<?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 Efficacy Trials </title>
<text>
<paragraph>The effectiveness of KOMBIGLYZE XR has been established in clinical trials of coadministration of oral saxagliptin and metformin HCl immediate-release tablets in adults with type 2 diabetes mellitus inadequately controlled on metformin HCl alone and in treatment-naive patients inadequately controlled on diet and exercise alone. In these two trials, treatment with saxagliptin dosed in the morning plus metformin HCl immediate-release tablets at all 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>In these two trials, decrease in body weight in the treatment groups given saxagliptin in combination with metformin HCl immediate-release was similar to that in the groups given metformin HCl immediate-release alone. Saxagliptin plus metformin HCl immediate-release was not associated with significant changes from baseline in fasting serum lipids compared to metformin HCl alone.</paragraph>
<paragraph>The coadministration of saxagliptin and metformin HCl immediate-release tablets has also been evaluated in an active-controlled trial comparing add-on therapy with saxagliptin to glipizide in 858 patients inadequately controlled on metformin HCl alone, in a placebo-controlled trial where a subgroup of 314 patients inadequately controlled on insulin plus metformin HCl received add-on therapy with saxagliptin or placebo, a trial comparing saxagliptin to placebo in 257 patients inadequately controlled on metformin HCl plus a sulfonylurea, and a trial comparing saxagliptin to placebo in 315 patients inadequately controlled on dapagliflozin and metformin HCl.</paragraph>
<paragraph>In a 24-week, double-blind, randomized trial, patients treated with metformin HCl immediate-release 500 mg twice daily for at least 8 weeks were randomized to continued treatment with metformin HCl immediate-release 500 mg twice daily or to metformin HCl extended-release either 1,000 mg once daily or 1,500 mg once daily. The mean change in A1C from baseline to Week 24 was 0.1% (95% confidence interval 0%, 0.3%) for the metformin HCl immediate-release treatment arm, 0.3% (95% confidence interval 0.1%, 0.4%) for the 1,000 mg metformin HCl extended-release treatment arm, and 0.1% (95% confidence interval 0%, 0.3%) for the 1,500 mg metformin HCl extended-release treatment arm. Results of this trial suggest that patients receiving metformin HCl immediate-release treatment may be safely switched to metformin HCl extended-release once daily at the same total daily dose, up to 2,000 mg once daily. Following a switch from metformin HCl immediate-release to metformin HCl extended-release, glycemic control should be closely monitored and dosage adjustments made accordingly.<content styleCode="underline"/>
</paragraph>
<paragraph>
<content styleCode="underline">Saxagliptin Morning and Evening Dosing</content>
</paragraph>
<paragraph>A 24-week monotherapy trial was conducted to assess a range of dosing regimens for saxagliptin. Treatment-naive patients with inadequately controlled diabetes (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 saxagliptin, or placebo. Patients who failed to meet specific glycemic goals during the trial were treated with metformin HCI rescue therapy added on to placebo or saxagliptin; the number of patients randomized per treatment group ranged from 71 to 74.</paragraph>
<paragraph> Treatment with either saxagliptin 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).</paragraph>
</text>
<effectiveTime value="20241011"/>
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<section ID="s14.1">
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<title>
<content styleCode="bold">Coadministration of Saxagliptin with Metformin HCI Immediate-Release in Treatment-Naive Patients</content>
</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 saxagliptin coadministered with metformin HCl immediate-release 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: saxagliptin 5 mg + metformin HCl immediate-release 500 mg, saxagliptin 10 mg + metformin HCl immediate-release 500 mg, saxagliptin 10 mg + placebo, or metformin HCl immediate-release 500 mg + placebo (the maximum recommended approved saxagliptin dose is 5 mg daily; the 10 mg daily dose of saxagliptin does not provide greater efficacy than the 5 mg daily dose and the 10 mg saxagliptin dosage is not an approved dosage). Saxagliptin was dosed once daily. In the 3 treatment groups using metformin HCl immediate-release, 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 this trial were treated with pioglitazone rescue as add-on therapy.</paragraph>
<paragraph>Coadministration of saxagliptin 5 mg plus metformin HCl immediate-release provided significant improvements in A1C, FPG, and PPG compared with placebo plus metformin HCl immediate-release (Table 7).</paragraph>
<table cellpadding="4.8pt" width="100%">
<caption>Table 7: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of Saxagliptin Coadministration with Metformin Immediate-Release in Treatment-Naive Patients<footnote ID="_Ref448321012">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="62%"/>
<col width="20%"/>
<col width="19%"/>
<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">Saxagliptin 5 mg</content>
<br/>
<content styleCode="bold">+ </content>
<br/>
<content styleCode="bold">Metformin HCI</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 HCI</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="_Ref448321099">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 HCI (adjusted mean<footnoteRef IDREF="_Ref448321099"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.5<footnote ID="_Ref448321530">p-value <0.0001 compared to placebo + metformin HCI.</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="_Ref448321605">p-value <0.05 compared to placebo + metformin HCI.</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="_Ref448321099"/>)</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 HCI (adjusted mean<footnoteRef IDREF="_Ref448321099"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−13<footnoteRef IDREF="_Ref448321605"/>
</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="_Ref448321099"/>)</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 HCI (adjusted mean<footnoteRef IDREF="_Ref448321099"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−41<footnoteRef IDREF="_Ref448321605"/>
</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"/>
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<section ID="s14.2">
<id root="48245dca-ae8e-4c37-89e6-36e3f5bcc1d8"/>
<code code="34092-7" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL STUDIES SECTION"/>
<title>
<content styleCode="bold">Addition of Saxagliptin to Metformin HCI Immediate-Release</content>
</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 saxagliptin in combination with metformin HCl immediate-release in patients with inadequate glycemic control (A1C ≥7% and ≤10%) on metformin HCl 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 immediate-release at their pre-trial dose, up to 2500 mg daily, for the duration of the trial. Following the lead-in period, eligible patients were randomized to 2.5 mg, 5 mg, or 10 mg of saxagliptin or placebo in addition to their current dose of open-label metformin HCl immediate-release (the maximum recommended approved saxagliptin dose is 5 mg daily; the 10 mg daily dose of saxagliptin does not provide greater efficacy than the 5 mg daily dose and the 10 mg dosage 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 saxagliptin and metformin HCl immediate-release were not permitted.</paragraph>
<paragraph>Saxagliptin 2.5 mg and 5 mg add-on to metformin HCl immediate-release provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to metformin HCl immediate-release (Table 8). 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 saxagliptin 2.5 mg add-on to metformin HCl immediate-release group, 13% in the saxagliptin 5 mg add-on to metformin HCl immediate-release group, and 27% in the placebo add-on to metformin HCl immediate-release group. </paragraph>
<table cellpadding="4.8pt" width="100%">
<caption>Table 8: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Metformin HCI Immediate-Release<footnote ID="_Ref448322095">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="43%"/>
<col width="21%"/>
<col width="19%"/>
<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">Saxagliptin 2.5 mg</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">Metformin HCI</content>
<br/>
<content styleCode="bold">N=192</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Saxagliptin 5 mg</content>
<br/>
<content styleCode="bold">+</content>
<br/>
<content styleCode="bold">Metformin HCI</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 HCI</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="_Ref448322139">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="_Ref448322139"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.7<footnote ID="_Ref448322880">p-value <0.0001 compared to placebo + metformin HCI.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.8<footnoteRef IDREF="_Ref448322880"/>
</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 align="center" styleCode="Rrule Lrule " valign="top">
<paragraph> </paragraph>
</td>
</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="_Ref448323108">p-value <0.05 compared to placebo + metformin HCI.</footnote> (69/186)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>44%<footnoteRef IDREF="_Ref448323108"/> (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="_Ref448322139"/>)</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="_Ref448322139"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−16<footnoteRef IDREF="_Ref448323108"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−23<footnoteRef IDREF="_Ref448323108"/>
</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="_Ref448322139"/>)</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="_Ref448322139"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−44<footnoteRef IDREF="_Ref448323108"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−40<footnoteRef IDREF="_Ref448323108"/>
</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 Saxagliptin as Add-On Combination Therapy with Metformin HCI Immediate-Release*</content>
</paragraph>
<table cellpadding="4.8pt" width="100%">
<col width="100%"/>
<tfoot>
<tr>
<td align="left" colspan="5" styleCode="Botrule" valign="top">* Includes patients with a baseline and week 24 value.<br/>
</td>
</tr>
<tr>
<td align="left" colspan="5" styleCode="Botrule" valign="top">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.</td>
</tr>
</tfoot>
<tbody>
<tr styleCode="Toprule">
<td align="center" valign="top">
<renderMultiMedia ID="id-879013796" referencedObject="ID_3e117c0f-0d83-4610-95ef-04bda1d6b18e"/>
</td>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20241011"/>
<component>
<observationMedia ID="ID_3e117c0f-0d83-4610-95ef-04bda1d6b18e">
<text>Figure 1</text>
<value mediaType="image/jpeg">
<reference value="Figure 1.jpg"/>
</value>
</observationMedia>
</component>
</section>
</component>
<component>
<section ID="s14.3">
<id root="30160185-9444-4983-ac3b-ab5a07c31fd9"/>
<code code="34092-7" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL STUDIES SECTION"/>
<title>
<content styleCode="bold">Saxagliptin Add-On Combination Therapy with Metformin HCI Immediate-Release versus Glipizide Add-On Combination Therapy with Metformin HCI Immediate-Release</content>
</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 immediate-release alone were randomized to double-blind add-on therapy with saxagliptin or glipizide. Patients were required to be on a stable dose of metformin HCl immediate-release (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 immediate-release (1,500-3,000 mg based on their pre-trial dose). Following the lead-in period, eligible patients were randomized to 5 mg of saxagliptin or 5 mg of glipizide in addition to their current dose of open-label metformin HCl immediate-release. Patients in the glipizide plus metformin HCl immediate-release 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, saxagliptin and glipizide resulted in similar mean reductions from baseline in A1C when added to metformin HCl immediate-release 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%). From a baseline mean body weight of 89 kg, there was a statistically significant mean reduction of 1.1 kg in patients treated with saxagliptin compared to a mean weight gain of 1.1 kg in patients treated with glipizide (p<0.0001).</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 saxagliptin 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 Saxagliptin versus Glipizide in Combination with Metformin HCI Immediate-Release<footnote ID="_Ref448323627">Intent-to-treat population using last observation on trial.</footnote>
</caption>
<col width="61%"/>
<col width="19%"/>
<col width="20%"/>
<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">Saxagliptin 5 mg</content>
<br/>
<content styleCode="bold">+ </content>
<br/>
<content styleCode="bold">Metformin HCI</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 HCI</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="_Ref448323674">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 HCI (adjusted mean<footnoteRef IDREF="_Ref448323674"/>)</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="_Ref448323868">Saxagliptin + metformin HCI is considered non-inferior to glipizide + metformin 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="_Ref448323674"/>)</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 HCI (adjusted mean<footnoteRef IDREF="_Ref448323674"/>)</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="_Ref448323883">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="s14.4">
<id root="b80a2aa3-29eb-469b-afa8-8a006655fd13"/>
<code code="34092-7" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL STUDIES SECTION"/>
<title>
<content styleCode="bold">Saxagliptin Add-On Combination Therapy with Insulin (with or without Metformin Immediate-Release)</content>
</title>
<text>
<paragraph>A total of 455 patients with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin 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 immediate-release (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 immediate-release if applicable) at their pretrial dose(s). Following the lead-in period, eligible patients were randomized to add-on therapy with either saxagliptin 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 saxagliptin 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 saxagliptin 5 mg add-on to insulin alone and saxagliptin 5 mg add-on to insulin in combination with metformin immediate-release (−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 saxagliptin group and 32% in the placebo group.</paragraph>
<paragraph>The mean daily insulin dose at baseline was 53 units in patients treated with saxagliptin 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 saxagliptin 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 Saxagliptin as Add-On Combination Therapy with Insulin<footnote ID="_Ref448324133">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="48%"/>
<col width="26%"/>
<col width="26%"/>
<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">Saxagliptin 5 mg</content>
<br/>
<content styleCode="bold">+ </content>
<br/>
<content styleCode="bold">Insulin</content>
<br/>
<content styleCode="bold">(+/− Metformin HCI)</content>
<br/>
<content styleCode="bold">N=304</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">Insulin</content>
<br/>
<content styleCode="bold">(+/− Metformin HCI)</content>
<br/>
<content styleCode="bold">N=151</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=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="_Ref448324150">Least squares mean adjusted for baseline value and metformin HCI 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="_Ref448324150"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.4<footnote ID="_Ref448324237">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="_Ref448324150"/>)</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="_Ref448324150"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−23<footnote ID="_Ref448324250">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 saxagliptin 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="s14.5">
<id root="f2223398-fca0-4ffc-945e-8661a6994847"/>
<code code="34092-7" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL STUDIES SECTION"/>
<title>
<content styleCode="bold"> Saxagliptin Add-On Combination Therapy with Metformin HCI 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 saxagliptin 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 saxagliptin (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>Saxagliptin 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 saxagliptin 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 Saxagliptin as Add-On Combination Therapy with Metformin HCI plus Sulfonylurea<footnote ID="_Ref448325449">Intent-to-treat population using last observation prior to discontinuation.</footnote>
</caption>
<col width="54%"/>
<col width="24%"/>
<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">Saxagliptin 5 mg</content>
<br/>
<content styleCode="bold">+ </content>
<br/>
<content styleCode="bold">Metformin plus</content>
<br/>
<content styleCode="bold">Sulfonylurea</content>
<br/>
<content styleCode="bold">N=129</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 plus</content>
<br/>
<content styleCode="bold">Sulfonylurea</content>
<br/>
<content styleCode="bold">N=128</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=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="_Ref448325602">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="_Ref448325602"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−0.7<footnote ID="_Ref448325793">p-value <0.0001 compared to placebo + metformin HCI 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="_Ref448325602"/>)</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="_Ref448325602"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule " valign="top">
<paragraph>−17<footnote ID="_Ref448325815">p-value <0.05 compared to placebo + metformin HCI 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 saxagliptin in combination with metformin HCI plus a sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested.</paragraph>
<paragraph>
<content styleCode="bold">Saxagliptin Add-on Combination Therapy with Metformin 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 saxagliptin 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 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 m<sup>2</sup>. 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 16 weeks of open-label metformin HCl and 10 mg dapagliflozin treatment. Following the lead-in period, eligible patients were randomized to saxagliptin 5 mg (N=153) or placebo (N =162).</paragraph>
<paragraph>The group treated with add-on saxagliptin 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 Saxagliptin as Add-On to Dapagliflozin and Metformin HCI<footnote ID="_Ref22729995">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="42%"/>
<col width="25%"/>
<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">Saxagliptin 5 mg </content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=153)</content>
<sup/>
<footnote ID="_Ref476140204">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="_Ref476140204"/>
</paragraph>
</td>
</tr>
<tr>
<td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">In combination with Dapagliflozin and Metformin HCI</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Hemoglobin A1C (%)</content>
<footnote ID="_Ref22730062">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="_Ref22730105">Least squares mean adjusted for baseline value.</footnote>)</paragraph>
<list listType="ordered">
<item>
<caption> </caption>95% Confidence Interval</item>
</list>
</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>
<list listType="ordered">
<item>
<caption> </caption>95% Confidence Interval</item>
</list>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>−0.4<footnote ID="_Ref476140324">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"/>
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</section>
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<component>
<section ID="ID_190cd3ef-e409-4605-9be4-13900c1e0d95">
<id root="17c24732-c68b-4a7b-a7ac-bf0ce958644e"/>
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<title>14.2 Cardiovascular Safety Trial </title>
<text>
<paragraph>The cardiovascular risk of saxagliptin was evaluated in SAVOR, a multicenter, multinational, randomized, double-blind trial comparing saxagliptin (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. 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) to severe (eGFR <30 mL/min) 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 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 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 13. 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 saxagliptin. The estimated hazard ratio of MACE associated with saxagliptin 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 13: 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 colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold">Saxagliptin</content>
</item>
</list>
</td>
<td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold">Placebo</content>
</item>
</list>
</td>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold">Hazard Ratio</content>
</item>
</list>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Number of Patients (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Rate per 100 PY</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Number of Patients (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Rate per 100 PY</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">(95.1% CI)</content>
</paragraph>
</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 align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=8280</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Total PY = 16308.8</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=8212</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Total PY = 16156.0</content>
</paragraph>
</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 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 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 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 saxagliptin 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>
<renderMultiMedia ID="id-671481323" referencedObject="ID_9c349ce0-3f24-473f-afe3-88fc45190f5f"/>
<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 saxagliptin group than in the placebo group (4.6%). The risk of deaths from all cause (Table 14) was not statistically different between the treatment groups (HR: 1.11; 95.1% CI: 0.96, 1.27).</paragraph>
<table width="100%">
<caption>Table 14: All-Cause Mortality 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">Saxagliptin</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 align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Number of Patients (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Rate per 100 PY</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Number of Patients (%)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Rate per 100 PY</content>
</paragraph>
</td>
<td align="center" 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 align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=8280</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">PY=16645.3</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=8212</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>
<content styleCode="bold">PY=16531.5</content>
</item>
</list>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All-cause mortality</content>
</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 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="ID_9c349ce0-3f24-473f-afe3-88fc45190f5f">
<text>Figure 2</text>
<value mediaType="image/jpeg">
<reference value="image-03.jpg"/>
</value>
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