In an exploratory study, administration of BoNT-A in accordance with the Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) protocol effectively reduced the number of monthly migraine days for patients with HFEM, meeting the primary outcome. It also diminished intake of acute medications. The PREEMPT proptocol is being studied in a phase 3 trial.
With the PREEMPT protocol, BoNT-A is injected into muscles of the head and neck in both fixed and follow-the-pain sites. Injections in additional specific follow-the-pain sites may occur, depending on individual patients’ symptoms.
“High-frequency episodic migraine is a risky condition for chronic migraine,” co-investigator Daniele Martinelli, MD, University of Pavia, Pavia, Italy, told meeting attendees.
“Focusing on preventive treatment…becomes extremely important both for lowering the migraine frequency and for preventing transition to chronic migraine, [inasmuch as] peripheral and central sensitization are deeply implicated in chronic migraine,” said Martinelli.
HFEM, he noted, is likely a transition state from low/moderate-frequency episodic migraine to chronic migraine. He said that a drug that prevents general sensitization would hold promise for treating HFEM as well.
The findings were presented at the XXV World Congress of Neurology (WCN), which was held online.
“Switching Off” Sensitization
BoNT-A acts through several mechanisms relevant in migraine, including the inhibitition of calcitonin-gene related peptide, substance P, and glutamate release, as well as translocation of TRPA1 and TRPV1, “thus switching off peripheral sensitization and, consequently, central sensitization,” Martinelli said.
After a 28-day baseline period, investigators in the open-label, single-arm, single-center trial administered 155 units of BoNT-A to each of 32 patients with HFEM.
The patients received the injections in sites in accordance with the PREEMPT protocol for four treatments. The treatments were administered 12 weeks apart. From the second treatment onward, participants could be injected in targets in accordance with a follow-the-pain approach on the basis of clinical judgment.
Throughout the study, patients kept daily diaries of headaches and other related measures, such as scores on the Migraine Disability Assessment Test (MIDAS). The primary endpoint of the trial was reduction in monthly migraine days during the 12-week period after the final treatment compared with baseline.
Study participants were aged 18 to 65 years. They fulfilled International Headache Classification criteria for migraine with or without aura and had had nine to 14 migraine days per month for the previous 3 months.
Women had to be incapable of pregnancy or were using birth control. Onset of migraine had to be prior to age 50 years. Participants were excluded if there had been previous failures of more than two adequate trials of medications from different drug classes for migraine prophylaxis. They were also excluded if they had been diagnosed with other primary or secondary headache disorders.
The mean age of the patients was 44.8 ± 11.9 years. The mean age at headache onset of 18.2 years, and the mean duration of headache was 26.6 years. Women composed 81% of the study cohort, and all participants were White. One third of the participants were using ongoing concomitant preventive medication.
Reduced Migraine Frequency
“The primary endpoint was met, and use of Botox showed to be able to reduce the number of migraine days by 3.62 days, which meant a 33% reduction in the last 3 months compared to baseline,” Martinelli reported.
“Thirty-four percent of the patients had at least 50% reduction in the migraine days,” he added. Use of BoNT-A was also associated with a significant reduction in intake of acute medications.
Table. Monthly Headache-Related Changes During Study’s Final 12 Weeks
|Outcome||Mean change from baseline (%)||95% CI||P value|
|Migraine days||-3.6 (-33.1)||-1.8 to -5.5||<.001|
|Moderate/severe headache days||-3.0 (-30.0)||-1.5 to -4.9||.008|
|Headache days||-3.9 (-33.9)||-2.0 to – 5.8||<.001|
|Acute headache pain medication, intakes||-2.3 (-22.9)||-0.2 to -4.4||.029|
|Acute headache pain medication, days of intake||-2.2 (-24.6)||-0.4 to -4.0||.021|
Statistically significant reductions in migraine days, headache days, and acute medication use occurred starting at the first 12-week measurement and were maintained at every subsequent time point.
There were also reductions from baseline in the secondary endpoints of the MIDAS score (P = .001) and the Migraine-Specific Quality of Life Questionnaire total score (P < .001). The Hospital Anxiety and Depression Scale scores for anxiety (HADS-A) and depression (HADS-D) also decreased, but the changes were not statistically significant.
Seventy-eight adverse events occurred. All were transient and mild to moderate; 15 of the adverse events were likely related to the treatment. Four participants dropped out of the study: two for withdrawal of consent, one for a cutaneous adverse reaction, and one because of the COVID-19 pandemic.
Machine Learning Predictions
In pursuit of furthering personalized medicine, the investigators also applied machine learning to identify patient characteristics associated with responsiveness to BoNT-A therapy.
Because no clinical variable was informative in this regard, the patients were categorized on the basis of their baseline characteristics and by their responsiveness to BoNT-A. Patients who experienced reduction in migraine of >50% in comparison with baseline were considered responders.
The artificial intelligence algorithm discriminated responders from nonresponders with 85.7% accuracy, 94.1% sensitivity, and 72.1% specificity.
Positive correlates for responsiveness at the 48-week point were baseline values for age at migraine onset (P = .009) and HADS-A score (P = .027). Negative correlates were ongoing opioid use as a headache abortive treatment (P = .006).
Martinelli noted that these features together can predict responsiveness to BoNT-A “even if each single feature is not enough to fully account for the results.”
He said that to his knowledge, this is the first study to adequately test BoNT-A for HFEM. Reasons why previous studies produced conflicting results are likely related to the use of markedly lower doses of the drug, limited injection sites, and short treatment durations, said Martinelli. However, one real-world study of 12-month duration showed a 41.2% reduction in migraines, similar to the findings of this study, he added.
Commenting on the findings for Medscape Medical News, Kiran Rajneesh, MBBS, a neurologist and pain medicine specialist at the Ohio State University Wexner Medical Center, Columbus, Ohio, said it would useful to have information about the parameters of the machine-learning algorithm.
“The mechanistic aspect of how they got to it is important because, as you make this a bigger study, if there are flaws, those flaws are going to get multiplied,” said Rajneesh, who was not involved with the research.
Aside from that criticism, he said the study was well done, and he commended the investigators for taking on a challenging problem. The episodic nature of this type of migraine makes it difficult to capture trends and to extrapolate them, he noted. The findings, he added, “look promising.”
He noted that botulinum toxin targets multiple pain mechanisms, which is likely the reason it “works much better than these other acute or chronic prophylaxis medications, because a lot of those are acting on only one receptor or one pathway.”
A number of new migraine therapies have been approved in the past 5 years, and Rajnessh said he is optimistic that there will be even more in the future. These options will offer migraine patients the opportunity to find the therapy that best suits their needs.
The investigator-initiated study was partially supported by Allergan-AbbVie. Martinelli and Rajneesh have reported no relevant financial relationships.
XXV World Congress of Neurology (WCN): Presented October 3–7, 2021.