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First-dose effects of fingolimod after switching from injectable therapies in the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis
Multiple Sclerosis and Related Disorders
In pivotal phase 3 studies, fingolimod treatment initiation was associated with a transient reduction in heart rate (HR). Atrioventricular (AV) conduction delays, which were typically asymptomatic, were detected in a small minority of patients.
We report the first-dose effects of fingolimod in patients who switched from injectable therapies during the Evaluate Patient OutComes (EPOC) study (ClinicalTrials.gov Identifier: NCT01216072).
This was a phase 4, 6-month, randomized, active-comparator, open-label, multicenter study. It included over 900 fingolimod-treated patients with relapsing multiple sclerosis, with subgroups of individuals who were receiving common concomitant HR-lowering medications or had pre-existing cardiac conditions (PCCs). Vital signs were recorded hourly for 6 h post-dose. A 12-lead electrocardiogram was obtained at baseline and at 6 h post-dose.
A transient decrease in mean HR and blood pressure occurred within 6 h of the first fingolimod dose. The incidence of symptomatic bradycardia was low (1%); eight patients reported dizziness and there was one case each of fatigue, palpitations, dyspnea, cardiac discomfort, and gait disturbance. These symptomatic events were typically mild or moderate in severity and all resolved spontaneously, without intervention or fingolimod discontinuation.
First-dose effects in patients with PCCs and in those receiving concomitant HR-lowering medications were consistent with effects observed in the overall study population and with results from previous clinical trials. The EPOC study provides additional data demonstrating the transient and generally benign nature of fingolimod first-dose effects on HR and AV conduction in a large population that is more representative of patients encountered in routine clinical practice than in the pivotal trials.
- In this phase 4 study over 900 patients received fingolimod for the treatment of MS.
- First-dose effects were examined in a population representative of real-world patients.
- A mild decrease in heart rate was the most common manifestation of the first-dose effect.
- Few patients (1.5%) required additional monitoring after the 6-hour observation period.
Keywords: Multiple sclerosis, Fingolimod, First-dose effects, Transient bradycardia, Patient outcomes.
Fingolimod (FTY720; Gilenya®, Novartis Pharma AG) is a first-in-class sphingosine 1-phosphate receptor (S1PR) modulator (Brinkmann et al, 2010 and Chun and Hartung, 2010). It is approved as a once-daily oral therapy at a dose of 0.5 mg for relapsing forms of multiple sclerosis (MS) (European Medicines Agency, 2011 and US Food and Drug Administration, 2010).
S1PRs are expressed in different tissues, including cells of the immune, cardiovascular, and central nervous systems ( Brinkmann, 2007 ). In the immune system, the therapeutic benefits of fingolimod are contingent on modulation of S1PRs expressed on lymphocytes, which results in the selective retention of circulating lymphocytes in the lymph nodes. Ultimately, this reduces the infiltration of autoreactive lymphocytes into the central nervous system, where they would otherwise be involved in inflammation and tissue damage (Brinkmann et al, 2010 and Chun and Hartung, 2010). The clinical effects of fingolimod in patients with relapsing MS have been evaluated in a clinical program that included three pivotal, phase 3, double-blind, randomized, controlled trials (Cohen et al, 2010, Cohen et al, 2013, and Kappos et al, 2010). Together, these studies demonstrated that fingolimod has superior efficacy to both intramuscular interferon beta-1a and placebo, based on clinical and magnetic resonance imaging measures.
Fingolimod is associated with a transient reduction in heart rate (HR) and atrioventricular (AV) conduction on treatment initiation, which is an expected pharmacodynamic effect ( Schmouder et al., 2006 ). Binding of fingolimod phosphate (the active phosphorylated compound) to S1PR subtype 1 on cardiac myocytes activates G-protein-gated inwardly-rectifying potassium (GIRK) channels (similar to the vagal stimulus), which leads to reduced HR. With continued administration of fingolimod, S1PRs are internalized and degraded, which leads to progressive resolution of the bradycardia over subsequent days of treatment ( Schmouder et al., 2006 ); therefore, long-term dosing beyond treatment initiation has no known effects on HR and AV conduction ( Schmouder et al., 2006 ).
Analyses of pooled data from more than 3600 patients in the randomized, double-blind, phase 3 FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis) ( Kappos et al., 2010 ), FREEDOMS II ( Calabresi et al., 2012 ), and TRANSFORMS (Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis) ( Cohen et al., 2010 ) clinical studies showed that fingolimod treatment initiation induced a transient slowing of HR and AV conduction ( DiMarco et al., 2012 ). The maximum decrease in mean HR of 8 beats per minute (bpm) occurred 4–5 h after the first dose ( DiMarco et al., 2012 ). This initial S1PR agonistic effect was asymptomatic in more than 99% of treated patients. Instances of symptomatic bradycardia were typically mild or moderate in severity ( DiMarco et al., 2012 ). First-degree AV block and Mobitz type I second-degree AV block were detected on electrocardiograms (ECG) in a small number of patients. Very few events were detected beyond the first 6 h ( DiMarco et al., 2012 ).
This study reports findings from the phase 4 Evaluate Patient OutComes (EPOC) study (ClinicalTrials.gov Identifier: NCT01216072), in which the first-dose effects of oral fingolimod therapy were evaluated in a large population of patients with relapsing MS who were switched from disease-modifying therapies (DMTs) at baseline. In contrast to the clinical development studies, enrolled individuals could also receive commonly prescribed HR-lowering medications and patients with certain pre-existing cardiac conditions (e.g. history of myocardial infarction) were eligible to enroll. Therefore, the EPOC study provides data from a population that is more representative of patients encountered in routine clinical practice than in the restrictive environment of pivotal phase 3 studies. This paper describes the first-dose observation data in patients who initiated fingolimod therapy during the core or extension phases of the EPOC study.
2. Patients and methods
2.1. Study design
The EPOC study (ClinicalTrials.gov Identifier: NCT01216072) was conducted in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ( ICH, 2013 ), the Harmonized Tripartite Guidelines for Good Clinical Practice with applicable local regulations ( ICH Expert Working Group, 1996 ), and the ethical principles of the Declaration of Helsinki ( World Medical Association, 2013 ). Prior to conducting the study, the Institutional Review Board at each participating medical center provided ethical approval of the study protocol as well as the case report forms, patient information, and informed consent forms. Written informed consent was obtained from each patient, or their legal representative, before enrollment.
EPOC was a 6-month, randomized, active-comparator, open-label, multicenter study conducted in North America, with an optional 3-month extension ( Fox et al., 2014 ). The study compared fingolimod 0.5 mg once daily with injectable DMTs (iDMT), by assessing patient-reported outcomes, adverse events, and tolerability in individuals with relapsing forms of MS who were considered eligible for a change in therapy by their neurologists. Fingolimod capsules (0.5 mg) were supplied, packaged, and labeled in accordance with the US Code of Federal Regulations governing the handling of investigational treatments. The capsules were dispensed by the study physician and supplied by Novartis Drug Supply Management. There was no washout period between previous DMT and fingolimod treatment. Patients randomized to DMT either remained on their existing DMT or changed to another DMT, based on the study investigator׳s judgment. Injectable DMT was defined as therapy with either: IFNβ-1b (Extavia®or Betaseron®) 0.25 mg injected subcutaneously (SC) every other day; IFNβ-1a (Avonex®) 30 µg injected intramuscularly (IM) once a week; IFNβ-1a (Rebif®) 22 µg or 44 µg injected SC thrice a week; or GA (Copaxone®) 20 mg injected SC once-daily. For the core study, visits occurred at screening, baseline, and weeks 1, 4, 12, and 24. Patients were considered to have completed the trial if they attended all study visits and completed all assessments. After the core study, an optional 3-month extension study was conducted to enable patients in the iDMT arm, who had completed all core study visits, to switch to treatment with oral fingolimod. Additional study visits then occurred during the extension study at weeks 28 and 36 for these patients.
Patients were enrolled from 152 centers in the USA and 6 centers in Canada between August 2010 and August 2012. All patients had been treated with an iDMT for at least 6 months before screening and entered the study without an intervening washout period. The study included adults (≤65 years old) with a diagnosis of relapsing MS in accordance with the 2005 McDonald criteria ( Polman et al., 2005 ), and an Expanded Disability Status Scale (EDSS) score of 0–5.5 ( Kurtzke, 1983 ). Patients were not eligible if they had received fingolimod treatment before the study. Key exclusion criteria (largely consistent with the pivotal phase 3 fingolimod clinical trials (Cohen et al, 2010 and Kappos et al, 2010) were as follows: history of chronic disease of the immune system (except for MS), history of active malignancy (except localized basal/squamous cell carcinoma of the skin), uncontrolled diabetes mellitus (glycated hemoglobin >7%), macular edema present at screening, active systemic bacterial, viral or fungal infections, pregnancy, and certain cardiovascular, pulmonary, and hepatic conditions. Unlike the pivotal trials, however, patients were not excluded from the EPOC study if they were receiving β-blockers (BBs) or calcium-channel blockers (CCBs), or had pre-existing cardiac conditions (PCCs: history of cardiac arrest, myocardial infarction, unstable ischemic heart disease, coronary spasm, congestive heart failure, HR <55 bpm, sick sinus syndrome, sinoatrial heart block, or any factors considered to be cardiac risk factors by the study investigator).
2.3. Study assessments
The results of primary and secondary study objectives are provided in Fox et al., 2014 . This paper describes the first-dose observation data in patients who initiated fingolimod therapy during the core or extension phases of the EPOC study.
2.4. First-dose monitoring procedures
Vital signs (sitting pulse rate and sitting BP) were recorded before the first dose of fingolimod and hourly thereafter for 6 h in all patients. A pre-dose ECG was performed in individuals with PCCs in addition to hourly monitoring of vital signs. If clinically indicated, a second ECG was performed 6 h after the first dose and the patient was discharged based on the investigator׳s judgment. Patients were discharged following a 6-hour observation period only if all the following criteria were met: HR of at least 45 bpm; HR was not at its lowest hourly value; there were no symptoms associated with the reduced HR; post-dose ECG did not show new-onset second-degree or higher AV block; and post-dose ECG did not reveal a QT interval of more than 500 ms. If these criteria were not met, additional monitoring of vital signs was conducted and an ECG was performed every 15-30 min until the issue had resolved.
2.5. Statistical analyses
The full analysis population (n=976) comprised all patients from the core phase (n=783; all of whom were from the fingolimod arm) and extension phase (n=193; all of whom had been on iDMTs during the core phase) who received at least one dose of fingolimod. The ECG analysis population comprised all patients for whom an ECG was recorded at 6 h post-dose. For those without a pre-dose ECG, any abnormality on a post-dose ECG was assumed to be new. Outcomes were summarized using descriptive statistics (sample size, mean, standard deviation [SD], minimum, median, and maximum). Descriptive summaries of the first-dose effect measurements were provided for the change from pre-dose to each hour post-dose and before discharge (including the possible extended observation period). The mean of the three pre-dose values was used to calculate the change from pre-dose.
3.1. Study population
Overall, age and sex distributions were typical of patients with mild-to-moderate relapsing forms of MS ( Table 1 ). Most patients were Caucasian (82.1%) and female (76.6 %). Mean age of patients was 45.8 years and mean MS duration was 12.1 years. Mean pre-dose sitting pulse rate was 73.9 bpm and mean sitting systolic/diastolic BP was 120.9/77.0 mmHg. PCCs were reported in 37 patients (3.8%) by the study investigator ( Table 1 ). Of these, 17 had cardiac conditions listed in their medical history and 10 had a HR of less than 55 bpm or an ECG abnormality; for the remaining 10 patients, details of the PCC were not specified by the investigator. A total of 249 patients (25.5%) had a history of hypertension. Overall, 63 (6.5%) were receiving treatment with BBs and 9 (0.9%) were receiving CCBs at the time of fingolimod first dose. A total of 7 (0.7%) patients who were receiving BB/CCBs had PCCs. A pre-dose ECG was available for 222 patients (22.7%). In total, 36 patients (16.2%) included in the study had an abnormality before receiving the first fingolimod dose, of whom 12 (5.4%) had a conduction abnormality ( Table 1 ).
|Full analysis population ( n =976)|
|Age, years||45.8 (9.8)|
|Women, n (%)||748 (76.6)|
|Race, n (%)|
|Multiple sclerosis disease characteristics|
|Duration of symptoms, years||12.1 (8.4)|
|Number of relapses in the previous year||0.8 (1.2)|
|Number of relapses in the previous 2 years||1.4 (2.0)|
|EDSS score||2.4 (1.4)|
|Pre-existing conditions and concomitant heart-rate-lowering medications|
|Patients with pre-existing cardiac conditions, a n (%)||37 (3.8) b|
|History of hypertension, n (%)||249 (25.5)|
|Patients receiving β-blocker therapy, n (%)||63 (6.5) c|
|Patients receiving calcium-channel blocker therapy, n (%)||9 (0.9) c|
|ECG subgroup findings|
|Pre-dose ECG recorded, n (%)||222 (22.7)|
|ECG findings detected on pre-dose ECG, n (%)||36 (16.2) d|
a History of cardiac arrest or myocardial infarction, unstable ischemic heart disease, coronary spasm, congestive heart failure, heart rate less than 55 bpm, sick sinus syndrome or sinoatrial heart block, or any factors considered to be cardiac risk factors by the study investigator.
b Seven patients with pre-existing cardiac conditions were receiving β-blocker or calcium-channel blocker therapy.
c Two patients were receiving both β-blocker and calcium-channel blocker therapy.
d Percentage calculated based on the number of patients for whom a pre-dose ECG was available (n=222).
All values are mean (SD) unless otherwise indicated.
ECG, electrocardiogram; EDSS, Expanded Disability Status Scale; SD, standard deviation.
3.2. HR during treatment initiation
Initiation of fingolimod treatment was associated with a transient reduction in HR ( Fig. 1 ). The lowest mean HR occurred at 5 h post-dose, with a mean (SD) decrease from baseline of 8.1 (8.3) bpm. At 6 h post-dose, mean decrease from baseline was 7.2 (8.4) bpm. All patients maintained a HR above 40 bpm throughout the 6-hour observation period, except for one who had a HR of 34 bpm at 4 h and 38 bpm at 5 h, and was subsequently discharged at 6 h with a HR of 58 bpm. ECG recordings at 6 h identified atrial premature complex in this patient.
Among patients with PCCs, the mean (SD) sitting HR change from pre-dose was −7.0 (8.3) bpm at the 5-hour time point ( Fig. 1 ). At the 6-hour time point, the HR change was −6.4 (8.6) bpm. In those receiving BBs/CCBs, the mean (SD) sitting HR change from pre-dose was −5.9 (5.9) bpm at the 5-hour time point ( Fig. 1 ). At the 6-hour time point, the HR change was −5.3 (6.1) bpm. All patients receiving BBs/CCBs maintained a HR above 40 bpm.
3.3. ECG findings at 6 h post-dose
A total of 181 patients (18.5%) had an ECG at 6 h post-dose. There were 34 reported new ECG abnormalities (in 33 individuals; 18.2%) that were not reported at the pre-dose ECG, the most common of which were first-degree AV block (n=16 [8.8%]) and sinus bradycardia (n=13 [7.2%]) ( Table 2 ). Of the 33 individuals with new ECG abnormalities, nine had PCCs; no patients were receiving BBs/CCBs. No Mobitz type 2 or higher AV block were observed with fingolimod, regardless of medical history, although two cases of Mobitz type 1 AV block were detected at unscheduled ECGs and had resolved by the 6-hour post-dose ECG after treatment initiation.
|ECG analysis population a n (%)|
|Patients who had a post-dose ECG||181 (100)|
|Patients with new abnormalities a||33 (18.2)|
|New abnormalities||34 (18.8) b , c|
|First-degree AV block||16 (8.8)|
|Sinus bradycardia||13 (7.2)|
|Left anterior hemiblock||1 (0.6)|
|Atrial premature complex||3 (1.7)|
|Biphasic T waves||1 (0.6)|
a For patients with an abnormality at 6 h and without a pre-dose ECG, it was assumed to be a new abnormality.
b Five additional abnormalities were detected at unscheduled post-dose ECGs (sooner than 6 h post-dose): two cases of AV Mobitz type 1 block; one case of sinus bradycardia; one of atrial premature complex and one of first-degree AV block. All of these abnormalities had resolved by the 6-hour post-dose ECG.
c Nine of these patients had PCCs: three cases of first-degree AV block, five cases of sinus bradycardia, one of atrial premature complex, and one case of biphasic T waves. None of these patients had received concomitant treatment with BBs/CCBs.
AV, atrioventricular; BB, β-blocker; CCB, calcium-channel blocker; ECG, electrocardiogram; PCC, pre-existing cardiac condition.
3.4. Clinical status during treatment initiation
Most patients (98.5%) were discharged at 6 h post-dose. A total of 13 patients (1.3%) required extended observation after 6 h on day 1 ( Table 3 ). Five patients (0.5%) required a second day of observation in the clinic, two of whom were patients with PCCs and one was taking a BB/CCB.
|Patients, n (%)||Full analysis population|
|( n =976)|
|Discharged at 6 h post-dose on day 1||961 (98.5) a|
|Required extended observation after 6 h on day 1 b||13 (1.3) c|
|Required extended observation on day 2 d||5 (0.5) e|
|Symptomatic bradycardia||12 (1.2)|
a Three patients returned for extended observation on day 2.
b Five patients were monitored for an additional 1–2 h until vital signs returned to normal, three were monitored for up to a further 1 h owing to abnormal ECG findings, two underwent extended monitoring at the investigator׳s discretion (unspecified), and three underwent monitoring for 23 h by default because this was the standard protocol of the treating clinic, which differed from the study protocol.
c Two of these patients had PCCs, and one was taking a BB/CCB.
d Reasons were not recorded.
e Two of these patients had PCCs, and one was taking a BB/CCB.
BB, β-blocker; CCB, calcium channel blocker; ECG, electrocardiogram; PCC, pre-existing cardiac condition.
Overall, 12 patients (1.2%) had symptomatic bradycardia. The lowest mean HR (SD) among these patients during their symptomatic event was 52.9 (10.5) bpm, and the lowest mean sitting systolic/diastolic BP was 109.5/66.4 mmHg. Eight patients reported dizziness (n=8) and there was one case each of fatigue, palpitations, dyspnea, cardiac discomfort, and gait disturbance ( Table 4 ). Two of these patients had PCCs. All bradycardia symptoms were mild, except for one report of dizziness, which was moderate in severity. Two individuals with symptomatic bradycardia underwent extended observation on day 1; one patient returned for a second day of observation, but did not undergo post-dose ECG and was discharged with a HR of 53 bpm. One individual with first-degree AV block and sinus bradycardia on day 1 returned for a repeat ECG, but no abnormalities were detected on day 2 and the patient was discharged with a HR of 60 bpm. Another individual with left anterior hemiblock at screening, pre-dose, and 6 h post-dose had the same abnormality on the morning and afternoon ECG readings on day 2; the patient was discharged with a HR of 53 bpm. No patients required treatment for bradycardia. Two individuals, one of whom had a PCC, discontinued fingolimod therapy within 2 days owing to bradycardia and another individual discontinued due to heart flutter (which resolved on day 2), respectively.
|Symptom, n (%)||Full analysis population|
|( n =976)|
|Gait disturbance||1 (0.1)|
|Cardiac discomfort||1 (0.1)|
|Heart rate decreased b||1 (0.1)|
a Multiple symptoms were reported in some patients; includes 11 patients with bradycardia events on day 1 and one patient with palpitations as a symptom of bradycardia reported on day 2.
b This patient was not recorded as having symptomatic bradycardia but the site recorded ‘heart rate decreased’ as a symptom of bradycardia.
3.5. BP during treatment initiation
A slight decrease in mean BP was observed in fingolimod-treated patients on day 1, which was maximal 4–5 h after the first dose. At the 4-hour time point, the change from pre-dose in mean sitting systolic/diastolic BP was −3.2/−4.7 mmHg. By the 6-hour time point, the decline in BP had started to attenuate (−1.3/−3.1 mmHg) ( Fig. 2 ). Among patients with PCCs, the mean sitting systolic/diastolic BP change from pre-dose was −2.0/−4.4 mmHg at the 4-hour time point. By the 6-hour time point, the decline in BP was −1.9/−1.8 ( Fig. 2 ). In those receiving BBs/CCBs, the mean sitting systolic/diastolic BP change from pre-dose was −3.4/−3.7 mmHg at the 4-hour time point. By the 6-hour time point, the decline in BP was −3.4/−3.4 mmHg ( Fig. 2 ).
This study provides additional data demonstrating the transient and generally benign nature of fingolimod first-dose effects on HR and AV conduction in a large population that is more representative of fingolimod-treated patients encountered in routine clinical practice than in the narrowly defined populations of pivotal phase 3 studies. The results are consistent with those of previously reported phase 3 clinical studies and subsequent pooled analyses of clinical trial data, which demonstrate the transient, benign, and mostly asymptomatic effects on HR during treatment initiation (Cohen et al, 2010, Kappos et al, 2006, and Kappos et al, 2010). In both FREEDOMS and TRANSFORMS, the maximum HR reduction of 8 bpm occurred 4–5 h after the first dose, with the changes starting to attenuate by 6 h after the first dose (Cohen et al, 2010 and Kappos et al, 2010). In the EPOC study, the observed HR reduction was of a similar magnitude, the nadir occurred at a similar time point, and attenuation of the effect was evident at 6 h after the first dose. A few patients experienced dizziness, fatigue, palpitations, or chest pain, which resolved spontaneously without intervention, while continuing fingolimod therapy.
Consistent with the phase 3 studies (Cohen et al, 2010 and Kappos et al, 2006; Kappos et al., 2010 ), ECG monitoring revealed the occurrence of new conduction abnormalities in only a small number of patients in the first 6 h after treatment initiation, without increased prevalence in the PCC subgroup or in those treated with BBs/CCBs. Overall, the most common abnormalities were first-degree AV block and sinus bradycardia. Two cases of Mobitz type 1 AV block were detected during the first 6 h after treatment initiation. Importantly, most patients (98.5%) were discharged at 6 h post-dose and bradycardia resolved without the need for intervention. In most patients, an asymptomatic, mild decrease in HR was the only manifestation of the first-dose effect of fingolimod.
Mean BP changes during treatment initiation in the EPOC study were of a similar magnitude and attenuated in a similar time frame to those reported in the previous phase 3 studies (Cohen et al, 2010, Kappos et al, 2006, and Kappos et al, 2010). In the BB/CCB subgroup, the transient reduction in BP was slightly greater than in the overall study population, but was asymptomatic. However, none of these patients had any new abnormalities detected on the 6-hour ECG, and only one required extended monitoring.
The EPOC study included a wider range of patients than those typically included in randomized, controlled clinical trials, with the aim of being more representative of individuals who present for MS therapy in routine clinical practice. Patients were generally older, some had PCCs, and many were taking common concomitant BP/HR-lowering medications. The first-dose observations in the patients with PCCs or in those receiving BBs/CCBs were similar to the overall population, with no apparent increased incidence of HR or conduction changes occurring as a result of fingolimod treatment initiation. Owing to small and uneven group sizes, inferential statistical testing was not performed, and care should be taken with interpretation of the results. Nevertheless, these findings are consistent with results from studies of longer duration, involving more patients with PCCs or individuals receiving BBs/CCBs (Gold et al, 2014 and Laroni et al, 2014).
This large, phase 4 study of over 900 patients who received fingolimod for the treatment of relapsing MS showed that the first-dose effects of fingolimod in a population of patients representative of those encountered in real-world clinical practice, including individuals with PCCs or those taking concomitant medications to lower BP or HR, remain consistent with results observed in the pivotal phase 3 studies.
Conflict of Interest
Bruce Hughes has received research support, served as an advisory board member, or been involved in a speaker׳s bureau for Acorda, Bayer, Biogen-Idec, EMD Serono, Genzyme, Questcor, Novartis, and Teva.
Mark Cascione has received research support, speaker fees, and/or consulting fees from Acorda Therapeutics, Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme, Novartis, Pfizer, Sanofi-Aventis, and Teva.
Mark Agius has received honoraria from Biogen Idec, Genzyme, Novartis and Teva Neuroscience, and has received research grant support from Actelion, Acorda, Biogen Idec, GSK, Medimmune, NEXT, Novartis, and Roche.
Mark S Freedman has received research or educational grants from BayerHealthcare and Genzyme, has received honoraria or consultation fees from Actelion, BayerHealthcare, BiogenIdec, Celgene, EMD Canada, Genzyme, Glycominds, Hoffman La-Roche, Novartis, Opexa, Sanofi-Aventis, and Teva Canada Innovation, has been a member of a company advisory board, board of directors, or other similar group for Actelion, BayerHealthcare, BiogenIdec, Celgene, Hoffman La-Roche, Merck Serono, Novartis, Opexa, and Sanofi-Aventis, and has participated in a company sponsored speaker׳s bureau for Genzyme.
Daniel Kantor has received consulting fees, research support, and speaking honoraria from Novartis.
Mark Gudesblatt has received consulting and or speaking fees from Biogen-Idec, Medtronic, TEVA, Genzyme, Novartis, and Sanofi.
Lawrence P. Goldstick has nothing to disclose.
Neetu Agashivala, Lesley Schofield, Kevin McCague, Ron Hashmonay, and Luigi Barbato are employees of Novartis Pharmaceuticals Corporation.
This study was funded by Novartis Pharmaceuticals Corporation. Oxford PharmaGenesis™Ltd provided editorial support for this manuscript. Funding for this editorial support was provided by Novartis Pharmaceuticals Corporation.
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a Mercy Ruan Neuroscience Center, Des Moines, IA, USA
b Tampa Neurology Associates, Tampa, FL, USA
c University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada
d University of California Davis, Veterans Affairs Northern California Health Care System (VANCHCS), CA, USA
e Neurologique Foundation, Inc., Jacksonville, FL, USA
f Multiple Sclerosis Comprehensive Care Center, St Islip, NY, USA
g Neurology Specialists Inc, Dayton, OH, USA
h Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
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