THE CHAMPS STUDY Steven L. Galetta, MD Philadelphia, Pennsylvania

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1 THE CHAMPS STUDY Steven L. Galetta, MD Philadelphia, Pennsylvania INTRODUCTION The optic neuritis treatment trial (ONTI) confirmed the strong association between optic neuritis and multiple sclerosis by identifying those at highest risk for the development of recurrent demyelinating events. 1-3 For instance, those patients with three or more white matter lesions had a 51% chance of developing multiple sclerosis over the subsequent five years. 3 In contrast, those with normal MR scans only had a 16% chance of developing clinically definite MS over the same time period. The ONTI also demonstrated that those patients with optic neuritis treated with intravenous methylprednisolone had a. reduced rate of developing multiple sclerosis in a two year follow-up period. 2 This effect was most evident in those patients with three or more white matter lesions on their brain MRI. However, this beneficial effect was short lived and by three years all groups had a similar cumulative probability of developing multiple sclerosis. 4 T h e ONTT and several other studies have demonstrated that patients with isolated acute demyelinating syndromes and brain MRI scans demonstrating other demyelinating lesions were at high risk of developing clinically definite multiple sclerosis. 5-7 These findings provided the rationale to study interferon beta 1-A (Avonex) vs. placebo in a group of patients at high risk for the development of multiple sclerosis. Interferon beta 1-A had already demonstrated a beneficial effect in reducing disability and relapses in a group of patients with relapsing/remitting multiple sclerosis. 8 METHODS The controlled high risk Avonex multiple sclerosis study (CHAMPS) was initiated at 5 centers across the United States and Canada. 9 Each patient enrolled was between the ages of 18 to 5 and had an acute isolated demyelinating event involving either the optic nerve, spinal cord or brainstem/cerebellum. In addition, each patient had to have at least two clinically silent brain MR lesions which were greater or equal to 3 mm in size. One of these lesions needed to be periventricular in location or ovoid in shape. All patients received intravenous methylprednisolone 1 gram 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 lmg/kg for 11 days and ending with a 4 day oral taper (2mg, 1mg, Omg, lomg). Patients were randomized by the nature of their clinical events and number oft2lesions seen on their brain MRI scan (2, 3-4, 5-7, ~ 8) patients in one group were given a once a week intramuscular injection of interferon beta 1-A (Avonex) while the other group was given placebo. Therapy was initiated after the intravenous methylprednisolo!j.e pulse and during the oral prednisone taper. All patients took acetaminophen for a twenty-four hour period after injection to minimize interferon induced flu like sideeffects. Compliance was monitored by review of patient's diaries and counting of used vials. Each. patient was examined by a "treating" and "examining" neurologist. All physicians and the pati~nts were masked to treatment assignment. Patients were examined one month after treatment initiation and thereafter in six month intervals. If a patient was not stable after their month one visit, a visit was scheduled at month two to document stability. The treating neurologist would document adverse events and new neurologic symptoms. The examining neurologist only performed examinations without taking a history. The primary outcome measure was the development of clinically definite multiple sclerosis. This was defined by the appearance of new neurologic or ophthalmologic events or progressive neurologic deterioration. Patients had to have their symptoms for greater than forty-eight hours and documented by an examination. Progressive deterioration required a 1.5 greater or increase in their expanded disability status score (EDSS) from baseline. Patients were also considered to reach the primary endpoint if neurologic worsening was observed at the month two visit. All outcomes were verified by a separate masked endpoint committee. Serial brain MRI studies provided secondary outcome measures. T2 weighted and enhanced Tl weighted images were obtained per a standard protocol. These films were then sent to a single. reading center. Imaging was obtained at baseline, 6, 12, and 18 months for those remaining in the study. Baseline scans were obtained while the patient was taking oral prednisone. The study was scheduled to extend three years based on an estimated three year rate of CDMS (clinically definite multiple sclerosis) of 5% in the placebo group. A treatment effect of at least 33% was also anticipated. These calculations were made adjusting for a 15% withdrawal rate before the diagnosis of CDMS. The primary outcome was determined on an intent to treat analysis. All P values were t-tailed and a Kaplan-Meier analysis was used to document treatment effect. 159

2 RESULTS The trial was terminated in March of 2 after a data monitoring committee determined that the primary outcome measure was met with a P value of less then Despite an early termination of the study, all active patients completed at least 22 months. 383 patients entered the trial between April 1996 and April There were 193 patients in the interferon beta 1- A group and 19 in the placebo group. Baseline -characteristics were similar (table 1). The cumulative probability of developing clinically definite multiple sclerosis was significantly lower in patients receiving interferon beta 1-A compared to placebo (rate ratio.56, P=.2, percent confidence interval.38 to.81).(figure 1) At the end of three years, the cumulative probability of CPMS was 5% in the placebo and 35% in the interferon 1-A group. The treatment effect was slightly stronger (adjusted rate ratio =.49, P=<.1, percent confidence interval.33 to.73) when adjusting for age, type of presenting event, T2 lesion volume and gadolinium enhancing lesions. Furthermore, the treatment effect was statistically similar among subgroups (P=.49). In other words, the type of presenting event did not predict any better or worse outcome. The diagnosis of clinically definite multiple sclerosis was established by the occurrence of a second demyelinating event in all but five patients. One interferon beta 1-A patient and two placebo 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. BRAIN MR FINDINGS Interferon beta 1-A treated patients showed a significant treatment benefit at all intervals based on a variety of brain MR. measurements (figures 2-4). Those patients on active treatment have less T2 lesion volume (P<. 1 at 18 months), decreased accumulation of new and enlarging T2 lesions (P=<.OOl at 18 months) and reduced number of gadolinium enhanced lesions ( 67% lower at 18 months, P<.1). FOLLOW-UP DATA The mean follow-up for active patients was 3.9 ± 4.9 months for the interferon 1-A group and 3.6 ± 5.1 months for placebo group. 16% of patients withdrew early from the interferon group and 14% in the placebo group. ADVERSE EVENTS: 54% of patients in the nterferon beta 1-A group and 26% in the placebo group had flu-like side-effects (P<.1). The only other side effect to reach statistical significance was depression, which was reported in 2o/r of the interferon beta 1-A group and 13% in the placeb~ group (P=.5). There were no significant differences in laboratory tests between the two groups. Neutralizing antibodies were found in less than 1% of patients treated at 12 and 18 months and 2% of those tested at 24 months. Therapy was discontinued by 19% of patients in the interferon group and 15% in the placebo group~ In both groups, the most common reason for discontinuation was "patient request". Over 9% of patients were at least 8% compliant with their study medication.. IMPLICATIONS The CHAMPS study showed that interferon beta 1-A may reduce the conversion to multiple sclerosis in high risk patients by approximately 5%. 9 Even more compelling is the MR. data, 82% in the placebo group who remained active in the study showed new but silent MR. lesions by 18 months (table 2). This finding, mice again, emphasizes that many demyelinating lesions may go undetected clinically. In addition, it shows that a large number of high risk patients have ongoing demyelination. A prior longitudinal study of acute isolated demyelinating events showed that the amount of demyelinating disease seen op. initial MR predicted neurologic disability ten years later. 5 6 Furthermore, the amount of brain atrophy in the initial phases of the disease also predicts subsequent clinical outcome. 1 n The difference observed between the two treatment groups in the CHAMPS study highlights the importance of early therapy for multiple sclerosis. Although the CHAMPS study does not provide any long-term data about treatment effect, it stands to reason that reducing both the clinical and imaging abnormalities may produce prolonged benefit. In my limited experience to date, the vast majority ofhighrisk patients choose to initiate interferon therapy. The remaining patients opt. for serial MR. studies at. six month intervals. FUTURE STUDY Further analysis of the CHAMPS data is ongoing~ Treatment and MR differences among the subgroups will be examined. For instance, did.the number ofmr lesions at baseline provide increased risk for the development of CDMS? Furthermore, The CHAMPIONS Study (Controlled High Risk Avo~ex Multiple Sclerosis Prevention Surveillance) will study the long term effects and the factors associated with the development of CDMS. This study will end in May 23 when the last enrolled patient in the champs Study reaches their 5th year anniversary; 16

3 FIGURE! IFN~ - la (A VONEX ) REDUCED CDMS BY 44%.6 2 -» :!:::: :.c co.q a...1 Risk Ratio =.56 p =.2 AVON EX. 1 2 Year 3 Number of Patients at Risk AVONEX Placebo CHAMPS 7/ FIGURE2 NUMBER OF NEW OR ENLARGING T2 LESIONS D IFNP-1a (AVONEX ) 6 D Placebo 5... p =.1.Q E 4 p =.12 ::;, z 3 c co :E. 2 1 p < n=165 n=152 n=149 n=126 n=132 n= Months 161

4 FIGURE3 NUMBER OF ENHANCING LESIONS Number of Enhancing Lesions Months FIGURE4 CHANGE IN T2 LESION VOLUME D IFNP-1a (AVONEX ) p =.1 D Plac~bo p =.4.., 25 E 2 E 91% 15 -c p =.3 Reduction 11:1. 1 :s 5 :ie Months 162

5 TABLEt BASELINE PATIENT CHARACTERISTICS IFNJ3-1a (AVONE~) Placebo Characteristic n=193 n=19- Age (y) Mean±SD 33±8 33±7 Range Gender,% female Neurologic event,% Optic neuritis Brainstem syndrome 3 27 Spinal cord syndrome TABLE2 DISTRIBUTION OF NEW ENLARGING T2 LESIONS (18MONTBS) No. oflesions 1-3 >4 Avonex 47% 31% 22% Placebo 18% 4% 42% 163

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