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Original Contribution |

Enhanced Benefit of Increasing Interferon Beta-1a Dose and Frequency in Relapsing Multiple Sclerosis The EVIDENCE Study FREE

Steven R. Schwid, MD; John Thorpe, MD; Mohammad Sharief, MD; Magnhild Sandberg-Wollheim, MD; Kottil Rammohan, MD; Jeanette Wendt, MD; Hillel Panitch, MD; Douglas Goodin, MD; David Li, MD; Peter Chang, PhD; Gordon Francis, MD ; for the EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) Study Group and the University of British Columbia MS/MRI Research Group
[+] Author Affiliations

Author Affiliations: Departments of Neurology, University of Rochester, Rochester, NY (Dr Schwid), Cambridge University, Cambridge, England (Dr Thorpe), Guy’s Hospital, London, England (Dr Sharief), University Hospital, Lund, Sweden (Dr Sandberg-Wollheim), The Ohio State University, Columbus (Dr Rammohan), University of Vermont College of Medicine, Burlington (Dr Panitch), and University of California–San Francisco (Dr Goodin); Tucson Neurology Associates, Tucson, Ariz (Dr Wendt); Department of Radiology, University of British Columbia, Vancouver (Dr Li); and Serono Inc, Rockland, Mass (Drs Chang and Francis).


Arch Neurol. 2005;62(5):785-792. doi:10.1001/archneur.62.5.785.
Text Size: A A A
Published online

Background  The EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) Study demonstrated that patients with multiple sclerosis (MS) who initiate interferon beta-1a therapy with 44 μg 3 times weekly (TIW) were less likely to have a relapse or activity on magnetic resonance imaging (MRI) compared with those who initiate therapy at a dosage of 30 μg 1 time weekly (QW).

Objective  To determine the effect of changing the dosage from 30 μg QW to 44 μg TIW in this extension of the EVIDENCE Study.

Design/Patients  Patients with relapsing MS originally randomized to interferon beta-1a, 30 μg QW, during the comparative phase of the study changed to 44 μg TIW, whereas patients originally randomized to 44 μg TIW continued that regimen. Patients were followed up, on average, for an additional 32 weeks.

Main Outcome Measure  The within-patient pretransition to posttransition change in relapse rate.

Results  At the transition visit, 223 (73%) of 306 patients receiving 30 μg QW converted to 44 μg TIW, and 272 (91%) of 299 receiving 44-μg TIW continued the same therapy. The posttransition annualized relapse rate decreased from 0.64 to 0.32 for patients increasing the dose (P<.001) and from 0.46 to 0.34 for patients continuing 44-μg TIW (P = .03). The change was greater in those increasing dose and frequency (P = .047). Patients converting to the 44-μg TIW regimen had fewer active lesions on T2-weighted MRI compared with before the transition (P = .02), whereas those continuing the 44-μg TIW regimen had no significant change in T2 active lesions. Patients who converted to high-dose/high-frequency interferon beta-1a therapy had increased rates of adverse events and treatment terminations consistent with the initiation of high-dose subcutaneous interferon therapy.

Conclusions  Patients receiving interferon beta-1a improved on clinical and MRI disease measures when they changed from 30μg QW to 44 μg TIW.

Figures in this Article

Pharmacological data13 and many clinical trials demonstrate a dose effect of interferon in relapsing multiple sclerosis (MS), suggesting that a higher dose given more than once weekly48 leads to superior efficacy outcomes. By contrast, doubling the dose administered once weekly seems not to have such added benefit.9 The EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) Study, a direct comparison of the relative efficacy of 2 different dosing regimens of interferon beta-1a, found significant benefit on relapse and magnetic resonance imaging (MRI) measures for high-dose/high-frequency compared with low-dose weekly interferon therapy after 48 weeks,10 benefits that were sustained up to 64 weeks.11 Data are limited, however, regarding the effects of changing from low-dose weekly to high-dose/high-frequency interferon treatment. Following completion of the comparative phase of the EVIDENCE Study, patients receiving low-dose weekly therapy were given the opportunity to convert to 44 μg 3 times weekly (TIW), permitting prospective assessment of this issue.

PATIENTS

In the EVIDENCE Study, 677 interferon-naive patients with definite relapsing remitting MS12 and Expanded Disability Status Scale scores of 0 to 5.5 were enrolled at 56 centers worldwide. Patients were randomly assigned to receive subcutaneous interferon beta-1a (Rebif; Serono International SA, Geneva, Switzerland), 44 μg TIW, or intramuscular interferon beta-1a (Avonex; Biogen Idec, Cambridge, Mass), 30 μg 1 time weekly (QW) for a median of 62 weeks. At the completion of the comparative phase of the study, 299 (88%) of 339 patients originally randomized to the 44-μg TIW and 306 (91%) of 338 patients originally randomized to the 30-μg QW regimen continued to receive therapy. All patients were then offered the opportunity to receive the high-dose/high-frequency regimen for an additional interval, permitting an assessment of the impact of a change in therapy. The patients continuing the 44-μg TIW regimen from the start of the study provided a concurrent assessment of no change in treatment. Approval was obtained from the institutional review boards or ethics committees of all participating institutions before study continuation, and written informed consent was obtained from all patients before continuing beyond the transition visit.

PROCEDURES

The transition visit was the point at which patients completed their participation in the comparative phase of the study. At the transition visit, patients converting to the subcutaneous 44-μg TIW regimen underwent a complete neurological examination and proton-density T2-weighted MRI. Subsequent clinical assessments occurred every 24 weeks and as needed for relapse assessments. The MRI procedures were repeated at 12 or 24 weeks after transition (depending on the date of the last pretransition MRI) and then every 24 weeks. Although patients and examiners were not blinded to the initial treatment assignments after the transition, MRI assessments remained fully blinded. Blood samples were obtained every 12 weeks for hematologic, biochemical, and thyroid function testing and every 24 weeks for neutralizing antibody (NAb) titers as described previously.13 A relapse was defined as the appearance of a new symptom or worsening of an old symptom, accompanied by an appropriate objective change on results of the neurological examination that lasted at least 24 hours in the absence of fever and was preceded by at least 30 days of clinical stability or improvement. Corticosteroids (intravenous methylprednisolone sodium succinate, 1.0 g/d for 3 days) were permitted to treat relapses, and study-related MRI was performed before beginning methylprednisolone therapy or at least 7 days after the last dose. Magnetic resonance imaging was performed according to a protocol under the direction of the University of British Columbia MS/MRI Research Group.

OUTCOME MEASURES

The preplanned primary outcome measure was the annualized relapse rate, comparing the within-patient change from the 24-week interval immediately prior to transition to the posttransition interval. The group continuing the 44-μg TIW regimen from the start of the study served as a reference point for outcomes in patients with no change in therapy in addition to providing further data on safety and immunogenicity of interferon. The proportion of patients remaining free of relapses during weeks 0 to 24 of the comparative phase compared with the posttransition interval was a secondary outcome measure.

Preplanned secondary MRI end points included pretransition to posttransition change in the number of new, enlarging, or reappearing lesions on T2-weighted MRI (hereafter referred to as T2 active lesions) per patient per scan, the proportion of T2 active scans per patient, and the proportion of patients without T2 active scans. All MRI analyses were performed by radiologists unaware of treatment allocation in the University of British Columbia MS/MRI Research Group.

The effect of NAb on relapse and MRI measures was assessed by comparing subgroups with (NAb+) and without (NAb−) NAb, with NAb positivity defined as a value of at least 20 neutralizing U/mL at any time. The NAb assays were performed in the same manner before and after the transition.10

Safety evaluations included the recording of new-onset adverse events, withdrawals due to adverse events, serious adverse events, and monitoring of laboratory abnormalities after transition. Grading of laboratory abnormalities was based on the World Health Organization (WHO) system, in which grade 1 of elevated alanine aminotransferase (ALT) levels is less than 2.5 times the upper limit of the reference range (ULR); grade 2 is 2.5 to 5 times the ULR; and grade 3 is 5 to 20 times the ULR. For white blood cell count, grade 1 is below normal but greater than 3 × 103/μL, grade 2 is greater than 2 × 103/μL but no more than 3 × 103/μL, and grade 3 is more than 1 × 103/μL but no more than 2 × 103/μL.

STATISTICAL CONSIDERATIONS

Analyses were performed on all patients who entered the posttransition phase. Statistical tests were 2 sided and were performed at the 5% significance level. Demographic and disease characteristics at transition were presented by treatment group. The annualized relapse rate was derived by dividing relapse count by time in the study (in years) and analyzed using the Wilcoxon signed rank test to compare pretransition and posttransition rates within treatment groups. We compared between-group and within-group pretransition to posttransition changes using 2-sided Wilcoxon rank sum tests. Each of the other continuous efficacy end points was analyzed using similar methods. The proportions of patients remaining relapse free and without T2 active lesions were summarized by period for each treatment group and analyzed using the McNemar test for a significant pretransition to posttransition distribution shift within each treatment group.

Outcomes based on NAb status were analyzed in the same fashion as overall analyses. To determine whether longer observation would alter conclusions regarding the impact of NAb development on efficacy, we performed a secondary analysis including only patients in the study for at least 72 weeks.

All patients who entered the posttransition interval were included in the safety analyses. Patients withdrawing prematurely from the study were listed and summarized by the primary reason for withdrawal for each treatment group.

We performed all analyses using SAS software, version 6.12 (SAS Institute, Cary, NC), and P<.05 denoted statistical significance.

PATIENT DISPOSITION AND BASELINE CHARACTERISTICS

Of 605 patients still receiving therapy at the end of the comparative phase of the EVIDENCE Study, 272 (91%) of the 299 receiving subcutaneous interferon beta-1a, 44 μg TIW, and 223 (73%) of the 306 receiving intramuscular interferon beta-1a, 30 μg QW, entered the posttransition phase (Figure 1). Patients from 6 centers (25 patients originally randomized to 44 μg TIW and 22 randomized to 30 μg QW) did not participate in the posttransition phase of the study. Patients otherwise deciding not to continue included 2 in the group originally randomized to the 44-μg TIW regimen and 61 in the group randomized to the 30-μg QW regimen. In the original study, 2 sites did not conduct MRI, such that 27 of 677 patients never underwent MRI. Of the 495 patients continuing after the transition, 67 patients (n = 34 for 44 μg TIW and n = 33 for 30 μg QW) had missing MRI films or had unusable films owing to imager change or imaging errors.

Place holder to copy figure label and caption
Figure 1.

Patient disposition during the EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) Study. Transition marks the end of the comparative study, at which time patients receiving the 30-μg regimen 1 time weekly (QW) could switch to the 44-μg regimen 3 times weekly (TIW), and those receiving the 44-μg TIW regimen from study start could continue it.

Graphic Jump Location

Comparisons between patients entering and not entering the posttransition phase are shown in Table 1. In the group originally randomized to the 30-μg QW regimen, patients not entering the posttransition phase were more likely to be relapse free and had a lower pretransition relapse count compared with those converting to higher-dose therapy. Looked at differently, 98 (68%) of 145 patients who were relapse free before the transition converted to the 44-μg TIW regimen compared with 125 (78%) of 161 who were not relapse free. Despite these differences in clinical measures, there were no differences in pretransition T2 active lesions between these 2 groups (Table 1).

Table Graphic Jump LocationTable 1. Demographic and Disease Characteristics by Treatment Group at Transition*

The median posttransition time in the study was 34 weeks (range, 0.1-45 weeks) and was almost identical for both treatment arms, as was all pretransition and posttransition time in the study (median, 96 weeks; range, 56-128 weeks).

EFFICACY

Patients converting from the 30-μg QW to the 44-μg TIW regimen had a 50% relative reduction in relapse rate (Figure 2 and Table 2) when the immediate 24-week pretransition interval was compared with the posttransition interval (P<.001). The group continuing the 44-μg TIW regimen also had a reduction in relapse rate (26%; P = .03). The change in relapse rates was greater in patients changing from the lower-dose to the higher-dose, more frequently administered interferon regimen than those receiving that regimen from the study start (P = .047).

Place holder to copy figure label and caption
Figure 2.

Annualized relapse rate for patients continuing treatment after the transition comparing within-patient rates during the pretransition interval with those during the posttransition period. The change in relapse rate is significantly greater for patients changing their dosage regimen than for those continuing the regimen unchanged (P = .047). QW indicates 1 time per week; TIW, 3 times weekly.

Graphic Jump Location
Table Graphic Jump LocationTable 2. Outcome Measures Based on Comparison Between Pretransition Interval and Posttransition Interval*

In patients converting from the low-dose QW interferon regimen, 180 (81%) of 223 remained relapse free during the interval after they initiated high-dose/high-frequency therapy. For those continuing the 44-μg TIW regimen from the start of the study, 223 (82%) of 272 remained relapse free after the transition.

The MRI outcome measures are presented in Table 2. Similar to relapse outcomes, MRI posttransition outcomes improved significantly in patients converting from the 30-μg QW to the 44-μg TIW regimen (P = .02), but not in patients continuing the 44-μg TIW regimen from the original randomization (Table 2). Again, the between-group difference significantly favored patients switching from low-dose to high-dose/high-frequency therapy (P = .02). As patients converted to high-dose/high-frequency treatment, T2 active lesions and the proportion of active scans per patient decreased, but the proportion of patients without active scans did not change.

NEUTRALIZING ANTIBODIES

Of the 495 patients continuing after the transition, 487 had NAb data available in both the pretransition and posttransition phases. In the pretransition period, NAb developed in 3 (1%) of 219 converting patients. During the posttransition phase, NAb developed in 12 additional patients after starting 44-μg TIW therapy, and no seroreversion occurred, leaving 7% of the patients NAb+ at the end of the study. For patients continuing the 44-μg TIW regimen from the original randomization, NAb developed in 72 (27%) of 268 before the transition; 60 (22%) were still NAb+ at the transition. During the posttransition phase, NAb developed in 5 additional patients, and seroreversion to NAb− status occurred in 14, leaving 63 (24%) of 268 NAb+ at the end of the study. Considering all patients randomized to the 44-μg TIW regimen from the start of the study, 74 of 336 (22%) were NAb+ at their last assessment.

Outcomes based on NAb status demonstrated no significant impact on relapses in either group, but NAb− patients had fewer T2 active lesions (P<.001) (Table 3). A sensitivity analysis, including only patients receiving therapy for at least 18 months, provided similar results.

Table Graphic Jump LocationTable 3. Outcome Measures Based on NAb Status*
SAFETY AND TOLERABILITY

Treatment was generally well tolerated in both groups, although more patients changing to high-dose/high-frequency treatment stopped therapy for adverse events (13 patients vs 2 patients). Principal causes for stopping therapy were injection site pain (n = 2), injection site inflammation (n = 2), elevated liver enzyme levels (n = 3), and influenzalike symptoms (n = 2). Skin necrosis was reported in 3 patients, none of whom required treatment discontinuation or plastic surgery. Patients converting to the 44-μg TIW regimen, compared with their time receiving the 30-μg QW regimen, also experienced new or worsening adverse events involving injection site reactions and asymptomatic liver and white blood cell abnormalities (Table 4), consistent with the higher dose and change in route of administration. New or worsening flu-like symptoms occurred infrequently after increasing the interferon dose and frequency. Of 758 new-onset events in converting patients, 71% were mild, 27% were moderate, 2% were severe, and 0% were very severe events, based on WHO classification guidelines. For continuing patients, of 483 new-onset events, 64% were mild, 34% were moderate, 2% were severe, and 0.2% were very severe. Twelve serious adverse events were reported in 10 (2%) of 495 patients, of which only asymptomatic grade 3 ALT level elevation (5-20 times ULR), was considered by the investigator to be related to interferon treatment.

Table Graphic Jump LocationTable 4. Proportions of Patients With New or Worsening Adverse Events Comparing Pretransition and Posttransition Intervals

Asymptomatic laboratory abnormalities (whether or not they were considered to be adverse events) were noted in both groups. Elevated ALT levels were noted in 52% of patients converting to the 44-μg TIW regimen, including 41% grade 1, 7% grade 2, and 4% grade 3. In patients continuing the 44-μg TIW regimen, 24% had elevated ALT levels, including 22% at WHO grade 1 and 2% at WHO grade 2. These proportions were lower than those observed when interferon-naive patients initiated 44-μg TIW therapy at the start of the study (65% total) but higher than when patients initiated therapy at 30 μg QW (41% total).10,11 The most common white blood cell abnormality was leukopenia, noted in 22% of patients converting to the 44-μg TIW regimen (14% grade 1, 7% grade 2, and <1% grade 3) and in 13% of patients continuing it (10% grade 1, 2% grade 2, and <1% grade 3). As with ALT abnormalities, these proportions were lower than those observed when interferon-naive patients initiated the 44-μg TIW regimen at the start of the study (27%) but higher than those when patients initiated the 30-μg QW regimen (9%) at the start.

Of patients converting from the 30-μg QW to the 44-μg TIW regimen, 13 (5.8%) stopped therapy because of adverse events during the posttransition phase.

The randomized, controlled, assessor-blinded comparative phase of the EVIDENCE Study demonstrated significant benefits on relapse and MRI measures of disease activity in patients with relapsing MS receiving interferon beta-1a, 44 μg TIW compared with 30 μg QW, during an average of 64 weeks.10,11 The posttransition extension of the EVIDENCE Study, during which all patients received the 44-μg TIW regimen, provides supportive data demonstrating that patients converting from 30 μg QW to 44 μg TIW achieve significant reductions in relapse rate and T2 lesion activity with the increasing interferon beta-1a dose and frequency. Patients switching to 44 μg TIW showed a 50% reduction in relapse rate after the change in therapy. Patients continuing on therapy also experienced a reduction in relapse rate, suggesting that a component of the observed rate reduction is due to either the natural history of the disease or a regression to the mean. Nevertheless, the reduction in relapse rate was significantly greater (50% vs 26%) in the group switching therapies, indicating that switching to high-dose/high-frequency therapy had a clinical impact over and above any effect of these considerations. Similarly, the MRI outcomes in the posttransition period improved significantly in patients switching from 30 μg QW to 44 μg TIW, but not in patients continuing to receive 44 μg TIW, and again, the between-group difference favored the group switching to high-dose/high-frequency therapy.

We must consider the possible impact of methodological limitations on the conclusions drawn from these results. In the posttransition phase, all patients received 44 μg TIW and, consequently, clinical assessors were aware of their treatment assignments. Furthermore, at transition, all study participants were informed of the results of the comparative phase of the EVIDENCE Study. Both aspects could potentially bias the posttransition clinical assessments. However, the fact that clinical observations are consistent with the blinded MRI results supports the claim of the enhanced efficacy of the 44-μg TIW regimen. In addition, the posttransition relapse rates and the proportions who were relapse free for both groups are virtually identical, further suggesting the lack of any systematic bias in the study.

Dropouts at transition might also have affected our results. On average, patients receiving the 30-μg QW regimen who chose to convert to 44 μg TIW had a higher pretransition relapse rate and were less likely to be relapse free compared with those who chose to discontinue the study (Table 1). This is not surprising because it is expected that patients who are doing well receiving low-dose weekly interferon would be less motivated to change therapy than those with active disease.

Bias could work 2 ways in this setting. Patients with ongoing active disease receiving low-dose therapy might be resistant to interferon therapy in general, biasing against seeing a difference once therapy was changed. On the other hand, such patients may also have greater potential to show improvements than those with less active disease.

Patients converting to high-dose/high-frequency interferon beta-1a therapy experienced an increase in interferon-related adverse effects. Most notable was an increase in injection site events consistent with the change in route of administration. The increase in asymptomatic laboratory abnormalities was modest, with little impact on adherence to therapy. No new safety findings were noted, and the proportions of patients in whom any new individual adverse event developed after conversion were generally less than 20%. The dropout rate due to adverse events in converting patients (5.8%) is consistent with findings in other studies using high-dose/high-frequency therapy and comparable to the rate seen in the EVIDENCE Study during the first year of therapy for interferon-naive patients (4.8%).10 The very low rate of adverse event dropouts in the continuing patients (<1%) demonstrates that once therapy continues beyond approximately 6 months, dropouts are rarely due to adverse events. This also suggests that educating patients and actively managing adverse effects in the early months of interferon therapy is crucial to long-term compliance.

The development of NAb during the first 32 weeks of high-dose therapy after approximately 64 weeks of low-dose therapy (5.6%) appears less than in patients who were naive to interferon, as seen in the first phase of the EVIDENCE Study (15% by week 24). This could have several possible explanations, including biological variability in different patient groups, differential impact of dropouts before transition, or induction of tolerance during low-dose therapy before conversion. Further prospective studies will be needed to address this.

For patients converting to high-dose/high-frequency therapy, development of NAb had little or no impact on MRI or clinical measures, although the follow-up interval was too short to provide complete information about NAb persistence and its impact on therapeutic effects. As reported previously,10 for patients continuing interferon therapy from the start of the EVIDENCE Study, the presence of NAb was associated with significantly higher MRI activity (P<.001), but not clinical activity, during the posttransition interval, again noting short follow-up. During the entire duration of treatment (average, 24 months) for patients receiving the 44-μg TIW dose from study start, again no significant difference was noted on relapse measures, whereas MRI activity was significantly greater for NAb+ compared with NAb− patients.

This study adds to data indicating that high-dose/high-frequency interferon beta-1a therapy (44 μg TIW) provides greater therapeutic benefit on relapse and MRI measures than a low-dose, less frequent (30-μg QW) regimen, regardless of whether therapy is used in interferon-naive patients or those already receiving therapy. Although the posttransition follow-up was relatively brief, these results suggest that increasing the interferon beta-1a dose and frequency can rapidly reduce ongoing disease activity in patients receiving low-dose weekly therapy. These findings are consistent with a growing body of literature on the interferon dose response from preclinical work, pharmacokinetic and pharmacodynamic data,13,14 and clinical trials.48,15

Box Section Ref ID

EVIDENCE Study Group and University of British Columbia MS/MRI Research Group

The EVIDENCE Study Group for the posttransition phase includes the following centers and investigators: United States: G. Garmany, P. Brownstone, and J. Lee (Alpine Clinical Research Center, Boulder, Colo); C. Blake, I. Chang, S. Gulevich, G. McIlvenna, L. McLaughlin, D. Shacklett, and D. Solsberg (Blake Neurology, Englewood, Colo); M. Kaufman, A. Dietrich, G. Evans, and B. Hawick (Carolinas Medical Center, Charlotte, NC); B. Hurwitz, V. Chilukuri, W. Davis, J. Hurwitz, R. Link, J. MacFall, J. Morgenlander, L. Poole, J. Provenzale, M. Rozear, and S. Wyne (Duke University Medical Center, Durham, NC); M. Picone, C. Finn, D. Habif, S. Kamin, and B. Johnson (Gimble MS Center at Holy Name Hospital, Teaneck, NJ); C. Markowitz, L. Balcer, L. Desiderio, and M. Mills (Hospital of the University of Pennsylvania, MS Center, Philadelphia); D. Mattson, J. Fleck, L. Hayward, C. Hingtgen, D. Jackson, and M. Phillips (Indiana University Medical Center, Indianapolis); J. Rosenberg, A. Blumenfeld, R. Glass, V. Harkins, R. Kaplan, H. Noack, G. Tsukada, and P. Viens (Kaiser Permanente, San Diego, Calif); A. Miller, M. Charny, E. Drexler, H. Elinzano, C. Fraser, M. Keilson, L. Morgante, W. Tse, and R. Wolintz (Maimonides Medical Center, Brooklyn, NY); B. Weinshenker, A. Adams, M. Botten, B. Erickson, C. Lucchinetti, J. Noseworthy, and D. Raygor (Mayo Clinic Rochester, Rochester, Minn); J. Carter, J. Buckner, R. Caselli, D. Dodick, K. Nelson, J. Takata, and D. Wingerchuk (Mayo Clinic Scottsdale, Scottsdale, Ariz); W. Tyor, L. Ambrose, and A. Walker (Medical University of South Carolina Multiple Sclerosis Center, Columbia); H. Rossman, W. Boudouris, D. Edds, S. Lawson, G. McDaniel, and S. Seidman (Michigan Institute for Neurological Disorders [MIND], Farmington Hills); J. Wendt, M. Hodges, J. Krikawa, J. Laguna, W. Sibley, and R. Wachter (Neurological Associates of Tucson, Tucson, Ariz); J. Simsarian, M. Monteferrante, L. Pansky, C. Saunders, and R. Stephenson (Neurology Center of Fairfax Ltd, Fairfax, Va); B. Apatoff, C. Filippi, E. Hong, I. Khan, C. Orapello, and J. Powell (New York Presbyterian Hospital, New York); K. Rammohan, D. Chakeres, S. Garner, and D. Lynn (The Ohio State University, Columbus); D. Bourdette, R. Frank, M. Mass, G. Nesbit, and J. Saunders (Oregon Health Sciences, Portland); L. Myers, R. Baumhefner, J. Bentson, S. Craig, and V. Gausche (University of California–Los Angeles Multiple Sclerosis Research and Treatment Program); P. Riskind, V. Brown, J. Knorr, M. Moonis, and A. Serio (University of Massachusetts Memorial Healthcare Center, Worcester); P. Coyle, M. Luongo, R. Mahnken, F. Reynolds, and S. Rizvi (University Hospital Medical Center, State University of New York at Stony Brook); S. Van den Noort, R. Dietrich, S. Niswonger, A. Semon, G. Thai, and J. Wrock (University of California–Irvine); D. Goodin, J. Cooper, W. Dillon, Jr, C. Luzzio, S. Massa, and K. Stanley (University of California–San Francisco); B. Arnason, R. Balabanov, E. Jamison, R. Ladsaria, A. Reder, P. Manning, S. Mojtahedi, and A. Noronha (University of Chicago Medical Center, Chicago, Ill); C. Bever, K. Henschel, F. Kursch, D. Lefkowitz, and H. Panitch (University of Maryland, Baltimore); C. Ford, M. Lebiednik, J. Maldonado, F. Rupp, and A. Schmitt (University of New Mexico Health Science Center, Albuquerque); G. Mitchell, M. Balog, and R. Heyman (University of Pittsburgh Medical Center, Pittsburgh, Pa); S. R. Schwid, W. Badger, A. Goodman, E. Scheid, B. Segal, and D. Shrier (University of Rochester, Rochester, NY); P. Dunne, S. Anderson, J. Gonzalez, and L. Murray (University of South Florida, Tampa); S. Brod, G. Bramlett, J. W. Lindsey, and J. Wolinsky (The University of Texas, Houston); J. Bowen, G. Garden, E. Kraus, N. Watson, and K. Maravilla (University of Washington Medical Center, Seattle); N. Kachuck, C. Cooper, J. Hermogino, M. Hijazin, S. Schreiber, S. Valencerina, and C. Zee (University of Southern California [USC] Multiple Sclerosis Comprehensive Care Center and USC University Hospital [MRI Group], Los Angeles); J. Rose, S. Baggaley, J. Burns, N. Carr, J. Klein, and K. Moore (Veterans Affairs Medical Center and University of Utah, Salt Lake City); H. Moses, R. Andal, R. Banks, and R. Kessler (Vanderbilt Stallworth Rehabilitation Hospital, Nashville, Tenn); A. Cross, T. Conturo, D. Derrington, G Foster, J. James, and J. Lauber (Washington University, St Louis, Mo); and T. Vollmer, A. Andersen, and M. Rizzo (Yale School of Medicine, New Haven, Conn). Europe: A. Compston, N. Antoun, I. Bjornson, M. Fraser, C. Pittock, and J. Thorpe (Department of Neurology, Addenbrookes Hospital, Cambridge, England); T. Berger, F. Deisenhammer, E. Dilitz, R. Egg, S. Felber, and A. Schuster (Department of Neurology and Institute of MRI and MRS, University of Innsbruck, Innsbruck, Austria); E. Mauch and F. Waechter (Fachklinik für Neurologie Dietenbronn GmbH Akademisches Krankenhaus der Universität Ulm, Ulm, Germany); M. Sharief and O. A. Seidi (Guy’s Hospital, London, England); R. Hohlfeld, P. Eppmann, N. Heydari, and S. Müller Schunk (Institute for Clinical Neuroimmunology and Department of Neurology, Klinikum Grosshadern, University of Munich, Munich, Germany); M. Färkkilä, M. Kallela, P. Keto, and M. Kuutti (Neurologian Klinikka HYKS, Helsinki, Finland); M. Sandberg-Wollheim, E.M. Larsson, K. Lennartsson, P. Nilsson, A. Risedal, and C. von Essen (Neurologkliniken Universitetssjukhuset, Lund, Sweden); J. Palace, A. Cavey, A. Cifelli, H. Moon, A. Parry, and G. Quaghebeur (Radcliffe Infirmary, Oxford, England); and C. Young, A. Dennis, B. Lecky, A.G. Marshall, D. Marshall, T. Nixon, L. Owen, D. Rogi, and D. Watling (Walton Centre for Neurology and Neurosurgery, Liverpool, England). Canada: G. Rice, T. Bentall, M. Hopkins, K. Kennedy, M. Kremenchutzky, and D. Lee (London Health Science Center, London, Ontario); Y. Lapierre, D. Arnold, W. Barkas, A. Bar Or, C. Hurst, S. Lafontaine, and R. Plesiak (Montreal Neurological Hospital, Montreal, Quebec); P. O’Connor, T. Gray, M. Laurel, and D. H. Selchen (St Michael’s Hospital, University of Toronto, Toronto, Ontario); J. Hooge, K. Chapman-Howard, L. Costley, V. Devonshire, M. Genton, S. Hashimoto, O. Hrebicek, L. Kastrukoff, D. Li, J. McCord, W. Morrison, J. Oger, S. Renneberg, C. Rieckhoff, T. Shaw, K. Smith, S. Spacey, and L. Zimmer (University of British Columbia, Vancouver); and L. M. Metz, D. Patry, W. F. Murphy, and M. Yeung (University of Calgary, Calgary, Alberta).

The University of British Columbia MS/MRI Research Group includes the following investigators: Y. Cheng, D. Li, D. Paty, A. Riddehough, B. Rhodes, X. Y. Wang, G. J. Zhao, and W. Zubyk.

Investigator Liaison Panel

P. K. Coyle, D. S. Goodin, P. O’Connor, H. Panitch, and B. Weinshenker.

Publications Committee

Steven R. Schwid (chair), M. Sharief, M. Sandberg, J. Thorpe, K. Rammohan, J. Wendt, H. Panitch, D. Goodin, P. Chang (statistician), G. Francis, and D. Li.

Correspondence: Steven R. Schwid, MD, Department of Neurology, University of Rochester, 601 Elmwood Ave, Box 605, Rochester, NY 14642 (steven_schwid@urmc.rochester.edu).

Accepted for Publication: November 5, 2004.

Group Information: A list of members of the EVIDENCE Study and University of British Columbia MS/MRI Research groups appears above.

Author Contributions:Study concept and design: Li and Francis. Acquisition of data: Schwid, Thorpe, Sharief, Sandberg-Wollheim, Rammohan, Wendt, Panitch, Goodin, Chang, and Francis. Analysis and interpretation of data: Schwid, Thorpe, Sandberg-Wollheim, Rammohan, Wendt, Panitch, Goodin, Li, and Francis. Drafting of the manuscript: Schwid, Goodin, and Francis. Critical revision of the manuscript for important intellectual content: Schwid, Thorpe, Sharief, Sandberg-Wollheim, Rammohan, Wendt, Panitch, Li, Chang, and Francis. Statistical analysis: Goodin and Chang. Obtained funding: Francis. Administrative, technical, and material support: Sharief, Wendt, and Francis. Study supervision: Rammohan, Li, and Francis.

Funding/Support: This study was supported by Serono International SA, Geneva, Switzerland.

Financial Disclosure: Drs Schwid, Thorpe, Sharief, Sandberg-Wollheim, Rammohan, Wendt, Panitch, Goodin, and Li have received research funding and honoraria from Serono International SA. Drs Chang and Francis are employees of Serono International SA, which sponsored the study.

Williams  GJ, Witt  PL.  Comparative study of the pharmacodynamic and pharmacologic effects of Betaseron and Avonex. J Interferon Cytokine Res. 1998;18:967-975.
PubMed
Stürzebecher  S, Maibauer  R, Heuner  A, Beckmann  K, Aufdembrinke  B.  Pharmacodynamic comparison of single doses of IFN-β1a and IFN-β1b in healthy volunteers. J Interferon Cytokine Res. 1999;19:1257-1264.
PubMed   |  Link to Article
Rothuizen  LE, Buclin  T, Spertinei  F,  et al.  Influence of interferon β-1a dose frequency of PBMC cytokine secretion and biological effect markers. J Neuroimmunol. 1999;99:131-141.
PubMed   |  Link to Article
IFNβ Multiple Sclerosis Study Group.  Interferon beta-1b is effective in relapsing-remitting multiple sclerosis, I: clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43:655-661.
PubMed   |  Link to Article
IFNB Multiple Sclerosis Study Group, University of British Columbia MS/MRI Analysis Group.  Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45:1277-1285.
PubMed   |  Link to Article
PRISMS Study Group.  Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352:1498-1504.
PubMed   |  Link to Article
Li  DK, Paty  DW.  Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-β1a in relapsing-remitting multiple sclerosis. Ann Neurol. 1999;46:197-206.
PubMed   |  Link to Article
PRISMS Study Group, University of British Columbia MS/MRI Analysis Group.  PRISMS-4: long-term efficacy of interferon-β-1a in relapsing MS. Neurology. 2001;56:1628-1636.
PubMed   |  Link to Article
Clanet  M, Radue  EW, Kappos  L,  et al.  A randomized, double-blind, dose-comparison study of weekly interferon β-1a in relapsing MS. Neurology. 2002;59:1507-1517.
PubMed   |  Link to Article
Panitch  H, Goodin  DS, Francis  G,  et al.  Randomized, comparative study of interferon β-1a treatment regimens in MS: the EVIDENCE Trial. Neurology. 2002;59:1496-1506.
PubMed   |  Link to Article
Panitch  H.  Differences between IFN beta-1A 44 mcg TIW and 30 mcg QW sustained to 16 months: final EVIDENCE results [abstract]. Int J MS Care. 2003;5:80.
Poser  CM, Paty  DW, Scheinberg  L,  et al.  New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983;13:227-231.
PubMed   |  Link to Article
Abdul-Ahad  A, Galazka  AR, Revel  M, Biffoni  M, Borden  EC.  Incidence of antibodies to interferon-β in patients treated with recombinant human interferon-β1a from mammalian cells. Cytokines Cell Mol Ther. 1997;3:27-32.
PubMed
Munafo  A, Trinchard-Lugan  II, Nguyen  TX, Buraglio  M.  Comparative bioavailability of recombinant human interferon beta-1a after intramuscular and subcutaneous administration. Eur J Neurol. 1998;5:187-193.
PubMed   |  Link to Article
Durelli  L, Verdun  E, Barbero  P,  et al.  Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359:1453-1460.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Patient disposition during the EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) Study. Transition marks the end of the comparative study, at which time patients receiving the 30-μg regimen 1 time weekly (QW) could switch to the 44-μg regimen 3 times weekly (TIW), and those receiving the 44-μg TIW regimen from study start could continue it.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Annualized relapse rate for patients continuing treatment after the transition comparing within-patient rates during the pretransition interval with those during the posttransition period. The change in relapse rate is significantly greater for patients changing their dosage regimen than for those continuing the regimen unchanged (P = .047). QW indicates 1 time per week; TIW, 3 times weekly.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic and Disease Characteristics by Treatment Group at Transition*
Table Graphic Jump LocationTable 2. Outcome Measures Based on Comparison Between Pretransition Interval and Posttransition Interval*
Table Graphic Jump LocationTable 3. Outcome Measures Based on NAb Status*
Table Graphic Jump LocationTable 4. Proportions of Patients With New or Worsening Adverse Events Comparing Pretransition and Posttransition Intervals

References

Williams  GJ, Witt  PL.  Comparative study of the pharmacodynamic and pharmacologic effects of Betaseron and Avonex. J Interferon Cytokine Res. 1998;18:967-975.
PubMed
Stürzebecher  S, Maibauer  R, Heuner  A, Beckmann  K, Aufdembrinke  B.  Pharmacodynamic comparison of single doses of IFN-β1a and IFN-β1b in healthy volunteers. J Interferon Cytokine Res. 1999;19:1257-1264.
PubMed   |  Link to Article
Rothuizen  LE, Buclin  T, Spertinei  F,  et al.  Influence of interferon β-1a dose frequency of PBMC cytokine secretion and biological effect markers. J Neuroimmunol. 1999;99:131-141.
PubMed   |  Link to Article
IFNβ Multiple Sclerosis Study Group.  Interferon beta-1b is effective in relapsing-remitting multiple sclerosis, I: clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43:655-661.
PubMed   |  Link to Article
IFNB Multiple Sclerosis Study Group, University of British Columbia MS/MRI Analysis Group.  Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45:1277-1285.
PubMed   |  Link to Article
PRISMS Study Group.  Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352:1498-1504.
PubMed   |  Link to Article
Li  DK, Paty  DW.  Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-β1a in relapsing-remitting multiple sclerosis. Ann Neurol. 1999;46:197-206.
PubMed   |  Link to Article
PRISMS Study Group, University of British Columbia MS/MRI Analysis Group.  PRISMS-4: long-term efficacy of interferon-β-1a in relapsing MS. Neurology. 2001;56:1628-1636.
PubMed   |  Link to Article
Clanet  M, Radue  EW, Kappos  L,  et al.  A randomized, double-blind, dose-comparison study of weekly interferon β-1a in relapsing MS. Neurology. 2002;59:1507-1517.
PubMed   |  Link to Article
Panitch  H, Goodin  DS, Francis  G,  et al.  Randomized, comparative study of interferon β-1a treatment regimens in MS: the EVIDENCE Trial. Neurology. 2002;59:1496-1506.
PubMed   |  Link to Article
Panitch  H.  Differences between IFN beta-1A 44 mcg TIW and 30 mcg QW sustained to 16 months: final EVIDENCE results [abstract]. Int J MS Care. 2003;5:80.
Poser  CM, Paty  DW, Scheinberg  L,  et al.  New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983;13:227-231.
PubMed   |  Link to Article
Abdul-Ahad  A, Galazka  AR, Revel  M, Biffoni  M, Borden  EC.  Incidence of antibodies to interferon-β in patients treated with recombinant human interferon-β1a from mammalian cells. Cytokines Cell Mol Ther. 1997;3:27-32.
PubMed
Munafo  A, Trinchard-Lugan  II, Nguyen  TX, Buraglio  M.  Comparative bioavailability of recombinant human interferon beta-1a after intramuscular and subcutaneous administration. Eur J Neurol. 1998;5:187-193.
PubMed   |  Link to Article
Durelli  L, Verdun  E, Barbero  P,  et al.  Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359:1453-1460.
PubMed   |  Link to Article

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