Multiple Sclerosis and Related Disorders (2013) 2, 45–56

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Rebifs Quality of Life (RebiQoL): A randomized, multicenter, Phase IIIb study evaluating qualityof-life measures in patients receiving the serum-free formulation of subcutaneous interferon beta-1a for the treatment of relapsing forms of multiple sclerosis$ D. Bandaria,n, D. Wynnb, T. Millerc, B. Singerd, S. Wraye, R. Bennettf, B. Haywardf, F. Dangondf, on behalf of the RebiQoL Study Group a

Multiple Sclerosis Center of Southern California and Research Group, Newport Beach, CA, USA Consultants in Neurology, Ltd, 1535 Lake Cook Road, Suite 601, Northbrook, IL 60062, USA c Advanced Neurology of Colorado, LLC, Fort Collins, CO, USA d Missouri Baptist Medical Center, St. Louis, MO, USA e Hope Neurology MS Center, 10800 Parkside Dr., Suite 202, Knoxville, TN 37934, USA f EMD Serono, Inc., One Technology Place, Rockland, MA 02370, USA b

Received 21 December 2011; received in revised form 1 June 2012; accepted 17 July 2012

KEYWORDS Interferon beta; Multiple sclerosis; Quality of life; Randomized clinical trial; Rebifs new

Abstract Background: In clinical studies, treatment with subcutaneous interferon beta-1a (IFNb-1a) has been shown to reduce relapse rates and slow the progression of physical disability in patients with relapsing forms of multiple sclerosis (MS). A formulation of subcutaneous IFNb-1a has been developed that is free of fetal bovine serum and human serum albumin. Objective: To evaluate (a) the impact on quality of life (QoL) and treatment satisfaction of transitioning from the original formulation of subcutaneous IFNb-1a to the serum-free formulation in patients with relapsing forms of MS; and (b) the impact of dose titration versus non-titration

Abbreviations: AE, Adverse event; BDI-II, Beck Depression Inventory II; CI, Confidence interval; DMD, Disease-modifying drug; FLS, Flu-like symptoms; FSS, Fatigue Severity Scale; IFNb-1a, Interferon beta-1a; ISRs, Injection-site reactions; ITT, Intent-to-treat; LOCF, Last observation carried forward; MRI, Magnetic resonance imaging; MSTCQ, Multiple Sclerosis Treatment Concerns Questionnaire; QoL, Quality of life; sc, Subcutaneous(ly); SD, Standard deviation; SF-36, Short Form-36; SF-MPQ, Short-Form McGill Pain Questionnaire; tiw, Three times weekly $ ClinicalTrials.gov identifier NCT00472797. n Correspondence to: Multiple Sclerosis Center of Southern California, 3900 West Coast Highway, Suite 330, Newport Beach, CA 92663, USA. Tel.: +1 949 706 5580; fax: +1 949 706 5585. E-mail addresses: [email protected] (D. Bandari), [email protected] (D. Wynn), [email protected] (T. Miller), [email protected] (B. Singer), [email protected] (S. Wray), [email protected] (R. Bennett), brooke. [email protected] (B. Hayward), [email protected] (F. Dangond). 2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2012.07.005

46

D. Bandari et al. formulation; Safety

1.

during the transition on tolerability and patterns of analgesic use. QoL was measured by the Multiple Sclerosis Treatment Concerns Questionnaire Global Side Effects (GSE) score. Methods: Patients who had received the original formulation of IFNb-1a subcutaneously for Z24 weeks were randomized to receive the serum-free formulation of IFNb-1a 44 mg subcutaneously three times weekly for 12 weeks, with or without a dose titration over a 4-week period. After week 12, patients continued to receive serum-free subcutaneous IFNb-1a during a safety extension phase until they completed between 84 and 112 weeks of treatment. The primary endpoint was the percentage change from baseline to week 12 in GSE score in all patients. Results: A total of 232 patients were randomized (titrated n=113; non-titrated n=119). The mean percent change (improvement) from baseline to week 12 in the GSE score was 5.0% (po0.001 for mean change in GSE score from baseline); this change was similar between titrated and nontitrated patients and met criteria for non-inferiority to the original formulation. Adverse event (AE) incidence and use of analgesics for the treatment of flu-like symptoms (FLS) were less common in the titrated group. Few patients (o2%) discontinued due to AEs during weeks 0 to 12. Conclusion: Patients with relapsing forms of MS who transitioned from original-formulation subcutaneous IFNb-1a to serum-free subcutaneous IFNb-1a had overall improved QoL scores at 12 weeks of treatment. Titration during the transition resulted in a lower requirement for analgesic treatment of FLS and fewer AEs. & 2012 Elsevier B.V. All rights reserved.

Introduction

Because of the chronic and inflammatory nature of multiple sclerosis (MS), patients with relapsing forms of the disease often experience changes in physical, psychological, and cognitive abilities that reduce their health-related quality of life (HRQoL) (Benedict et al., 2005; Janardhan and Bakshi, 2000). While most assessments in MS focus on relapses, disability, and magnetic resonance imaging (MRI) changes, monitoring QoL is becoming increasingly important. Routine HRQoL assessment should help physicians understand and address the factors that negatively impact patients (Bandari et al., 2010; Benedict et al., 2005). Ultimately, the goal of MS therapy is to provide a treatment that has a beneficial impact on both disease progression and QoL. Treatment with disease-modifying drugs (DMDs) has transformed the management of MS, with DMDs demonstrating various improvements in clinical and MRI parameters (Jacobs et al., 2000; Johnson et al., 2003; Knobler et al., 1993; Panitch et al., 2002, 2005; Polman et al., 2006; PRISMS Study Group, 1998, 2001). In clinical studies, treatment with subcutaneous (sc) interferon beta-1a (IFNb-1a; Rebifs; EMD Serono, Inc., Rockland, MA, USA) has been shown to reduce relapse rates, decrease MRI lesion activity and burden of disease, and slow the progression of physical disability in patients with relapsing forms of MS (PRISMS Study Group, 1998, 2001). IFNb-1a has an established tolerability profile at the doses approved for use in patients with relapsing MS (Kappos et al., 2006). Neutralizing antibodies (NAbs) have been detected in up to 31% of patients (Rebifs prescribing information, 2009). A number of factors may influence the immunogenicity of therapeutic proteins (Schellekens, 2005). In particular, studies have shown that IFN and human serum albumin can form aggregates that may increase immunogenicity compared with

IFN monomers (Braun et al., 1997; Hochuli, 1997). Therefore, a serum-free formulation of sc IFNb-1a (free of fetal bovine serum and human serum albumin) has been developed with the aim of reducing immunogenicity and improving injection tolerability. The Rebifs Quality of Life (RebiQoL) study was designed to evaluate the impact on QoL and treatment satisfaction of transitioning from the original formulation of sc IFNb-1a to the serum-free formulation in patients with relapsing forms of MS. As some authors have suggested that dose titration and concomitant analgesic use may reduce the incidence of flu-like symptoms (FLS) associated with IFNb treatment (Brandes et al., 2007; Rice et al., 1999), this study also evaluated the impact of titration versus non-titration during the transition on tolerability and analgesic use.

2. 2.1.

Materials and methods Study design and patients

RebiQoL (ClinicalTrials.gov NCT00472797) was a randomized, multicenter, 2-arm, non-inferiority, Phase IIIb study conducted at 25 sites in the United States. The study was conducted in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice and the ethical principles of the Declaration of Helsinki. All patients provided written, informed consent. This study was open-label, except for assessments of injection-site reactions (ISRs), which were performed by healthcare professionals blinded to the treatment assignment. Eligible patients were 18–60 years of age with relapsing forms of MS, diagnosed in accordance with the 2005 revised McDonald criteria (Polman et al., 2005). Patients were required to be currently taking IFNb-1a 44 mg sc three times weekly (tiw) and to have been on this treatment for at least

Serum-free formulation sc IFNb-1a in MS: quality of life

47

24 weeks before study enrollment; currently using the Rebiject IIs autoinjector (EMD Serono, Inc., Rockland, MA, USA) and a 29-gauge needle; not pregnant or breastfeeding; and treatment-naive to the sc IFNb-1a serum-free formulation. Key exclusion criteria were: the regular use of injectable medications other than IFNb-1a in the week prior to screening or during the study; MS therapy in addition to IFNb-1a within 3 months prior to study enrollment or during the study; chronic pain syndrome; complete transverse myelitis or bilateral optic neuritis; oral or systemic corticosteroids or adrenocorticotrophic hormone within 30 days prior to study enrollment; inadequate liver function or bone marrow reserve; or other current autoimmune diseases.

2.2.

Treatment

Patients were randomized in a 1:1 ratio (stratified by site) to receive serum-free IFNb-1a 44 mg sc tiw for 12 weeks (Figure 1), either with a 4-week titration to the full dose (Table 1) using the same titration schedule as recommended in the package labeling for Rebifs (Rebifs United States prescribing information, Sep 2009) or without the standard titration to transition directly to the full dose of 44 mg. All patients self-administered the serum-free sc IFNb-1a formulation using the Rebiject IIs autoinjector. After week 12, patients continued receiving serum-free sc IFNb-1a during a safety extension phase until the last enrolled patient completed a total of 84 weeks of treatment. The length of the extension varied depending on the patient’s date of enrollment, but all patients received between 84 and 112 weeks of treatment.

2.3.

with treatment for MS; a higher score indicates a more favorable response. The GSE domain, in which patients are asked questions about their overall satisfaction with treatment, was selected to reflect patient perceptions of QoL. Secondary endpoints included the following: change from baseline in other MSTCQ domain scores (Cramer et al., 2006); changes from baseline in Short Form-36 (SF-36) Quality-of-Life Survey version 2 (Ware et al., 2000), Beck Depression Inventory II (BDI-II) (Beck et al., 1996), and Fatigue Severity Scale (FSS) (Krupp et al., 1989) scores; blinded assessment of ISRs; injection-site pain (patientreported Short-Form McGill Pain Questionnaire [SF-MPQ]) (Melzack, 1987); analgesic use; and total number of relapses. Patients were also instructed to bring both opened and unopened study drug packages to each visit during the first 12 weeks to allow the assessment of treatment compliance. Safety assessments included adverse events (AEs) and changes in laboratory assessments and vital signs. Serum samples were analyzed for antibodies to IFNb-1a and were deemed positive for NAbs if titers were Z20 neutralizing units/mL.

2.4.

Statistical analyses

The intent-to-treat (ITT) population consisted of all randomized patients. The safety population consisted of all patients who received at least one dose of the serum-free formulation of sc IFNb-1a and had post-baseline safety data. The primary objective of the study, to determine if the serum-free formulation of sc IFNb-1a was non-inferior to the original formulation of sc IFNb-1a, was met if the lower Table 1

Study assessments and endpoints

The schedules for key study assessments are shown in Figure 2. The primary endpoint was the percentage change from baseline to week 12 in the Global Side Effects (GSE) score (questions 9, 10, and 11 of the Multiple Sclerosis Treatment Concerns Questionnaire [MSTCQ]; Figure 3) in all patients combined (Cramer et al., 2006). The MSTCQ is designed to evaluate the patient’s degree of satisfaction

Titration schedule for IFNb-1a sc tiw.

Study week

Percentage of total dose Titration dose of IFNb-1a, lg

1–2 3–4 5+

20 50 100

8.8 22 44

IFN, interferon; sc, subcutaneously; tiw, three times weekly.

Prestudy evaluation Screening

Baseline

Extension phase (up to week 112)

Comparison phase

Original formulation IFNβ-1a 44 μg sc tiw

N=232

Randomization

Serum-free formulation IFNβ-1a 44 μg sc tiw, no titration to full dose (n=119)

Serum-free formulation IFNβ-1a 44 μg sc tiw, titration to full dose (n=113)

–4*

–2

(Study day 1)

4

12 Weeks

Figure 1

112 maximum

Study design. IFN, interferon; sc, subcutaneously; tiw, three times weekly. nUp to 30 days before randomization.

48

D. Bandari et al. R a n d o m iz a tio n

Comparison phase

Serum-free formulation Full dose*

Serum-free formulation Full dose*

Original formulation Full dose* for ≥6 months

B

S a fe ty e x te n s io n phase

Serum-free formulation Titration B

Serum-free formulation Full dose* B

B

B

Assessments Short Form-36 B Injection-site redness (blinded)

B

MSTCQ/McGill pain at clinic Laboratory testing Adverse event/relapse docs Fatigue Severity Scale Beck Depression Inventory –2

Study day 1

2

4

8

12

36

84 minimum

Duration of study, weeks

Figure 2 Study assessment schedule. IFN, interferon; MSTCQ, Multiple Sclerosis Treatment Concern Questionnaire; sc, subcutaneous(ly); tiw, three times weekly. nFull dose = 44 mg sc tiw.

9. Overall, are you satisfied with your current treatment? 1 Not at all satisfied

2 A little satisfied

4 Mostly satisfied

5 Extremely satisfied

3 Somewhat satisfied

10. Do you feel that the potential benefits of the treatment are worth the bother of the injections? 1 Not at all

2 A little

4 Mostly

5 Extremely

3 Somewhat

11. Considering the side effects and injection issues reviewed above, how well are you coping overall?

Figure 3

1 Not coping at all

2 Coping a little

4 Coping moderately well

5 Coping very well

3 Coping somewhat

GSE component of the MSTCQ. GSE, Global Side Effects; MSTCQ, Multiple Sclerosis Treatment Concerns Questionnaire.

bound of the 97.5% one-sided confidence interval (CI) for the primary endpoint was Z10%. The primary objective was analyzed using a last observation carried forward (LOCF) approach on the primary endpoint for all ITT patients combined. Results were summarized with descriptive statistics by treatment group and in the overall study population. A one-sided paired t-test was performed on change from baseline to week 12 in mean GSE score within each treatment group and across all patients. Changes from baseline in other domains of the MSTCQ for each treatment group and all patients combined were evaluated using a t-test; differences between the titrated and non-titrated groups were evaluated using a two-way analysis of variance (ANOVA) model adjusted for treatment and center. The changes from baseline in injection site redness and SF-36, SF-MPQ, BDI-II, and FSS scores were summarized with descriptive statistics and p-values calculated as described for the MSTCQ. The numbers of MS relapses from week 0 to the exit visit were summarized by treatment group and overall, and differences between the treatment groups were analyzed using a Poisson regression

model adjusted for treatment. Results of other secondary and safety outcomes were summarized using descriptive statistics. All statistical tests used a significance level of a =0.025 for one-sided tests and a =0.050 for two-sided tests. No correction to the significance level was made for multiple comparisons. Statistical analyses were carried out with SASs Version 8.2 (SAS Institute, Inc., Cary, NC, USA) or later.

2.5.

Sample size calculation

A total of 222 ITT patients would provide 80% power to declare non-inferiority of GSE score at week 12 when compared with the baseline GSE score in the combined titrated and non-titrated treatment groups, along with a non-inferiority margin of 10%, a 10% dropout rate and a Type I error rate of 2.5%. The sample size was calculated using a one-sided paired t-test based on the assumptions that the GSE score at week 12 was 90% of the baseline GSE score under the null hypothesis and was 102% of the baseline GSE

Serum-free formulation sc IFNb-1a in MS: quality of life score under the alternative hypothesis. The mean baseline GSE score was assumed to be 12.5 and the standard deviation (SD) of the difference as 1.5, with the correlation between baseline and week 12 as 0.64.

3. 3.1.

Results Patient disposition and demographics

A total of 232 patients (mean [SD] age 43.7 [9.2] years [range, 20–61 years]; 77.6% female) were randomized and included in

49 the ITT population (titrated, n=113; non-titrated, n=119; Figure 4). Of these, 231 received at least one dose of study drug. The first patient was screened on April 16, 2007, and the last patient visit was on July 30, 2009. No notable differences were observed between the treatment groups in patient demographics and baseline characteristics (Table 2). Overall, approximately half of the patients (51.9%) had used sc IFNb-1a for more than 24 months (mean [SD] 27.9 [16.7] months [range, 5.8–69.3 months]) prior to study initiation. A similar proportion of patients had used sc IFNb-1a for more than 24 months in the titrated (51.3%) and non-titrated (52.5%) groups.

262 patients were assessed for eligibility 30 were excluded 13 did not meet inclusion criteria 9 excluded based on exclusion criteria 5 withdrew consent 3 other reasons

Comparison phase

232 underwent randomization

Titrated group 113 randomized to serum-free formulation IFNβ-1a 44 μg sc tiw with a 4-week titration to full dose

Non-titrated group 119 randomized to serum-free formulation IFNβ-1a 44 μg sc tiw with no titration to full dose

113 included in ITT population

119 included in ITT population 1 was not treated (withdrew consent on day of randomization)

113 included in safety population

1 lost to follow-up

112 completed 12-week comparison phase

Safety extension phase

6 discontinued treatment 2 adverse events 1 lost to follow-up 2 failure to comply with protocol requirements 1 other reason 106 completed weeks 0–36

118 included in safety population 3 discontinued treatment 2 adverse events 1 lack of efficacy 115 completed 12-week comparison phase

1 discontinued treatment due to adverse event

114 completed weeks 0–36

36 discontinued treatment 9 adverse events 2 lost to follow-up 2 lack of efficacy 2 withdrew consent 2 pregnancy 8 investigator’s decision not to participate following protocol amendment 6 entered another clinical trial 4 closure of clinic 1 other reason

35 discontinued treatment 3 adverse events 2 lost to follow-up 1 failure to comply with protocol requirements 1 lack of efficacy 2 withdrew consent 1 pregnancy 8 investigator’s decision not to participate following protocol amendment 9 entered another clinical trial 4 closure of clinic 4 other reasons

70 completed extension phase

79 completed extension phase

Figure 4 Patient enrollment and disposition. IFN, interferon; ITT, intent-to-treat; sc, subcutaneously; tiw, three times weekly.

50

D. Bandari et al.

Table 2

Patient characteristics at baseline (ITT population).

Characteristic

Mean age, years (SD) Female, n (%) Caucasian, n (%) Diagnosis of RRMS, n (%) Mean time from first MS onset to randomization, months (SD) Time since most recent MS attack to randomizationa r6 months, n (%) 46 to 24 months, n (%) 424 months, n (%) Steroid treatment required for most recent MS relapse, n (% of those with known relapse)b

IFNb-1a 44 lg sc tiw (serum-free formulation) Titrated (n=113)

Non-titrated (n=119)

All patients (n=232)

42.8 89 100 113 90.8

(9.4) (78.8) (88.5) (100) (74.3)

44.6 91 112 117 113.4

43.7 180 212 230 102.4

(9.2) (77.6) (91.4) (99.1) (89.2)

21 50 41 70

(18.8) (44.6) (36.6) (63.1)

13 59 45 80

34 109 86 150

(14.8) (47.6) (37.6) (65.2)

(9.0) (76.5) (94.1) (98.3) (100.5)

(11.1) (50.4) (38.5) (67.2)

IFN, interferon; RRMS, relapsing–remitting multiple sclerosis; sc, subcutaneously; SD, standard deviation; tiw, three times weekly. a Based on total number of patients for whom time since relapse is known (titrated, n=112; non-titrated, n=117). b Based on total number of patients for whom steroid use is known (titrated, n=111; non-titrated, n=119).

During the first 12 weeks, 88.7% (205/231) of patients were 495% compliant with the study treatment and compliance was similar in the two groups.

12); the difference between the groups was not statistically significant (p=0.833).

3.3. 3.2. Primary endpoint: change in Global Side Effects score At baseline, the mean scores for the GSE component of the MSTCQ were the same in the titrated and non-titrated groups (mean [SD] score 13.4 [1.8] versus 13.4 [1.7], respectively, on a scale of 3 to 15; a higher score indicates a more favorable response). The mean (SD) percent change from baseline to week 12 in GSE score in the ITT population was 4.5% (18.8%) in the titrated group (p=0.003 for mean change) and 5.5% (16.5%) in the non-titrated group (po0.001 for mean change; p-values were calculated for the mean changes in GSE score at week 12 versus baseline and were statistically significant). Across all patients, the mean (SD) percent change in GSE score from baseline to week 12 was 5.0% (17.7%) (po0.001 for mean change in GSE score at week 12 versus baseline; Figure 5A). This elevation over baseline GSE scores for all patients was observed at earlier timepoints (Figure 5B); results for the separate titrated and non-titrated groups were superimposed with the time course for all patients and so are not shown. The 97.5% one-sided lower CI for the mean percent change in GSE score from baseline to week 12 across all patients was 2.73%, which met the predefined criterion (Z10%) for non-inferiority compared with the original formulation of sc IFNb-1a. The difference between the titrated and non-titrated groups was not statistically significant (p= 0.466). Mean [SD] changes in GSE scores during the extension phase (week 12 to the exit visit) reflected improvement and were significant for both groups (titrated, 0.5 [2.1], p=0.010 versus week 12; non-titrated, 0.4 [1.7], p=0.012 versus week

Secondary endpoints

3.3.1. Other domains of the Multiple Sclerosis Treatment Concerns Questionnaire From baseline to week 12, significant improvements were observed in each of the other MSTCQ domain scores in both the titrated and non-titrated groups (Figure 6). Significant improvements were also observed in the MSTCQ injection system satisfaction, side-effects, and ISR domains in both groups from baseline to the exit visit (all po0.05 versus baseline). The mean change (improvement) from baseline to the exit visit in the MSTCQ FLS domain was statistically significant in the non-titrated group (p=0.005 versus baseline) but not in the titrated group. Differences between the two groups in changes from baseline were not statistically significant at either week 12 or the exit visit for any of the MSTCQ domains. 3.3.2. Blinded assessment of injection-site reactions The mean diameter of the area of injection-site redness decreased after baseline in both groups starting at day 1 and the decrease was maintained through week 36, although the decrease was less pronounced over time. The mean [SD] decreases at day 1 were statistically significant in both the titrated (12.4 [27.2] mm) and non-titrated groups (15.0 [23.3] mm; po0.001 for each group versus baseline). The mean (SD) decrease from baseline to week 36 was 3.7 (26.1) mm in the titrated group (p=0.311 versus baseline) and 7.6 (23.2) mm in the non-titrated group (p=0.002 versus baseline; difference between groups, p =0.017). There were no notable differences between the groups in evaluations of injection-site swelling, bruising, or itching. Most cases of swelling, bruising, or itching were

Change in GSE score, baseline to week 12 (mean %)

Serum-free formulation sc IFNb-1a in MS: quality of life

51

6

5.5† 5.0† 4.5*

4

2

0 Non-titrated (n = 117)

Titrated (n = 113)

All patients (n = 230) 5% improvement from baseline

15

GSE score

14 13 12 11 10 7 0 1 2 3 4 5 6 8 9 10 11 12 Weeks after transition to serum-free IFNβ-1a (all patients)

Change in MSTCQ domain score, baseline to week 12 (mean)

Figure 5 Primary and secondary endpoint changes in GSE: (A) Mean percent change in GSE scores from baseline to week 12 (ITT population); (B) Time course of mean GSE from baseline to week 12. GSE, Global Side Effects; ITT, intent-to-treat. A higher score indicates a more favorable response. np=0.003 based on mean change from baseline. ypo0.001 based on mean change from baseline.

7 6

Titrated (n = 113) Non-titrated (n = 117)

6.5* 5.3*

5 4 3

2.9*

3.3*

3.2* 2.3*

2

1.8*

1

0.7

0.9

1.2*

0 Injection system satisfaction

Side-effects

Flu-like symptoms

Injection-site reactions

Total scores§

Figure 6 Mean change in MSTCQ domain scores from baseline to week 12. MSTCQ, Multiple Sclerosis Treatment Concerns Questionnaire. A higher score indicates a more favorable response. npo0.001. yp =0.028. zp= 0.008. ySummary of the injectionsystem satisfaction and side-effect domains.

mild or moderate; no cases of severe itching and only one case each of severe swelling or bruising were observed. 3.3.3. Flu-like symptoms and use of analgesics The percentage of patients with any FLS related to the study drug (at any time from baseline to the exit visit) was lower in the titrated group (33.6%) than in the non-titrated group (44.5%); the largest differences between the groups occurred with respect to myalgia (0.9% versus 10.1%, respectively) and headache (15.9% versus 23.5%, respectively). The percentage of patients who took analgesics at any time from baseline to the exit visit was 72.6% in the titrated group and 76.5% in the non-titrated group. Overall, few patients took analgesics to prevent ISRs (titrated, 6.2%; nontitrated, 4.2%; p=0.3). The percentage of patients taking

analgesics to prevent FLS at any time from baseline to the exit visit was similar between the titrated and non-titrated groups (69.9% and 63.9%, respectively; p=0.334), while the percentage of patients taking an analgesic for the treatment of FLS at any time from baseline to the exit visit was lower in the titrated group (27.4% versus 40.3%; p=0.052). Figure 7 shows the time course of FLS in terms of percentages of patients with or without FLS at each visit up to week 36, grouped according to analgesic use. 3.3.4. Short Form-36 scores In both groups combined, the mean (SD) change in the SF-36 Physical Component Score was 1.9 (5.0) from baseline to week 12 (po0.001; an increase in component score indicates improvement), 0.6 (7.0) from baseline to week 36

52

D. Bandari et al. 60

50

Patients (%)

40

No FLS and did not use analgesic No FLS and used analgesic

30

FLS and used analgesic 20

FLS and did not use analgesic

10

0 0

Figure 7

4

8

12

24

16 20 Week

28

32

36

Flu-like symptoms (FLS) and analgesic use assessment (ITT population, N =232). ITT, intent-to-treat.

(p= 0.234), and 0.9 (6.4) from baseline to the exit visit (p= 0.036). The mean (SD) change in the SF-36 Mental Component Score in both treatment groups combined was 1.9 (8.9) from baseline to week 12 (p=0.002), 0.5 (10.4) from baseline to week 36 (p=0.468), and 0.0 (10.5) from baseline to the exit visit (p =0.991). Differences between the two groups in the changes from baseline in component scores were not statistically significant. 3.3.5. Injection-site pain Between baseline and subsequent visits, small increases were observed in pain scores. Baseline mean (SD) score for all patients on the SF-MPQ was 1.6 (3.4) on a scale of 0 to 45 where higher scores indicate more severe pain. The mean (SD) change in both groups combined was 0.9 (3.7) from baseline to week 12, 0.9 (3.5) from baseline to week 36, and 1.5 (4.2) from baseline to the exit visit (all po0.001). Differences between the two groups were not statistically significant. At baseline, 57.1% (132/232) of all patients reported pain, as evaluated by the SF-MPQ visual analog score (VAS); this percentage did not change greatly at subsequent visits (range, 52.9–59.7%). There were no notable differences between the groups in the proportions of patients with and without pain, as evaluated by the SF-MPQ VAS at week 12 (Figure 8). The percentage of patients who reported pain as an AE is described in Section 3.4.1 and Table 3. 3.3.6. Beck Depression Inventory II scores Decreases (improvements) in mean [SD] BDI-II scores from baseline to week 36 (1.5 [6.2]; po0.001) and from baseline to the exit visit (1.7 [6.8]; po0.001) were noted in both treatment groups combined; differences between the two groups were not statistically significant. 3.3.7. Fatigue Severity Scale scores Decreases (improvements) in mean [SD] FSS scores from baseline to week 36 (0.3 [1.2]; po0.001) and from baseline to the exit visit (0.2 [1.3]; p =0.08) occurred in both treatment groups combined; differences between the two groups were not statistically significant.

Pain-free* 56.8

60

Patients (%)

50

Not pain-free

43.2

55.3

53.9 46.1

44.7

40 30 20 10 0 Titrated (n = 111)

Non-titrated (n = 115)

All patients (n = 226)

Figure 8 Proportions of patients with or without injection site pain (as evaluated by the VAS) by treatment group at week 12. VAS, visual analog score. nPain-free defined as VAS o5 mm.

3.3.8. Relapses The percentage of patients who experienced one or more relapses during the study (week 0 to the exit visit) was 33.6% (38/113) in the titrated group and 37.8% (45/119) in the nontitrated group (relative risk, 1.0 [95% CI: 0.70, 1.57]).

3.4.

Safety

3.4.1. Adverse events The safety population included 231 patients (one patient withdrew consent on the day of randomization and did not receive treatment). Of these, 87.4% reported Z1 AE during the study (titrated, 84.1% [95/113]; non-titrated, 90.7% [107/118]). A smaller percentage of patients reported an AE during weeks 412–36 (53.7% [122/227]) than in weeks 0–12 (72.7% [168/231]); after week 36, AEs were reported by 62.4% (131/210) of patients. AEs reported by Z5% of the safety population from week 0 to the exit visit are summarized in Table 3. The percentage of patients with at least one AE was lower in the titrated group than in the non-titrated group during weeks 0–12 (69.0% [78/113] versus 76.3% [90/ 118], respectively) and weeks 412–36 (52.7% [59/112]

Serum-free formulation sc IFNb-1a in MS: quality of life

Table 3

53

Treatment-emergent AEs reported by Z5% of all patients, week 0 to exit visita (safety population).

Adverse event, n (%)

Any adverse event Headache Pain Urinary tract infection Nasopharyngitis Flu-like illness Arthralgia Sinusitis Pain in extremity Upper respiratory tract infection Chills Depression Myalgia Back pain Pyrexia Nausea Bronchitis Injection-site reaction Insomnia

IFNb-1a 44 lg sc tiw (serum-free formulation) Titrated (n=113)

Non-titrated (n =118)

All patients (n= 231)

95 31 20 18 16 15 11 10 10 9 7 9 3 3 7 2 8 4 11

107 42 23 16 16 14 14 15 9 10 9 7 13 12 8 11 4 8 1

202 73 43 34 32 29 25 25 19 19 16 16 16 15 15 13 12 12 12

(84.1) (27.4) (17.7) (15.9) (14.2) (13.3) (9.7) (8.8) (8.8) (8.0) (6.2) (8.0) (2.7) (2.7) (6.2) (1.8) (7.1) (3.5) (9.7)

(90.7) (35.6) (19.5) (13.6) (13.6) (11.9) (11.9) (12.7) (7.6) (8.5) (7.6) (5.9) (11.0) (10.2) (6.8) (9.3) (3.4) (6.8) (0.8)

(87.4) (31.6) (18.6) (14.7) (13.9) (12.6) (10.8) (10.8) (8.2) (8.2) (6.9) (6.9) (6.9) (6.5) (6.5) (5.6) (5.2) (5.2) (5.2)

IFN, interferon; sc, subcutaneously; tiw, three times weekly. a The exit visit occurred between week 84 and week 112, depending on the patient’s date of enrollment.

versus 54.8% [63/115]); however, after week 36, more patients in the titrated group reported AEs (67.0% [67/100] versus 58.2% [64/110]). A total of 127 patients (55.0%) had Z1 AE that was possibly or probably related to the study drug. The percentage of patients reporting a study drugrelated AE was slightly lower in the titrated group (54.0% [61/113]) than in the non-titrated group (55.9% [66/118]). During weeks 0–12, the most frequently reported AEs in the titrated and non-titrated groups were headache (24.8% and 32.2% of patients, respectively), pain (14.2% and 16.9%), and influenza-like illness (8.0% and 9.3%). During this period, other AEs that were less common (by 45%) in the titrated group than in the non-titrated group included myalgia (0.9% versus 11.0% of patients, respectively) and nausea (0% versus 6.8%). Most AEs were mild to moderate in intensity; severe AEs were reported by 44 (19.0%) patients. All reports of injection-site pain were mild to moderate in intensity. The percentage of patients with severe AEs was lower in the titrated group (16.8% [19/113]) than in the non-titrated group (21.2% [25/118]). With both groups combined, severe depression and severe anxiety were reported by 1.7% (4/231) and 1.3% (3/231) of patients, respectively. No other severe AEs were reported by more than 2 (0.9%) patients. Sixteen (6.9%) patients had Z1 serious AE; only one of these events (suicidal ideation in 1 patient in the nontitrated group) was considered possibly related to the study drug. This patient had a history of depression that was considered potentially responsible for this serious AE. During the first 12 weeks, no patients in the titrated group and 2 (1.7%) patients in the non-titrated group discontinued due to AEs. Between weeks 12 and 36, 2 (1.8%) patients in

the titrated group and 1 (0.8%) patient in the non-titrated group discontinued due to AEs. Between week 36 and the exit visit, 9 (8.0%) patients in the titrated group and 3 (2.5%) patients in the non-titrated group discontinued because of AEs. The only AEs that led to the discontinuation of more than one patient were influenza-like illness (2 [0.9%] patients) and increased hepatic enzymes (3 [1.3%] patients).

3.4.2. Laboratory values and vital signs Changes in clinical chemistry values were uncommon. Differences were observed between the two groups in changes from baseline in ferritin values. Between baseline and week 12, 5.4% (12/224) of patients had normal-to-high shifts in ferritin; the percentage of patients with normal-tohigh shifts was lower in the titrated group than in the nontitrated group (2.7% [3/111] versus 8.0% [9/113] of patients). Between baseline and week 36, 7.1% (14/195) of patients had normal-to-high shifts in ferritin. As at week 12, the percentage of patients with normal-to-high shifts for ferritin was lower in the titrated group than in the nontitrated group (5.3% [5/94] versus 8.9% [9/101]); however, at the exit visit (LOCF) the percentage of patients with shifts from normal at baseline to high was similar between the groups (5.3% [6/113] versus 5.9% [7/118]). The mean (SD) change in ferritin from baseline to week 36 was 21.44 (270.66) pmol/L in the titrated group and 96.93 (469.90) pmol/L in the non-titrated group. However, the change in ferritin from baseline to the exit visit was 0.16 (361.34) pmol/L in the titrated group and 15.66 (293.55) pmol/L in the non-titrated group, suggesting that the ferritin increases that appeared during the trial were transitory. A

54

D. Bandari et al.

pattern of ferritin shifts from high baseline values to normal values at subsequent visits was observed in the titrated group but not in the non-titrated group. The mean [SD] changes from baseline to week 12 and from baseline to week 36 in alanine aminotransferase (ALT) levels were higher in the titrated group (week 12, 4.97 [42.86] IU/L; week 36, 1.65 [22.08] IU/L) than in the nontitrated group (week 12, 0.82 [11.50] IU/L; week 36, 0.27 [20.57] IU/L); at the exit visit both groups showed a slight decline from baseline (2.29 [22.22] IU/L and 2.56 [15.68] IU/L, respectively). Mean [SD] changes from baseline to week 12 in aspartate aminotransferase (AST) levels were also higher in the titrated group (3.36 [29.40] IU/L) than in the non-titrated group (1.33 [9.34] IU/L); however, changes from baseline in AST were comparable between groups at week 36 (0.64 [10.39] IU/L versus 1.34 [17.56] IU/L, respectively) and at the exit visit (0.42 [11.07] IU/L versus 0.47 [12.10] IU/L). With these exceptions, no clinically relevant differences between the groups were noted in changes from baseline in clinical chemistry values. No clinically relevant changes were observed in either group in mean hematology values or in vital signs between baseline and week 12 or between baseline and the exit visit.

3.5.

Antibodies

At screening (when patients were receiving the original formulation of sc IFNb-1a), 28/249 (11.2% of all patients; 14.2% of the titrated and 9.5% of the non-titrated group) were positive for NAbs. This proportion was marginally lower at subsequent timepoints: 20/189 (10.6% of all patients; 12.2% of the titrated and 9.1% of the non-titrated group) patients were NAb-positive at week 36, and 20/200 (10.0% of all patients; 12.1% of the titrated and 7.9% of the non-titrated group) were NAb-positive at the exit visit. Longitudinal antibody data were available for 217 patients. Among these patients, 20/217 (9.2% of all patients; 10.5% of the titrated and 8.0% of the non-titrated group) were NAbpositive at screening and remained positive at their final assessment (week 36 for 2 patients and the exit visit for 18 patients). Two of 217 (0.9%, both in the titrated group) patients started out NAb-negative, seroconverted after screening, and were NAb-positive at their exit visit. Conversely, 5/217 (2.3%; 4 titrated patients and 1 non-titrated patient) were NAb-positive at screening and/or week 36, but became NAb-negative by the exit visit.

4.

Discussion

We evaluated the impact on QoL and treatment satisfaction of transitioning patients with relapsing forms of MS from the original formulation of sc IFNb-1a to the serum-free formulation. The 5% improvement in the mean percentage change from baseline GSE score for both titrated and nontitrated serum-free sc IFNb-1a compared with original formulation demonstrates that the serum-free formulation is non-inferior to the original formulation (i.e., results did not fall outside the lower, pre-defined bound of 10%). As this was the primary objective of the study, clinical effect sizes were not calculated to provide an estimate of clinically meaningful differences in MSTCQ scores, so the

clinical relevance of the 5% change is unclear. In any case, the mean GSE score at baseline (e.g., as patients transitioned from original formulation sc IFNb-1a) was already high at 13.4 and achieving a perfect score of 15 would only have amounted to a 12% change from baseline. The 97.5% CI lower bound for the mean percent change in MSTCQ GSE score from baseline (when patients had previously been receiving the original formulation of sc IFNb-1a) to week 12 was 2.73% (i.e., greater than zero), indicating an improvement in QoL of patients after 12 weeks of treatment with the serum-free formulation. Statistically significant improvements were also observed from baseline to week 12 in all other MSTCQ components assessed (injection system satisfaction, side-effects, FLS, and ISRs) in both the titrated and nontitrated groups, suggesting that the serum-free formulation of sc IFNb-1a is associated with a better tolerability profile compared with the original formulation. Results from the MSTCQ are supported by the results obtained from blinded assessment of ISRs, which found that injection-site redness decreased after baseline in both groups, starting as early as day 1; however, at week 36, the decrease was statistically significant in the non-titrated group only (p=0.002). A similar, but shorter, European study, in which 117 patients with relapsing MS who had been receiving the original formulation of sc IFNb-1a for at least 6 months were transitioned to the serum-free formulation for 4 weeks, found that MSTCQ injection system satisfaction and GSE scores were unchanged, while MSTCQ total and ISR scores improved moderately between baseline and week 4 (Camu et al., 2010). We observed small increases in the SF-MPQ VAS-based pain scores when patients were transitioned to the serumfree IFN formulation; however, the mean baseline score started out low and changes from baseline scores at 4 of 6 timepoints were considered mild (i.e., a change of 1.0 or less). Although these results could reflect a small clinical difference, we cannot rule out potential confounding of the results by the inherent variability introduced by a subjective measure such as the VAS, especially in an unblinded setting. A limitation of the present study with regard to QoL outcomes and treatment satisfaction was the lack of a randomized control group of patients that continued on original formulation IFNb-1a. It is therefore not possible to be certain that the observed improvements in QoL and treatment satisfaction were not simply due to the passage of time. In addition, as patients were not blinded to the change in their treatment, the expectation of improvement may have contributed to the reported improvements in MSTCQ GSE scores. However, the design of the present study is more directly applicable to the likely real-world clinical situation in which patients transition from the original to the serum-free formulation of sc IFNb-1a. This study also provides valuable insights into the tolerability benefits of dose titration when transitioning from the original sc IFNb1a formulation and analgesic use for either prevention or treatment of FLS. Overall, AEs were less common in the titrated group than in the non-titrated group. Although the percentages of patients experiencing AEs did not differ significantly between groups (p=0.3), the difference seen (6.6%) may be clinically significant. During weeks 0–12, headache,

Serum-free formulation sc IFNb-1a in MS: quality of life myalgia, back pain, and nausea occurred with a 45% lower frequency in the titrated group than in the non-titrated group. Discontinuations due to AEs also occurred less frequently in the titrated group than in the non-titrated group during the first 12 weeks. The rate of discontinuations due to AEs was low during weeks 0–12: during this period, only 2 (1.7%) patients, both in the non-titrated group, discontinued due to an AE. No new safety observations were revealed. The percentage of patients taking analgesics for the prevention of FLS did not differ between the titrated and nontitrated groups. However, titration resulted in a lower requirement for analgesic treatment of FLS, which is likely attributable to the fact that fewer titrated patients had FLS. The percentage of patients who experienced FLS despite using an analgesic was greatest at week 2 and decreased thereafter. Differences between the titrated and non-titrated groups were not statistically significant for changes from baseline to week 36 and the exit visit in SF-36 Physical and Mental Component Scores, BDI-II scores, and FSS scores. Pain levels and the percentage of patients with relapses also did not significantly differ between the titrated and non-titrated groups. A pattern of shifts from high initial ferritin values to normal values at subsequent visits was observed in the titrated group, suggesting that titration may have helped to normalize ferritin values. Although small increases from baseline in ALT and AST levels were seen in both groups during the study, these levels had declined slightly from baseline in each group at the exit visit, favouring the serumfree sc IFNb-1a formulation. Previous results from two studies suggest that the serumfree sc IFNb-1a formulation may be associated with the development of fewer NAbs than the original formulation. In a 96-week study in IFNb-naive patients, the percentage of patients treated with the serum-free sc IFNb-1a formulation who were NAb-positive at any time during the study was 18.9% (Giovannoni et al., 2009). In contrast, in a separate study with the original formulation in IFNb-naive patients, 27.1% of patients were NAb-positive at any time during 96 weeks (Panitch et al., 2005). In the RebiQoL study, results regarding the development of NAbs are consistent with these earlier data, and suggest that transitioning patients from the original formulation of IFNb-1a to the serum-free formulation does not lead to enhanced immunogenicity. On the contrary, a trend towards a decrease in the rate of NAbs was observed in patients who completed the study (10%; 12.1% of titrated; 7.9% of non-titrated) compared with screening levels (11.2%; 14.2% of titrated; 9.5% of non-titrated). In addition, from screening to the final assessment, more patients converted from NAb-positive to seronegative status (n=5; 4 titrated; 1 non-titrated) than from seronegative to NAb-positive status (n=2; both titrated). Taken together, these results support the hypothesis that a human serum albumin- and fetal bovine serum-free formulation of IFNb-1a may contribute to reduced immunogenicity, or at least not result in enhanced immunogenicity in patients switching from the original formulation.

5.

Conclusions

Patients with relapsing forms of MS who transitioned from the original formulation of sc IFNb-1a to the serum-free

55 formulation reported significant improvements in QoL, injection system satisfaction, FLS, and ISRs at 12 weeks of treatment. In addition, few patients (o1%) discontinued due to AEs during the first 12 weeks of treatment with the serum-free formulation. These results support the findings of previous studies demonstrating improved local tolerability with the serum-free formulation of sc IFNb-1a compared with the original formulation. Improvements in QoL scores were similar between the titrated and non-titrated groups, but the incidences of myalgia and headache were lower in the titrated group. Titrating medication to the full dose may therefore be a beneficial treatment approach in patients with relapsing forms of MS, including those who are transitioned from the original formulation to the serum-free formulation of sc IFNb-1a.

Role of funding source This work was sponsored by EMD Serono, Inc., Rockland MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, and Pfizer Inc, New York, NY, USA.

Conflict of interest statement Dr Bandari has been a speaker and/or consultant for Acorda, Biogen Idec, EMD Serono, Pfizer, Novartis, and Teva Neuroscience. Dr Wynn has received has received research support, serves as a consultant and/or serves on speakers bureau for Acorda, Biogen Idec, EMD Serono, Pfizer, Novartis, Teva, Ono, Genentech, Roche, Avanir, GlaxoSmithKline, MedImmune, Eli Lilly, Sanofi Aventis, Opexa, Questcor, Forest, Elan, UCB, XenoPort, DepoMed, National Multiple Sclerosis Society, National Institute of Health, and the State of Illinois. Dr Miller has been a speaker for Allergan, Bayer, Biogen Idec, Eli Lilly, EMD Serono, Inc., and Forest Pharmaceuticals. Dr Singer has been a speaker and/or consultant for Acorda, Bayer, Biogen Idec, EMD Serono, Pfizer, Novartis, and Teva. Dr Wray has received compensation for consulting and/or honoraria for speaking from Acorda, Bayer, Biogen Idec, BioMarin, EMD Serono, Genentech, Novartis, and Teva Neuroscience, and research support from Bayer, Biogen Idec, EMD Serono, Genzyme, Novartis, Ono, and Teva Neuroscience. Dr Bennett, Dr Hayward, and Dr Dangond are employees of EMD Serono, Inc.

Acknowledgments This clinical study was sponsored by EMD Serono, Inc., Rockland MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, and by Pfizer Inc, New York, NY, USA. Medical writing and editorial assistance was provided by Callie Grimes, PhD and Reza Sayeed of Caudex Medical, New York, NY, funded by EMD Serono, Inc. and Pfizer Inc. Data analysis was provided by Clint Dart of Health Decisions.

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