Treating migraine before the pain starts: New research shows ubrogepant eases premonitory symptoms, offering hope for millions seeking earlier and more effective relief.
Study: Ubrogepant for the treatment of migraine prodromal symptoms: an exploratory analysis from the randomized phase 3 PRODROME trial. Image Credit: GoodStudio / Shutterstock
The most recent exploratory analysis from the phase 3 PRODROME trial reveals that ubrogepant, a calcitonin gene-related peptide receptor antagonist, administered at the initial phase of a migraine attack, may ameliorate common premonitory symptoms, including fatigue, light and sound sensitivity, neck pain, and dizziness. A detailed report is published in the journal Nature Medicine.
Background
Migraine is a common neurological disorder characterized by recurrent attacks of moderate-to-severe headache and other symptoms of brain dysfunction. Migraine has four distinct, but often overlapping, phases including premonitory (prodrome), aura, headache, and postdrome phases.
Premonitory phase symptoms are broadly categorized into three groups: cognitive impairment, characterized by difficulty concentrating or thinking and fatigue; homeostatic dysfunction, characterized by food cravings; and headache phase-associated symptoms, including light and sound sensitivity.
Premonitory symptoms are highly predictive of approaching headache and are associated with the activation of the brain’s hypothalamus region. These findings, along with others discussed in the paper, lend support to the understanding of migraine attacks potentially originating in the central nervous system. The identification of the role of calcitonin gene-related peptide as a causative neurotransmitter associated with migraine attacks has offered the possibility of exploring migraine pathophysiology. Small-molecule inhibitors of calcitonin gene-related peptide receptor have shown promising outcomes in preventing migraine attacks.
The PRODROME phase 3 multicenter, randomized, double-blind, placebo-controlled, crossover trial was designed to explore the efficacy of ubrogepant, a calcitonin gene-related peptide receptor antagonist, in preventing the development of headache and resolving premonitory phase symptoms. This article focuses on an exploratory analysis of its effects on premonitory symptoms.
Trial design
The trial recruited migraine patients who could reliably identify migraine attacks with premonitory phase symptoms that were reliably followed by headache within 1–6 hours at least 75% of the time. Qualifying prodromal events were defined by the presence of premonitory phase symptoms that the participant was confident would be followed by a headache within 1–6 hours.
The participants were randomly assigned to two groups. In one group, participants received a placebo drug to treat the first qualifying premonitory event and ubrogepant 100 mg to treat the second qualifying event. In another group, participants received ubrogepant 100 mg to treat the first qualifying premonitory event and the placebo drug to treat the second qualifying event. The two treatments were separated by at least a 7-day washout period.
Trial findings
The trial included 480 participants for safety analysis and 477 participants for efficacy analysis. The safety population had a mean age of 42.3 years and was predominantly female (87.7%) and White (88.1%), which may be a consideration for generalizability. The most common premonitory symptoms identified at baseline before treatment were light and sound sensitivity, fatigue, neck pain, and dizziness.
Both drugs (ubrogepant and placebo) were administered at the premonitory phase of migraine, and the outcomes were recorded over a period of 48 hours.
Efficacy analysis
The exploratory efficacy analysis, for which the paper provides precise percentages, odds ratios, and confidence intervals, revealed an absence of light sensitivity in approximately 19% and 12% of ubrogepant- and placebo-treated events, respectively, at 2-hour post-treatment; an absence of fatigue in approximately 27% and 16% and an absence of neck pain in approximately 28% and 15% of ubrogepant- and placebo-treated events, respectively, at 3-hour post-treatment; an absence of sound sensitivity in approximately 50% and 35% of respective events at 4-hour post-treatment; and an absence of dizziness in approximately 88% and 82% of respective events at 24-hour post-treatment.
Among cognitive impairment symptoms, difficulty concentrating resolved in approximately 8% and 2% of ubrogepant and placebo-treated events, respectively, at 1 hour post-treatment, and difficulty thinking resolved in approximately 56% and 41% of respective events at 6 hours post-treatment. Additionally, the use of rescue medication within 24 hours post-dose was lower for ubrogepant-treated events (21.7%) compared with placebo-treated events (39.4%).
Safety analysis
Treatment-related treatment-emergent adverse events (TEAEs) were identified in 9% of placebo-treated events and 13% of ubrogepant-treated events. Overall, treatment-emergent adverse events, regardless of perceived relation to treatment, were reported for 12% of placebo-treated events and 17% of ubrogepant-treated events. The most common adverse events (≥2%) after placebo and ubrogepant administration were nausea, fatigue, dizziness, and somnolence (drowsiness). None of these events were serious or led to study discontinuation.
Significance
The trial suggests that ubrogepant may be a therapeutic drug that can help resolve disabling symptoms that appear in the premonitory phase of migraine. When administered in this phase, ubrogepant may improve common premonitory symptoms, with improvements possibly starting as early as one hour after treatment.
Premonitory phase symptoms are highly predictive of impending headache. Existing evidence indicates that a considerable proportion of migraine patients can recognize these symptoms on the day before their headache. Therefore, treatments aiming at resolving these symptoms have high potential to prevent the onset of headache.
As mentioned by researchers, greater awareness of the clinical symptomatology of the premonitory phase, as well as the availability of effective treatment, offers a major opportunity to improve the treatment of acute migraine. The paper also emphasizes that reversing these symptoms with a CGRP receptor antagonist like ubrogepant underscores the importance of the brain in migraine pathophysiology and suggests that targeting central nervous system mechanisms could be a fruitful avenue for new therapeutics.
The primary objective of the PRODROME trial was to evaluate the efficacy of ubrogepant in preventing the onset of headache following administration during the premonitory phase of a migraine attack. The evaluation of the efficacy of ubrogepant in resolving premonitory symptoms was an exploratory analysis of additional endpoints, as detailed in this Nature Medicine paper. The authors note these analyses were not controlled for multiple comparisons, highlighting the need for additional studies specifically designed to evaluate the effect of acute treatment on premonitory symptoms.
Furthermore, the trial participants were instructed to consume ubrogepant when they recognized premonitory symptoms and felt confident that a headache would follow within 1–6 hours. However, the trial did not analyze the differences in symptom resolution between participants who developed and did not develop headaches. These parameters should be considered in future studies.
