Sample size
We screened the 1218 headache patients who suffered from headaches and sought medical advice in Kafr El-Sheik University Hospital from June 2022 to June 2023. Five hundred forty patients had migraine (380 patients had episodic migraine, 160 had chronic migraine). According to ICHD-3 [
9], 200 patients had episodic migraine, met our inclusion criteria, and agreed to participate in our trial after getting written informed consent from the patients or their first-of-kin relatives and after approval from the ethical committee of the faculty of medicine at Kafr El-Sheik University.
We used G.power software to calculate the power of our study based on the mean and the standard deviation of the absolute reduction in CGRP-LI in each group, which was 2.8 ± 1.07 in the lacosamide group and 1.73 ± 1.76 in the control group, 95% two-sided confidence level, alpha error of 5%, effect size of 0.73, and 5% loss to follow-up rate. The power of our study was 99%.
We used a web-based centralized blocked randomization plan to allocate 200 episodic migraine in a one-to-one ratio to receive either lacosamide 50 mg Bid and ibuprofen 200–400 mg on acute attacks only or ibuprofen 200–400 mg on acute attacks only. Still, all clinical investigators were blind to the block size of the randomization plan, but the patients were aware of the treatment used in the study.
Our trial had two groups: the lacosamide group, which included 100 episodic migraines (those with migraines who have less than 15 headache days per month) following ICHD-3 [
9] and received fixed daily dose of lacosamide (50 mg Bid) and ibuprofen 200–400 mg only during acute migraine attack [
10] for three months, and the control group which included 100 episodic migraine patients who were diagnosed following ICHD-3 [
9] and received ibuprofen 200–400 mg only during acute migraine attack [
10] for three months, and we identified their migraine features (disease duration, migraine monthly days, attack duration, pain intensity assessed by visual analogic scale) with the help of a questionnaire.
Our investigation was explicitly intended to serve as a pilot study to investigate the preliminary effect of lacosamide on the serum level of CGRP-LI to identify its possible role in episodic migraine management, as well as to determine whether it would be feasible to proceed with a large-scale randomized clinical trial that would be sufficiently powered to evaluate the safety and effectiveness of lacosamide in episodic migraine sufferers.
Inclusion criteria:
Our trial enrolled patients aged 10–55 years suffering from episodic migraines following ICHD-3. [
11], and all the patients did not receive any migraine preventive treatment or triptans in the last month.
Exclusion criteria
We ruled out patients with major neurological conditions, such as (primary headaches other than episodic migraine, stroke, epilepsy, and brain tumors, as well as patients with significant systemic diseases, such as malignancy, liver cell failure, renal failure, patients with MRI contraindications, patients who received any migraine preventive treatment or triptans in the last month pregnant, and lactating patients, patients who had cardiovascular diseases as heart failure, ischemic heart disease, heart block, and atrial fibrillation, and those who had lacosamide hypersensitivity or contraindications.
Study procedures
We screened 1218 patients, and all underwent clinical neurological and general physical examinations. Migraine history, type, and associated phenotypic features were established. We measured blood pressure on three different occasions and did laboratory tests, including (renal functions, coagulation profile, fasting, postprandial blood sugar, liver functions, and complete blood count). We excluded 1018 patients; 200 patients underwent randomization, received at least one treatment dose, and were included in the analysis.
One hundred twenty participants in our trial were females; 56 patients had migraine with aura, the median monthly migraine days was seven days, the median migraine attack duration was six hours, the median duration of migraine was eight months, 163 patients had photophobia in association to migraine, 158 had phonophobia in association to migraine, 157 had nausea associated with migraine, 137 had dizziness with migraine, and 71 patients suffered from vomiting concomitant with migraine.
All the patients who fulfilled the inclusion criteria were invited to the hospital before starting treatment and three months after treatment to analyze the serum level of CGRP-like immunoreactivity (CGRP-LI).
Blood samples were collected from the antecubital vein at both time points while subjects rested in a sitting position. The blood was then allowed to clot and was centrifuged at room temperature for 20 min at 622 g/2000 rpm to separate serum. Samples were then immediately analyzed. For radioimmunoassay (RIA), a commercial kit (CGRP (Human)—RIA Kit (Phoenix Pharmaceuticals, Burlingame, California, United States), detection range 0.53–660 pmol/l), was used following manufacturer's instructions to measure CGRP-like immunoreactivity (CGRP-LI) levels. All samples were analyzed in the same laboratory, under the same environmental conditions, and with the same batch for samples from different patients and study days to avoid a possible batch effect. Samples with values outside the detection range were set on the limits of the detection range. Biochemical assays were performed by an experienced lab technician blinded to the patient identity, study day, and treatment effect of lacosamide.
After three months of treatment, we assessed the difference in CGRP-LI levels in the two groups to evaluate the effect of lacosamide on CGRP-LI levels; also, we assessed the safety of lacosamide by assessing the different adverse effects through open‐ended patient interviews in the two groups, in addition, we evaluated the percentage of patients who achieved ≥ 50% reduction in the migraine monthly days (MMD) frequency compared to the baseline frequency [
12], and the percentage of patients who achieved pain freedom within two hours in ≥ 4 of 5 attacks [
13], Although migraine is a chronic disease, in our study, we assessed the lacosamide effects on CGRP-LI level and the clinical outcomes after three months [
14‐
17] as our trial was a pilot one aimed mainly to investigate the preliminary effect of lacosamide on the serum level of CGRP-LI and evaluate the feasibility of conducting a larger blinded study.
Primary endpoint: To assess the effect of Lacosamide on CGRP-LI by detecting the difference in CGRP-LI level after three months of treatment in the two groups.
Secondary endpoint: The secondary safety endpoint was to assess the safety of lacosamide by assessing the different adverse effects through open‐ended patient interviews in the two groups.
The secondary efficacy endpoints evaluated the percentage of patients who achieved ≥ 50% reduction in the migraine monthly days (MMD) frequency compared to the baseline frequency and the percentage of patients who achieved pain freedom within 2 h in ≥ 4 of 5 attacks.
Statistical analysis of the data
We used the IBM SPSS software package, version 20.0 (Armonk, NY: IBM Corp.), to analyze our data and base all efficacy analyses on the intention-to-treat principle. Both the primary and secondary outcomes underwent separate statistical analyses. Depending on their distribution, as determined by the Shapiro–Wilk test, we described numerical data as means S.D. or median and interquartile range (IQR). We also reported categorical data using numbers and percentages. The Mann–Whitney U test was used to compare the irregularly distributed numerical data, while Pearson's chi-square was utilized to correlate categorical data. In our study, there were all the data. All statistical analyses were two-sided, and differences with a P-value of less than 0.05 were considered statistically significant. To avoid type 1 statistical error in the analysis of secondary efficacy endpoints, we used correction for multiple comparisons, and secondary efficacy outcomes differences with an adjusted P-value of less than 0.025 were considered statistically significant.