Study design
The REPOSE Study is an ongoing 24-month, prospective, non-interventional, observational study being conducted among 78 clinics throughout Germany, Italy, Norway, Russia, Spain, Sweden, and the United Kingdom. Patients prescribed onabotulinumtoxinA (BOTOX®, Allergan plc, Dublin, Ireland) for symptom relief of CM are recruited over a 6- to 12-month period. The 24-month treatment period, including follow-up, is carried out per the treating physician’s best clinical judgment and standard of care, guided by the terms of the marketing authorisation described in the Summary of Product Characteristics [
34]. Treatment, therefore, reflects the individual physician’s usual clinical routine and country-specific standards of care. The total study duration is 30 to 36 months and consists of enrollment, a baseline visit (visit 1) and follow-up visits approximately every 3 months. A window of at least 15 days spanned the 3-month follow-up time point, such that 3 slightly different groups could be defined as follows: less than 3 months, <75 days since the last injection; every 3 months, ≥75 and <105 days since the last injection; more than 3 months, ≥105 days since the last injection. OnabotulinumtoxinA injections are administered at baseline and each follow-up visit. All participating clinics obtain appropriate ethics committee approval and the study is being conducted in accordance with International Conference on Harmonisation Good Clinical Practice. All patients provide written informed consent.
Study treatment
Treating physicians are trained on onabotulinumtoxinA injection patterns as described in the Summary of Product Characteristics [
34] and the PREEMPT study paradigm [
35]; although there was no mandate for physician’s to comply with these injection paradigms. OnabotulinumtoxinA is administered in 0.1 mL injections (5 U) using a 30-gauge, 0.5-in. needle. The minimum recommended dose of onabotulinumtoxinA is 155 U injected bilaterally into 31 sites among 7 head and neck muscles. At the physician’s discretion, the protocol allows for an additional 8 injections according to the ‘follow-the-pain’ strategy for a total dose of 195 U [
35]. Injection sites and recommended doses are outlined in Table
1.
Table 1
OnabotulinumtoxinA Injection Sites and Doses [
35]
Frontalis | 20 U, 4 sites | NA |
Corrugator | 10 U, 2 sites | NA |
Procerus | 5 U, 1 site | NA |
Occipitalis | 30 U, 6 sites | 10 U, 2 sites |
Temporalis | 40 U, 8 sites | 10 U, 2 sites |
Trapezius | 30 U, 6 sites | 20 U, 4 sites |
Cervical paraspinal muscle group | 20 U, 4 sites | NA |
The cost of onabotulinumtoxinA and treatments reflected real-world costs, and varied depending on country and insurance status of the patient.
Patient selection
This report includes patients who participated for ≥6 months based on an interim analysis date of February 12, 2015. Male and female patients aged ≥18 years who are prescribed onabotulinumtoxinA for CM symptom relief are enrolled. Patients are excluded if they had received any botulinum toxin serotype within the previous 26 weeks, if they are currently participating in the Botox Chronic Migraine Post-Authorisation Safety Study (CM PASS), or if they are contraindicated for treatment with onabotulinumtoxinA per the prescribing information. Given the observational nature of this study, no other formal exclusion criteria have been defined. Patients are free to leave the study at any time, independent of their response to treatment. Any pregnancies that occur during the study are reported to Allergan via the electronic case report form (eCRF) within 24 h of confirmation. In addition, the patient’s primary care physician is notified that the patient has been treated with onabotulinumtoxinA. The patient is then withdrawn from the study with a safety follow up of at least 12 weeks and is followed to term by the treating physician. A final pregnancy outcome report is then provided to Allergan.
Assessments
At the baseline visit, patients are screened for inclusion criteria, provide informed consent, and receive their first treatment with onabotulinumtoxinA. Baseline assessments include demographics (ie, age, gender, height, weight, body mass index [BMI], education and employment status), medical history, and migraine history (ie, diagnosis, age of onset, time since diagnosis of migraine, and time since diagnosis of CM). All efficacy, healthcare resource utilisation, onabotulinumtoxinA utilisation, safety, and tolerability data are assessed at baseline and each follow-up visit as described below.
Efficacy
Patient-reported efficacy measures include the Migraine-Specific Quality of Life Questionnaire (MSQ) version 2.1, the EuroQol Group EQ-5D Questionnaire, patient-reported estimation of headache day frequency, and patient-reported treatment satisfaction.
The MSQ version 2.1 is a 14-item quality of life questionnaire that measures the impact of migraine on daily activities. The scale consists of 3 domains: 1) role restriction (questions 1–7) describes the degree which daily activities are limited; 2) role prevention (questions 8–11) describes the degree which daily activities are interrupted; and 3) emotional function (questions 12–14) describes the feelings of helplessness and frustration resulting from migraine. Each item is scored on a 6-point scale (1 = none of the time; 2 = a little bit of the time; 3 = some of the time; 4 = a good bit of the time; 5 = most of the time; 6 = all of the time); dimension and total scores are calculated as the sum of the raw item scores rescaled from 0 to 100, where a higher score indicates a better quality of life [
7,
36,
37]. The MSQ is reported as change from baseline in total and dimension scores.
The EuroQol Group EQ-5D questionnaire assigns an overall health state classification, reported as an index score and a patient-reported visual analog scale (VAS) health state score. The index score is calculated on the basis of 5 dimensions: 1) mobility; 2) self-care; 3) usual activities; 4) pain/discomfort; and 5) anxiety/depression, with each dimension rated on a 3-point scale (1 = no problems; 2 = some problems; 3 = extreme problems). Starting with a score of 1.0, weighted scores are deducted on the basis of each dimension’s rating to yield an outcome score ranging from −0.59 to 1.00. A score of 1.00 indicates ‘full health,’ a score of 0 indicates ‘death,’ and a negative score indicates a health state that is perceived to be worse than death [
38]. The VAS score is a patient-reported measure of the current health state ranging from 0 (worst health imaginable) to 100 (best imaginable health state). The EQ-5D is reported as change from baseline in the index and health state scores, as well as a frequency distribution of perceived problems for each dimension.
The frequency of headache days is estimated by each patient as the number of days within the past month with ≥4 h of continuous headache.
Satisfaction with onabotulinumtoxinA treatment is assessed by both the patient and the prescribing physician as ‘insufficient,’ ‘moderate,’ ‘good,’ or ‘very good’ and is reported as a frequency distribution of satisfaction level as well as the proportion of patients and physicians who rated satisfaction as ‘good’ or ‘very good.’
Healthcare utilisation
The frequency of headache-related healthcare professional (HCP) visits (by type: primary care consultation, outpatient consultation, accident and emergency visit, alternative practitioner, and other) and hospital admissions for headache are recorded for each period between visits. The total number of HCP visits and hospital admissions are normalised to 90 days using the following formula: (90 ÷ number of days between periods) × number of visits to HCPs or admissions to hospitals between periods. The frequency and proportion of patients who had visits or admissions between each visit is compared with those of the 3 months before baseline. At baseline, a complete medication history is documented, including headache medication used at any time before baseline, headache medication or therapy prescribed in the 26 weeks before baseline, and headache medication prescribed in the 26 weeks before baseline and in use at baseline. In addition, medication overuse, as assessed by the treating physician (not required to be based on ICHD criteria), is also recorded. All headache medications and therapies are categorised by indication (ie, acute, preventative, complementary) and drug class, and any changes in medication use are documented at each follow-up visit.
OnabotulinumtoxinA utilisation
Details of injection dose and site are documented during each treatment visit. For each visit, treating physicians document the total dose per treatment session and dose per muscle injected, as well as the number of muscle areas injected and the total number and locations of injection sites. These data are recorded for all patients receiving the PREEMPT recommended basic injections as well as for those patients who are treated with the ‘follow-the-pain’ strategy.
Safety and tolerability
The safety of onabotulinumtoxinA treatment is assessed via adverse drug reaction (ADR) reporting, including frequency, severity (ie, mild, moderate, severe), and relation (ie, definite, probable, possible, not assessable) to onabotulinumtoxinA. All treating physicians are required to document ADRs in the eCRF. Physician- and patient-reported onabotulinumtoxinA tolerability is rated as ‘insufficient,’ ‘moderate,’ ‘good,’ or ‘very good,’ and reported as the proportion of patients and physicians who rate the tolerability to be ‘good’ or ‘very good.’
Statistical analysis
All baseline, demographic, efficacy, and safety analyses are performed in the safety analysis set (ie, all patients who receive ≥1 dose of onabotulinumtoxinA). Descriptive statistics are used to describe continuous variables; frequency and proportion distributions are used to report categorical data. Changes from baseline at each follow-up visit are analysed at the two-sided 5% level using a nonparametric Wilcoxon signed rank test. All data are analysed as reported in the database using SAS® version 9.3 (SAS Institute, Inc., Cary, NC); any missing data are reported as such. If any dimension score on the EQ-5D or question on the MSQ is missing, the corresponding dimension and total scores are reported as missing.