Effect of Ubrogepant on Patient-Reported Outcomes When Administered During the Migraine Prodrome
Results From the Randomized PRODROME Trial
Abstract
Background and Objectives
Ubrogepant is a calcitonin gene–related peptide receptor antagonist approved for the acute treatment of migraine. The PRODROME trial previously demonstrated that ubrogepant treatment during prodrome prevents the onset of moderate or severe headache. In this analysis of the PRODROME trial, the benefits of ubrogepant treatment during the prodrome on patient-reported outcomes (PROs) are evaluated.
Methods
PRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial that enrolled adults who experienced 2–8 migraine attacks per month with moderate-severe headache pain. Eligible participants treated 2 qualifying prodrome events, defined as a migraine attack with prodromal symptoms when the participant was confident a headache would follow within 1–6 hours. Participants were randomized to treatment sequence A (placebo then ubrogepant 100 mg) or sequence B (ubrogepant 100 mg then placebo). This analysis evaluated the ability to function normally over 24 hours (secondary end point) and at specific time points after dose (additional end point). Other PRO end points included activity limitation over 24 hours and satisfaction with study medication at 8 and 24 hours.
Results
Of 518 randomized participants, 477 comprised the modified intent-to-treat population. After treatment of qualifying prodrome events, a significantly greater ability to function normally over 24 hours was observed for participants after treatment with ubrogepant 100 mg compared with placebo (odds ratio [OR] 1.66, 95% CI 1.40–1.96; p < 0.0001). As early as 2 hours after dose, a greater proportion of ubrogepant-treated participants reported “no disability, able to function normally” compared with placebo (OR 1.76, 95% CI 1.32–2.35; nominal p = 0.0001). Ubrogepant administered during the prodrome was also associated with a greater reduction in activity limitations over 24 hours after dose (OR 2.07, 95% CI 1.61–2.67; nominal p < 0.0001). At 8 and 24 hours after dose, rates of being “satisfied” or “extremely satisfied” were greater for ubrogepant than for placebo (8 hours: OR 2.37, 95% CI 1.78–3.15; nominal p < 0.0001; 24 hours: OR 2.32, 95% CI 1.78–3.02; nominal p < 0.0001).
Discussion
Ubrogepant 100 mg administered during the prodrome was associated with significantly greater ability to function normally, greater reduction in activity limitations over 24 hours, and greater satisfaction with study medication, compared with placebo.
Trial Registration Information
ClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; first patient enrolled: August 21, 2020. clinicaltrials.gov/ct2/show/NCT04492020.
Classification of Evidence
This study provides Class II evidence that taking ubrogepant 100 mg during a migraine prodrome allows more patients to function normally over the next 24 hours.
Introduction
Migraine is one of the most prevalent diseases worldwide, affecting an estimated 1.1 billion individuals in 2019.1,2 Migraine presents with recurring attacks of head pain and associated symptoms of nausea, vomiting, and sensitivities to light and sound.3,4 According to the 2019 Global Burden of Disease Study, migraine is the second leading cause of disability worldwide and the first among young adult women.1,5 Despite its burden, only 67% of patients with episodic migraine who meet the American Migraine Study/American Migraine Prevalence and Prevention Study diagnostic module criteria are prescribed acute treatments supported by best clinical data, practice, or guidelines.6 Moreover, even fewer patients with chronic migraine (44%) who meet the Silberstein-Lipton criteria for chronic migraine are prescribed standard care (acute and preventive treatment) for migraine.6 In addition, nearly 40% of patients are dissatisfied with their acute treatment regimen.7 Improving care is necessary because inadequate acute treatment is associated with disease progression from episodic to chronic migraine.8 It is important to note that acute treatment while pain is mild is associated with improved outcomes.9,10
Restoration of function and resolution of activity limitations are high-priority treatment outcomes for patients with migraine.11,12 Patients with migraine experience a reduced health-related quality of life (HRQoL), with impaired physical and emotional functioning, inability to perform daily activities, negative impacts on social relationships, and loss of work productivity.13 In patients with more severe migraine attacks, HRQoL is worsened and disability is increased.14,15 Patients with migraine experience burden not only during a migraine attack but also between migraine attacks, experiencing fear and worry of when the next attack may occur.16 The 2021 American Headache Society (AHS) consensus statement addresses the impact of migraine on HRQoL and outlines a goal of acute treatment of migraine to be “restored ability to function.”17
The prodromal phase (aka the premonitory phase) of migraine is the earliest phase of the migraine attack and includes symptoms such as photophobia, fatigue, neck pain and/or stiffness, phonophobia, dizziness, and irritability.18 Prodromal symptoms most often occur within 4–6 hours of headache onset, but mood changes, difficulty concentrating, and sensitivities to light and sound can precede headache onset by up to 48 hours.19 Estimated prevalence of prodromal symptoms varies between studies. Data from a meta-analysis of migraine studies revealed that the prevalence of at least 1 prodromal symptom was 29% (95% CI 8–63; I2 = 99%) in population-based studies and 66% (95% CI 45–82; I2 = 99%) in clinical-based studies.19 A recent, large, cross-sectional study identified that 77% of the 2,700 patients reported a prodrome after receiving prodrome education.20 Prodrome symptoms are also predictive of the headache phase although predictive ability varies with symptoms and among patients.21,22 Indeed, 35.3% (n = 12/34) of patients with migraine in a recent study were able to predict over 50% of migraine attacks based on the presence of prodromal symptoms.22
Patients with more severe migraine attacks have been shown to experience a higher burden of prodrome symptoms in clinical-based studies.20 In addition, clinical studies reveal that patients who have a higher frequency of prodrome symptoms experience a longer duration of migraine attacks and increased nausea.23 These findings highlight the unmet need for addressing the burden associated with the prodrome phase in addition to the headache phase of migraine.
Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist that is Food and Drug Administration (FDA) approved for the acute treatment of migraine.24 The PRODROME trial evaluated the efficacy, safety, and tolerability of ubrogepant 100 mg compared with placebo for the acute treatment of migraine when administered during the prodrome. The primary end point of absence of moderate-to-severe intensity headache within 24 hours was achieved after ubrogepant-treated qualifying prodrome events.25 The primary research question being addressed in the study was how does treatment with ubrogepant 100 mg affect patient-reported outcome (PRO) measures when administered during the prodrome in people with migraine? In this study, we report the results of PRO measures evaluated during the PRODROME trial, including the ability to function normally, activity limitations, and satisfaction with study medication.
Methods
Trial Design
Detailed methods on the PRODROME trial have been previously reported.25 PRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial conducted from August 2020 to April 2022 at 73 sites in the United States. The trial consisted of a 60-day screening period and 60-day double-blind treatment period in which participants were asked to treat 2 qualifying prodrome events (eFigure 1). Eligible participants were randomized 1:1 to 2 treatment sequences, A or B. Participants in sequence A received placebo to treat the first qualifying prodrome event, followed by ubrogepant 100 mg to treat the second qualifying prodrome event. Participants in sequence B received ubrogepant 100 mg for the first event, followed by placebo for the second event. A “qualifying prodrome event” was defined by the presence of prodromal symptoms that the participant was confident would be followed by a headache within 1–6 hours. Headache could not be present during the prodrome, and the participant could not have had a headache or used acute treatment within 48 hours before the onset of the qualifying prodrome event.
Randomization was managed using an automated interactive web response system. Blinding was performed by dispensing blister cards at randomization (visit 2) and the visit after the first treated attack (visit 3). Each blister card contained 2 identical tablets of either placebo or ubrogepant 50 mg. Participants in treatment sequence A received a card with placebo at visit 2 and ubrogepant at visit 3 while participants in treatment sequence B received a card with ubrogepant at visit 2 and placebo at visit 3. Each participant was instructed to take 2 tablets of the study drug at the onset of each qualifying prodrome event during the double-blind treatment period.
Participants
Eligible participants were adults aged 18–75 years with at least a 1-year history of migraine with or without aura consistent with a diagnosis according to the International Classification of Headache Disorders, Third Edition and a history of 2–8 migraine attacks per month with moderate-severe headache in each of the 3 months before screening.18 At the screening visit, participants were asked whether they could identify migraine attacks in which prodrome symptoms are present and likely to be followed by headache within 1–6 hours at least 75% of the time. Participants who responded in the affirmative were enrolled in a 60-day screening period. In this phase, they reported qualifying prodrome events in an eDiary, and the study assessed the subsequent occurrence of headache. To be eligible for randomization after the screening period, the participant needed to record 3–16 qualifying prodrome events and at least 75% of these events followed by a headache of any intensity within 1–6 hours.
Additional inclusion criteria included current or past use of at least 1 prescription medication for the acute treatment of migraine or prescription medication for the preventive treatment of migraine. Exclusion criteria included the following: participants who had difficulty distinguishing migraine from tension types or other headache types or had chronic migraine, trigeminal autonomic cephalalgia, or painful cranial neuropathy and participants who overused medication for migraine or had previous exposure to an injectable anti-CGRP monoclonal antibody within the previous 3 months.
Patient-Reported Outcome Measures
Ability to Function Normally
A prespecified secondary end point of the PRODROME trial was the ability to function normally over 24 hours. Additional end points included the ability to function normally at hours 1, 2, 3, 4, 6, 8, 24, and 48 after double-blind study intervention for treating the first and second qualifying prodrome event. Ability to function normally was measured with the Functional Disability Scale (FDS), a single-item measure of the participant's level of functional disability at the time of the assessment. Participants were asked to rate their ability to perform daily activities in their eDiary on a 4-point scale (0, no disability, able to function normally; 1, mildly impaired, can still do everything but with difficulty; 2, moderately impaired, unable to do some things; 3, severely impaired, cannot do all or most things, bed rest may be necessary). Participants who reported “no disability, able to function normally” were considered responders at each posttreatment time point.
Activity Limitation
The prespecified activity limitation end point assessed participants for activity limitation over 24 hours after double-blind study intervention for treating the first and second qualifying prodrome event. Participants evaluated activity limitation in their eDiary using a 5-point scale (0, not at all limited—I could do everything; 1, a little limited; 2, somewhat limited; 3, very limited; 4, extremely limited). Participants who reported “not at all limited—I could do everything” or “a little limited” were considered responders at each time point.
Satisfaction With Study Medication
The prespecified study medication satisfaction end point assessed participants for overall satisfaction with study medication at 8 hours and 24 hours after double-blind study intervention for treating the first and second qualifying prodrome event. Participants were asked to answer a single-item question in their eDiary and rate their satisfaction on a 7-point scale (0, extremely satisfied; 1, satisfied; 2, slightly satisfied; 3, neither satisfied nor dissatisfied; 4, slightly dissatisfied; 5, dissatisfied; 6, extremely dissatisfied). Participants who reported “extremely satisfied” or “satisfied” were considered responders at each time point.
Statistical Analyses
All analyses used the modified intent-to-treat (mITT) population, defined as all randomized participants with ≥1 assessment of headache occurrence within 24 hours after taking the double-blind study drug for ≥1 qualifying prodrome event during the double-blind treatment period. Participants were not required to treat the same prodromal symptom before both treated attacks. The safety population included all treated participants who took ≥1 dose of the study drug.
It was estimated that 480 participants in the mITT population would provide 95% power to detect a 16%-point treatment difference for the primary end point at a 2-sided 5% significance level (80% for ubrogepant 100 mg vs 64% for placebo). This estimation was performed with the nQuery Advisor 7.0 (Statistical Solutions, Boston, MA). A blinded sample size re-estimation was performed, which determined that 7% of participants would have no determinable primary end point. For this reason, 516 participants needed to be randomized to maintain the effect sample size of 480 participants.
The ability to function normally over 24 hours after taking the double-blind study drug was assessed using repeated measures of dichotomized FDS responses. The dichotomized response had a value of 1 if the participant recorded no disability and a value of 0 otherwise. The repeated binary responses at each postdose time point over 24 hours were analyzed using a generalized estimating equation model. The model included period, treatment, time, and treatment-by-time interaction as categorical fixed effects; predose baseline FDS score for the period; and predose baseline-by-time interaction as covariates. An unstructured working correlation matrix was used for the repeated measures within each participant. The treatment effect was expressed as the geometric mean of the odds ratios (ORs) of ubrogepant 100 mg relative to placebo estimated at the scheduled time points within 24 hours after taking the double-blind study drug. The time point analysis by FDS was performed using a generalized linear mixed model (GLMM) with treatment group and treatment period as categorical fixed effects and predose baseline FDS scores. An unstructured correlation matrix was used for the covariance matrix of residual effect for the repeated measurements (corresponding to the 2 qualifying prodrome events) within a participant.
The activity limitation responder analysis was performed using GLMM with the treatment group and treatment period as categorical fixed effects. The satisfaction with study medication responder analysis was assessed using GLMM with the treatment group and treatment period as categorical fixed effects, at 8 hours and 24 hours, separately. Descriptive statistics at 24 hours for activity limitation and at 8 hours and 24 hours for satisfaction with study medication were presented by study intervention. A hierarchical gatekeeping procedure was followed to control the family-wise type I error rate at 0.05 for multiplicity across the hypothesis tests in the primary and secondary analyses. All analyses were performed with participants with nonmissing assessments at the prespecified time point(s) after dose.
Standard Protocol Approvals, Registration, and Patient Consents
The independent ethics committee or institutional review board at each study site approved the study protocol, informed consent forms, and recruitment materials before patient enrollment. The studies were conducted in accordance with the International Conference for Harmonisation guidelines, applicable regulations, and the Declaration of Helsinki. All participants provided written informed consent before screening. The study is registered with ClinicalTrials.gov (NCT04492020). The study protocol and statistical analysis plan have been published.25
Data Availability
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (e.g., protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research and will be provided after review and approval of a research proposal, statistical analysis plan, and execution of a data sharing agreement. Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this article for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the link vivli.org/ourmember/abbvie/ and then select “Home.”
Results
Participants and Baseline Characteristics
From August 21, 2020, through April 19, 2022, 1,087 participants were screened and 518 were randomized to double-blind treatment (Figure 1). The safety population included 480 participants, and the mITT population included 477 participants. The mean age of participants was 42.3 years, 87.7% (421/480) of the participants were female, and 88.1% (423/480) were White (Table 1). Of the randomized participants, 84.6% (438/518) completed the trial. The most common reason for discontinuation was failure to treat 2 qualifying prodrome events (10% [52/518]) within the 60-day double-blind treatment period. Of these, 21 did not treat any qualifying prodrome event and 31 treated only 1 qualifying prodrome event.
The safety population included all treated participants who took ≥1 administration of the study drug. The modified intent-to-treat (mITT) population included all randomly assigned participants with at least 1 assessment of headache occurrence within 24 hours after taking the double-blind study drug for at least 1 qualifying prodrome event. Reprinted from Dodick DW, Goadsby PJ, Schwedt TJ, et al. Ubrogepant for the treatment of migraine attacks during the prodrome: a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial in the USA. Lancet. 2023;402(10419):2307-2316. Copyright © 2023, with permission from Elsevier.25
| Treatment sequence | Total (N = 480) | ||
|---|---|---|---|
| Sequence A Placebo/ubrogepant 100 mg (n = 247) | Sequence B Ubrogepant 100 mg/placebo (n = 233) | ||
| Age, y, mean (SD) | 41.7 (12.6) | 42.9 (13.1) | 42.3 (12.9) |
| Sex, n (%) | |||
| Male | 31 (12.6) | 28 (12.0) | 59 (12.3) |
| Female | 216 (87.4) | 205 (88.0) | 421 (87.7) |
| Race, n (%) | |||
| White | 214 (86.6) | 209 (89.7) | 423 (88.1) |
| Black or African American | 22 (8.9) | 15 (6.4) | 37 (7.7) |
| Asian | 7 (2.8) | 4 (1.7) | 11 (2.3) |
| Native Hawaiian or Other Pacific Islander | 1 (0.4) | 1 (0.4) | 2 (0.4) |
| Multiplea | 2 (0.8) | 4 (1.7) | 6 (1.3) |
| Missing | 1 (0.4) | 0 | 1 (0.2) |
| Ethnicity, n (%) | |||
| Hispanic | 17 (6.9) | 15 (6.4) | 32 (6.7) |
| Non-Hispanic | 229 (92.7) | 216 (92.7) | 445 (92.7) |
| Other | 1 (0.4) | 2 (0.9) | 3 (0.6) |
a
Participants who reported multiple races are only included in the multiple category.
Outcomes
The most commonly reported prodrome symptoms at baseline in the double-blind treatment period are listed in eTable 1. At baseline, during the prodrome, participants were able to function normally at the time of treatment during only 25.2% (113/449) of placebo-treated qualifying events and 27.0% (121/448) of ubrogepant 100 mg–treated events, before the onset of headache (eTable 2). A significantly higher response for the ability to function normally over 24 hours was observed for ubrogepant 100 mg treatment compared with placebo treatment for participants who treated a qualifying prodrome event (geometric mean of the OR vs placebo, OR 1.66, 95% CI 1.40–1.96; p < 0.0001). In addition, the ability to function normally at individual time points over 48 hours after dose was evaluated. As early as 2 hours after dose, a greater proportion of qualifying events treated with ubrogepant 100 mg were associated with “no disability, able to function normally” compared with placebo (OR 1.76, 95% CI 1.32–2.35; nominal p = 0.0001). This effect was sustained through 24 hours (OR 1.44, 95% CI 1.01–2.06; nominal p = 0.0457) (Figure 2, eTable 2).
Responders were those with a Functional Disability Scale score of 0 (no disability, able to function normally). Percentages were calculated as the number of responders over the number of participants with nonmissing ability to function normally assessed at each time point after dose. Baseline data were collected before dose. *p < 0.05 vs placebo; ‡p < 0.001 vs placebo. p Values represent nominal p values, without adjustment for multiplicity.
At 24 hours, a greater proportion of qualifying prodrome events treated with ubrogepant 100 mg compared with placebo were associated with little or no activity limitations, reporting that they were “not at all limited—I could do everything” or “a little limited” (OR 2.07, 95% CI 1.61–2.67; nominal p < 0.0001) (Figure 3). A greater proportion of participants whose qualifying prodrome event was treated with ubrogepant 100 mg reported being “satisfied” or “extremely satisfied” with treatment compared with placebo (OR 2.37, 95% CI 1.78–3.15; nominal p < 0.0001) 8 hours after dose. This response rate for treatment satisfaction was similar at 24 hours after dose (OR 2.32, 95% CI 1.78–3.02; nominal p < 0.0001) (Figure 4).
Responders were those who reported “not at all limited—I could do everything” or “a little limited.” Percentages were calculated as the number of responders over the number of participants with nonmissing activity limitation assessment at each time point after dose. ‡p < 0.001 vs placebo. p Values represent nominal p values, without adjustment for multiplicity.
Responders were those who reported that they were “satisfied” or “extremely satisfied.” Percentages were calculated as the number of responders over the number of participants with nonmissing satisfaction with study medication assessment at each time point after dose. ‡p < 0.001 vs placebo. p Values represent nominal p values, without adjustment for multiplicity.
Safety
Adverse events (AEs) were reported by 16.9% (77/456) of participants after administration of ubrogepant 100 mg and 11.9% (55/462) of participants after administration of placebo. After ubrogepant or placebo administration, the most commonly reported AEs were nausea (5.0% [23/456] vs 3.2% [15/462]), dizziness (2.4% [11/456] vs 2.6% [12/462]), fatigue (2.6% [12/456] vs 1.5% [7/462]), and somnolence (2.4% [11/456] vs 1.1% [5/462]) (eTable 3).
Discussion
This PRO analysis of the PRODROME trial evaluated key functional measures after the treatment of qualifying prodrome events with ubrogepant 100 mg or placebo. At the time of treatment, 75% of participants had at least some degree of functional limitations before headache began. Although previous studies have demonstrated functional limitations before the onset of headache, the high relative frequency of functional limitations is striking.26-28 The treatment of a qualifying prodrome event with ubrogepant resulted in a significantly greater ability to function normally and a greater reduction in activity limitations over 24 hours, compared with placebo. As early as 2 hours after dose, and continuing through 24 hours after dose, a greater proportion of prodromal events treated with ubrogepant 100 mg demonstrated “no disability, able to function normally.” When administered during the prodrome, ubrogepant 100 mg was also associated with a greater satisfaction with study medication compared with placebo. The previously reported PRODROME trial, registered on ClinicalTrials.gov (NCT04492020), demonstrated that ubrogepant 100 mg significantly reduced the development of moderate or severe headache within 24 and 48 hours after administration compared with placebo.25 Collectively, ubrogepant has demonstrated efficacy, safety, and tolerability for the treatment of acute migraine when administered during the prodrome and, as reported here, has demonstrated the ability to restore function in participants with migraine.
The FDA has issued guidance stating that “drug administration as early as practicable during the course of acute migraine is typically recommended by migraine experts.”29 In addition, the AHS consensus statement recommends acute treatment goals as “rapid and consistent freedom from pain and associated symptoms” and “restored ability to function.”17 These recommendations highlight the need to treat migraine early in the attack to address or prevent the pain of the headache, as well as the function of the patient. Treatment during the prodrome may address both of these needs before the headache phase for patients who experience prodrome symptoms that are reliable harbingers of impending headache.
When administered during the headache phase of migraine, ubrogepant has previously shown a favorable efficacy, safety, and tolerability profile in clinical trial participants.30,31 The PRODROME trial has recently demonstrated that administration of ubrogepant during the prodrome phase was effective and well tolerated with no new safety concerns in people with migraine who experience prodrome symptoms reliably followed by headache.25 Treatment with ubrogepant when administered during both the prodromal and headache phases can allow patients to achieve freedom from pain, absence of most bothersome symptoms, and a return to normal daily activities, supporting the use of this treatment for migraine relief.
The prodrome phase can present with symptoms such as photophobia, phonophobia, fatigue, neck pain and/or stiffness, dizziness, and mood changes. Many of these symptoms also occur in the headache phase.3,4 These symptoms, in addition to the pain of the headache, have a significant impact on the quality of life and functioning of patients with migraine.13,15 Both the prodrome and headache phases impose significant burden based on the symptom profile and measures of function.1,5 These data demonstrate baseline functional disability scores during prodrome, well before headache begins.26-28 One reason to treat during the prodrome is to reduce the probability of developing a migraine headache. Another reason to treat during the prodrome is to reduce the disability and functional limitations of the prodrome itself.
Migraine burden is further influenced by treatment satisfaction. A literature review showed that higher treatment satisfaction is associated with improved treatment compliance and persistence and with lower treatment burden.32 Identifying a treatment approach that addresses both the headache pain and associated symptoms, as well as the impact on patients' daily functions, may help to ameliorate the high burden and disability within the migraine population.
Ability to function normally and patient satisfaction have been assessed when ubrogepant or placebo is taken to relieve the moderate or severe headache of an acute attack (ACHIEVE I and II studies) and during the prodrome phase before headache onset (PRODROME study).25,33 Of interest, although treatment occurred at different time points in the migraine attack across these studies, the percentage of participants with normal function treated with ubrogepant 100 mg compared with placebo significantly increased from 2 hours after dose to 8 hours after dose in both ACHIEVE and PRODROME trials and at 24 hours in the PRODROME trial. Functional disability was not recorded through 24 hours in the ACHIEVE trials. In addition, the percentage of satisfied ubrogepant-treated participants significantly increased after treatment with ubrogepant compared with placebo at 24 hours after dose in both ACHIEVE and PRODROME trials.25,33 While these studies cannot be directly compared, the improvements to patient-reported outcomes indicate that ubrogepant is effective at restoring normal function when taken either during the prodrome or after headache has started.
Gepants have a number of advantages for treatment during the prodrome. These medications are well tolerated and have not been associated with an increased risk of medication overuse.30,31,34,35 This reduces the potential risks of overtreatment of false-positive warning symptoms for impending headache.
This study has limitations regarding efficacy and timing. The PRO measures other than the disability measure assessed in this study had 24-hour recall periods, potentially introducing recall bias. The ability to function was measured over 48 hours, and satisfaction with study medication and activity limitations were assessed over 24 hours. Inferences about treatment benefit are limited to the time of assessment. This study was also limited in that it only included participants who could identify prodrome symptoms reliably followed by headache within 1–6 hours. Further work is needed to better understand the prevalence of prodrome symptoms and the degree to which they are followed by the headache phase. Participants were allowed to treat the same or different prodrome symptoms at the first and second qualifying prodrome event, which may have resulted in differential outcome responses. In addition, while this study included neck pain/stiffness as a prodromal symptom, there remains discussion in the community regarding whether neck pain should be considered a prodromal symptom of migraine or a symptom of migraine headache.36 Although not uncommon in migraine clinical trials, the homogeneity of the race and ethnicity of the study population (88.1% White and 92.7% non-Hispanic) should be considered. The PRODROME trial represents the first trial design to study the effect of an acute migraine treatment when administered during the prodromal phase, before the onset of headache. While prodrome symptoms can appear up to 48 hours before headache during a migraine attack, the 1–6 hour time range for the administration of ubrogepant was chosen so that there would be enough time for the study drug to be effective while also reducing the risk that the study drug would be administered so early in the prodrome that the prevention of the development of or attenuation of the severity of the headache phase would be compromised by the reduction in drug levels. Future studies should evaluate PROs such as work productivity or quality-of-life measures, which may provide further insight into the benefits of ubrogepant.
In PRODROME, ubrogepant was superior to placebo in reducing the development of moderate or severe headache within 24 and 48 hours after treating a qualifying prodrome event.25 Compared with placebo, ubrogepant treatment when administered during the prodrome resulted in a significantly greater proportion of patients being able to function normally over 24 hours, a reduction in activity limitations at 24 hours, and a greater proportion of participants reporting satisfaction with study medication at 8 and 24 hours. Taken together, these results demonstrate the functional benefits of ubrogepant for the treatment of acute migraine when administered during the prodrome.
Glossary
- AE
- adverse event
- AHS
- American Headache Society
- CGRP
- calcitonin gene–related peptide
- FDA
- Food and Drug Administration
- FDS
- Functional Disability Scale
- GLMM
- generalized linear mixed model
- HRQoL
- health-related quality of life
- mITT
- modified intent-to-treat
- OR
- odds ratio
- PRO
- patient-reported outcome
Acknowledgment
Editorial assistance was provided to the authors by Angela T. Hadsell, BA, of AbbVie (North Chicago, IL) and was funded by AbbVie. AbbVie and the authors thank all trial investigators and the patients who participated in this clinical trial. All authors had access to relevant data and participated in the drafting, review, and approval of this publication.
Appendix Authors
| Name | Location | Contribution |
|---|---|---|
| Richard B. Lipton, MD | Albert Einstein College of Medicine, Bronx, NY | Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data |
| Andrea M. Harriott, MD, PhD | Massachusetts General Hospital, Boston | Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data |
| Julia Y. Ma, BS | AbbVie, Madison, NJ | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
| Jonathan H. Smith, MD | AbbVie, North Chicago, IL | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
| Jonathan Stokes, MBA | AbbVie, Madison, NJ | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
| Pranav Gandhi, PhD | AbbVie, Madison, NJ | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
| Krutika Jariwala-Parikh, MS, PhD | AbbVie, North Chicago, IL | Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data |
| Gabriel S. Jensen, PhD | AbbVie, North Chicago, IL | Drafting/revision of the manuscript for content, including medical writing for content |
| Joel M. Trugman, MD | AbbVie, Madison, NJ | Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data |
| David W. Dodick, MD | Department of Neurology, Mayo Clinic, Scottsdale, AZ; Atria Academy of Science and Medicine, New York, NY | Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data |
Supplementary Material
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Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Publication History
Received: December 4, 2023
Accepted: June 26, 2024
Published online: August 28, 2024
Published in print: September 24, 2024
Disclosure
R.B. Lipton has received research support from the National Institutes of Health, the FDA, and the National Headache Foundation, serves as consultant for, advisory board member of, or has received honoraria or research support from AbbVie/Allergan, Amgen, Biohaven, electroCore, Eli Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Teva, Vector, and Vedanta Research, receives royalties from Wolff's Headache, 8th edition (Oxford University Press, 2009), and Informa, and holds stock/options in Axon, Biohaven, Cooltech, and Manistee. A.M. Harriott has received personal compensation for serving as an officer or member of the Board of Directors for Headache Cooperative of New England, their institution has received research support from electroCore, and has a non-compensated relationship as an author with AbbVie that is relevant to AAN interests or activities. D.W. Dodick reports the following conflicts: Consulting: Amgen, Atria, CapiThera Ltd., Cerecin, Ceruvia Lifesciences LLC, CoolTech, Ctrl M, Allergan, AbbVie, Biohaven, GlaxoSmithKline, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, WL Gore, Genentech, Nocira, Perfood, Praxis, AYYA Biosciences, Revance, and Pfizer. Honoraria: American Academy of Neurology, the Headache Cooperative of the Pacific, the Canadian Headache Society, MF Med Ed Research, Biopharm Communications, CEA Group Holding Company (Clinical Education Alliance LLC), Teva (speaking), Amgen (speaking), Eli Lilly (speaking), Lundbeck (speaking), Pfizer (speaking), Vector Psychometric Group, Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin LLC, Medlogix Communications, Medica Communications LLC, MJH Lifesciences, Miller Medical Communications, WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, and Cambridge University Press. Non-profit board membership: American Brain Foundation, American Migraine Foundation, ONE Neurology, Precon Health Foundation, International Headache Society Global Patient Advocacy Coalition, Atria Health Collaborative, Arizona Brain Injury Alliance, and the Domestic Violence HOPE Foundation/Panfila. Research support: Department of Defense, National Institutes of Health, the Henry Jackson Foundation, the Sperling Foundation, the American Migraine Foundation, and the Patient Centered Outcomes Research Institute (PCORI). Stock options/shareholder/patents/board of directors: Ctrl M (options), Aural Analytics (options), ExSano (options), Palion (options), Man and Science, Healint (options), Theranica (options), Second Opinion/Mobile Health (options), Epien (options/board), Nocira (options), Matterhorn (shares/board), Ontologics (shares/board), King-Devick Technologies (options/board), Precon Health (options/board), AYYA Biosciences (options), Axon Therapeutics (options/board), Cephalgia Group (options/board), Atria Health (options/employee). Patent 17189376.1-1466:vTitle: Onabotulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis (Nonroyalty bearing). Patent application submitted: Synaquell (Precon Health). J.Y. Ma, J.H. Smith, J. Stokes, P. Gandhi, K. Jariwala-Parikh, G.S. Jensen, and J.M. Trugman are employees of AbbVie and may hold AbbVie stock. Go to Neurology.org/N for full disclosures.
Study Funding
AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. No honoraria or payments were made for authorship.
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