Singer et al. BMC Neurology 2012, 12:154
`http://www.biomedcentral.com/1471-2377/12/154
`
`R ES EAR CH A R T I C LE
`Open Access
`Comparative injection-site pain and tolerability
`of subcutaneous serum-free formulation of
`interferonβ-1a versus subcutaneous interferonβ-
`1b: results of the randomized, multicenter,
`Phase IIIb REFORMS study
`Barry Singer1*, Daniel Bandari2, Mark Cascione3, Christopher LaGanke4, John Huddlestone5, Randy Bennett6
`and Fernando Dangond6on behalf of the REFORMS Study Group
`
`Abstract
`Background: In patients with relapsing–remitting multiple sclerosis (RRMS), subcutaneous (sc) interferon (IFN)β-1a
`and IFNβ-1b have been shown to reduce relapse rates. A formulation of IFNβ-1a has been produced without
`fetal bovine serum and without human serum albumin as an excipient (not currently approved for use in the US).
`The objectives of this study were to evaluate tolerability, injection-site redness, subject-reported satisfaction with
`therapy, and clinical safety and efficacy of the serum-free formulation of IFNβ-1a versus IFNβ-1b in
`IFNβ-treatment-naïve patients with RRMS. The objectives of the extension phase were to evaluate long-term safety
`and tolerability of IFNβ-1a.
`Methods: This randomized, parallel-group, open-label study was conducted at 27 clinical sites in the US. Eligible
`patients aged 18–60 years were randomized to receive either IFNβ-1a, titrated to 44 μg sc three times weekly
`(tiw) (n = 65), or IFNβ-1b, titrated to 250 μg sc every other day (n = 64) over 12 weeks. Following this, all patients
`received IFNβ-1a 44 μg tiw for 82–112 weeks. Primary endpoint was mean change in patient-reported pain, as
`assessed by visual analog scale (VAS) diary pain score (from 0 mm [no pain] to 100 mm [worst possible pain]) at
`the injection site, from pre-injection to 30 min post-injection over the first 21 full-dose injections. Secondary
`assessments included proportion of patients pain-free as recorded by VAS diary and the Short-Form McGill Pain
`questionnaire VAS.
`Results: A total of 129 patients were included in the intent-to-treat analysis. Mean (standard deviation) change in
`VAS diary pain score was not significantly different between groups, although numerically lower with IFNβ-1a
`versus IFNβ-1b from pre-injection to immediately post-injection (1.46 [2.93] vs. 4.63 [10.57] mm), 10 min
`post-injection (0.70 [1.89] vs. 1.89 [5.75] mm), and 30 min post-injection (0.67 [2.32] vs. 1.14 [4.94] mm). Proportion
`of patients pain-free at all time periods post-injection was also not significantly different between groups. Adverse
`events were consistent with the known safety profiles of these treatments.
`Conclusions: In IFNβ-treatment-naïve patients with RRMS, both the serum-free formulation of IFNβ-1a and IFNβ-1b
`treatments were generally accompanied by low-level injection-site pain and were well tolerated.
`(Continued on next page)
`
`* Correspondence: bnvsinger@earthlink.net
`1Missouri Baptist Medical Center, St. Louis, MO, USA
`Full list of author information is available at the end of the article
`
`© 2012 Singer et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
`Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
`reproduction in any medium, provided the original work is properly cited.
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`(Continued from previous page)
`Trial registration: ClinicalTrials.gov NCT00428584
`Keywords: Randomized controlled trial, Interferonβ-1a, Interferonβ-1b, Relapsing–remitting multiple sclerosis,
`Subcutaneous injections, Injection-site pain, Pain measurement
`
`Background
`Clinical studies of subcutaneous (sc) interferon (IFN)β-1a
`and IFNβ-1b have shown that these disease-modifying
`drugs reduce relapse rates in patients with relapsing–
`remitting multiple sclerosis (RRMS) [1-4]. At the doses
`approved for the treatment of RRMS, both IFNβ-1a and
`IFNβ-1b have established long-term safety and tolerability
`profiles [5,6]. However,
`injections with these drugs are
`commonly associated with injection-site reactions (ISRs),
`injection-site pain, and flu-like symptoms (FLS), which can
`lead to poor adherence to treatment in some patients [7,8].
`A formulation of IFNβ-1a has been developed without
`fetal bovine serum and without human serum albumin
`as an excipient, although this formulation is not cur-
`rently approved for use within the US. In a 96-week
`study in patients with relapsing MS, the serum-free for-
`mulation of IFNβ-1a was associated with a lower preva-
`lence of ISRs than had been seen in two earlier studies
`with the original IFNβ-1a formulation [9-11]. No rando-
`mized clinical study has yet compared the injection-site
`pain and tolerability profile of the serum-free formulation
`IFNβ-1a with that of another disease-modifying drug.
`The primary objective of this study was to compare
`the tolerability of the serum-free formulation of IFNβ-
`1a, 44 μg sc three times weekly (tiw), with IFNβ-1b,
`250 μg sc every other day (qod), as measured by the
`mean change in subject-reported injection-site pain
`from pre-injection to 30 min post-injection in IFNβ-
`treatment-naïve patients with RRMS during a 12-week
`period (comparative phase). During the extension phase,
`the primary objective was to evaluate long-term safety
`and tolerability of IFNβ-1a sc tiw.
`the mean
`included:
`Secondary efficacy endpoints
`difference in injection-site pain from pre-injection to
`immediately post-injection and to 10 min post-injection,
`the proportion of pain-free patients, number and severity
`of relapses, assessments of the treatment of side effects,
`patient-rated treatment satisfaction, and rater-blinded
`assessment of injection-site redness.
`Safety endpoints included analysis of adverse events
`(AEs), laboratory tests, physical examinations, vital signs,
`and concomitant medications.
`
`Methods
`Study design and patients
`The Rebif New Formulation Versus Betaseron Toler-
`ability Study (REFORMS) (ClinicalTrials.gov identifier:
`
`NCT00428584) was a randomized, multicenter, 2-arm,
`Phase IIIb study conducted at 27 clinical sites in the US.
`The study consisted of a 12-week randomized compara-
`tive phase, which was followed by a safety-extension
`phase of up to 112 weeks (range 82–112 weeks). The
`study was open-label, except for blinded assessments of
`ISRs. The initial central Institutional Review Board (IRB)
`submission was approved by Coast
`IRB, Colorado
`Springs, Colorado and, later, Schulman Associates IRB,
`Cincinnati, Ohio. For those sites that were not permitted
`to use a central IRB for study approval, submissions
`were made to the local IRB. This study was performed
`in accordance with the study protocol, the Declaration
`of Helsinki, the International Conference on Harmoni-
`zation (ICH) Harmonized Tripartite Guideline for Good
`Clinical Practice (GCP), and all applicable regulatory
`requirements. Patients provided written informed con-
`sent for participation in the study.
`Eligible patients were 18–60 years of age, had a pri-
`mary diagnosis of RRMS as defined by the Poser or 2005
`revised McDonald criteria [12,13], and had not previ-
`ously received IFNβ treatment. Patients were not eligible
`if they had used any other approved disease-modifying
`treatment for MS (e.g. glatiramer acetate) or any cyto-
`kine or anti-cytokine treatment within 3 months before
`study initiation, used any immunomodulatory or im-
`munosuppressive treatment within 12 months before
`study initiation, used any investigational drug or experi-
`mental procedure within 12 weeks before screening,
`received oral or systemic corticosteroids or adrenocorti-
`cotropic hormone within 30 days of study initiation, or
`used other injectable medications on a regular basis dur-
`ing the week before screening. Other exclusion criteria
`included having an alternative diagnosis to RRMS and
`being pregnant or breastfeeding. Women of childbearing
`potential were required to use appropriate contracep-
`tion. All patients provided written informed consent.
`
`Treatments
`Patients were randomized 1:1 to receive either the
`serum-free formulation of IFNβ-1a 44 μg sc tiw or
`IFNβ-1b 250 μg sc qod for the 12 weeks of the compara-
`tive phase. Treatments were allocated using a computer-
`generated randomization code. The doses of IFNβ-1a
`and IFNβ-1b were up-titrated at the beginning of the
`study according to the US prescribing information for
`each drug (Figure 1) [14,15]. Following the 12-week
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`Figure 1 Titration schedules for subcutaneous IFNβ-1a and IFNβ-1b. The first 21 injections of full-dose IFNβ-1a and IFNβ-1b treatment were
`termed the “full-dose period”. IFN, interferon; qod, every other day; tiw, three times weekly.
`
`comparative phase, all patients received the serum-free
`formulation of IFNβ-1a 44 μg sc tiw during the safety-
`extension phase. Patients who transitioned from IFNβ-
`1b to IFNβ-1a could be up-titrated to the full dose of
`IFNβ-1a at the discretion of the investigator. Patients
`who did not wish to transition from IFNβ-1b to IFNβ-1a
`were withdrawn from the study. The length of the exten-
`sion phase varied between 82 and 112 weeks, depending
`on the patient’s date of enrollment. The extension phase
`ended within 14 days of when the last enrolled patient
`completed the last visit at Week 94.
`All patients self-administered IFNβ using the Rebi-
`ject IIW autoinjector (EMD Serono, Inc., Rockland, MA,
`USA) with a 29-gauge needle for IFNβ-1a or BetajectW
`(with a 27-gauge needle), Betaject LiteW (with a 30-
`gauge needle), or BetajectW 3 (with a 27-gauge needle)
`(Bayer HealthCare Pharmaceuticals Inc., Montville, NJ,
`USA). Acetaminophen was given prophylactically at the
`discretion of the treating physician and dosed as needed
`to ameliorate constitutional symptoms (e.g. fever, myal-
`gia, and FLS). Nonsteroidal anti-inflammatory drugs
`were given and dosed as needed at the discretion of the
`treating physician if acetaminophen failed to alleviate
`or prevent constitutional symptoms or if patients were
`allergic to, or unable to tolerate, acetaminophen.
`
`Assessments
`Patient-reported pain was evaluated in a visual analog
`scale (VAS) diary and the Short-Form McGill Pain
`Questionnaire (SF-MPQ) [16]. Patients used the VAS
`diary to record the level of pain on a scale from 0 mm
`(no pain) to 100 mm (worst possible pain), immediately
`before, immediately after, 10 min after, and 30 min after
`the injection. The SF-MPQ also included a VAS for
`patients to record the level of the maximum amount of
`pain experienced during the 60 min after injection, from
`0 mm (no pain) to 100 mm (worst possible pain). In
`addition, patients were requested to describe the types
`of pain that they experienced during the 60 min after
`
`injection. Patients completed the VAS diary and the SF-
`MPQ after every injection during the comparative phase
`and for the first 4 weeks of the safety-extension phase.
`The Multiple Sclerosis Treatment Satisfaction Ques-
`tionnaire (MSTSQ) adapted from Cramer et al. [17]
`included patient assessments of mood, treatment satis-
`faction, FLS, and ISRs. The MSTSQ was issued to
`patients at Weeks 2, 4, 6, 8, 12, 16, 24, 36, and 48. Mean
`values are reported for each treatment phase.
`ISRs were assessed at each visit during the first
`48 weeks by a healthcare professional who was blinded
`to treatment assignment. ISR measures included the
`diameter of injection-site redness, injection-site swelling,
`bruising, and consideration of patient-reported itching,
`within 72 h of the most recent injection.
`Compliance was recorded throughout the study and
`was defined as the actual number of injections divided
`by the expected number of injections, expressed as a
`percentage. Safety assessments included AEs (coded
`to system organ class and preferred term using the
`MedDRA dictionary [Version 9.1] and summarized by
`severity and relationship), vital signs, hematology, and
`serum chemistry. Analgesic use among patients with
`and without AEs related to FLS was summarized by
`treatment group during the comparative phase and by
`treatment group and overall population during the
`extension phase.
`The primary endpoint was the mean change in the
`VAS diary pain score from pre-injection to 30 min post-
`injection over the first 21 injections of full-dose IFNβ-1a
`and IFNβ-1b treatment (“full-dose period”). Due to the
`different titration schedules and dose frequencies of each
`treatment, the first 21 full-dose injections were adminis-
`tered during Weeks 5–11 in the IFNβ-1a group and
`during Weeks 7–12 in the IFNβ-1b group (Figure 1).
`Secondary endpoints included mean changes in the VAS
`diary pain score from pre-injection to immediately post-
`injection and 10 min post-injection; MSTSQ assess-
`ments; rater-blinded assessment of the mean diameter of
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`injection-site redness; and SF-MPQ assessments, includ-
`ing the proportion of patients pain-free as recorded on
`the SF-MPQ VAS. Types of pain and severity experi-
`enced by the patient were also recorded on the SF-MPQ.
`The number of relapses and severity were secondary effi-
`cacy endpoints. Relapses were patient-reported and not
`objectively assessed; the number and severity of relapses
`were observational clinical assessments.
`
`Statistical analysis
`The primary analysis population was the intent-to-treat
`population (all patients randomized to treatment). The
`safety population consisted of all patients who received
`at least one injection of study drug. The safety-extension
`population consisted of all patients who received at
`least one injection of study drug and had available exten-
`sion phase data. Baseline characteristics of the two treat-
`ment groups were compared using analysis of variance
`(ANOVA) with effects for treatment group and pooled
`site for continuous variables and the Cochran–Mantel–
`Haenszel general association test, adjusted for pooled
`site, for categorical variables.
`The null hypothesis was that there would be no differ-
`ence in mean change in VAS pain score at 30 min post-
`injection from pre-injection across the treatments at
`full dose. The primary endpoint was evaluated with a
`two-way ANOVA model on signed ranked data, includ-
`ing treatment group and pooled site as main effects. The
`same method was also used to analyze treatment com-
`parisons of the mean changes in the VAS diary pain
`score from pre-injection to immediately post-injection
`and 10 min post-injection, as well as mean SF-MPQ
`pain score at 60 min post-injection. An ANOVA model
`was used for between-group comparisons; for MSTQ
`scores,
`treatment group and pooled site were main
`effects; for injection-site redness, treatment group and
`site were main effects. The proportion of patients pain-
`free on SF-MPQ VAS was analyzed using the Cochran–
`Mantel–Haenszel general association test, adjusted for
`site, or Fisher’s exact test, if appropriate. Injection-site
`swelling, bruising, and itching were compared between
`groups using a Cochran–Armitage trend test. In the
`comparative phase, all statistical tests were two-sided
`and used a significance level of α = 0.05. No adjustment
`was made for multiple comparisons.
`comparative
`Patient-reported relapses during the
`phase were compared using a Poisson regression model
`with the total number of relapses as the dependent vari-
`able and treatment group and pooled site as independ-
`ent variables.
`
`Determination of sample size
`A total of 100 patients (50 per arm) was calculated to
`provide at least 90% power to detect the difference
`
`between treatment groups for the primary objective,
`when the expected treatment effect size (the difference
`between the treatment groups divided by the standard
`deviation [SD]) was at least 0.735. The effect size was
`based on a difference between the treatment groups of
`0.025 mm and an SD value of 0.034 mm. The difference
`between the treatment groups was based on a mean
`change of 0.1 mm in the IFNβ-1a group and 0.125 mm
`in the IFNβ-1b group, and assumed that the mean VAS
`diary pain scores at pre-injection in the two treatment
`groups were similar. The calculation also assumed a
`two-sided Wilcoxon rank sum test, a common SD of
`the change of ≤0.034 mm, and a Type I error rate of 5%.
`
`Results
`Patient disposition and baseline characteristics
`Between May 2006 and July 2009, a total of 129 patients
`were enrolled: 65 were randomized to IFNβ-1a and
`64 to IFNβ-1b (Figure 2). Patient baseline characteristics
`(Table 1) did not differ significantly between groups.
`Fifty-six patients in the IFNβ-1a group completed the
`comparative phase and entered the safety-extension
`phase, and these were termed the “Always IFNβ-1a”
`group (Figure 2). Of the 63 patients in the IFNβ-1b
`group who completed the comparative phase, 60 entered
`the extension phase and were termed the “Delayed
`IFNβ-1a” group. During the extension phase, the mean
`(SD) duration of treatment with IFNβ-1a was longer in
`the Always IFNβ-1a group (436 [251] days) than in the
`Delayed IFNβ-1a group (338 [260] days).
`
`Tolerability
`Comparative phase
`During the full-dose period, the VAS diary pain score
`was very low across both treatments. Mean changes in
`pain scores from pre-injection to immediately, 10 min,
`and 30 min after injection were all <5 mm with both
`treatments (Figure 3). The mean (SD) pre-injection VAS
`diary pain score was 0.43 (2.06) mm in the IFNβ-1a
`group and 0.40 (1.64) mm in the IFNβ-1b group. The
`primary endpoint of mean change in the VAS diary
`pain score from pre-injection to 30 min post-injection
`during the full-dose period was not statistically different
`between IFNβ-1a and IFNβ-1b (mean [SD] 0.67 [2.32]
`mm vs. 1.14 [4.94] mm, respectively, p = 0.524; Figure 3)
`but was numerically lower with IFNβ-1a than with
`IFNβ-1b. Mean changes in the VAS diary pain score
`from pre-injection to immediately and 10 min post-
`injection during the full-dose period were also not statis-
`tically different across groups (Figure 3).
`The proportions of patients who were pain-free on the
`VAS diary during the full-dose period (score of 0 mm
`for all full-dose injections) immediately, 10 min, and
`30 min after injection were not statistically different
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`145 patients were assessed for eligibility
`
`16 were excluded
`11 did not meet eligibility criteria
`5 other reasons (withdrew consent, lost
`to follow-up, laboratory findings)
`
`129 underwent randomization
`
`sc IFNβ-1a group
`65 randomized to serum-free formulation
`IFNβ-1a 44 μg sc tiw
`
`IFNβ-1b group
`64 randomized to IFNβ-
`
`65 included in ITT and safety populations
`
`64 included in ITT and safety populations
`
`9 discontinued treatment
`6 adverse events
`2 lost to follow-up
`1 other reason
`
`1 lost to follow-up
`
`56 completed 12-week comparative phase
`
`63 completed 12-week comparative phase
`
`3 did not enter safety extension
`phase
`3 other reasons (wanted to take
`pain medication, MS symptoms,
`did not want to discontinue
`Betaseron)
`
`Always sc IFNβ-1a group
`56 continued treatment with serum-free
`formulation IFNβ-1a 44 μg sc tiw
`
`Delayed sc IFNβ-1a group
`60 transitioned to serum-free formulation
`IFNβ-1a 44 μg sc tiw
`
`56 included in safety extension population
`
`60 included in safety extension population
`
`21 discontinued treatment
`8 adverse events
`1 lost to follow-up
`1 protocol violation
`4 disease progression
`7 other reasons
`
`26 discontinued treatment
`9 adverse events
`6 lost to follow-up
`1 protocol violation
`3 disease progression
`7 other reasons
`
`Comparative phase
`
`Safety extension phase
`
`35 completed safety extension phase
`
`34 completed safety extension phase
`
`Figure 2 Patient enrollment and disposition. IFN, interferon; ITT, intent-to-treat; qod, every other day; sc, subcutaneous; tiw, three
`times weekly.
`
`across groups, but scores were numerically higher with
`IFNβ-1a than with IFNβ-1b (Figure 4). The mean SF-
`MPQ VAS pain scores were similar between the two
`groups, as were the proportions of patients who were
`pain-free on the SF-MPQ VAS (Table 2). During the
`full-dose period, the most common types of pain experi-
`enced during the 60 min after injection (incidence of
`≥20% in either group) were hot-burning (reported by
`40.0% of patients in the IFNβ-1a group vs. 53.1% of
`patients in the IFNβ-1b group), aching (29.2% vs. 45.3%),
`sharp (35.4% vs. 42.2%), tender (33.8% vs. 35.9%), shoot-
`ing (26.2% vs. 34.4%), stabbing (29.2% vs. 32.8%), throb-
`bing (27.7% vs. 32.8%), and heavy (9.2% vs. 23.4%).
`
`The proportion of patients who reported any occur-
`rence of FLS during the entire 12-week comparative
`phase on the MSTSQ was 84.6% with IFNβ-1a and
`93.8% for IFNβ-1b; for the titration period, the occur-
`rence of FLS was 75.4% and 87.5% with IFNβ-1a and
`IFNβ-1b, respectively. For the full-dose period, the FLS
`score was 84.6% and 76.6% with IFNβ-1a versus IFNβ-
`1b, respectively. The difference in frequency of FLS be-
`tween IFNβ-1a (mean 3.55; SD 1.45) and IFNβ-1b (mean
`2.78; SD 1.4) was significant (p = 0.003). The ratio of the
`percentage of patients reporting ISRs on the MSTQ dur-
`ing the full-dose period was similar to that of the FLS
`score. The difference in frequency of
`ISRs between
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`Table 1 Baseline characteristics of patients (intent-to-treat population) randomized to receive subcutaneous IFNβ-1a or
`IFNβ-1b
`Baseline characteristic
`Age, years
`
`IFNβ-1a (N = 65)
`
`IFNβ-1b (N = 64)
`
`Mean (SD)
`
`Median (range)
`
`Female, n (%)
`
`Race, n (%)
`
`White
`
`Black
`
`Asian
`
`Other
`BMI, kg/m2, mean (SD)
`
`Classification of MS, n (%)
`
`Poser criteria
`
`McDonald criteria
`
`Time since first signs and/or symptoms of MS (onset), years, mean (SD)
`
`Time since MS diagnosis, years, mean (SD)
`
`Patients with no relapse during the 12 months before informed consent, n (%)
`Relapses per patient,a mean (SD)
`Time since last relapse,a months, mean (SD)
`Number of steroid courses required for relapses per patient,a mean (SD)
`Patients who required ≥1 course of steroids,a n (%)
`aBased on total number of patients with relapses during the 12 months before informed consent.
`BMI, body mass index; IFN, interferon; MS, multiple sclerosis; SD, standard deviation.
`
`40.26 (9.80)
`40.0 (20–60)
`46 (70.8)
`
`55 (84.6)
`
`6 (9.2)
`
`2 (3.1)
`
`2 (3.1)
`
`29.66 (6.76)
`
`19 (29.2)
`
`46 (70.8)
`
`4.51 (6.70)
`
`1.01 (2.35)
`
`10 (15.4)
`
`1.36 (0.52)
`
`3.52 (2.94)
`
`0.53 (0.60)
`
`26 (47.3)
`
`40.78 (9.56)
`40.0 (19–59)
`44 (68.8)
`
`58 (90.6)
`
`5 (7.8)
`
`0
`
`1 (1.6)
`
`30.23 (8.35)
`
`17 (26.6)
`
`47 (73.4)
`
`5.74 (6.66)
`
`1.93 (4.02)
`
`14 (21.9)
`
`1.30 (0.46)
`
`4.01 (2.93)
`
`0.46 (0.50)
`
`23 (46.0)
`
`IFNβ-1a (mean 3.72; SD 1.56) and IFNβ-1b (mean 2.92;
`SD 1.45) was significant (p = 0.005). The mean MSTSQ
`scores for overall satisfaction,
`injection system, and
`background information were similar between the two
`groups during the full-dose period (Table 2).
`Blinded assessment of ISRs during the full-dose period
`found that the diameter of injection-site redness was simi-
`lar between the two groups (Table 2). The proportions of
`
`patients with injection-site swelling and itching were
`similar between the two groups, but the incidence of
`injection-site swelling was
`significantly greater with
`IFNβ-1b than with IFNβ-1a during the uptitration period
`(28.1% vs. 18.5%, respectively; p = 0.042). Injection-site
`bruising was significantly more common with IFNβ-1a
`
`Figure 3 Mean change in VAS diary pain score during full-dose
`treatment in the comparative phase (intent-to-treat
`population). The VAS ranged from 0 mm (no pain) to 100 mm
`(worst possible pain). The mean change was calculated from the
`mean of 21 full-dose injections for each patient. IFN, interferon; SD,
`standard deviation; VAS, visual analog scale.
`
`Figure 4 Patients who reported as pain-free on the VAS diary
`in the comparative phase (intent-to-treat population). Pain-free
`was defined as a VAS diary pain score of 0 mm (on a scale from
`0 [no pain] to 100 mm [worst possible pain]) for all 21 full-dose
`injections. IFN, interferon; VAS, visual analog scale.
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`Table 2 MSTSQ, ISR, and SF-MPQ endpoints during the full-dose period of the comparative phase (intent-to-treat
`population)
`
`IFNβ-1a (N = 65)
`
`IFNβ-1b (N = 64)
`
`p-value
`
`MSTSQ assessments
`MSTSQ overall satisfaction score,a mean (SD)
`MSTSQ injection system score,a mean (SD)
`MSTSQ score for background information,a mean (SD)
`Blinded assessment of ISRs
`
`1.51 (0.56)
`
`1.68 (0.41)
`
`2.28 (0.91)
`
`1.53 (0.63)
`
`1.80 (0.45)
`
`2.28 (0.86)
`
`Diameter of injection-site redness, mm, mean (SD)
`
`11.32 (14.88)
`
`11.75 (15.53)
`
`Patients, n (%), with:
`
`Injection-site swelling
`
`Injection-site bruising
`
`Injection-site itching
`
`19 (29.2)
`
`21 (32.3)
`
`7 (10.8)
`
`16 (25.0)
`
`7 (10.9)
`
`6 (9.4)
`
`0.616
`
`0.156
`
`0.734
`
`0.986
`
`0.848
`
`0.019
`
`0.366
`
`SF-MPQ assessments
`SF-MPQ VAS pain score,b mm, mean (SD)
`Patients pain-free on SF-MPQ VAS,b,c n (%)
`0.852
`17 (26.6)
`17 (26.2)
`aOn the MSTSQ, a lower score indicates a more favorable response to treatment. bThe SF-MPQ VAS recorded the maximum amount of pain experienced during
`the 60 min after injection, from 0 mm (no pain) to 100 mm (worst possible pain). cPain-free was defined as an SF-MPQ VAS score of 0 mm.
`IFN, interferon; ISR, injection-site reaction; MSTSQ, Multiple Sclerosis Treatment Satisfaction Questionnaire; SD, standard deviation; SF-MPQ, Short-Form McGill Pain
`Questionnaire; VAS, visual analog scale.
`
`2.54 (7.98)
`
`3.24 (8.78)
`
`0.612
`
`than with IFNβ-1b during the full-dose period of the
`comparative phase (32.3% vs. 10.9%, respectively; p =
`0.019) (Table 2). However, most incidents were mild
`in severity.
`
`Safety-extension phase
`During the first 4 weeks of the safety-extension phase,
`the mean changes in VAS diary pain scores from before
`injection to all timepoints after injection were all <3 mm
`in both the Always and Delayed IFNβ-1a groups. More
`than half of all patients were pain-free on the VAS diary
`10 min after injection. MSTSQ assessments for FLS,
`overall satisfaction, injection system background infor-
`mation, and ISRs were similar in the Always and
`Delayed groups, although blinded assessment of ISRs
`were numerically lower (7.46 mm) for the Delayed group
`than the Always group (10.79 mm). The mean MSTSQ,
`ISRs, and SF-MPQ during the safety-extension phase are
`summarized in Additional file 1: Table S1.
`
`Compliance and analgesic use
`Treatment compliance during the comparative phase
`was high: 64/65 (98.5%) patients receiving IFNβ-1a and
`62/64 (96.9%) patients receiving IFNβ-1b adhered to
`their medication schedule ≥90% of the time. Similarly, of
`the patients enrolled in the safety-extension phase, 102/
`116 (87.9%) were ≥90% compliant. Throughout
`the
`study, analgesics were used by the majority of patients.
`The percentage of patients using analgesics did not differ
`greatly between groups in either phase of the study; dur-
`ing the full-dose period of the safety population, anal-
`gesic use in the IFNβ-1a and IFNβ-1b was 61.5% and
`
`57.8%, respectively, and mean total (SD) dose was 16,652
`(16,941) mg and 12,862 (10,159) mg, respectively. Post-
`injection analgesic use for the treatment of an ISR was
`recorded by 1/64 patients in the IFNβ-1b group. During
`the full dose period, concomitant analgesic use for treat-
`ment of an ISR was recorded by 4/65 patients in the
`IFNβ-1a group and by 1/64 patients in the IFNβ-1b
`group. During the extension phase, analgesic use in the
`Always IFNβ-1a group and Delayed IFNβ-1b group was
`80.4% and 78.3%, respectively.
`The most commonly used (>3 individuals) analgesics
`during both study phases included ibuprofen, paraceta-
`mol, naproxen, and acetylsalicylic acid.
`
`Safety
`AEs during the comparative phase
`AEs reported in ≥5% of patients in either group during
`the comparative phase are shown in Table 3. AEs that
`were more common in the IFNβ-1a group than in the
`IFNβ-1b group included ISRs, nausea, increased alanine
`aminotransferase (ALT),
`increased serum ferritin, and
`abnormal liver-function test. AEs that were more com-
`mon in the IFNβ-1b group than in the IFNβ-1a group
`included depression, fatigue, and dizziness. Most AEs
`occurring during the comparative phase were mild to
`moderate in severity. Severe AEs that occurred in at
`least one patient in the IFNβ-1a group were influenza-
`like illness (n = 2), back pain (n = 2), and headache
`(n = 2). Severe AEs that occurred in at least one patient
`in the IFNβ-1b group were back pain (n = 2) and head-
`ache (n = 2). During the comparative phase, six patients
`(all in the IFNβ-1a group) discontinued due to an AE.
`
`Mylan Pharms. Inc. Exhibit 1031 Page 7
`
`

`
`Singer et al. BMC Neurology 2012, 12:154
`http://www.biomedcentral.com/1471-2377/12/154
`
`Page 8 of 11
`
`Table 3 TEAEs reported by ≥5% of patients in either
`group during the comparative phase (safety population)
`Adverse event
`Number of patients (%)
`IFNβ-1a
`IFNβ-1b
`(N = 65)
`(N = 64)
`20 (30.8)
`18 (28.1)
`
`Influenza-like illness
`
`Headache
`
`Injection-site reaction
`
`Injection-site erythema
`
`Depression
`
`Fatigue
`
`Urinary tract infection
`
`Extremity pain
`
`Nausea
`
`Insomnia
`
`Injection-site pain
`
`Alanine aminotransferase increased
`
`Back pain
`
`Dizziness
`
`Muscle spasms
`
`Pain
`
`Diarrhea
`
`Chills
`
`Influenza
`
`Injection-site bruising
`
`Serum ferritin increased
`
`Liver-function test abnormal
`
`17 (26.2)
`
`18 (27.7)
`
`8 (12.3)
`
`4 (6.2)
`
`3 (4.6)
`
`7 (10.8)
`
`6 (9.2)
`
`7 (10.8)
`
`5 (7.7)
`
`4 (6.2)
`
`8 (12.3)
`
`4 (6.2)
`
`2 (3.1)
`
`5 (7.7)
`
`4 (6.2)
`
`2 (3.1)
`
`5 (7.7)
`
`5 (7.7)
`
`5 (7.7)
`
`6 (9.2)
`
`5 (7.7)
`
`16 (25.0)
`
`9 (14.1)
`
`8 (12.5)
`
`8 (12.5)
`
`9 (14.1)
`
`5 (7.8)
`
`6 (9.4)
`
`3 (4.7)
`
`5 (7.8)
`
`5 (7.8)
`
`1 (1.6)
`
`4 (6.3)
`
`6 (9.4)
`
`3 (4.7)
`
`3 (4.7)
`
`5 (7.8)
`
`2 (3.1)
`
`2 (3.1)
`
`2 (3.1)
`
`0
`
`0
`
`IFN, interferon; TEAE, treatment-emergent adverse event.
`
`The AEs resulting in discontinuation were elevated liver
`function tests (n = 2) and elevated liver function tests
`plus the following: muscle cramps and spasms, chills,
`and headache (n = 1); elevated ferritin (n = 1);
`leukopenia and neutropenia plus ISR (n = 1); and preg-
`nancy (n = 1).
`Serious AEs were reported in two patients. One pa-
`tient receiving IFNβ-1a had high ferritin levels and was
`subsequently diagnosed with grade 3, stage 2, chronic
`hepatitis; the investigator considered this event probably
`related to the study medication. One patient receiving
`IFNβ-1b had cholelithiasis, which required cholecys-
`tectomy; this event was considered unrelated to the
`study medication.
`
`AEs during the safety-extension phase
`Most AEs occurring during the extension phase were
`mild to moderate in severity. AEs occurring in >5%
`of patients are listed in Additional file 2: Table S2. Se-
`vere AEs that occurred in the Always IFNβ-1a group
`were non-study-related post-surgery pain (n = 1), tooth
`
`extraction pain (n = 1) and headache (n = 2). Severe AEs
`that occurred in at least one patient in the Delayed
`IFNβ-1a group were influenza-like illness (n = 2), and
`headache (n = 2). During the extension phase, 17
`patients (eight patients in the Always IFNβ-1a group
`and nine patients in the Delayed IFNβ-1a group) dis-
`continued due to an AE.
`Serious AEs were reported in three patients in the
`Always IFNβ-1a group: one patient had an accidental
`overdose of IFNβ-1a, one patient developed cholecystitis
`(the same patient who had high ferritin and chronic
`hepatitis in the comparative phase), and one patient
`experienced vertigo. Serious AEs were reported in four
`patients in the Delayed IFNβ-1a group: one patient
`experienced intestinal obstruction, one patient experi-
`enced diverticulitis, one patient had an accidental over-
`dose of study drug, and one patient had a hip fracture.
`Both cases of accidental overdose were due to misunder-
`standing of the dosing regimen. The case of cholecystitis
`was considered unlikely to be related to the study medi-
`cation, and the other four serious AEs that occurred dur-
`ing the extension phase were considered to be unrelated
`to the study medication.
`
`Other safety assessments
`The mean values of hemoglobin, hematocrit, red blood
`cell counts, platelet counts, white blood cell counts, and
`alkaline phosphatase were within normal limits in each
`arm throughout the entire study. In the IFNβ-1a group,
`mean aspartate aminotransferase (AST) and ALT values
`become elevated above normal limits during the com-
`parative phase. Mean AST (normal range 0–35 U/L)
`p