14 CLINICAL STUDIES

14.1 Episodic Migraine

The efficacy of QULIPTA for the preventive treatment of episodic migraine in adults was demonstrated in two randomized, multicenter, double-blind, placebo-controlled studies (Study 1 and Study 2). The studies enrolled patients with at least a 1-year history of migraine with or without aura, according to the International Classification of Headache Disorders (ICHD-3) diagnostic criteria.

In Study 1 (NCT03777059), 910 patients were randomized 1:1:1:1 to receive QULIPTA 10 mg (N = 222), QULIPTA 30 mg (N = 230), QULIPTA 60 mg (N = 235), or placebo (N = 223), once daily for 12 weeks. In Study 2 (NCT02848326), 652 patients were randomized 1:2:2:2 to receive QULIPTA 10 mg (N = 94), QULIPTA 30 mg (N = 185), QULIPTA 60 mg (N = 187), or placebo (N = 186), once daily for 12 weeks. In both studies, patients were allowed to use acute headache treatments (i.e., triptans, ergotamine derivatives, NSAIDs, acetaminophen, and opioids) as needed. The use of a concomitant medication that acts on the CGRP pathway was not permitted for either acute or preventive treatment of migraine. The studies excluded patients with myocardial infarction, stroke, or transient ischemic attacks within six months prior to screening.

Study 1

The primary efficacy endpoint was the change from baseline in mean monthly migraine days (MMD) across the 12-week treatment period. Secondary endpoints included the change from baseline in mean monthly headache days, the change from baseline in mean monthly acute medication use days, the proportion of patients achieving at least a 50% reduction from baseline in mean MMD (3-month average), the change from baseline in mean monthly Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) domain scores, the change from baseline in mean monthly AIM-D Physical Impairment (PI) domain scores, across the 12-week treatment period, and the change from baseline at Week 12 for Migraine Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR) domain scores.

The AIM-D evaluates difficulty with performance of daily activities (PDA domain) and physical impairment (PI domain) due to migraine, with scores ranging from 0 to 100. Higher scores indicate greater impact of migraine, and reductions from baseline indicate improvement. The MSQ v2.1 Role Function-Restrictive (RFR) domain score assesses how often migraine impacts function related to daily social and work-related activities over the past 4 weeks, with scores ranging from 0 to 100. Higher scores indicate lesser impact of migraine on daily activities, and increases from baseline indicate improvement.

Patients had a mean age of 42 years (range 18 to 73 years), 89% were female, 83% were White, 14% were Black, and 9% were of Hispanic or Latino ethnicity. The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar across treatment groups. A total of 805 (88%) patients completed the 12-week double-blind study period. Key efficacy results of Study 1 are summarized in Table 3.

Table 3: Efficacy Endpoints in Study 1
	QULIPTA 10 mg N=214	QULIPTA 30 mg N=223	QULIPTA 60 mg N=222	Placebo N=214
Monthly Migraine Days (MMD) across 12 weeks
Baseline	7.5	7.9	7.8	7.5
Mean change from baseline	-3.7	-3.9	-4.2	-2.5
Difference from placebo	-1.2	-1.4	-1.7
p-value	<0.001	<0.001	<0.001
Monthly Headache Days across 12 weeks
Baseline	8.4	8.8	9.0	8.4
Mean change from baseline	-3.9	-4.0	-4.2	-2.5
Difference from placebo	-1.4	-1.5	-1.7
p-value	<0.001	<0.001	<0.001
Monthly Acute Medication Use Days across 12 weeks
Baseline	6.6	6.7	6.9	6.5
Mean change from baseline	-3.7	-3.7	-3.9	-2.4
Difference from placebo	-1.3	-1.3	-1.5
p-value	<0.001	<0.001	<0.001
≥ 50% MMD Responders across 12 weeks
% Responders	56	59	61	29
Difference from placebo (%)	27	30	32
p-value	<0.001	<0.001	<0.001
MSQ v2.1 RFR Domain* at week 12
Baseline	44.9	44.0	46.8	46.8
Mean change from baseline	30.4	30.5	31.3	20.5
Difference from placebo	9.9	10.1	10.8
p-value	<0.001	<0.001	<0.001
AIM-D PDA Domain** across 12 weeks
Baseline	15.5	16.9	15.9	15.2
Mean change from baseline	-7.3	-8.6	-9.4	-6.1
Difference from placebo	-1.2	-2.5	-3.3
p-value	NS†	<0.001	<0.001
AIM-D PI Domain*** across 12 weeks
Baseline	11.7	13.0	11.6	11.2
Mean change from baseline	-5.1	-6.0	-6.5	-4.0
Difference from placebo	-1.1	-2.0	-2.5
p-value	NS†	0.002	<0.001
* Migraine Specific Quality of Life Questionnaire version 2.1 Role Function-Restrictive domain score Activity Impairment in Migraine-Diary Performance of Daily Activities domain score * Activity Impairment in Migraine-Diary Physical Impairment domain score †Not statistically significant (NS)

Figure 1 shows the mean change from baseline in MMD in Study 1. Patients treated with QULIPTA had greater mean decreases from baseline in MMD across the 12-week treatment period compared to patients who received placebo.

Figure 1: Change from Baseline in Monthly Migraine Days in Study 1

Figure 1: Change from Baseline in Monthly Migraine Days in Study 1

Figure 2 shows the distribution of change from baseline in mean MMD across the 12-week treatment period, in 2-day increments, by treatment group. A treatment benefit over placebo for all doses of QULIPTA is seen across a range of mean changes from baseline in MMD.

Figure 2: Distribution of Change from Baseline in Mean Monthly Migraine Days by Treatment Group in Study 1

Figure 2: Distribution of Change from Baseline in Mean Monthly Migraine Days by Treatment Group in Study 1

Study 2

The primary efficacy endpoint was the change from baseline in mean monthly migraine days across the 12-week treatment period.

Patients had a mean age of 40 years (range: 18 to 74 years), 87% were female, 76% were White, 20% were Black, and 15% were of Hispanic or Latino ethnicity. The mean migraine frequency at baseline was approximately 8 migraine days per month. A total of 541 (83%) patients completed the 12-week double-blind study period.

In Study 2, there was a significantly greater reduction in mean monthly migraine days across the 12-week treatment period in all three QULIPTA treatment groups, compared with placebo, as summarized in Table 4.

Table 4: Efficacy Endpoints in Study 2
	QULIPTA 10 mg N=92	QULIPTA 30 mg N=182	QULIPTA 60 mg N=177	Placebo N=178
Monthly Migraine Days (MMD) across 12 weeks
Baseline	7.6	7.6	7.7	7.8
Mean change from baseline	-4.0	-3.8	-3.6	-2.8
Difference from placebo	-1.1	-0.9	-0.7
p-value	0.024	0.039	0.039
Monthly Headache Days across 12 weeks
Baseline	8.9	8.7	8.9	9.1
Mean change from baseline	-4.3	-4.2	-3.9	-2.9
Difference from placebo	-1.4	-1.2	-0.9
p-value	0.024	0.039	0.039

Figure 3 shows the mean change from baseline in MMD in Study 2. Patients treated with QULIPTA had greater mean decreases from baseline in MMD across the 12-week treatment period compared to patients who received placebo.

Figure 3: Change from Baseline in Monthly Migraine Days in Study 2

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Figure 4 shows the distribution of change from baseline in mean MMD across the 12-week treatment period, in 2-day increments, by treatment group. A treatment benefit over placebo for all doses of QULIPTA is seen across a range of mean changes from baseline in MMD.

Figure 4: Distribution of Change from Baseline in Mean Monthly Migraine Days by Treatment Group in Study 2

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14.2 Chronic Migraine

Study 3

The efficacy of QULIPTA for the preventive treatment of chronic migraine in adults was demonstrated in a randomized, multicenter, double-blind, placebo-controlled study (Study 3). The study enrolled patients with at least a 1-year history of chronic migraine, according to the ICHD-3 diagnostic criteria.

Study 3 (NCT03855137) included randomization of patients to QULIPTA 60 mg once daily (N = 262) or placebo (N = 259) for 12 weeks. A subset of patients (11%) was allowed to use one concomitant migraine preventive medication. Patients were allowed to use acute headache treatments (i.e., triptans, ergotamine derivatives, NSAIDs, acetaminophen, and opioids) as needed. Patients with medication overuse headache also were enrolled. The use of a concomitant medication that acts on the CGRP pathway was not permitted for either acute or preventive treatment of migraine. The study excluded patients with myocardial infarction, stroke, or transient ischemic attacks within six months prior to screening.

The primary efficacy endpoint was the change from baseline in mean MMD across the 12-week treatment period. Secondary endpoints included the change from baseline in mean monthly headache days, the change from baseline in mean monthly acute medication use days, the proportion of patients achieving at least a 50% reduction from baseline in mean MMD (3-month average), the change from baseline in mean monthly AIM-D PDA domain scores, the change from baseline in mean monthly AIM-D PI domain scores, across the 12-week treatment period, and the change from baseline at Week 12 for MSQ v2.1 RFR domain scores.

Patients had a mean age of 42 years (range 18 to 74 years), 87% were female, 60% were White, 3% were Black, 36% were Asian, and 4% were of Hispanic or Latino ethnicity. The mean migraine frequency at baseline was approximately 19 migraine days per month and was similar across treatment groups. A total of 463 (89%) of these patients completed the 12-week double-blind study period.

Key efficacy results of Study 3 are summarized in Table 5.

Table 5: Efficacy Endpoints in Study 3
	QULIPTA 60 mg QD N=256	Placebo N=246
Monthly Migraine Days (MMD) across 12 weeks
Baseline	19.2	18.9
Mean change from baseline	-6.9	-5.1
Difference from placebo	-1.8
p-value	<0.001
Monthly Headache Days across 12 weeks
Baseline	21.5	21.4
Mean change from baseline	-7.0	-5.1
Difference from placebo	-1.9
p-value	<0.001
Monthly Acute Medication Use Days across 12 weeks
Baseline	15.5	15.4
Mean change from baseline	-6.2	-4.1
Difference from placebo	-2.1
p-value	<0.001
≥ 50% MMD Responders across 12 weeks
% Responders	41	26
Difference from placebo (%)	15
p-value	<0.001
MSQ v2.1 RFR Domain* at week 12
Baseline	43.4	43.9
Mean change from baseline	23.3	17.2
Difference from placebo	6.2
p-value	<0.001
AIM-D PDA Domain** across 12 weeks
Baseline	31.2	29.5
Mean change from baseline	-12.8	-9.4
Difference from placebo	-3.4
p-value	<0.001
AIM-D PI Domain*** across 12 weeks
Baseline	27.1	25.2
Mean change from baseline	-10.6	-7.9
Difference from placebo	-2.7
p-value	0.003

* Migraine Specific Quality of Life Questionnaire version 2.1 Role Function-Restrictive domain score

** Activity Impairment in Migraine-Diary Performance of Daily Activities domain score

*** Activity Impairment in Migraine-Diary Physical Impairment domain score

Figure 5 shows the mean change from baseline in MMD in Study 3. Patients treated with QULIPTA had greater mean decreases from baseline in MMD across the 12-week treatment period compared to patients who received placebo.

Figure 5: Change from Baseline in Monthly Migraine Days in Study 3

Figure 5: Change from Baseline in Monthly Migraine Days in Study 3

Figure 6 shows the distribution of change from baseline in mean MMD across the 12-week treatment period, in 2-day increments, by treatment group. A treatment benefit of QULIPTA over placebo is seen across a range of mean changes from baseline in MMD.

Figure 6: Distribution of Change from Baseline in Mean Monthly Migraine Days by Treatment Group in Study 3

Figure 6: Distribution of Change from Baseline in Mean Monthly Migraine Days by Treatment Group in Study 3