CADTH Reimbursement Review

Eptinezumab (Vyepti)

Sponsor: Lundbeck Canada Inc.

Therapeutic area: Migraine

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Introduction

Migraine is a complex neurologic disorder, the precise cause of which is not completely understood. Patients with migraine report migraine attacks characterized by severe headaches (throbbing and diffuse pain) accompanied by other symptoms, such as nausea and/or vomiting, dizziness, sensory hypersensitivity, and tingling or numbness in the extremities and/or face. Migraines can occur with or without aura, and the aura is characterized by a wide range of primarily neurologic symptoms that can affect vision, speech, sensations, muscle strength, and cognitive function. All of these symptoms associated with migraine can impair quality of life. Patients report numerous social and financial impacts of migraine — including disruption to social relationships — which can be affected by exhaustion and frequent migraine attacks. Based on a study published in 2011, at least 2.6 million adult females and almost 1 million adult males in Canada have migraine,^1,2 although this may be an underestimate, as not everyone who has migraine seeks medical help, which is required for an official diagnosis. Approximately three-quarters of patients experiencing migraine report impaired function, and one-third require bedrest during a migraine attack.³

Two approaches are available to treat migraine: management of acute attacks and prophylaxis, the latter of which is typically only considered for those with more frequent migraine attacks (≥ 4 migraine days per month). Topiramate is an oral anticonvulsant that is indicated in adults for the prophylaxis of migraine headache.⁴ Onabotulinum toxin A has a Health Canada indication for chronic migraine prophylaxis⁴ and was previously reviewed by CADTH. Several calcitonin gene–related peptide (CGRP) receptor inhibitors (erenumab, fremanezumab, galcanezumab, and eptinezumab) have been approved by Health Canada for the prevention of migraine.⁴ Many other therapies used for migraine prophylaxis are used off-label, as they lack an official indication for this purpose from Health Canada. Broadly speaking, the main categories are antidepressants, anticonvulsants, and cardiovascular drugs. While they are well-established drugs, they all have various tolerability issues for patients, and this is important given that they are to be used on a chronic basis in migraine prophylaxis.

Eptinezumab is a CGRP inhibitor indicated for the prevention of migraine in adults who have at least 4 migraine days per month. Eptinezumab is administered as an IV infusion at a dose of 100 mg every 12 weeks. According to the Health Canada product monograph, the dosage of eptinezumab may be increased to eptinezumab 300 mg every 12 weeks. The need for dose escalation should be assessed within 12 weeks of treatment initiation. The sponsor has requested a recommendation for reimbursement of eptinezumab for the prevention of migraine in adults who have at least 4 migraine days per month and have experienced an inadequate response, intolerance, or contraindication to at least 2 oral prophylactic migraine medications.

The objective of this report was to perform a systematic review of the beneficial and harmful effects of eptinezumab for the prevention of migraine in adults who have at least 4 migraine days per month.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from 1 clinical expert consulted by CADTH for the purpose of this review.

Patient Input

• Patient input was provided as a joint submission by 2 groups, Migraine Canada and Migraine Québec, for the review of eptinezumab, and data were collected via 2 online surveys and in the form of direct input from patients with experience with eptinezumab who reside in the US.

• Patients report migraine as affecting their quality of life and sleep, mental health, social relationships, and day-to-day functioning at work and school. Patients identified improving quality of life and decreasing the frequency and intensity of headaches, as well as symptoms other than pain, as key outcomes of interest.

• According to the surveys conducted in 2021 and 2022, 30% and 24% of respondents, respectively, reported having found a preventive treatment that provided greater than 50% improvement in the frequency and intensity of migraine with no significant side effects. According to the 2021 survey, 66% of respondents reported discontinuing their preventive medication due to side effects. Additionally, 57% of respondents in the 2021 survey indicated they had not filled their prescription in the past 6 months due to lack of coverage.

Clinician Input

Input From Clinical Experts Consulted by CADTH

• The clinical expert consulted by CADTH for this review identified the following unmet needs: patients who have a delayed response with migraine prevention treatment, patients whose migraines are refractory to current treatment options, lack of therapies that reverse the course of the disease, and bioavailability (lack of an IV formulation).

• With respect to place in therapy, the clinical expert indicated that eptinezumab would complement onabotulinum toxin A, and that, ideally, eptinezumab would be administered in the first line along with other CGRP monoclonal antibodies (mAbs); however, the expert also noted that, in real-world use, eptinezumab is likely to be used as a later treatment due to cost and insurance coverage requirements.

• The clinical expert noted that the patients most likely to benefit from eptinezumab are those with episodic migraine (EM) or chronic migraine (CM). The patients most in need of an intervention such as eptinezumab are those having difficulty self-administering subcutaneous injections, and those with chronic daily headache and medication overuse headache (MOH).

• According to the clinical expert, a clinically meaningful response could include a reduction in monthly headache days (MHDs) and monthly migraine days (MMDs) and a 50% response (50% reduction in MMDs). The clinical expert also indicated that patient-reported outcomes should also be taken into account, as well as a reduction in use of acute medications for migraine.

• According to the clinical expert, indications for discontinuing treatment would include lack of response after a 6-month trial, intolerable side effects, allergy and/or anaphylaxis, patient preference, or switching to another CGRP mAb due to inconvenience with IV administration.

Clinician Group Input

No clinician group input was received for the review of eptinezumab.

Drug Program Input

• In response to a question about whether prior treatment with another preventive therapy, including another CGRP mAb, should be considered when determining eligibility for reimbursement, the clinical expert consulted by CADTH for this review replied that some patients may respond to an alternative CGRP mAb despite failure on a previous 1, and that failure on another CGRP mAb should not be a criterion for determining eligibility for reimbursement for a subsequent CGRP mAb.

• With respect to initiation criteria, the clinical expert agreed that the initiation criteria for fremanezumab and galcanezumab (confirmed diagnosis of EM or CM and inadequate response, intolerance, or contraindication to at least 2 oral prophylactic medications, with physicians providing the numbers of MHDs and MMDs at the time of initial request) would be appropriate for application to eptinezumab. However, they believed that, if approved for reimbursement, the maximum duration of initial authorization should be greater than 6 months instead of 6 months or less, as eptinezumab is administered every 3 months.

• With respect to renewal criteria, the clinical expert noted that, if the criterion for at least a 50% reduction in the number of migraine days per month was not met, the prescriber should be given the opportunity to provide a rationale for continued use, given that some patients will respond but not achieve a 50% reduction.

• In response to whether there were circumstances in which patients could be initiated at the eptinezumab 300 mg dose rather than starting at eptinezumab 100 mg, the clinical expert stated that there was uncertainty in this context due to the lack of data for switching between doses. The clinical expert added that this would depend on the cost of the drug.

• With respect to whether eptinezumab could be combined with onabotulinum toxin A, the clinical expert noted that, although there are no data on a combination of eptinezumab and onabotulinum toxin A, there are data showing that a combination therapy of onabotulinum toxin A and other CGRP mAbs can be effective in some patients and that eptinezumab could be used with onabotulinum toxin A.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

Three pivotal sponsor-funded, multicentre, double-blind, randomized controlled trials (RCTs) were included in this review, each comparing 2 different dosages of eptinezumab, 100 mg and 300 mg every 12 weeks, to placebo. Totals of 892 patients with either EM or CM in the DELIVER trial,⁵ 674 patients with frequent EM in the PROMISE-1 trial,⁶ and 1,050 patients with CM in the PROMISE-2 trial⁷ were randomized at a ratio of 1:1:1 to the eptinezumab 100 mg, eptinezumab 300 mg, or placebo group. In each study, patients received 2 doses of eptinezumab or placebo, 1 at baseline and 1 at week 12. The primary outcome in each of the 3 studies was the change from baseline to weeks 1 to 12 in MMDs. Key secondary outcomes, all controlled for multiplicity, included the number of patients achieving at least a 75% or at least a 50% reduction in MMDs, the number of patients with migraine 1 day after dosing, migraine prevalence on days 1 to 28 postdose, change from baseline in Headache Impact Test 6-item (HIT-6) scores, and acute medication usage.

In the DELIVER trial,⁵ the mean age of patients was approximately 44 years, while in the PROMISE studies the mean age of patients was approximately 40 years. In all studies, the majority of patients were female (approximately 90% in the DELIVER trial, 82% in the PROMISE-1 trial,⁶ and 88% in the PROMISE-2 trial⁷) and white (96% in the DELIVER trial, 84% in the PROMISE-1 trial, and 91% in the PROMISE-2 trial). In the DELIVER trial, 60% of patients had EM, ||||| had 14 or fewer MHDs, 62% had 2 prior migraine prophylaxis failures, 31% had 3 prior failures, 7% had 4 prior failures, and 12% had a diagnosis of MOH. In the PROMISE-1 trial, 36% had more than 9 MMDs, and in the PROMISE-2 trial, 45% had 17 or more MMDs.

Efficacy Results

In the DELIVER trial,⁵ for weeks 1 to 12, MMDs were estimated to be reduced by 2.7 days among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% confidence interval [CI], −3.4 to −2.0; P < 0.0001) and by 3.2 days for the 300 mg dose (95% CI, −3.9 to −2.5; P < 0.0001). For weeks 13 to 24, MMDs were estimated to be reduced by 3.0 days among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −3.8 to −2.2; P < 0.0001) and by 3.7 days for the 300 mg dose (95% CI, −4.5 to −3.0; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing. Sensitivity analyses of the primary outcome were consistent with that of the primary analysis. In the PROMISE-1 trial,⁶ for weeks 1 to 12, MMDs were estimated to be reduced by 0.7 days among patients on eptinezumab for the 100 mg dose (95% CI, −1.3 to −0.1; P = 0.0182) and by 1.1 days for the 300 mg dose (95% CI, −1.7 to −0.5; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing. Results of the sensitivity analyses were consistent with that of the primary analysis. For weeks 13 to 24, MMDs were estimated to be reduced by 1.0 days among patients on eptinezumab for the 100 mg dose (95% CI, −1.7 to −0.2) and by 1.2 days on the 300 mg dose (95% CI, −2.0 to −0.4). Because these comparisons fell outside of the multiple-testing procedure (MTP), no P values are reported here. In the PROMISE-2 trial,⁷ for weeks 1 to 12, MMDs were estimated to be reduced by 2.0 days among patients on eptinezumab for the 100 mg dose (95% CI, −2.9 to −1.2; P = 0.0182) and by 2.6 days for the 300 mg dose (95% CI, −3.5 to −1.7; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing. For weeks 13 to 24, MMDs were estimated to be reduced by 2.0 days among patients on eptinezumab for the 100 mg dose (95% CI, −2.9 to −1.0) and by 2.7 days for the 300 mg dose (95% CI, −3.6 to −1.7). Because these comparisons fell outside of the MTP, no P values are reported here. Results of the sensitivity analysis were consistent with that of the primary analysis. Data for prespecified subgroup analyses of the primary outcome in the DELIVER, PROMISE-1, and PROMISE-2 trials are presented in Table 34 and Table 35 in Appendix 3. No formal analyses were performed for the PROMISE-1 and PROMISE-2 trials. In the DELIVER trial, analyses were conducted with no control for multiplicity. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Reduction of 50% in MMDs

In the DELIVER trial,⁵ the proportions of patients achieving a 50% or greater reduction in MMDs at weeks 1 to 12 were 42% in the eptinezumab 100 mg group, 50% in the eptinezumab 300 mg group, and 13% with placebo, with odds ratios (ORs) of 4.91 (95% CI, 3.29 to 7.47; P < 0.0001) in the eptinezumab 100 mg group and 6.58 (95% CI, 4.41 to 10.01; P < 0.0001) in the eptinezumab 300 mg group. These comparisons were statistically significant based on the prespecified sequence of testing. The proportion of patients achieving a 50% or greater reduction in MMDs at weeks 1 to 12 was also reported in the PROMISE-1 trial,⁶ with mean differences in proportions of 12.4% (95% CI, 3.2 to 21.5) between eptinezumab 100 mg and placebo, and 18.9% (95% CI, 9.8 to 28.0; P = 0.0001) between eptinezumab 300 mg and placebo. The comparison between eptinezumab 300 mg and placebo was statistically significant based on the prespecified sequence of testing; however, the P value for the comparison between eptinezumab 100 mg and placebo is not reported here due to early failure of the hierarchy. The proportion of patients achieving a 50% or greater reduction in MMDs at weeks 1 to 12 was also reported in the PROMISE 2 trial,⁷ with differences in proportions of 18.2% (95% CI, 11.1 to 25.4; P < 0.0001) between eptinezumab 100 mg and placebo and 22.1% (95% CI, 14.9 to 29.2; P < 0.0001) between eptinezumab 300 mg and placebo. These comparisons were statistically significant based on the prespecified sequence of testing.

Reduction of 75% in MMDs

In the DELIVER trial,⁵ the proportions of patients achieving a 75% or greater reduction in MMDs at weeks 1 to 12 were 16% in the eptinezumab 100 mg group, 19% in the eptinezumab 300 mg group, and 2% with placebo, for ORs of 9.19 (95% CI, 4.16 to 24.35; P < 0.0001) in the eptinezumab 100 mg group, and 11.43 (95% CI, 5.22 to 30.15; P < 0.0001) in the eptinezumab 300 mg group. These comparisons were statistically significant based on the prespecified sequence of testing. The proportion of patients achieving a 75% or greater reduction in MMDs for weeks 1 to 4 was also reported in the PROMISE-1 trial,⁶ with differences in proportions of 10.5% (95% CI, 2.4 to 18.6; P = 0.0112) between eptinezumab 100 mg and placebo, and 11.3% (95% CI, 3.2 to 19.3; P = 0.0066) between eptinezumab 300 mg and placebo, both in favour of eptinezumab. These comparisons were statistically significant based on the prespecified sequence of testing. From weeks 1 to 12 in the PROMISE-1 trial, the differences in proportions were 6.0% (95% CI, −1.4 to 13.3; P = 0.1126) between eptinezumab 100 mg and placebo, and 13.5% (95% CI, 5.8 to 21.2; P = 0.0007) between eptinezumab 300 mg and placebo. The comparison between eptinezumab 300 mg and placebo was statistically significant based on the prespecified sequence of testing; however, the comparison between eptinezumab 100 mg and placebo was not statistically significant, and this is where the hierarchy failed in the PROMISE-1 trial. The proportion of patients achieving a 75% or greater reduction in MMDs at weeks 1 to 4 was also reported in the PROMISE-2 trial,⁷ with differences in proportions of 15.3% (95% CI, 9.3 to 21.4) between eptinezumab 100 mg and placebo, and 21.3% (95% CI, 15.0 to 27.6; P < 0.0001) between eptinezumab 300 mg and placebo. These comparisons were statistically significant based on the prespecified sequence of testing. From weeks 1 to 12, the difference between eptinezumab 100 mg and placebo was 11.7% (95% CI, 5.8 to 17.5; P < 0.0001) and the difference between eptinezumab 300 mg and placebo was 18.1% (95% CI, 12.0 to 24.3; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing.

Reduction of 100% in MMDs

In the DELIVER trial,⁵ the proportions of patients achieving a 100% or greater reduction in MMDs (100% responders) for weeks 1 to 12 were also reported: 5.9% versus 7.7% versus 1.1% for eptinezumab 100 mg versus eptinezumab 300 mg versus placebo, respectively. The proportions of 100% responders for weeks 1 to 4 were also reported for eptinezumab 100 mg, eptinezumab 300 mg, and placebo: 9% versus 15% versus 6%, respectively, in the PROMISE-1 trial,⁶ and 8% versus 13% versus 3%, respectively, in the PROMISE-2 trial.⁷ The proportions of 100% responders for weeks 9 to 12 were also reported for eptinezumab 100 mg, eptinezumab 300 mg and placebo: 13%, 16%, and 10%, respectively, in the PROMISE-1 trial, and 11%, 17%, and 6%, respectively, in the PROMISE-2 trial.

Patients With Migraine the First Day After Dosing

The proportion of patients who had a migraine the first day after dosing was a secondary outcome of the DELIVER trial.⁵ From a baseline of |||||| of patients with migraine, 27.2% had a migraine on the first day after dosing in the eptinezumab 100 mg group, while from a baseline of ||||||, 24.4% had a migraine the day after dosing in the eptinezumab 300 mg group, and in placebo, from a baseline of ||||||, 43.7% had a migraine the first day after dosing. The proportion of patients with a migraine the first day after dosing was a key secondary outcome of the PROMISE-1⁶ and PROMISE-2 trials.⁷ In the PROMISE-1 trial, from a baseline of 31.0% with migraine, 14.8% of patients had a migraine the day after dosing in the eptinezumab 100 mg group, while from a baseline of 30.8% with migraine, 13.9% had a migraine the day after dosing in the eptinezumab 300 mg group, and in placebo, from a baseline of 29.8% with migraine, 22.5% had a migraine the day after dosing. The P values reported by the sponsor were tested after failure of the statistical hierarchy and are not reported here. In the PROMISE-2 trial, from a baseline of 57.5% of patients with migraine, 28.6% had a migraine the day after dosing in the eptinezumab 100 mg group, while from a baseline of 57.4% with migraine, 27.8% had migraine the day after dosing in the eptinezumab 300 mg group, and with placebo, from a baseline of 58.0% with migraine, 42.3% had a migraine the day after dosing. When compared to placebo, the differences between eptinezumab 100 mg and placebo (P < 0.0001) and eptinezumab 300 mg and placebo (P < 0.0001) were statistically significant based on the prespecified sequence of testing.

Headache Frequency

In the DELIVER trial,⁵ the MHD mean change from baseline to weeks 1 to 12 was −4.6 (standard error [SE] = 0.37) from a baseline of 14.5 (SE = 5.6) for eptinezumab 100 mg; −5.1 (SE = 0.37) from a baseline mean of 14.4 (standard deviation [SD] = 5.5) for eptinezumab 300 mg; and −2.1 (SE = 0.38) from a baseline mean of 14.5 (SD = 5.8) for placebo. Because the change from baseline in MHDs was not part of the MTP, the P values were not reported. In the PROMISE-1 trial,⁶ the difference in the mean change from baseline to weeks 1 to 12 in MHDs versus placebo for eptinezumab 100 mg was |||||||||||||||||||||||| from a baseline mean of 10.0 (SD = 3.0), and for eptinezumab 300 mg was −|||||||||||||||||||||||||| from a baseline mean of 10.1 (SD = 3.1). Change from baseline in MHDs was not part of the MTP and P values are not reported. In the PROMISE-2 trial,⁷ the difference in the mean change from baseline to weeks 1 to 12 in MHDs versus placebo for eptinezumab 100 mg was −1.7 (95% CI, −2.6 to −0.9) from a baseline mean of 20.4 (SD = 3.1), and for eptinezumab 300 mg it was −2.3 (95% CI, −3.2 to −1.4) from a baseline mean of 20.4 (SD = 3.2). Change from baseline in MHDs was not part of the MTP and P values were not reported.

Acute Medication Use

In the DELIVER trial,⁵ for weeks 1 to 12, monthly days using migraine medications were estimated to be reduced by 2.5 days from a mean baseline of 11.2 days (SD = 5.5) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −3.2 to −1.9) and by 3.0 days from a mean baseline of 11.0 days (SD = 5.3) for the 300 mg dose (95% CI, −3.6 to −2.4). In the DELIVER trial, for weeks 13 to 24, monthly days using migraine medications were estimated to be reduced by 2.9 days for the 100 mg dose (95% CI, −3.6 to −2.2) among patients on eptinezumab compared to those on placebo and by 3.5 days for the 300 mg dose (95% CI, −4.2 to −2.8). As these comparisons were not part of the MTP, the P values are not reported here. In the PROMISE-1 trial,⁶ for weeks 1 to 12, monthly days using migraine medications were estimated to be reduced by 0.5 days from a mean baseline of 1.5 days (SD = 2.6) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −0.7 to −0.3) and by 0.4 days from a mean baseline of 1.6 (SD = 2.7) for the 300 mg dose (95% CI, −0.6 to −0.2). No P values are reported here because this outcome was not part of the MTP. In the PROMISE-2 trial,⁷ for weeks 1 to 12, monthly days using migraine medications were estimated to be reduced placebo by 1.2 days from a mean baseline of 6.6 days (SD = 6.9) among patients on eptinezumab compared to those on for the 100 mg dose (95% CI, −1.7 to −0.7) and by 1.4 days from a mean baseline of 6.7 days (SD = 6.5) for the 300 mg dose (95% CI, −1.9 to −0.9; P < 0.0001). No P value is reported here for the 100 mg dose in the PROMISE-2 trial because testing was not part of the MTP.

Other Patient-Reported Outcomes

Patient Global Impression of Change (PGIC) scores were reported in the DELIVER trial,⁵ and the differences at week 24 versus placebo were |||||||||||||||||||||||||||||| in the eptinezumab 100 mg group and |||||||||||||||||||||||||||||| in the eptinezumab 300 mg group. As PGIC was not part of the MTP, the P values are not reported here. Improvement in PGIC scores was reported as a binary outcome in the PROMISE-2 trial,⁷ with the percentage of patients who were “very much improved” for eptinezumab 100 mg versus eptinezumab 300 mg versus placebo being ||||||||||||||||||, and the percentage for patients who were “much improved” being ||||||||||||||||||||||||||||||. This outcome was not assessed in the PROMISE-1 trial.

Health-Related Quality of Life

In the DELIVER trial,⁵ the change from baseline to week 24 in the 5-Level EQ-5D (EQ-5D-5L) visual analogue scale (VAS) scores was estimated to be improved by 4.7 points from a baseline mean of 75.9 (SD = ||||||) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, 1.8 to 7.7) and by 8.0 points from a baseline mean of 74.5 (SD = ||||||) for the 300 mg dose (95% CI, 5.1 to 10.8). In the PROMISE-1 trial,⁶ the VAS mean change from baseline to week 24 was |||||||||||| for eptinezumab 100 mg, |||||||||||| for eptinezumab 300 mg, and |||||||||||| for placebo. In the PROMISE-2 trial,⁷ the VAS mean change from baseline to week 32 was |||||||||||| for eptinezumab 100 mg, |||||||||||| for eptinezumab 300 mg, and |||||||||||| for placebo. Positive changes indicate improvement on this scale.

In the DELIVER trial,⁵ for the Migraine-Specific Quality of Life Questionnaire (MSQ), the change from baseline to week 24 in the role function restrictive domain was estimated to be improved by 15.1 points from a baseline mean of 35.7 (SD = ||||||) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, 11.7 to 18.5) and by 15.0 points from a baseline mean of 35.7 (SD = ||||||) for the 300 mg dose (95% CI, 11.6 to 18.4). For the MSQ role function preventive domain, the mean change from baseline to week 24 was estimated to be improved by 12.6 points from a mean baseline of 50.2 (SD = ||||||) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, 9.4 to 15.8) and by 13.2 points from a mean baseline of 51.0 (SD = ||||||) for the 300 mg dose (95% CI, 10.1 to 16.4). For the MSQ emotional function domain, the change from baseline to week 24 was estimated to be improved by 14.1 points from a mean baseline of 50.3 (SD = ||||||) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, 10.5 to 17.7) and by 14.1 points from a mean baseline of 48.6 (SD = ||||||) for the 300 mg dose (95% CI, 10.6 to 17.7).

Symptoms

In the DELIVER trial,⁵ the mean change from baseline to week 12 in the HIT-6 score was estimated to be decreased (improved) by −3.8 points from a mean baseline of 66.6 (SD = 4.7) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −5.0 to −2.5; P < 0.0001) and by −5.4 points from a mean baseline of 66.5 (SD = 4.4) for the 300 mg dose (95% CI, −6.7 to −4.2; P < 0.0001). In the PROMISE-2 trial,⁷ the mean change from baseline to week 12 in the HIT-6 score was estimated to have decreased (improved) by −1.7 points from a mean baseline of 65.0 (SD = 4.9) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −2.8 to −0.7; P < 0.0001) and by −2.9 points from a mean baseline of 65.1 (SD = 5.0) for the 300 mg dose (95% CI, −3.9 to −1.8; P < 0.0001).

In the DELIVER trial,⁵ most bothersome symptom (MBS) scores were also reported under symptoms, and the mean scores at week 24 were estimated to be decreased (improved) placebo by |||||||||||||||||||||||||||||||||||| among patients on eptinezumab compared to those on eptinezumab 100 mg and by |||||||||||||||||||||||||||||| for eptinezumab 300 mg. In the PROMISE-2 trial,⁷ MBS scores at week 32 were reported as very much improved, eptinezumab 100 mg, 300 mg and placebo of |||||||||||||||||||||||| and much improved as ||||||, |||||||||||||||||||||||| respectively. The HIT-6 and the MBS scores were not assessed in the PROMISE-1 trial.

Health Care Resource Utilization

In the DELIVER trial,⁵ for health care resource utilization (HCRU), the number of patients with no visit to a family physician in the eptinezumab 100 mg versus eptinezumab 300 mg versus placebo groups was ||||||||||||||||||||||||, the number of patients who had no visit to a specialist was ||||||||||||||||||||||||, and the number of those with no emergency department visits due to migraine was ||||||||||||||||||||||||||||||||||||||||||, respectively. There were few hospitalizations due to migraine (|||||| of patients in each group) and similar numbers were reported for overnight hospital stays due to migraine.

Work Days Lost

In the DELIVER trial,⁵ the mean change from baseline to week 24 in absenteeism score on the Workplace Productivity and Activity Impairment (WPAI) instrument was estimated to be decreased (improved) by −4.5 points from a mean baseline of 11.4 (SD = ||||||) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −7.8 to −1.1) and by −4.7 points from a mean baseline of 12.0 (SD = ||||||) for the 300 mg dose (95% CI, −8.0 to −1.5). Outcomes related to the loss of work days were not assessed in the PROMISE-1 trial and PROMISE-2 trials.

Harms Results

No deaths were reported in any of the studies.

Adverse events (AEs) among patients randomized to the eptinezumab 100 mg, eptinezumab 300 mg, and placebo groups were reported by 43%, 41%, and 40% of those in the DELIVER trial;⁵ 63%, 58%, and 60% in the PROMISE-1 trial;⁶ and 44%, 52% and 47% in the PROMISE-2 trial,⁷ respectively.

Serious adverse events (SAEs) among patients who were randomized to eptinezumab 100 mg, eptinezumab 300 mg, and placebo occurred in 2%, 2%, and 1% of those in the DELIVER trial; 2%, 1%, and 3% in the PROMISE-1 trial; and less than 1%, 1%, and less than 1% in the PROMISE-2 trial, respectively. No SAEs occurred in more than 1 patient.

In the DELIVER trial, treatment stoppages due to an AE occurred in 0.3% of patients in the eptinezumab 100 mg and placebo groups and 2% of patients in the eptinezumab 300 mg group. In the PROMISE-1 trial, 3% of patients in the eptinezumab 100 mg and placebo groups and 2% in the eptinezumab 300 mg group stopped treatment due to an AE; and in the PROMISE-2 trial, less than 1%, less than 1%, and 2% of patients stopped treatment due to an AE in the eptinezumab 100 mg, placebo, and eptinezumab 300 mg groups, respectively.

Notable harms identified by the review team included anaphylaxis or hypersensitivity reactions, antibody formation, cardiovascular events, suicidality, alopecia, and fatigue. The most common notable harms in the DELIVER trial were hypersensitivity and/or anaphylaxis, occurring in 2% of patients in each of the eptinezumab 100 mg and placebo groups and 3% of patients in the eptinezumab 300 mg group, and cardiovascular or cerebrovascular disorders, occurring in 3% of patients in the eptinezumab 100 mg and placebo groups and 1% in the eptinezumab 300 mg group. All other notable harms occurred in 1% of patients or less, and in the PROMISE-1 trial and PROMISE-2 trials, notable harms occurred in 1% of patients or less.

Critical Appraisal

Issues related to internal validity included a large number of withdrawals in the PROMISE-1 trial⁶ (> 20% across groups) that may have affected results for efficacy and harms, most notably by changing the mix of baseline characteristics in the study population. According to the sponsor, 94% of patients remained in the study at the time of the 12-week assessment for the primary and a number of key secondary outcomes; however, this large number of withdrawals may have affected results after week 12, particularly those for harms, and if the patients who already discontinued the study would have been more or less likely to experience harm from continued use of eptinezumab. None of the health-related quality of life (HRQoL) hypothesis-testing procedures were controlled for multiplicity in any of the included studies, limiting any conclusions that can be drawn from these important outcomes as the lack of control for multiple statistical comparisons increases the risk of type I error.

With respect to external validity, because none of the included studies featured an active comparator, any comparisons to other drugs for migraine prophylaxis are indirect; the limitations of these analyses are outlined in the following section. In 2 of the 3 included studies, patients only received 2 doses of eptinezumab, for a total double-blind observation period of 24 weeks. This is not a sufficient period of time to adequately assess the durability of response to eptinezumab or long-term harms. Although a longer-term study, PREVAIL,⁸ is available, it did not include a control group, limiting any conclusions that can be drawn regarding long-term efficacy or harms.

Indirect Comparisons

Description of Studies

The sponsor submitted an unpublished network meta-analysis (NMA), informed by a systematic literature review (SLR), to identify all existing RCTs that aimed to compare eptinezumab with key comparators (erenumab, fremanezumab, galcanezumab, and onabotulinum toxin A) for the prevention of EM or CM in adults who have experienced an inadequate response, intolerance, or contraindication to at least 2 oral prophylactic migraine medications.⁹

A feasibility assessment was conducted by the sponsor to assess the suitability of an NMA for the comparison of the identified studies with the DELIVER trial. A total of 11 studies were included in the Bayesian NMA, evaluating the comparative impact of eptinezumab, key CGRP mAbs, and placebo on efficacy and HRQoL in EM and CM patients. Characteristics of trials reporting on anti-CGRPs and onabotulinum toxin A in EM and CM were assessed for heterogeneity of study characteristics and baseline characteristics. Given the differences in treatment by migraine type, separate analyses were conducted for EM and CM.⁹

The NMA was conducted in a Bayesian framework using fixed-effect models as base-case analyses due to the limited number of studies per comparison. As no closed loops were formed in the networks, it was not possible to assess consistency between direct and indirect evidence.⁹

The primary analysis of the NMA consisted of comparisons between eptinezumab and anti-CGRPs for EM and CM separately. The outcomes included in the NMA were 50% migraine response rate (MRR), change from baseline in MMDs at 12 weeks, change from baseline in MMDs at 12 weeks with acute medication use, change from baseline in MSQ v2.1 (Migraine-Specific Quality of Life Questionnaire [MSQ version 2.1]) domains (role function restrictive, emotional function, and role function preventive) at 12 weeks, 75% MRR, and change from baseline in HIT-6 score at 12 weeks.⁹

Two secondary analyses were conducted. The first consisted of comparisons with onabotulinum toxin A for the end points of change from baseline in MMDs and 50% MRR using data from 24 weeks for onabotulinum toxin A and 12 weeks for eptinezumab due to limited data availability. The other secondary analysis consisted of comparisons with anti-CGRPs, adjusting for the route of administration for change from baseline in MMDs at week 12, given that eptinezumab is the only treatment administered by IV, and may demonstrate greater placebo effects.⁹

Efficacy Results

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Harms Results

Harms were not evaluated in the sponsor-submitted NMA.

Critical Appraisal

Given the common comparator of placebo in RCTs of migraine treatments, the sponsor conducted a Bayesian NMA, which was considered appropriate. The NMA was informed by an adequately conducted SLR that included planned searches of multiple databases, conference proceedings, and clinical trial registries, as well as regulatory and health technology assessment agency websites, updated to mid-2021.

The CADTH team and the clinical expert consulted by CADTH agreed that the methods used by the sponsor for inclusion of studies in the NMA was reasonable. However, additional sources of heterogeneity, including differences in dosing schedules and time of assessment, were noted but not explored in the sponsor’s feasibility analyses. Concurrent with the feasibility assessment, the sponsor identified the following potential treatment-effect modifiers, based on the results of subgroup analyses from the included trials: MOH (for CM patients only), baseline severity (i.e., EM versus CM and baseline MMDs) and number of prior treatment failures. Given the lack of comparability of EM and CM patients due to differences in migraine frequency and severity, all analyses were conducted separately based on the diagnosis of EM or CM, and only patients with 2 or more prior treatment failures were included.

Outcomes included in the NMA were relevant to the treatment of both EM and CM in Canada. Outcomes focused on reductions from baseline in migraine frequency (50% MMR and 75% MRR and change from baseline in MMDs [with use of acute medication]) and HRQoL (MSQ v2.1 domains and HIT-6). Because no outcomes related to safety were evaluated, the comparative safety of eptinezumab and other CGRP mAbs remains unknown.

The NMA was conducted within a Bayesian framework using fixed effects for all efficacy outcomes. Model statistics (i.e., deviance information criterion) for model selection were generated, although the results were not reported. Based on the lack of available data, only arm-level data were used for comparisons. Given the absolute outcome measures considered in the analyses, this was considered appropriate; however, because arm-based models do not preserve randomization, comparative estimates are at a greater risk of bias in relative treatment effects.

While some NMAs suggested that eptinezumab is favoured when compared with erenumab and galcanezumab for certain outcomes (50% MRR, change from baseline in MMDs) it is worth noting that the results are produced using fixed-effect models, and it is uncertain if the fixed-effect model was the appropriate model to use in these comparisons due to the lack of reporting of a deviance information criterion. As a result, it is impossible to conclude that eptinezumab was superior to erenumab and galcanezumab. Moreover, in all fixed-effects analyses, results were associated with wide 95% credible intervals (CrIs), with most estimates crossing the threshold of no effect, resulting in notable imprecision in the results. Results for random-effects analyses for the 2 main outcomes were generally associated with even wider 95% CrIs.

Other Relevant Evidence

One open-label, phase III study, PREVAIL,⁸ was summarized to provide additional information on the long-term safety and efficacy of repeated, IV infusions of eptinezumab administered quarterly in patients with CM for the preventive treatment CM.

Description of Studies

The PREVAIL trial⁸ was conducted to evaluate the long-term safety of up to 8 IV infusions of eptinezumab 300 mg administered at 12-week intervals in 128 adult patients with CM for up to 84 weeks of treatment. The secondary objective was to evaluate the efficacy of eptinezumab by assessing its impact on patient-reported outcomes. The inclusion and exclusion criteria were generally consistent with the pivotal PROMISE-2 clinical trial.⁷ Patients were eligible to enrol in PREVAIL if they were diagnosed with migraine at an age of 50 years or greater and had a history of CM for 1 or more years before screening. The duration of the study was 106 weeks, which included a 2-week screening period, 48-week primary treatment period, 36-week secondary treatment period, and 20-week follow-up period. In each treatment period, patients received 4 IV infusions of eptinezumab every 12 weeks; only patients who received all 4 infusions in the primary treatment period were permitted to enter the secondary treatment period. Patients were evaluated at day 0, weeks 2, 4, 8, and 12, and every 12 weeks thereafter. Patients who failed to receive all 4 infusions of eptinezumab in the primary treatment period or did not provide consent for participation in the secondary treatment period were followed up at weeks 48 and 56.

The mean age of patients in the PREVAIL trial was 41.5 years (SD = 11.33). The majority of patients were female (85.2%) and white (95.3%). The mean duration of migraine diagnosis at baseline was 21.2 years (SD = 11.65). The patient-reported mean numbers of headache days, migraine days, and migraine attacks per 28-day period in the 3 months before screening were 20.3 (SD = 3.68), 14.1 (SD = 4.25), and 10.5 (SD = 4.29), respectively.⁸

A total of 128 patients were enrolled in PREVAIL and all patients received at least 1 dose of eptinezumab (safety population). A total of 22 patients (17.2%) prematurely discontinued the study, with the most common reason being withdrawal by patient in 18 patients (14.1%). Overall, 100 patients (78.1%) completed the study (week 104). A total of 86 patients (67.2%) received a total of 8 doses of the study drug. The concomitant use of at least 1 acute and 1 prophylactic treatment for headaches was reported in 127 patients (99.2%) and 46 patients (35.9%), respectively.⁸

Efficacy Results

Health-Related Quality of Life

For the EQ-5D-5L VAS, the mean scores at baseline and week 48 were |||||||||||||||||||||| and ||||||||||||||||||||||, respectively, demonstrating improvement (n = 114).⁸

Headache Symptoms

For the HIT-6, the mean total scores at baseline and weeks 101 to 104 were 65.2 (SD = 4.76) and 56.1 (SD = 9.07), respectively, demonstrating improvement (n = 96).⁸

At baseline, the MBSs reported were sensitivity to light in 31 patients (24.2%), nausea in 14 patients (10.9%), sensitivity to sound in 10 patients (7.8%), pain with activity in 10 patients (7.8%), mental cloudiness in 4 patients (3.1%), vomiting in 2 patients (1.6%), mood changes in 2 patients (1.6%), and other symptoms in 55 patients (43.0%). Most patients reported being “very much improved” (35.7%) or “much improved” (39.3%) at week 48 relative to baseline (n = 112). “No change” was reported by 11 patients (9.8%). No patients reported being “minimally worse,” “much worse,” and “very much worse” at week 48 relative to baseline.⁸

Other Patient-Reported Outcomes

For the PGIC, most patients reported being “very much improved” (49.0%) or “much improved” (34.4%) at week 104 relative to baseline (n = 96). “No change” was reported by 5 patients (5.2%). No patients reported being “minimally worse,” “much worse,” and “very much worse” at week 104 relative to baseline.⁸

Harms Results

A total of 91 patients (71.1%) reported at least 1 treatment-emergent adverse event (TEAE), with the most common event being nasopharyngitis in 18 patients (14.1%). A total of 5 patients (3.9%) reported at least 1 serious TEAE; no single event was reported in more than 1 patient (< 1%). A total of 8 patients (6.3%) reported any TEAE that led to study drug withdrawal, 3 (2.3%) of whom reported study drug withdrawal due to hypersensitivity. No other single event was reported in more than 1 patient (1%). No deaths were reported for the duration of the study. For notable TEAEs, hypersensitivity was reported in 5 patients (3.9%), hypertension was reported in 2 patients (1.6%), and anaphylactic reaction, hypotension, and deep vein thrombosis were reported in 1 patient (< 1%).⁸

Critical Appraisal

In the absence of an active comparator or placebo group, our ability to interpret the safety and efficacy results from the open-label study, PREVAIL,⁸ is limited. The interpretation of the safety and efficacy results may be further limited by the missing data in patient-reported outcomes at week 104, and the fact that only 86 patients (67.2%) received all 8 doses of eptinezumab. An open-label study design can bias the reporting of end points, particularly in any subjective measures included in the efficacy and safety parameters due to the unblinding of the study drug during the treatment period, and the direction and magnitude of the bias is therefore uncertain. Of note, 28 patients (21.9%) had participated in a prior clinical trial of eptinezumab. These patients were eligible to enrol if the investigator determined they had not experienced any clinically significant AEs related to the study drug during the previous study. Consequently, these patients may be more tolerant to eptinezumab, and their inclusion may result in lower AE rates than would be expected in a nonselected population.

The baseline characteristics in patients with CM in PREVAIL were generally consistent with the baseline characteristics in the PROMISE-2 trial,⁷ which also included patients with CM. The clinical expert consulted by CADTH for this review estimated that at least 80% of patients presenting with migraines in clinical practice are females; 109 patients (85.2%) were female in PREVAIL. Because only eptinezumab 300 mg was evaluated in PREVAIL, the generalizability of the safety and efficacy results in the open-label study to eptinezumab 100 mg is limited.

Conclusions

Evidence from 3 double-blind RCTs suggests that eptinezumab 100 mg and 300 mg given intravenously every 12 weeks reduces monthly migraine frequency, relative to placebo, when used as prophylaxis in patients with EM or CM. This reduction in migraine frequency may be accompanied by a reduction in use of acute migraine medication and there is evidence of a reduction in symptoms on the HIT-6. No conclusions can be drawn regarding the impact of eptinezumab on HRQoL as there was no adjustment for multiplicity in the statistical analyses for this outcome. Eptinezumab appears to result in a relatively low risk of treatment discontinuations due to AEs, and no safety issues were identified beyond what is described in the product monograph. However, double-blind treatment consisted of only 2 infusions in 2 studies and a maximum of 4 infusions in the other study, and findings from a longer-term study are limited by the lack of a control group. No evidence from a direct comparison between eptinezumab and other prophylactic treatments for migraine was identified for this review. Results from an indirect comparison between eptinezumab and other CGRP inhibitors and onabotulinum toxin A were inconclusive due to methodological limitations with the analysis, and the indirect comparison did not assess safety.

Introduction

Disease Background

Migraine is a complex neurologic disorder whose precise cause is not completely understood. Patients with migraine report migraine attacks characterized by severe headache (throbbing and diffuse pain), accompanied by other symptoms such as nausea and/or vomiting, dizziness, sensory hypersensitivity, and tingling or numbness in the extremities and/or face. Migraines can occur with or without aura, and the aura is characterized by a wide range of primarily neurologic symptoms that can affect vision, speech, sensations, and muscle strength. Cognitive function can also be affected. All of these symptoms associated with migraine can impair quality of life, and patients also report that their quality of life is affected even when they do not have a migraine, as they fear the next attack. Patients report numerous social and financial impacts, including disrupted social relationships, due to exhaustion and frequent migraine attacks. Based on a study published in 2011, in Canada, at least 2.6 million adult females and almost 1 million adult males have migraine,^1,2 although this may be an underestimate, as not everyone who has migraine seeks medical help, which is required for an official diagnosis. Approximately 3-quarters of patients experiencing migraine report impaired function, and one-third require bedrest during a migraine attack.³

Standards of Therapy

Two approaches are available to treat migraine: management of acute attacks and prophylaxis, which is typically only considered for those with more frequent migraines (≥ 4 migraine days per month). Topiramate is an oral anticonvulsant that is indicated in adults for the prophylaxis of migraine headache.⁴ Onabotulinum toxin A, which has a Health Canada indication for CM prophylaxis,⁴ was previously reviewed by CADTH. It is administered by multiple and technically challenging subcutaneous injections in various muscles of the head and neck. Many other therapies used for migraine prophylaxis are used off-label, as they lack an official indication for this purpose from Health Canada. Broadly speaking, the main categories are antidepressants (tricyclics and serotonin-norepinephrine reuptake inhibitors), anticonvulsants (various), and cardiovascular drugs (beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers). There is a lack of understanding of how the mechanisms of these drugs relate to migraine prophylaxis. While they are generally safe and well-established drugs, they all have various tolerability issues for patients, and this is important given that they are to be used on a chronic basis in migraine prophylaxis.

In clinical practice, patients on migraine prophylaxis frequently discontinue or switch treatments due to lack of efficacy or tolerability.^10,11

Drug

Eptinezumab is administered as an IV infusion at a dosage of 100 mg every 12 weeks. According to the Health Canada product monograph,⁴ the dosage of eptinezumab may be increased to 300 mg every 12 weeks. The need for dose escalation should be assessed within 12 weeks of treatment initiation. Eptinezumab is indicated for the prevention of migraine in adults who experience at least 4 migraine days per month. Eptinezumab is a CGRP mAb, and CGRP is thought to play an important role in the pathophysiology of migraine. The sponsor’s requested reimbursement criteria is for the prevention of migraine in adults who have at least 4 migraine days per month and have experienced an inadequate response, intolerance, or contraindication to at least 2 oral prophylactic migraine medications. Eptinezumab was submitted for review by CADTH following receipt of a Notice of Compliance on January 11, 2021, and underwent the standard review process at Health Canada.

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient input received by CADTH is included in the stakeholder section at the end of this report.

Patient input was provided as a joint submission by 2 groups, Migraine Canada and Migraine Québec, for the review of eptinezumab. Migraine Canada is a national federally registered charity and Migraine Québec is a provincial nonprofit patient organization. Both organizations have a mission to support and inform individuals living with migraine and raise awareness about the impact of the disease, and both advocate for optimal care for patients with migraine and support research to find cures to improve quality of life.

The information used to inform the submission was based on 2 online surveys conducted by Migraine Canada with promotional support by Migraine Québec in late fall of 2021 and June 2022, as well as direct input from 13 patients living in the US who have experience with eptinezumab. A total of 1,165 adult patients in Canada with migraine and their caregivers responded to the 2021 survey; the majority (68%) of patients ranged in age from 30 to 59 years. Among the respondents to this survey, 19% lived with 1 to 6 migraine days per month, 28% lived with 8 to 14 migraine days per month, and 52% lived with 15 or more migraine days per month (CM). A total of 132 patients (114 in Canada and 18 in the US) responded to the 2022 survey; the majority (71%) of patients ranged in age from 30 to 59 years. Among the respondents to this survey, 11% lived with 1 to 6 migraine days per month, 20% lived with 8 to 14 migraine days per month, and 70% lived with 15 or more migraine days per month.

Respondents to the 2021 survey described how living with migraine has affected their quality of life and sleep, mental health, social relationships, and day-to-day functioning at work and school. The majority (73%) of respondents indicated they live in fear of the next migraine attack and have difficulty planning ahead. Further, 67% of respondents reported regularly needing to change or cancel plans or avoid interacting with others. More than 20% of respondents indicated they are on short- or long-term disability or have retired early due to migraine. Thirty-eight percent of respondents indicated their migraines have always or regularly disrupted their sleep. With respect to caregiver burden, 31% and 35% of respondents described themselves as a burden to others for 16 to 30 and 6 to 15 days per month, respectively. According to the 2022 survey, migraines have led to the development of moderate-to-severe depression and/or anxiety requiring counselling and/or medications in 48% of respondents.

Most (78%) of the 2021 survey respondents indicated they have taken a prescription medication for the prevention of migraine; the most commonly prescribed were topiramate, amitriptyline, and botulinum toxin. Similarly, 74% of respondents to the 2022 survey reported taking more than 5 preventive treatments. Approximately 30% and 24% of respondents to the 2021 and 2022 survey, respectively, reported having found a preventive treatment that provides greater than 50% improvement in frequency and intensity of migraine attacks with no significant side effects. According to the 2021 survey, 66% of respondents reported discontinuing their preventive medication for migraine due to side effects. Further, 57% of respondents to the 2021 survey indicated they have not filled their prescription in the past 6 months due to the cost and lack of coverage, and 33% of respondents to the 2022 survey indicated their preference for an infusion every 3 months as the mode of administration.

A total of 13 patients in the US provided direct input on their experience with eptinezumab. Of these, 6 patients reported a 50% benefit and 3 patients reported a 75% benefit with eptinezumab versus previous therapies used; 4 patients either reported no improvement or not having taken eptinezumab for a sufficient amount of time to comment. According to the patients, the advantages of eptinezumab included reduced frequency and intensity of migraines leading to improved day-to-day functioning. The disadvantages included cost, having to travel to an infusion centre, and discontinued treatment due to severe joint aches. According to the patients, side effects were tolerable and included insomnia, hypersensitivity reaction, and sore throat for 24 to 48 hours postinfusion; 67% reported no side effects. Finally, 83% indicated eptinezumab was easier and more convenient to use when compared to other therapeutic options.

The majority (73%) of respondents to the 2021 survey indicated there is a need for a new preventive medication. According to respondents to both surveys, the most valuable outcomes for preventive treatment are improvement in quality of life, and decrease in headache intensity, headache frequency, and symptoms other than pain (e.g., sensitivity to light, sound, nausea, and brain fog). When selecting therapy, respondents to the 2022 survey indicated the trade-offs they would consider included efficacy versus side effects, cost, and taking daily medications. Overall, patients in Canada living with migraine expect to have access to new treatment options that will address the gaps in the currently available options, many of which are not effective and are associated with intolerable side effects.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of migraine.

Unmet Needs

The clinical expert consulted by CADTH for this review identified the following unmet needs:

• delayed response for migraine prevention treatment

• not all patients respond to available treatments

• patients become refractory to current treatment options

• no treatments are available that reverse the course of the disease

• lack of availability of different routes of administration, such as IV.

The clinical expert noted that current limitations include cost, coverage, access, delayed response, and intolerability to oral medications.

Place in Therapy

The clinical expert consulted by CADTH for this review noted that CGRP inhibitors target an important aspect of the pathophysiology of migraine, as opposed to the other drugs used for migraine, antidepressants, antihypertensives, and antiseizure medications, which act more indirectly. The current guidelines are older (published between 2012 and 2013) and therefore did not include the CGRP mAbs, although onabotulinum toxin A is included for CM. The current treatment paradigm is to try 2 to 3 oral medications (due to evidence and cost) before proceeding to other, more expensive options, such as CGRP mAbs.

The clinical expert noted that eptinezumab can be used in patients who have contraindications to other oral treatments and who have problems with self-administration of subcutaneous injections, such as the other CGRP mAbs. They also noted that use of eptinezumab does not represent a shift in the treatment paradigm but provides another option.

Patient Population

The clinical expert consulted by CADTH for this review stated that the patients most likely to respond to eptinezumab are those with EM or CM. The clinical expert identified patients having trouble self-administering CGRP mAbs and chronic daily headache and those with MOH as most in need of an effective prophylactic measure for EM. The clinical expert did not anticipate that this would depend on disease characteristics. The expert noted that the patients best suited for treatment could be identified through clinical judgment and/or exams. The expert added that misdiagnosis is unlikely, and that migraine tends to be an underdiagnosed condition.

Assessing Response to Treatment

The clinical expert identified key outcomes of interest when assessing treatment response as MHDs, MMDs, a 50% reduction in MMDs, and improvement in Migraine Disability Assessment Scale (MIDAS) and HIT-6 scores. The clinical expert noted that a clinically meaningful response could be indicated by a reduction in MHDs and MMDs and a 50% reduction in MMDs; however, patient-reported outcomes should also be considered, as well as a reduction in use of acute medications for migraine.

Discontinuing Treatment

The clinical expert consulted by CADTH for this review noted possible reasons for discontinuing treatment include a lack of treatment response (subjectively reported by the patient) after a 6- to 12-month trial, intolerable side effects, allergy and anaphylaxis, patient preference, or a switch to other CGRP mAbs due to the inconvenience associated with IV infusions.

Prescribing Conditions

The clinical expert stated that doses could be delivered at an infusion centre or specialty pharmacy, and that a specialist would not be required to diagnose patients. However, the clinical expert indicated that a specialist should manage the patient initially and provide education on the product. The clinical expert noted that subsequent monitoring of the patient could be carried out by nonspecialists if the patient has not experienced any issues with treatment.

Additional Considerations

The clinical expert consulted by CADTH for this review added that infusion treatment could offer advantages over previous options due to the potential for more rapid onset and 100% bioavailability.

Clinician Group Input

No clinician group input was received for the review of eptinezumab.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Responses

CDEC = CADTH Canadian Drug Expert Committee; CGRP = calcitonin gene–related peptide; HIT-6 = Headache Impact Test 6-item; pCPA = pan-Canadian Pharmaceutical Alliance.

Clinical Evidence

The clinical evidence included in the review of eptinezumab is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of eptinezumab for the prevention of migraine in adults who have at least 4 migraine days per month.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect those considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; CGRP = calcitonin gene–related peptide; HIT-6 = Headache Impact Test 6-item; mAbs = monoclonal antibodies; MBS = most bothersome symptoms; MIDAS = Migraine Disability Assessment Scale; MSQ = Migraine-Specific Quality of Life questionnaire; PGIC = Patient Global Impression of Change; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.¹²

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in EndNote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Vyepti (eptinezumab). Clinical trials registries searched included the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Appendix 1 provides detailed search strategies.

The initial search was completed on July 7, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on October 26, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.¹³ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Appendix 1 provides more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the sponsor of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

Three studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of Included Studies

AE = adverse event; ASC-12 = Allodynia Symptom Checklist-12; CGRP = calcitonin gene–related peptide; CFB = change from baseline; CM = chronic migraine; C-SSRS = Columbia Suicide Severity Rating Scale; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; ECG = electrocardiogram; eDiary = electronic diary; EM = episodic migraine; EQ-5D-5L = 5-Level EQ-5D questionnaire; HCRU = health care resource utilization; HIT-6 = Headache Impact Test 6-item; HRT = hormone replacement therapy; ICHD-3 = International Classification of Headache Disorders, Third Edition; IHS = International Headache Society; MBS = most bothersome symptom; MHD = monthly headache day; MMD = monthly migraine day; MOH = medication overuse headache; MSQ = Migraine-Specific Quality of Life questionnaire; PGIC = Patient Global Impression of Change; RCT = randomized controlled trial; SAE = serious adverse event; SF-36 = Short Form (36) Health Survey; VAS = visual analogue scale; WPAI = Workplace Productivity and Activity Impairment.

Note: Six additional reports were included (sponsor’s submission, Health Canada Review).

Sources: Clinical Study Reports for DELIVER,⁵ PROMISE-1,⁶ and PROMISE-2 studies.⁷

Description of Studies

Three pivotal, sponsor-funded, multinational, double-blind RCTs were included in this review. All studies compared eptinezumab 100 mg and eptinezumab 300 mg to placebo.

The primary objective of the DELIVER⁵ trial was to evaluate the efficacy of eptinezumab for the prevention of migraine in patients with unsuccessful prior preventive treatments. Secondary objectives were to evaluate the HRQoL and work productivity impact of eptinezumab, and the effect of long-term treatment with eptinezumab. The DELIVER trial randomized 892 patients with either EM or CM at a ratio of 1:1:1 to eptinezumab 100 mg, eptinezumab 300 mg, or placebo. This was a multinational study with 96 sites in 17 countries (US and Europe), and no Canadian sites. Randomization was stratified by country and MHDs at baseline (≤ 14 MHDs, > 14 MHDs).

The primary objective of the PROMISE-1⁶ and PROMISE-2 trials⁷ was to evaluate the efficacy of repeat doses of eptinezumab administered by IV infusion compared to placebo in patients with frequent EM (PROMISE-1) and CM (PROMISE-2) and the secondary objectives were to evaluate safety and pharmacokinetics. The PROMISE-1 trial randomized 674 patients with EM and the PROMISE-2 trial randomized 1,050 patients with CM at a ratio of 1:1:1 to eptinezumab 100 mg, eptinezumab 300 mg, or placebo. In the PROMISE-1 trial, randomization was stratified by migraine days during screening (≤ 9 days or > 9 days) and in the PROMISE-2 trial, randomization was stratified by migraine days during screening (< 17 days or ≥ 17 days) and prophylactic medication use during the 3 months before screening (yes or no). The PROMISE-1 trial was conducted at 84 sites in 2 countries (US and Georgia) and the PROMISE-2 trial was conducted at 128 sites in 13 countries (US and Europe). No Canadian sites were included in the PROMISE-1 or PROMISE-2 trial.

Populations

Inclusion and Exclusion Criteria

In the DELIVER trial,⁵ patients had to fulfill criteria for either EM or CM, with at least 4 MMDs during screening, and a 12-month history of EM or CM. Patients in the PROMISE-1 trial⁶ had to have at least a 12-month history of migraine with no more than 14 MHDs, of which at least 4 had to be migraine days in the 3 months before screening, while in the PROMISE-2 trial,⁷ patients were to have a history of CM for at least 12 months before screening, and between 15 and 26 MHDs during the 28-day screening, with no more than 8 MMDs. In the DELIVER trial, patients had to have evidence of failure to 2 to 4 different preventive migraine medications in the past 10 years. Patients in the PROMISE-1 trial were not regularly using prophylactic medications for migraine in the 2 months before screening, while patients in the PROMISE-2 trial had to be stable on migraine prophylaxis for at least 3 months before entering the study.

Patients were excluded from the DELIVER trial⁵ if they had failed valproate and/or divalproex or botulinum toxin A or B and had tried other preventive medications since the failure of valproate or onabotulinum toxin A before study inclusion. Otherwise, all studies excluded patients with clinically significant pain syndromes that might act as confounders, as well as patients with specific migraine or headache subtypes that might also act as confounders. Patients with a history of certain psychiatric disorders such as psychosis or mania were also excluded from all studies.

Baseline Characteristics

In the DELIVER trial,⁵ patients were approximately 44 years of age, while in the PROMISE studies, patients were approximately 40 years of age (Table 7 and Table 8). In all studies, the majority of patients were female (approximately 90% in the DELIVER trial, 82% in the PROMISE-1 trial,⁶ and 88% in the PROMISE-2 trial)⁷ and white (96% in the DELIVER trial, 84% in the PROMISE-1 trial, and 91% in the PROMISE-2 trial). In the DELIVER trial, 60% of patients had EM, |||||| had 14 or fewer MHDs, 62% had 2 prior migraine prophylaxis failures, 31% had 3 prior failures, 7% had 4 prior failures, and 12% had a diagnosis of MOH. In the PROMISE-1 trial, 36% had more than 9 MMDs, and in the PROMISE-2 trial, 45% had 17 or more MMDs.

With respect to imbalances in baseline characteristics within studies, for eptinezumab 100 mg versus eptinezumab 300 mg versus placebo in the DELIVER trial,⁵ differences were observed in the proportion of female patients in each treatment group (93% versus 89% versus 88%, respectively), and the proportion of patients with EM in each treatment group (59% versus 64% versus 58%, respectively). In the PROMISE-1 trial,⁶ imbalances between the eptinezumab 100 mg versus eptinezumab 300 mg versus placebo treatment groups were observed for the proportion of female patients (80% versus 89% versus 84%, respectively), race (white: 88% versus 84% versus 82%, respectively), and the percent of migraines with severe intensity (33.9% versus 28.2% versus 33.6%). In the PROMISE-2 trial,⁷ imbalances were observed for race (white: 93% versus 92% versus 88% for eptinezumab 100 mg versus eptinezumab 300 mg versus placebo, respectively).

Table 7: Summary of Baseline Characteristics (DELIVER Trial)

CM = chronic migraine; EM = episodic migraine; MHD = migraine headache day; MOH = medication overuse headache; SD = standard deviation.

Source: Clinical Study Report for DELIVER.⁵

Table 8: Baseline Characteristics (PROMISE-1 and PROMISE-2 Trials)

EPT100 = eptinezumab 100 mg; EPT300 = eptinezumab 300 mg; MHD = migraine headache day; MMD = monthly migraine day; MOH = medication overuse headache; NR = not reported; SD = standard deviation.

Sources: Clinical Study Reports for PROMISE-1⁶ and PROMISE-2 trials.⁷

Interventions

Eptinezumab 100 mg, eptinezumab 300 mg, and placebo treatments were administered as IV infusions at baseline and at week 12 for the double-blind treatment period in the DELIVER⁵ and PROMISE-2 trials.⁷ In the PROMISE-1 trial,⁶ infusions were administered at baseline and at weeks 12, 24, and 36. Infusions were administered by blinded study personnel over a maximum of 1 hour.

Patients were not allowed to use prophylactic treatments for migraine within a week of the screening visit and during the study. This included beta-blockers (propranolol or metoprolol), anticonvulsants (topiramate, valproate, or divalproex), tricyclic antidepressants (amitriptyline), calcium channel blockers (flunarizine), angiotensin-2 receptor blockers (candesartan), and other medications locally approved for migraine prevention. Other drugs in these classes were allowed if prescribed for nonmigraine indications. Acute treatment of migraine (by prescription or over the counter as recommended by a health care professional) was allowed provided the dose had been stable for at least 12 weeks before screening. Patients were also not allowed to use central nervous system (CNS) and migraine-related devices or injectable therapies within 8 weeks of screening, onabotulinum toxin A for any reason within 16 weeks of screening, or monoamine oxidase inhibitors, ketamine, methysergide, methylergonovine or nimesulide within 12 weeks of screening. Barbiturates and prescription opioids were allowed for no more than 4 days per month, provided that the patient did not meet the criteria for MOH and had been on a stable regimen (no more than 4 days per month) for at least 2 months before screening.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 9. These end points are summarized in the following section. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Table 9: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

CFB = change from baseline; EPT = eptinezumab; EQ-5D-5L = 5-Level EQ-5D questionnaire; HCRU = health care resource utilization; HIT-6 = Headache Impact Test 6-item; MBS = most bothersome symptom; MHD = monthly headache day; MMD = monthly migraine day; MOH = migraine overuse headache; MSQ = Migraine-Specific Quality of Life questionnaire; PGIC = Patient Global Impression of Change; SF-36 = Short Form (36) Health Survey; VAS = visual analogue scale; WPAI = Work Productivity and Activity Impairment.

Note: Numbers in square brackets [-] indicate ranking in multiple-testing procedure.

Sources: Clinical Study Reports for DELIVER,⁵ PROMISE-1,⁶ and PROMISE-2.⁷

Migraine Frequency

The change from baseline in MMDs from weeks 1 to 12 was the primary outcome in each of the included studies. Headache episodes were self-reported by the patient. An episode is a single headache event that the patient reported as having a start and an end and lasting at least 30 minutes. The term headache encompassed both headaches and migraine headaches. The migraine and headache end points were summarized at 4-week intervals (weeks 1 to 4, 5 to 8, 9 to 12, 13 to 16,17 to 20, and 21 to 24), 12-week intervals (weeks 1 to 12 and 13 to 24) and the 24-week interval (weeks 1 to 24). The characteristics of each headache were collected in an electronic diary (eDiary) at the end of the headache, and for each headache it was determined whether it qualifies as a migraine. If a headache qualified as migraine, every day the headache lasted counted as a migraine day.^5-7

A migraine day is defined as any day with a headache that meets the CM definition as outlined in the International Headache Society International Classification of Headache Disorders (ICHD, third edition, beta version 2013). A migraine is defined as a self-reported headache that:

• lasted 4 hours or more or 30 minutes to 4 hours, and was believed by the patient to be a migraine that was relieved by medication

• had at least 2 of the following: a unilateral location, pulsating quality, moderate or severe pain intensity, and aggravation by or causing avoidance of routine physical activity

• had at least 1 of the following: nausea and/or vomiting and photophobia and phonophobia.

Headache Impact Test 6-Item

The HIT-6 (version 1.0) was assessed as a key secondary outcome in the DELIVER⁵ and PROMISE-2 trials.⁷ The HIT-6 is a tool used to measure the impact and effect on the ability to function normally in daily life when a headache occurs. The HIT-6 is a 6-question, Likert-type, self-reporting questionnaire with responses ranging from “Never” to “Always” with the following response scores: Never = 6, Rarely = 8, Sometimes = 10, Very Often = 11, Always = 13.^14,15 The total score for the HIT-6 is the sum of each response score and is treated as missing if the response is missing for 1 or more questions. The HIT-6 total score ranges from 36 to 78, with scores of 60 or greater indicating a “severe” impact on life, 56 to 59 a “substantial” impact, 50 to 55 “some” impact, and 49 or lower “little to no” impact.^14,15 The estimated between-group minimal important difference (MID) in migraine for the HIT-6 was 1.5¹⁶ and the estimated within-group MID was 6 in patients with CM.¹⁷ With respect to validity, support has been demonstrated for construct validity when compared to other headache-related assessments in patients with EM, CM, and nonmigraine headaches,¹⁸ and support has been demonstrated for construct and convergent validity¹⁹ and for convergent and known-groups validity in patients with CM.²⁰ Internal consistency²⁰ and test-retest reliability were adequate in patients with CM, EM, and nonmigraine headaches.^18,19 Responsiveness to change was demonstrated in patients with CM.^19,20

Five-Level EQ-5D Questionnaire

The EQ-5D-5L VAS was reported in each of the included studies as a secondary or “other” secondary outcome. The EQ-5D-5L is a descriptive system of HRQoL states consisting of 5 dimensions (mobility, self-care, usual activities, pain and/or discomfort, and anxiety and/or depression) each of which can take 1 of 5 responses. The responses record 5 levels of severity (no problems, slight problems, moderate problems, severe problems, and extreme problems) within a particular EQ-5D dimension. The EQ-5D-5L additionally includes a VAS scale, which ranges from 0 (worst health imaginable) to 100 (best health imaginable).²¹ No MID specific to migraine was found for the EQ-5D-5L and no studies were identified that assessed the validity, reliability, and responsiveness to change in patients with migraine.

Patient Global Impression of Change

PGIC was assessed as a secondary outcome in the DELIVER trial and as an “other” secondary outcome in the PROMISE-2 trial. PGIC is a single patient-reported item reflecting the patient’s impression of change in disease status since the start of the study (in relation to activity limitations, symptoms, emotions, and overall quality of life). The item is rated on a 7-point scale (very much improved, much improved, minimally improved, no change, minimally worse, much worse, and very much worse), with a high score indicating worsening.⁵ No MID specific to migraine was found for PGIC and none of the identified studies assessed the validity, reliability, and responsiveness to change in patients with migraine.

Most Bothersome Symptom

MBS scores were assessed as a secondary outcome in the DELIVER trial and as a tertiary outcome in the PROMISE-2 trial. Investigators verbally obtained the MBS associated with a given patient’s migraines during the baseline visit. Patients were asked to rate the improvement in this symptom from baseline on a 7-point scale identical to the scale used for PGIC. The MBS areas included: nausea, vomiting, sensitivity to light, sensitivity to sound, mental cloudiness, fatigue, pain with activity, mood changes, and other.⁵ No MID specific to migraine was found for the MBS and no studies were identified that assessed the validity, reliability, and responsiveness to change in patients with migraine.

Migraine-Specific Quality of Life Questionnaire

The change from baseline in MSQ subscores for role function restrictive, role function preventive, and emotional function were assessed as secondary outcomes in the DELIVER trial. The MSQ is a 14-item questionnaire used to assess quality of life in patients with migraine across 3 domains: role function restrictive (7 items), role function preventive (4 items), and emotional function (3 items). Items are rated on a 6-point scale (1 = none of the time; 6 = all of the time). The overall score for each domain is obtained by summing the item responses then rescaling then to a 0- to 100-point scale, with higher scores indicative of better quality of life.²² In patients with 3 to 12 migraines per month but not more than 15 headache days per month, the estimated group-level MIDs were 3.2 for role function restrictive, 4.6 for role function preventive, and 7.5 for emotional function.²³ Support was demonstrated for construct and known-groups validity when compared to other headache-related and HRQoL instruments in patients with EM and CM.^22,24,25 Internal consistency and test-retest reliability were adequate in patients with EM and CM,^22,24,25 and support was demonstrated for the responsiveness to change in patients with EM and CM.^24,25

WPAI Questionnaire

The change from baseline in WPAI subscores (absenteeism, presenteeism, work productivity loss, and activity impairment) was assessed as a secondary outcome in the DELIVER trial. The WPAI is a 6-item questionnaire used to assess the impact of migraine on work productivity and activity impairment. Items were employment status, work-hours missed due to migraine, work-hours missed due to other reasons, hours worked, impact of migraine on productivity at work, and impact of migraine on daily activity performance, other than work.⁵ No MID specific to migraine was found for the WPA and none of the identified studies assessed the validity, reliability, and responsiveness to change in patients with migraine.

Statistical Analysis

Primary Outcome of the Studies

Power Calculation

In the DELIVER trial,⁵ power was determined by simulations of the end points in the testing strategy. Randomization of 280 patients per treatment group provided approximately 94% power for a comparison of eptinezumab 100 mg to placebo and 99% power for a comparison of eptinezumab 300 mg to placebo. This sample size also provided at least 68% power for the individual key secondary end points to show an effect, with a combined power of 58% for seeing an effect on all primary and key secondary end points and both doses in the testing strategy.

In the PROMISE-1 trial,⁶ a total of 200 patients per group provided at least 95% power for each change in frequency of migraine days (weeks 1 to 12), individually, assuming a treatment effect of at least 1 day and a common SD of 2.7 days or less. The sample-size calculations were performed using PASS 2008 software and based on t-tests that approximated the analysis of covariance (ANCOVA).

In the PROMISE-2 trial,⁷ a total of 350 patients per group provided at least 90% power for the primary end point for each comparison, assuming a treatment effect of at least 1 day and a common SD of 4 days or less. For the key secondary 75% responder rate end points, 90% power was achieved for the pairwise comparisons, assuming a placebo responder rate of 20% and an eptinezumab responder rate of 31%. These sample-size calculations were performed using PASS 2008 and based upon a t-test and chi-square test that approximated ANCOVA and Cochran-Mantel-Haenszel (CMH) tests.

Statistical Test or Model

Changes from baseline in the number of MMDs for the first six 4-week intervals were analyzed using a restricted maximum likelihood–based MMRM. The model included the fixed effects of month (weeks 1 to 4, 5 to 8, 9 to 12, 13 to 16, 17 to 20, and 21 to 24), country, stratification (MHDs at baseline: ≤ 14 MHDs versus > 14 MHDs), and treatment as factors; baseline MMDs as a continuous covariate; treatment-by-month interaction; baseline score-by-month interaction; and stratum-by-month interaction. An unstructured variance structure was used to model within-patient errors. The Kenward-Roger approximation was used to estimate denominator degrees of freedom.^5-7

In the PROMISE-1 trial,⁶ an ANCOVA model was used to test for a difference between treatment arms. This model included the change from baseline measure as the response variable. Treatment and baseline migraine days (continuous covariate) were the independent variables. In addition, model-based estimates, including confidence intervals for the treatment differences, were used to summarize the results for the primary end point. In the PROMISE-2 trial,⁷ an ANCOVA model was also used, and the model included the change from baseline measure as the response variable. Treatment and variables measuring the stratification factors concepts, baseline migraine days (continuous covariate), and prophylactic medication use (binary covariate: use versus no use) were the independent variables.

Data Imputation Methods

If a patient completed at least 21 days of diary entries within each 28 day period, then normalization was used to account for the missing data. This was accomplished by multiplying the observed results by the inverse of the completion rate. If the diary was completed for fewer than 21 days in a 28-day period, then the results for the 28-day interval were a weighted function of the observed data for the current 4 week interval and the results from the previous interval. The weights were proportional to how many days the diary was completed and provided greater weight to the results from the current interval as the diary completion rate increased.^5-7

Subgroup Analyses

In the DELIVER trial,⁵ the primary efficacy analysis was repeated for the following subgroups relevant to the protocol developed by the CADTH review team: EM (MMDs ≥ 4, MHDs ≤ 14) and CM (MMDs ≥ 8, MHDs > 14), MOH diagnosis, number of failed treatments (2, > 2) and low-frequency EM (4 MMDs to < 8), high-frequency EM (8 to 14 MMDs), and CM (MMDs ≥ 8). The assumption of an equal treatment effect across subgroups was investigated on an exploratory basis for all these subgroups. For the PROMISE-1⁶ and PROMISE-2 trials,⁷ prespecified subgroup data were presented descriptively; no formal analyses were performed.

Sensitivity Analyses

In the DELIVER trial,⁵ to explore the assumptions related to the behaviour of the patients who withdrew due to AEs or lack of efficacy, a sensitivity analysis exploring the assumptions was performed in which monthly values for all patients were calculated using the prorating imputation rule without penalization for withdrawal due to AEs or lack of efficacy. To explore the robustness of the results to missing eDiary data during the first 4 weeks after infusion, a sensitivity analysis similar to the primary analysis was performed. In this analysis, baseline values were used to calculate values for weeks 1 to 4 for patients with fewer than 14 days of eDiary data in the first 4 weeks after their first infusion.

In the PROMISE-1 trial,⁶ the primary end point and key secondary end points were analyzed using a modification to Missing Data Rule 2 to evaluate the robustness of the selected algorithm. The analysis replaced Xp with Xb, where Xb was the baseline average daily result, if the patient withdrew from the study due to an AE, study burden, lack of efficacy, or worsening of study indication, or if the patient died.

In the PROMISE-2 trial,⁷ the first group of sensitivity analyses implemented the missing-data rules as follows: The primary end point was analyzed using a modification to the Missing Date Rule 2 (eDiary completed for fewer than 21 days) to better understand the robustness of the selected algorithm. The analysis replaced Xp with Xb, where Xb was the baseline average daily result, if the patient withdrew from the study due to an AE, study burden, lack of efficacy, or worsening of study indication, or if the patient died. 2. The primary end point was analyzed using repeated measures if the individual time periods (weeks 1 to 4, 5 to 8, and 9 to 12) were included in the model and Missing Date Rule 2 (eDiary completed for fewer than 21 days) was not used. Patients who did not complete the diary for more than 7 days out of 28 were not included for that 4-week period. The model specified an unstructured variance-covariance matrix and included the treatment group, time point, baseline, and treatment group–by–time point interaction. The Kenward-Roger approximation was used to estimate the degrees of freedom. The second group of sensitivity analyses changed the definition of baseline, which was redefined using 28 days of headache diary data ending on the day of the first dose. The primary analysis was repeated using this updated definition of the baseline. Finally, a repeated measures model that included all six 4-week intervals and both Missing Data Rule 1 and Missing Data Rule 2 was run. This model was identical in structure to the model specified for the missing-data sensitivity analysis outlined earlier but looked at how the primary analysis, based upon the ANCOVA model, compared to a repeated measures analysis.

Secondary Outcomes of the Studies

In the DELIVER trial,⁵ the key secondary end points related to 50% and 75% responses were analysed using logistic regression with baseline MMDs as a continuous covariate and treatment and stratification (MHDs at baseline: ≤ 14 MHDs versus > 14 MHDs) as factors. The logistic regression model was fitted using the maximum-likelihood method and the logit link function. The key secondary end point, change from baseline to week 12 in HIT-6 score, was analyzed using an MMRM similar to the 1 used for the primary end point. All the visits from the placebo-controlled period were included in the analysis. The comparisons were the contrasts between each dose of eptinezumab and placebo at week 12. The MTP strategy was a sequence of tests, either testing 1 end point at a time or using the Bonferroni-Holm method to test a group of end points. If the results of the first step were statistically significant, the formal testing continued with the next step, ensuring protection of the type I error. For the last 2 steps, the Bonferroni-Holm method was used to test the group of end points. The consecutive order of the smallest (P[1]), second smallest (P[2]), and largest P value (P[3]) had to be less than alpha/3, less than alpha/2, and less than alpha, where alpha is less than 0.05, respectively, in favour of the dose tested to consider the effect on all 3 key secondary outcomes to be statistically significant. The MTP for the DELIVER trial is depicted in Figure 2.

In the PROMISE-1 trial,⁶ for the key secondary end points (responder rates and percentage of patients with a migraine on the day after dosing) this testing was based upon CMH) and/or extended CMH tests. The tests were stratified by the randomization stratification factor. The change in acute migraine medication day end points was tested using an ANCOVA model with change from baseline measure as the response, and treatment and baseline acute migraine medication days as independent variables. In the PROMISE-1 trial, the MTP started with the comparison of the eptinezumab 300 mg and placebo groups as the primary end point. If this was significant, testing continued to a subset of the key secondary end points for eptinezumab 300 mg (first the weeks 1 to 4, 75% responder end point followed by the weeks 1 to 12, 75% responder end point, and then the weeks 1 to 12, 50% responder end point). The procedure then moved on to the primary end point for the eptinezumab 100 mg group, and subsequently to the same subset of key secondary end points as tested for the eptinezumab 300 mg dose. The procedure then moved on to the remaining key secondary end points for eptinezumab 300 mg and eptinezumab 100 mg groups (i.e., percentage of patients with a migraine on the day after dosing). Figure 3 depicts the MTP for the PROMISE-1 trial.

Figure 2: Multiple-Testing Procedure for DELIVER Trial

HIT-6 = Headache Impact Test 6-item; MMD = monthly migraine day.

Source: Clinical Study Report for DELIVER trial.⁵

Figure 3: Multiple-Testing Procedure for PROMISE-1 Trial

ALD403 = eptinezumab.

Source: Clinical Study Report for PROMISE-1 trial.⁶

In the PROMISE-2 trial,⁷ testing of the 75% MRR (weeks 1 to 4), 75% MRR (weeks 1 to 12), and 50% MRR (weeks 1 to 12) end points was performed with a CMH test controlling for the randomization stratification factors of baseline migraine days (< 17 days or ≥ 17 days) and prophylactic medication use (yes or no). For the percent of patients with migraine on the day after dosing, an extended CMH test was used, as patients with missing data had a value imputed between 0 and 1. Continuous outcomes such as change from baseline in HIT-6 and acute migraine medication usage were tested in a similar manner as the primary outcome (ANCOVA) using treatment and the baseline HIT-6 total score (continuous covariate), along with the stratification factors (baseline migraine days [< 17 days or ≥ 17 days]) and prophylactic med use (yes or no), and for acute medication usage, the model included the acute migraine medication usage change from baseline as the response variable. Treatment and the baseline acute migraine medication (continuous covariate), along with the baseline stratification variables as the independent variables. The MTP procedure first evaluated the comparison of the 300 mg and placebo groups for the primary end point. If this was significant, testing continued to the first set of key secondary end points for 300 mg. Within this set, the Holm procedure was used. If a significant difference was detected for all tests within this group, the procedure then moved on to the second set of key secondary end points for 300 mg (the Holm procedure was used within this set). The procedure then moved on to the 100 mg group for the primary end point and subsequently the secondary end points groups. If these end points were significant, the procedure moved to the final secondary end points for 300 mg. Within each end point group, the Holm procedure was used. Figure 4 depicts the MTP for the PROMISE-2 trial.

Figure 4: Multiple-Testing Procedure for PROMISE-2 Trial

Wks = weeks.

Source: Clinical Study Report for PROMISE-2 trial.⁷

Table 10: Statistical Analysis of Efficacy End Points

AE = adverse event; ANCOVA = analysis of covariance; CMH = Cochran-Mantel-Haenszel; eDiary = electronic diary; HIT-6 = Headache Impact Test 6-item; MHD = monthly headache day; MMD = monthly migraine day; MMRM = mixed model for repeated measures; MSQ = Migraine-Specific Quality of Life questionnaire; VAS = visual analogue scale; WPAI = Workplace Productivity and Activity Impairment.

Sources: Clinical Study Report for DELIVER,⁵ PROMISE-1,⁶ and PROMISE-2 trials.⁷

Analysis Populations

The all-patients-randomized set in the DELIVER trial⁵ included all patients randomized into the study while the all-patients-treated set included all patients who received at least 1 infusion of the study drug. The full analysis set included all patients in the all-patients-treated set who had a valid baseline assessment and at least 1 valid postbaseline 4-week assessment of MMDs in weeks 1 to 12.

In the PROMISE-1⁶ and PROMISE-2 trials,⁷ the full analysis population comprised all randomized patients who received the study drug or placebo. Patients were summarized within the treatment group to which they were randomly assigned. This population was used for efficacy analysis. The safety population included all patients who received the study drug or placebo. Patients were summarized within the treatment group for which they actually received treatment. If a patient was treated with 2 different doses, they were summarized in the treatment arm of the highest dose received. This population was used for the safety analyses.

Results

Patient Disposition

Study discontinuations were lower in the DELIVER trial⁵ (eptinezumab 100 mg: 4%; eptinezumab 300 mg: 3%; and placebo: 2%) than in the PROMISE-1 trial⁶ (22%, 24%, and 26%, respectively) and the PROMISE-2 trial⁷ (9%, 8%, and 11%, respectively). The most common reasons for study withdrawal in the DELIVER trial were AEs and withdrawn consent (Table 11). The most common reasons for study withdrawal in the PROMISE-1 and PROMISE-2 trials were lost to follow-up and (in the PROMISE-1 trial only) and study burden (Table 12).

Table 11: Patient Disposition (DELIVER Trial)

EPT100 = eptinezumab 100 mg every 12 weeks; EPT300 = eptinezumab 300 mg every 12 weeks.

Source: Clinical Study Report for DELIVER trial.⁵

Table 12: Patient Disposition (PROMISE-1 and PROMISE-2 Trials)

EPT100 = eptinezumab 100 mg every 12 weeks; EPT300 = eptinezumab 300 mg every 12 weeks; NR = not reported.

Sources: Clinical Study Report for PROMISE-1⁶ and PROMISE-2 trials.⁷

Exposure to Study Treatments

In the DELIVER trial,⁵ 98% of patients in each of eptinezumab 100 mg and 300 mg groups received both infusions, and 99% of patients in the placebo group received both infusions. In the PROMISE-1 trial,⁶ 79% of patients in the eptinezumab 100 mg group, 80% of patients in the eptinezumab 300 mg group, and 75% of patients in the placebo group received 4 doses of the study drug, while 5% in each of the eptinezumab 100 mg and 300 mg groups and 4% of patients in the placebo group received 3 doses, 8%, 9%, and 10% of patients, respectively, received 2 doses, and 8%, 6%, and 10% of patients, respectively, received 1 dose. In the PROMISE-2 trial,⁷ 2 doses were received by 96% of patients in the eptinezumab 100 mg group, 97% of patients in the eptinezumab 300 mg group, and 93% of patients in the placebo group.

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in the following section. Appendix 3 provides detailed efficacy data.

Migraine Frequency

The change from baseline in MMDs from weeks 1 to 12 was the primary outcome of all 3 included studies.

In the DELIVER trial,⁵ for weeks 1 to 12, MMDs were estimated to be reduced by 2.7 days among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −3.4 to −2.0; P < 0.0001) and by 3.2 days for the 300 mg dose (95% CI, −3.9 to −2.5; P < 0.0001) (Table 13). For weeks 13 to 24 MMDs were estimated to be reduced by 3.0 days among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −3.8 to −2.2; P < 0.0001) and by 3.7 days for the 300 mg dose (95% CI, −4.5 to −3.0; P < 0.0001). These comparisons were statistically significant based on the prespecified sequence of testing. Sensitivity analyses of the primary outcome using prorating to account for patients who withdrew during weeks 1 to 4 and weighting to account for patients with more than 14 days of eDiary reporting yielded results that were consistent with that of the primary analysis. These data are not reported in this review.

In the PROMISE-1 trial,⁶ for weeks 1 to 12, MMDs were estimated to be reduced by 0.7 days among patients on eptinezumab for the 100 mg dose (95% CI, −1.3 to −0.1; P = 0.0182) and by 1.1 days among those on the 300 mg dose (95% CI, −1.7 to −0.5; P < 0.0001) (Table 14). These comparisons were statistically significant based on the prespecified sequence of testing. Results of the sensitivity analyses were consistent with that of the primary analysis (data not included in this report). For weeks 13 to 24, MMDs were estimated to be reduced by 1.0 days among patients on eptinezumab on the 100 mg dose (95% CI, −1.7 to −0.2) and by 1.2 days among those on the 300 mg dose (95% CI, −2.0 to −0.4). As these comparisons fell outside of the MTP, no P values are reported here.

In the PROMISE-2 trial,⁷ for weeks 1 to 12, MMDs were estimated to be reduced by 2.0 days among patients on eptinezumab for the 100 mg dose (95% CI, −2.9 to −1.2; P = 0.0182) and by 2.6 days for the 300 mg dose (95% CI, −3.5 to −1.7; P < 0.0001) (Table 14). These comparisons were statistically significant based on the prespecified sequence of testing. For weeks 13 to 24 MMDs were estimated to be reduced by 2.0 days among patients on eptinezumab for the 100 mg dose (95% CI, −2.9 to −1.0) and by 2.7 days for the 300 mg dose (95% CI, −3.6 to −1.7). As these comparisons fell outside of the MTP, no P values are reported here. Results of the sensitivity analysis were consistent with that of the primary analysis.

Data for prespecified subgroup analyses of the primary outcome in the DELIVER,⁵ PROMISE-1,⁶ and PROMISE-2 trials⁷ are presented in Table 34 and Table 35 in Appendix 3. No formal analyses were performed for the PROMISE-1 and PROMISE-2 trials. In the DELIVER trial, analyses were conducted with no control for multiplicity. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Reduction of 50% in MMDs

In the DELIVER trial,⁵ the proportions of patients achieving a 50% or greater reduction in MMDs at weeks 1 to 12 were 42% in the eptinezumab 100 mg group, 50% in the eptinezumab 300 mg group, and 13% with placebo, with ORs9 of 4.91 (95% CI, 3.29 to 7.47; P < 0.0001) in the eptinezumab 100 mg group and 6.58 (95% CI, 4.41 to 10.01; P < 0.0001) in the eptinezumab 300 mg group (Table 13). These comparisons were statistically significant based on the prespecified sequence of testing.

The proportion of patients achieving a 50% or greater reduction in MMDs at weeks 1 to 12 was also reported in the PROMISE-1 trial,⁶ with mean differences in proportions of 12.4% (95% CI, 3.2 to 21.5) between eptinezumab 100 mg and placebo and 18.9% (95% CI, 9.8 to 28.0; P = 0.0001) between eptinezumab 300 mg and placebo (Table 14). The comparison between eptinezumab 300 mg and placebo was statistically significant based on the prespecified sequence of testing; however, the P value for the comparison between eptinezumab 100 mg and placebo will not be reported here due to early failure of the hierarchy.

The proportion of patients achieving a 50% or greater reduction in MMDs at weeks 1 to 12 was also reported in the PROMISE 2 trial,⁷ with differences in proportions of 18.2% (95% CI, 11.1 to 25.4; P < 0.0001) between eptinezumab 100 mg and placebo and 22.1% (95% CI, 14.9 to 29.2; P < 0.0001) between eptinezumab 300 mg and placebo (Table 14). These comparisons were statistically significant based on the prespecified sequence of testing.

Reduction of 75% in MMDs

In the DELIVER trial,⁵ the proportions of patients achieving a 75% or greater reduction in MMDs at weeks 1 to 12 were 16% in the eptinezumab 100 mg group, 19% in the eptinezumab 300 mg group, and 2% with placebo, for ORs of 9.19 (95% CI, 4.16 to 24.35; P < 0.0001) in the eptinezumab 100 mg group and 11.43 (95% CI, 5.22 to 30.15; P < 0.0001) in the eptinezumab 300 mg group (Table 13). These comparisons were statistically significant based on the prespecified sequence of testing.

The proportion of patients achieving a 75% or greater reduction in MMDs weeks 1 to 4 was also reported in the PROMISE-1 trial,⁶ with differences in proportions of 10.5% (95% CI, 2.4 to 18.6, P = 0.0112) between eptinezumab 100 mg and placebo and 11.3% (95% CI, 3.2 to 19.3, P = 0.0066) between eptinezumab 300 mg and placebo, both in favour of eptinezumab (Table 14). From weeks 1 to 12 in the PROMISE-1 trial, the differences in proportions were 6.0% (95% CI, −1.4 to 13.3; P = 0.1126) between eptinezumab 100 mg and placebo and 13.5% (95% CI, 5.8 to 21.2; P = 0.0007) between eptinezumab 300 mg and placebo. The comparison between eptinezumab 300 mg and placebo was statistically significant based on the prespecified sequence of testing; however, the comparison between eptinezumab 100 mg and placebo was not statistically significant, and this is where the hierarchy failed in the PROMISE-1 trial.

The proportion of patients achieving a 75% or greater reduction in MMDs at weeks 1 to 4, was also reported in the PROMISE-2 trial,⁷ with differences in proportions of 15.3% (95% CI, 9.3 to 21.4) between eptinezumab 100 mg and placebo and 21.3% (95% CI, 15.0 to 27.6; P < 0.0001) between eptinezumab 300 mg and placebo. These comparisons were statistically significant based on the prespecified sequence of testing. From weeks 1 to 12, the differences in proportions were 11.7% (95% CI, 5.8 to 17.5; P < 0.0001) between eptinezumab 100 mg and placebo and 18.1% (95% CI, 12.0 to 24.3; P < 0.0001) between eptinezumab 300 mg and placebo. These comparisons were statistically significant based on the prespecified sequence of testing.

Reduction of 100% in MMDs

In the DELIVER trial,⁵ the proportions of patients achieving a 100% or greater reduction in MMDs (100% responders) for weeks 1 to 12 for eptinezumab 100 mg versus eptinezumab 300 mg versus placebo were 5.9% versus 7.7% versus 1.1%, respectively (Table 13).

In the PROMISE-1 trial,⁶ the 100% response rates for weeks 1 to 4 for eptinezumab 100 mg, eptinezumab 300 mg, and placebo were 9% versus 15% versus 6%, respectively, and in the PROMISE-2 trial⁷ the 100% response rates were 8% versus 13% versus 3%, respectively. For weeks 9 to 12 for eptinezumab 100 mg, eptinezumab 300 mg, and placebo, the 100% responses rates were 13%, 16%, and 10%, respectively, in the PROMISE-1 trial, and 11%, 17%, and 6%, respectively, in the PROMISE-2 trial (Table 14).

Patients With Migraine the First Day After Dosing

The proportion of patients who had a migraine the first day after dosing was a secondary outcome in the DELIVER trial.⁵ From a baseline of |||||| of patients with migraine, 27.2% of patients in the eptinezumab 100 mg group had a migraine the day after dosing, while from a baseline of ||||||, 24.4% of patients in the eptinezumab 300 mg group had a migraine the day after dosing, and in placebo, from a baseline of ||||||, 43.7% had a migraine the first day after dosing.

The proportion of patients with a migraine the first day after dosing was a key secondary outcome of the PROMISE-1⁶ and PROMISE-2 trials.⁷ In the PROMISE-1 trial, from a baseline of 31.0% with migraine, 14.8% of patients in the eptinezumab 100 mg group had a migraine the day after dosing, and from a baseline of 30.8% with migraine, 13.9% of patients in the eptinezumab 300 mg group had a migraine the day after dosing, and in placebo, from a baseline of 29.8% with migraine, 22.5% had a migraine the day after dosing. The P values reported by the sponsor were tested after failure of the statistical hierarchy and are not reported here. In the PROMISE-2 trial, from a baseline of 57.5% of patients with migraine, 28.6% of patients in the eptinezumab 100 mg group had a migraine the day after dosing; from a baseline of 57.4% with migraine, 27.8% of patients in the eptinezumab 300 mg group had migraine the day after dosing; and with placebo, from a baseline of 58.0% with migraine, 42.3% had a migraine the day after dosing. When compared to placebo, the differences between eptinezumab 100 mg and placebo (P < 0.0001) and eptinezumab 300 mg and placebo (P < 0.0001) were statistically significant based on the prespecified sequence of testing.

Headache Frequency

In the DELIVER trial,⁵ the MHD mean changes from baseline to weeks 1 to 12 were |||||||||||| from a baseline of 14.5 (SD = 5.6) for eptinezumab 100 mg, |||||||||||| from a baseline mean of 14.4 (SD = 5.5), and |||||||||||| from a baseline mean of 14.5 (SD = 5.8) for placebo (Table 13). Because change from baseline in MHDs was not part of the MTP, no P values were reported.

In the PROMISE-1 trial,⁶ the differences in the mean change from baseline to weeks 1 to 12 in MHDs versus placebo were |||||||||||||||||||||||||||||| from a baseline mean of 10.0 (SD = 3.0) for eptinezumab 100 mg, and |||||||||||||||||||||||||||||||||||| from a baseline mean of 10.1 (SD = 3.1) for eptinezumab 300 mg (Table 14). Because change from baseline in MHDs was not part of the MTP, no P values were reported.

In the PROMISE-2 trial,⁷ the differences in the mean change from baseline to weeks 1 to 12 in MHDs versus placebo were −1.7 (95% CI, −2.6 to −0.9) from a baseline mean of 20.4 (SD = 3.1) for eptinezumab 100 mg and −2.3 (95% CI, −3.2 to −1.4) from a baseline mean of 20.4 (SD = 3.2) for eptinezumab 300 mg (Table 14). Because change from baseline in MHDs was not part of the MTP, no P values were reported.

Acute Medication Use

In the DELIVER trial,⁵ for weeks 1 to 12, monthly days using migraine medications were estimated to be reduced by 2.5 days from a mean baseline of ||||||||||||||||||||||||||||||) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −3.2 to −1.9) and by 3.0 days (from a mean baseline of |||||||||||| days) for the 300 mg dose (95% CI, −3.6 to −2.4) (Table 13). In the DELIVER trial, for weeks 13 to 24, monthly days using migraine medications were estimated to be reduced by 2.9 days among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −3.6 to −2.2) and by 3.5 days for the 300 mg dose (95% CI, −4.2 to −2.8). As these comparisons were not part of the MTP, no P values are reported here.

In the PROMISE-1 trial,⁶ for weeks 1 to 12, monthly days using migraine medications were estimated to be reduced by 0.5 days placebo from a mean baseline of 1.5 (SD = 2.6 days) among patients on eptinezumab compared to those on the 100 mg dose (95% CI, −0.7 to −0.3) and by 0.4 days from a mean baseline of 1.6 (SD = 2.7 days) for the 300 mg dose (95% CI, −0.6 to −0.2) (Table 14). As this outcome was not part of the MTP, no P values are reported here. In the PROMISE-2 trial,⁷ for weeks 1 to 12, monthly days using migraine medications were estimated to be reduced by 1.2 days from a mean baseline of 6.6 (SD = 6.9 days) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −1.7 to −0.7) and by 1.4 days from a mean baseline of 6.7 (SD = 6.5 days) for the 300 mg dose (95% CI, −1.9 to −0.9; P < 0.0001) (Table 14). No P values were reported for the 100 mg dose in the PROMISE-2 trial because testing was not part of the MTP.

Other Patient-Reported Outcomes

PGIC scores were reported in the DELIVER trial,⁵ and the differences at week 24 versus placebo were ||||||||||||||||||||||||||) in the eptinezumab 100 mg group and |||||||||||||||||||||||| in the eptinezumab 300 mg group. As PGIC was not part of the MTP, no P values are reported here. Improvement in PGIC scores was reported as a binary outcome in the PROMISE-2 trial,⁷ with the percentages of patients who were “very much improved” in the eptinezumab 100 mg versus eptinezumab 300 mg versus placebo groups reported as ||||||||||||||||||||||||, respectively and the percentages of patients who were “much improved” reported as ||||||||||||||||||, respectively. This outcome was not assessed in the PROMISE-1 trial.

Health-Related Quality of Life

In the DELIVER trial,⁵ the changes from baseline to week 24 in EQ-5D-5L VAS scores were estimated to be improved by 4.7 points from a baseline mean of 75.9 (SD = ||||||) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, 1.8 to 7.7) and by 8.0 points from a baseline mean of 74.5 (SD = ||||||) for the 300 mg dose (95% CI, 5.1 to 10.8) (Table 13).

In the DELIVER trial,⁴ for the MSQ, the changes from baseline to week 24 in the role function restrictive domain were estimated to be improved by 15.1 points from a baseline mean of 35.7 (SD = ||||||) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, 11.7 to 18.5) and by 15.0 points from a baseline mean of 35.7 (SD = ||||||) for the 300 mg dose (95% CI, 11.6, 18.4). For the MSQ role function preventive domain, the mean changes from baseline to week 24 were estimated to be improved by 12.6 points from a mean baseline of 50.2 (SD = ||||||) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, 9.4 to 15.8) and by 13.2 points from a mean baseline of 51.0 (SD = ||||||) for the 300 mg dose (95% CI, 10.1, 16.4). For MSQ emotional function domain, the changes from baseline to week 24 were estimated to be improved by 14.1 points from a mean baseline of 50.3 (SD = ||||||) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, 10.5 to 17.7) and by 14.1 points from a mean baseline of 48.6 (SD = ||||||) for the 300 mg dose (95% CI, 10.6 to 17.7) (Table 13).

In the PROMISE-1 trial,⁶ the mean changes from baseline to week 24 in the EQ-5D-5L VAS were |||||||||||| for eptinezumab 100 mg, |||||||||||||||||| for eptinezumab 300 mg, and |||||||||||| for placebo (Table 14). In the PROMISE-2 trial,⁷ the mean changes from baseline to week 32 in the EQ-5D-5L VAS were |||||||||||| for eptinezumab 100 mg, |||||||||||| for eptinezumab 300 mg, and |||||||||||| for placebo (Table 14). Values above zero indicate improvement on this scale.

Symptoms

In the DELIVER trial,⁵ the mean changes from baseline to week 12 in the HIT-6 score were estimated to be decreased (improved) by −3.8 points from a mean baseline of 66.6 (SD = 4.7) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −5.0 to −2.5; P < 0.0001) and by −5.4 points from a mean baseline of 66.5 (SD = 4.4) for the 300 mg dose (95% CI, −6.7 to −4.2; P < 0.0001) (Table 13).

In the DELIVER trial,⁴ MBS scores were also reported under symptoms, and the mean scores at week 24 were estimated to be decreased (improved) by |||||||||||||||||||||||||||||| among patients on eptinezumab compared to those on placebo for eptinezumab 100 mg and by |||||||||||||||||||||||||||||| for eptinezumab 300 mg (Table 13).

In the PROMISE-2 trial,⁷ the mean changes from baseline to week 12 in the HIT-6 score were estimated to be decreased (improved) by −1.7 points from a mean baseline of 65.0 (SD = 4.9) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −2.8 to −0.7; P < 0.0001) and by −2.9 points from a mean baseline of 65.1 (SD = 5.0) for the 300 mg dose (95% CI, −3.9 to −1.8; P < 0.0001) (Table 14).

In the PROMISE-2 trial,⁷ MBS scores were reported as “very much improved” in the eptinezumab 100 mg, eptinezumab 300 mg, and placebo groups by ||||||||||||||||||, respectively, while ||||||||||||||||||, respectively, reported scores as “much improved” (Table 14). The HIT-6 and the MBS were not assessed in the PROMISE-1 trial.

Health Care Resource Utilization

In the DELIVER trial,⁵ for HCRU, the percentages of patients with no visit to a family physician were ||||||||||||||||||||||||% in the eptinezumab 100 mg, eptinezumab 300 mg, and placebo groups, respectively, with ||||||||||||||||||||||| reporting no visit to a specialist and ||||||||||||||||||||||||||||||, reporting no emergency department visits due to migraine, respectively. There were few hospitalizations due to migraine (|||||| of patients in each group) and similar numbers were seen for overnight hospital stays due to migraine (Table 13).

Work Days Lost

In the DELIVER trial,⁵ the mean changes from baseline to week 24 in absenteeism score on the WPAI instrument were estimated to be decreased (improved) by −4.5 points from a mean baseline of 11.4 (SD = 19.4) among patients on eptinezumab compared to those on placebo for the 100 mg dose (95% CI, −7.8 to −1.1) and by −4.7 points from a mean baseline of 12.0 (SD = 19.3) for the 300 mg dose (95% CI, −8.0 to −1.5) (Table 13). Outcomes related to the loss of work days were not assessed in the PROMISE-1 and PROMISE-2 trials.

Table 13: Efficacy Results (DELIVER Trial, Full Analysis Set)

CFB = change from baseline; CI = confidence interval; EPT100 = eptinezumab 100 mg every 12 weeks; EPT300 = eptinezumab 300 mg every 12 weeks; EQ-5D-5L = 5-Level EQ-5D questionnaire; HIT-6 = Headache Impact Test 6-item; MSQ = Migraine-Specific Quality of Life questionnaire; MBS = most bothersome symptom; MHD = monthly headache day; MMD = monthly migraine day; MMRM = mixed model for repeated measures; NA = not applicable; NR = not reported; PGIC = Patient Global Impression of Change; SD = standard deviation; SE = standard error; VAS = visual analogue scale; WPAI = Workplace Productivity and Activity Impairment.

^aThe estimated means, mean differences from placebo, and 95% CIs are from an MMRM with month (weeks 1 to 4, weeks 5 to 8, weeks 9 to 12, weeks 13 to 16, weeks 17 to 20, and weeks 21 to 24), country, stratification factor (MHDs at baseline: ≤ 14 vs. > 14) and treatment as factors, baseline score as a continuous covariate, treatment-by-month interaction, baseline score-by-month interaction, and stratum-by-month interaction.

^bThe comparison is based on logistic regression model including baseline MMDs as a continuous covariate, and treatment and stratification (MHDs at baseline ≤ 14 vs. > 14) as factors.

^cP values are computed separately for each active treatment group using an extended CMH test, adjusting for the stratification factor (MHDs at baseline ≤ 14 vs. > 14).

^dEstimated means, mean differences from placebo, and 95% confidence intervals are from an MMRM with month (weeks 1 to 4, weeks 5 to 8, weeks 9 to 12, weeks 13 to 16, weeks 17 to 20, and weeks 21 to 24), country, stratification factor (MHDs at baseline: ≤ 14 vs. > 14) and treatment as factors, baseline score as a continuous covariate, treatment-by-month interaction, baseline score-by-month interaction, and stratum-by-month interaction.

^eMMRM includes the following fixed effects: visit, country, stratification factor (MHDs at baseline: ≤ 14 vs. > 14) and treatment as factors; baseline HIT-6 total score, EQ-5D VAS score, MSQ subscores, and WPAI subscores as a continuous covariate (HIT-6, EQ-5D, MSQ, and WPAI outcomes only); baseline score-by-visit interaction, treatment-by-visit interaction, and stratum-by-visit interaction.

^fThese P values have not been adjusted for multiplicity.

Source: Clinical Study Report for DELIVER trial.⁵

Table 14: Efficacy Results (PROMISE-1 and PROMISE-2 Trials, Full Analysis Set)

ANCOVA = analysis of covariance; CFB = change from baseline; CI = confidence interval; EPT100 = eptinezumab 100 mg every 12 weeks; EPT300 = eptinezumab 300 mg every 12 weeks; EQ-5D-5L = 5-Level EQ-5D questionnaire; HIT-6 = Headache Impact Test 6-item; MBS = most bothersome symptom; MHD = monthly headache day; MMD = monthly migraine day; NA = not applicable; NR = not reported; PGIC = Patient Global Impression of Change; SD = standard deviation; SE = standard error.

^aANCOVA with treatment as a factor and the stratification variables: baseline migraine days and prophylactic medication used as independent variables.

^bCochran-Mantel-Haenszel test stratified by randomized baseline migraine days (≤ 9 days or > 9 days) in the PROMISE-1 trial and baseline migraine days (< 17 days or ≥ 17 days) and prophylactic medication use (yes vs. no) in the PROMISE-2 trial.

^cNominal P values are obtained from a repeated measure model including treatment group, visit (weeks 1, 2, 3, and 4), baseline migraine prevalence and treatment group–by–visit interaction.

^dANCOVA with treatment as a factor and baseline migraine days as a covariate in the PROMISE-1 trial and with treatment as a factor and baseline medication and the stratification variables; baseline migraine days and prophylactic medication use as covariates in the PROMISE-2 trial.

^eANCOVA model with treatment as a factor and baseline HIT-6 and the stratification variables: baseline migraine days and prophylactic medication use as independent variables.

^fThese P values have not been adjusted for multiplicity.

^gThese P values were tested after failure of the statistical hierarchy and therefore should be considered supportive.

Sources: Clinical Study Report for PROMISE-1⁶ and PROMISE-2 trials.⁷

Harms

Only those harms identified in the review protocol are reported below. Table 15 and Table 16 provide detailed harms data.

Adverse Events

In the DELIVER trial,⁵ AEs were reported by 43%, 41%, and 40% of patients (Table 15). AEs were reported by 63%, 58%, and 60% of patients in the PROMISE-1 trial⁶ and 44%, 52%, and 47% of patients in the PROMISE-2 trial⁷ (Table 16) who were randomized to eptinezumab 100 mg, eptinezumab 300 mg, and placebo, respectively.

Serious Adverse Events

SAEs occurred in 2%, 2%, and 1% of patients in the DELIVER trial⁵ (Table 15); 2%, 1%, and 3% of patients in the PROMISE-1 trial;⁶ and less than 1%, 1%, and less than 1% of patients in the PROMISE-2 trial⁷ (Table 16) who were randomized to eptinezumab 100 mg, eptinezumab 300 mg, and placebo, respectively. No specific SAEs occurred in more than 1 patient.

Withdrawals due to Adverse Events

In the DELIVER trial,⁵ treatment stoppages due to an AE occurred in 0.3% of patients in the eptinezumab 100 mg and placebo groups and 2% of patients in the eptinezumab 300 mg group (Table 15). In the PROMISE-1 trial,⁶ 3% of patients in the eptinezumab 100 mg and placebo groups, and 2% in the eptinezumab 300 mg group stopped treatment due to an AE, and in the PROMISE-2 trial⁷ less than 1% in the eptinezumab 100 mg and placebo groups, and 2% of patients on eptinezumab 300 mg stopped treatment due to an AE (Table 16).

Mortality

No deaths occurred in any of the studies.^5-7

Table 15: Summary of Harms (DELIVER Trial)

EPT100 = eptinezumab 100 mg every 12 weeks; EPT300 = eptinezumab 300 mg every 12 weeks.

^aFrequency greater than 2% in any group.

Source: Clinical Study Report for DELIVER trial.⁵

Table 16: Summary of Harms (PROMISE-1 and PROMISE-2 Trials)

ALT = alanine transaminase; AST = aspartate transaminase; EPT100 = eptinezumab 100 mg every 12 weeks; EPT300 = eptinezumab 300 mg every 12 weeks; NR = not reported; URTI = upper respiratory tract infection.

^aFrequency greater than 2% in any group.

Sources: Clinical Study Reports for PROMISE-1⁶ and PROMISE-2 trials.⁷

Notable Harms

Notable harms identified by the review team included: anaphylaxis or hypersensitivity reactions, antibody formation, cardiovascular events, suicidality, alopecia, and fatigue. The most common notable harms that were reported in the included studies were hypersensitivity and/or anaphylaxis, occurring in 2% of patients in each of the eptinezumab 100 mg and placebo groups, and 3% of patients in the eptinezumab 300 mg group in the DELIVER trial,⁵ and cardiovascular or cerebrovascular disorders, occurring in 3% of patients in the eptinezumab 100 mg and placebo groups, and 1% in the eptinezumab 300 mg group in the DELIVER trial. All other notable harms in the DELIVER trial occurred in 1% of patients or less, and in the PROMISE-1⁶ and PROMISE-2⁷ trials, notable harms occurred in 1% of patients or less.

Critical Appraisal

Internal Validity

All 3 studies appeared to have been well designed, with steps taken to maintain allocation concealment during the randomization process, maintain blinding during the treatment period, and control for multiplicity. Some issues with respect to critical appraisal are noted in the following section.

While the study withdrawal rates were less than 5% across groups in the DELIVER trial,⁵ they were notably higher in the PROMISE-2 trial⁷ (approximately 10% of patients) and particularly in the PROMISE-1 trial,⁶ in which study withdrawals ranged from 22% to 26% of patients across groups. The most common reasons for discontinuing the study in the PROMISE-1 trial were “study burden” and “loss to follow-up,” neither of which provided much insight into why there were such high withdrawals in the PROMISE-1 trial compared to the other studies, although patients in the PROMISE-1 trial were to receive 4 infusions, double the amount of the other 2 studies, suggesting that the longer duration of treatment may have played a role. No further explanation was provided in the Clinical Study Report, although the sponsor noted that 94% of patients remained in the study until week 12, which was the time point at which the primary outcome was assessed. Although there were no clear differences in withdrawals between study groups, such a large number of withdrawals may confound assessment of outcomes after week 12, as the equal distribution of prognostic characteristics between groups achieved at the time of randomization may no longer be the case.

Although HRQoL was assessed in the included studies, none of the HRQoL outcomes were controlled for multiplicity and therefore this limits any conclusions that can be drawn from this data, which should be considered supportive in nature. As it is clear from the patient input provided to CADTH that migraine has a significant impact on HRQoL, the lack of multiplicity control for any of the HRQoL outcomes should be considered a limitation of the evidence from the studies included in this review.

The validity and reliability of the MSQ and HIT-6 were reviewed by the CADTH review team and were considered to be adequate. No studies were found that reported on the validity or reliability for the MBS, while no studies specific to migraine were found for the EQ-5D-5L, WPAI, or PGIC. MIDs for patients with migraine were found for the MSQ and HIT-6, but not for the other instruments. The lack of studies assessing validity and reliability, or reporting MIDs, is a limitation when trying to interpret these outcomes.

Although prespecified subgroup data were reported for the subgroups of interest in our protocol, any analyses that have been reported were exploratory and were not adjusted for multiple comparisons, limiting any conclusions that can be drawn.

Migraine and headache-related outcomes were assessed by use of an eDiary. The sponsor noted in the clinical study reports that whether a migraine occurred was determined from eDiary entries; however, it was not clear whether the investigator or the patient made the determination. Compliance to eDiary entries was only reported in the DELIVER trial, and for each of the 4-week intervals it was reported as greater than 96% for patients with at least 14 days of compliance and greater than 90% for patients with at least 21 days of compliance, which the sponsor described as a “high level” of compliance. If patients made fewer than 21 days of entries in a 28-day period, then the results were calculated as a weighted function of the observed data for the current 4-week interval and the results for the previous interval. This approach assumes that the rate of MMDs was the same for days with missing and those with nonmissing data, and there are limitations to making such an assumption. For example, patients who are experiencing a migraine may be less likely to complete their diary entry, and this may lead to an underestimate of MMDs.

External Validity

The clinical expert consulted by CADTH on this review described the populations enrolled in the included studies as reflective of the populations that would be treated with this drug in Canada. The DELIVER study was the only trial that enrolled patients who had failed at least 2 prior prophylaxis regimens, and this is therefore the only trial that features a population that reflects the reimbursement criteria proposed by the sponsor. For example, in the PROMISE-2 trial, only 37% of patients had used migraine prophylaxis at all before the study, and the number of patients using prior prophylaxis was not reported in the PROMISE-1 trial. There were no notable differences between groups in baseline characteristics within studies. The clinical expert consulted by CADTH for this review stated that the number of prior prophylaxis drugs would have no impact on the efficacy of CGRP mAbs.

None of the included studies featured an active comparator, and there are therefore no direct comparisons available of eptinezumab versus other CGRP mAbs or other drugs in the therapeutic class, such as botulinum toxin. Indirect treatment comparisons (ITCs) were available, and their limitations are noted in the following section. The lack of direct comparative data limits our ability to assess the claim, for example, that eptinezumab has a faster onset of action than other drugs in its class.

In 2 of the included studies, patients received only 2 doses of eptinezumab during the blinded treatment period, and in the other study the maximum number of doses received was 4. This limits our ability to draw conclusions regarding the longer-term efficacy or harms of eptinezumab. Most of the outcomes that were controlled for multiplicity, including the primary outcome in each study, were assessed at the 12-week time point, after patients had received only a single dose of eptinezumab. It is therefore not known whether the efficacy of eptinezumab begins to wane with time, and the long-term safety is also unclear.

The primary outcome of each of the included studies was the change from baseline in MMDs for weeks 1 to 12. Change in MMDs is a common and widely accepted outcome for assessing response to therapies for migraine prophylaxis, and is an appropriate and relevant primary outcome, according to the clinical expert consulted by CADTH for this review. In their input to CADTH, patients made it clear that migraine frequency is of paramount importance. The clinical expert noted that the instruments used in the included studies to assess patient-reported outcomes such as HRQoL and symptoms are not used in clinical practice, while an instrument such as MIDAS, which is sometimes used in clinical practice, was not assessed in any of the included trials. It is clear that migraine has a significant impact on patients’ HRQoL; however, although HRQoL instruments were included in the clinical trials, the fact that none of the statistical testing procedures were controlled for multiplicity limits any conclusions that can be drawn regarding this important outcome.

Across the studies the sponsor tended to use ORs in their primary analyses instead of relative risks (RRs). ORs tend to exaggerate the effect estimate compared to RRs, which are more intuitive. It is unclear why the sponsor used ORs instead of RRs.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

The objective of this section is to summarize and critically appraise the methods and findings of the sponsor-submitted review of the literature and NMA comparing eptinezumab with key comparators for the prevention of EM or CM in adults who have experienced an inadequate response, intolerance, or contraindication to at least 2 oral prophylactic migraine medications.

A focused literature search for NMAs dealing with migraines was run in MEDLINE All (1946–) on July 6, 2022. No limits were applied to the search. The literature search identified 56 articles, 5 of which were retrieved for scrutiny. Upon further review of the 5 potential studies, no additional ITCs were included in the review as the evidence was associated with many limitations in conduct and did not address any additional gaps in the literature.

Description of the Indirect Evidence

The sponsor conducted an SLR in May 2020 and updated it in June 2021 to identify evidence for inclusion in the NMA. A feasibility assessment was conducted to determine the comparability of eligible studies with the DELIVER trial for eptinezumab. A total of 11 studies were included in the Bayesian network, evaluating the comparative impact of eptinezumab, key CGRP mAbs (erenumab, fremanezumab, and galcanezumab), and placebo on efficacy and HRQoL in patients with EM and CM.⁹

Methods of Sponsor-Submitted NMA

Objectives

The objective of the sponsor-submitted NMA was to provide comparative estimates of efficacy and HRQoL for eptinezumab and key comparators for the prevention of migraine in adults who have at least 4 migraine days per month and have experienced an inadequate response, intolerance, or contraindication to at least 2 oral prophylactic migraine medications. Given the differences in treatment by migraine type, separate analyses were conducted for EM and CM.⁹

Study Selection Methods

The sponsor-submitted NMA was informed by an SLR (updated to June 2021) to identify all existing RCTs for the treatment of EM and CM. Methods for identification of citations included database searches of Embase, MEDLINE, MEDLINE In-Process, MEDLINE Daily, MEDLINE Epub Ahead of Print, the Cochrane Database for Systematic Reviews and Cochrane Central Register of Controlled Trials, and the University of York Centre for Reviews and Dissemination platform (only for the original SLR). Manual searches of conference proceedings, clinical trial databases, health technology assessment websites, and reference lists were also conducted.⁹ No information on screening or data extraction methods, or methods for assessing data quality included in the SLR were provided.

Eligibility criteria for inclusion in the NMA were more refined than in the SLR. Table 17 summarizes the predefined study selection criteria for the SLR and NMA. The main population of interest for the NMA was patients with documented treatment failure of at least 2 preventive migraine medications.⁹ The list of eligible interventions, comparators, and outcomes was also more restricted in the NMA compared with the SLR. Key outcomes in the NMA included 50% MRR, and changes from baseline at week 12 in MMDs, MMDs with acute medication use, MSQ v2.1 domains, and HIT-6 scores. Assessment time points of interest for the NMA were changes evaluated at 12 weeks. Time points varied between comparators, including anti-CGRPs and onabotulinum toxin A. For CGRP mAbs, when changes from weeks 1 to 12 were not available, the outcome corresponding to the primary end point (i.e., week 9 to 12) or the latest available time point up until week 12 (i.e., week 4 to 8) was preferred. For onabotulinum toxin A, data were not available at week 12, and data from week 24 were used instead, applying the same principles for CGRP mAbs.⁹

NMA Methods

Feasibility Assessment

A feasibility assessment was conducted to assess the suitability of an NMA for the comparisons of interest. Characteristics of trials reporting the effects of anti-CGRPs and onabotulinum toxin A on EM and CM were assessed for heterogeneity via study and baseline characteristics. Study characteristics assessed included participants’ country, trial start date, route of administration, diagnostic criteria for EM and CM, and migraine-day definition. Baseline characteristics considered in the feasibility assessment included age, sex, race or ethnicity, weight, migraine severity (EM or CM), disease duration, MHDs, MMDs, monthly migraine frequency, preventive medication use, acute medication use, and codiagnosis of MOH. Baseline characteristics were also assessed for prior treatment–failure subgroups.⁹

Table 17: Study Selection Criteria for Sponsor-Submitted SLR and Network Meta-Analysis

AE = adverse event; CFB = change from baseline; CGRP = calcitonin gene–related peptide; CM = chronic migraine; EM = episodic migraine; HIT-6 = Headache Impact Test 6-item; HRQoL = health-related quality of life; MHD = monthly headache day; MMD = monthly migraine day; MRR = migraine response rate; MSQ = Migraine-Specific Quality of Life questionnaire; MSQ v2.1 = Migraine-Specific Quality of Life Questionnaire version 2.1; PICOS = population, intervention, comparison, outcomes and study; q4w = every 4 weeks; q12w = every 12 weeks; RCT = randomized controlled trial; SLR = systematic literature review; WPAI = Work Productivity and Activity Impairment.

Source: Sponsor-submitted network meta-analysis.⁹

NMA Methods

The NMA was conducted in a Bayesian framework using fixed-effect models as base-case analyses due to the limited number of studies per comparison. Random-effects models were also fitted for the 2 priority outcomes (MMDs and 50% MRR). Due to data availability, only arm-level data were used for comparisons, and contrast-level data were not required.⁹ As no closed loops were formed in the networks, there was no potential for conflict between direct and indirect evidence, and inconsistency was not assessed.

The primary analysis of the NMA consisted of comparisons between eptinezumab and anti-CGRPs for both EM and CM separately, to control for potential differences identified during the feasibility assessment. Potential differences in baseline MOH across CM populations were a limitation of the analyses, although it was not feasible to assess the extent of any differences in MOH due to a lack of reporting across studies. Two secondary analyses were conducted. The first consisted of comparisons with onabotulinum toxin A for the end points of change from baseline in MMDs and 50% MRR using data from 24 weeks for onabotulinum toxin A and 12 weeks for eptinezumab due to limited data availability. Additionally, changes from baseline in MHDs data were used for onabotulinum toxin A, while changes from baseline in MMDs were used for eptinezumab. The other secondary analysis consisted of comparisons with anti-CGRPs, adjusting for the route of administration for change from baseline in MMDs at week 12, given that eptinezumab is the only treatment administered by IV. This secondary analysis was conducted because it was deemed likely that patients receiving placebo through IV rather than subcutaneously had an elevated response (greater reduction) in terms of MMDs. As such, in this analysis, a random additive effect of 1.34 MMDs was subtracted from the mean differences of treatments with subcutaneous administration, to mimic an IV placebo effect.⁹

For continuous data, a normal likelihood and an identity link were assumed. For binary outcomes, it was assumed that the data followed a binomial distribution. All analyses were carried out by Markov chain Monte Carlo simulation, using 3 different chains with dispersed initial values. A total of 30,000 burn-in samples were used and the remaining samples of the posterior distributions of the model parameters were used for inference. Fixed-effect models were run for a total of 100,000 runs per chain, implying that 210,000 samples of the posterior distribution were used for inference. Models including random effects were run for a total of 200,000 runs per chain, implying that 510,000 samples were used to draw inference. Posterior medians were reported along with 95% CrIs, and statistical superiority or inferiority was determined by whether the 95% CrIs crossed the value of no treatment effect. Vague prior distributions were supplied for basic parameters and trial baselines. Vague prior distributions were also assigned in random effects models with a binomial likelihood. For random-effect models with a normal likelihood and identity link (i.e., change from baseline in MMDs), the prior distribution of the between-study variance was informed by the posterior distribution of an NMA conducted for phase III trials in patients with EM. Specifically, the posterior distribution of the between-trial SD followed an approximate log-normal distribution with a mean of −1.1 and an SD of 1.17 on the logarithmic scale.⁹

Convergence was confirmed by visual inspection of the trace plots for the 3 chains. Three types of plots were produced for each basic parameter: a Gelman-Rubin plot, an autocorrelation plot, and a density plot. For cases in which studies reported zero events, a 0.5 correction was applied to all treatment arms to ensure model convergence. Due to the limited number of studies per treatment comparison, generation of model statistics for model selection between fixed- and random-effect models was not performed as fixed effects were chosen as the base case.

For continuous outcomes, the mean and SE were required for the analysis. If the mean was not reported, the observation was not included in the analysis. If the SE was not reported, then the SE was derived from the SD and number of patients or the CI, if available. When necessary, standard errors were digitized. No model for imputation of SDs was required to be applied. Where missing, 50% MRR data stratified by subgroups of interest was calculated. For the FOCUS study, 50% MRR was reported using a mixed EM and CM group for 2 or more prior treatment failures, and the percentage of responders per arm for patients with 2, 3, and 4 prior treatment failures stratified by migraine type was reported. As no sample sizes were reported, sample sizes were imputed using the total number of EM and CM patients per arm and the distribution of 2, 3, and 4 prior treatment failures for the full trial population under the assumption that the treatment-failure distribution was independent of EM or CM classification. The imputed sample sizes enabled the pooling of the percentage of responders per arm for 2, 3, and 4 prior treatment failures in patients with EM or CM to give 50% MRR rates for patients with EM and 2 or more treatment failures and those with CM and 2 or more treatment failures. For binary outcomes, the number of events and sample size was required. If these data were not available but percentages were reported, then the number of events were derived from the percentages, and, where applicable, it was assumed the sample size was equal to the number randomized and rounded to the nearest integer.⁹

Results of Sponsor-Submitted NMA

Summary of Included Studies and Results of the Feasibility Assessment

Complete results of the SLR were not provided. A total of 11 studies were identified as being suitable for inclusion in the NMA; 10 of which were identified in the SLR, with the final study being the DELIVER clinical trial for eptinezumab.⁹ A summary of key study and baseline characteristics from the intention-to-treat population of each included study is reported in Table 18.

The year of the study start date ranged from 2006 to 2020. All trials were multinational, ranging from 2 countries to 17. Treatments were administered by subcutaneous injection in 8 of 11 studies, intramuscular injection of onabotulinum toxin A in 2 studies, and IV of eptinezumab in 1 study. The migraine classifications of each study were generally consistent. CM was consistently defined as headache on 15 or more days per month, with at least 8 days fulfilling migraine criteria or having migraine features. EM was consistently defined as headache on fewer than 15 days per month, with 4 to 14 having migraine features. There was a general consistency in definition of migraine days across studies. Migraine days were consistently defined as a day with a headache with features meeting the ICHD criteria for a migraine. There was some inconsistency regarding how long the headache meeting ICHD criteria was required to last (≥ 30 or ≥ 4 hours), and some inconsistency in which version of the ICHD was used. Additionally, there was some inconsistency in definition of migraine days in terms of whether days on which migraine-specific acute preventive medications were taken were counted as migraine days. In some studies, these medications needed to be taken alongside a headache (meeting the ICHD criteria), whereas in others they did not.⁹

When reported, demographic and baseline characteristics were similar across studies included in the feasibility assessment. In the studies evaluated, the majority of patients were white (range, 70.27% to 95.96%) and female (range, 81.3% to 89.89%), with ages ranging between 40 and 47 years. The authors noted that there were differences in many baseline characteristics, including MHDs, MMDs, migraine frequency, and days of acute medication use or medication overuse across studies, likely because some populations were specific to EM or CM, or consisted of both EM and CM patients.⁹

During the feasibility assessment, subgroup results from the RCTs included from the SLR and subgroup results from the DELIVER clinical trial were reviewed to identify potential treatment effect–modifying variables. Based on the results of subgroup analyses from different RCTs (NCT02066415 for erenumab; FOCUS for fremanezumab; REGAIN and CONQUER for galcanezumab; and DELIVER for eptinezumab) it was concluded that the number of prior treatment failures, baseline severity (i.e., EM or CM, and baseline MMDs), and MOH (for CM patients only) were potential treatment-effect modifiers.⁹