<?xml version="1.0" encoding="UTF-8"?><section ID="ID_87f36f0e-09d0-4356-8575-7cd6a0114a6a">
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<code code="34092-7" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL STUDIES SECTION"/>
<title>14 CLINICAL STUDIES </title>
<text>
<paragraph>
<content styleCode="underline">Primary Prevention of CV Disease</content>
</paragraph>
<paragraph>In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of CRESTOR on the occurrence of major CV disease events was assessed in 17,802 males (≥50 years) and females (≥60 years) who had no clinically evident CV disease, LDL‑C levels <130 mg/dL and hsCRP levels ≥2 mg/L. The study population had an estimated baseline coronary heart disease risk of 11.6% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL‑C levels (23%), cigarette smoking (16%), or a family history of premature CHD (12%). Patients had a median baseline LDL‑C of 108 mg/dL and hsCRP of 4.3 mg/L. Patients were randomly assigned to placebo (n=8901) or CRESTOR 20 mg once daily (n=8901) and were followed for a mean duration of 2 years. The JUPITER study was stopped early by the Data Safety Monitoring Board due to meeting predefined stopping rules for efficacy in CRESTOR-treated subjects.</paragraph>
<paragraph>The primary end point was a composite end point consisting of the time-to-first occurrence of any of the following major CV events: CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina or an arterial revascularization procedure.</paragraph>
<paragraph>CRESTOR significantly reduced the risk of major CV events (252 events in the placebo group vs. 142 events in the rosuvastatin group) with a statistically significant (p<0.001) relative risk reduction of 44% and absolute risk reduction of 1.2% (see Figure 1). The risk reduction for the primary end point was consistent across the following predefined subgroups: age, sex, race, smoking status, family history of premature CHD, body mass index, LDL‑C, HDL‑C, and hsCRP levels.</paragraph>
<paragraph>
<content styleCode="bold">Figure 1. Time to First Occurrence of Major CV Events in JUPITER</content>
</paragraph>
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<paragraph>The individual components of the primary end point are presented in Figure 3. CRESTOR significantly reduced the risk of nonfatal myocardial infarction, nonfatal stroke, and arterial revascularization procedures. There were no significant treatment differences between the CRESTOR and placebo groups for death due to CV causes or hospitalizations for unstable angina.</paragraph>
<paragraph>CRESTOR significantly reduced the risk of myocardial infarction (6 fatal events and 62 nonfatal events in placebo-treated subjects vs. 9 fatal events and 22 nonfatal events in CRESTOR-treated subjects) and the risk of stroke (6 fatal events and 58 nonfatal events in placebo-treated subjects vs. 3 fatal events and 30 nonfatal events in CRESTOR-treated subjects).</paragraph>
<paragraph>In a post-hoc subgroup analysis of JUPITER subjects (rosuvastatin=725, placebo=680) with a hsCRP ≥2 mg/L and no other traditional risk factors (smoking, BP ≥140/90 or taking antihypertensives, low HDL‑C) other than age, after adjustment for high HDL‑C, there was no significant treatment benefit with CRESTOR treatment.</paragraph>
<paragraph>
<content styleCode="bold">Figure 2. Major CV Events by Treatment Group in JUPITER</content>
</paragraph>
<renderMultiMedia ID="id814838945" referencedObject="C08F9F32-FA39-48D7-9DFC-AD8CE87FE051"/>
<paragraph>At one year, CRESTOR increased HDL‑C and reduced LDL‑C, hsCRP, total cholesterol and serum triglyceride levels (p<0.001 for all versus placebo).</paragraph>
<paragraph>
<content styleCode="underline">Primary Hyperlipidemia in Adults</content>
</paragraph>
<paragraph>CRESTOR reduces Total‑C, LDL‑C, ApoB, non‑HDL‑C, and TG, and increases HDL‑C, in adult patients with hyperlipidemia and mixed dyslipidemia.</paragraph>
<paragraph>In a multicenter, double‑blind, placebo‑controlled study in patients with hyperlipidemia, CRESTOR given as a single daily dose (5 to 40 mg) for 6 weeks significantly reduced Total‑C, LDL‑C, non‑HDL‑C, and ApoB, across the dose range (Table 10).</paragraph>
<table ID="_RefID0E3WBI" width="100%">
<caption>Table 10: Lipid-Modifying Effect of CRESTOR in Adult Patients with Hyperlipidemia (Adjusted Mean % Change from Baseline at Week 6)</caption>
<col width="29%"/>
<col width="7%"/>
<col width="12%"/>
<col width="11%"/>
<col width="16%"/>
<col width="8%"/>
<col width="7%"/>
<col width="11%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Dose</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">N</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Total</content>‑<content styleCode="bold">C</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">LDL</content>‑<content styleCode="bold">C</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Non-HDL</content>‑<content styleCode="bold">C</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">ApoB</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">TG</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">HDL</content>‑<content styleCode="bold">C</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Placebo</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>13</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>CRESTOR 5 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-33</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-45</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-44</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-38</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-35</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>13</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>CRESTOR 10 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-36</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-52</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-48</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-42</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-10</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>14</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>CRESTOR 20 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>17</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-40</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-55</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-51</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-46</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-23</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>8</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>CRESTOR 40 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>18</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-46</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-63</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-60</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-54</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-28</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>10</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>CRESTOR was compared with the statins (atorvastatin, simvastatin, and pravastatin) in a multicenter, open-label, dose‑ranging study of 2,240 patients with hyperlipidemia or mixed dyslipidemia. After randomization, patients were treated for 6 weeks with a single daily dose of either CRESTOR, atorvastatin, simvastatin, or pravastatin (see Figure 3 and Table 11).</paragraph>
<paragraph>
<content styleCode="bold">Figure 3. Percent LDL</content>‑<content styleCode="bold">C Change by Dose of CRESTOR, Atorvastatin, Simvastatin, and Pravastatin at Week 6 in Adult Patients with Hyperlipidemia or Mixed Dyslipidemia</content>
</paragraph>
<renderMultiMedia ID="id-115150869" referencedObject="B08BB823-9C9F-4769-991F-6EAFB0B85894"/>
<paragraph>Box plots are a representation of the 25th, 50th, and 75th percentile values, with whiskers representing the 10th and 90th percentile values. Mean baseline LDL‑C: 189 mg/dL.</paragraph>
<table ID="_RefID0EHACI" width="100%">
<caption>Table 11: Percent Change in LDL-C by Dose of CRESTOR, Atorvastatin, Simvastatin, and Pravastatin From Baseline to Week 6 (LS Mean<footnote ID="_Ref119925405">Corresponding standard errors are approximately 1.00.</footnote>) in Adult Patients with Hyperlipidemia or Mixed Dyslipidemia (Sample Sizes Ranging from 156–167 Patients Per Group)</caption>
<col width="28%"/>
<col width="18%"/>
<col width="18%"/>
<col width="18%"/>
<col width="18%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<td colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Treatment Daily Dose</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Treatment</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">10 mg</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">20 mg</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">40 mg</content>
</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">80 mg</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>CRESTOR</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-46<footnote ID="_Ref119925449">CRESTOR 10 mg reduced LDL-C significantly more than atorvastatin 10 mg; pravastatin 10 mg, 20 mg, and 40 mg; simvastatin 10 mg, 20 mg, and 40 mg. (p<0.002)</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-52<footnote ID="_Ref119925479">CRESTOR 20 mg reduced LDL-C significantly more than atorvastatin 20 mg and 40 mg; pravastatin 20 mg and 40 mg; simvastatin 20 mg, 40 mg, and 80 mg. (p<0.002)</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-55<footnote ID="_Ref119925490">CRESTOR 40 mg reduced LDL‑C significantly more than atorvastatin 40 mg; pravastatin 40 mg; simvastatin 40 mg, and 80 mg. (p<0.002)</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>---</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Atorvastatin</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-37</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-43</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-48</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-51</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Simvastatin</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-28</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-35</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-39</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-46</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>Pravastatin</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-20</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-24</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-30</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>---</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="underline">Slowing of the Progression of Atherosclerosis</content>
</paragraph>
<paragraph>In the <content styleCode="italics">Measuring Effects on Intima Media Thickness: an Evaluation Of Rosuvastatin 40 mg (METEOR</content>) study, the effect of therapy with CRESTOR on carotid atherosclerosis was assessed by B-mode ultrasonography in patients with elevated LDL‑C, at low risk (Framingham risk <10% over ten years) for symptomatic coronary artery disease and with subclinical atherosclerosis as evidenced by carotid intimal-medial thickness (cIMT). In this double-blind, placebo-controlled clinical study 984 adult patients were randomized (of whom 876 were analyzed) in a 5:2 ratio to CRESTOR 40 mg or placebo once daily. Ultrasonograms of the carotid walls were used to determine the annualized rate of change per patient from baseline to two years in mean maximum cIMT of 12 measured segments. The estimated difference in the rate of change in the maximum cIMT analyzed over all 12 carotid artery sites between patients treated with CRESTOR and placebo-treated patients was -0.0145 mm/year (95% CI –0.0196, –0.0093; p<0.0001).</paragraph>
<paragraph>The annualized rate of change from baseline for the placebo group was +0.0131 mm/year (p<0.0001). The annualized rate of change from baseline for the group treated with CRESTOR was -0.0014 mm/year (p=0.32).</paragraph>
<paragraph>At an individual patient level in the group treated with CRESTOR, 52.1% of patients demonstrated an absence of disease progression (defined as a negative annualized rate of change), compared to 37.7% of patients in the placebo group.</paragraph>
<paragraph>
<content styleCode="underline">HeFH in Adults</content>
</paragraph>
<paragraph>In a study of adult patients with HeFH (baseline mean LDL of 291 mg/dL), patients were randomized to CRESTOR 20 mg or atorvastatin 20 mg. The dose was increased at 6-week intervals. Significant LDL-C reductions from baseline were seen at each dose in both treatment groups (see Table 12).</paragraph>
<table ID="_RefID0ETFCI" width="100%">
<caption>Table 12: LDL-C Percent Change from Baseline</caption>
<col width="17%"/>
<col width="13%"/>
<col width="33%"/>
<col width="37%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">CRESTOR (n=435)</content>
<br/>
<content styleCode="bold">LS Mean</content>
<footnote ID="_Ref119925756">LS Means are least square means adjusted for baseline LDL-C</footnote>
<content styleCode="bold"> (95% CI)</content>
</th>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Atorvastatin (n=187)</content>
<br/>
<content styleCode="bold"> LS Mean<content styleCode="italics">
<sup>1</sup>
</content> (95% CI)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Week 6</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-47% (-49%, -46%)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-38% (-40%, -36%)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Week 12</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>40 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-55% (-57%, -54%)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-47% (-49%, -45%)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>Week 18</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>80 mg</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>NA</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-52% (-54%, -50%)</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="underline">HeFH in Pediatric Patients</content>
</paragraph>
<paragraph>In a double-blind, randomized, multicenter, placebo-controlled, 12-week study, 176 (97 male and 79 female) pediatric patients with HeFH were randomized to rosuvastatin 5 mg, 10 mg or 20 mg or placebo daily. Patients ranged in age from 10 to 17 years (median age of 14 years) with approximately 30% of the patients 10 to 13 years and approximately 17%, 18%, 40%, and 25% at Tanner stages II, III, IV, and V, respectively. Females were at least 1-year postmenarche. Mean LDL-C at baseline was 233 mg/dL (range of 129 to 399). The 12-week double-blind phase was followed by a 40-week open-label dose-titration phase, where all patients (n=173) received 5 mg, 10 mg or 20 mg rosuvastatin daily.</paragraph>
<paragraph>Rosuvastatin significantly reduced LDL-C (primary end point), total cholesterol and ApoB levels at each dose compared to placebo. Results are shown in Table 13 below.</paragraph>
<table ID="_RefID0E6ICI" width="100%">
<caption>Table 13: Lipid-Modifying Effects of CRESTOR in Pediatric Patients 10 to 17 years of Age with HeFH (Least-Squares Mean Percent Change from Baseline To Week 12)</caption>
<col width="20%"/>
<col width="13%"/>
<col width="15%"/>
<col width="13%"/>
<col width="13%"/>
<col width="11%"/>
<col width="15%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Dose (mg)</content>
</th>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">N</content>
</th>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">LDL</content>‑<content styleCode="bold">C</content>
</th>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">HDL</content>‑<content styleCode="bold">C</content>
</th>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Total</content>‑<content styleCode="bold">C</content>
</th>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">TG</content>
<footnote ID="_Ref119926127">Median percent change</footnote>
</th>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">ApoB</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Placebo</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>46</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-1%</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>+7%</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0%</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-7%</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-2%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>5</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>42</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-38%</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>+4%<footnote ID="_Ref119926193">Difference from placebo not statistically significant</footnote>
</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-30%</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-13%<footnoteRef IDREF="_Ref119926193"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-32%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>10</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>44</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-45%</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>+11%<footnoteRef IDREF="_Ref119926193"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-34%</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-15%<footnoteRef IDREF="_Ref119926193"/>
</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-38%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>20</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>44</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-50%</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>+9%<footnoteRef IDREF="_Ref119926193"/>
</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-39%</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>16%<footnoteRef IDREF="_Ref119926193"/>
</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-41%</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Rosuvastatin was also studied in a two-year open‑label, uncontrolled, titration-to-goal trial that included 175 pediatric patients with HeFH who were 8 to 17 years old (79 males and 96 females). All patients had a documented genetic defect in the LDL receptor or in ApoB. Approximately 89% were White, 7% were Asian, 1% were Black or African American, and fewer than 1% were Hispanic or Latino ethnicity. Mean LDL-C at baseline was 236 mg/dL. Fifty-eight (33%) patients were prepubertal at baseline. The starting rosuvastatin dosage for all pediatric patients was 5 mg once daily. Pediatric patients aged 8 to less than 10 years (n=41 at baseline) could titrate to a maximum dosage of 10 mg once daily, and pediatric patients aged 10 to 17 years could titrate to a maximum dosage of 20 mg once daily.</paragraph>
<paragraph>The reductions in LDL‑C from baseline were generally consistent across age groups within the trial as well as with previous experience in both adult and pediatric controlled trials.</paragraph>
<paragraph>
<content styleCode="underline">HoFH in Adult and Pediatric Patients</content>
</paragraph>
<paragraph>In an open-label, forced-titration study, HoFH patients (n=40, 8‑63 years) were evaluated for their response to CRESTOR 20 to 40 mg titrated at a 6‑week interval. In the overall population, the mean LDL‑C reduction from baseline was 22%. About one-third of the patients benefited from increasing their dose from 20 mg to 40 mg with further LDL‑C lowering of greater than 6%. In the 27 patients with at least a 15% reduction in LDL‑C, the mean LDL‑C reduction was 30% (median 28% reduction). Among 13 patients with an LDL‑C reduction of <15%, 3 had no change or an increase in LDL‑C. Reductions in LDL‑C of 15% or greater were observed in 3 of 5 patients with known receptor negative status.</paragraph>
<paragraph>
<content styleCode="underline">HoFH in Pediatric Patients</content>
</paragraph>
<paragraph>CRESTOR was studied in a randomized, double-blind, placebo-controlled, multicenter, cross-over study in 14 pediatric patients with HoFH. The study included a 4‑week dietary lead‑in phase during which patients received CRESTOR 10 mg daily, a cross‑over phase that included two 6‑week treatment periods with either CRESTOR 20 mg or placebo in random order, followed by a 12‑week open‑label phase during which all patients received CRESTOR 20 mg. Patients ranged in age from 7 to 15 years of age (median 11 years), 50% were male, 71% were White, 21% were Asian, 7% were Black or African American, and no patients were of Hispanic or Latino ethnicity. Fifty percent were on apheresis therapy and 57% were taking ezetimibe. Patients who entered the study on apheresis therapy or ezetimibe continued the treatment throughout the entire study. Mean LDL-C at baseline was 416 mg/dL (range 152 to 716 mg/dL). A total of 13 patients completed both treatment periods of the randomized cross-over phase; one patient withdrew consent due to inability to have blood drawn during the cross-over phase.</paragraph>
<paragraph>CRESTOR 20 mg significantly reduced LDL-C, total cholesterol, ApoB, and non-HDL-C compared to placebo (see Table 14).</paragraph>
<table ID="_RefID0EBRCI" width="100%">
<caption>Table 14: Lipid-Modifying Effects of CRESTOR in Pediatric Patients 7 to 15 years of Age with HoFH After 6 Weeks</caption>
<col width="24%"/>
<col width="17%"/>
<col width="24%"/>
<col width="36%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>
<content styleCode="bold">Placebo</content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=13)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>
<content styleCode="bold">CRESTOR 20 mg</content>
</paragraph>
<paragraph>
<content styleCode="bold">(N=13)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Percent difference (95% CI)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>LDL-C (mg/dL)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>481</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>396</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-22.3% (-33.5, -9.1)<footnote ID="_Ref119927054">p=0.005</footnote>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Total-C (mg/dL)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>539</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>448</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-20.1% (-29.7, -9.1)<footnote ID="_Ref119927063">p=0.003</footnote>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Non-HDL-C (mg/dL)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>505</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>412</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>-22.9% (-33.7, ‑10.3)<footnoteRef IDREF="_Ref119927063"/>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>ApoB (mg/dL)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>268</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>235</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-17.1% (-29.2, -2.9)<footnote ID="_Ref119927098"> p=0.024</footnote>
</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Botrule " valign="top">
<paragraph>% Difference estimates are based on transformations of the estimated mean difference in log LDL measurements between CRESTOR and placebo using a mixed model adjusted for study period.</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="underline">Primary Dysbetalipoproteinemia in Adults</content>
</paragraph>
<paragraph>In a randomized, multicenter, double-blind crossover-study, 32 adult patients (27 with є2/є2 and 4 with apo E mutation [Arg145Cys] with primary dysbetalipoproteinemia entered a 6‑week dietary lead-in period on the NCEP Therapeutic Lifestyle Change (TLC) diet. Following dietary lead-in, patients were randomized to a sequence of treatments for 6 weeks each: rosuvastatin 10 mg followed by rosuvastatin 20 mg or rosuvastatin 20 mg followed by rosuvastatin 10 mg. CRESTOR reduced non-HDL‑C (primary end point) and circulating remnant lipoprotein levels. Results are shown in the table below.</paragraph>
<table ID="_RefID0EYVCI" width="100%">
<caption>Table 15: Lipid-Modifying Effects of CRESTOR 10 mg and 20 mg in Adult Patients with Primary Dysbetalipoproteinemia (Type III hyperlipoproteinemia) After Six Weeks by Median Percent Change (95% CI) from Baseline (N=32)</caption>
<col width="22%"/>
<col width="15%"/>
<col width="30%"/>
<col width="33%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Median at Baseline (mg/dL)</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Median percent change from baseline (95% CI)</content>
<br/>
<content styleCode="bold">CRESTOR 10 mg</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Median percent change from baseline (95% CI)</content>
<br/>
<content styleCode="bold">CRESTOR 20 mg</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Total‑C</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>342.5</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-43.3</paragraph>
<paragraph>(-46.9, - 37.5)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-47.6</paragraph>
<paragraph>(-51.6,-42.8)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Triglycerides</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>503.5</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-40.1</paragraph>
<paragraph>(-44.9, -33.6)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-43.0</paragraph>
<paragraph>(-52.5, -33.1)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Non-HDL‑C</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>294.5</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-48.2</paragraph>
<paragraph>(-56.7, -45.6)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-56.4</paragraph>
<paragraph>(-61.4, -48.5)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>VLDL‑C + IDL‑C</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>209.5</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-46.8</paragraph>
<paragraph>(-53.7, -39.4)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-56.2</paragraph>
<paragraph>(-67.7, -43.7)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>LDL‑C</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>112.5</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-54.4</paragraph>
<paragraph>(-59.1, -47.3)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-57.3</paragraph>
<paragraph>(-59.4, -52.1)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>HDL‑C</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>35.5</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>10.2</paragraph>
<paragraph>(1.9, 12.3)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>11.2</paragraph>
<paragraph>(8.3, 20.5)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>RLP‑C</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>82.0</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-56.4</paragraph>
<paragraph>(-67.1, -49.0)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-64.9</paragraph>
<paragraph>(-74.0, -56.6)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>Apo‑E</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>16.0</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-42.9</paragraph>
<paragraph>(-46.3, -33.3)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-42.5</paragraph>
<paragraph>(-47.1, -35.6)</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="underline">Hypertriglyceridemia in Adults</content>
</paragraph>
<paragraph>In a double-blind, placebo-controlled study in adult patients with baseline TG levels from 273 to 817 mg/dL, CRESTOR given as a single daily dose (5 to 40 mg) over 6 weeks significantly reduced serum TG levels (Table 16).</paragraph>
<table ID="_RefID0EN4CI" width="100%">
<caption>Table 16: Lipid-Modifying Effect of CRESTOR in Adult Patients with Primary Hypertriglyceridemia After Six Weeks by Median (Min, Max) Percent Change from Baseline to Week 6</caption>
<col width="16%"/>
<col width="14%"/>
<col width="15%"/>
<col width="17%"/>
<col width="19%"/>
<col width="19%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Dose</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Placebo </content>
<br/>
<content styleCode="bold">(n=26)</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">CRESTOR </content>
<br/>
<content styleCode="bold">5 mg</content>
<br/>
<content styleCode="bold">(n=25)</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">CRESTOR </content>
<br/>
<content styleCode="bold">10 mg </content>
<br/>
<content styleCode="bold">(n=23)</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">CRESTOR </content>
<br/>
<content styleCode="bold">20 mg </content>
<br/>
<content styleCode="bold">(n=27)</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">CRESTOR </content>
<br/>
<content styleCode="bold">40 mg </content>
<br/>
<content styleCode="bold">(n=25)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>Triglycerides</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1 (-40, 72)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-21 (-58, 38)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-37 (-65, 5)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-37 (-72, 11)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-43 (-80, -7)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Non-HDL-C</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>2 (-13, 19)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-29 (-43, -8)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-49 (-59, -20)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-43 (-74, 12)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-51 (-62, -6)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Total-C</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1 (-13, 17)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-24 (-40, -4)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-40 (-51, -14)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-34 (-61, -11)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-40 (-51, -4)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>LDL-C</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>5 (-30, 52)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-28 (-71, 2)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-45 (-59, 7)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-31 (-66, 34)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-43 (-61, -3)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>HDL-C</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-3 (-25, 18)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>3 (-38, 33)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>8 (-8, 24)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>22 (-5, 50)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>17 (-14, 63)</paragraph>
</td>
</tr>
</tbody>
</table>
</text>
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