<?xml version="1.0" encoding="UTF-8"?><section ID="s14">
<id root="7a1a4059-5efa-48d0-ae46-b2b7404dddee"/>
<code code="34092-7" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL STUDIES SECTION"/>
<title>14 CLINICAL STUDIES</title>
<text>
<paragraph>ONGLYZA has been studied as monotherapy
and in combination with metformin, 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. 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 Caucasian, 16% were Asian,
4% were black, and 9% were of other racial groups. An additional 423 patients,
including 315 who received ONGLYZA, participated in a placebo-controlled,
dose-ranging study 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 a saxagliptin dose of
10 mg daily. The 10 mg daily dose of saxagliptin did not provide greater efficacy
than the 5 mg daily dose. Treatment with ONGLYZA at all doses produced clinically
relevant and statistically significant improvements in hemoglobin A1c (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 three additional trials in patients with type 2 diabetes: an active-controlled trial comparing add-on therapy with ONGLYZA to glipizide in 858 patients inadequately controlled on metformin alone, a trial comparing ONGLYZA to placebo in 455 patients inadequately controlled on insulin alone or on insulin in combination with metformin, and a trial comparing ONGLYZA to placebo in 170 patients with type 2 diabetes and moderate or severe renal impairment or ESRD.</paragraph>
</text>
<effectiveTime value="20111216"/>
<component>
<section ID="s14.1">
<id root="fea114e6-c839-4a44-b94a-59b7f22b3416"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.1 Monotherapy</title>
<text>
<paragraph>A total of 766 patients with type
2 diabetes 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. Patients who failed to meet specific glycemic goals during the
study were treated with metformin 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 5). 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>
</text>
<component>
<section ID="s14.1.2">
<id root="5a415bbf-9bea-4e3a-ba7c-4708188db83e"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<text>
<table ID="i869e9daa-6c26-4012-8e1a-fb7e51ce4ca5" border="0" cellpadding="2" cellspacing="1" width="100%">
<caption>Table 5: Glycemic Parameters at Week 24 in a Placebo-Controlled Study
of ONGLYZA Monotherapy in Patients with Type 2 Diabetes*</caption>
<colgroup>
<col width="40%"/>
<col width="20%"/>
<col width="20%"/>
<col width="20%"/>
</colgroup>
<thead>
<tr>
<th align="left" styleCode="Lrule Toprule Rrule Botrule" valign="top">
<content styleCode="bold">Efficacy
Parameter</content>
</th>
<th align="center" styleCode="Lrule Toprule Rrule Botrule" valign="top">
<content styleCode="bold">ONGLYZA<br/>2.5
mg<br/>N=102</content>
</th>
<th align="center" styleCode="Lrule Toprule Rrule Botrule" valign="top">
<content styleCode="bold">ONGLYZA<br/>5
mg<br/>N=106</content>
</th>
<th align="center" styleCode="Lrule Toprule Rrule Botrule" valign="top">
<content styleCode="bold">Placebo<br/>
<br/>N=95</content>
</th>
</tr>
</thead>
<tfoot>
<tr>
<td colspan="4">* Intent-to-treat population
using last observation on study or last observation prior to metformin rescue
therapy for patients needing rescue.</td>
</tr>
<tr>
<td colspan="4">
<sup>†</sup> Least
squares mean adjusted for baseline value.</td>
</tr>
<tr>
<td colspan="4">
<sup>‡</sup> p-value
<0.0001 compared to placebo</td>
</tr>
<tr>
<td colspan="4">
<sup>§</sup> p-value
<0.05 compared to placebo</td>
</tr>
<tr>
<td colspan="4">
<sup>¶</sup> Significance
was not tested for the 2-hour PPG for the 2.5 mg dose of ONGLYZA.</td>
</tr>
</tfoot>
<tbody>
<tr>
<td styleCode="Lrule Toprule Rrule">
<content styleCode="bold">Hemoglobin A1C (%)</content>
</td>
<td align="center" styleCode="Lrule Toprule Rrule">
<content styleCode="bold">N=100</content>
</td>
<td align="center" styleCode="Lrule Toprule Rrule">
<content styleCode="bold">N=103</content>
</td>
<td align="center" styleCode="Lrule Toprule Rrule">
<content styleCode="bold">N=92</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule">7.9</td>
<td align="center" styleCode="Lrule Rrule">8.0</td>
<td align="center" styleCode="Lrule Rrule">7.9</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule">−0.4</td>
<td align="center" styleCode="Lrule Rrule">−0.5</td>
<td align="center" styleCode="Lrule Rrule">+0.2</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Difference
from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule">−0.6<sup>‡</sup>
</td>
<td align="center" styleCode="Lrule Rrule">−0.6<sup>‡</sup>
</td>
<td align="center" styleCode="Lrule Rrule"> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule">(−0.9, −0.3)</td>
<td align="center" styleCode="Lrule Rrule">(−0.9, −0.4)</td>
<td align="center" styleCode="Lrule Rrule"> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> Percent
of patients achieving A1C <7%</td>
<td align="center" styleCode="Lrule Rrule Botrule">35% (35/100)</td>
<td align="center" styleCode="Lrule Rrule Botrule">38%<sup>§</sup> (39/103)</td>
<td align="center" styleCode="Lrule Rrule Botrule">24% (22/92)</td>
</tr>
<tr>
<td styleCode="Lrule Toprule Rrule ">
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Lrule Toprule Rrule ">
<content styleCode="bold">N=101</content>
</td>
<td align="center" styleCode="Lrule Toprule Rrule ">
<content styleCode="bold">N=105</content>
</td>
<td align="center" styleCode="Lrule Toprule Rrule ">
<content styleCode="bold">N=92</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">178</td>
<td align="center" styleCode="Lrule Rrule ">171</td>
<td align="center" styleCode="Lrule Rrule ">172</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−15</td>
<td align="center" styleCode="Lrule Rrule ">−9</td>
<td align="center" styleCode="Lrule Rrule ">+6</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−21<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule ">−15<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−31, −10)</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−25, −4)</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
<tr>
<td styleCode="Lrule Toprule Rrule ">
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Lrule Toprule Rrule ">
<content styleCode="bold">N=78</content>
</td>
<td align="center" styleCode="Lrule Toprule Rrule ">
<content styleCode="bold">N=84</content>
</td>
<td align="center" styleCode="Lrule Toprule Rrule ">
<content styleCode="bold">N=71</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">279</td>
<td align="center" styleCode="Lrule Rrule ">278</td>
<td align="center" styleCode="Lrule Rrule ">283</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−45</td>
<td align="center" styleCode="Lrule Rrule ">−43</td>
<td align="center" styleCode="Lrule Rrule ">−6</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−39<sup>¶</sup>
</td>
<td align="center" styleCode="Lrule Rrule ">−37<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−61, −16)</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−59, −15)</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
</tbody>
</table>
</text>
</section>
</component>
<component>
<section ID="s14.1.3">
<id root="1f76baa6-8ec5-4ac9-82eb-781ef96afb77"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<text>
<paragraph>A second 24-week monotherapy trial
was conducted to assess a range of dosing regimens for ONGLYZA. 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 ONGLYZA, or placebo. Patients who failed to meet specific glycemic goals
during the study were treated with metformin 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>
</section>
</component>
</section>
</component>
<component>
<section ID="s14.2">
<id root="55b050b2-98fa-4d05-a6b6-3b78decddb8c"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.2 Combination Therapy</title>
<component>
<section ID="s14.2.1">
<id root="a57f19f7-3607-43e5-bd4c-9d70916de4b2"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Add-On Combination Therapy with Metformin</title>
<text>
<paragraph>A total of 743 patients with type 2 diabetes
participated in this 24-week, randomized, double-blind, placebo-controlled
trial to evaluate the efficacy and safety of ONGLYZA in combination with metformin
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 (1500-2550 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
at their pre-study dose, up to 2500 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. Patients who failed to meet specific glycemic goals
during the study were treated with pioglitazone rescue therapy, added on to
existing study medications. Dose titrations of ONGLYZA and metformin 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 6). 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 ID="ib942d808-c446-4785-8dd4-edfe64bd4f0f" border="0" cellpadding="2" cellspacing="1" width="100%">
<caption>Table 6: Glycemic Parameters at Week 24 in a Placebo-Controlled Study
of ONGLYZA as Add-On Combination Therapy with Metformin*</caption>
<colgroup>
<col width="40%"/>
<col width="20%"/>
<col width="20%"/>
<col width="20%"/>
</colgroup>
<thead>
<tr>
<th align="left" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Efficacy
Parameter</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">ONGLYZA
2.5 mg<br/>+<br/>Metformin<br/>N=192</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">ONGLYZA
5 mg<br/>+<br/>Metformin<br/>N=191</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Placebo<br/>+<br/>Metformin<br/>N=179</content>
</th>
</tr>
</thead>
<tfoot>
<tr>
<td colspan="4">* Intent-to-treat population
using last observation on study or last observation prior to pioglitazone
rescue therapy for patients needing rescue.</td>
</tr>
<tr>
<td colspan="4">
<sup>†</sup> Least
squares mean adjusted for baseline value.</td>
</tr>
<tr>
<td colspan="4">
<sup>‡</sup> p-value
<0.0001 compared to placebo + metformin</td>
</tr>
<tr>
<td colspan="4">
<sup>§</sup> p-value
<0.05 compared to placebo + metformin</td>
</tr>
</tfoot>
<tbody>
<tr>
<td styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">Hemoglobin A1C (%)</content>
</td>
<td align="center" styleCode="Lrule Toprule Rrule">
<content styleCode="bold">N=186</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=186</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=175</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule">8.1</td>
<td align="center" styleCode="Lrule Rrule ">8.1</td>
<td align="center" styleCode="Lrule Rrule ">8.1</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule">−0.6</td>
<td align="center" styleCode="Lrule Rrule ">−0.7</td>
<td align="center" styleCode="Lrule Rrule ">+0.1</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule">−0.7<sup>‡</sup>
</td>
<td align="center" styleCode="Lrule Rrule ">−0.8<sup>‡</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule">(−0.9, −0.5)</td>
<td align="center" styleCode="Lrule Rrule ">(−1.0, −0.6)</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> Percent
of patients achieving A1C <7%</td>
<td align="center" styleCode="Lrule Rrule Botrule">37%<sup>§</sup> (69/186)</td>
<td align="center" styleCode="Lrule Rrule Botrule">44%<sup>§</sup> (81/186)</td>
<td align="center" styleCode="Lrule Rrule Botrule">17% (29/175)</td>
</tr>
<tr>
<td styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Lrule Toprule Rrule ">
<content styleCode="bold">N=188</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=187</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=176</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">174</td>
<td align="center" styleCode="Lrule Rrule ">179</td>
<td align="center" styleCode="Lrule Rrule ">175</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−14</td>
<td align="center" styleCode="Lrule Rrule ">−22</td>
<td align="center" styleCode="Lrule Rrule ">+1</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−16<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule ">−23<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−23, −9)</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−30, −16)</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
<tr>
<td styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Lrule Toprule Rrule ">
<content styleCode="bold">N=155</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=155</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=135</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">294</td>
<td align="center" styleCode="Lrule Rrule ">296</td>
<td align="center" styleCode="Lrule Rrule ">295</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−62</td>
<td align="center" styleCode="Lrule Rrule ">−58</td>
<td align="center" styleCode="Lrule Rrule ">−18</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−44<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule ">−40<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−60, −27)</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−56, −24)</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
</tbody>
</table>
<table ID="ibf13934b-6ef1-47ae-8543-89466fbca07f" border="0" cellpadding="2" cellspacing="1">
<caption>Figure 1: Mean Change from Baseline in A1C in a Placebo-Controlled
Trial of ONGLYZA as Add-On Combination Therapy with Metformin*</caption>
<colgroup>
<col/>
</colgroup>
<tfoot>
<tr valign="middle">
<td>* Includes patients with a baseline
and week 24 value.<br/>Week 24 (LOCF) includes intent-to-treat population
using last observation on study prior to pioglitazone rescue therapy for
patients needing rescue. Mean change from baseline is adjusted for baseline
value.</td>
</tr>
</tfoot>
<tbody>
<tr>
<td>
<renderMultiMedia referencedObject="mm347"/>
</td>
</tr>
</tbody>
</table>
</text>
<component>
<observationMedia ID="mm347">
<text>Figure 1</text>
<value mediaType="image/jpeg">
<reference value="figure-1.jpg"/>
</value>
</observationMedia>
</component>
</section>
</component>
<component>
<section ID="s14.2.2">
<id root="b99380ce-8d7d-4cfa-9450-6d24fb0f10e5"/>
<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 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-study 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 study were treated with metformin rescue, added
on to existing study medications. Dose titration of ONGLYZA or TZD was not
permitted during the study. 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 7). 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 ID="i27e951f1-f525-4361-829c-64e5088aa254" border="0" cellpadding="2" cellspacing="1" width="100%">
<caption>Table 7: Glycemic Parameters at Week 24 in a Placebo-Controlled Study
of ONGLYZA as Add-On Combination Therapy with a Thiazolidinedione*</caption>
<colgroup>
<col width="40%"/>
<col width="20%"/>
<col width="20%"/>
<col width="20%"/>
</colgroup>
<thead>
<tr>
<th align="left" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Efficacy
Parameter</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">ONGLYZA
2.5 mg<br/>+<br/>TZD<br/>N=195</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">ONGLYZA
5 mg<br/>+<br/>TZD<br/>N=186</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Placebo<br/>+<br/>TZD<br/>N=184</content>
</th>
</tr>
</thead>
<tfoot>
<tr>
<td colspan="4">* Intent-to-treat population
using last observation on study or last observation prior to metformin rescue
therapy for patients needing rescue.</td>
</tr>
<tr>
<td colspan="4">
<sup>†</sup> Least
squares mean adjusted for baseline value.</td>
</tr>
<tr>
<td colspan="4">
<sup>‡</sup> p-value
<0.0001 compared to placebo + TZD</td>
</tr>
<tr>
<td colspan="4">
<sup>§</sup> p-value
<0.05 compared to placebo + TZD</td>
</tr>
</tfoot>
<tbody>
<tr>
<td styleCode="Toprule Lrule Rrule">
<content styleCode="bold">Hemoglobin A1C (%)</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule">
<content styleCode="bold">N=192</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule">
<content styleCode="bold">N=183</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule">
<content styleCode="bold">N=180</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">8.3</td>
<td align="center" styleCode="Lrule Rrule ">8.4</td>
<td align="center" styleCode="Lrule Rrule ">8.2</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−0.7</td>
<td align="center" styleCode="Lrule Rrule ">−0.9</td>
<td align="center" styleCode="Lrule Rrule ">−0.3</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−0.4<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule ">−0.6<sup>‡</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule ">(−0.6, −0.2)</td>
<td align="center" styleCode="Lrule Rrule ">(−0.8, −0.4)</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> Percent
of patients achieving A1C <7%</td>
<td align="center" styleCode="Lrule Rrule Botrule">42%<sup>§</sup> (81/192)</td>
<td align="center" styleCode="Lrule Rrule Botrule">42%<sup>§</sup> (77/184)</td>
<td align="center" styleCode="Lrule Rrule Botrule">26% (46/180)</td>
</tr>
<tr>
<td styleCode="Toprule Lrule Rrule">
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule">
<content styleCode="bold">N=193</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule">
<content styleCode="bold">N=185</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule">
<content styleCode="bold">N=181</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">163</td>
<td align="center" styleCode="Lrule Rrule ">160</td>
<td align="center" styleCode="Lrule Rrule ">162</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−14</td>
<td align="center" styleCode="Lrule Rrule ">−17</td>
<td align="center" styleCode="Lrule Rrule ">−3</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−12<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule ">−15<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−20, −3)</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−23, −6)</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
<tr>
<td styleCode="Toprule Lrule Rrule">
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule">
<content styleCode="bold">N=156</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule">
<content styleCode="bold">N=134</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule">
<content styleCode="bold">N=127</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">296</td>
<td align="center" styleCode="Lrule Rrule ">303</td>
<td align="center" styleCode="Lrule Rrule ">291</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−55</td>
<td align="center" styleCode="Lrule Rrule ">−65</td>
<td align="center" styleCode="Lrule Rrule ">−15</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−40<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule ">−50<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−56, −24)</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−66, −34)</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
</tbody>
</table>
</text>
</section>
</component>
<component>
<section ID="s14.2.3">
<id root="82fa7be1-26a7-4199-b435-798291664ed8"/>
<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 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 study, 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 study 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 study period. Patients who failed to meet specific glycemic
goals during the study were treated with metformin rescue, added on to existing
study medication. Dose titration of ONGLYZA was not permitted during the study. </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 8). 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 ID="ia1e8d550-2f25-4a11-8c2d-3c66e7bd19f5" border="0" cellpadding="2" cellspacing="1" width="100%">
<caption>Table 8: Glycemic Parameters at Week 24 in a Placebo-Controlled Study
of ONGLYZA as Add-On Combination Therapy with Glyburide*</caption>
<colgroup>
<col width="40%"/>
<col width="20%"/>
<col width="20%"/>
<col width="20%"/>
</colgroup>
<thead>
<tr>
<th align="left" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Efficacy
Parameter</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">ONGLYZA<br/>2.5
mg<br/>+ <br/>Glyburide<br/>7.5 mg<br/>N=248</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">ONGLYZA<br/>5
mg<br/>+ <br/>Glyburide<br/>7.5 mg<br/>N=253</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Placebo<br/>
<br/>+ <br/>Up-Titrated
Glyburide<br/>N=267</content>
</th>
</tr>
</thead>
<tfoot>
<tr>
<td colspan="4">* Intent-to-treat population
using last observation on study or last observation prior to metformin rescue
therapy for patients needing rescue.</td>
</tr>
<tr>
<td colspan="4">
<sup>†</sup> Least
squares mean adjusted for baseline value.</td>
</tr>
<tr>
<td colspan="4">
<sup>‡</sup> p-value
<0.0001 compared to placebo + up-titrated glyburide</td>
</tr>
<tr>
<td colspan="4">
<sup>§</sup> p-value
<0.05 compared to placebo + up-titrated glyburide</td>
</tr>
</tfoot>
<tbody>
<tr>
<td styleCode="Lrule Rrule Toprule ">
<content styleCode="bold">Hemoglobin A1C (%)</content>
</td>
<td align="center" styleCode="Lrule Rrule Toprule ">
<content styleCode="bold">N=246</content>
</td>
<td align="center" styleCode="Lrule Rrule Toprule ">
<content styleCode="bold">N=250</content>
</td>
<td align="center" styleCode="Lrule Rrule Toprule ">
<content styleCode="bold">N=264</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule">8.4</td>
<td align="center" styleCode="Lrule Rrule">8.5</td>
<td align="center" styleCode="Lrule Rrule">8.4</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule">−0.5</td>
<td align="center" styleCode="Lrule Rrule">−0.6</td>
<td align="center" styleCode="Lrule Rrule">+0.1</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Difference
from up-titrated glyburide (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule">−0.6<sup>‡</sup>
</td>
<td align="center" styleCode="Lrule Rrule">−0.7<sup>‡</sup>
</td>
<td align="center" styleCode="Lrule Rrule"> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule">(−0.8, −0.5)</td>
<td align="center" styleCode="Lrule Rrule">(−0.9, −0.6)</td>
<td align="center" styleCode="Lrule Rrule"> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> Percent
of patients achieving A1C <7%</td>
<td align="center" styleCode="Lrule Rrule Botrule">22%<sup>§</sup> (55/246)</td>
<td align="center" styleCode="Lrule Rrule Botrule">23%<sup>§</sup> (57/250)</td>
<td align="center" styleCode="Lrule Rrule Botrule">9% (24/264)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule Toprule ">
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Lrule Rrule Toprule ">
<content styleCode="bold">N=247</content>
</td>
<td align="center" styleCode="Lrule Rrule Toprule ">
<content styleCode="bold">N=252</content>
</td>
<td align="center" styleCode="Lrule Rrule Toprule ">
<content styleCode="bold">N=265</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule">170</td>
<td align="center" styleCode="Lrule Rrule">175</td>
<td align="center" styleCode="Lrule Rrule">174</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule">−7</td>
<td align="center" styleCode="Lrule Rrule">−10</td>
<td align="center" styleCode="Lrule Rrule">+1</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Difference
from up-titrated glyburide (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule">−8<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule">−10<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule"> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−14, −1)</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−17, −4)</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Toprule ">
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Lrule Rrule Toprule ">
<content styleCode="bold">N=195</content>
</td>
<td align="center" styleCode="Lrule Rrule Toprule ">
<content styleCode="bold">N=202</content>
</td>
<td align="center" styleCode="Lrule Rrule Toprule ">
<content styleCode="bold">N=206</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule">309</td>
<td align="center" styleCode="Lrule Rrule">315</td>
<td align="center" styleCode="Lrule Rrule">323</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule">−31</td>
<td align="center" styleCode="Lrule Rrule">−34</td>
<td align="center" styleCode="Lrule Rrule">+8</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Difference
from up-titrated glyburide (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule">−38<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule">−42<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule"> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−50, −27)</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−53, −31)</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
</tbody>
</table>
</text>
</section>
</component>
<component>
<section ID="s14.2.4">
<id root="3199aa0d-4d50-4736-b919-1e6f7478646a"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Coadministration with Metformin 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 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 study. </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 500 mg, saxagliptin 10 mg + metformin 500 mg, saxagliptin
10 mg + placebo, or metformin 500 mg + placebo. ONGLYZA was dosed once daily.
In the 3 treatment groups using metformin, the metformin dose was up-titrated
weekly in 500 mg per day increments, as tolerated, to a maximum of 2000 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 provided significant improvements in A1C, FPG,
and PPG compared with placebo plus metformin (Table 9).</paragraph>
<table ID="i3aebfd61-a126-48c7-80e4-377ae3671915" border="0" cellpadding="2" cellspacing="1" width="100%">
<caption>Table 9: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial
of ONGLYZA Coadministration with Metformin in Treatment-Naive Patients*</caption>
<colgroup>
<col width="50%"/>
<col width="25%"/>
<col width="25%"/>
</colgroup>
<thead>
<tr>
<th align="left" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Efficacy
Parameter</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">ONGLYZA
5 mg<br/>+ <br/>Metformin<br/>N=320</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Placebo<br/>+<br/>Metformin<br/>N=328</content>
</th>
</tr>
</thead>
<tfoot>
<tr>
<td colspan="3">* Intent-to-treat population
using last observation on study or last observation prior to pioglitazone
rescue therapy for patients needing rescue.</td>
</tr>
<tr>
<td colspan="3">
<sup>†</sup> Least
squares mean adjusted for baseline value.</td>
</tr>
<tr>
<td colspan="3">
<sup>‡</sup> p-value
<0.0001 compared to placebo + metformin</td>
</tr>
<tr>
<td colspan="3">
<sup>§</sup> p-value
<0.05 compared to placebo + metformin</td>
</tr>
</tfoot>
<tbody>
<tr>
<td styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">Hemoglobin A1C (%)</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=306</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=313</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">9.4</td>
<td align="center" styleCode="Lrule Rrule ">9.4</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−2.5</td>
<td align="center" styleCode="Lrule Rrule ">−2.0</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo + metformin (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−0.5<sup>‡</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule ">(−0.7, −0.4)</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> Percent
of patients achieving A1C <7%</td>
<td align="center" styleCode="Lrule Rrule Botrule">60%<sup>§</sup> (185/307)</td>
<td align="center" styleCode="Lrule Rrule Botrule">41% (129/314)</td>
</tr>
<tr>
<td styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=315</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=320</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">199</td>
<td align="center" styleCode="Lrule Rrule ">199</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−60</td>
<td align="center" styleCode="Lrule Rrule ">−47</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo + metformin (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−13<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−19, −6)</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
<tr>
<td styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=146</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=141</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">340</td>
<td align="center" styleCode="Lrule Rrule ">355</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−138</td>
<td align="center" styleCode="Lrule Rrule ">−97</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo + metformin (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−41<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−57, −25)</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
</tbody>
</table>
</text>
</section>
</component>
<component>
<section ID="s14.2.5">
<id root="1a27a020-9ee9-43fe-a0e0-9ef342851a8c"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>Add-On Combination Therapy with Metformin versus Glipizide Add-On Combination Therapy with Metformin</title>
<text>
<paragraph>In this 52-week, active-controlled trial, a total of 858 patients with type 2 diabetes and inadequate glycemic control (A1C >6.5% and ≤10%) on metformin alone were randomized to double-blind add-on therapy with ONGLYZA or glipizide. Patients were required to be on a stable dose of metformin (at least 1500 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 (1500-3000 mg based on their pre-study 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. Patients in the glipizide plus metformin 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 therapy (Table 10). 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 ID="i99b7f6b9-805f-4dea-8e2a-7e95afa1ba1a" border="0" cellpadding="2" cellspacing="1" width="100%">
<caption>Table 10: Glycemic Parameters at Week 52 in an Active-Controlled Trial of ONGLYZA versus Glipizide in Combination with Metformin*</caption>
<colgroup>
<col width="50%"/>
<col width="25%"/>
<col width="25%"/>
</colgroup>
<thead>
<tr>
<th align="left" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Efficacy Parameter</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">ONGLYZA 5 mg<br/>+ <br/>Metformin<br/>N=428</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Titrated Glipizide <br/>+<br/>Metformin<br/>N=430</content>
</th>
</tr>
</thead>
<tfoot>
<tr>
<td colspan="3">* Intent-to-treat population using last observation on study.</td>
</tr>
<tr>
<td colspan="3">
<sup>†</sup> Least squares mean adjusted for baseline value.</td>
</tr>
<tr>
<td colspan="3">
<sup>‡</sup> Saxagliptin + metformin 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%.</td>
</tr>
<tr>
<td colspan="3">
<sup>§</sup> Significance not tested.</td>
</tr>
</tfoot>
<tbody>
<tr>
<td styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">Hemoglobin A1C (%)</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=423</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=423</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">7.7</td>
<td align="center" styleCode="Lrule Rrule ">7.6</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−0.6</td>
<td align="center" styleCode="Lrule Rrule ">−0.7</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference from glipizide + metformin (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">0.1
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> 95% Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule ">(−0.02, 0.2)<sup>‡</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=420</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=420</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">162</td>
<td align="center" styleCode="Lrule Rrule ">161</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−9</td>
<td align="center" styleCode="Lrule Rrule ">−16</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference from glipizide + metformin (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">6 </td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95% Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(2, 11)<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
</tbody>
</table>
</text>
</section>
</component>
<component>
<section ID="s14.2.6">
<id root="b1870305-76dd-4a1b-9eee-7923785736d8"/>
<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)</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 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 (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 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 11). 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 (−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 ID="i3d5ab8b0-c753-49fa-850b-23831081a9cb" border="0" cellpadding="2" cellspacing="1" width="100%">
<caption>Table 11: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Insulin*</caption>
<colgroup>
<col width="50%"/>
<col width="25%"/>
<col width="25%"/>
</colgroup>
<thead>
<tr>
<th align="left" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Efficacy
Parameter</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">ONGLYZA
5 mg<br/>+ <br/>Insulin<br/>(+/− Metformin)<br/>N=304</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Placebo<br/>+<br/>Insulin<br/>(+/− Metformin)<br/>N=151</content>
</th>
</tr>
</thead>
<tfoot>
<tr>
<td colspan="3">* Intent-to-treat population using last observation on study or last observation prior to insulin rescue therapy for patients needing rescue.</td>
</tr>
<tr>
<td colspan="3">
<sup>†</sup> Least squares mean adjusted for baseline value and metformin use at baseline.</td>
</tr>
<tr>
<td colspan="3">
<sup>‡</sup> p-value
<0.0001 compared to placebo + insulin</td>
</tr>
<tr>
<td colspan="3">
<sup>§</sup> p-value <0.05 compared to placebo + insulin</td>
</tr>
</tfoot>
<tbody>
<tr>
<td styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">Hemoglobin A1C (%)</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=300</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=149</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">8.7</td>
<td align="center" styleCode="Lrule Rrule ">8.7</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−0.7</td>
<td align="center" styleCode="Lrule Rrule ">−0.3</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−0.4<sup>‡</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule ">(−0.6, −0.2)</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> Percent
of patients achieving A1C <7%</td>
<td align="center" styleCode="Lrule Rrule Botrule">17% (52/300)</td>
<td align="center" styleCode="Lrule Rrule Botrule">7% (10/149)</td>
</tr>
<tr>
<td styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">Fasting Plasma Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=300</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=149</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">173</td>
<td align="center" styleCode="Lrule Rrule ">173</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−10</td>
<td align="center" styleCode="Lrule Rrule ">−6</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−4
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−13, 5)</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
<tr>
<td styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">2-hour Postprandial Glucose (mg/dL)</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=262</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=129</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">251</td>
<td align="center" styleCode="Lrule Rrule ">255</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from
baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−27</td>
<td align="center" styleCode="Lrule Rrule ">−4</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference
from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−23<sup>§</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule Botrule"> 95%
Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule Botrule">(−37, −9)</td>
<td align="center" styleCode="Lrule Rrule Botrule"> </td>
</tr>
</tbody>
</table>
</text>
</section>
</component>
</section>
</component>
<component>
<section ID="s14.3">
<id root="7fba0490-697c-4dae-a29e-6fde2f1c0796"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.3 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 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 12). 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 ID="i8249d432-f380-443e-8de0-5733504381ec" border="0" cellpadding="2" cellspacing="1" width="100%">
<caption>Table 12: A1C at Week 12 in a Placebo-Controlled Trial of ONGLYZA in Patients with Renal Impairment*</caption>
<colgroup>
<col width="50%"/>
<col width="25%"/>
<col width="25%"/>
</colgroup>
<thead>
<tr>
<th align="left" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Efficacy Parameter</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">ONGLYZA 2.5 mg<br/>N=85</content>
</th>
<th align="center" styleCode="Toprule Lrule Rrule Botrule" valign="top">
<content styleCode="bold">Placebo<br/>N=85</content>
</th>
</tr>
</thead>
<tfoot>
<tr>
<td colspan="3">* Intent-to-treat population using last observation on study.</td>
</tr>
<tr>
<td colspan="3">
<sup>†</sup> Least squares mean adjusted for baseline value.</td>
</tr>
<tr>
<td colspan="3">
<sup>‡</sup> p-value <0.01 compared to placebo</td>
</tr>
</tfoot>
<tbody>
<tr>
<td styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">Hemoglobin A1C (%)</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=81</content>
</td>
<td align="center" styleCode="Toprule Lrule Rrule ">
<content styleCode="bold">N=83</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Baseline (mean)</td>
<td align="center" styleCode="Lrule Rrule ">8.4</td>
<td align="center" styleCode="Lrule Rrule ">8.1</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Change from baseline (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−0.9</td>
<td align="center" styleCode="Lrule Rrule ">−0.4</td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> Difference from placebo (adjusted mean<sup>†</sup>)</td>
<td align="center" styleCode="Lrule Rrule ">−0.4<sup>‡</sup>
</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
<tr>
<td styleCode="Lrule Rrule "> 95% Confidence Interval</td>
<td align="center" styleCode="Lrule Rrule ">(−0.7, −0.1)</td>
<td align="center" styleCode="Lrule Rrule "> </td>
</tr>
</tbody>
</table>
</text>
</section>
</component>
</section>
What is an AstraZeneca authorized person?