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J Neuroophthalmol 2001 December;21(4):292-295
Steven L. Galetta, MD
Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania.

JOURNAL OF NEURO-OPHTHALMOLOGY 2001;21:292-295

The Controlled High Risk Avonex® Multiple Sclerosis Study (CHAMPS) tested whether interferon beta la (Avonex®) treatment would benefit patients who had experienced a first acute demyelinating event involving the optic nerve, brain stem/cerebellum, or spinal cord, and who displayed MRI brain signal abnormalities that have previously predicted a high likelihood of future MS-like events. The study randomized 383 patients into an Avonex®-treated and a placebo-treated group; both groups received intravenous methylprednisolone 1 gm/d followed by prednisone 1 mg/kg for 11 days. The Avonex®-treated group demonstrated a 44% reduction in the 3-year cumulative probability of developing clinically definite multiple sclerosis (rate ratio 0.56, 95% confidence interval 0.38 to 0.8; P = 0.002). At 18 months, treatment with Avonex® was associated with a significant reduction of new T2 lesions, gadolinium enhanced lesions and T2 lesion volume. Among placebo-treated patients, 82% had developed a new subclinical MRI signal abnormality by the eighteenth month after study entry. Treatment benefit was observed irrespective of the qualifying event. The findings of this study support the efficacy of Avonex® therapy in significantly reducing the 3-year likelihood of future neurologic events and worsening of the brain MRI in patients with a first acute CNS demyelinating event.

Interferon beta 1-A (Avonex®) has demonstrated a beneficial effect in reducing disability and relapses in a group of patients with relapsing/remitting multiple sclerosis (8). The Optic Neuritis Trial (ONTT) has shown that patients with first-attack optic neuritis treated acutely with intravenous methylprednisolone have a reduced rate of developing future MS-like neurologic events within a two year follow-up period, (1,2) an effect most evident among patients with two or more white matter MRI signal abnormalities typical of MS. However, this beneficial effect proved to be short lived, as corticosteroid-treated and placebo-treated groups had a similar cumulative probability of developing multiple sclerosis by three years (3,4). Several other studies have demonstrated that patients with isolated acute demyelinating syndromes and brain MRI scans demonstrating multiple signal abnormalities are at high risk of developing clinically definite multiple sclerosis (CDMS) (5–7).

These findings provided the rationale to compare the effect of interferon beta 1-A (Avonex®) to placebo in a group of patients at high risk for the development of CDMS.

METHODS

The Controlled High Risk Avonex® Multiple Sclerosis Study (CHAMPS) was conducted at 50 centers across the United Stated and Canada (9). Patients ranged in age between 18 and 50 years and had had an acute isolated demyelinating event involving the optic nerve, spinal cord or brainstem/cerebellum. Each patient had at least two clinically silent brain MRI signal abnormalities greater or equal to 3 mm in diameter, one of which was periventricular or ovoid.

All patients received intravenous methylprednisolone 1 g per day for three days within 14 days of the onset of their neurologic symptoms. This was followed by an oral prednisone taper beginning with 1mg/kg for 11 days and ending with a 4-day oral taper (20mg, 10mg, 10mg, 10mg). Patients were randomized by the nature of their clinical events and number of T2 MRI signal abnormalities (2, 3–4, 5–7, >= 8). Patients in the first group were treated with a once-weekly intramuscular injection of interferon beta 1-A (Avonex®), while those in the second group were treated with placebo. Interferon therapy was initiated during the prednisone taper. All patients took acetaminophen for a twenty-four hour period after injection to minimize interferon-induced side effects. Compliance was monitored by review of patient diaries and counting of used vials. Each patient was examined by a “treating” and an “examining” neurologist. All physicians and patients were masked to treatment assignment. Patients were examined one month after treatment initiation and thereafter at six-month intervals. If a patient was not stable after the month one visit, a visit was scheduled at month two to document stability. The treating neurologist documented adverse events and new neurologic symptoms. The examining neurologist performed examinations without taking histories.

The primary outcome measure was the development of CDMS, defined by the appearance of new neurologic or ophthalmologic events or progressive neurologic deterioration. Events had to persist for at least forty-eight hours and be documented by neurologic examination. Progressive deterioration was defined as a 1.5-point or greater increase in the expanded disability status (EDSS) score relative to baseline. Patients were also considered to have reached the primary endpoint if neurologic worsening was observed at the month two visit. All outcomes were verified by a masked endpoint committee.

Serial brain MRI studies provided secondary outcome measures. T2-weighted and enhanced T1-weighted images were obtained according to a standard protocol at baseline (while the patient was taking oral prednisone) and at 6, 12, and 18 months after study entry for those still enrolled. MRIs were interpreted at a single reading center.

The study was scheduled to extend for three years, based on an estimated three-year rate of development of CDMS of 50% in the placebo-treated group. A treatment effect of at least 33% was anticipated, together with a 15% study withdrawal rate before the diagnosis of CDMS. The primary outcome was determined on an intent-to-treat analysis. All P values were two-tailed; Kaplan-Meier analysis was used to document treatment effect.

RESULTS

The study enrolled 383 patients between April 1996 and April 1998. There were 193 patients in the interferon beta 1-A group and 190 in the placebo group. Baseline characteristics were similar in the two groups (Table 1). The trial was terminated in March 2000 when a data monitoring committee determined that the primary outcome measure had been met with a P value of less than .029 (9). Despite a premature termination, all active patients remained enrolled for at least 22 months.

 TABLE 1. Baseline patient characteristics
 
Clinical findings

The cumulative probability of developing clinically definite multiple sclerosis was significantly lower in patients receiving interferon beta 1-A than in those receiving placebo (rate ratio .56, P = <.002, percent confidence interval .38 to .81) (Fig. 1). At the end of three years, the cumulative probability of CDMS was 50% in the placebo-treated group and 35% in the interferon 1-A-treated group. The treatment effect was slightly stronger (adjusted rate ratio = .49, P = <.001, percent confidence interval .33 to .73) when adjusting for age, type of presenting event, T2 lesion volume and gadolinium-enhancing lesions. There was no difference in treatment among patients presenting with optic neuritis, brain stem/cerebellar, or spinal cord events (P =.49). The diagnosis of CDMS was established by the occurrence of a second demyelinating event in all but five patients. One interferon beta 1-A-treated patient and two placebo-treated patients had an increase of the EDSS score by greater than 1.5 without an acute exacerbation. One placebo patient and one interferon beta 1-A were still progressing at the month two visit.

 FIG 1. Effect of interferon beta 1A (Avonex®) on the development of clinically definite multiple sclerosis (Kaplan-Meier analysis).
 
Brain MRI findings

Interferon beta 1-A-treated patients showed a significant treatment benefit at all intervals in a variety of brain MRI measures (Fig. 2, Fig. 3 and Fig. 4). Patients on active treatment had a lower T2 lesion volume (9% reduction, P < 0.001 at 18 months), decreased accumulation of new and enlarging T2 lesions (57% reduction, P = <0.001 at 18 months), and a reduced number of gadolinium-enhanced lesions (67% fewer at 18 months, P < 0.001). Treatment benefit was observed irrespective of baseline MRI T2 lesion number or volume.

 FIG 2. Effect of interferon beta 1A (Avonex®) on the development of new or enlarging T2 MRI signal abnormalities.
 

 FIG 3. Effect of interferon beta 1A (Avonex®) on the development of enhancing brain MRI signal abnormalities.
 

 FIG 4. Effect of interferon beta 1A (Avonex®) on the volume of brain MRI T2 signal abnormalities.

Follow-up data

The mean follow-up for active patients was 30.9 ± 4.9 months in the interferon 1-A-treated group and 30.6 ± 5.1 months in placebo-treated group. In the interferon-treated group, 16% of patients withdrew prior to study termination; in the placebo-treated group, 14% withdrew prematurely.

Adverse events

Influenza-like symptoms affected 54% of patients in the interferon-treated group and 26% in the placebo-treated group (P <.001). The only other side effect to reach statistical significance was depression, which was reported in 20% of the interferon-treated group and in 13% of the placebo-treated group (P =.05). There were no significant differences in laboratory test results between the two groups. Neutralizing antibodies were found in less than 1% of patients tested at 12 and 18 months and in 2% of those tested at 24 months. Therapy was discontinued by 19% of patients in the interferon-treated group, and by 15% in the placebo-treated group. The most common reason for discontinuation was “patient request”. Over 90% of patients were at least 80% compliant with study medication.

Implications

The CHAMPS study has shown that interferon beta 1-A reduces the conversion to CDMS in high-risk patients by approximately 50% (9). Even more compelling is the MRI data. New but silent MRI signal abnormalities appeared within 18 months in 82% in the placebo-treated patients who remained active in the study (Table 2). This finding indicates that a large number of such high-risk patients have ongoing silent demyelination. A prior longitudinal study of acute isolated demyelinating events had shown that the volume of MRI signal abnormalities at baseline is correlated with the degree of neurologic disability ten years later (5,6).

 TABLE 2. Comparison of T2 MRI signal abnormalities in Avonex-treated and Placebo-treated patient groups at 18 months after study entry
 
The CHAMPS trial suggests that Avonex® therapy significantly reduces the two-year likelihood of future neurologic events and worsening of the brain MRI in patients with a first acute CNS demyelinating event. It provides no information about the effect of Avonex® treatment on short-term disability or any long-term data on its effect on clinical relapses.

Future study

Further analysis of the CHAMPS data is ongoing. Treatment and MRI differences among the subgroups will be examined. For instance, did the number of MRI lesions at baseline predict increased risk for the development of CDMS? The CHAMPIONS Study (Controlled High Risk Avonex® Multiple Sclerosis Prevention Surveillance) will study the long-term effects and the factors associated with the development of CDMS. It will end in May 2003 when the last enrolled patient in the CHAMPS Study reaches the fifth anniversary of study entry.

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