Abstract
Objective: The 16-Year Long-Term Follow-Up (LTF) to the pivotal interferon-β-1b (IFNβ-1b) trial explored clinical, MRI, cognitive, and patient-reported outcomes. Here, we report the safety assessments.
Methods: In the pivotal study, 372 patients were randomized to placebo (n = 123), IFNβ-1b 50 μg (n = 125), or IFNβ-1b 250 μg (n = 124) subcutaneously every other day for up to 5 years. Sixteen years later, patients were asked to participate in this cross-sectional follow-up study. No particular therapy was stipulated during follow-up. Adverse events experienced since the pivotal trial were recorded. Neutralizing antibodies (NAbs) to IFNβ-1b were measured using the myxovirus protein A induction assay. Statistical analyses were descriptive.
Results: In total, 88.2% of patients (328/372) were identified. Some centers achieved 100% ascertainment, obviating selection bias. Treatment-related adverse events (e.g., leukopenia and liver and thyroid dysfunction) reported by LTF participants were in keeping with those previously established. Based on a follow-up period that includes 2,000 patient-years of IFNβ-1b treatment, no new adverse events were observed that were associated with long-term IFNβ-1b exposure. By LTF, NAbs to IFNβ-1b disappeared in the majority (76%) of NAb-positive patients. NAb status during the pivotal study appeared to have no impact on long-term clinical and MRI outcomes. There were more deaths among patients assigned to placebo in the pivotal study (20/109 [18.3%]) compared with patients who received IFNβ-1b 50 μg (9/108 [8.3%]) or IFNβ-1b 250 μg (6/111 [5.4%]).
Conclusion: The results from the 16-Year Long-Term Follow-Up study support the long-term safety of interferon-β-1b therapy in multiple sclerosis.
Classification of evidence: This study provides Class III evidence that patients with relapsing-remitting MS taking IFNβ-1b 50 μg or 250 μg subcutaneously every other day for up to 5 years, with subsequent unspecified treatment, have fewer deaths after 16 years of follow-up than similar patients on placebo for up to 5 years, with subsequent unspecified treatment (risk difference 11.5%, 95% confidence interval 4–19).
Glossary
- AE=
- adverse event;
- BOD=
- burden of disease;
- CI=
- confidence interval;
- EDSS=
- Expanded Disability Status Scale;
- EQ-5D=
- European Quality of Life–5-Dimensional questionnaire;
- IFN=
- interferon;
- LTF=
- Long-Term Follow-Up;
- MS=
- multiple sclerosis;
- MSFC=
- Multiple Sclerosis Functional Composite;
- MSSS=
- Multiple Sclerosis Severity Score;
- NAbs=
- neutralizing antibodies;
- RRMS=
- relapsing-remitting multiple sclerosis;
- SPMS=
- secondary progressive multiple sclerosis.
Multiple sclerosis (MS) has a mean age at onset of 30 years, but patients often live for a further 3 to 4 decades with the disease.1 Interferon-β (IFNβ)–based therapies are used for the treatment of MS. IFN-α/β therapy affects leukocyte count and liver functioning.2,3 Thyroid function abnormalities4 and thyroid autoantibodies were not observed during a 2-year study of patients with secondary progressive MS (SPMS) treated with IFNβ-1b (Betaseron®, Bayer HealthCare Pharmaceuticals, Wayne, NJ).5 These findings were corroborated by a 1-year prospective study of patients with RRMS, where thyroid autoantibody levels and thyroid dysfunction did not differ significantly between baseline and IFNβ-1b treatment periods.6
Though IFNβ-1b had a benign safety profile in the pivotal study, long-term data are necessary to determine safety and to exclude unexpected events, particularly those affecting mortality. The 16-Year Long-Term Follow-Up (LTF) was a cross-sectional, observational study that assessed outcomes (e.g., adverse events [AEs] and neutralizing antibodies [NAbs]) over the long term in patients with relapsing-remitting MS (RRMS) who participated in the pivotal IFNβ-1b study.7,8
METHODS
Study design and procedures.
The 16-Year LTF study was a multicenter, observational study, whose study design and procedures have been published.9
Patients.
A total of 372 patients with RRMS participated in the pivotal IFNβ-1b study conducted in 11 clinical centers in North America.7,8,10 Between June 1988 and May 1990, patients were randomized to receive placebo (n = 123), IFNβ-1b 50 μg (n = 125), or IFNβ-1b 250 μg (n = 124) SC every other day.7,10 After completion of the initial 2-year study, all patients were allowed to continue double-blind treatment and evaluations for an additional 3 years (up to 5 years in total). Upon approval of IFNβ-1b 250 μg in 1993, placebo-treated and IFNβ-1b 50 μg–treated patients were switched to the commercially available product (Betaseron®). All pivotal trial participants were eligible for the 16-Year LTF study, and all centers identified as many of their original participants as possible between January and November 2005.
Outcome variables.
The 16-Year LTF study assessed the prevalence of AEs, including laboratory abnormalities, NAbs, and death. Patients were prompted via structured questionnaire to disclose relevant IFNβ-1b–induced AEs. In the pivotal and long-term follow-up studies, NAbs were measured by the viral cytopathic effect induction assay and confirmed by the myxovirus protein A assay.11 Titers ≥20 NU/mL were considered NAb-positive.
Statistical analysis.
For continuous data, mean, SD, and median are presented. Categorical data are described in frequency tables displaying counts and percentages. Laboratory and mortality data and AE incidence were evaluated for patients stratified according to treatment assignments in the original IFNβ-1b study.
AE incidence was calculated for subgroups (e.g., centers with 100% ascertainment, patients using IFNβ-1b therapy over the 2 years prior to LTF visit, patients using IFNβ-1b 250 μg for ≥80% of the time since initiation of the pivotal trial). Analysis of centers with 100% ascertainment obviated selection bias due to patient dropout. For some patients, the duration of MS therapies could not be ascertained accurately, so a conservative minimal exposure scenario was applied to define time on IFNβ-1b 250 μg.
NAb titer at LTF was compared with NAb status during the pivotal study (e.g., maximum titer, titer at end of pivotal study). Clinical and MRI outcomes at LTF were compared for patients who were NAb-positive and NAb-negative during the pivotal study. Analyses were performed for the 250 μg group, as well as for the pooled IFNβ-1b groups (50 μg + 250 μg).
Proportions were compared using Fisher exact or McNemar tests. Depression at LTF was assessed using the European Quality of Life–5-Dimensional (EQ-5D) questionnaire.12 MRI outcomes at LTF were compared with NAb-positive and NAb-negative patients during the pivotal study using nonparametric analysis of covariance with MRI T2 burden of disease (BOD) at pivotal trial baseline as a covariate.
Study protocol approvals, registrations, and patient consents.
For the 16-Year LTF study (NCT00206635), ethical approval was obtained from the centers' institutional review boards or independent ethical committees, and all participants or their proxy (i.e., legal representative or relative) provided written informed consent.
RESULTS
Study population.
Demographic data for the original and LTF study populations are detailed elsewhere.9 A total of 328 of the original 372 patients (88.2%) were identified. The numbers and proportions of patients identified were similar among placebo (109/123, 88.6%), IFNβ-1b 50 μg (108/125, 86.4%), and IFNβ-1b 250 μg groups (111/124, 89.5%). Of these, 293 (89%) were alive and 35 (11%) were deceased. A total of 260 patients (70% of original total, 79% of identified) agreed to participate in the LTF trial. This population included 7 deceased patients via proxy consent. Eight centers identified between 71% and 94% of their original patients. Three of 11 centers identified 100% of patients (n = 80). Demographic characteristics of this subpopulation did not differ from those of all identified patients or those who consented to LTF (table 1).
Table 1 Clinical and baseline characteristics at the start of the pivotal study, of all identified patients and of patients identified by centers with 100% patient identification, compared with all 16-Year Long-Term Follow-Up patients
Seventy-four of the 260 participants (29%) had taken IFNβ-1b 250 μg within 30 days of the LTF visit and 33% within the prior 2 years. Overall, IFNβ discontinuation rates were high; some patients discontinued and restarted therapy over 16 years. Consolidating the 3 pivotal trial randomization groups, the median duration of exposure to IFNβ-1b was 7.9 years, constituting nearly 2,000 patient-years of IFNβ-1b 250 μg therapy.
For the pooled treatment groups, 69 patients were using IFNβ-1b continuously in the 2 years prior to the LTF visit. Eighty-five patients had been on IFNβ-1b at some time in the last 2 years and 175 received no IFNβ-1b during the last 2 years. Other therapies used after the original IFNβ-1b study included prednisone, glatiramer acetate, IFNβ-1a, and mitoxantrone. The great number of therapy sequences renders individual analyses and commentary difficult, but some observed AEs are likely derived from treatment with other agents and not from IFNβ-1b.
AEs for patients continuously using IFNβ-1b in the 2 years prior to LTF.
Patients receiving IFNβ-1b continuously in the 2 years prior to the LTF visit (n = 69) experienced typical AEs: flu-like symptoms (31.9%), fever (21.7%), headache (27.5%), injection-site reactions (erythema, pain, or swelling, 81.2%), malaise (23.2%), myalgia (21.7%), or elevated liver transaminases (10.1%) (table 2). No skin necrosis was recorded. In the pivotal trial, IFNβ-1b increased the frequency of fever, malaise, and high transaminases.7 Sixteen years later, 29% of patients were taking IFNβ-1b; the frequency of fever or malaise was the same in these patients as those not receiving IFNβ-1b at follow-up. However, 55% had received some MS therapy within 30 days before providing consent; therefore, fever and malaise could have been due to use of other drugs or chemotherapy. Only 3.4% of patients not receiving IFNβ-1b at follow-up had increased transaminases (table 2).
Table 2 Incidence of adverse events in followed patients treated with 250 μg IFNβ-1b or placebo in the pivotal trial vs incidence of the same adverse events at 16-Year Long-Term Follow-Up
Twenty-eight patients used the approved dose of IFNβ-1b for ≥80% over the 16 years (i.e., almost continuously since the beginning of the pivotal study). Within this continuously IFNβ-1b–treated group, the incidence of AEs was low.
Laboratory data at LTF.
Laboratory measurements at LTF, including leukocyte counts, rheumatoid factor, and thyroid function, were similar across original treatment assignments (table e-1 on the Neurology® Web site at www.neurology.org). Antithyroid peroxidase levels were 17 IU/mL for patients originally randomized to placebo, 21 IU/mL for the IFNβ-1b 50 μg group, and 24 IU/mL for the IFNβ-1b 250 μg group (normal is a titer of <50). Thyrotropin values were normal, ranging from 1.38 to 1.51 mIU/L (normal = 0.4 to 4.0).
NAbs at LTF visit.
In subjects who received IFNβ-1b 50 μg or IFNβ-1b 250 μg, and who were NAb-positive at some time during the pivotal trial, NAb frequency and titer declined by the end of the trial. At some point during the pivotal trial, 52/124 (41.9%) patients prescribed IFNβ-1b 250 μg had titers ≥20 NU/mL, but by the end of the trial only 25/124 (20.2%) remained NAb-positive.
Of the 124 patients originally assigned to IFNβ-1b 250 μg, 111 were identified at LTF and 80 had NAb data. Thirty-seven of 80 patients (46.3%) were NAb-positive at some point during the pivotal trial. At the end of the 5-year pivotal trial, 18 patients (22.5%) had titers ≥20 NU/mL; 8 (10.0%) had titers ≥100 NU/mL; 7 (8.8%) had titers ≥200 NU/mL; and 6 (7.5%) had titers ≥400 NU/mL (these numbers are cumulative, so the number of patients with a titer ≥20 NU/mL includes those with titers ≥100 NU/mL, ≥200 NU/mL, and ≥400 NU/mL). At LTF, only 9/80 (11.3%) patients originally assigned to IFNβ-1b 250 μg were NAb-positive (figure 1). Thus, NAb frequency decreased by 76% compared with peak NAb frequency during the pivotal study. However, some of the 80 patients discontinued IFNβ-1b therapy. We recognize that NAb-positive patients who are doing well are more likely to remain on IFNβ-1b therapy, while NAb-negative patients who are doing poorly are more likely to cease IFNβ-1b treatment. To circumvent this potential source of bias, we analyzed a subgroup of patients (n = 20) who were originally assigned to the IFNβ-1b 250 μg group, who were treated continuously with IFNβ-1b during the last 2 years of LTF, and who had NAb data at LTF. During the pivotal trial, 6/20 (30.0%) of these patients were NAb-positive. By the end of the 5-year pivotal trial, 4/20 (20.0%) had titers ≥20 NU/mL. At LTF, 2/20 (10.0%) had titers ≥20 NU/mL. For patients randomized to IFNβ-1b 50 μg or 250 μg during the pivotal trial, who had received any IFNβ-1b during the 2 years prior to the LTF visit, and who provided NAb data at LTF, only 4/60 (6.7%) had a NAb titer ≥20 NU/mL, and 2 (3%) of these had a titer ≥400 NU/mL at LTF (figure 2). NAb positivity declined over time in patients treated with IFNβ-1b 50 μg or 250 μg during the pivotal trial. Similar trends were observed for patients treated continuously or during the 2 years prior to LTF visit with IFNβ-1b (figure 2).
Figure 1 Neutralizing antibodies (NAbs) to interferon-β (IFNβ)
(A) NAbs in the original 250 μg dose group, at any time in the 5 years of the pivotal trial (n = 124) vs (B) NAbs in the subgroup of 16-Year Long-Term Follow-Up (LTF) patients from the original 250 μg dose group at the time of the pivotal trial (n = 80) (rematched at 16 years). NAb positivity was defined as 2 consecutive positive titers at any time during the pivotal study. The p value was calculated using McNemar test. (NAbs are not corrected for potential IFNβ use.)
Figure 2 Neutralizing antibody (NAb) titers in the pivotal trial and at 16-Year Long-Term Follow-Up (LTF) for patients receiving interferon-β-1b (IFNβ-1b) 50 μg or 250 μg in the pivotal trial
(A) Maximum NAb titer during the pivotal study; (B) NAb titer at the end of the pivotal study; (C) NAb titer at LTF. Note different y-axis values.
Mortality.
At LTF, death occurred more frequently in patients originally assigned to placebo than to either of the IFNβ-1b treatments. Of those identified from the placebo group, 20/109 (18.3%) had died, compared with 9/108 (8.3%) in the IFNβ-1b 50 μg group and 6/111 (5.4%) in the IFNβ-1b 250 μg group.9 Of the 15 patients in the IFNβ-1b treatment groups who died, 9 were NAb-negative and 6 were NAb-positive. The mean age at death of patients assigned to placebo was 49.9 years compared with 45.0 years for IFNβ-1b 50 μg-treated and 45.3 years for IFNβ-1b 250 μg-treated patients (table 3). Causes of death were identified for 9 patients and included MS-related complications (n = 2), cardiogenic shock, pneumonia-related complications, drowning, seizures, acetaminophen overdose, hepatic failure/pancreatic cancer, and lung cancer.
Table 3 Mortality in all identified patients vs the subgroup from centers with complete patient ascertainment
The journal considers this Class III evidence because 1) it is conceivable that the placebo group could have made different choices in therapy or lifestyle, despite what appears to be roughly equivalent drug use after the randomized trial ended, and 2) analysis of the number of living patients shows a risk difference of 11.5% (95% CI 4–19).
Clinical and MRI outcomes at LTF visit vs NAb status during pivotal study.
When the IFNβ-1b 50 μg and 250 μg groups were pooled, NAb positivity was seen in 75 of 181 patients (41.4%) in the pivotal trial subset that was later evaluated in the LTF. High-titer NAb and confirmed NAb-positive subgroups were too small for reliable statistical analyses. In the subset who received IFNβ-1b 250 μg in the pivotal trial, NAb positivity was observed in 44 of 96 patients (45.8%).
In this subgroup of 96 patients, NAb status had no impact on clinical outcome at the 16-year visit. These outcomes included duration of disease since onset of clinical symptoms to LTF evaluation (median = 23.5 years in NAb-negative from pivotal trial vs 23.4 in NAb-positive); duration of MS since diagnosis (20.0 vs 19.0 years); Expanded Disability Status Scale (EDSS) score at LTF (6.0 vs 6.0); change in EDSS score from baseline of the pivotal trial (2.5 vs 2.5); Multiple Sclerosis Functional Composite (MSFC) measure (−0.50 vs −0.43); Multiple Sclerosis Severity Score (MSSS) (4.35 vs 5.02); change in MSSS from pivotal trial baseline (0.15 vs 0.35); reaching EDSS = 6.0 (21/52 [40%] vs 23/44 [52%]); time from onset of clinical symptoms to EDSS = 6.0 (17.4 vs 15.9 years); time from diagnosis to EDSS = 6.0 (13.0 vs 12.0 years); time from start of pivotal trial to EDSS = 6.0 (3.4 vs 9.0 years); number developing SPMS (23/52 [44.2%] vs 19/44 [43.2%]); time from onset of clinical symptoms to SPMS (17.5 vs 17.2 years); time from diagnosis of MS to SPMS (15.0 vs 12.0 years); time from start of pivotal trial to SPMS (9.3 vs 10.5 years); death (0/52 vs 2/44 [4.5%]); and negative outcome (EDSS ≥6.0 or SPMS) (29/52 [55.8%] vs 26/44 [59.1%]).
Depression rates in patients who received IFNβ-1b for ≥80% of the time during the pivotal study were 25.0% and during the last 2 years of LTF were 32.1% (p = 0.53). Differences in depression rates at LTF between patients originally assigned to placebo relative to those initially randomized to IFNβ-1b were nonsignificant (table 2).
MRI at 16 years was performed in 70% of patients in the original IFNβ-1b 250 μg group. Differences between pivotal trial NAb-negative and NAb-positive groups at LTF were not significant for T2 BOD (median of 16,553 mm2 in NAb-negative in pivotal trial vs 14,464 mm2 in NAb-positive); T1 BOD (7,976 mm2vs 4,272 mm2); normalized brain volume (72.2% vs 73.4%); and cervical cord cross-sectional area (65.0 mm2vs 62.6 mm2).
DISCUSSION
This LTF study identified 88.2% of patients enrolled in the original IFNβ-1b trial after 16 years with nearly 70% evaluated in detail. Some individuals did not consent to detailed assessment and were included only in survival analyses. The potential contribution of patients lost to follow-up or who declined participation was compared with patients who followed up regularly with investigating physicians. No differences were found in clinical status or AE frequencies during the pivotal trial between patients who did and did not participate in the LTF. These findings are consistent with an ongoing natural history study that has found no differences in demographic characteristics or clinical outcomes between patients who were easy or difficult to trace.13
Physical examination and laboratory data were analyzed for evidence of safety issues associated with long-term IFNβ-1b use. One strength of this study was the ability to compare baseline and follow-up data for specific patients and patient subgroups. IFNβ-1b treatment-associated AEs decreased with time and were less frequent in the last 2 years of LTF compared with treatment during the pivotal trial. Frequency was low despite patients being prompted on the LTF questionnaire to remember all AEs. The slight increase in reported malaise may be attributable to disease progression. Routine autoinjector use, dose escalation at therapy initiation, and concomitant use of nonsteroidal anti-inflammatory drugs—all introduced after the pivotal trial—have reduced treatment-associated AEs and increased IFNβ-1b tolerability.14 These practices have likely contributed to the decline in AEs seen during LTF and in clinical trials initiated during the last 5 to 10 years.15
Mild lymphopenia and elevated liver enzymes were detected in the pivotal trial,7 but were seldom observed at LTF. No case of chronic liver disease was identified throughout 16 years of follow-up. Concerns that IFNβ-1b therapy increases the rate of autoimmune thyroid disease4 were not supported by comparison of placebo and IFNβ-1b populations. Many of those patients originally assigned to placebo were ultimately treated with IFNβ-1b and other drugs. Though thyroid functions were normal in all groups at LTF (table 3), subtle effects on the thyroid could have been missed at LTF because many patients eventually had high exposure to IFNβ and other drugs. Lack of induction of thyroid function abnormalities and autoantibodies by IFNβ-1b is supported by other studies in RRMS6 and SPMS.5
NAbs to interferon occur with all IFNβ products used to treat MS, but the clinical importance of NAbs remains controversial.16–18 In the pivotal trial, NAb frequency was 41.9% during years 1 to 5 among patients receiving IFNβ-1b 250 μg. While the incidence of NAbs had begun to decline by 5 years,19 interim analysis of a small cohort of these patients (n = 59) at 8 years revealed that 60% of NAb-positive patients reverted to NAb negativity.20 Prevalence of NAb positivity was further reduced at 11.5 years,21 and at 16 years, it was only 10% for those who had received IFNβ-1b in the pivotal trial and continuously during the 2 years before LTF. Among those patients, only 1 (1.5%) had a titer ≥100 NU/mL. In the larger cohort of LTF patients who received IFNβ-1b 250 μg in the pivotal trial, 9/80 (11.3%) remained NAb-positive at LTF. The percentage of NAb-positive patients decreased over time in all treatment subgroups, although this decline was less pronounced among patients with the highest NAb titers (≥400 NU/mL) during the pivotal study.
The mortality rate (18.3%) for patients from the placebo arm of the IFNβ-1b study was lower than expected based on natural history studies. For example, a follow-up study of 251 patients with MS demonstrated a mortality rate of 28% after 18.1 years.22 Mortality rate was even lower in patients originally randomized to IFNβ-1b (6.8%, 15/219). To conclude that mortality is delayed in one assignment group over another, however, death rates will be reassessed for the entire cohort in a planned 20-year follow-up.
The depression rate in patients who received IFNβ-1b for ≥80% of the time at the LTF visit was 32.1%. This falls within the range of validated point prevalence rates for significant depression in the general MS population, which is between 27% and 54%.23 Using the EQ-5D test, we found no evidence that depression was linked to IFNβ-1b.
A unique feature of this study was the identification of most patients from the North American pivotal IFNβ-1b study. The length of follow-up and the number of patient observation years were higher than in any other LTF study of an MS therapy, increasing the importance of our findings. Our data suggest that there are no high-frequency AEs associated with long-term IFNβ-1b therapy. However, patients' and doctors' views of efficacy—and possibly safety and AEs—likely played a role in drug choice and compliance. Patients continuing on long-term therapy are self-selected for positive outcomes, regardless of whether this outcome is due to nonaggressive disease or to treatment effects. Sources of bias in the LTF study and the analytical approaches undertaken to mitigate these biases are discussed in more detail elsewhere.24
These study results support the long-term safety of IFNβ-1b therapy in MS. However, we acknowledge that our LTF sample, and those of other LTF studies, has a low statistical power to detect rare AEs. The long-term pharmacovigilance of patients enrolled in all experimental trials is thus encouraged.
AUTHOR CONTRIBUTIONS
Statistical analysis was supervised by Karola Beckmann.
COINVESTIGATORS
The 16-Year Long-Term Follow-Up Study Investigators included the following: Barry G.W. Arnason, MD (University of Chicago, Principal Investigator [PI]); Anthony T. Reder, MD, Adil Javed, MD, Avertano Noronha, MD (University of Chicago, Investigators [I]); Barbara Harding-Clay, Mildred O. Valentine, Krystal Q. Ivy (University of Chicago, Study Coordinators [SC]); Joseph Fink, PhD, Todd Nader, PhD, Maureen Lacy, PhD (University of Chicago, Neuropsychological Testers [NT]); Douglas S. Goodin, MD (University of California, San Francisco, PI); Elena Kornyeyeva, MD (University of California, San Francisco, SC); David Cox (University of California, San Francisco, NT); Jeff Greenstein, MD (Greenstein Associates & MS Institute, Philadelphia, PI); I. Gold (Greenstein Associates & MS Institute, Philadelphia, SC); Kenneth Johnson, MD (University of Maryland, Baltimore, PI); Christopher Bever, MD, Horea Rus, MD, Robert K. Shin, MD (University of Maryland, Baltimore, I); Elenor Katz, Valerie Wells, Kerry Naunton (University of Maryland, Baltimore, SC); Maureen Rogerson (University of Maryland, Baltimore, NT); Thomas Leist, MD (Jefferson University Hospital, Philadelphia, PI); S. Gallardo, J. Davis (Jefferson University Hospital, Philadelphia, SC); Anette Okai (Jefferson University Hospital, Philadelphia, NT); William A. Sibley, MD (University of Arizona, Tucson, PI); Jeanette K. Wendt, MD, David A. Weidman, MD, Richard D. Wachter, MD (University of Arizona, Tucson, I); Joan Laguna, Brian Peterson (University of Arizona, Tucson, SC); Drennen Brown (University of Arizona, Tucson, NT); Khurram Bashir, MD (University of Alabama at Birmingham, PI); Beverly Layton (University of Alabama at Birmingham, SC); Jennifer Castillo, Sara Krzywanski (University of Alabama at Birmingham, NT); Pierre Duquette, MD (Hôpital Notre-Dame, Montréal, PI); R. Dubois (Hôpital Notre-Dame, Montréal, SC); J. Poirier (Hôpital Notre-Dame, Montréal, NT); Yves Lapierre, MD (Institut et Hôpital Neurologiques de Montréal, PI); Stanley Hum (Institut et Hôpital Neurologiques de Montréal, SC and NT); Joel Oger, MD, FRCPC (University of British Columbia, Vancouver, BC, PI); Virginia Devonshire, MD, FRCPC, John P. Hooge, MD, FRCPC, Anthony Traboulsee, MD, FRCPC, Penelope S. Smyth, MD, FRCPC, Shiori Hashimoto, MD, FRCPC, Lorne F. Kastrukoff, MD, FRCPC (University of British Columbia, Vancouver, I); Wendy Morrison, RN, F. Lum (University of British Columbia, Vancouver, SC); B. Kosaka (University of British Columbia, Vancouver, NT); George P.A. Rice (London Health Sciences Centre, Ontario, PI); Marcelo Kremenchutzky, MD, Rains Deshpande, MD (London Health Sciences Centre, Ontario, I); Jane Lesaux (London Health Sciences Centre, Ontario, SC); Holly Armstrong (London Health Sciences Centre, Ontario, NT); Jennifer Moussa, Tracey Bentall (London Health Sciences Centre, Ontario, Research Assistants); George C. Ebers, MD (University of Oxford, Signatory Investigator); Antonio Scalfari, MD (University of Oxford, I); Dawn Langdon (University of London, Neuropsychology Coordinator); Jennifer Gurd (Radcliffe Infirmary, Oxford, Neuropsychology Coordinator); David Li, MD, Anthony Traboulsee, MD, FRCPC (MRI Center, PI); R. Tam (MRI Center, Research Assistant); and Marco Medina, A. Riddlebough (MRI Center, SC).
ACKNOWLEDGMENT
The authors thank the team at PAREXEL MMS Europe for editorial support during the development of this manuscript. This includes Rebecca Gardner for preparing the initial outline of this manuscript, which was a transcript of a face-to-face meeting attended by all authors; Maria Bell, David Morgan and Sarah Hadfield for proofreading the manuscript and preparing the figures; and Catherine Amey, Ray Ashton and Alison Plummer for collating revisions from coauthors. PAREXEL MMS Europe received payments from Bayer HealthCare Pharmaceuticals for this editorial support.
DISCLOSURE
Dr. Reder serves on a scientific advisory board, as a consultant for, and/or has received funding for travel from Abbott, ImmunoScience, Inc., AstraZeneca, Merck Serono, Athena Diagnostics, Inc., sanofi- aventis, Bayer Schering Pharma, Biogen Idec, BioMS Medical, Blue Cross Blue Shield, Boehringer Ingelheim, Caremark Rx, Centocor Ortho Biotech Inc., Cephalon, Inc., Connetics Corp., CroMedica Global Inc., Eli Lilly and Company, Elan Corporation, Genentech, Inc., Genzyme Corporation, GlaxoSmithKline, Hoechst Marion Roussel Canada Research, Inc., Roche, Immunex Corporation, Institute for Health Care Quality, Johnson & Johnson, Yale University, Barrow Neurological Institute, National Multiple Sclerosis Society & Paralyzed Veterans of America, Neurocrine Biosciences, Novartis, Parke-Davis, Pfizer Inc, Pharmacia & Upjohn, Protein Design Labs, Inc., Quantum Biotechnologies, Inc., Quintiles, Inc., EMD Serono, Inc., Sention, Inc, Smith Kline-Beecham, Specialized Therapeutics (a division of Berlipharm, Inc.), Takeda Pharmaceutical Company Limited, and Teva Pharmaceutical Industries Ltd.; serves on editorial boards for Medlink/Neurobase, the Turkish Journal of Medical Sciences, and Türk Nöroloji Dergisi (Turkish Journal of Neurology); and receives research support from Novartis, BioMS Medical, Eli Lilly and Company, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, EMD Serono, Inc., Pfizer Inc, Genentech, Inc., Biogen Idec, the NIH (NINDS RO1 NS 051591 [Site PI] and 1 K24 RR021948 [PI]), the National MS Society, the Brain Research Foundation, the American Academy of Allergy & Immunology, Howard Hughes Foundation, Egypt Arab Republic Peace Fellowship, Turkish Ministry of Defense Fellowship Award, and from the State of Illinois, USA. Dr. Ebers serves on the editorial boards of the International Multiple Sclerosis Journal and Multiple Sclerosis; has received a speaker honorarium from Roche; served as a consultant to UCB; and receives research support from Bayer Schering Pharma, the Multiple Sclerosis Society of the United Kingdom, and the Multiple Sclerosis Society of Canada Scientific Research Foundation. Dr. Traboulsee serves on a scientific advisory board for BioMS Medical; serves on the editorial advisory board for Neura; has received speaker honoraria from Bayer Schering Pharma, Teva Pharmaceutical Industries Ltd., and EMD Serono, Inc.; and receives research support from the MS Society of Canada. Dr. Li serves on a scientific advisory board for Roche; serves as a consultant for Genzyme Corporation; performs MRI (50% effort) in his clinical practice; serves as the Director of the UBC MS/MRI Research Group which has been contracted to perform central analysis of MRI scans for therapeutic trials with Angiotech, Bayer Schering Pharma, BioMS Medical, Centocor Ortho Biotech Inc., Daiichi Sankyo, Roche, Merck Serono, Schering-Plough Corp., Teva Pharmaceutical Industries Ltd., sanofi-aventis, and Transition Therapeutics Inc.; and receives research support from the MS Society of Canada. Dr. Langdon has served on scientific advisory boards for Roche, Merck Serono, Bayer Schering Pharma, and Novartis; has served on speakers' bureaus for and received funding for travel from Bayer Schering Pharma, sanofi-aventis, and Novartis; and has received research support from Bayer Schering Pharma. Dr. Goodin has served on a scientific advisory board and a speakers' bureau for, and has received funding for travel, speaker honoraria, and received research support from Bayer Schering Pharma; serves as Editor-in-Chief of the International MS Journal; and has served as an expert witness on various neurological topics. Dr. Bogumil is a salaried employee of and holds stock in Bayer Schering Pharma. Dr. Beckmann was a full-time employee of Bayer Schering Pharma at time of the study. Dr. Konieczny was a full-time employee of and consultant to Bayer Schering Pharma at the time of the study.
Footnotes
-
Supplemental data at www.neurology.org
Study funding: The pivotal interferon-β-1b trial was sponsored by Berlex Laboratories and the16-Year Long-Term Follow-Up study was sponsored by Bayer Schering Pharma.
Disclosure: Author disclosures are provided at the end of the article.
Received February 26, 2009. Accepted in final form March 1, 2010.
REFERENCES
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You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.