Abstract
Objective
To examine the safety and efficacy of ubrogepant for acute treatment of migraine across cardiovascular (CV) disease risk categories.
Methods
ACHIEVE I and II were multicenter, double-blind, single-attack, phase 3 trials in adults with migraine, with or without aura. Participants were randomized 1:1:1 to placebo or ubrogepant (50 or 100 mg in ACHIEVE I; 25 or 50 mg in ACHIEVE II), to treat one migraine attack of moderate or severe headache pain intensity. This post-hoc analysis pooled data from ubrogepant 50 mg and placebo groups from the ACHIEVE trials to examine the safety and efficacy of ubrogepant by baseline cardiovascular disease risk factors. Using a cardiovascular risk assessment algorithm, participants were categorized as having no cardiovascular risk, low cardiovascular risk or moderate-high cardiovascular risk at baseline. Treatment-emergent adverse events were documented 48 h and 30 days after taking the trial medication. Co-primary efficacy outcomes were 2-h pain freedom and 2-h absence of most bothersome migraine-associated symptom.
Results
Overall, 3358 participants were randomized in the ACHIEVE trials (n = 2901 safety population; n = 2682 modified intent-to-treat population). In the safety population, 11% of participants were categorized as moderate-high (n = 311), 32% low (n = 920), and 58% no cardiovascular risk factors (n = 1670). The proportion of ubrogepant participants reporting a treatment-emergent adverse event was comparable across risk categories and similar to placebo. The treatment effects of ubrogepant versus placebo were consistent across cardiovascular risk categories for all efficacy outcomes.
Conclusion
The safety and efficacy of ubrogepant for the acute treatment of a single migraine attack did not differ by the presence of major cardiovascular risk factors. No evidence of increased treatment-emergent adverse events or cardiac system organ class adverse events with ≥2 major cardiovascular risk factors and no safety concerns were identified.
Abbreviations
AE: adverse event
CV: cardiovascular
CGRP: calcitonin gene-related peptide
MBS: most-bothersome symptom
TEAE: treatment-emergent adverse event
Introduction
Migraine is a chronic neurologic disease with episodic attacks characterized by often incapacitating symptoms such as headache pain, sensitivity to light and sound, and nausea. Acute treatment options for migraine include analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), ergot derivatives, and triptans, though in some individuals with migraine these treatment options are limited by incomplete efficacy, poor tolerability, and/or contraindications (1).
Effective acute treatment of migraine is challenging in people who have or are at risk for cardiovascular (CV) disease, which is prevalent in people with migraine (2,3). Results from the American Migraine Prevalence and Prevention (AMPP) study showed that among men and women with episodic migraine, 69.5% of women and 73.4% of men had at least one Framingham CV risk factor (4), 38.9% of women and 41.6% of men had ≥2 risk factors, and 18.6% of women and 19.1% of men had ≥3 risk factors (3). Migraine-specific treatment options are restricted in people with CV disease or associated risk factors; triptans and ergots are vasoconstrictors and are contraindicated in people with existing CV disease. Precautions are recommended for those with multiple CV risk factors.
People with migraine that have conditions that limit the use of triptans, ergot alkaloids and NSAIDs are more likely to receive opioids or barbiturates for treatment. Recent observational data show that people with migraine who have ≥1 CV risk factor are 56% more likely to receive an opioid as an acute treatment than those with no CV risk factors, which is concerning since opioids and barbiturates have limited efficacy and tolerability in the acute treatment of migraine (5).
Ubrogepant is a recently FDA-approved, oral calcitonin gene-related peptide (CGRP) receptor antagonist (gepant) developed for the acute treatment of migraine. In two pivotal phase 3 clinical trials, ACHIEVE I and ACHIEVE II, ubrogepant met its two co-primary endpoints, superiority to placebo in achieving 2-h pain freedom and 2-h absence of most bothersome migraine-associated symptom (MBS) (6,7). These trials also demonstrated that ubrogepant was safe, well-tolerated, and superior to placebo in achieving prespecified secondary efficacy outcomes. Additionally, there were no clinically relevant changes in other laboratory parameters, vital signs, or electrocardiogram (ECG) parameters (6,7). In this post-hoc analysis, we evaluate the safety and efficacy of ubrogepant by the presence of major cardiovascular risk factors in the ACHIEVE trials and address two crucial issues: i) Does the tolerability and safety profile of ubrogepant differ with CV risk status and ii) does the efficacy of ubrogepant in the acute treatment of migraine differ by CV risk status?
Methods
Trial design
The designs of the ACHIEVE clinical trials have previously been published in detail (6,7). Briefly, the ACHIEVE trials were multi-center, randomized, double-blind, placebo-controlled, parallel-group, single-attack phase 3 trials conducted in the USA. Participants were randomized 1:1:1 to placebo, ubrogepant 50 mg, or ubrogepant 100 mg in ACHIEVE I or placebo, ubrogepant 25 mg, or ubrogepant 50 mg in ACHIEVE II, and had up to 60 days to treat a single qualifying migraine attack of moderate to severe pain intensity at home. An optional blinded second dose of study medication (active or placebo) or a dose of their own rescue medication, which could include triptans, analgesics (e.g. acetaminophen, NSAIDs, opioids), or anti-emetics, was allowed from 2–48 h after the initial dose of study medication if the headache pain remained moderate or severe or returned to being moderate or severe. Participants reported headache severity, absence or presence of migraine-associated, non-headache symptoms, use of rescue medication or an optional second dose of trial medication, functional disability scale assessment, and recurrence of headache pain in an electronic diary. The protocols and all amendments were approved by a properly constituted Institutional Review Board.
Participants
Eligible participants included adults 18–75 years old with a minimum 1-year history of migraine with or without aura, diagnosed by the International Classification of Headache Disorders, 3rd edition (beta version) (ICHD-3 beta) criteria (8). Individuals with clinically significant CV or cerebrovascular disease (per the investigator’s opinion), with recent CV/cerebrovascular events, as well as those with clinically uncontrolled hypertension (defined by sitting systolic blood pressure (BP) > 160 mm Hg or sitting diastolic BP > 100 mm Hg at visits 1 or 2), were excluded. A detailed list of inclusion/exclusion criteria is provided in
Cardiovascular risk assessment
At baseline, participants were classified into one of three cardiovascular risk categories (high, moderate, low) using an algorithm based on the National Cholesterol Education Program (NCEP; National Institutes of Health, 2001) and Framingham risk factors along with the presence of CV heart disease or other forms of vascular disease, as well as diabetes (Figure 1). A fourth category was created for this analysis to separate participants in the low-risk subgroup with no CV risk factors identified. This group was not included in the original protocol and is not a category in NCEP or Framingham algorithms. For analytical purposes, moderate- and high-risk participants were grouped due to small sample size. CV risk was therefore categorized as moderate to high risk (≥10% 10-year CV risk), low risk (<10% 10-year CV risk), and no known major CV risk factors present.
Cardiovascular risk assessment algorithm.
Safety
Safety parameters included adverse events (AEs), clinical laboratory findings, vital signs, ECG parameters, and the Columbia-Suicide Severity Rating Scale (C-SSRS). AEs were collected throughout the duration of the ACHIEVE trials. Study investigators provided an assessment of the severity and causal relationship to the trial medication for all AEs. The primary safety analysis evaluated AEs that occurred within 48 h after the administration of the initial dose or optional second dose of the trial medication. Secondary safety analyses included AEs that occurred within 30 days after the administration of any dose. Vital sign measurements, including sitting and standing BP, sitting and standing pulse rate, respiratory rates, temperature, and body weight were performed at every visit.
Efficacy outcomes
The co-primary efficacy endpoints were pain freedom and absence of MBS 2 h after the initial dose of trial medication. Pain freedom was defined as a reduction in headache severity from moderate/severe pre dose, to no pain 2 h after the initial dose. Absence of MBS 2 h after the initial dose reflected freedom from the most bothersome migraine-associated symptom identified by participants immediately before treating the qualifying migraine attack. Participants’ level of functional disability (derived from the Functional Disability Scale (9)) at 1, 2, 4, and 8 h post dose were additional efficacy endpoints. Secondary efficacy endpoints included pain relief (i.e. reduction of a moderate/severe migraine headache to mild or no pain) at 2 h, sustained relief from 2 to 24 h with no administration of either rescue medication or second dose of trial medication, sustained pain freedom from 2 to 24 h with no administration of either rescue medication or second dose of trial medication, absence of photophobia at 2 h, absence of phonophobia at 2 h, and absence of nausea at 2 h.
Statistical analysis
The safety analyses were performed using the safety population, which included all randomized participants who received ≥1 dose of the study medication. An AE was considered a treatment-emergent adverse event (TEAE) if it occurred after the initial dose of trial medication or was present before the initial dose and increased in severity after the initial dose. The number and percentage of TEAEs in each treatment group were tabulated by system organ class and preferred term and further categorized by severity and causal relationship to the trial medication.
Efficacy analyses were conducted in the modified intent-to-treat (mITT) population, which included all randomized participants who received at least one dose of trial medication, recorded a pre-dose migraine headache severity measurement, and had at least one post-dose migraine headache severity or migraine-associated symptom measurement at or before the 2-h time point. To test the hypothesis that the efficacy of ubrogepant versus placebo to achieve pain freedom 2 h post dose did not differ by underlying CV risk, an interaction p-value was calculated using logistic regression. Treatment group, CV risk category (moderate/high, low, no risk factors), historical triptan response, use of medication for migraine prevention, pre-dose headache severity, and a treatment group by CV risk category interaction term were included as explanatory variables. For 2-h absence of MBS, a similar logistic regression model was used to calculate an interaction p-value with the addition of a categorical term for the symptom identified as the most bothersome at pre-dose baseline. The last-observation-carried-forward (LOCF) approach was the primary imputation method for the missing post-treatment values. Secondary efficacy outcomes were analyzed using similar statistical methods.
Ubrogepant 50 mg and placebo treatment groups from the individual trials were pooled for analysis. All statistical tests were two-sided hypothesis tests performed at the 5% level of significance for main effects and interactions. All confidence intervals were two-sided 95% confidence intervals unless otherwise noted. A detailed description of the assumptions used to obtain the detectable treatment-by-CV risk category interaction with 80% power at a 5% significance level for a given endpoint is available in Supplemental Table 2.
Results
Participant characteristics
A total of 3358 participants were randomized into the ACHIEVE I and ACHIEVE II trials (intent-to-treat (ITT) population); 2901 took ≥1 dose of the trial medication (safety population), and the 2682 participants who took ≥1 dose of the trial medication, recorded baseline migraine headache severity, and provided at least one post-dose efficacy assessment were included in the mITT population (Figure 2). Baseline demographics and clinical characteristics of the pooled safety population (n = 1938) by baseline CV risk and treatment group are presented in Table 1. In the pooled placebo and ubrogepant 50 mg groups, participants had a mean age of 41 years and were predominantly female (90%) and white (82%). Additional demographic data are available in Supplemental Tables 3 and 4. Characteristics of qualifying migraine attacks in participants in the overall mITT population (n = 2682) are summarized in Supplemental Table 5. The distribution of participants across CV risk categories was consistent between trials and treatment groups. Approximately 11% of participants in the overall safety population (n = 2901) were categorized as moderate/high risk (n = 311), 32% as low risk (n = 920), and 58% as no CV risk factors (n = 1670). The distribution of major CV risk factors is shown in Supplemental Table 6.
Participant disposition.
Baseline demographic and clinical characteristics for ubrogepant 50 mg and placebo (pooled safety population).
BMI: body mass index; CV: cardiovascular; NSAID: nonsteroidal anti-inflammatory drugs.
aAge relative to informed consent date.
bmITT population.
Safety
The proportion of participants reporting a TEAE was generally consistent across CV risk categories, as shown for the pooled analyses in Table 2(a). Results for the individual ACHIEVE trials were similar and are presented in Table 2(b). Within 48 h of the initial dose or optional second dose in the pooled analysis, 36/311 participants (11.6%) in the moderate to high CV risk group, 106/920 participants (11.5%) in the low CV risk group, and 201/1670 participants (12.0%) in the no CV risk factor group reported TEAEs. No serious AEs (SAEs) occurred within the first 48 h. Additional participants reported TEAEs within 30 days of taking the study medication, the proportion of which was also comparable across CV risk categories. Commonly reported TEAEs included nausea, dry mouth, and somnolence (all less than 5%). There were no AEs leading to participant discontinuation.
(a). Adverse events by cardiovascular risk category for ubrogepant 50 mg (pooled safety population).
TEAE: treatment-emergent adverse event; SAE: serious adverse event.
aEvents reported by ≥2% of all participants in any treatment group of ACHIEVE I and II.
bTriptan-like AE class consists of the following individual AEs: Chest pain, chest discomfort, throat tightness, asthenia, paresthesia, dysesthesia, and hyperesthesia.
(b). Adverse events by cardiovascular risk category for ubrogepant 25 mg (ACHIEVE II) and ubrogepant 100mg (ACHIEVE I) (safety population).
aEvents reported by ≥2% of all participants in any treatment group of ACHIEVE I and II.
bTriptan-like AE class consists of the following individual AEs: chest pain, chest discomfort, throat tightness, asthenia, paresthesia, dysesthesia, and hyperesthesia.
Within 48 h of taking the trial medication, the rate of TEAEs in the cardiac disorder system organ class (e.g. palpitations and cardiac flutter) was low and similar between ubrogepant and placebo treatment groups; 1/984 (0.1%) participants in the placebo groups and 5/1917 (0.3%) participants in the ubrogepant groups, none of whom were in the moderate to high CV risk category, reported a cardiac disorder system organ class TEAE. Within 30 days, a total of 3/984 (0.3%) participants in the placebo groups and 14/1917 (0.7%) participants in the ubrogepant treatment groups reported TEAEs in the cardiac disorder system organ class. Six participants, all of whom were in the no CV risk factors category, reported SAEs within 30 days of dosing. One participant in the ubrogepant 50 mg group experienced an SAE in the cardiac disorder system organ class, pericardial effusion, which was not treatment related. Only one of the SAEs (seizure) was considered to be related to the trial medication by the investigator but was confounded by possible alprazolam withdrawal. Overall, the trials provided no evidence of increased AEs in participants with higher baseline CV risk.
Efficacy outcomes
The efficacy of ubrogepant 50 mg versus placebo was comparable across CV risk categories for the co-primary efficacy endpoints (Figure 3). Both the pooled and individual regression analyses produced non-significant (>0.05) interaction p-values, indicating that underlying CV risk did not significantly affect the efficacy of ubrogepant to achieve 2-h pain freedom and absence of MBS at 2 h. In the pooled analyses, the magnitude of effect (ubrogepant vs. placebo) did not differ significantly across CV risk categories for pain freedom at 2 h post dose (interaction p-value = 0.1358) or absence of MBS at 2 h post dose (interaction p-value = 0.7014). Results for the individual trials for the 25 mg dose and the 100 mg dose did not show an influence of CV risk on 2-h pain freedom or 2-h absence of the MBS (Supplemental Figures 1 and 2). The treatment effect of pooled ubrogepant 50 mg versus placebo on the secondary efficacy outcomes was consistent with the findings for the primary endpoints, with no evidence that treatment effect differed by baseline CV risk, as evidenced by non-significant interaction p-values (Table 3, Supplemental Figure 3, Supplemental Tables 7–8).
Pooled analysis co-primary efficacy endpoints: Pain freedom and absence of most bothersome migraine-associated symptom at 2 h after initial dose (mITT).
Secondary efficacy endpoint responder rates by CV risk category for ubrogepant 50 mg: Pooled analysis (mITT population).
aThe interaction p-value tests the hypothesis that the magnitude of the difference between ubrogepant 50 mg and placebo differs by level of CV risk; the non-significant interaction p-values indicate the response rates did not significantly differ among categories of baseline CV risk.
bSustained pain freedom: Pain freedom at 2 h with no administration of either rescue medication or the second dose of study drug, and with no occurrence thereafter of a mild/moderate/severe headache 24 h after dosing with study drug.
cResponder: Response to the Functional Disability Scale is “no disability, able to function normally”.
dPercentages calculated as 100 × (n/N1).
Discussion
Effective acute treatment of migraine is challenging in people with vascular disease and risk factors, due to limitations of the currently available acute treatment options. Data from longitudinal, population-based cohort studies in the United States have identified vascular disease or risk as an important unmet treatment need in people with migraine (10,11). Ubrogepant, a novel oral CGRP receptor antagonist (gepant), was developed, in part, because it lacked the vasoconstrictive effects of triptans and ergot alkaloids (12). In this pooled analysis of the pivotal efficacy studies, we found that ubrogepant safety and efficacy for the acute treatment of migraine does not vary with level of CV risk defined by the presence of major CV risk factors. The adverse event profile of ubrogepant was similar across CV risk categories and was similar to placebo. The treatment effect of ubrogepant versus placebo did not significantly differ across CV risk categories for 2-h pain freedom, 2-h absence of MSB, 2-h pain relief, sustained pain freedom, sustained pain relief, absence of photophobia, phonophobia, and nausea. The proportion of participants reporting the ability to function normally post dose was not affected by CV risk category.
Despite the availability of migraine-specific acute treatments, observational data show that in the USA, among those who use prescription medication for the acute treatment of migraine, less than half currently use migraine-specific prescription medications (13), and less than one-third are very satisfied with their usual acute treatment (14).1 Triptans are the most commonly prescribed class of migraine-specific medication (15). Though the efficacy of triptans is well established from clinical trial data (16), real-world studies have demonstrated low persistence and adherence to triptans, often due to lack of efficacy and side effects (17–20). In addition, because of their vasoconstrictive properties, triptan use is contraindicated in people with CV conditions and limited in those with multiple CV risk factors (21). Individuals with CV comorbidities are more likely to receive an opioid or barbiturate than those without CV risk (5,22), perhaps a reflection of limited treatment options. Opioid and barbiturate medications have demonstrated limited efficacy and tolerability in the acute treatment of migraine (22–24) and are not recommended for use on a regular basis due to concern about tolerance, addiction, and medication overuse/medication overuse headaches (1,25). Use of opiods and barbiturates are associated with an increased risk of migraine disease progression (26). There is an urgent unmet need for new acute treatment options for migraine with improved benefit-risk profiles.
A growing body of evidence demonstrates that the treatment response to gepants has been positive while avoiding tolerability issues and contraindications seen with triptans and opioid/barbiturate-containing analgesics (1,6,7,27–29). The results of this analysis support the safety and tolerability of ubrogepant in individuals for whom other treatment options may be limited due to the presence of multiple CV risk factors. These findings are consistent with the results of a phase 3, multi-center, open-label, 52-week extension trial that evaluated the long-term safety of ubrogepant 50 mg and 100 mg (30). In this trial, the frequency of TEAEs in the pre-defined categories of cardiac arrhythmia, central nervous system vascular disorders, embolic and thrombotic events, hypertension, and ischemic heart disease was similar for the ubrogepant treatment groups and the usual care group and did not suggest any increased risk of CV events with ubrogepant use. No CV TEAEs occurred at a rate > 2% and no CV events related to myocardial infarction or stroke were reported in either ubrogepant treatment arm (30).
The mechanism of action of gepants as CGRP receptor antagonists differs from triptans, as well as from anti-nociceptive opioids (12). Although ubrogepant does not show vasoconstrictive effects in human coronary and cerebral arteries, CGRP is a potent vasodilator and therefore it is important to consider potential implications of CGRP blockade. As a vasodilator, CGRP is involved in blood flow regulation in physiological and pathophysiological conditions (e.g. cerebral and cardiac ischemia) (31) with receptors located in the central nervous system, peripheral nervous system, and cardiovascular system, including blood vessels and the heart (32). As one of many endogenous vasodilators, the impact of the CGRP pathway in humans under these conditions remains unclear. Using a mouse model, Mulder et al. investigated the effect of two gepants (olcegepant and rimegepant) on cerebral ischemia and found that both drugs worsened ischemic stroke in mice. The authors note, however, the limitations of extrapolating experimental data to clinical settings. The murine dose ranges, pharmacokinetics, formulations, and delivery routes of the drugs used in the study were different from those in humans (33). Olcegepant was not developed beyond phase 2 clinical trials (34) and there was no evidence of adverse vascular effects in the rimegepant phase 3 clinical trial, though the trial population did not include a substantial number of participants with CV disease (29).
A recent interventional study by Depre et al. (35) examined the effect of CGRP blockade with erenumab, a human anti-CGRP receptor monoclonal antibody developed for the preventive treatment of migraine, on myocardial ischemia in patients with stable angina due to documented coronary artery disease. Following a single intravenous infusion of erenumab 140 mg or placebo, investigators measured total exercise time, time to exercise-induced angina, and ST-segment depression during a treadmill test. The results showed that the change from baseline in total exercise time in the erenumab group was no worse than placebo. In addition, there was no significant difference in time to exercise-induced angina or time to onset of ≥1 mm ST-segment depression in the erenumab and placebo groups, demonstrating that in a high CV risk population, inhibiting the CGRP receptor does not worsen myocardial ischemia. However, post-marketing data led to the recent addition of a warning to the erenumab label regarding the potential for hypertension, reinforcing the need for continued surveillance of all new vasoactive drugs. Chronic antagonism of the CGRP receptor with a monoclonal antibody differs significantly from intermittent use of a small molecule with a half-life of less than 10 h, so the relevance of this finding to the use of ubrogepant for the acute treatment of migraine remains unknown. Clinical trial data provide useful information about the safety of medication, but definitive evidence relies on ongoing surveillance of populations with high CV risk in long-term trials and in real-world studies. Ongoing studies and post-marketing data collection will further clarify the role of the CGRP pathway in pathophysiological conditions, and establish a comprehensive safety profile of gepants for the acute treatment of migraine.
Ditans, another recently approved class of acute treatmet for migraine, activate 5-HT1f receptors. This class, as represented by Lasmitidan, does not have labeling that restricts use in patients with cardiovascular disorders and risk factors. Patients with cardiovascular disorders were enrolled in the development program without evidence of safety concerns (36).
The randomized, blinded, placebo-controlled design of the ACHIEVE trials and comprehensive assessment of CV risk severity strengthen the results of this analysis. Several limitations may impact the interpretation and generalizability of these results. First, individuals with clinically significant CV or cerebrovascular disease (per the investigator’s opinion), with recent CV/cerebrovascular events, as well as those with clinically uncontrolled hypertension (defined by sitting systolic blood pressure (BP) > 160 mm Hg or sitting diastolic BP > 100 mm Hg at Visits 1 or 2) were excluded per the study design. Therefore, the findings for the moderate to high CV risk group in this study are generalizable to individuals at risk for CV disease but conclusions regarding the safety and efficacy of ubrogepant in populations with clinically significant CV and cerebrovascular disease, recent cardiovascular events, and uncontrolled hypertension are limited. This attenuation of the severe end of the CV risk spectrum reduces power to detect a treatment-by-subgroup interaction. Clinical trials are usually designed to detect the main treatment effect and as a result, the statistical power to detect interaction effects is often low (Supplemental Table 2). Despite these limitations, the results do not suggest a treatment interaction by CV risk category and, as discussed above, are consistent with the results of a phase 3 long-term safety trial (30). The study population was representative of the general migraine population; however, it should be noted that the high and moderate CV risk groups in this trial were relatively small compared with the low-risk group. The safety population in this analysis includes individuals who may have taken an optional rescue medication to treat the qualifying attack, making it unclear which medication was associated with the AE.
Conclusions
This post-hoc analysis was designed to answer two crucial questions. Our results showed that the tolerability and safety profile of ubrogepant does not differ across the three categories of CV disease risk status studied (no risk factors, low risk (<2 major risk factors), and moderate to high risk (≥2 major risk factors)). We also showed that the efficacy of ubrogepant in the acute treatment of migraine does not differ by CV risk status.
Clinical implications
Ubrogepant for the acute treatment of migraine showed no evidence of increased incidence of adverse events in participants with moderate to high CV risk compared with participants with low CV risk. The efficacy of ubrogepant to achieve greater 2-h pain freedom and 2-h absence of the most bothersome migraine-associated symptom than placebo was consistent across categories of CV risk.
Supplemental Material
sj-pdf-1-cep-10.1177_03331024211000311 - Supplemental material for Safety and efficacy of ubrogepant in participants with major cardiovascular risk factors in two single-attack phase 3 randomized trials: ACHIEVE I and II
Supplemental material, sj-pdf-1-cep-10.1177_03331024211000311 for Safety and efficacy of ubrogepant in participants with major cardiovascular risk factors in two single-attack phase 3 randomized trials: ACHIEVE I and II by Susan Hutchinson, Stephen D Silberstein, Andrew M Blumenfeld, Richard B Lipton, Kaifeng Lu, Sung Yun Yu and Lawrence Severt in Cephalalgia
Supplemental Material
sj-pdf-2-cep-10.1177_03331024211000311 - Supplemental material for Safety and efficacy of ubrogepant in participants with major cardiovascular risk factors in two single-attack phase 3 randomized trials: ACHIEVE I and II
Supplemental material, sj-pdf-2-cep-10.1177_03331024211000311 for Safety and efficacy of ubrogepant in participants with major cardiovascular risk factors in two single-attack phase 3 randomized trials: ACHIEVE I and II by Susan Hutchinson, Stephen D Silberstein, Andrew M Blumenfeld, Richard B Lipton, Kaifeng Lu, Sung Yun Yu and Lawrence Severt in Cephalalgia
Footnotes
Ethic approval and patient consent
The ACHIEVE trials were approved by a local or central institutional review board at each participating institution. All participants provided written informed consent before enrolment in the trials.
Acknowledgements
The sponsor and authors would like to thank study participants and their families, the study investigators, research coordinators, and study staff. Writing and editorial assistance was provided to the authors by Kristin Hirahatake, PhD, of AbbVie.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SH serves on advisory boards and speakers bureaus for Alder, Allergan (now AbbVie), Amgen, Biohaven, Currax, ElectroCore, Eli Lilly, Novartis, Teva, Theranica, and Upsher-Smith.
SS has served as a consultant, advisory board member, or received honoraria from the following companies: Alder, Allergan (now AbbVie), Amgen, Autonomic Technologies, Avanir, Dr. Reddy’s, ElectroCore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Novartis, Supernus, Teva, and Theranica
AB has consulted and/or received honoraria from Allergan (now AbbVie), Amgen, Alder, Biohaven, Lilly, Novartis, Teva, Theranica, Impel, Equinox, Zosano.
RL has served as a consultant, advisory board member, or received honoraria from the following companies: Alder, Allergan (now AbbVie), Amgen, Autonomic Technologies, Avanir, Boston Scientific, Dr. Reddy’s, ElectroCore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Teva, and Vedanta and has also received support from the Migraine Research Foundation and the National Headache Foundation.
KL, SY, and LS are fulltime employees and stockholders of AbbVie.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: ACHIEVE I (NCT02828020) and ACHIEVE II (NCT02867709) were funded by Allergan plc (prior to its acquisition by AbbVie). Neither honoraria nor payments were made for authorship.
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References
Supplementary Material
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