONGLYZA or placebo. The 10 mg dosage is not an approved dosage. Patients who failed to meet specific glycemic goals during the trial were treated with metformin HCl rescue therapy, added on to placebo or ONGLYZA. Efficacy was evaluated at the last measurement prior to rescue therapy for patients needing rescue. Dose titration of ONGLYZA was not permitted. </paragraph>
<paragraph>Treatment with ONGLYZA 2.5 mg and 5 mg daily provided significant improvements in A1C, FPG, and PPG compared to placebo (Table 4). The percentage of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 16% in the ONGLYZA 2.5 mg treatment group, 20% in the ONGLYZA 5 mg treatment group, and 26% in the placebo group.</paragraph>
<table cellpadding="4.8pt" width="100%">
<caption>Table 4: Glycemic Parameters at Week 24 in a Placebo-Controlled trial of ONGLYZA Monotherapy in Patients with Type 2 Diabetes Mellitus<footnote ID="_Ref448141760">Intent-to-treat population using last observation on trial or last observation prior to metformin HCl rescue therapy for patients needing rescue.</footnote>
</caption>
<col width="49%"/>
<col width="17%"/>
<col width="18%"/>
<col width="16%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Efficacy Parameter</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">ONGLYZA</content>
<br/>
<content styleCode="bold">2.5 mg</content>
<br/>
<content styleCode="bold">N=102</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">ONGLYZA</content>
<br/>
<content styleCode="bold">5 mg</content>
<br/>
<content styleCode="bold">N=106</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Placebo</content>
<br/>
<br/>
<content styleCode="bold">N=95</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Hemoglobin A1C (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=100</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=103</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=92</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>7.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>7.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref448142083">Least squares mean adjusted for baseline value.</footnote>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>+0.2</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448142083"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.6<footnote ID="_Ref448142398">p-value <0.0001 compared to placebo.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.6<footnoteRef IDREF="_Ref448142398"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>(−0.9, −0.3)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>(−0.9, −0.4)</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Percent of patients achieving A1C <7%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>35% (35/100)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>38%<footnote ID="_Ref448142478">p-value <0.05 compared to placebo.</footnote> (39/103)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>24% (22/92)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=101</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=105</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=92</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>178</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>171</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>172</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448142083"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−15</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>+6</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448142083"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−21<footnoteRef IDREF="_Ref448142478"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−15<footnoteRef IDREF="_Ref448142478"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>(−31, −10)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>(−25, −4)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=78</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=84</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=71</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>279</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>278</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>283</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448142083"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−45</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−43</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−6</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448142083"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−39<footnote ID="_Ref448142684">Significance was not tested for the 2-hour PPG for the 2.5 mg dose of ONGLYZA.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−37<footnoteRef IDREF="_Ref448142478"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(−61, −16)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(−59, −15)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
<paragraph>A second 24-week monotherapy trial was conducted to assess a range of dosing regimens for ONGLYZA. </paragraph>
<paragraph>Treatment-naive patients with inadequately controlled type 2 diabetes mellitus (A1C ≥7% to ≤10%) underwent a 2-week, single-blind diet, exercise, and placebo lead-in period. A total of 365 patients were randomized to 2.5 mg every morning, 5 mg every morning, 2.5 mg with possible titration to 5 mg every morning, or 5 mg every evening of ONGLYZA, or placebo. Patients who failed to meet specific glycemic goals during the trial were treated with metformin HCl rescue therapy added on to placebo or ONGLYZA; the number of patients randomized per treatment group ranged from 71 to 74.</paragraph>
<paragraph>Treatment with either ONGLYZA 5 mg every morning or 5 mg every evening provided significant improvements in A1C versus placebo (mean placebo-corrected reductions of −0.4% and −0.3%, respectively). Treatment with ONGLYZA 2.5 mg every morning also provided significant improvement in A1C versus placebo (mean placebo-corrected reduction of −0.4%).</paragraph>
</text>
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<title>
<content styleCode="bold">Combination Therapy</content>
</title>
<effectiveTime value="20241011"/>
<component>
<section ID="ID_82b03bd9-2512-4b52-a214-decca97cc848">
<id root="9e31cf34-bda1-4ebe-9aed-d13daf647354"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Add-On Combination Therapy with Metformin HCl</title>
<text>
<paragraph>A total of 743 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with metformin HCl in patients with inadequate glycemic control (A1C ≥7% and ≤10%) on metformin alone. To qualify for enrollment, patients were required to be on a stable dose of metformin HCl (1,500-2,550 mg daily) for at least 8 weeks.</paragraph>
<paragraph>Patients who met eligibility criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin HCl at their pre-trial dose, up to 2,500 mg daily. Following the lead-in period, eligible patients were randomized to 2.5 mg, 5 mg, or 10 mg of ONGLYZA or placebo in addition to their current dose of open-label metformin HCl. The 10 mg dosage of ONGLYZA is not an approved dosage. Patients who failed to meet specific glycemic goals during the trial were treated with pioglitazone rescue therapy, added on to existing trial medications. Dose titrations of ONGLYZA and metformin HCl were not permitted.</paragraph>
<paragraph>ONGLYZA 2.5 mg and 5 mg add-on to metformin provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to metformin (Table 5). Mean changes from baseline for A1C over time and at endpoint are shown in Figure 1. The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 15% in the ONGLYZA 2.5 mg add-on to metformin group, 13% in the ONGLYZA 5 mg add-on to metformin group, and 27% in the placebo add-on to metformin group.</paragraph>
<table cellpadding="4.8pt" width="100%">
<caption>Table 5: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Metformin HCl<footnote ID="_Ref448409848">Intent-to-treat population using last observation on trial or last observation prior to pioglitazone rescue therapy for patients needing rescue.</footnote>
</caption>
<col width="44%"/>
<col width="21%"/>
<col width="20%"/>
<col width="15%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Efficacy Parameter</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">ONGLYZA 2.5 mg</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">Metformin HCl</content>
<br/>
<content styleCode="bold">N=192</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">ONGLYZA 5 mg</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">Metformin HCl</content>
<br/>
<content styleCode="bold">N=191</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Placebo</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">Metformin HCl</content>
<br/>
<content styleCode="bold">N=179</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Hemoglobin A1C (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=186</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=186</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=175</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref448467186">Least squares mean adjusted for baseline value.</footnote>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>+0.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448467186"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.7<footnote ID="_Ref448468155">p-value <0.0001 compared to placebo + metformin HCl.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.8<footnoteRef IDREF="_Ref448468155"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>(−0.9, −0.5)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>(−1.0, −0.6)</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Percent of patients achieving A1C <7%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>37%<footnote ID="_Ref448468313">p-value <0.05 compared to placebo + metformin HCl.</footnote> (69/186)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>44%<footnoteRef IDREF="_Ref448468313"/> (81/186)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>17% (29/175)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=188</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=187</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=176</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>174</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>179</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>175</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448467186"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−14</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−22</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>+1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448467186"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−16<footnoteRef IDREF="_Ref448468313"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−23<footnoteRef IDREF="_Ref448468313"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>(−23, −9)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>(−30, −16)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=155</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=155</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=135</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>294</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>296</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>295</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448467186"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−62</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−58</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−18</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448467186"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−44<footnoteRef IDREF="_Ref448468313"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−40<footnoteRef IDREF="_Ref448468313"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(−60, −27)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(−56, −24)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="bold">Figure 1: Mean Change from Baseline in A1C in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Metformin HCl*</content>
</paragraph>
<content styleCode="bold">
<renderMultiMedia ID="id268739899" referencedObject="F6B35BE6-1564-4506-BB85-61B66E782B43"/>
</content>
<paragraph>*Includes patients with a baseline and week 24 value.<br/>Week 24 (LOCF) includes intent-to-treat population using last observation on trial prior to pioglitazone rescue therapy for patients needing rescue. Mean change from baseline is adjusted for baseline value.</paragraph>
</text>
<effectiveTime value="20241011"/>
<component>
<observationMedia ID="F6B35BE6-1564-4506-BB85-61B66E782B43">
<text>Figure 1</text>
<value mediaType="image/jpeg">
<reference value="ONGLYZA_Figure1.jpg"/>
</value>
</observationMedia>
</component>
</section>
</component>
<component>
<section ID="ID_f94162eb-627f-4f13-b386-1edc7cc3f4d1">
<id root="6e85fc95-e22c-4c41-b413-aace863d2ca7"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Add-On Combination Therapy with a Thiazolidinedione</title>
<text>
<paragraph>A total of 565 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with a thiazolidinedione (TZD) in patients with inadequate glycemic control (A1C ≥7% to ≤10.5%) on TZD alone. To qualify for enrollment, patients were required to be on a stable dose of pioglitazone (30-45 mg once daily) or rosiglitazone (4 mg once daily or 8 mg either once daily or in two divided doses of 4 mg) for at least 12 weeks.</paragraph>
<paragraph>Patients who met eligibility criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received TZD at their pre-trial dose. Following the lead-in period, eligible patients were randomized to 2.5 mg or 5 mg of ONGLYZA or placebo in addition to their current dose of TZD. Patients who failed to meet specific glycemic goals during the trial were treated with metformin HCl rescue, added on to existing trial medications. Dose titration of ONGLYZA or TZD was not permitted during the trial. A change in TZD regimen from rosiglitazone to pioglitazone at specified, equivalent therapeutic doses was permitted at the investigator’s discretion if believed to be medically appropriate.</paragraph>
<paragraph>ONGLYZA 2.5 mg and 5 mg add-on to TZD provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to TZD (Table 6). The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 10% in the ONGLYZA 2.5 mg add-on to TZD group, 6% for the ONGLYZA 5 mg add-on to TZD group, and 10% in the placebo add-on to TZD group.</paragraph>
<table cellpadding="4.8pt" width="100%">
<caption>Table 6: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with a Thiazolidinedione<footnote ID="_Ref448468913">Intent-to-treat population using last observation on trial or last observation prior to metformin HCl rescue therapy for patients needing rescue</footnote>
</caption>
<col width="44%"/>
<col width="21%"/>
<col width="20%"/>
<col width="15%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Efficacy Parameter</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">ONGLYZA 2.5 mg</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">TZD</content>
<br/>
<content styleCode="bold">N=195</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">ONGLYZA 5 mg</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">TZD</content>
<br/>
<content styleCode="bold">N=186</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Placebo</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">TZD</content>
<br/>
<content styleCode="bold">N=184</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Hemoglobin A1C (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=192</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=183</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=180</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.2</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref448468955">Least squares mean adjusted for baseline value</footnote>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448468955"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.4<footnote ID="_Ref448469261">p-value <0.0001 compared to placebo + TZD</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.6<footnote ID="_Ref448469276">p-value <0.05 compared to placebo + TZD</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>(−0.6, −0.2)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>(−0.8, −0.4)</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Percent of patients achieving A1C <7%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>42%<footnoteRef IDREF="_Ref448469261"/> (81/192)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>42% (77/184)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>26% (46/180)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=193</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=185</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=181</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>163</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>160</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>162</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448468955"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−14</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448468955"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−12<footnoteRef IDREF="_Ref448469261"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−15<footnoteRef IDREF="_Ref448469261"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>(−20, −3)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>(−23, −6)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=156</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=134</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=127</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>296</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>303</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>291</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448468955"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−55</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−65</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−15</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448468955"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−40<footnoteRef IDREF="_Ref448469261"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−50<footnoteRef IDREF="_Ref448469261"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(−56, −24)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(−66, −34)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20241011"/>
</section>
</component>
<component>
<section ID="ID_bcaff256-f972-4d60-bd8a-b0c2e15fece9">
<id root="73359a53-a192-4aac-bd3d-41f1f104d384"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Add-On Combination Therapy with Glyburide</title>
<text>
<paragraph>A total of 768 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with a sulfonylurea (SU) in patients with inadequate glycemic control at enrollment (A1C ≥7.5% to ≤10%) on a submaximal dose of SU alone. To qualify for enrollment, patients were required to be on a submaximal dose of SU for 2 months or greater. In this trial, ONGLYZA in combination with a fixed, intermediate dose of SU was compared to titration to a higher dose of SU.</paragraph>
<paragraph>Patients who met eligibility criteria were enrolled in a single-blind, 4-week, dietary and exercise lead-in period, and placed on glyburide 7.5 mg once daily. Following the lead-in period, eligible patients with A1C ≥7% to ≤10% were randomized to either 2.5 mg or 5 mg of ONGLYZA add-on to 7.5 mg glyburide or to placebo plus a 10 mg total daily dose of glyburide. Patients who received placebo were eligible to have glyburide up-titrated to a total daily dose of 15 mg. Up-titration of glyburide was not permitted in patients who received ONGLYZA 2.5 mg or 5 mg. Glyburide could be down-titrated in any treatment group once during the 24-week trial period due to hypoglycemia as deemed necessary by the investigator. Approximately 92% of patients in the placebo plus glyburide group were up-titrated to a final total daily dose of 15 mg during the first 4 weeks of the trial period. Patients who failed to meet specific glycemic goals during the trial were treated with metformin HCl rescue, added on to existing trial medication. Dose titration of ONGLYZA was not permitted during the trial. </paragraph>
<paragraph>In combination with glyburide, ONGLYZA 2.5 mg and 5 mg provided significant improvements in A1C, FPG, and PPG compared with the placebo plus up-titrated glyburide group (Table 7). The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 18% in the ONGLYZA 2.5 mg add-on to glyburide group, 17% in the ONGLYZA 5 mg add-on to glyburide group, and 30% in the placebo plus up-titrated glyburide group.</paragraph>
<table cellpadding="4.8pt" width="100%">
<caption>Table 7: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Glyburide<footnote ID="_Ref448469624">Intent-to-treat population using last observation on trial or last observation prior to metformin HCl rescue therapy for patients needing rescue.</footnote>
</caption>
<col width="50%"/>
<col width="14%"/>
<col width="14%"/>
<col width="22%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Efficacy Parameter</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">ONGLYZA</content>
<br/>
<content styleCode="bold">2.5 mg</content>
<br/>
<content styleCode="bold">+ </content>
<br/>
<content styleCode="bold">Glyburide</content>
<br/>
<content styleCode="bold">7.5 mg</content>
<br/>
<content styleCode="bold">N=248</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">ONGLYZA</content>
<br/>
<content styleCode="bold">5 mg</content>
<br/>
<content styleCode="bold">+ </content>
<br/>
<content styleCode="bold">Glyburide</content>
<br/>
<content styleCode="bold">7.5 mg</content>
<br/>
<content styleCode="bold">N=253</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Placebo</content>
<br/>
<br/>
<content styleCode="bold">+ </content>
<br/>
<content styleCode="bold">Up-Titrated Glyburide</content>
<br/>
<content styleCode="bold">N=267</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Hemoglobin A1C (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=246</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=250</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=264</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref448469671">Least squares mean adjusted for baseline value.</footnote>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>+0.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from up-titrated glyburide (adjusted mean<footnoteRef IDREF="_Ref448469671"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.6<footnote ID="_Ref448470025">p-value <0.0001 compared to placebo + up-titrated glyburide.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.7<footnoteRef IDREF="_Ref448470025"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>(−0.8, −0.5)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>(−0.9, −0.6)</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Percent of patients achieving A1C <7%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>22%<footnote ID="_Ref448470321">p-value <0.05 compared to placebo + up-titrated glyburide.</footnote> (55/246)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>23%<footnoteRef IDREF="_Ref448470321"/> (57/250)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>9% (24/264)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=247</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=252</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=265</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>170</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>175</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>174</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448469671"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−10</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>+1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from up-titrated glyburide (adjusted mean<footnoteRef IDREF="_Ref448469671"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−8<footnoteRef IDREF="_Ref448470321"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−10<footnoteRef IDREF="_Ref448470321"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>(−14, −1)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>(−17, −4)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=195</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=202</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=206</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>309</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>315</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>323</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448469671"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−31</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−34</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>+8</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from up-titrated glyburide (adjusted mean<footnoteRef IDREF="_Ref448469671"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−38<footnoteRef IDREF="_Ref448470321"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−42<footnoteRef IDREF="_Ref448470321"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(−50, −27)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(−53, −31)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20241011"/>
</section>
</component>
<component>
<section ID="ID_0af33a8a-02f2-47d7-b2d9-0349bb443b58">
<id root="ffe6602f-b4da-411d-9410-8cc5b06c43be"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Coadministration with Metformin HCl in Treatment-Naive Patients</title>
<text>
<paragraph>A total of 1306 treatment-naive patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, active-controlled trial to evaluate the efficacy and safety of ONGLYZA coadministered with metformin HCl in patients with inadequate glycemic control (A1C ≥8% to ≤12%) on diet and exercise alone. Patients were required to be treatment-naive to be enrolled in this trial. </paragraph>
<paragraph>Patients who met eligibility criteria were enrolled in a single-blind, 1-week, dietary and exercise placebo lead-in period. Patients were randomized to one of four treatment arms: ONGLYZA 5 mg + metformin HCl 500 mg, saxagliptin 10 mg + metformin HCl 500 mg, saxagliptin 10 mg + placebo, or metformin HCl 500 mg + placebo. The 10 mg saxagliptin dosage is not an approved dosage. ONGLYZA was dosed once daily. In the 3 treatment groups using metformin HCl, the metformin HCl dose was up-titrated weekly in 500 mg per day increments, as tolerated, to a maximum of 2,000 mg per day based on FPG. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue as add-on therapy. </paragraph>
<paragraph>Coadministration of ONGLYZA 5 mg plus metformin HCl provided significant improvements in A1C, FPG, and PPG compared with placebo plus metformin (Table 8).</paragraph>
<table cellpadding="4.8pt" width="100%">
<caption>Table 8: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA Coadministration with Metformin HCl in Treatment-Naive Patients<footnote ID="_Ref448470810">Intent-to-treat population using last observation on trial or last observation prior to pioglitazone rescue therapy for patients needing rescue.</footnote>
</caption>
<col width="61%"/>
<col width="21%"/>
<col width="18%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Efficacy Parameter</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">ONGLYZA 5 mg</content>
<br/>
<content styleCode="bold">+ </content>
<br/>
<content styleCode="bold">Metformin HCl</content>
<br/>
<content styleCode="bold">N=320</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Placebo</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">Metformin HCl</content>
<br/>
<content styleCode="bold">N=328</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Hemoglobin A1C (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=306</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=313</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>9.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>9.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref448470874">Least squares mean adjusted for baseline value.</footnote>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−2.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−2.0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo + metformin HCl (adjusted mean<footnoteRef IDREF="_Ref448470874"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.5<footnote ID="_Ref448471468">p-value <0.0001 compared to placebo + metformin HCl.</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>(−0.7, −0.4)</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Percent of patients achieving A1C <7%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>60%<footnote ID="_Ref448471788">p-value <0.05 compared to placebo + metformin HCl.</footnote> (185/307)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>41% (129/314)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=315</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=320</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>199</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>199</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448470874"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−60</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−47</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo + metformin HCl (adjusted mean<footnoteRef IDREF="_Ref448470874"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−13<footnoteRef IDREF="_Ref448471788"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>(−19, −6)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=146</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=141</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>340</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>355</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448470874"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−138</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−97</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo + metformin HCl (adjusted mean<footnoteRef IDREF="_Ref448470874"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−41<footnoteRef IDREF="_Ref448471788"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(−57, −25)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20241011"/>
</section>
</component>
<component>
<section ID="ID_3bcdf954-1732-420a-a333-ac7163670405">
<id root="2b421c1d-a3ec-497d-8389-74e3ae9b9f96"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Add-On Combination Therapy with Metformin HCl versus Glipizide Add-On Combination Therapy with Metformin HCl</title>
<text>
<paragraph>In this 52-week, active-controlled trial, a total of 858 patients with type 2 diabetes mellitus and inadequate glycemic control (A1C >6.5% and ≤10%) on metformin HCl alone were randomized to double-blind add-on therapy with ONGLYZA or glipizide. Patients were required to be on a stable dose of metformin HCl (at least 1,500 mg daily) for at least 8 weeks prior to enrollment.</paragraph>
<paragraph>Patients who met eligibility criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin HCl (1,500-3,000 mg based on their pre-trial dose). Following the lead-in period, eligible patients were randomized to 5 mg of ONGLYZA or 5 mg of glipizide in addition to their current dose of open-label metformin HCl. Patients in the glipizide plus metformin HCl group underwent blinded titration of the glipizide dose during the first 18 weeks of the trial up to a maximum glipizide dose of 20 mg per day. Titration was based on a goal FPG ≤110 mg/dL or the highest tolerable glipizide dose. Fifty percent (50%) of the glipizide-treated patients were titrated to the 20-mg daily dose; 21% of the glipizide-treated patients had a final daily glipizide dose of 5 mg or less. The mean final daily dose of glipizide was 15 mg.</paragraph>
<paragraph>After 52 weeks of treatment, ONGLYZA and glipizide resulted in similar mean reductions from baseline in A1C when added to metformin HCl therapy (Table 9). This conclusion may be limited to patients with baseline A1C comparable to those in the trial (91% of patients had baseline A1C <9%).</paragraph>
<paragraph>From a baseline mean body weight of 89 kg, there was a statistically significant mean reduction of 1.1 kg in patients treated with ONGLYZA compared to a mean weight gain of 1.1 kg in patients treated with glipizide (p<0.0001).</paragraph>
<table cellpadding="4.8pt" width="100%">
<caption>Table 9: Glycemic Parameters at Week 52 in an Active-Controlled Trial of ONGLYZA versus Glipizide in Combination with Metformin HCl<footnote ID="_Ref448472169">Intent-to-treat population using last observation on trial.</footnote>
</caption>
<col width="59%"/>
<col width="20%"/>
<col width="21%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Efficacy Parameter</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">ONGLYZA 5 mg</content>
<br/>
<content styleCode="bold">+ </content>
<br/>
<content styleCode="bold">Metformin HCl</content>
<br/>
<content styleCode="bold">N=428</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Titrated Glipizide </content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">Metformin HCl</content>
<br/>
<content styleCode="bold">N=430</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Hemoglobin A1C (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=423</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=423</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>7.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>7.6</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref448472231">Least squares mean adjusted for baseline value.</footnote>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from glipizide + metformin HCl (adjusted mean<footnoteRef IDREF="_Ref448472231"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>0.1</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>(−0.02, 0.2)<footnote ID="_Ref448472446">ONGLYZA + metformin HCl is considered non-inferior to glipizide + metformin HCl because the upper limit of this confidence interval is less than the prespecified non-inferiority margin of 0.35%.</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=420</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=420</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>162</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>161</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448472231"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−16</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from glipizide + metformin HCl (adjusted mean<footnoteRef IDREF="_Ref448472231"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>6</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(2, 11)<footnote ID="_Ref448472467">Significance not tested.</footnote>
</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20241011"/>
</section>
</component>
<component>
<section ID="ID_46a8a08a-8054-4ed2-8c1a-f9b16a9768b0">
<id root="01e43c17-f782-4574-8b6b-e6c3523015f2"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Add-On Combination Therapy with Insulin (with or without metformin HCl)</title>
<text>
<paragraph>A total of 455 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with insulin in patients with inadequate glycemic control (A1C ≥7.5% and ≤11%) on insulin alone (N=141) or on insulin in combination with a stable dose of metformin HCl (N=314). Patients were required to be on a stable dose of insulin (≥30 units to ≤150 units daily) with ≤20% variation in total daily dose for ≥8 weeks prior to screening. Patients entered the trial on intermediate- or long-acting (basal) insulin or premixed insulin. Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a premixed insulin.</paragraph>
<paragraph>Patients who met eligibility criteria were enrolled in a single-blind, four-week, dietary and exercise placebo lead-in period during which patients received insulin (and metformin HCl if applicable) at their pretrial dose(s). Following the lead-in period, eligible patients were randomized to add-on therapy with either ONGLYZA 5 mg or placebo. Doses of the antidiabetic therapies were to remain stable but patients were rescued and allowed to adjust the insulin regimen if specific glycemic goals were not met or if the investigator learned that the patient had self-increased the insulin dose by >20%. Data after rescue were excluded from the primary efficacy analyses.</paragraph>
<paragraph>Add-on therapy with ONGLYZA 5 mg provided significant improvements from baseline to Week 24 in A1C and PPG compared with add-on placebo (Table 10). Similar mean reductions in A1C versus placebo were observed for patients using ONGLYZA 5 mg add-on to insulin alone and ONGLYZA 5 mg add-on to insulin in combination with metformin HCl (−0.4% and −0.4%, respectively). The percentage of patients who discontinued for lack of glycemic control or who were rescued was 23% in the ONGLYZA group and 32% in the placebo group.</paragraph>
<paragraph>The mean daily insulin dose at baseline was 53 units in patients treated with ONGLYZA 5 mg and 55 units in patients treated with placebo. The mean change from baseline in daily dose of insulin was 2 units for the ONGLYZA 5 mg group and 5 units for the placebo group.</paragraph>
<table cellpadding="4.8pt" width="100%">
<caption>Table 10: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Insulin<footnote ID="_Ref448472606">Intent-to-treat population using last observation on trial or last observation prior to insulin rescue therapy for patients needing rescue.</footnote>
</caption>
<col width="53%"/>
<col width="24%"/>
<col width="23%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Efficacy Parameter</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">ONGLYZA 5 mg</content>
<br/>
<content styleCode="bold">+ </content>
<br/>
<content styleCode="bold">Insulin</content>
<br/>
<content styleCode="bold">(+/− Metformin HCl)</content>
<br/>
<content styleCode="bold">N=304</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Placebo</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">Insulin</content>
<br/>
<content styleCode="bold">(+/− Metformin HCl)</content>
<br/>
<content styleCode="bold">N=151</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Hemoglobin A1C (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=300</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=149</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref448472631">Least squares mean adjusted for baseline value and metformin HCl use at baseline.</footnote>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448472631"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.4<footnote ID="_Ref448472709">p-value <0.0001 compared to placebo + insulin.</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>(−0.6, −0.2)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=262</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=129</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>251</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>255</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448472631"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−27</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448472631"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−23<footnote ID="_Ref448472765">p-value <0.05 compared to placebo + insulin.</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(−37, −9)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
<paragraph>The change in fasting plasma glucose from baseline to Week 24 was also tested, but was not statistically significant. The percent of patients achieving an A1C <7% was 17% (52/300) with ONGLYZA in combination with insulin compared to 7% (10/149) with placebo. Significance was not tested.</paragraph>
</text>
<effectiveTime value="20241011"/>
</section>
</component>
<component>
<section ID="ID_7f3562e4-9eda-4c6e-8478-18fcf5038020">
<id root="929b6f8a-2d96-4cd9-b5a8-a1c777d2b4fb"/>
<code code="34092-7" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL STUDIES SECTION"/>
<title>
<content styleCode="bold">Add-On Combination Therapy with Metformin HCl plus Sulfonylurea</content>
</title>
<text>
<paragraph>A total of 257 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with metformin HCl plus a sulfonylurea in patients with inadequate glycemic control (A1C ≥7% and ≤10%). Patients were to be on a stable combined dose of metformin HCl extended-release or immediate-release (at maximum tolerated dose, with minimum dose for enrollment being 1,500 mg) and a sulfonylurea (at maximum tolerated dose, with minimum dose for enrollment being ≥50% of the maximum recommended dose) for ≥8 weeks prior to enrollment.</paragraph>
<paragraph>Patients who met eligibility criteria were entered in a 2-week enrollment period to allow assessment of inclusion/exclusion criteria. Following the 2-week enrollment period, eligible patients were randomized to either double-blind ONGLYZA (5 mg once daily) or double-blind matching placebo for 24 weeks. During the 24-week double-blind treatment period, patients were to receive metformin HCl and a sulfonylurea at the same constant dose ascertained during enrollment. Sulfonylurea dose could be down titrated once in the case of a major hypoglycemic event or recurring minor hypoglycemic events. In the absence of hypoglycemia, titration (up or down) of trial medication during the treatment period was prohibited.</paragraph>
<paragraph>ONGLYZA in combination with metformin HCl plus a sulfonylurea provided significant improvements in A1C and PPG compared with placebo in combination with metformin HCl plus a sulfonylurea (Table 11). The percentage of patients who discontinued for lack of glycemic control was 6% in the ONGLYZA group and 5% in the placebo group.</paragraph>
<table cellpadding="4.8pt" width="100%">
<caption>Table 11: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Metformin HCl plus Sulfonylurea<footnote ID="_Ref448473030">Intent-to-treat population using last observation prior to discontinuation</footnote>
</caption>
<col width="54%"/>
<col width="24%"/>
<col width="22%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Efficacy Parameter</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">ONGLYZA 5 mg</content>
<br/>
<content styleCode="bold">+ </content>
<br/>
<content styleCode="bold">Metformin HCl plus</content>
<br/>
<content styleCode="bold">Sulfonylurea</content>
<br/>
<content styleCode="bold">N=129</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Placebo</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">Metformin HCl plus</content>
<br/>
<content styleCode="bold"> Sulfonylurea</content>
<br/>
<content styleCode="bold">N=128</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Hemoglobin A1C (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=127</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=127</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.2</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref448473219">Least squares mean adjusted for baseline value</footnote>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448473219"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.7<footnote ID="_Ref448473497">p-value <0.0001 compared to placebo + metformin HCl plus sulfonylurea</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>(−0.9, −0.5)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=115</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>
<content styleCode="bold">N=113</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>268</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>262</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref448473219"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−12</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref448473219"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−17<footnote ID="_Ref448473606">p-value <0.05 compared to placebo + metformin HCl plus sulfonylurea</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(−32, −2)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
<paragraph>The change in fasting plasma glucose from baseline to Week 24 was also tested, but was not statistically significant. The percent of patients achieving an A1C <7% was 31% (39/127) with ONGLYZA in combination with metformin HCl plus a sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested.</paragraph>
<paragraph>
<content styleCode="bold">Add-on Combination Therapy with Metformin HCl plus an SGLT2 Inhibitor</content>
</paragraph>
<paragraph>A total of 315 patients with type 2 diabetes mellitus participated in this 24-week randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA added to dapagliflozin (an SGLT2 inhibitor) and metformin HCl in patients with a baseline of HbA1c ≥7% to ≤10.5%. The mean age of these patients was 54.6 years, 1.6% were 75 years or older and 52.7% were female. The population was 87.9% White, 6.3% Black or African American, 4.1% Asian, and 1.6% other races. At baseline the population had diabetes mellitus for an average of 7.7 years and a mean HbA1c of 7.9%. The mean eGFR at baseline was 93.4 mL/min/1.73 m2. Patients were required to be on a stable dose of metformin HCl (≥1,500 mg per day) for at least 8 weeks prior to enrollment. Eligible patients who completed the screening period entered the lead in treatment period, which included open-label metformin HCl and 10 mg dapagliflozin treatment. Following the lead-in period, eligible patients were randomized to ONGLYZA 5 mg (N=153) or placebo (N =162).</paragraph>
<paragraph>The group treated with add-on ONGLYZA had statistically significant greater reductions in HbA1c from baseline versus the group treated with placebo (see Table 12).</paragraph>
<table width="100%">
<caption>Table 12: HbA1c Change from Baseline at Week 24 in a Placebo-Controlled Trial of ONGLYZA as Add-on to Dapagliflozin and Metformin HCl<footnote ID="_Ref476118119">There were 6.5% (n=10) of randomized patients in the saxagliptin arm and 3.1% (n=5) in the placebo arm for whom change from baseline HbA1c data was missing at week 24. Of the patients who discontinued trial medication early, 9.1% (1 of 11) in the saxagliptin arm and 16.7% (1 of 6) in the placebo arm had HbA1c measured at week 24.</footnote>
</caption>
<col width="40%"/>
<col width="27%"/>
<col width="33%"/>
<tbody>
<tr>
<td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>
<content styleCode="bold">ONGLYZA 5 mg</content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=153)</content>
<footnote ID="_Ref476119448">Number of randomized and treated patients.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>
<content styleCode="bold">Placebo</content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=162)</content>
<footnoteRef IDREF="_Ref476119448"/>
</paragraph>
</td>
</tr>
<tr>
<td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">In combination with Dapagliflozin and Metformin HCl</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Hemoglobin A1C (%)</content>
<footnote ID="_Ref476119482">Analysis of Covariance including all post-baseline data regardless of rescue or treatment discontinuation. Model estimates calculated using multiple imputation to model washout of the treatment effect using placebo data for all patients having missing Week 24 data.</footnote>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>8.0</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 from baseline (adjusted mean<footnote ID="_Ref476119518">Least squares mean adjusted for baseline value.</footnote>)</paragraph>
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.5</paragraph>
<paragraph>(−0.6, −0.4)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>−0.2</paragraph>
<paragraph>(−0.3, −0.1)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>Difference from placebo (adjusted mean)</paragraph>
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>−0.4<footnote ID="_Ref476119531">p-value <0.0001</footnote>
</paragraph>
<paragraph>(−0.5, −0.2)</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>The known proportion of patients achieving HbA1c <7% at Week 24 was 35.3% in the saxagliptin treated group compared to 23.1% in the placebo treated group.</paragraph>
</text>
<effectiveTime value="20241011"/>
</section>
</component>
</section>
</component>
</section>
</component>
<component>
<section ID="s14.3">
<id root="1412217c-b890-4dab-9731-9746487077b8"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.2 Renal Impairment</title>
<text>
<paragraph>A total of 170 patients participated in a 12-week, randomized, double-blind, placebo-controlled trial conducted to evaluate the efficacy and safety of ONGLYZA 2.5 mg once daily compared with placebo in patients with type 2 diabetes mellitus and moderate (n=90) or severe (n=41) renal impairment or ESRD (n=39). In this trial, 98% of the patients were using background antidiabetic medications (75% were using insulin and 31% were using oral antidiabetic medications, mostly sulfonylureas).</paragraph>
<paragraph>After 12 weeks of treatment, ONGLYZA 2.5 mg provided significant improvement in A1C compared to placebo (Table 13). In the subgroup of patients with ESRD, ONGLYZA and placebo resulted in comparable reductions in A1C from baseline to Week 12. This finding is inconclusive because the trial was not adequately powered to show efficacy within specific subgroups of renal impairment.</paragraph>
<paragraph>After 12 weeks of treatment, the mean change in FPG was −12 mg/dL with ONGLYZA 2.5 mg and −13 mg/dL with placebo. Compared to placebo, the mean change in FPG with ONGLYZA was −12 mg/dL in the subgroup of patients with moderate renal impairment, −4 mg/dL in the subgroup of patients with severe renal impairment, and +44 mg/dL in the subgroup of patients with ESRD. These findings are inconclusive because the trial was not adequately powered to show efficacy within specific subgroups of renal impairment.</paragraph>
<table cellpadding="4.8pt" width="100%">
<caption>Table 13: A1C at Week 12 in a Placebo-Controlled Trial of ONGLYZA in Patients with Renal Impairment<footnote ID="_Ref420595751">Intent-to-treat population using last observation on trial.</footnote>
</caption>
<col width="58%"/>
<col width="29%"/>
<col width="13%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Efficacy Parameter</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">ONGLYZA 2.5 mg</content>
<br/>
<content styleCode="bold">N=85</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Placebo</content>
<br/>
<content styleCode="bold">N=85</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Hemoglobin A1C (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=81</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">N=83</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>8.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref420595820">Least squares mean adjusted for baseline value.</footnote>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref420595820"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.4<footnote ID="_Ref420595837">p-value <0.01 compared to placebo.</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> 95% Confidence Interval</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>(−0.7, −0.1)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20241011"/>
</section>
</component>
<component>
<section ID="ID_823f0de6-d8d4-419d-ac42-cc4620a82d4a">
<id root="5caa9a38-10ce-4603-a92c-8f0b7906984f"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.3 Cardiovascular Safety Trial </title>
<text>
<paragraph>The cardiovascular risk of ONGLYZA was evaluated in SAVOR, a multicenter, multinational, randomized, double-blind trial comparing ONGLYZA (N=8280) to placebo (N=8212), both administered in combination with standard of care, in adult patients with type 2 diabetes mellitus at high risk for atherosclerotic cardiovascular disease. Of the randomized trial patients, 97.5% completed the trial, and the median duration of follow-up was approximately 2 years. The trial was event-driven, and patients were followed until a sufficient number of events were accrued.</paragraph>
<paragraph>Patients were at least 40 years of age, had A1C ≥6.5%, and multiple risk factors (21% of randomized patients) for cardiovascular disease (age ≥55 years for men and ≥60 years for women plus at least one additional risk factor of dyslipidemia, hypertension, or current cigarette smoking) or established (79% of the randomized patients) cardiovascular disease defined as a history of ischemic heart disease, peripheral vascular disease, or ischemic stroke. Overall, the use of diabetes medications was balanced across treatment groups (metformin HCl 69%, insulin 41%, sulfonylureas 40%, and TZDs 6%). The use of cardiovascular disease medications was also balanced (angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) 79%, statins 78%, aspirin 75%, beta-blockers 62%, and non-aspirin antiplatelet medications 24%).</paragraph>
<paragraph>The majority of patients were male (67%) and White (75%) with a mean age of 65 years. Approximately 16% of the population had moderate (estimated glomerular filtration rate [eGFR] ≥30 to ≤50 mL/min/1.73 m<sup>2</sup>) to severe (eGFR <30 mL/min/1.73 m<sup>2</sup>) renal impairment, and 13% had a prior history of heart failure. Patients had a median duration of type 2 diabetes mellitus of approximately 10 years, and a mean baseline A1C level of 8.0%. Approximately 5% of patients were treated with diet and exercise only at baseline. Overall, the use of diabetes medications was balanced across treatment groups (metformin HCl 69%, insulin 41%, sulfonylureas 40%, and TZDs 6%). The use of cardiovascular disease medications was also balanced (ACE inhibitors or ARBs 79%, statins 78%, aspirin 75%, beta-blockers 62%, and non-aspirin antiplatelet medications 24%). </paragraph>
<paragraph>The primary analysis in SAVOR was time to first occurrence of a Major Adverse Cardiac Event (MACE). A major adverse cardiac event in SAVOR was defined as a cardiovascular death or a nonfatal myocardial infarction (MI) or a nonfatal ischemic stroke. The trial was designed as a non-inferiority trial with a pre-specified risk margin of 1.3 for the hazard ratio of MACE and was also powered for a superiority comparison if non-inferiority was demonstrated. </paragraph>
<paragraph>The results of SAVOR, including the contribution of each component to the primary composite endpoint, are shown in Table 14. The incidence rate of MACE was similar in both treatment arms: 3.8 MACE per 100 patient-years on placebo vs. 3.8 MACE per 100 patient-years on ONGLYZA. The estimated hazard ratio of MACE associated with ONGLYZA relative to placebo was 1.00 with a 95.1% confidence interval of (0.89, 1.12). The upper bound of this confidence interval, 1.12, excluded a risk margin larger than 1.3.</paragraph>
<table width="100%">
<caption>Table 14: Major Adverse Cardiovascular Events (MACE) by Treatment Group in the SAVOR Trial</caption>
<col width="17%"/>
<col width="17%"/>
<col width="17%"/>
<col width="17%"/>
<col width="17%"/>
<col width="17%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">ONGLYZA</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Placebo</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Hazard Ratio</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold">Number of Patients (%) </content>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold">Rate per 100 PY</content>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold">Number of Patients (%) </content>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold">Rate per 100 PY</content>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold"> (95.1% CI)</content>
</item>
</list>
</td>
</tr>
<tr>
<td rowspan="2" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Composite of first event of CV death, non-fatal MI or non-fatal ischemic stroke (MACE)</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold">N=8280</content>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold">Total PY = 16308.8</content>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold">N=8212</content>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold">Total PY = 16156.0</content>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>613 (7.4)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>609 (7.4)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.00 (0.89, 1.12)</paragraph>
</td>
</tr>
<tr>
<td align="justify" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>CV death</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>245 (3.0)</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>234 (2.8)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.4</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td align="justify" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Non-fatal MI</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>233 (2.8)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>260 (3.2)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.6</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td align="justify" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>Non-fatal ischemic stroke</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>135 (1.6)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0.8</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>115 (1.4)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
</tr>
</tbody>
</table>
<paragraph>The Kaplan-Meier-based cumulative event probability is presented in Figure 2 for time to first occurrence of the primary MACE composite endpoint by treatment arm. The curves for both ONGLYZA and placebo arms are close together throughout the duration of the trial. The estimated cumulative event probability is approximately linear for both arms, indicating that the incidence of MACE for both arms was constant over the trial duration.</paragraph>
<paragraph>
<content styleCode="bold">Figure 2: Cumulative Percent of Time to First MACE</content>
</paragraph>
<renderMultiMedia ID="id-2002186682" referencedObject="F7257248-79CA-49B9-A2F7-531DA75DB42F"/>
<paragraph>Vital status was obtained for 99% of patients in the trial. There were 798 deaths in the SAVOR trial. Numerically more patients (5.1%) died in the ONGLYZA group than in the placebo group (4.6%). The risk of deaths from all cause (Table 15) was not statistically different between the treatment groups (HR: 1.11; 95.1% CI: 0.96, 1.27).</paragraph>
<table width="100%">
<caption>Table 15: All-cause mortality by Treatment Group in the SAVOR Trial</caption>
<col width="17%"/>
<col width="17%"/>
<col width="17%"/>
<col width="16%"/>
<col width="17%"/>
<col width="17%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">ONGLYZA</content>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Placebo</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Hazard Ratio</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Number of Patients (%)</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Rate per 100 PY</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Number of Patients (%)</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Rate per 100 PY</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">(95.1% CI)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=8280</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">PY=16645.3</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=8212</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">PY=16531.5</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>All-cause mortality</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>420 (5.1)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>378 (4.6)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>2.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.11 (0.96, 1.27)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> CV death</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>269 (3.2)</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>260 (3.2)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1.6</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph> Non-CV death</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>151 (1.8)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0.9</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>118 (1.4)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>0.7</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20241011"/>
<component>
<observationMedia ID="F7257248-79CA-49B9-A2F7-531DA75DB42F">
<text>Figure 2</text>
<value mediaType="image/jpeg">
<reference value="ONGLYZA_Figure2.jpg"/>
</value>
</observationMedia>
</component>
</section>
</component>
</section>