The objective of this study was to assess short-term adherence and tolerability of sc IFN β-1a, self-administered using an electronic autoinjection device, in patients with RRMS who had switched from another injectable DMD or a different injection system for sc IFN β-1a. Over 85% of patients were adherent to treatment over the 12-week course of the study, as recorded by the device dosing log. When adherence was adjusted to account for missed injections by patients who withdrew from the study for non-device-related reasons, adherence was 92%. The high adherence rates reported in this study are consistent with findings of a previous study, in which most patients found the same autoinjection device to be suitable or very suitable for self-injection of sc IFN β-1a [14
]. Notably, this earlier study did not assess adherence, as recorded objectively by the device dosing log.
Adherence did not correlate with baseline cognitive function (measured using the PASAT) and no predictors of adherence were identified. The absence of identified predictors may reflect certain characteristics of the study population: most patients were under 40 years of age with low levels of disability and very good cognitive function. Overall, the safety profile of IFN β-1a serum-free formulation in the current study was consistent with previous observations with the original IFN β-1a formulation [23
Adherence rates were very high at the start of the study but decreased as the study progressed. This may have been due to patients experiencing IFN-specific AEs once the drug was administered at full dose, particularly FLS, one of the most common AEs associated with IFN therapy. However, the most common reason for missing injections changed from medical reasons at Weeks 4 and 8 to 'other' reasons at Week 12. Forgetfulness, one of the most common reasons for missed injections [5
], was responsible for 21% of missed injections overall and may be particularly problematic in patients with impaired cognitive function due to MS. Baseline cognitive function was very good in the majority of patients and did not predict adherence in this study. However, the PASAT test, which was used to assess cognitive function in this study, measures attention and working memory rather than the long-term memory skills that are required for processes such as remembering to perform regular injections, so the lack of association between PASAT score and adherence may not be surprising. Therefore, no conclusions could be drawn regarding the relation between cognitive function and adherence using the autoinjection device. In addition, to what extent different cognitive functions influence adherence in general is not fully understood. Furthermore, it should be considered that patients may prefer to give 'forgetfulness' as the reason for missing one or more injections rather than other reasons which may be considered more problematic by their neurologist, such as treatment fatigue.
No significant baseline predictors of adherence were identified; however, depression may have influenced treatment outcome. Depression, a common symptom of MS, may reduce motivation, which may in turn reduce adherence. Indeed, depression has previously been reported to be a cause of treatment discontinuation [8
]. No significant correlation between depression and adherence was observed in this study, however, and a longer study period would be required to explore the relation between depression and adherence to MS therapy. The positive correlation between baseline HADS scores and reported FLS and GSE over the course of the study suggests that depression and anxiety may increase the extent to which patients are aware of side effects and also their perception of the magnitude of such events.
The high adherence rates in this 12-week study are encouraging, particularly as the use of an autoinjection device to collect adherence data likely provides a more reliable indication of adherence to treatment than other measures of adherence such as MPR or retrospective self-reporting by patients used in other studies [3
]. The high level of adherence may indicate that most patients found the device convenient and easy to use. Convenience, less injection pain and fewer FLS were rated by patients as the most important benefits of the autoinjection device. Overall, convenience was reported as the main benefit throughout the study, consistent with previous studies of this device [14
]. Notably, device features associated with handling and ease of use were rated highly. The majority of patients found it 'very easy' to change the multidose cartridge and needle, hold the device and perform the injection. Simplification of the injection process, for example through the use of an autoinjection device that only needs to be loaded once a week, may encourage patients to perform injections and alleviate treatment fatigue. Such features may also be particularly beneficial to patients who have impaired dexterity due to MS [2
], increasing treatment satisfaction and independence. The majority of patients also thought the device was 'very easy' to transport, which may assist patients with MS to adhere to treatment while travelling and on holiday.
Patients considered 'less injection pain' to be the second most important benefit of the autoinjection device at Week 4 and the third most important benefit at Weeks 8 and 12. As the study progressed, patients reported an increase in both pain at the injection site and pain upon injection. Repeated injections may cause progressive damage (e.g. nodules, bruises) to sc tissue, thus increasing injection pain. These side effects may be particularly problematic to patients who are unaccustomed to sc injections, such as patients who switched from im IFN β-1a, which comprised 63% of our study population. As data regarding injection-related pain with prior treatment were not collected, it is not known how injection pain during the study compared with previous injection experience.
All injectable DMDs are associated with ISRs; however, symptoms and reaction severity vary depending on the drug and the route of administration. ISRs are more commonly associated with sc rather than im injections [8
]. As 63% of patients in this study switched from im to sc injections, an increase in ISRs in either this subset of patients or the total patient population would not be unexpected. Mean ISR score, however, did not change from baseline over the course of the study, suggesting that patients did not note an increase in ISRs when switching to sc injection. Despite this, 'fewer ISRs' was reported as the most important benefit of the device by 7% of patients in this subgroup at Week 8. 'Fewer ISRs' was rated as the most important benefit of the device at Week 12, and second most important benefit at Week 8, by patients previously receiving sc GA therapy. ISRs are the most common side effect associated with GA injections [29
], therefore the reported reduction may have been due to a switch in both DMD and device.
Overall, patients reported a decrease in FLS over the course of the study despite a concurrent reduction in ibuprofen usage, and 'fewer FLS' was reported as the second most important benefit at Weeks 8 and 12. However, it should be noted that the autoinjection device is unlikely to be implicated in the observed reduction in FLS. As discussed previously, pre-study DMD therapy would have likely influenced AEs experienced during the study. FLS are one of the most common AEs associated with IFN β therapy, which was being received by 87% of patients prior to the study. No change in FLS during the study would have been expected in patients receiving pre-study sc IFN β. FLS may have worsened in some patients previously receiving im IFN β-1a owing to increased IFN dose and injection frequency [30
]; however, increased injection frequency may favour tachyphylaxis, therefore reducing the presence and severity of FLS (authors' personal observations) [31
]. Indeed, fewer FLS were consistently reported as the second most important benefit of the autoinjection device by patients receiving pre-study im IFN β-1a at Weeks 4, 8 and 12. Patients switching from GA would have been unaccustomed to FLS, which are particularly prevalent in the first few weeks of treatment with IFN β [8
] and occur most frequently for the first 6 months. In addition to FLS, global side effects improved over the course of the trial. As ibuprofen usage was mandatory for the first 4 weeks of the study, whether reduction in ibuprofen usage was a result of reduced AEs is unknown. Recent reports on side effects related to ibuprofen use, however, may suggest that its usage should be adjusted according to the presence and severity of side effects [33
Limitations of the study should be considered when interpreting the study findings. At 12 weeks, the study was only able to assess short-term adherence; however, we are exploring the possibility of assessing safety, tolerability and treatment adherence/persistence after longer-term follow-up in this patient population. Absence of data on adherence to previous medication and pre-study or baseline injection pain precludes inferences on the benefits of switching to the autoinjection device with respect to adherence and injection pain. In addition, patient perception and reporting of pain is subjective. Pre-study DMDs were not equally represented among patients, with the majority switching from im IFN β-1a; this imbalance limited the conclusions that could be drawn regarding the influence of previous treatment on subsequent outcomes. For example, pre-study DMD may have influenced AEs, patient perception of injection-related AEs and, therefore, opinion of the autoinjection device. Finally, there was no control group in this observational study, so we were not able to discriminate between the effects of the new device and those of changing treatment in patients who had switched to sc IFN β-1a from a different DMD at study entry. However, a previous international study of this new device recruited only patients already being treated with sc IFN β-1a [14
]; therefore, the effects of changing device have only previously been reported for some of the parameters investigated in the current study.