IM interferon β-1a delays definite multiple sclerosis 5 years after a first demyelinating event

Patients.

All patients who initially participated in the CHAMPS Study (and could be followed at one of the participating CHAMPIONS study sites) were eligible to participate in CHAMPIONS, regardless of outcome or treatment during/after CHAMPS, if they met the following criteria: 1) completion of the 1-month follow-up visit in CHAMPS, 2) signed informed consent, 3) willingness to enroll in CHAMPIONS less than 5 years after CHAMPS enrollment, 4) no evidence of systemic disease with significant organ dysfunction or potential mortality within 3 years of CHAMPIONS enrollment, 5) no alternative neurologic diagnosis other than MS following enrollment in CHAMPS, and 6) no participation in another clinical trial of an investigational drug or device. Women receiving disease-modifying therapy who were unwilling to practice an effective method of contraception were excluded.

The protocol and informed consent forms were approved by the institutional review board at each study site, and all patients gave written informed consent.

Study design.

The planned treatment duration of CHAMPS was 3 years; however, the study was terminated early based on the recommendation of an independent data monitoring committee that reviewed a preplanned interim efficacy analysis. All patients in CHAMPS not reaching the study endpoint (CDMS) or withdrawing for other reasons were followed for at least 2 years before the final study closeout visit. These closeout visits were completed in March 2000. At that time, all patients were informed of the study results and offered participation in a safety extension study without knowledge of their treatment assignment during CHAMPS. Patients participating in the safety extension study received treatment with IFNβ-1a 30 μg IM once weekly.

CHAMPIONS is an ongoing, open-label, investigator-initiated extension study organized after completion of CHAMPS. Of the original 50 CHAMPS study sites, 32 agreed to participate. Patients were enrolled in CHAMPIONS between February 2001 and March 2003. All patients were offered, but not required to take, IFNβ-1a 30 μg IM once weekly at enrollment. Study visits occur every 6 months with additional urgent visits to evaluate relapses within 2 weeks of symptom onset. Because patients were enrolled in the CHAMPIONS Study at variable time points after randomization into CHAMPS, the study schedule was adjusted to allow for a uniform study visit 5 years following CHAMPS randomization. All patients were then placed on the same 6-month follow-up schedule. The last 5-year follow-up evaluation occurred in June 2003.

Study outcomes.

The primary outcome measure in CHAMPS and CHAMPIONS was CDMS. This was determined by review of suspected cases by an independent blinded outcomes committee that maintained the same members and outcome definitions as used in CHAMPS.

The following secondary outcomes in CHAMPIONS were determined by the unblinded site neurologist at 5 years: the number of confirmed relapses, disease course classification, and neurologic disability as measured by the Expanded Disability Status Scale (EDSS; conducted during a period of neurologic stability defined as no relapses or corticosteroid treatments in the previous 2 months). The following secondary outcomes were determined by the central MRI reading center (blinded to previous/current treatment): the number of new or enlarging T2 lesions and change in T2 lesion volume from CHAMPS baseline to 5 years and the percentage of patients with Gd+ lesions at 5 years.

Serious adverse events were monitored throughout the study.

Study drug.

IFNβ-1a (Avonex), a natural sequence, glycosylated, recombinant protein derived from Chinese hamster ovary cell line, was provided by Biogen Idec, Inc. IFNβ-1a was packaged as a lyophilized powder in vials containing 30 μg. Drug was administered by IM injection once weekly.

Concomitant medications.

The use of corticosteroids for the treatment of relapses and alternative disease-modifying therapies, including combination therapy with IFNβ-1a, was left to the discretion of the investigator. Investigational disease-modifying therapies were not allowed.

Statistical methods.

Statistical analysis of CHAMPIONS data was conducted as in the CHAMPS trial, as appropriate. Two-sided tests of significance were used; all analyses were conducted as intent to treat, with no correction for time on or off treatment. Kaplan–Meier rates of CDMS were calculated separately for the immediate treatment (IT) and delayed treatment (DT) groups and compared with the Mantel log-rank test, timed from month 1. Patients who did not reach CDMS were censored on the date of the last neurologic evaluation. Unadjusted and adjusted hazard ratios were determined from a proportional hazards model. A multivariate model was used to adjust for recipient age, clinical center, baseline brain MRI T2 lesion volume (log transformation), and the number of Gd+ lesions at baseline. Effect modification related to these factors was assessed with interaction terms in the model. Possible violations of the proportional hazards assumption were checked using time-dependent variables. Other outcomes were compared between the IT and DT groups using Fisher exact test or the Wilcoxon rank sum test as indicated. Because of the large number of statistical comparisons performed in the analysis, p values above 0.01 were not considered significant for the secondary outcomes.

Accounting of patients and treatments.

Of the original 50 CHAMPS study sites, 32 participated in CHAMPIONS. Only 1 of the 18 nonparticipating sites chose not to participate for reasons other than a lack of eligible patients. Fifty-three percent (203/383) of CHAMPS patients enrolled in CHAMPIONS (figure 1). Of these 203 patients, 28% (57/203) developed CDMS during CHAMPS, 6% (12/203) withdrew from the CHAMPS Study (but elected to return for CHAMPIONS), and 66% (134/203) completed the CHAMPS Study per protocol without CDMS. Participation in CHAMPIONS according to these three CHAMPS outcomes was similar comparing original randomization groups. An equal distribution of patients from the original CHAMPS IFNβ-1a (n = 100) and placebo groups (n = 103) enrolled in CHAMPIONS.

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Figure 1. Accounting of patients in Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance (CHAMPIONS). Three patients originally randomized at a non-CHAMPIONS site transferred to participate in CHAMPIONS. Patients on “alternative” therapy do not include those who received single-dose corticosteroids for treatment of relapse. Therapy at 5 years known for 198 patients (given retrospectively for 3 patients at a subsequent visit who missed the 5-year visit).

The 100 patients from the original CHAMPS IFNβ-1a group received IFNβ-1a immediately after onset of their first symptoms and thus are referred to as the “immediate treatment” (IT) group in CHAMPIONS. The 103 patients from the original CHAMPS placebo group initiated IFNβ-1a at the time CDMS developed or after the CHAMPS closeout visit and thus are referred to as the “delayed treatment” (DT) group. The median time to initiation of IFNβ-1a or the first disease-modifying therapy in the DT group was 29 months (25th, 75th percentiles: 23, 36) after CHAMPS randomization. Of 203 patients, 198 (98%) completed the 5-year or subsequent yearly visits per protocol (figure 1) and 195 (96%) patients completed their 5-year visits.

The majority of patients (93%) were receiving IFNβ-1a or no therapy at CHAMPIONS baseline; 154 patients (76%) were receiving IFNβ-1a, 14 patients (7%) an alternative therapy, and 35 patients (17%) no therapy (figure 1). Alternative therapies included IFNβ-1b, IFNβ-1a (Rebif, interferon β-1a; Serono, Inc., Rockland, MA), and glatiramer acetate. Similar proportions were observed at the 5-year visit.

Comparison of CHAMPS baseline characteristics for CHAMPIONS IT and DT groups.

Table 1 shows baseline demographic and clinical characteristics of all patients in CHAMPIONS, the IT group, and the DT group (original CHAMPS patients on IFNβ-1a and placebo). Overall, these comparisons suggest that the IT and DT groups were similar at entry into CHAMPS.

Primary outcome.

The cumulative probability of developing CDMS was lower in the IT group compared with the DT group at 5 years (36 ± 9 vs 49 ± 10%, unadjusted hazard ratio 0.65, 95% CI: 0.43 to 0.97, p = 0.03; figure 2). The treatment effect was stronger after adjusting for the potential confounding effects of age, CHAMPS qualifying event, CHAMPS baseline brain MRI T2 lesion volume, and baseline number of Gd+ lesions (table 2: adjusted hazard ratio 0.57, 95% CI: 0.38 to 0.86, p = 0.008). In this Cox proportional hazards model, a younger age at onset was associated with a higher rate of CDMS over 5 years independent of randomization group, qualifying event at onset, or CHAMPS baseline T2 lesion volume and Gd+ status.

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Figure 2. Kaplan–Meier estimates of the development rate of clinically definite multiple sclerosis (CDMS) in the immediate treatment vs delayed treatment groups in Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance (CHAMPIONS).

Additional clinical outcomes at 5 years.

The majority of patients (72%) in CHAMPIONS had relapsing-stable disease (table 3). In the IT group, a lower proportion of patients (19%) had relapsing-active disease, as reported at the 5-year visit, compared with the DT group (32%); however, this did not meet the 0.01 level of significance (p = 0.04).

At 5 years, very few patients had developed significant neurologic disability, as measured by the EDSS. The majority of patients (71%) had an EDSS score ≤1.5 points, 16% had an EDSS score from 2.0 to 2.5, and 13% reached an EDSS of at least 3.0. No significant differences were seen between the IT and DT groups in the distribution of EDSS scores.

Annualized relapse rates for different treatment epochs were calculated to determine if the reduction in relapses during the placebo-controlled phase of the study (i.e., during the first 2 years for the majority of patients) was sustained once patients given placebo were switched to active treatment. A reduction in annualized relapse rates comparing the IT with the DT group is observed between years 0 and 2 (0.15 ± 0.31 vs 0.31 ± 0.45; p = 0.004) and to a lesser extent over the entire 5 years (0.17 ± 0.24 vs 0.32 ± 0.51; p = 0.02). Between years 3 and 5, a period in which both groups were receiving treatment in equal proportions, annualized relapse rates remain reduced, although the differences does not reach the level of significance established for our secondary outcomes (0.18 ± 0.36 vs 0.32 ± 0.71; p = 0.28).

MRI outcomes at 5 years.

MRI measures included the number of new or enlarging T2 lesions over 5 years, change in T2 lesion volume over 5 years, and number of Gd+ lesions at 5 years. As shown in table 3, the median number of new or enlarging T2 lesions was lower in the IT group compared with the DT group (3.5 vs 6.0); however, this did not achieve the 0.01 level of significance. No significant difference in the change in T2 lesion volume from CHAMPS baseline to CHAMPIONS 5 years was seen when comparing the IT and DT groups, suggesting that any differences in T2 lesion number on MRI between the two groups are modest at 5 years. Percentages of patients with at least one and at least two Gd+ lesions were not different between the two treatment groups. This result is expected because equal proportions of patients were receiving a disease-modifying therapy at the time of the 5-year MRI scan.

Safety.

Thirteen serious adverse events occurred in 12 of the 203 patients on or within a month of discontinuation of IFNβ-1a therapy, including hospitalizations for MS relapses (n = 4), deep vein thrombosis (n = 1), infection/sepsis (n = 3), atrial fibrillation (n = 1), supraventricular tachycardia (n = 1), and a suicide attempt by overdose (n = 1). There was one hospitalization for elective plastic surgery (n = 1) and cervical cancer developed in one patient. Unblinded investigators considered all serious adverse events to be unlikely related or unrelated to the study drug. No new safety concerns with IFNβ-1a therapy arose during the CHAMPIONS Study.

Writing Committee.

Chair: R. Philip Kinkel, MD, Multiple Sclerosis Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Members: Craig Kollman, PhD, Jaeb Center for Health Research, Tampa, FL; Paul O’Connor, MD, University of Toronto, Toronto, Ontario, Canada; Thomas Jock Murray, MD, Center for Clinical Research, QE II Health Sciences Centre, Halifax, Nova Scotia, Canada; Jack Simon, MD, University of Colorado Health Sciences Center, Denver CO. Principal investigators: Douglas Arnold, MD, Montreal Neurologic Institute, McGill University, Montreal, Quebec, Canada; Rohit Bakshi, MD, Buffalo General Hospital, Buffalo, NY; Bianca Weinstock-Gutman, MD, Buffalo General Hospital, Buffalo, NY; Staley Brod, MD, University of Texas Health Sciences Center at Houston; Joanna Cooper, MD, East Bay Neurology, Berkeley, CA; Pierre Duquette, MD, Notre Dame Hospital, Montreal, Quebec, Canada; Eric Eggenberger, MD, Michigan State University, East Lansing; Warren Felton, MD, Virginia Commonwealth, Richmond; Robert Fox, MD, Cleveland Clinic Foundation, OH; Mark Freedman, MD, Ottawa General Hospital, Ontario, Canada; Steven Galetta, MD, University of Pennsylvania, Philadelphia; Andrew Goodman, MD, University of Rochester, NY; Joseph Guarnaccia, MD, Griffin Hospital, Derby, CT; Stanley Hashimoto, MD, University of British Columbia, Vancouver, Canada; Steven Horowitz, MD, University of Missouri–Columbia; Jeffrey Javerbaum, MD, California Kaiser Permanente; Lloyd Kasper, MD, Dartmouth Hitchcock, Lebanon, NH; Michael Kaufman, MD, Carolinas Medical Center, Charlotte, NC; Lawrence Kerson, MD, Neurology Group, Sewickley, PA; Michelle Mass, MD, Oregon Health Sciences Center, Portland; Thomas Jock Murray, MD, QE II Health Sciences Center, Halifax, Nova Scotia, Canada; Paul O’Connor, MD, University of Toronto, Ontario, Canada; Kottil Rammohan, MD, Ohio State University, Columbus; Merrell Reiss, MD, Beta Research Inc., Westmont, IL; Loren Rolak, MD, Marshfield Clinic, Marshfield, WI; John Rose, MD, Neurovirology Research Laboratory, Salt Lake City, UT; Thomas Scott, MD, Allegheny Neurologic Associates, Pittsburgh, PA; John Selhorst, MD, St. Louis University, MO; Robert Shin, MD, University of Maryland, Baltimore; Craig Smith, MD, Swedish Medical Center, Seattle, WA; William Stuart, MD, MS Center, Atlanta, GA; Stephen Thurston, MD, Neurologic Associates Inc., Richmond, VA; Michael Wall, MD, University of Iowa, Iowa City.