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<title>14 CLINICAL STUDIES</title>
<text>
<paragraph>The safety and efficacy of BEVESPI AEROSPHERE was evaluated in a clinical development program that included 8 dose-ranging trials and two placebo-controlled lung function trials of 24-weeks duration that included a 28-week extension study to evaluate safety over 1 year. The efficacy of BEVESPI AEROSPHERE is based on the dose ranging trials in 822 subjects with COPD and the 2 placebo-controlled confirmatory trials in 3,705 subjects with COPD.</paragraph>
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<title>14.1 Dose-Ranging Trials</title>
<text>
<paragraph>Dose selection for BEVESPI AEROSPHERE for COPD was primarily based on data for the individual components, glycopyrrolate and formoterol fumarate, in COPD patients. Based on the findings from these studies, glycopyrrolate/formoterol fumarate 18/9.6 mcg administered twice-daily was evaluated in the confirmatory COPD trials. </paragraph>
<paragraph>
<content styleCode="underline">Glycopyrrolate</content>
</paragraph>
<paragraph>Dose selection for glycopyrrolate was supported by a 14-day, randomized, double-blind, placebo-controlled, incomplete-block crossover trial evaluating 6 doses of glycopyrrolate (GP MDI 18 to 0.6 mcg) administered twice daily and an open-label active control in 140 subjects with COPD. A dose ordering was observed, with the glycopyrrolate 18 mcg demonstrating larger improvements in FEV<sub>1</sub> over 12 hours compared with glycopyrrolate 9, 4.6, 2.4, 1.2, and 0.6 mcg (Figure 1).</paragraph>
<paragraph>
<content styleCode="bold">Figure 1 - Mean Change from Baseline in FEV<sub>1</sub> over Time on Day 14 (MITT Population)</content>
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<paragraph>The difference from placebo in change from baseline in trough FEV<sub>1</sub> after 14 days for the 18, 9, 4.6, 2.4, 1.2, and 0.6 mcg doses were 97 mL (95% CI: 45, 149), 88 mL (95% CI: 37, 139), 75 mL (95% CI: 24, 125), 84 mL (95% CI: 33, 135), 76 mL (95% CI: 22, 129), and 37 mL (95% CI: -17, 91), respectively. Two additional dose ranging trials (single-dose and 7-day trials) in subjects with COPD demonstrated minimal additional benefit at doses above 18 mcg of glycopyrrolate. The results supported the selection of 18 mcg of glycopyrrolate twice daily in the confirmatory COPD trials.</paragraph>
<paragraph>Evaluations of the appropriate dosing interval for glycopyrrolate were conducted by comparing to open-label ipratropium bromide inhalation aerosol administered four times daily. The results supported the selection of a twice-daily dosing interval for further evaluation in the confirmatory COPD trials.</paragraph>
<paragraph>
<content styleCode="underline">Formoterol Fumarate</content>
</paragraph>
<paragraph>Dose selection for formoterol fumarate was supported by a single-dose, randomized, double-blind, placebo-controlled, crossover trial evaluating 3 doses of formoterol fumarate (FF MDI 9.6, 4.8, and 2.4 mcg), an open-label active control, and placebo in 34 subjects with COPD. A dose ordering was observed with the formoterol fumarate 9.6 mcg dose demonstrating larger improvements in FEV<sub>1</sub> over 12 hours compared with the lower doses of 4.8 and 2.4 mcg (Figure 2).</paragraph>
<paragraph>
<content styleCode="bold">Figure 2 - Mean Change from Baseline in FEV<sub>1</sub> over Time on Day 1</content>
</paragraph>
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<paragraph>The differences in mean change from baseline in normalized FEV<sub>1</sub> AUC<sub>0-12</sub> for formoterol fumarate 9.6, 4.8, and 2.4 mcg compared to placebo were 176 mL (95% CI: 138, 214), 103 (95% CI: 66, 140), and 81 (95% CI: 45, 118), respectively. These results provided support for the selection of 9.6 mcg of formoterol fumarate twice daily in the confirmatory COPD trials.</paragraph>
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<text>Figure 1 - Mean Change from Baseline in FEV1 over Time on Day 14 (MITT Population)</text>
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<text>Figure 2 - Mean Change from Baseline in FEV1 over Time on Day 1</text>
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<title>14.2 Confirmatory Trials</title>
<text>
<paragraph>The clinical development program for BEVESPI AEROSPHERE included two (Trial 1 and Trial 2) 24-week, randomized, double-blind, placebo-controlled, parallel-group trials in subjects with moderate to very severe COPD designed to evaluate the efficacy of BEVESPI AEROSPHERE on lung function. The 24-week trials included 3,699 subjects that had a clinical diagnosis of COPD, were between 40 and 80 years of age, had a history of smoking greater than or equal to 10 pack-years, had a post-albuterol FEV<sub>1</sub> less than 80% of predicted normal values, and had a ratio of FEV<sub>1</sub>/FVC of less than 0.7. The majority of patients were male (56%) and Caucasian (91%) with a mean age of 63 years and an average smoking history of 51 pack-years (54% current smokers). During screening, mean post-bronchodilator percent predicted FEV<sub>1</sub> was 51% (range: 19% to 82%) and mean percent reversibility was 20% (range: -32% to 135%).</paragraph>
<paragraph>Trial 1 and Trial 2 evaluated BEVESPI AEROSPHERE (glycopyrrolate/formoterol fumarate) 18 mcg/9.6 mcg, glycopyrrolate 18 mcg, formoterol fumarate 9.6 mcg, and placebo administered twice daily (BID). Trial 1 also included an open-label active control. The primary endpoint was change from baseline in trough FEV<sub>1</sub> at Week 24 compared with placebo, glycopyrrolate 18 mcg BID, and formoterol fumarate 9.6 mcg BID. The comparison of BEVESPI AEROSPHERE with glycopyrrolate 18 mcg and formoterol fumarate 9.6 mcg was assessed to evaluate the contribution of the individual components to BEVESPI AEROSPHERE. In both trials, BEVESPI AEROSPHERE demonstrated a larger increase in mean change from baseline in trough FEV<sub>1</sub> at Week 24 relative to placebo, glycopyrrolate 18 mcg, and formoterol fumarate 9.6 mcg (Table 2). </paragraph>
<paragraph>
<content styleCode="bold">Table 2 – Least Square (LS) Mean Change from Baseline in Morning Pre-dose Trough</content>
<br/>
<content styleCode="bold">FEV<sub>1</sub> (mL) at Week 24 in Trial 1 and Trial 2 (Intent-to-Treat Population)</content>
</paragraph>
<table width="100%">
<col width="21%"/>
<col width="9%"/>
<col width="23%"/>
<col width="23%"/>
<col width="25%"/>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="bottom"/>
<td styleCode="Rrule Lrule Toprule " valign="bottom"/>
<td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Trough FEV<sub>1</sub> (mL) at Week 24</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule " valign="top"/>
<td styleCode="Rrule Lrule " valign="top"/>
<td align="center" colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">Difference from</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">Treatment</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">N</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">Placebo</content>
<footnote ID="_Ref9314194">The placebo, glycopyrrolate and formoterol fumarate comparators used the same inhaler and excipients as BEVESPI AEROSPHERE.</footnote>
<br/>
<content styleCode="bold">LS Mean</content>
<br/>
<content styleCode="bold">(95% CI)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">Glycopyrrolate </content>
<br/>
<content styleCode="bold">18 mcg BID</content>
<footnoteRef IDREF="_Ref9314194"/>
<br/>
<content styleCode="bold">LS Mean</content>
<br/>
<content styleCode="bold">(95% CI)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">Formoterol Fumarate </content>
<br/>
<content styleCode="bold">9.6 mcg BID</content>
<footnoteRef IDREF="_Ref9314194"/>
<br/>
<content styleCode="bold">LS Mean</content>
<br/>
<content styleCode="bold">(95% CI)</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">Trial 1</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>BEVESPI AEROSPHERE </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>429</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>N=161<br/> <br/>150 mL<br/>(114, 186)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>N=344<br/> <br/>59 mL<br/>(31, 88)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>N=367<br/> <br/>64 mL<br/>(36, 92)</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>
<content styleCode="bold">Trial 2</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>BEVESPI<br/>AEROSPHERE</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>433</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom">
<paragraph>N=170<br/> <br/>103 mL<br/>(67, 140)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>N=367<br/> <br/>54 mL<br/>(25, 83)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>N=350<br/> <br/>56 mL<br/>(27, 85)</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Toprule " valign="top">
<paragraph>N = Number in the intent to treat population</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>With the limited data available, there were consistent improvements in trough FEV<sub>1</sub> with respect to age, sex, degree of airflow limitation, GOLD stage, smoking status, or inhaled corticosteroid use.</paragraph>
<paragraph>In Trials 1 and 2, serial spirometric evaluations were performed throughout the 12-hour dosing interval in a subset of subjects (n=718 and n=585, respectively) at Day 1 and Week 12. Results from Trial 1 are shown in Figure 3. In Trial 2, the results for BEVESPI AEROSPHERE in FEV<sub>1</sub> AUC<sub>0-12h </sub>were similar to those observed in Trial 1.</paragraph>
<paragraph>
<content styleCode="bold">Figure 3 - Mean Change from Baseline in FEV<sub>1</sub> over Time at Day 1 and Week 12 (Trial 1) </content>
</paragraph>
<paragraph>
<content styleCode="bold">Day 1</content>
</paragraph>
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<paragraph>
<content styleCode="bold">Week 12</content>
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<paragraph>In both trials, peak FEV<sub>1</sub> was defined as the maximum FEV<sub>1</sub> recorded within 2 hours after the dose of trial medication. The mean peak FEV<sub>1</sub> improvement from baseline with BEVESPI AEROSPHERE compared with placebo at Week 24 was 291 mL (95% CI: 252, 331) and 267 mL (95% CI: 226, 308) in Trial 1 and Trial 2, respectively. BEVESPI AEROSPHERE demonstrated an onset of bronchodilatory treatment effect at 5 minutes after the first dose based on a mean increase in FEV<sub>1</sub> compared to placebo of 187 mL (95% CI: 168, 205) and 186 mL (95% CI: 164, 207) in Trial 1 and Trial 2, respectively. In both Trial 1 and 2, subjects treated with BEVESPI AEROSPHERE used less daily rescue albuterol compared to subjects treated with placebo.</paragraph>
<paragraph>The St. George’s Respiratory Questionnaire (SGRQ) was assessed in Trials 1 and 2. In Trial 1, the SGRQ responder rate (defined as an improvement in score of 4 or more as threshold) was 37%, 30%, 35%, and 28% for BEVESPI AEROSPHERE, glycopyrrolate, formoterol fumarate, and placebo, respectively, with odds ratios of 1.4 (95% CI: 1.1, 1.8), 1.1 (95% CI: 0.9, 1.5), and 1.5 (95% CI: 1.1, 2.1), for BEVESPI AEROSPHERE vs. glycopyrrolate, BEVESPI AEROSPHERE vs. formoterol fumarate, and BEVESPI AEROSPHERE vs. placebo, respectively. In Trial 2, the trends were similar, with odds ratios of 1.2 (95% CI: 0.9, 1.6), 1.3 (95% CI: 1.0, 1.7), and 1.3 (95% CI: 0.9, 1.8), for BEVESPI AEROSPHERE vs. glycopyrrolate, BEVESPI AEROSPHERE vs. formoterol fumarate, and BEVESPI AEROSPHERE vs. placebo, respectively.</paragraph>
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<text>Figure 3 - Mean Change from Baseline in FEV1 over Time at Day 1 and Week 12 (Trial 1) Day 1 </text>
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<text>Week 12</text>
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