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Khalil et al. The Journal of Headache and Pain 2014, 15:54 http://www.thejournalofheadacheandpain.com/content/15/1/54

RESEARCH ARTICLE Open Access

Prospective analysis of the use of OnabotulinumtoxinA (BOTOX) in the treatment of chronic migraine; real-life data in 254 patients from Hull, UK Modar Khalil1, Hassan W Zafar1, Victoria Quarshie2 and Fayyaz Ahmed3*

Abstract

Background: Chronic migraine affects 2% of the population. It results in substantial disability and reduced quality of life. Medications used for prophylaxis in episodic migraine may also work in chronic migraine. The efficacy and safety of OnabotulinumtoxinA (BOTOX) in adults with chronic migraine was confirmed in the PREEMPT programme. However, there are few real-life data of its use.

Method: 254 adults with chronic migraine were injected with OnabotulinumtoxinA BOTOX as per PREEMPT Protocol between July 2010 and May 2013, their headache data were collected using the Hull headache diary and analysed to look for headache, migraine days decrements, crystal clear days increment in the month post treatment, we looked at the 50% responder rate as well.

Results: Our prospective analysis shows that OnabotulinumtoxinA, significantly, reduced the number of headache and migraine days, and increased the number of headache free days. OnabotulinumtoxinA Botox also improved patients’ quality of life. We believe that these results represent the largest post-marketing cohort of patients treated with OnabotulinumtoxinA in the real-life clinical setting.

Conclusion: OnabotulinumtoxinA is a valuable addition to current treatment options in patients with chronic migraine. Our results support findings of PREEMPT study in a large cohort of patients, we believe, is representative of the patients seen in an average tertiary headache centre. While it can be used as a first line prophylaxis its cost may restrict its use to more refractory patients who failed three oral preventive treatments.

Background Chronic migraine, defined as headaches on ≥15 days per month for ≥3 months, of which ≥8 days meet criteria for migraine without aura or respond to migraine-specific treatment [1,2], is estimated to affect 2% of the popula- tion [3,4]. It results in substantial disability and reduced quality of life (QoL) [5-7] and leads to an increased risk of anxiety and depression [8]. Chronic migraine has significant health, economic and

social consequences [2,4,9-13]; patients with chronic mi- graine are more likely to use healthcare resources than those with episodic migraine (defined as migraine and <15

* Correspondence: [email protected] 3Consultant Neurologist, Hull Royal Infirmary, Anlaby Road, Hull HU3 2JZ, UK Full list of author information is available at the end of the article

© 2014 Khalil et al.; licensee Springer. This is an Attribution License (http://creativecommons.or in any medium, provided the original work is p

headache days per month) [2], and one in five chronic mi- graine sufferers cannot work due to the effect of the condi- tion on their ability to lead a productive life [14]. Chronic migraine sufferers are also significantly more likely to re- port depression, anxiety, chronic pain and respiratory dis- orders than non-chronic migraine sufferers [13]. Medications used for prophylaxis in episodic migraine

may also work in chronic migraine, although only topir- amate has established evidence [15,16]. However, this and other unlicensed oral agents have limitations due to poor tolerability and/or adverse effects, and a considerable number of patients do not respond [1,17,18]. More inva- sive and costly options include greater occipital nerve block (invasive) and occipital nerve stimulation (costly) that have their own limitations and disadvantages to pa- tients and the health service [19]. Chronic migraine

Open Access article distributed under the terms of the Creative Commons g/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction roperly credited.

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management is further complicated by analgesic overuse [6,20-23]. Observational and clinical trials have shown that 50-80% of patients with chronic migraine overuse acute medication [24]. As to whether the two are separ- ate entities or a complication of one another remains uncertain [25]. For patients who fail on oral therapies, there is also now the option of treatment with Onabotu- linumtoxinA before resorting to these invasive and ex- pensive options. The efficacy and safety of OnabotulinumtoxinA in adults

with chronic migraine was shown in the phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical programme [18,26-29]. These data led to the li- censing authorities granting approval for this toxin in chronic migraine. OnabotulinumtoxinA has also more recently been shown to result in clinically meaningful reductions in headache impact and improvements in Health-Related Quality of Life (HRQoL) [30]. Further- more, recent long-term data have confirmed that most chronic migraine patients who initially respond to Onabo- tulinumtoxinA will maintain the response over at least two years, and a substantial minority will be able to dis- continue treatment and do well without prophylactic ther- apy. However, some patients showed reduced response on repeated injections [31]. Despite being the only drug licensed for prophylaxis in

chronic migraine [28,32], few patients are being offered OnabotulinumtoxinA due to widespread funding restric- tions and few data exist in the real-life setting. The aim of this study was to examine the change in the frequency of migraine symptoms before and after treatment in the real-life setting.

Methods The data was collected in a public sector clinic in the United Kingdom where patients were treated free of charge on the National Health Service (NHS) under the guidance of National Institute of Clinical Excellence (NICE); the or- ganisation often regarded as a watchdog to determine the cost-effectiveness of a treatment before recommending it on the NHS. The funding implications faced in other countries may be different, although the authors feel that the NICE recommendations may have impact in some other countries.

Study participants Adult patients with chronic migraine (defined according to the 2004 International Headache Society Criteria) [2] attending the Hull Migraine Clinic between the first of July 2010 and the 31st of May 2013 were offered Onabotu- linumtoxinA after discussion of all available treatment op- tions, depending on the treatments that they had already received. The Hull Migraine Clinic (Hull Royal Infirmary and Spire Hospital Hull and East Riding) is a tertiary

headache centre that sees 1,200 new headache referrals each year from across the North of England. Patients seen towards the start of the study period were either approved through an Individual Funding Request (IFR) or volun- teered for the Allergan sponsored training sessions. A number of these patients had only tried a single preventive treatment. However, following publication of National In- stitute for Health and Clinical Excellence (NICE) guidance in June 2012 [33], subsequent patients included were treated within the National Health Service (NHS) and were only given OnabotulinumtoxinA treatment after hav- ing failed at least three preventive treatments as per NICE guidance. All patients received free treatment at the point of entry. Patients had to consent to OnabotulinumtoxinA treatment according to the PREEMPT study protocol [29]. There was no randomisation in this prospective analysis; subjects were selected according to their clinical need if they had chronic migraine that was not satisfactorily managed by their current therapy. Of note, patients who fulfilled the criteria for medication overuse were not ex- cluded since they represent patients in the real-life set- ting. Due to the high prevalence of medication overuse in chronic migraine, the IHS has allowed these subjects to be included in their guidelines for chronic migraine trials provided that they are stratified accordingly [34]. According to expert opinion, inclusion of medication overuse patients should be allowed within the classifica- tion of chronic migraine to accurately reflect the patient population seen in actual clinical practice [1].

Study design Subjects were injected intramuscularly with Onabotuli- numtoxinA according to the PREEMPT protocol, i.e. 155 units injected into 31 injection sites around the head and neck [29]. The paradigm includes follow the pain injections of up to further 45 units, although none of our patients re- ceived additional injections. Patients were asked to main- tain a headache diary for at least 30 days prior to and continuously after receiving OnabotulinumtoxinA treat- ment. The Hull Headache Diary (shown below) (Figure 1) was used to capture data on headache [35]. The continu- ous diary filling was mandatory to assess response to treat- ment in order to determine whether patients were offered a repeat treatment.

Study measures From the completed patient diaries, assessments were made of headache days, migraine days and headache- free days; also, of analgesic medication use, triptan use, adverse events and days off work (if applicable). Quality of life was also measured through the Headache Impact Test (HIT-6) in patients receiving injections after the NICE guidance was published. For purpose of repeat treatment we used the responder criteria defined by NICE i.e. at least

Figure 1 Hull headache diary.

Khalil et al. The Journal of Headache and Pain 2014, 15:54 Page 3 of 9 http://www.thejournalofheadacheandpain.com/content/15/1/54

30% reduction in headache days. As some patients showed marked reduction in migraine days than headache days we devised our own responder criteria (Hull Criteria) for ana- lysing prospective patients in this study. A responder was defined as one with a 50% reduction in headache or mi- graine days, or an increment in headache free days twice that of the baseline in a 30-day period. Those with less than three headache free days were only classed as a re- sponder if they achieved a minimum of six headache free days after the treatment. Some patients who failed all three parameters could still receive another Onabotulinumtox- inA injection if they perceived that the first injection had improved their QoL based on the patient’s perception or improvement on at least six points on the HIT-6 score, al- though as they did not fulfil the NICE responder criteria, further funding applications were made on exceptional grounds. A 50% and 75% response for each of the parame- ters, and those fulfilling two or all the three above parame- ters, were also analysed.

Statistical analysis The primary aim of the analysis was to compare the dif- ference between outcome measurements made before

and after treatment. All outcomes were measured on a continuous scale. A statistical examination of the distribution of these out-

comes found that they were skewed in their distribution for each set of measurements, and in terms of the change in values from pre- to post-treatment. As a result of these skewed distributions, the Wilcoxon matched-pairs test was used to compare the change in values over time. For each patient, it was calculated whether they were a

‘responder’ based on either a 50% or 75% reduction in the number of days with symptoms. The exception was for headache free days where a responder was defined by either a two- or three-fold increase in the number of crystal clear days, provided there were at least three headache free days prior to treatment. P- Values of less than 0.05 were regarded as evidence of a statistically sig- nificant result. HIT-6 was used to quantify the change in QoL. The

HIT-6 score was analysed on a continuous scale, and an examination of the change in values over time indicated that the changes were normally distributed. As a result, the paired t-test was used to compare theHIT-6 values on the two occasions.

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Results Demographic and baseline headache characteristics A total of 455 treatment cycles were given in all; of 284 patients injected, full data were available on 254 patients (55 male, mean age 48.6 years; range 19–77 years, 199 fe- male (78% of cohort), mean age 44.06 years, range 19–91 years). Patients had the diagnosis of chronic migraine for a mean of 1.4 years (range ten months to three years) and reported daily headaches for a mean of 8.8 years (range 18 months to 30 years).

Prior prophylactic treatments Of the 254 patients, 240 (94.4%) had received (and failed due to lack of efficacy or intolerable side effects) three or more preventative treatments prior to Onabotulinum- toxinA; twelve patients (4.7%) had received two preventa- tive drugs, and two patients (0.7%) had received one preventative treatment and opted by choice for Onabotuli- numtoxinA treatment. Note that patients who received OnabotulinumtoxinA following failure to respond to one or two preventative treatments were given the treatment before NICE guidance was published.

Acute analgesics overuse Full data on acute analgesic use were available on 242 pa- tients, of whom 122 (50.4%) fulfilled the criteria for misus- ing painkillers and/or triptans as per The International Classification of Headache Disorders [2] definition.

Efficacy results A comparison of all pre- and post-treatment outcomes is shown in Table 1. As the outcomes were skewed in their distribution, the median and inter-quartile ranges (IQR) were used to summarise the responses at each time-point. The median change over time, correspond- ing confidence interval (CI) and p-values are also reported. Graphical illustrations of key pre- and post-treatment

results are shown in Figures 2, 3, 4 and 5.

Table 1 Change in outcomes pre- to post-treatment

Outcome n Pre-treatment Median (IQR) Post-t

Headache days 254 27 (22, 30)

Migraine days 254 15 (10, 19)

Crystal clear days 254 3 (0, 8)

Mild days 254 10 (7, 15)

Painkiller days 242 12 (7 ,20)

Triptan days 241 5 (0, 8)

Days off work 58 4 (3, 6)

The analysis suggested statistically significant differences between the pre-and pos migraine days, mild days, painkiller days, triptan days and days off work were all fo example, the median number of headache days was 27 before treatment reduced t the number of headache free days from pre- to post-treatment (3 to 12 days respe

The 50% or 75% reduction data (and ≥2 and ≥3-fold increase in crystal clear days) are summarised in Table 2. Of the cohort, 80/254 (32%) reported at least a 50%

reduction in headache days, 128/254 (50%) reported at least a 50% reduction in migraine days and 128/254 (50%) reported at least an increase in headache free days twice that of baseline. Also, 66 out of 254 (26%) re- ported an improvement in all three parameters, 106 (42%) in at least two of the three parameters and 167 (65.7%) in at least one of the three parameters. Of the cohort, 36/254 (14%) reported at least a 75% reduction in headache days, 58/254 (24%) reported at least a 75% reduction in migraine days and 79/254 (31%) reported at least an increase in crystal clear days three times that of baseline. Also, twenty out of 254 (7.8%) reported an improvement in all three parameters, 47 (18.5%) in at least two of the three parameters and 107 (42%) in at least one of the three parameters.

Responders as per study criteria As per the study criteria, responders were defined as hav- ing a 50% reduction in headache or migraine days or an increment in headache free days twice that of the baseline in a 30-day period. From this, the following responder criteria were

achieved:

� 87 patients (34%) met none of the criteria � 61 patients (24%) met only one of the three criteria � 40 patients (16%) met two of the three criteria � 66 patients (26%) meet all three criteria.

Using Hull criteria, the authors found nearly two thirds of patients showed a meaningful response. The reduction in headache days was 32% compared to the reduction in migraine days (50%) or an increment in headache free days twice the baseline (50%). Evaluation of migraine and headache free days were, therefore, more sensitive in assessing response than headache days.

reatment Median (IQR) Change Median (95% CI) p-value

18 (10, 25) −7 (−8, −5) <0.001

7 (3, 12) −6 (−8, −5) <0.001

12 (5, 20) 7 (5, 8) <0.001

8 (4, 13) −1 (−2, −1) <0.001

6 (2, 12) −3 (−4, −3) <0.001

2 (0, 6) 0 (−1, 0) <0.001

1 (0, 4) 2 (3, 1) <0.001

t- treatment measurements for all outcomes examined. Headache days, und to be significantly reduced after compared with before treatment. For o 18 after treatment (p < 0.001). Conversely, there was a significant increase in ctively) (p < 0.001).

Figure 2 Change in headache days pre- and post-BOTOX in chronic migraine sufferers*. *In this box plot, the middle line is the median. The ‘box’ part represents the inter-quartile range (IQR), i.e. the middle half of the data. The ‘whiskers’ (i.e. the lines that come out from the box) then typically represent the minimum to max- imum points. The exception is for points that are more than 1.5 times the IQR away from the box, in which case these are plotted separately. The value of 1.5 IQRs is chosen by convention in statistics.

Figure 4 Change in crystal-clear days pre- and post-BOTOX in chronic migraine sufferers.

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Change in migraine severity There were 3,855 moderate to severe headache days pre-OnabotulinumtoxinA treatment. Post- treatment, the number of moderate to severe headache days were reduced to 2,164 (−44%). There were 2,645 mild days pre- OnabotulinumtoxinA

treatment; of these, 2,234 (−16%) remained mild after treatment. There were 1,131 crystal clear days pre- Ona- botulinumtoxinA treatment and 2,502 post- Onabotuli- numtoxinA treatments.

Productivity Data on overall days off work was available for 58/254 patients (23%); in these, the median number of days off

Figure 3 Change in migraine days pre- and post-BOTOX in chronic migraine sufferers.

work per month reduced from 3.5 to 1 days after Ona- botulinumtoxinA (Table 1) (Figure 6). Furthermore, 53% achieved ≥50% reduction – and 29% achieved ≥75% re- duction in days off work (Table 2).

Safety and tolerability Of the 254 patients (with all patients given the PRE- EMPT paradigm of 155 units injected into 31 sites), the following adverse events were observed (Table 3).

Impact on quality of life Full HIT-6 scores were available for 177/254 patients (69.9%) in the cohort. The mean and standard deviation score at each time point is shown in Table 4, along with the mean change over time, the corresponding confi- dence interval (CI) and the p-value. There was a mean reduction of almost 10 units in the HIT-6 score from pre- to post-treatment (p < 0.001). A graphical illustra- tion of the before and after treatment scores is shown in Figure 7.

Figure 5 Change in days taking painkillers pre- and post-BOTOX in chronic migraine sufferers + .

Table 2 The number of patients who achieved a ≥50% or ≥75% reduction in outcome measures following BOTOX treatment

Outcome ≥50% reduction n (%) ≥75% reduction n (%)

Headache days 80/254 (32%) 36/254 (14%)

Migraine days 128/254 (50%) 58/254 (24%)

Mild days 70/254 (28%) 32/254 (13%)

Painkiller days 87/243 (36%) 47/243 (19%)

Triptan days 76/242 (31%) 36/242 (15%)

Days off work 30/58 (53%) 19/58 (29%)

≥2-fold increase n (%) ≥3-fold increase n (%)

Crystal clear days 128/254 (50%) 79/254 (31%)

Table 3 Adverse events

Adverse event observed Number of patients/254 (%)

Pain at the site of injection for at least 24 hours 38 (14.9)

Neck Stiffness 37 (14.56)

Ptosis 28 (11)

Reported but did not complain of inability to frown 15 (5.9)

Exacerbation of headache for five days 11 (4.3)

Difficulty in swallowing 5 (1.96)

Fainting during injection 3 (1.2)

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Discussion This prospective analysis has shown that, in a real-life clinical setting, OnabotulinumtoxinA can effectively re- duce headache days and migraine days by at least 50%, and increase headache free days from baseline in chronic migraine sufferers. OnabotulinumtoxinA use also resulted in increased work productivity. The percentage of patients who achieved at least a 50% reduction in headache days and migraine days were 32% and 50% respectively; the percentage of patients who achieved at least a 75% reduc- tion in headache days and migraine days were 14% and 24% respectively. Furthermore, 50% of patients achieved at least a 50% increment in headache free days twice that of the baseline in a 30-day period, and 31% achieved at least a 75% increment in crystal clear days three times the baseline in a 30-day period. This analysis introduces the Hull criteria for responders

as a tool to evaluate response to OnabotulinumtoxinA. It includes headache days, migraine days and headache free days due to the importance of considering severity of headache as well as frequency. The authors noticed that

Figure 6 Change in days off work pre- and post-BOTOX in chronic migraine sufferers.

patients with mild headache days often reported as head- ache free unless they were prompted with the term ‘crystal clear’. We propose to use the term ‘crystal clear’ in estab- lishing true headache free days. Our data showed a reduc- tion in headache days (32%) less than migraine days (50%) or increment in headache free days twice the baseline (50%). NICE guidance [32] used a 30% reduction in headache days as its only criteria to define a meaningful response to OnabotulinumtoxinA. However, from ex- tensive experience, the authors believe that evaluation of headache severity through migraine days is a more valuable measure of efficacy in clinical practice. The au- thors propose that NICE revisits its definition of a re- sponder. However, applying the NICE criteria of 30% reduction (rather than 50% used in the Hull criteria), the responder rate for headache days in this analysis increased from 32% to 46.5%. Our study provides the first large prospective data on

patients treated with OnabotulinumtoxinA in a real life clinical setting since the publication of PREEMPT. The PREEMPT 56-week clinical trial programme was the largest clinical programme investigating the use of OnabotulinumtoxinA as a prophylactic treatment for chronic migraine using a defined set of diagnostic cri- teria and defined clinically relevant outcome measures. The pooled analysis of the entire 56-week PREEMPT clinical programme supports the safety and efficacy of OnabotulinumtoxinA for the prophylactic treatment of chronic migraine. Statistically significant reductions were observed for OnabotulinumtoxinA vs. placebo for the pri- mary efficacy variable of headache day frequency at week 56, as well as change from baseline in mean migraine days, moderate/severe headache days, and total cumulative hours of headache on headache days. Furthermore, there were statistically significant reductions in the frequency of

Table 4 HIT-6 score before and after treatment with BOTOX

Outcome n Before treatment mean (SD)

After treatment mean (SD)

Change mean (95% CI)

p-value

HIT6 score 177 68.9 (4.3) 59.2 (8.2) −9.7 (−11.0, −8.4) <0.001

Figure 7 Change in HIT-6 score before and after treatment with BOTOX.

Khalil et al. The Journal of Headache and Pain 2014, 15:54 Page 7 of 9 http://www.thejournalofheadacheandpain.com/content/15/1/54

acute headache medication use at week 56; also, of triptan intake favouring OnabotulinumtoxinA versus placebo at week 24 and statistically significant improvements from baseline at week 56 [18]. Our data supports the results and outcome from PRE-

EMPT, although in some aspects our population was different to PREEMPT patients. In our study, 94.4% of pa- tients had received three or more preventative treatments prior to OnabotulinumtoxinA. In the PREEMPT study, 35% of patients failed three oral therapies and 65% failed one oral therapy, suggesting a more severely affected population in our cohort. Furthermore, the number of headache days before receiving treatment was higher in this analysis [27] compared with the PREEMPT study (19.9 days in OnabotulinumtoxinA group in pooled ana- lysis) [25], also suggesting a more severely affected popula- tion. However, only 50% of patients in this cohort fulfilled the criteria for medication overuse compared to 67% in the PREEMPT study. OnabotulinumtoxinA related ad- verse events were extremely low in this analysis, and no newly emerging safety signals were noted, although pain at the site of injection and neck stiffness was reported in significantly more patients than in the PREEMPT. The relatively low rate of adverse events is consistent with known tolerability profile of OnabotulinumtoxinA, and with results from the PREEMPT study. Although this analysis is only subjective according to

patient diaries, the HIT-6 results suggest an improved quality of life for chronic migraine patients using Ona- botulinumtoxinA who often suffer pain, disability and anxiety from their symptoms. In addition, the improved productivity (assessed by reduced days off work) further supports this suggestion. Patients with chronic migraine represent a treatment

challenge [1,17,23], and are an important clinical, social and financial burden [4,12,13,36-38]. One analysis showed that, although the direct costs of migraine are high, 70-90%

of the total cost of migraine is generally as a result of in- direct costs [39]. Oral therapies traditionally used in chronic migraine are associated with limitations, e.g. lack of evidence base to support their use, adverse events and contraindications. Apart from OnabotulinumtoxinA, only topiramate (licensed for both episodic and chronic migraine) is supported by randomised, double-blind, placebo-controlled trial data [15,16]. From the authors’ clinical experience seeing hundreds of patients with chronic migraine in the specialist clinic, the authors feel that OnabotulinumtoxinA should be given after first-line treatments (e.g. tricyclic antidepressants, beta- blockers and topiramate) have been tried and failed, and before some other preventive treatments, such as sodium valproate, methysergide, and greater occipital nerve block/nerve stimulation. The authors feel that the responder rate observed in PREEMPT and this analysis justifies this position for OnabotulinumtoxinA in the care pathway. OnabotulinumtoxinA may well be pre- ferred as a first choice prophylaxis in chronic migraine although authors feel its cost may well hinder its use as a first line. In terms of how representative the patient cohort in

this analysis is to clinical practice, from the authors’ ex- perience, it is felt that this cohort is representative of patients seen in an average tertiary headache centre. For this reason, it can be projected that clinicians in other centres could observe similar benefits from using Ona- botulinumtoxinA in their chronic migraine patients who fail oral prophylactic therapies. Concerning study limitations, a well-known effect in

migraine studies is the high placebo response rate. Fur- thermore, parenteral procedures are additionally associ- ated with increased placebo response rates [40]. Clearly, this cannot be assessed in this analysis. Furthermore, the absence of an active comparator precludes comparison of the efficacy of OnabotulinumtoxinA with other ther- apies. However, patients included in this analysis had failed other traditional treatment options (at least one), were suffering from a considerable number of headache and migraine days and were heavily overusing acute pain medications. All of these measures improved with OnabotulinumtoxinA. The authors do not have a comparison between those

who tried one versus two versus three or more preventive treatments prior to OnabotulinumtoxinA but such an analysis will be performed as these data will become avail- able. The authors also do not have data as to whether there is correlation between the number of headache days prior to treatment and response to OnabotulinumtoxinA. There is no doubt that patient expectations play an im- portant role in determining whether a given treatment is effective. However, in the authors’ experience, no differ- ence was observed between those who were treated in

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