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GLACIER: An open-label, randomized, multicenter study to assess the safety and tolerability of glatiramer acetate 40 mg/ml three-times weekly versus 20 mg/ml daily in patients with relapsing-remitting multiple sclerosis

Multiple Sclerosis and Related Disorders, Volume 4, Issue 4, July 2015, Pages 370–376

Abstract

Background

The efficacy and safety of glatiramer acetate (GA) 20 mg/mL once-daily subcutaneous injections (GA20) in relapsing-remitting multiple sclerosis (RRMS) is well-established. However, injection-related adverse events (IRAEs) may impede treatment adherence and tolerability. GA 40 mg/mL three-times weekly (GA40) also has a favorable efficacy and safety profile.

Objective

To evaluate the safety, tolerability, and patient experience when converting from GA20 to GA40.

Methods/trial design

GLACIER was an open-label, randomized, parallel-group trial conducted at 31 sites in the US between June 2013 and December 2013. Stable RRMS patients on GA20 were randomized in a 1:1 ratio to continue with GA20 or convert to GA40. The adjusted mean annualized rate of IRAEs was the primary endpoint for this study. Additionally, the severity of IRAEs, rate of injection-site reactions (ISRs), and patient-reported MS impact and treatment satisfaction were compared for the two treatment groups over the 4-month core study.

Results

A total of 209 patients were randomized to convert to GA40 (n=108) or continue with GA20 (n=101). The adjusted mean annualized rate of IRAEs was reduced by 50% with GA40 (35.3 events per year; n=108) versus GA20 (70.4 events per year; n=101) (risk ratio (RR)=0.50; 95% confidence interval [CI]=0.34–0.74; p=0.0006). There was a 60% reduction in the rate of moderate/severe events (GA40 (n=108): 0.9 events per year versus GA20 (n=101): 2.2 events per year; RR=0.40; p=0.0021). Perception of treatment convenience improved for GA40-treated patients soon after converting and was sustained.

Conclusions

The GLACIER study demonstrates a favorable IRAE and convenience profile of GA40 for RRMS patients.

Trial registration

NCT01874145 available at clinicaltrial.gov.

Highlights

 

  • Glatiramer acetate 40 mg three-times weekly (GA40) is approved for relapsing MS.
  • Experiences of MS patients using daily GA20 were studied after random switch to GA40.
  • All injection-related adverse events were reduced 50% on GA40 compared with GA20.
  • Moderate and severe events were 60% lower on GA40 compared with GA20.
  • GA40 appears to be an acceptable alternative to GA20 in relapsing MS patients.

Keywords: Glatiramer acetate, Relapsing-remitting multiple sclerosis, Dose regimen, Safety, Convenience, Patient adherence.

1. Introduction

Disease-modifying therapies (DMTs) that reduce the frequency of relapses, reduce accumulation of disability, and control symptoms have improved the care of patients with relapsing-remitting multiple sclerosis (RRMS) (Damal et al, 2013 and Compston and Coles, 2002). Glatiramer acetate (GA), a first-line therapy approved for the treatment of RRMS ( TEVA Neuroscience, Inc. 2014 ), has a well-characterized long-term safety profile (TEVA Neuroscience, Inc, 2014 and Boster et al, 2011), with more than 2 million patient-years of overall exposure to GA 20 mg/mL administered once daily by subcutaneous injection (GA20) (data on file), and reduces the frequency of relapses and magnetic resonance imaging (MRI) disease activity (Johnson et al, 1995, Martinelli Boneschi et al, 2003, Comi et al, 2001, and Bornstein et al, 1987).

Several first-line treatment regimens for RRMS require long-term, frequent injection of the drug, making adherence a challenge for many patients despite satisfactory efficacy (Verdun di Cantogno et al, 2011 and Devonshire et al, 2011). Factors contributing to non-adherence and reduced tolerability in MS treatment include problems with injecting, perceived lack of efficacy, and perhaps most importantly, the high incidence of injection-related adverse events (IRAEs) (Devonshire et al, 2011, Treadaway et al, 2009, and Costello et al, 2008). IRAEs associated with injectable DMTs and GA include systemic immediate post-injection reactions (IPIRs) such as flushing and anxiety and, more often, local injection-site reactions (ISRs), such as pain and redness ( TEVA Neuroscience, Inc. 2014 ). More severe ISRs, such as lipoatrophy and skin necrosis, occur less frequently ( Costello et al., 2008 ). Modified treatment regimens – alternative dosages and low-frequency administration schedules – have the potential to reduce the rate and severity of IRAEs. Therefore, modifying the treatment regimen of drugs with proven, long-term efficacy can result in better adherence and tolerability while maintaining efficacy and improving treatment convenience and patient experience (Remington et al, 2013 and Tan et al, 2011). The value of such alternative regimens is enhanced given the importance of treatment adherence in ensuring optimal clinical outcomes (Tan et al, 2011 and Al-Sabbagh et al, 2008).

In 2014, based largely on the results of the Glatiramer Acetate Low-frequency Administration (GALA) study, GA 40 mg/mL administered three-times weekly by subcutaneous injection (GA40) was approved for the treatment of RRMS by regulatory authorities in an increasing number of countries worldwide. The low-frequency GA40 was shown to have favorable efficacy and safety profiles ( Khan et al., 2013 ).

Previous GA40 trials only enrolled patients who were naïve to GA treatment and did not examine those converting from GA20 to GA40. The GLACIER (GLatiramer Acetate low frequenCy safety and patIent ExpeRience) study was performed to assess the safety and tolerability of GA40 compared with GA20 in clinically stable patients who had been treated continuously with GA20 for a minimum of 6 months before screening. This study provides insight into whether GA40 provides improved safety, tolerability, and patient experience compared with the established GA20 regimen.

2. Materials and methods

2.1. Study design and patients

The GLACIER study was an open-label, randomized, parallel-group study conducted at 31 sites in the United States between June 2013 and December 2013. Investigators were neurologists, and sites consisted of individual and group neurology practices, neurology and MS research centers, and independent clinic trial facilities. All institutional review boards or ethics committees of the participating centers approved the protocol, and all patients gave written informed consent before any study-related procedures were performed.

Key eligibility criteria required patients to be least 18 years of age, with a confirmed and documented RRMS diagnosis (according to the revised McDonald criteria ( Polman et al., 2011 )) and an Expanded Disability Status Scale (EDSS) score of ≤5.5 at screening and baseline visits. All patients were required to be on continuous GA20 treatment for ≥6 months before screening and to be neurologically stable and relapse-free for ≥60 days before randomization.

Patients with progressive forms of MS, or those with neuromyelitis optica, were excluded. Other exclusion criteria included treatment with experimental or investigational drugs; concomitant use of other MS disease-modifying drugs; chronic (>30 days) systemic corticosteroid treatment within 6 months of screening; and prior use of mitoxantrone, cladribine, alemtuzumab, rituximab, or natalizumab.

At the baseline visit, eligible patients were randomized in a 1:1 ratio to either continue with GA20 or convert to GA40. The computerized randomization sequence was generated and maintained by the Clinical Supply Chain department at Teva Pharmaceuticals (Netanya, Israel), and randomization was conducted centrally using the Interactive Response Technology system. Patients were randomized according to the randomization scheme of constrained blocks by site, and treatment group assignment was not biased by patient or trial center preferences. Investigators and participants were not blinded or masked to the open-label treatment assignment. Patients were treated with either a single-use, pre-filled syringe containing GA20 or GA40 (Teva Pharmaceutical Industries) in a 1-mL suspension of 40 mg of mannitol USP/Ph.Eur dissolved in water. Five scheduled site visits occurred during the core phase at months –1 (screening), 0 (baseline), 1, 2, and 4 (termination). Eligible patients from both treatment arms who completed the core phase were offered the opportunity to participate in an extension phase, during which they would receive GA40 treatment.

2.2. Procedures

The primary endpoint was the rate of IRAEs in each treatment arm. Secondary endpoints included the rate of ISRs, patient-reported impact of MS on physical and psychological well-being using the Multiple Sclerosis Impact Scale-29 (MSIS-29) questionnaire, and patient perceptions of convenience and overall satisfaction using subscales of the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). Additional endpoints included baseline patient expectations for efficacy, safety, and convenience of GA40 compared with GA20.

Assessments of IRAEs were performed throughout the study based on the patient's diary card recordings of occurrence and severity of IRAEs. IRAEs included all local ISRs or symptoms or events related to IPIRs, such as flushing, chest pain, palpitations, anxiety, dyspnea, throat constriction, or urticaria. Severity was defined by the patient as mild if the IRAE is ‘easily tolerated,’ moderate if the IRAE ‘interferes with normal daily activity’, or severe if the IRAE ‘prevents normal daily activity’.

Study drug compliance was evaluated during each visit after the initial dispensation of the study drug, and study drug accountability records were completed. Compliance was calculated as a percentage by dividing the number of used syringes by the number of total syringes expected to be used, multiplied by 100. The incidence of patients in each arm of the study with ≥75% overall compliance to the study drug was an exploratory trial outcome.

The MSIS-29 questionnaire and TSQM-9 were performed at baseline and Months 1, 2, and 4. The validated, 29-item MSIS-29 questionnaire was used to assess patient-reported impact of MS on physical well-being and psychological well-being. Responses were scored using a five-point Likert scale range, with higher aggregate scores corresponding to greater impact on well-being. The validated TSQM-9 was used to assess patient-reported perceptions of convenience (items 4–6) and overall satisfaction (items 1–3), with higher scores representing more positive perceptions.

Patients' expectations of convenience were assessed at baseline using a study-specific questionnaire, in which patients reported whether they expected GA40 to be less, equally, or more convenient compared with GA20. Similarly, patients reported whether they expected GA40 to be less, equally, or more safe, as well as effective, compared with GA20.

Safety assessments included adverse events (AEs), vital signs, electrocardiographic (ECG) measurements, and standard clinical laboratory tests, including complete blood count and comprehensive metabolic panel.

2.3. Statistical analyzes

A sample size of 200 patients (100 patients per arm) was considered necessary to provide 80% power to detect a statistically significant difference in the IRAE rates between treatment arms. This calculation utilized estimated event rates from previous studies of each treatment regimen and accounted for an expected relative risk of 0.48 (52% reduction in the risk for IRAEs) in the GA40-treated population compared with GA20 and a dropout rate of 15%. The overall significance level for this study was 5% using a two-tailed test, and to protect the study from Type I error inflation, the secondary endpoints were only analyzed if a statistically significant treatment effect was detected in the primary analysis.

The principal analysis for the primary endpoint of rate of IRAEs during the core phase was performed on the safety analysis cohort, defined as all randomized patients who received at least one dose of the study drug. For each patient, multiple IRAEs starting on the same day were only counted as one IRAE event. The GA40 group was compared with the GA20 group using a baseline-adjusted, quasi-likelihood (over-dispersed) Poisson regression with the natural log of treatment duration (in years) as an offset variable. In addition to treatment group, the following covariates were included in the regression model: baseline EDSS score, age, gender, and number of relapses in the 2 years before screening. A similar post hoc analysis assessed risk ratio (RR) for annualized rate of moderate or severe IRAEs.

To keep the overall Type I error of 5% from inflating, a gatekeeping approach was utilized for secondary endpoints, with a pre-specified hierarchical sequence: 1, ISR rate; 2, MSIS-29 physical score change from baseline to Month 4; 3, MSIS-29 psychological score change from baseline to Month 4; 4, TSQM-9 convenience score change from baseline to Month 4; and 5, TSQM-9 satisfaction score change from baseline to Month 4.

The secondary endpoint of rate of ISRs in each treatment group was assessed using the same cohort and statistical analysis method as the IRAE rate. Secondary analyzes for the other secondary endpoints were performed on the full analysis cohort, defined as all randomized patients who received at least one dose of the study drug and had at least one post-baseline assessment of either the MSIS-29 or TSQM-9. Change from baseline to Month 4 in physical well-being and psychological well-being using the MSIS-29, and patient perceptions of convenience and overall satisfaction using the TSQM-9, were analyzed using mixed model repeated measures analysis of covariance. In addition to treatment group, the following covariates were used in this model: baseline questionnaire score, categorical month, and treatment by month interaction. Additionally, month was specified as a repeated effect, and an unstructured correlation matrix was used to model intra-subject correlation.

Analysis of patient-reported expectations for GA40 at baseline was performed on the full analysis cohort, and patient counts and percentages were provided.

3. Results

3.1. Patients

Of the 218 patients screened for entry into the GLACIER study, 209 were randomized to the study treatment (GA20, n=101; GA40, n=108) ( Fig. 1 ). Baseline demographics showed no discernable differences between the two treatment arms ( Table 1 ). The proportions of patients who prematurely discontinued treatment were similar for GA20 (3.0%, n=3) and for GA40 (6.5%, n=7) groups, and one patient in the GA40 treatment arm prematurely discontinued the study because of injection-site necrosis ( Fig. 1 ). Overall compliance with study medication use was good, with 100% of GA20 patients and 99% GA40 patients in the ITT cohort taking >75% of all expected doses. The safety analysis cohort consisted of all 209 patients, and the full analysis cohort consisted of 208 patients (GA20, n=100; GA40, n=108). Of the 98 patients who completed GA20 treatment, 97 (99%) elected to participate in the extension phase; all 101 of the patients who completed GA40 treatment (100%) elected to continue GA40 treatment during the extension phase.

gr1

Fig. 1 Patient disposition. GA20, glatiramer acetate 20 mg/mL daily; GA40, glatiramer acetate 40 mg/mL three-times weekly.

Table 1 Baseline patient and disease characteristics.

  GA20 (n=101) GA40 (n=108)
Age, years, mean (±SD) 50.4 (9.3) 50.9 (11.0)
Female, n (%) 83 (82.2) 89 (82.4)
Race    
 Caucasian 96 (95.0) 100 (92.6)
 Black/African American 5 (5.0) 5 (4.6)
 Asian 0 (0.0) 3 (2.8)
 Native American/Alaskan Native 0 (0.0) 0 (0.0)
Body mass index, mean (±SD) 29.3 (6.4) 27.9 (6.2)
EDSS, mean (±SD) 2.4 (1.4) 2.5 (1.4)
Years from onset of first MS symptoms, mean (±SD) 16.2 (11.0) 15.7 (11.1)
Years from MS diagnosis, mean (±SD) 12.1 (10.0) 10.8 (8.6)
Exacerbations over 1 year prior to study initiation, mean (±SD) 0.2 (0.4) 0.2 (0.5)
Exacerbations over 2 years prior to study initiation, mean (±SD) 0.4 (0.7) 0.4 (0.6)
Years of GA20 exposure prior to study initiation, mean (±SD) 6.6 (4.3) 6.9 (5.2)

EDSS: Expanded Disability Status Scale, GA20: glatiramer acetate 20 mg/mL daily, GA40: glatiramer acetate 20 mg/mL three-times weekly, MS: multiple sclerosis, SD: standard deviation.

3.2. Rate of IRAEs

Patients receiving GA40 demonstrated a 50% lower annualized IRAE rate than those receiving GA20 (adjusted mean annualized event rate, 70.4 vs 35.3 events per year; RR=0.50; 95% confidence interval [CI]=0.34–0.74; p=0.0006) ( Fig. 2 ). The total number of individually reported IRAEs on GA40 was 2670; on GA20, there were 5770 IRAEs. Of these, moderate or severe reactions were less frequent in GA40-treated patients (9.1%) than in GA20-treated patients (18.8%) ( Table 2 ). Post hoc analyzes showed that patients receiving GA40 demonstrated a 60% reduction in the annualized event rate of moderate/severe IRAEs compared with GA20 (adjusted mean annualized event rate, 0.9 vs 2.2 events per year; RR=0.40; 95% CI=0.23–0.72; p=0.0021) ( Fig. 3 ). The proportion of patients experiencing at least one IRAE was similar between treatment arms (56.4% for GA20 versus 58.3% for GA40) ( Table 2 ).

gr2

Fig. 2 Annualized rate of IRAEs. *Event rate per year equals the total number of events/exposure to study drug (in years). Adjusted mean and other statistics were derived from a baseline-adjusted, quasi-likelihood (over-dispersed) Poisson regression model with natural log of treatment duration (in years as an offset variable, adjusted for baseline Expanded Disability Status Scale score, treatment group, age, sex, and number of relapses in the 2 years prior to screening. CI: confidence interval, GA20: glatiramer acetate 20 mg/mL daily, GA40: glatiramer acetate 40 mg/mL three-times weekly, IRAE: injection-related adverse event, RR: risk ratio.

Table 2 IRAE and ISR frequency and severity.

  GA20 (n=101) GA40 (n=108)
Total number of IRAEs a 5770 2670
Number of moderate or severe IRAEs (% of total) 1083 (18.8) 244 (9.1)
Patients with ≥1 IRAE, n (%) 57 (56.4) 63 (58.3)
Total number of ISRs a 5537 2610
Number of moderate or severe ISRs (% of total) 854 (15.4) 240 (9.2)
Patients with ≥1 ISR, n (%) 57 (56.4) 61 (56.5)

a The number of IRAEs and ISRs represent individually reported events.

GA20: glatiramer acetate 20 mg/mL daily, GA40: glatiramer acetate 40 mg/mL three-times weekly, IRAE: injection-related adverse event, ISR: injection-site reaction

gr3

Fig. 3 Annualized rate of moderate or severe IRAEs. *Event rate per year equals the total number of events/exposure to study drug (in years). Adjusted mean and other statistics were derived from a baseline-adjusted, quasi-likelihood (over-dispersed) Poisson regression model with natural log of treatment duration (in years as an offset variable, adjusted for baseline Expanded Disability Status Scale score, treatment group, age, sex, and number of relapses in the 2 years prior to screening. CI: confidence interval, GA20: glatiramer acetate 20 mg/mL daily, GA40: glatiramer acetate 40 mg/mL three-times weekly, IRAE: injection-related adverse event, RR: risk ratio.

3.3. Rate of ISRs

Most IRAEs were ISRs ( Table 2 ), and consequently, the ISR and IRAE rate reductions for GA40 versus GA20 were almost identical. Patients receiving GA40 demonstrated a 50% reduction in the annualized ISR rate compared with GA20 (mean annualized event rate, 70.4 vs 35.2 events per year; RR=0.50; 95% CI=0.34–0.74; p=0.0006) ( Fig. 4 ). The total number of individually reported ISRs on GA40 was 2610 compared to 5537 events with GA20. Of these, moderate or severe ISRs were less frequent in GA40-treated patients (9.2%) than in GA20-treated patients (15.4%) ( Table 2 ).

gr4

Fig. 4 Annualized rate of ISRs. *Event rate per year equals the total number of events/exposure to study drug (in years). Adjusted mean and other statistics were derived from a baseline-adjusted, quasi-likelihood (over-dispersed) Poisson regression model with natural log of treatment duration (in years as an offset variable, adjusted for baseline Expanded Disability Status Scale score, treatment group, age, sex, and number of relapses in the 2 years prior to screening. CI: confidence interval, GA20: glatiramer acetate 20 mg/mL daily, GA40: glatiramer acetate 40 mg/mL three times weekly, ISR: injection-site reaction, RR: risk ratio.

The reduced ISR frequency and event rates on GA40 were observed in all common ISR types, as categorized by MedDRA 16.0 preferred terms ( Table 3 ). In particular, common ISR events such as injection-site pain, erythema, mass, swelling, and pruritus had notably lower rates of occurrence among GA40-treated patients. The rates of injection-site atrophy and necrosis were minimal (≤0.1 events per year), with no observable difference between treatment groups. Furthermore, the annualized IPIR rate with GA40 (1.9 events per year) was lower than that of GA20 (3.9 events per year).

Table 3 ISR frequency and annualized rates.

Number of ISRs (annualized event rate) GA20 (n=101) GA40 (n=108)
Injection-site atrophy 0 (0.0) 1 (0.0)
Injection-site bruising 166 (5.4) 8 (0.2)
Injection-site discoloration 4 (0.1) 9 (0.3)
Injection-site discomfort 4 (0.1) 0 (0.0)
Injection-site dryness 0 (0.0) 48 (1.5)
Injection site erythema 1331 (43.5) 692 (21.4)
Injection-site hematoma 1 (0.0) 0 (0.0)
Injection-site hemorrhage 43 (1.4) 17 (0.5)
Injection-site induration 2 (0.1) 0 (0)
Injection site inflammation 1 (0.0) 0 (0.0)
Injection-site irritation 0 (0.0) 1 (0.0)
Injection-site mass 669 (21.9) 381 (11.8)
Injection-site necrosis 0 (0.0) 4 (0.1)
Injection-site pain 1692 (55.3) 803 (24.8)
Injection site pruritus 398 (13.0) 253 (7.8)
Injection-site rash 13 (0.4) 12 (0.4)
Injection-site reaction 0 (0.0) 2 (0.1)
Injection-site swelling 594 (19.4) 170 (5.3)
Injection-site urticaria 377 (12.3) 175 (5.4)
Injection-site vesicles 14 (0.5) 10 (0.3)
Injection-site warmth 228 (7.5) 24 (0.7)

GA20: glatiramer acetate 20 mg/mL daily, GA40: glatiramer acetate 40 mg/mL three-times weekly, ISR: injection-site reaction

3.4. Patient-reported impact on physical and psychological well-being using the MSIS-29

Although the MSIS-29 physical score change from baseline to Month 4 showed a trend toward improvement in the GA40 treatment group versus the GA20 group, this outcome did not reach statistical significance (adjusted mean MSIS-29 physical score change from baseline to Month 4, 1.54 vs –0.52; treatment effect, –2.1; 95% CI=–4.4 to 0.3; p=0.090) ( Supplementary Fig. 1 a and b).

As no significant treatment effect was shown in the MSIS-29 physical score change from baseline to Month 4, subsequent secondary endpoints were not tested for inferential differences because of the multiplicity adjustment used in this study; associated p-Values for the following secondary endpoints presented in this paper are nominal.

There was no difference in the MSIS-29 psychological score change from baseline to Month 4 between GA40 and GA20 treatment groups (adjusted mean MSIS-29 psychological score change from baseline to Month 4, 0.74 vs 0.02; treatment effect, –0.7; 95% CI=–2.2 to 0.7; p=0.33) ( Supplementary Fig. 1 a and d).

3.5. Patient-reported perceptions of convenience and overall satisfaction using the TSQM-9

An increase of more than 10 points from baseline in the unadjusted TSQM-9 convenience score was already seen at Month 1 and was sustained throughout the study for patients treated with GA40. However, the TSQM-9 convenience score for patients treated with GA20 changed only marginally throughout the study ( Fig. 5 a). Patients receiving GA40 demonstrated a nominally greater increase in the TSQM-9 convenience score from baseline to Month 4 compared with those receiving GA20 (adjusted mean TSQM-9 convenience score change from baseline to Month 4, 8.8 vs 1.7; treatment effect, 7.0; 95% CI=3.0–11.0; p=0.0006) ( Fig. 5 b).

gr5

Fig. 5 (a) TSQM-9 convenience score. (b) Change from baseline to Month 4 in TSQM-9 convenience score. *Treatment effect (95% CI) and adjusted means (95% CI) derived from mixed model repeated measures analysis, adjusted for TSQM-9 subscale score at baseline, treatment group, month, and treatment by month interaction. CI: confidence interval, GA20: glatiramer acetate 20 mg/mL daily, GA40: glatiramer acetate 40 mg/mL three-times weekly, SE: standard error, TSQM-9: Treatment Satisfaction Questionnaire for Medication-9.

There was no difference for TSQM-9 overall satisfaction score change from baseline to Month 4 between GA40 and GA20 treatment groups (adjusted mean TSQM-9 overall satisfaction score change from baseline to Month 4, 0.7 vs 1.6; treatment effect, –0.9; 95% CI: –4.9 to 3.2; p=0.68) (data not shown).

3.6. Additional endpoints

Assessment of baseline patient-reported expectations showed that 87% of all patients anticipated that GA40 would be more convenient than GA20, 86% anticipated that GA40 would be equally effective as GA20, and 91% expected that GA40 would be as safe as GA20 ( Supplementary Fig. 2 ).

4. Discussion

The efficacy and safety of GA20 in RRMS is well established, as evidenced by multiple clinical trials and extensive post-marketing clinical experience (TEVA Neuroscience, Inc, 2014 and Boster et al, 2011). Despite satisfactory efficacy, the rate of IRAEs may present a barrier to maintaining appropriate adherence and tolerability levels in RRMS treatment (Treadaway et al, 2009 and Costello et al, 2008). Given that non-adherence to DMTs is associated with increased risk of relapse and poor clinical outcomes in RRMS (Tan et al, 2011 and Al-Sabbagh et al, 2008), strategies that reduce the incidence of IRAEs and enhance patient experience are of considerable interest. Furthermore, the implementation of such approaches in long-standing, efficacious treatments like GA, further enhance clinical outcomes in MS ( Remington et al., 2013 ).

The GLACIER study demonstrated that treatment with GA40 was associated with a 50% reduction in the annualized rate of IRAEs and ISRs compared with GA20. Furthermore, a 60% reduction in the annualized rate of moderate/severe IRAEs was observed with GA40 versus GA20. The frequency and event rates for the most common ISR types, as categorized by MedDRA 16.0 preferred terms, was also reduced with GA40. These safety outcomes are particularly notable as patients had an average of more than 6 years of exposure to GA20 prior to the study initiation and were likely familiar with IRAEs. In this setting, initiation of treatment with GA at a higher concentration could have led to greater reporting of AEs but the results presented here show that the GA40 regimen led to a lower IRAE rate. These outcomes suggest that the safety profile of the new regimen has the potential to improve patient adherence, treatment tolerability, and clinical outcomes. While the observed rates of local lipoatrophy and injection-site necrosis were quite low with GA40 over this 4 month study and have been low in 1 year studies of GA 40 mg/mL used daily ( Comi et al., 2011 ) or three-times weekly ( Khan et al., 2013 ), long-term follow-up is required to determine if the reduced IRAE frequency with GA40 injections will be maintained over time.

The GA40 dosing regimen provides the convenience of fewer subcutaneous injections per week than the GA20 regimen. Both GA40 and GA20 have been shown to be effective in reducing relapse and MRI activity compared with placebo, and both regimens have demonstrated a favorable safety profile (Johnson et al, 1995, Martinelli Boneschi et al, 2003, Comi et al, 2001, Bornstein et al, 1987, and Khan et al, 2013). In GLACIER, at baseline, 87% of enrolled patients expected GA40 to be more convenient than GA20. Following the open-label, head-to-head treatment assignment, patients' expectations that GA40 injections three-times weekly would be more convenient than daily injections of GA20 were confirmed.

At baseline, 86% of GLACIER participants expected that GA40 and GA20 would have similar effectiveness. Indeed, GA20 and GA40 had similar effects on patient-reported measures of physical and psychological well-being using the MSIS-29. While changes in MSIS-29 scores were similar between treatment regimens, the treatment advantage of GA40 over GA20 is best represented by safety, tolerability, and convenience outcomes.

Because investigators and participants were neither blinded nor masked to the treatment assignment, GLACIER study outcomes should be interpreted in the context of this acknowledged study limitation. However, these trial design features were intentional, so as to recapitulate actual clinical and patient experiences.

5. Conclusions

The GLACIER study provides open-label, randomized, parallel-arm, prospective, comparative data demonstrating that GA40 has a favorable safety profile with significant improvement in the rate of IRAEs, and an enhanced patient experience in the form of improved perceptions of convenience compared with GA20. Along with results from the placebo-controlled GALA study, the GLACIER study establishes GA40 as a favorable treatment option for patients who want GA treatment but prefer fewer injections.

Statement of ethical standards

All institutional review boards or ethics committees of the participating centers approved the protocol, and all patients gave written informed consent before any study-related procedures were performed.

Declaration of conflict of interest

Dr. Wolinsky has received compensation for serving on steering committees or data monitoring boards for Novartis, Roche, Sanofi, and Teva; reimbursement for services as a consultant to AbbVie, Acetilon, Alkermes, Athersys, EMD Serono, Genzyme, Novartis, Roche, Teva, and XenoPort; royalty payments through the University of Texas Health Science Center at Houston for monoclonal antibodies out-licensed to Chemicon International; and research support from Genzyme, Sanofi, and the National Institutes of Health through the University of Texas Health Science Center at Houston.

Dr. Borresen has received compensation from Roche, Novartis, and Teva.

Dr. Dietrich has received compensation for speaking for Biogen IDEC, Novartis, and Teva and performing advisory board services for Teva.

Dr. Wynn has received compensation for speaking and/or consulting for Acorda Therapeutics, Avanir Pharmaceuticals, EMD Serono, Genzyme, GlaxoSmithKline, Sanofi, Teva, and Xenoport; and research support from Acorda Therapeutics, Avanir Pharmaceuticals, EMD Serono, Genentech/Hoffman LaRoche, Sanofi/Genzyme, GlaxoSmithKline, Novartis, Osmotica, Xenoport, Teva, and the National MS Society.

Drs. Sidi, Steinerman, Knappertz, and Kolodny are employees of Teva Pharmaceutical Industries.

Funding

Trial NCT01874145 was funded by Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel.

Acknowledgments

We thank the patients and site personnel involved with this study, Robin Everts and Svetlana Rubinchick (of Teva Pharmaceuticals) for assistance with study conduct and statistical analyzes, and Peter Feldman, PhD (Teva Pharmaceuticals) and Rhonda Charles, PhD (Chameleon Communications International with funding from Teva Pharmaceutical Industries Ltd) for editorial assistance in the preparation of this report. This study was funded by Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel.

Appendix A. Supplementary material

 

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Supplementary material

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Footnotes

a University of Texas Health Science Center at Houston, Houston, TX, USA

b Mecklenburg Neurological Associates, Charlotte, NC, USA

c Advanced Neurological Specialists, Great Falls, MT, USA

d Consultants in Neurology, Northbrook, IL, USA

e Teva Pharmaceuticals, Netanya, Israel

f Global Clinical Development, Teva Pharmaceuticals, Frazer, PA, USA

g Heinrich‐Heine Universität Düsseldorf, Düsseldorf, Germany

h Teva Pharmaceuticals, Cleveland, OH, USA

Corresponding author. Fax: +1 713 500-7040.

1 See Supplementary material for a listing of investigators and sites.


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  • Prof Timothy Vartanian

    Timothy Vartanian, Professor at the Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College, Cornell...
  • Dr Claire S. Riley

    Claire S. Riley, MD is an assistant attending neurologist and assistant professor of neurology in the Neurological Institute, Columbia University,...
  • Dr Rebecca Farber

    Rebecca Farber, MD is an attending neurologist and assistant professor of neurology at the Neurological Institute, Columbia University, in New...

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