Single-use autoinjector for peginterferon-β_1a treatment of relapsing-remitting multiple sclerosis: safety, tolerability and patient evaluation data from the Phase IIIb ATTAIN study

Abstract

Objectives: A sub-study to evaluate safety, tolerability, ease-of-use and patient satisfaction with a single-use autoinjector administering subcutaneous peginterferon-β_1a (a pegylated interferon-β_1a in clinical development) in a subset of relapsing-remitting multiple sclerosis (MS) patients participating in ATTAIN, a long-term dose-frequency blinded extension of the Phase III randomized ADVANCE study.

Methods: Over 8 weeks, patients self-administered peginterferon-β_1a 125 µg or placebo every 2 weeks (two injections via manual pre-filled syringe [PFS]; two injections via single-use autoinjector). Primary end points were incidence of adverse events (AEs), patient assessment of injection pain score (10-point Visual Analog Scale), and clinician assessment of injection site reactions (ISRs). Secondary objectives included patient assessment of ease-of-use and satisfaction with the autoinjector and evaluation of autoinjector training materials.

Results: In 39 patients, the safety profile of peginterferon-β_1a was similar when delivered via autoinjector or PFS; AEs were mostly mild or moderate in severity. Clinicians and patients reported a similar tolerability profile using both PFS and autoinjector, and pain scores were low (< 1), with no reports of clinician-assessed ISRs after administration with the autoinjector. Patients perceived the single-use autoinjector to be easy to use and convenient; overall patient satisfaction with the autoinjector and accompanying training materials was high.

Conclusion: The safety and tolerability profile of peginterferon-β_1a delivered via autoinjector was similar to delivery via PFS. Patients found the autoinjector easy to use and convenient; this device may simplify the injection process for MS patients who require long-term therapy, thereby potentially improving patient’s quality of life and adherence.

Keywords::

• dosing frequency
• drug delivery system
• IFN-β1a
• multiple sclerosis
• patient outcomes assessments
• peginterferon
• pegylation

1. Introduction

Despite recent approvals of new therapeutic agents for the treatment of multiple sclerosis (MS), there continues to be a high unmet medical need in this patient population for effective therapies that have an established long-term safety profile and are convenient, characteristics which may help improve medication adherence to medication [1]. The importance of treatment adherence across disease areas is undisputed, and, among patients with MS, poor adherence is shown to significantly increase the risk of MS relapses and MS-related hospitalizations [2]. Discontinuation of injected MS treatments (interferon [IFN]-β_1a, IFN-β_1b and glatiramer acetate) due to poor tolerability or inconvenience is common, particularly in the first few months of therapy [3]. Peginterferon-β_1a has been developed by attaching a polyethylene glycol chain to the parent IFN molecule [4], an established process known as pegylation. Pegylation has been shown to increase the half-life and reduce the immunogenicity of certain drugs with either increased or sustained efficacy [5,6]. In previous Phase I studies, compared with non-pegylated IFN-β_1a, peginterferon-β_1a had a longer half-life (t_1/2) and greater exposure (peak serum concentration [C_max] and area under the cruve [AUC]), supporting the contention that pegylation of IFN-β_1a would allow for less frequent dosing [5,6]; a single-use, disposable autoinjector is under development to simplify the process of subcutaneous (SC) self-injection of peginterferon-β_1a from a pre-filled syringe (PFS).

The pharmacokinetic and safety profiles of peginterferon-β_1a delivered by autoinjector or PFS have been shown to be similar in a Phase I healthy volunteer study [6]. Peginterferon-β_1a has also been tested in patients with relapsing-remitting MS (RRMS) in a recent pivotal Phase III trial – the ADVANCE study [7]. After 1 year of treatment, compared with placebo, peginterferon-β_1a 125 μg (SC every 2 or 4 weeks) significantly reduced annualized relapse rate, new or newly enlarging T2 lesions, and the risk of relapse and disability progression, with a safety profile reflecting that of established IFN-β_1a therapies. Here, we report data from a subset of patients participating in the ATTAIN study, an ongoing dose-frequency blinded extension to the ADVANCE trial, that is examining the long-term efficacy and safety profile of peginterferon-β_1a (all patients on active treatment). The primary objective of this sub-study was to evaluate the safety and tolerability of the single-use autoinjector in a subset of patients with RRMS participating in the ATTAIN study. Secondary objectives included the evaluation of patient perceptions regarding ease-of-use of, and overall satisfaction with, the single-use autoinjector, along with patient assessment of the clarity of the autoinjector training materials.

2. Patients and methods

2.1 Study design

ATTAIN is a multi-centre, dose-frequency blinded extension study of the Phase III, randomized, double-blind, multi-centre ADVANCE study, the detailed methodology and key outcomes of which have been reported elsewhere [7]. In this 8-week, single-arm sub-study, patients were recruited from the ongoing ATTAIN study and participated in parallel to their participation in the ATTAIN study. Patients received an SC injection (self-administered peginterferon-β_1a 125 μg or placebo) every 2 weeks. The first two injections used the manual PFS and the next two injections used the single-use autoinjector with peginterferon-β_1a or placebo. Patients remained on the dose schedule to which they were assigned during the ADVANCE study (i.e., active drug every 2 or 4 weeks) and continued to be blinded to dose frequency (each sub-study participant received one injection of peginterferon-β_1a or placebo every 2 weeks [i.e., over a 4-week period, participants randomized to every 2-week dosing would receive two injections of peginterferon-β_1a; those randomized to every 4-week dosing would receive one injection of peginterferon-β_1a and one injection of placebo]). The autoinjector is a spring-powered injector, with an integrated, concealed needle and a medication window to visualize the PFS (insertion of the needle is not automated [attachment of the needle is not required]; the injection itself is automated). It incorporates a needle shield; the needle is deployed automatically when manually pushing down on the injector, and there is a visible indication of the initiation and end of each dosing administration step.

The protocol was approved by each site’s institutional review board and was conducted according to the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki.

2.2 Patients

Patients in ATTAIN were given the option to be included in this sub-study; they provided separate informed consent if their country of residence and clinical site was participating in the sub-study. All patients from participating clinical sites were invited to participate in the sub-study; however, patients exceeding > 2 weeks since their last dose of study treatment were not eligible to participate. Patients eligible for the sub-study had previously been enrolled in the ADVANCE study; therefore, enrollment criteria were identical. As reported previously [7], the ADVANCE study included 1512 randomized and dosed male and female patients aged 18 – 65 years with a confirmed diagnosis of RRMS and baseline Expanded Disability Status Scale score of ≤ 5.0, who had experienced ≥ 2 relapses within the last 3 years and ≥ 1 relapse in the 12 months prior to randomization. The ADVANCE study excluded patients with progressive MS, those who had received prior treatment with IFN-β for MS exceeding 4 weeks, and those who had discontinued IFN-β treatment < 6 months prior to baseline [7].

2.3 Study end points and assessments

There were three primary end points for the autoinjector sub-study: i) Incidence of adverse events (AEs) associated with the use of the single-use autoinjector; AEs and concomitant medication use were monitored throughout the study, with a follow-up assessment scheduled 8 weeks after the first injection; ii) Patient assessment of injection pain score, assessed using a Visual Analog Scale (VAS; where 0 = no pain; 10 = extremely painful) within 1 h pre-injection, immediately post-injection, and at 30 and 60 min post-injection; and iii) Clinician assessment of injection site reactions (ISRs); clinicians at the study center assessed injection sites pre-injection and within 1 h post-injection. The injection site was specifically examined for erythema, induration, tenderness (rated as mild, moderate, severe or no reaction) and temperature (rated as normal, warm or hot).

Secondary end points included: i) ease-of-use profile of the single-use autoinjector; following the final injection of the sub-study, patients responded to questions as shown in Table 1; ii) patient satisfaction with the single-use autoinjector (patients completed an Autoinjector Satisfaction Questionnaire [developed by Biogen Idec Inc.] following the final injection of the sub-study; questions and response options as shown in Table 1) and iii) patient assessment of the autoinjector training materials – patients were first trained in the proper use of the autoinjector prior to the first injection using the ‘Instructions for Use’ materials. Patients also undertook subsequent practice sessions using an injection pad. After completion of the first administration of treatment using the autoinjector, patients completed an Assessment of Training Materials questionnaire (developed by Biogen Idec, Inc.; questions and response options are shown in Table 1).

Table 1. Summary of questions used and patient response options to investigate secondary objectives.

Evaluation	Questions	Patient response options
Ease-of-use profile of the single-use autoinjector	How easy or difficult was it to set up the injector? How easy or difficult was it to hold and grip the injector? How easy or difficult was it to perform the injection? How easy or difficult was it to dispose of the injector?	Extremely easy Easy Somewhat easy Difficult Extremely difficult
Patient satisfaction with the single-use autoinjector	How convenient or inconvenient was it to administer your medication with this injector? How convenient or inconvenient would it be to use this injector in your home on a regular basis, that is, once or twice a month? How convenient or inconvenient would it be to use this injector when you are travelling or away from home?	Extremely convenient Convenient Somewhat convenient Inconvenient Extremely inconvenient
	Overall, how satisfied or dissatisfied are you with the injector used to administer your medication?	Extremely satisfied Satisfied Somewhat satisfied Dissatisfied Extremely dissatisfied
	How likely would you be to continue to use this injector to administer your medication?	Extremely likely to continue using Likely to continue using Somewhat likely to continue using Unlikely to continue using Extremely unlikely to continue using
Patient assessment of the autoinjector training materials	Did you review the Autoinjector Information for Patients, written instruction, before or during your self-administration with the single-use autoinjector?	Yes No
	How easy was it to understand the Autoinjector Information for Patients?	Very difficult Somewhat difficult Neutral Somewhat easy Very easy
	How satisfied are you with the level of detail in the Autoinjector Information for Patients? How satisfied are you with the organization and presentation of the Autoinjector Information for Patients?	Extremely dissatisfied Somewhat dissatisfied Neutral Somewhat satisfied Extremely satisfied
	Overall, how effective were the printed instructions in educating you on how to use the Autoinjector Information for Patients?	Not effective at all Somewhat ineffective Neutral Somewhat effective Very effective

2.4 Data analysis

Data from all patients enrolled in the sub-study were included in the analysis of safety and questionnaire outcome measures. Safety and tolerability data were summarized separately for PFS and autoinjector injection periods. As data for patient assessment of injection pain and clinician assessment of injection-site reactions were summarized for each injection, only patients who received injections using the planned schedule (i.e., the first two injections used the manual PFS and the next two injections used the peginterferon-β_1a or placebo autoinjector) were included. Questionnaire data were summarized using basic and descriptive statistics. This study was designed to be descriptive and was not powered for formal statistical analyses. Therefore, sample size was not based on formal statistical considerations but based on an estimation of the number of patients anticipated to generate appropriate data. Approximately 40 patients were determined to be sufficient to permit descriptive characterization of the utility an autoinjector versus a PFS.

3. Results

3.1 Patients

In total, 39 patients were enrolled in the sub-study, all of whom completed the study treatment, and received two injections with the PFS and two injections with the autoinjector. Patient demographics are presented in Table 2.

Table 2. Patient demographics and baseline clinical characteristics.

Characteristic	Total (N = 39)
Age, years, mean (SD)	40.92 (9.77)
Gender, female, n (%)	26 (67)
BMI, kg/m^2, mean (SD)	24.73 (4.66)
Geographical location, n (%)
Poland	24 (62)
Bulgaria	11 (28)
USA	4 (10)
Race, Caucasian, n (%)	39 (100)
ATTAIN baseline EDSS score, mean (SD)	2.68 (1.40)

BMI: Body mass index; EDSS: Expanded disability status scale; SD: Standard deviation.

3.2 Safety and tolerability

The incidence of AEs was similar when peginterferon-β_1a was administered via PFS or autoinjector, with the majority of AEs being mild or moderate in severity (Table 3).

Table 3. Summary of AEs.

AE incidence, n (%)	PFS N = 39	Autoinjector N = 39
Any AE(s)	27 (69)	23 (59)
AE severity
Mild	10 (26)	8 (21)
Moderate	15 (38)	14 (36)
Severe	2 (5)	1 (3)
Any treatment-related event	24 (62)	22 (56)
Any AE leading to withdrawal	0 (0)	0 (0)
Any SAEs	2 (5)*	1 (3)^‡
Most common AEs^§
Pyrexia	13 (33)	13 (33)
Injection site erythema	11 (28)	9 (23)
Headache	5 (13)	7 (18)
Influenza-like illness	7 (18)	6 (15)
Injection site pain	9 (23)	6 (15)
Myalgia	7 (18)	6 (15)
Arthralgia	4 (10)	5 (13)
Chills	6 (15)	5 (13)

*MS relapses and ureterolithiasis.

^‡MS relapse.

^§AEs occurring in ≥ 10% of subjects (by preferred term).

AE: Adverse event; MS: Multiple sclerosis PFS: Pre-filled syringe; SAE: Serious adverse event.

A similar number of patients reported experiencing injection-site pain for injection via PFS and autoinjector (n = 21 [54%] and n = 19 [49%] versus n = 23 [59%] and n = 19 [49%], respectively, for injections 1 and 2). The majority of these patients indicated that pain occurred at ‘needle in’ (for injections 1 and 2: PFS 36 and 31%; autoinjector 28 and 26%, respectively) and ‘during injection’ (for injections 1 and 2: PFS 26 and 23%; autoinjector 33 and 21%, respectively). Following injection with the autoinjector and the PFS, mean pain score was low, below 1.0 (out of 10) assessed within 60 min post-injection (Figure 1).

Figure 1. Mean pain scores following injection with the PFS and single-use autoinjector.

Clinician injection-site assessments within 60 min post-injection indicated no reports of erythema, induration, tenderness or local temperature increases following injection with the autoinjector; a single case of mild erythema was reported at first injection via the PFS.

3.3 Ease-of-use and patient satisfaction with the single-use autoinjector

The majority of patients indicated that the single-use autoinjector was ‘extremely easy’ or ‘easy’ to set-up (92.3%), hold and grip (89.7%), perform injections with (87.2%), and dispose of (94.9%; Figure 2).

Figure 2. Patient responses to ease-of-use questions for the single-use autoinjector.

The majority of patients indicated that the single-use autoinjector was ‘extremely convenient’ or ‘convenient’; none of the patients reported that the device was ‘inconvenient’ to use (Figure 3). Most patients (89.8%) rated their overall satisfaction with the autoinjector as ‘extremely satisfied’ or ‘satisfied’; 87.2% of patients indicated that they would be ‘extremely likely’ or ‘likely’ to continue using the autoinjector to administer their medication.

Figure 3. Patient responses to convenience questions for the single-use autoinjector.

3.4 Patient assessment of autoinjector training materials

All but one patient confirmed that they had reviewed the autoinjector training materials (materials were provided to the outlier as per protocol). In addition, 95% of patients reported that they were ‘very easy’ (57.9%) or ‘somewhat easy’ (36.8%) to understand; 95% of patients reported that they were ‘extremely satisfied’ (47.4%) or ‘somewhat satisfied’ (47.4%) with the level of detail provided; 90% of patients reported that they were ‘extremely satisfied’ (57.9%) or ‘somewhat satisfied’ (31.6%) with the organization and presentation; overall, 92% of patients felt that the printed instructions were ‘very effective’ (63.2%) or ‘somewhat effective’ (28.9%) in educating patients on the use of the autoinjector.

4. Discussion

This sub-study of patients with RRMS participating in ATTAIN, an extension of the ADVANCE study, reports the favorable tolerability and safety profile of peginterferon-β_1a self-administration using either the autoinjector or PFS, and high patient satisfaction and convenience associated with the autoinjector. In patients with RRMS, the safety profile of peginterferon-β_1a was similar when delivered using an autoinjector or a PFS. The safety profile in this sub-study is consistent with that reported at Year 1 of the ADVANCE study (n = 1512 randomized and dosed; placebo n = 500; peginterferon-β_1a Q2W n = 512; peginterferon-β_1a Q4W n = 500) [7], and similar to other established IFN-β therapies for relapsing MS; AEs that were reported by ≥10% patients in this sub-study were among the most commonly reported AEs in ADVANCE, and the finding that the majority of reported AEs were of mild or moderate severity was consistent with that in ADVANCE [7]. The low incidence of AEs compared with that reported at Year 1 of the ADVANCE study [7] may be due to mitigation of some tolerability issues, in particular ISRs, over time. This consistency of outcomes supports the validity of the sub-study evaluation of just two or four injections of peginterferon over an 8-week period. Similarly, the validity of the patient assessments in this sub-study is supported by the finding that clinicians and patients reported a similar tolerability profile when peginterferon-β_1a was administered using an autoinjector or a PFS; pain scores were low post-injection with the autoinjector, with no reports of clinician-assessed injection-site reactions. Overall patient perception of the autoinjector and accompanying training materials was very high. Autoinjector ease-of-use was rated high among patients, with > 90% reporting autoinjector set-up and disposal, and > 85% reporting hold and grip and performing injections as ‘easy’ or ‘extremely easy’. Similarly, ∼ 90% of patients reported that they were ‘satisfied’ or ‘extremely satisfied’ with the autoinjector, and > 85% stated that they would be extremely likely to continue using the autoinjector. Patients generally reported that the autoinjector training materials were very easy to understand and very effective. Patient understanding and ease of self-injection is highly important, as anxiety over self-injection can lead to treatment discontinuation [8].

These results should be considered in the context of sub-study limitations, which include the small patient population and resultant lack of statistical power for the analyses, along with the relatively short duration of study. A further limitation to consider is the impact of individual patient personalities on ease-of-use and satisfaction evaluation (e.g., previous studies have demonstrated that acquiescent responding to questionnaires can influence study results) [9]. It should also be noted that questionnaires included in this study were not specifically validated in the RRMS patient population and that at sites where these questionnaires would need to be translated into the local language (Poland and Bulgaria), interpretation of questions may have been confounded by translational or cultural differences. Patients in the sub-study were not specifically asked about autoinjector experience, and although ADVANCE study requirements excluded patients who had previously received > 4 weeks IFN treatment, previous autoinjector experience may have impacted study results. Finally, although increased ease-of-use may affect medication adherence in clinical practice, persistence could be further impacted by additional variables, including regional medication availability. Therefore, persistence may be higher in nations where there are fewer mediation options. Nevertheless, the consistency of these outcomes with those reported in Year 1 of the ADVANCE study lends support to the direction of the findings reported here. Data from this sub-study also compare well with tolerability and satisfaction data reported using other IFN self-injection devices [10-18]. In a 12-month open-label observational Phase IV study, 213 intent-to-treat patients self-administered 30 µg intramuscular IFN-β_1a once weekly via an autoinjector pen. In a 6-month interim analysis, > 95% of patients reported being satisfied or very satisfied with the autoinjector, and reported injection fear and anxiety decreased between day 1 and month 6 [11]. Although these studies cannot be directly compared with the current study given the differences in form of IFN, formulation, dose and frequency, in addition to differences in study designs and patient populations, a common theme across the studies is that autoinjectors improve patient satisfaction/ease-of-use [10-18], with further evidence of > 95% of patient-reported adherence after 6 months of IFN-β_1a administration via an autoinjector [11]. In the ADVANCE study, patient compliance was > 99% in all study arms [7]. An evaluation of patient adherence was beyond the scope of this current study; it should be noted that adherence assessments often rely on subjective, sometimes retrospective patient reporting which can lead to inaccurate results [14]. To date, we are not aware of any published head-to-head controlled studies evaluating MS therapy adherence with autoinjectors versus traditional PFSs. However, in the case of treatment using the peginterferon autoinjector, outcomes may be improved not only through the use of a convenient device but also through the administration of a pegylated IFN, which itself allows a reduction in dosing frequency [5], further improving tolerability and potential for treatment adherence.

Good medication adherence is essential to maintain the therapeutic efficacy of treatment, particularly in chronic and progressive conditions such as MS, for which the clinical and economic impact of adherence to MS treatments have been well documented [19,20]. The positive responses in patient questionnaires observed in this study provide an important indicator of the potential for improved treatment adherence, although further evaluation is required to assess this over the longer term, and in the real-world setting, for the peginterferon-β_1a autoinjector.

5. Conclusions

In this sub-study of patients with RRMS participating in ATTAIN, peginterferon-β_1a self-administration using an autoinjector resulted in a safety and tolerability profile that was comparable to that obtained using a PFS, with the advantage of high levels of patient satisfaction, ease of use and convenience. Delivery of peginterferon-β_1a via a single-use, disposable autoinjector may simplify the injection process for MS patients who require long-term therapy. Further research is required to confirm the benefits of using this device in the longer term.

Declaration of interest

This study was sponsored by Biogen Idec, Inc. (Cambridge, MA, USA). P Calabresi has received grant support from Biogen Idec, Inc., and Novartis; A Seddighzadeh, S Hung, Y Cui, S Liu and B Sperling are employees of Biogen Idec, Inc; K Selmaj has no conflicts of interest. The authors were assisted in the preparation of the manuscript by Shelley Davies PhD, a professional medical writer contracted to CircleScience (Tytherington, UK). Writing support was funded by Biogen Indec, Inc.

Acknowledgments

Prior presentation: Data were previously presented in poster format at the 2013 meeting of the American Academy of Neurology (AAN; March 16 – 23, 2013, San Diego, CA, USA). We wish to thank the patients who volunteered for this study and the site staff members who help to conduct the study. We also acknowledge Eric Falkner for his work in the design of the autoinjector device. Sub-study co-investigators: Gregory Anderson, Kenneth Carnes, Samuel Hunter, Ivaylo Tarnev, Zahari Zahariev, Lyubomir Haralanov, Ivan Staikov, Tomasz Zielinski, Waldemar Brola, Zbigniew Cebulski, Wieslaw Drozdowski, Hanka Hertmanowska, Magdalena Kleczkowska. The authors had full editorial control of the manuscript and provided their final approval of all content. AS, SH, YC and SL contributed to the design of the study, data collection, data analysis and critical review of the manuscript. PAC and BS assisted with data analysis and critical review of the manuscript. KS was an Investigator on the sub-study and contributed to critical review of the manuscript. Trial registration: NCT01332019 (ATTAIN).

Notes