Abstract
Abstract
Introduction
In this open label, single-arm trial we evaluated the efficacy of onabotulinum toxin-A in the prevention of high-frequency episodic migraine (8–14 migraine days/month).
Methods
We enrolled 32 high-frequency episodic migraine subjects (age 44.8 ± 11.9 years, 11.0 ± 2.2 migraine days, 11.5 ± 2.1 headache days, 7 females). After a 28-day baseline period, subjects underwent 4 subsequent onabotulinum toxin-A treatments according to the phase III research evaluating migraine prophylaxis therapy (PREEMPT) paradigm, 12-weeks apart. The primary outcome was the reduction of monthly migraine days from baseline in the 12-week period following the last onabotulinum toxin-A treatment
Results
Onabotulinum toxin-A reduced monthly migraine days by 3.68 days (−33.1%, p < 0.01). Thirty-nine percent of the patients experienced a ≥50% reduction in monthly migraine days. Onabotulinum toxin-A also reduced the number of headache days (−33.9%, p < 0.01) and the intake of acute medications (−22.9%, p = 0.03). Disability and quality of life (QoL) scores improved markedly (migraine disability assessment (MIDAS) −41.7%; migraine specific questionnaire (MSQ) −31.7%, p < 0.01).
Conclusions
The findings suggest that, when administered according to the PREEMPT paradigm, onabotulinum toxin-A is effective in the prevention of high-frequency episodic migraine.
Introduction
Migraine is a disabling condition that affects more than 14% of the population. The burden of migraine largely depends on the frequency of the attacks with which the disease manifests itself. Based on the number of monthly migraine days (MMD), migraine has been subdivided into low-to-moderate frequency (up to 7 MMD), high frequency (8–14 MMD) and chronic subtypes (≥
High frequency episodic migraine (HFEM) is associated to an increased risk of transformation into chronic migraine (CM) (1). In this frame, focusing on preventive treatments that address specifically HFEM becomes extremely important both for lowering migraine frequency and for preventing transition to chronic migraine.
In recent years, the headache field has witnessed a terrific development of new therapeutic strategies addressing the needs of migraine sufferers. Four monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) are now available for the treatment of migraine with at least 4 MMD, but they are expensive and, in most countries, their subsidization is restricted to subjects who have previously failed at least 3 preventive treatments (3).
Onabotulinum toxin-A (BoNT-A) proved effective in the prevention of chronic migraine in the large investigational program (Phase III REsearch Evaluating Migraine Prophylaxis Therapy, PREEMPT) (4). Prior to the PREEMPT program, the efficacy of BoNT-A had also been evaluated in episodic migraine (5–9) with conflicting results, probably due to methodological reasons. Indeed, the different studies used lower doses and less injection points as compared to the PRREMPT paradigm.
The aim of this exploratory study is to evaluate the efficacy and safety of BoNT-A delivered according to the PREEMPT paradigm in subjects with HFEM.
Methods
This is an open label, exploratory, single arm interventional trial conducted at a tertiary Headache Centre of the IRCCS Mondino Foundation Hospital in Pavia, Italy (March 2018- May 2020, reg. n° NCT 04578782 clinicaltrial.gov).
Inclusion criteria
Migraine without or with aura (10), with a documented frequency of 8–14 migraine days/month (MMD) in the 3 months before screening and in the 28 days run-in period (documented via a prospective headache diary);
18–65 years of age.
Exclusion criteria
Previous failure of >2 treatments with migraine preventive medications in order to avoid pharmacoresistance as a confounding variable;
Migraine onset after age 50; Other primary/secondary headaches. Episodic tension-type headache was allowed if the patient could clearly distinguish the two types of attacks;
Clinically relevant medical conditions; Hypersensitivity to BoNT-A or ‘Botox® ingredients.
This clinical trial was conducted in accordance with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964), the ICH guidelines for Good Clinical Practice and it was approved by the local Ethics Committee. All subjects signed an informed consent before enrolment.
Primary endpoints
Reduction from baseline (run-in period) in the number of MMD in the 12-week period following the last BoNT-A treatment.
Secondary endpoints
Changes from baseline of the following variables during the last 12 weeks of the study:
Monthly moderate-to-severe headache days; Monthly use of acute drugs; Migraine-related disability (MIDAS questionnaire); Quality of life (Migraine Specific Questionnaire, MSQ); Levels of anxiety and depression (Hospital Anxiety and Depression Scale, HADS).
Protocol design (Figure 1)
After the screening visit (V1), subjects entered the run-in period of 4 weeks. Enrolled subjects received BoNT-A according to the PREEMPT paradigm (155 U, 31 sites) (V2). Treatment was repeated 3 times every 12 weeks (V3-4-5). The final visit (V6) occurred at week 48. From the second BoNT-A cycle, the injection paradigm could be upgraded to the PREEMPT ‘follow-the-pain’ version (195 UI, 39 sites), based on clinical judgement.
From V1 to V6 subjects completed daily a headache diary. MIDAS, MSQ and HADs were obtained at all visits. A monthly phone call was scheduled to check for adverse events.
Statistical analysis
For the primary outcome, assuming a minimum clinically meaningful mean difference of 2.0 MMD and an SD of 2.0, power of 80%, and α=.05, a sample size of at least 32 records (that is at least 16 participants completing the trial) was required (calculated with Open Source Epidemiologic Statistic for Public Health (www.openepi.com) (11).
Analysis was performed in the per-protocol population formed by participants who received the intervention and completed the 48-week follow-up. No imputation was done for the missing values. Variables were assessed for normality of distribution by evaluating skewness and kurtosis. MANOVA (multivariate analysis of variance) for repeated measures, with post-hoc Bonferroni’s correction, was used to analyse comparison over time of variables.
Results
Of the 50 screened subjects, 32 were enrolled in the study and 28 completed the trial. Reasons for dropping out were: adverse events (n. 1), consent withdrawal (n. 2), SARS-CoV-2 pandemic outbreak (n. 1).
At baseline, the population enrolled (81% women) had a mean age of 44.8 ± 11.9 years, 11.5 ± 2.2 headache days, of which 11.1 ± 2.3 were migraine days. The disease duration was 26.6 ± 13.5 years and neither major comorbidity nor pharmacoresistance were reported. Notably most of the patient presented none or just one previous failure of preventive treatment.
Ten patients were on stable concomitant preventive therapy (betablockers: 6, calcium channel antagonists: 1 and antiepileptic drugs: 3) throughout the entire trial period.
Migraine-associated disability was severe in all patients (MIDAS grade IV). The overall characteristics of the enrolled cohort at baseline are shown in Table 1.
-Baseline characteristics of the cohort enrolled.
§ referred to the 28-day run-in period
Sd = standard deviation
MIDAS = Migraine Disability Assessment questionnaire
MSQ = Migraine-Specific Quality-of-Life Questionnaire
HADS = Hospital Anxiety and Depression Scale: A score for anxiety, D score for depression.
BoNT-A reduced the number of MMDs by 3.68 days (−33.1%, p < 0.001) on average in the last 12-week observation period compared to baseline (Figure 2a). Thirty-nine percent of the patients had at least a 50% reduction in migraine days. BoNT-A also significantly reduced the number of moderate-to-severe headache days (−33.9%, p < 0.001), the number of acute medications (−22.9%, p = 0.029) and the days of their intake (−24.6%, p = 0.021). All the endpoints were met already after the first administration and the benefits persisted throughout all the trial as shown in Figure 2b.
Schedule of visits and procedures across the 48 weeks of the protocol. The 4- week run-in baseline was comprised between V1 and V2.
a) Primary and secondary efficacy measures: absolute and percentage mean changes from baseline (run-in period) in the last 12 weeks of treatment, normalized to 28 days. CI = confidential interval, lower and upper bound; MIDAS = Migraine Disability Assessment questionnaire; MSQ = Migraine-Specific Quality-of-Life Questionnaire; HADS = Hospital Anxiety and Depression Scale: A score for anxiety, D score for depression. b) Absolute changes from baseline in mean migraine days, headache days and intakes of acute medications in each 12-week period. Statistical significance is expressed according to the comparison of each timepoint with the baseline.
MIDAS and MSQ scores significantly improved since the first trimester (−41.7%, p = 0.001 and −31.7%, p < 0.001 respectively in the last observation period). Anxiety and depression levels declined but the variation did not reach a statistical significance.
Adverse events were transient and mild-to-moderate in severity (see Appendix A). Only one patient discontinued the study drug due to a mild and self-limiting cutaneous allergic adverse reaction in the site of injection.
Discussion
To our knowledge, this is the first registered trial addressing the efficacy of BoNT-A delivered according to the PREEMPT paradigm specifically targeting subjects with HFEM. Our findings show that BoNT-A significantly reduced the frequency of migraine, the intake of acute medications and the burden of disease.
Previous studies investigating BoNT-A efficacy in episodic migraine yielded conflicting results. Some of these studies used markedly lower doses of drug, less or different injection sites, different volumes of injections and shorter treatment durations (5–7,9). Interestingly, using an approach similar to the present study over 3 treatment cycles, Aurora et al. failed to show efficacy in episodic migraine, but detected a signal of efficacy in the sub-group of migraine subjects with 12–15 headache days/month (8). The possible efficacy of BoNT-A in HFEM is also suggested by the findings reported in a real-world study where MMDs at 12 months decreased by 41.2% and analgesic use by 39.3% (12).
BoNT-A disrupts neuropeptide secretion and receptor translocation related to trigeminal nociception, hence preventing pain sensitization through peripheral and possibly central mechanisms. Peripheral and central sensitization are deeply implicated in chronic migraine (13), and HFEM is clinically, and probably also pathophysiologically, a transition state from low-moderate frequency episodic migraine to chronic migraine (1). Therefore, a drug that effectively counteracts trigeminal sensitization does hold promise in HFEM treatment, as already proven in CM.
In the evolving scenario of migraine prevention, the possibility to provide an additional therapeutic option to a subpopulation of migraine patients with a high burden of disease is extremely important to alleviate the impact of disease and, possibly, to prevent its transition to CM.
The limitations of the study are intrinsically linked to its design. It is however important to note that this is an investigator-initiated trial with very limited funding, but methodologically powered for the primary outcome measure. This latter was selected at a quite long follow-up to minimize the confounding effect of placebo. This said, caution is suggested with the present findings, until they are confirmed on larger-scale placebo-controlled studies.
Conclusion
In this study BoNT-A proved effective in the prevention of HFEM by significantly improving multiple outcome measures. The future possibility to use BONT-A in HFEM patients would be extremely important to improve their clinical condition and to minimize the risk of transformation into chronic migraine.
Clinical implications
BoNT-A significantly reduced the number of migraine days (−33.1%), the intakes of acute medications (−22.6%) and the burden of disease in a group of 28 subjects suffering from high frequency migraine. This is the first registered long-term single-arm trial that specifically addresses the efficacy of BoNT-A delivered according to the PREEMPT paradigm in migraine subjects at risk of progression to chronic migraine. BoNT-A may potentially become an additional option in the treatment of high frequency migraine (8–14 migraine days/month) These findings are a steppingstone for future studies to confirm the utility of BoNT-A in this subgroup of migraine subjects.
Footnotes
Institutional Review Board approval
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board (Comitato Etico Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Data used for this study are available on request to the corresponding author.
Acknowledgments
We thank the research nurses M Bianchi and V Busca for their collaboration during the study.
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: CT received honoraria from Allergan, Eli-Lilly, Novartis, and Teva for the participation in advisory boards or for speaking during industry-sponsored symposia or other meetings. CT has no ownership interest and does not own stocks of any pharmaceutical company.
GS received honoraria from Eli-Lilly and Novartis for the participation in advisory boards or for speaking during industry-sponsored symposia or other meetings.
MA received honoraria from Eli-Lilly and Teva for during industry-sponsored symposia or other meetings.
The remaining authors have no conflicts of interest to declare.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was a self-initiated study promoted by IRCCS Mondino Foundation with a partial support from Allergan – AbbVie.
Appendix A
eTable 2: summary of discontinuation’ reasons
| Reasons | n |
|---|---|
| Lost at follow up due to withdrawal of the consensus | 2 |
| Lost at follow up due to sars-cov-2 pandemic outbreak | 1 |
| Discontinuation related to adverse events: allergic reaction | 1 |