14 CLINICAL STUDIES

14.1 Migraine

The efficacy of EMGALITY was evaluated as a preventive treatment of episodic or chronic migraine in three multicenter, randomized, double-blind, placebo-controlled studies: two 6-month studies in patients with episodic migraine (Studies 1 and 2) and one 3-month study in patients with chronic migraine (Study 3).

Episodic Migraine

Study 1 (NCT02614183) and Study 2 (NCT02614196) included adults with a history of episodic migraine (4 to 14 migraine days per month). All patients were randomized in a 1:1:2 ratio to receive once-monthly subcutaneous injections of EMGALITY 120 mg, EMGALITY 240 mg, or placebo. All patients in the 120 mg EMGALITY group received an initial 240 mg loading dose. Patients were allowed to use acute headache treatments, including migraine-specific medications (i.e., triptans, ergotamine derivatives), NSAIDs, and acetaminophen during the study.

The studies excluded patients on any other migraine preventive treatment, patients with medication overuse headache, patients with ECG abnormalities compatible with an acute cardiovascular event and patients with a history of stroke, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening.

The primary efficacy endpoint for Studies 1 and 2 was the mean change from baseline in the number of monthly migraine headache days over the 6-month treatment period. Key secondary endpoints included response rates (the mean percentages of patients reaching at least 50%, 75%, and 100% reduction from baseline in the number of monthly migraine headache days over the 6-month treatment period), the mean change from baseline in the number of monthly migraine headache days with use of any acute headache medication during the 6-month treatment period, and the impact of migraine on daily activities, as assessed by the mean change from baseline in the average Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive domain score during the last 3 months of treatment (Months 4 to 6). Scores are scaled from 0 to 100, with higher scores indicating less impact of migraine on daily activities.

In Study 1, a total of 858 patients (718 females, 140 males) ranging in age from 18 to 65 years, were randomized. A total of 703 patients completed the 6-month double-blind phase. In Study 2, a total of 915 patients (781 female, 134 male) ranging in age from 18 to 65 years, were randomized. A total of 785 patients completed the 6-month double-blind phase. In Study 1 and Study 2, the mean migraine frequency at baseline was approximately 9 migraine days per month, and was similar across treatment groups.

EMGALITY 120 mg demonstrated statistically significant improvements for efficacy endpoints compared to placebo over the 6-month period, as summarized in Table 2. EMGALITY treatment with the 240 mg once-monthly dose showed no additional benefit over the EMGALITY 120 mg once-monthly dose.

Table 2: Efficacy Endpoints in Studies 1 and 2
a p<0.001
b N = 189 for EMGALITY 120 mg and N = 377 for placebo in Study 1; N = 213 for EMGALITY 120 mg and N = 396 for placebo in Study 2.
	Study 1		Study 2
	EMGALITY 120 mg N = 210	Placebo N = 425	EMGALITY 120 mg N = 226	Placebo N = 450
Monthly Migraine Headache Days (over Months 1 to 6)
Baseline migraine headache days	9.2	9.1	9.1	9.2
Mean change from baseline	-4.7	-2.8	-4.3	-2.3
Difference from placeboa	-1.9		-2.0
≥50% Migraine Headache Days Responders (over Months 1 to 6)
% Respondersa	62%	39%	59%	36%
≥75% Migraine Headache Days Responders (over Months 1 to 6)
% Respondersa	39%	19%	34%	18%
100% Migraine Headache Days Responders (over Months 1 to 6)
% Respondersa	16%	6%	12%	6%
Monthly Migraine Headache Days that Acute Medication was Taken (over Months 1 to 6)
Mean change from baseline (days)a	-4.0	-2.2	-3.7	-1.9
MSQ Role Function-Restrictive Domain Score (over Months 4 to 6)
Baseline	51.4	52.9	52.5	51.4
Mean change from baselineb	32.4	24.7	28.5	19.7
Difference from placeboa	7.7		8.8

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

a Least-square means and 95% confidence intervals are presented.

Figure 2: Change from Baseline in Monthly Migraine Headache Days in Study 2a

a Least-square means and 95% confidence intervals are presented.

Figure 3 shows the distribution of change from baseline in the mean number of monthly migraine headache days in bins of 2 days, by treatment group, in Study 1. A treatment benefit over placebo for EMGALITY is seen across a range of changes from baseline in monthly migraine headache days.

Figure 3: Distribution of Change from Baseline in Mean Monthly Migraine Headache Days over Months 1 to 6 by Treatment Group in Study 1

Figure 4 shows the distribution of change from baseline in the mean number of monthly migraine headache days in bins of 2 days, by treatment group, in Study 2. A treatment benefit over placebo for EMGALITY is seen across a range of changes from baseline in monthly migraine headache days.

Figure 4: Distribution of Change from Baseline in Mean Monthly Migraine Headache Days over Months 1 to 6 by Treatment Group in Study 2

Chronic Migraine

Study 3 (NCT02614261) included adults with a history of chronic migraine (≥15 headache days per month with ≥8 migraine days per month). All patients were randomized in a 1:1:2 ratio to receive once-monthly subcutaneous injections of EMGALITY 120 mg, EMGALITY 240 mg, or placebo over a 3-month treatment period. All patients in the 120 mg EMGALITY group received an initial 240 mg loading dose.

Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives), NSAIDs, and acetaminophen. A subset of patients (15%) was allowed to use one concomitant migraine preventive medication. Patients with medication overuse headache were allowed to enroll.

The study excluded patients with ECG abnormalities compatible with an acute cardiovascular event, and patients with a history of stroke, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening.

The primary endpoint was the mean change from baseline in the number of monthly migraine headache days over the 3-month treatment period. The secondary endpoints were response rates (the mean percentages of patients reaching at least 50%, 75% and 100% reduction from baseline in the number of monthly migraine headache days over the 3-month treatment period), the mean change from baseline in the number of monthly migraine headache days with use of any acute headache medication during the 3-month treatment period, and the impact of migraine on daily activities as assessed by the mean change from baseline in the MSQ v2.1 Role Function-Restrictive domain score at Month 3. Scores are scaled from 0 to 100, with higher scores indicating less impact of migraine on daily activities.

In Study 3, a total of 1113 patients (946 female, 167 male) ranging in age from 18 to 65 years, were randomized. A total of 1037 patients completed the 3-month double-blind phase. The mean number of monthly migraine headache days at baseline was approximately 19.

EMGALITY 120 mg demonstrated statistically significant improvement for the mean change from baseline in the number of monthly migraine headache days over the 3-month treatment period, and in the mean percentage of patients reaching at least 50% reduction from baseline in the number of monthly migraine headache days over the 3-month treatment period, as summarized in Table 3. EMGALITY treatment with the 240 mg once-monthly dose showed no additional benefit over the EMGALITY 120 mg once-monthly dose.

Table 3: Efficacy Endpoints in Study 3
a p<0.001
	EMGALITY 120 mg N = 273	Placebo N =538
Monthly Migraine Headache Days (over Months 1 to 3)
Baseline migraine headache days	19.4	19.6
Mean change from baseline	-4.8	-2.7
Difference from placeboa	-2.1
≥50% Migraine Headache Days Responders (over Months 1 to 3)
% Respondersa	28%	15%

Study 3 utilized a sequential testing procedure to control the Type-I error rate for the multiple secondary endpoints. Once a secondary endpoint failed to reach the required level for statistical significance, formal hypothesis testing was terminated for subsequent endpoints, and p-values were considered nominal only. In Study 3, EMGALITY 120 mg was not significantly better than placebo for the proportion of patients with ≥75% or 100% reduction in migraine headache days. Patients treated with EMGALITY 120 mg showed a nominally greater reduction in the number of monthly migraine headache days that acute medication was taken (-4.7 for EMGALITY 120 mg vs. -2.2 for placebo; nominal p-value <0.001), and the mean change from baseline in the MSQ Role Function-Restrictive Domain score at Month 3 was nominally greater in patients treated with EMGALITY 120 mg than in patients on placebo (21.8 for EMGALITY 120 mg vs. 16.8 for placebo; nominal p-value <0.001).

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

a Least-square means and 95% confidence intervals are presented.

Figure 6 shows the distribution of change from baseline in the mean number of monthly migraine headache days for the 3-month study period in bins of 3 days by treatment group. A treatment benefit over placebo for EMGALITY is seen across a range of changes from baseline in monthly migraine headache days.

Figure 6: Distribution of Change from Baseline in Mean Monthly Migraine Headache Days over Months 1 to 3 by Treatment Group in Study 3

14.2 Episodic Cluster Headache

The efficacy of EMGALITY was evaluated for the treatment of episodic cluster headache in a randomized, 8-week, double-blind, placebo-controlled study (Study 4).

Study 4 (NCT02397473) included adults who met the International Classification of Headache Disorders 3rd edition (beta version) diagnostic criteria for episodic cluster headache and had a maximum of 8 attacks per day, a minimum of one attack every other day, and at least 4 attacks during the prospective 7-day baseline period. All patients were randomized in a 1:1 ratio to receive once-monthly subcutaneous injections of EMGALITY 300 mg or placebo. Patients were allowed to use certain specified acute/abortive cluster headache treatments, including triptans, oxygen, acetaminophen, and NSAIDs during the study.

The study excluded patients on other treatments intended to reduce the frequency of cluster headache attacks; patients with medication overuse headache; patients with ECG abnormalities compatible with an acute cardiovascular event or conduction delay; and patients with a history of myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening. In addition, patients with any history of stroke, intracranial or carotid aneurysm, intracranial hemorrhage, or vasospastic angina; clinical evidence of peripheral vascular disease; or diagnosis of Raynaud’s disease were excluded.

The primary efficacy endpoint for Study 4 was the mean change from baseline in weekly cluster headache attack frequency across Weeks 1 to 3. A secondary endpoint was the percentage of patients who achieved a response (defined as a reduction from baseline of 50% or greater in the weekly cluster headache attack frequency) at Week 3.

In Study 4, a total of 106 patients (88 males, 18 females) ranging in age from 19 to 65 years were randomized and treated. A total of 90 patients completed the 8-week double-blind phase. In the prospective baseline phase, the mean number of weekly cluster headache attacks was 17.5, and was similar across treatment groups.

EMGALITY 300 mg demonstrated statistically significant improvements for efficacy endpoints compared to placebo, as summarized in Table 4.

Table 4: Efficacy Endpoints in Study 4
	EMGALITY 300 mg N = 49	Placebo N = 57
Mean Reduction in Weekly Cluster Headache Attack Frequency (over Weeks 1 to 3)
Prospective Baseline Cluster Headache Attack Frequency	17.8	17.3
Mean change from baseline	-8.7	-5.2
Difference from placebo	-3.5
p-value	0.036
≥50% Weekly Cluster Headache Attack Frequency Responders (at Week 3)
% Responders	71.4%	52.6%
Difference from placebo	18.8%
p-value	0.046

Figure 7: Mean Change in Weekly Cluster Headache Attack Frequency over Weeks 1 to 3 in Study 4a

a Abbreviations: BL = baseline; LS = least square; SE = standard error.

Figure 8 shows the distribution of the average percent change from baseline in weekly cluster headache attack frequency across Weeks 1 to 3 in bins of 25%, by treatment group, in Study 4.

Figure 8: Distribution of the Average Percent Change from Baseline in Weekly Cluster Headache Attack Frequency over Weeks 1 to 3 in Study 4a

a N = number of intent to treat patients with non-missing average percentage change from baseline in weekly cluster headache attack frequency over weeks 1 to 3.

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