EDITORIAL: 52nd ANNUAL MEETING OF THE AMERICAN ACADEMY OF NEUROLOGY

Peter Riskind, MD, Department of Neurology, Umass Memorial, Worcester, Massachusetts

Data presented at the 52nd Annual meeting of the American Academy of Neurology highlighted the potentially different effects of interferon therapy initiated at the earliest recognizable stages of multiple sclerosis versus late in established disease. Previous studies with interferon beta-1b (Betaseron®) and interferon beta-1a (Avonex®, Rebif®1) have demonstrated a clearcut benefit of prophylactic therapy in patients with relapsing forms of multiple sclerosis. Interferon beta therapy reduces the number of flares and retards progression of disability, and also has significant inhibitory effects upon MRI indices of disease activity.

Patients with clinically isolated, monosymptomatic demyelinative episodes and multiple clinically silent brain MRI lesions are known to have high risk of developing definite MS within three to five years. Treatment with high-dose corticosteroids has been previously shown to delay, but not to prevent, the ultimate development of MS in such patients.

Two studies reported at this meeting have investigated the efficacy of interferon therapy in "high-risk" patients after a single demyelinative flare. The CHAMPS results suggest that treatment with Avonex® dramatically delayed (or in some cases, perhaps prevented) the development of clinically definite MS. Moreover, active treatment with Avonex® had an impressive effect upon MRI indices of disease activity. Importantly, all patients were given high-dose corticosteroids prior to treatment with Avonex® or the placebo. The dose of Avonex® used in this study was 30 ug/week, identical to the recommended dose in patients with relapsing MS. In contrast, patients in the ETOMS study received a substantially lower dose of Rebif®, 22 ug sc/week, about one-sixth of the usual effective dose in MS patients. Although the results are not as pronounced as in the CHAMPS study, the ETOMS study also demonstrated that early interferon therapy significantly delays the development of MS and has a positive impact upon MRI abnormalities. A key unanswered question is whether early prophylactic interferon therapy can completely prevent further episodes (and further disability) or if treatment only delays the next flare for a few years.

These encouraging results contrast with the results of interferon therapy in patients with secondary progressive MS. Previously, interferon beta-1b (Betaseron®) had been shown to effectively slow progression of disability in secondary progressive patients in a European trial. Unfortunately, the results of the North American Betaseron® trial and also of the SPECTRIMS study (with Rebif®) in patients with secondary progressive MS did not confirm any benefit of interferon therapy with regard to progression of neurologic disability. Post hoc analyses suggest that interferon therapy may be effective in secondary progressive patients who are younger, and have a shorter duration of progressive disease. Persistence of relapses may also be a favorable factor for responsiveness to interferon therapy, perhaps because interferons principally affect early inflammatory mechanisms associated with flares. Interestingly, MRI indices of disease activity (the number of enhancing lesions and various measurements of T2 lesion activity) were significantly benefited by interferon treatment in secondary progressive patients, despite lack of an effect on disability. This divergence between clinical and MRI effects of therapy suggests that the respective MRI indices may not reflect key contributors to disability late in the illness.

Progressive brain atrophy has recently been shown to be present in many patients with MS, and may correlate with, or predict disability better than conventional MRI indices of disease activity. Data presented at this meeting indicate that the brain parenchymal fraction (BPF) has a moderate correlation with disability (EDSS score) eight years later; moreover, patients with the least amount of brain atrophy at baseline had a substantially reduced risk of reaching an EDSS score of six, eight years later, as compared to patients with more brain atrophy. Similar predictive effects were presented regarding a multi-dimensional clinical outcome measure, the MS Functional Composite (MSFC), based on tests of ambulatory speed, arm/hand function, and cognitive ability. Importantly, there is a great deal of variability between individuals and none of these methods is yet able to reliably and accurately predict an individual patient's future rate of progressive disability.

Together with the results of interferon therapy in early versus late demyelinative disease, these results suggest that prophylactic therapy should be initiated early in the disease.

TREATMENT TRIALS

Late-Breaking News: Results of the CHAMPS Study of Interferon Beta-1a in Patients at High-Risk for Developing MS

Lawrence D. Jacobs, MD, Professor of Neurology, University of Buffalo, New York

Avonex® (interferon beta-1a, Biogen), given after the first demyelinating event can significantly reduce the proportion of patients progressing to clinically definite multiple sclerosis, according to late-breaking news reported at the American Academy of Neurology. Patients who received interferon beta-1a very early in their disease course had 43 percent fewer conversions to clinically definite disease within three years (p = 0.002).

The interim findings were considered positive enough to justify early termination of CHAMPS (Controlled High Risk Subjects Avonex® Multiple Sclerosis Prevention Study). Patients randomized to placebo will now be allowed to go on interferon beta-1a. The investigators noted that findings make a strong case for even earlier treatment with immunomodulating agents, rather than waiting for a clinically definite diagnosis.

Over 50 percent of patients with monosymptomatic demyelinative syndromes have clinically silent lesions on brain MRI at diagnosis, and over 80 percent of patients with multiple silent lesions will progress to clinically definite MS. CHAMPS was designed to determine if treatment after only one demyelinating event could reduce the rate of progression to clinically definite disease and the occurrence of subclinical abnormalities on MRI.

The study involved 383 patients, ages 18-50, from 50 sites in the U.S. and Canada. Study participants had experienced a first occurrence of an isolated, well-defined neurologic event suggesting demyelination, such as optic neuritis, a spinal cord syndrome, or brainstem/cerebellar syndrome. They also had to have had multiple lesions on MRI scans that were consistent with MS. These two conditions place persons at high risk for developing the disease.

Patients were randomized to either 30 micrograms of interferon beta-1a injected once a week for up to three years, or placebo. They underwent neurologic exams at least every six months during the study and had MRI scans at six, 12, and 18 months. New neurologic demyelinating events were tracked, a blinded neurologist determined EDSS scores, and adverse events and side effects were noted.

At the pre-planned interim analysis on January 31, 2000, an independent data and safety monitoring committee determined that active treatment achieved a statistically significant delay of onset of clinically definite MS, and the study was terminated. MRI measures also showed significant reductions in the development of new brain lesions, consistent with the clinical result.

Impressive Results with Avonex®-treated Group

By Kaplan-Meier analysis, about 50 percent of placebo patients progressed to clinically definite MS by three years, compared to about 35 percent of patients treated with interferon beta-1a, Dr. Jacobs reported.

"There are more placebo patients progressing and doing it at a faster rate than in the Avonex® arm, where there are fewer patients progressing and doing so at a slower rate. Treatment reduced the conversion to clinically definite MS by 43 percent (p = 0.002)," he observed.

Relative Risk of Clinically Definite MS (CDMS)

Avonex® Placebo Relative Month n %CDMS n %CDMS Risk 6 164 8% 146 17% 0.48 12 143 15% 131 23% 0.65 18 109 19% 94 32% 0.60 24 69 21% 56 38% 0.56

Dr. Jacobs remarked, "This is the first time such an effect has been shown in a group at high risk for definite disease. The 43 percent discrepancy is clearly an Avonex® effect, and the p value of 0.002 is an order of magnitude beyond the preplanned stopping point of 0.02."

One of the investigators, Philip Kinkel, MD, Medical Director at The Mellen Center for Treatment and Research at the Cleveland Clinic, commented on the findings. "Our recommendation has always been to treat early. But earlier is better than just early. The major message from this study is that the disease is active right from the first symptoms and should be treated right from the first symptoms."

Richard A. Rudick, MD, Professor of Neurology at The Mellen Center, commented on the CHAMPS findings in light of other studies showing less benefit in secondary progressive disease. " The data are pretty clear that there is a therapeutic effect when you treat early before you get to the stage where the interferons are disappointing. It will be important to follow these patients to see how well they do over time."

Henry F. McFarland, MD, Chief of Cellular Immunology, the National Institute of Health's Neuroimmunology Branch added, "The basic outcome of the study is what we would have predicted, and is consistent with the consensus that interferon treatment probably works best early on."

Study of Avonex® (Interferon Beta-1a): MRI Results

Jack H. Simon, MD, PhD, Professor of Radiology and Neurology and MRI Chief, University of Colorado, Denver

In the recently reported CHAMPS study, early treatment with interferon beta-1a not only reduced the rate of conversion to clinically definite MS, but also reduced the rate of subclinical brain abnormalities on MRI. In fact, all predetermined MRI measures, at all time points, were positive and significant in favor of early interferon beta-1a (Avonex®) treatment, reported Jack H. Simon, MD.

At all intervals (six, 12, and 18 months), treatment with interferon beta-1a reduced the accumulation of T2 hyperintense lesion volumes, decreased the accumulation of individual new and enlarging T2 lesions, and reduced the number and volume of gadolinium-enhancing lesions. The following comparisons demonstrate the magnitude of the treatment effects at 18 months:

Magnitude of Treatment Effects at 18 Months on Brain MRI

MRI Lesions Avonex® Placebo % Reduction p value Group Group Comparing Avonex® (n=135) (n=119) to Placebo Group

Mean number of 2.1 5.0 57% p<0.0001 new or enlarging T2 lesions

Change in T2 lesion 28 313 91% p<0.0001 volume [median mm3]

Mean number of 0.5 1.4 67% p<0.0001 enhancing lesions

Volume of 37 108 66% p<0.0001 enhancing lesions [median mm3]

At 18 months, 47 percent of interferon recipients had no new or enlarging T2 hyperintense lesions, compared with only 18 percent of placebo recipients. Twice as many placebo recipients had four or more lesions at all time points, he reported.

"Some patients in the placebo group at 18 months had no clinically definite MS events but [did have] up to 63 new or enlarging lesions," Dr. Simon added.

In addition to demonstrating a treatment effect on brain lesions, these data suggest that MRI studies can be used to monitor the course and response to treatment. "From years of experience, we've known that you can identify patients on the basis of their MRIs, and the trials now show this is reliable data," he told neurologists.

In a separate poster presentation, also based on the CHAMPS population, Dr. Simon presented interesting new MRI findings that suggest even the acute focal lesions of early disease may give rise to patterns indicative of secondary tract injury. Secondary tract injury has traditionally been considered a consequence of long-standing disease or the sequela of relatively fulminant MS in the brain and spinal cord.

Longitudinal brain MRI studies (3 mm, non-gapped conventional proton density and T2 weighted) showed, in the corticospinal tract, a pattern identical to that seen in Wallerian degeneration from cerebrovascular accidents, both by time course and signal intensity patterns. In the 385 cases reviewed, this pattern was established with longitudinal confirmation in five cases (1.3 percent) and without longitudinal confirmation in 16 cases (four percent).

The MRIs also revealed a transcallosal band pattern in 16 percent of cases at both baseline and at six months. In rare cases, this could be followed longitudinally after an acute, isolated focal classic MS-like lesion. The transcallosal band is a rectangular T2 hyperintense lesion crossing the corpus callosum, whose lateral border is a larger focal T2 hyperintense MS-like lesion. This pattern may be the imaging counterpart explaining opposite hemisphere abnormalities, Dr. Simon explained.

"We believe these imaging patterns are suggestive of tract injury, and as they can be subtle, they have been largely underestimated," he commented.

Betaseron® (Interferon Beta-1b) in Secondary Progressive MS: Clinical and MRI Results of a 3-Year Randomized Controlled Trial

Donald E. Goodkin, MD, Professor of Neurology, University of California School of Medicine, San Francisco

Results were presented at the late-breaking trials session regarding the use of Betaseron® (interferon beta-1b) in secondary progressive MS (SPMS).

On behalf of the North American Study Group on Interferon Beta-1b in SPMS, Donald E. Goodkin, MD, reported the lack of a treatment effect on the primary outcome measure-sustained progression of disability. However, a treatment effect did emerge for secondary clinical and MRI endpoints.

The North American trial aimed to extend the results of the previous European trial of Betaseron® by studying two dosing regimens and a second cohort of patients with SPMS.

The North American study included 939 subjects from 35 centers who met the following criteria: relapsing-remitting MS followed by a progressive course of at least six months duration; clinically and laboratory supported definite MS for two or more years; increase of one or more EDSS points during two years prior to study; at least one documented relapse after an established diagnosis; and EDSS scores from 3.0-6.5. Baseline demographics were similar among the groups.

Patients were randomly assigned to placebo (n = 308), interferon beta-1b eight MIU daily (n = 317), or five MIU/m2 (n = 314) every other day, subcutaneously. The dose average for these patients was 9.6 MIU, which is higher than the recommended dose. Patients were examined every 12 weeks and unenhanced MRI scans were obtained yearly for three years.

Additionally, a subgroup of 163 patients underwent gadolinium-enhanced MRI scanning monthly. Approximately 75 percent of the patients completed the study on assigned treatment, and mean time on study was about 1,000 days.

The primary outcome measure was time to progressive neurologic impairment as defined by a confirmed increase of at least 1.0 EDSS point (sustained) over baseline, or 0.5 EDSS points if the baseline EDSS was 6.0 or higher. Secondary outcomes were relapse rate, MRI activity and lesion burden, and change in a composite score of neuropsychologic testing.

"There was no evidence of a treatment effect with [both Betaseron® doses on] the primary outcome. This result was unaffected by the presence or absence of clinical relapses during the two years prior to or during the study. No treatment effect was evident as measured by mean change in EDSS from baseline to final examination or in the proportion of patients who experienced confirmed progression of EDSS," Dr. Goodkin reported.

Patients receiving the eight MIU dose had the most benefit in terms of number of patients relapsing, time to first relapse, relapse severity and duration, and need for treatment with systemic steroids. Both dosage groups experienced significant reductions in annual relapse rate versus placebo.

Treatment effects were also detected by most MRI measures of disease activity. Both interferon dosage groups experienced less annual progression of T2-weighted MRI lesion area. These treatment effects were also evident in the monthly scanning cohort, as measured by reductions in newly enhancing lesions, number of new T2 lesions, newly enlarging T2 lesions, persistently enhancing T2 lesions, and persistently enlarging lesions, he reported.

Dr. Goodkin commented that the lack of an effect on primary outcome was not known in this study, but the investigators have formulated three hypotheses. These pertain to the biology of MS-in particular, the spontaneous decline of new gadolinium-enhancing lesions in the secondary progressive phase, so that treatments that target these lesions may be ineffective at this point; the possible variability in EDSS scoring; the relative lack of progression in the North American placebo recipients (35 percent) compared to the European cohort (50 percent); and the possibility that chance alone played a role.

Henry F. McFarland, MD, of the NIH, provided commentary regarding the divergent results of the North American and European trials of interferon beta-1b in SPMS, speaking on behalf of the steering committees and data and safety monitoring committees of the two trials.

By Kaplan-Meier analysis, there was a significant treatment effect on primary outcome in the European study (p = 0.0008), but a lack of treatment effect in the North American study. However, by secondary endpoints the studies are actually similar, he noted. Both found reductions in relapse rate, gadolinium-enhancing lesions, and T2 lesion load. "These are factors that we know are affected by interferon treatment and that probably represent a very early inflammatory component of lesion development," he said.

"But in terms of primary outcome, why were these trials different? We don't know for certain, but I think there are clues," he added.

Biological difference is the most likely explanation for the divergent results, he said. Although both studies required a documented history of SPMS, the European study was possibly skewed toward patients with more relapsing characteristics; in addition, European patients were slightly younger and had a shorter duration of MS and SPMS, and had more gadolinium-enhancing lesions and more active scans at entry.

In the placebo population, among patients without prior relapse, 43 percent of the European patients went on to have relapses during the study, compared to only 26 percent of the North American population, he added.

"But while there are clear differences in the biological properties of the two populations, we cannot identify any one feature that differentiates a responder from a nonresponder," he pointed out. "Based on the characteristics of the European study population, the consistent treatment effect on progression in this cohort, and on our understanding of the disease process, it is likely that interferon beta is effective in patients with secondary progressive disease who continue to have an inflammatory component to their disease progression," he said.

Like the Rebif® SPECTRIMS study, this study indicates a lack of dose to treatment effect in patients with secondary progressive MS.

Rebif® (Interferon Beta-1a) in Patients with Acute Neurological Syndromes Suggestive of MS

Giancarlo Comi, MD, Professor of Neurology, University of Milan, Italy, and the ETOMS Study Group

Very early treatment with Rebif® (interferon beta-1a) in a 22 mcg dose administered subcutaneously once a week, reduced disease activity, both clinically and by MRI parameters, in a randomized Phase III trial reported by Giancarlo Comi, MD, on behalf of the Early Treatment of Multiple Sclerosis (ETOMS) study.

While this very low dose is now known to be less effective in modifying the relapse rate of patients with already established relapsing-remitting MS, the study showed that 22 mcg may be preventive before the onset of clinically definite MS (CDMS), Dr. Comi said.

Their multi-center study aimed to evaluate efficacy of interferon beta-1a in preventing progression to clinically definite MS after the first suggestive neurological episode. The population included 308 patients who were less than three months from their first attack and whose MRI was strongly suggestive of MS. Baseline parameters were similar between patients receiving interferon beta-1a and those receiving placebo. Eighty two percent of patients originally randomized to interferon beta-1a completed two years of therapy, compared to 74 percent of placebo-treated patients.

Of the placebo-treated patients, 45 percent converted to CDMS, compared to 34 percent of the Rebif®-treated group. This corresponds to a 24 percent (p = 0.047) reduction in risk of conversion to CDMS. Furthermore, time to conversion was significantly longer in the interferon group: 533 days versus 251 for placebo (p = 0.034), he said.

Treatment with Rebif® also reduced the annual relapse rate by 23 percent (p = 0.045), from 0.43 to 0.33. Furthermore, the relative reduction in T2 activity was 44 percent in year one (p < 0.001), 27 percent in year two (p < 0.05), and 38 percent overall (p < 0.001). (The reduction was probably less in the second year because one quarter of patients converted to active treatment.)

Interferon also improved the burden of disease, as indicated by change in lesion load on MRI. In year one, MRI change was +6 percent in placebo recipients and -6 percent in interferon-treated patients; in year two, the changes were +9 percent and -13 percent (p = 0.002).

To conclude, Dr. Comi stressed the importance of very early treatment in suspected MS. "Almost all patients converted. 'Benign' cases are much in the minority," he remarked.

The results of the study are less pronounced than the CHAMPS results. The results do, however, indicate the importance of early interferon beta treatment in patients with high risk from developing MS. The effect of 22 ug (MIU) Rebif® used in ETOMS strongly contradicts the lack of effect seen with the same dose administered once a week subcutaneously in the OWIMS study.

Combination Therapy with Interferon Beta-1a plus Oral Methotrexate

Peter A. Calabresi, MD, Assistant Professor of Neurology, Brown University, Providence, Rhode Island

Preliminary results from an open-label study by Brown University investigators suggested that the combination of interferon beta-1a (Avonex®) and oral methotrexate (20 mg weekly) might reduce disease activity in patients who have clinically significant exacerbations, in spite of immunomodulating therapy, said Peter A. Calabresi, MD.

The combination actually reduced gadolinium-enhancing lesions by 50 percent, reported Dr. Calabresi, who commented, "To show a 50 percent reduction in lesions in ten patients and have this become statistically significant is quite good. I was actually surprised at how effective this combination was." According to reports by Goodkin and colleagues, interferon beta-1a reduces exacerbations and slows progression in relapsing forms of MS, while methotrexate preserves upper extremity function in SPMS and also may reduce activity on MRI. Methotrexate is a commonly prescribed drug for rheumatoid arthritis and psoriasis.

"It stands to reason, therefore, that methotrexate might be effective in the earlier stages of the disease, when there is more inflammation," Dr. Calabresi suggested. "Combination therapies have been effective in many other diseases, and we need to consider this possibility in MS."

Some clinicians are already using the combination of interferon beta-1a and methotrexate; however, it has not been formally evaluated for safety and tolerability, which served as the primary outcome measure in this pilot study. A secondary outcome measure was its effect on gadolinium-enhancing lesions.

Dr. Calabresi reported preliminary results in ten relapsing-remitting patients (of 15 enrolled) who had experienced at least one clinical exacerbation and at least two gadolinium-enhancing lesions despite receiving Avonex® for at least one year. Mean baseline characteristics were as follows: age of 39, EDSS of 2.35, number of exacerbations in the last year of 1.27, duration of disease of nine years, and time on Avonex® of 2.2 years.

The combination was tolerable, though all patients experienced some nausea and one patient could not tolerate more than ten mg weekly of methotrexate. One patient developed oral ulcers, which responded to a temporary dose reduction. There have been no serious adverse events to date.

After six months on combination therapy, several measurements suggested trends toward improvement. While on the combination, patients experienced fewer exacerbations. Total number of exacerbations in the six months prior to the study was eight, which decreased to three during the six months of the study. Exacerbations requiring steroids were reduced from three to zero.

The MS Functional Composite showed a nonsignificant trend toward improvement, and there was no worsening in mean EDSS. Patients also reported feeling better, he added. "Some patients came off their symptomatic treatments for depression, spasticity, and so forth."

Most importantly, a significant treatment effect was noted on triple-dose gadolinium scans (three mm slices), which demonstrated a 50 percent reduction in contrast-enhancing lesions, from a mean of 5.03 to 2.74 with combination therapy (p = 0.0486), Dr. Calabresi reported.

"On Avonex® alone, patients had quite a range of enhancing lesions, from a few to as many as 17. On combination therapy, there was a significant reduction in lesions, with most patients having five or fewer. Most large lesions virtually disappeared," he observed.

PREDICTORS OF DISEASE PROGRESSION

The Use of Brain Parenchymal Fraction for Predicting MS Disease Progression

Elizabeth Fisher, PhD, The Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Ohio

The rate of brain atrophy, as measured by changes in the brain parenchymal fraction (BPF) over two years, is an independent predictor of EDSS status six to eight years later. Results reported by Mellen Center researchers support the use of BPF as a surrogate marker in early disease. This information expands on data presented by Mellen Center researchers at the 1999 Academy meeting.

Last year, Richard Rudick, MD, reported that BPF is initially lower in relapsing-remitting patients than in normal controls, and that it decreases over two years. He added that there is a high degree of individual variability in the progression rate of atrophy. While some patients show no measurable atrophy changes, others demonstrate significant changes in BPF. The question arose as to the importance of atrophy, and whether it was related to current and subsequent levels of disability in relapsing-remitting MS.

Elizabeth Fisher, PhD, presented a multi-site follow-up study of patients who participated in the Phase III Avonex® trial for at least two years. Patients were evaluated at a mean of 8.1 years after the initiation of the study. BPF was calculated automatically for all MRIs using software developed at the Cleveland Clinic. Baseline BPF was compared to follow-up EDSS to determine its predictive validity. Follow-up evaluation was possible for 160 of the original 172 patients.

"Again, we saw a great deal of variability between individuals," she reported. "Some patients did not progress in atrophy, whereas others showed a great deal of progression." Mean baseline BPF was 0.850, whereas follow-up BPF was 0.839. Mean EDSS score at baseline was 2.3; at eight-year follow-up, 57 patients (35 percent), had reached EDSS of six or greater, she reported.

The relationships between BPF and EDSS at baseline, year two, and year eight were evaluated. The correlation between the two was found to be 0.289 at baseline, increasing to 0.416 by year eight, demonstrating progression from a weak to moderate correlation. The correlation between BPF and the MS Functional Composite (MSFC) was moderate and more consistent over time, ranging from 0.419 to 0.481. The MSFC comprises tests of leg, arm, and cognitive function, and all components were correlated.

Comparing the change in BPF and the change in EDSS, there is a correlation of 0.31. The decrease in BPF is associated with an increase in EDSS, Dr. Fisher noted.

The question of whether brain atrophy rate is predictive of disability status eight years later can be answered, Dr. Fisher noted, by dividing patients into quartiles according to their atrophy rate during the Phase III trial (baseline to year two). In the group with the least amount of atrophy (essentially immeasurable) only 12 percent reached EDSS six at eight-year follow-up. But in the quartile with the most atrophy (1.7 percent change in BPF), over 50 percent reached EDSS six, she reported, although individual variability was substantial.

Another way to evaluate the data is to determine which patients reached EDSS six, and which did not, and to compare their rate of atrophy over time. The two groups were found to have significantly different BPF values at baseline (p = 0.01), and significantly different rates of BPF diminishment during the trial. In the group who did not progress to EDSS six, there was a mean decrease of 0.4 percent per year in BPF compared to 0.87 percent in the group who did progress to EDSS six.

BPF, or brain atrophy, therefore, does correlate with concurrent disability in relapsing-remitting patients. BPF and two-year change in BPF also correlate with subsequent disability and EDSS status. In conclusion, she said that these results support the use of BPF as a surrogate marker in relapsing-remitting MS.

"We are now comparing BPF to conventional lesion-based MRI measures, and our preliminary analysis suggests BPF is more strongly related to subsequent outcome. It will probably be most useful, however, in combination."

One-Year Change in the MS Functional Composite and EDSS in Secondary Progressive MS (IMPACT)

Jeffrey A. Cohen, MD, Director of Experimental Therapeutics, Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Ohio

The MS Functional Composite (MSFC) appears to be a more sensitive measure of change in neurologic function than EDSS. Its validity is supported by its good correlation with the EDSS, both at baseline and at one year, IMPACT investigators reported at this meeting.

The MSFC is a multi-dimensional outcome measure comprising quantitative tests of leg function (timed 25-foot walk), arm function (nine-hole peg test), and cognitive function (three-second Paced Auditory Serial Addition Test, or PASAT). The units are standardized by converting them to a Z-score, in reference to a standard population; the MSFC score represents the average of the three Z-scores.

The test is being used as the primary outcome measure in IMPACT, an ongoing multinational Phase III clinical trial of interferon beta-1a (Avonex®) in SPMS patients with moderate to severe disability, while the EDSS is a secondary measure of disability. The aim of this study was to compare the two instruments prospectively over the first year of a Phase III clinical trial in 436 patients with SPMS; 403 patients form the basis of this report.

The MSFC detected deterioration over one year both in subjects with increased EDSS and in those with stable or improved EDSS. Over the course of the year, the MSFC at month 12 versus the baseline visit, found that 251 of 403 patients (60 percent) were judged to have worsened. For most patients, the deterioration was modest-less than one standard deviation unit-but about ten percent were substantially worse at one year, reported Jeffrey A. Cohen, MD.

In comparison, worsening on the EDSS (nonsustained change of 0.5 steps at month 12 versus month one) occurred in 27 percent of patients (110/403). In these patients, the mean MSFC change was 0.283 standard deviations. In patients defined as stable or improved on EDSS at month 12 (73 percent), the mean MSFC change was much less (0.097), Dr. Cohen reported.

"Very few, if any, patients who worsened on the EDSS did not show some change on the composite," he added.

By a more stringent definition of change (worsening of EDSS by 1.0 in patients beginning with EDSS of 3.5-5.5, and by .05 in patients with EDSS of 6.0-6.5), only 18.6 percent of patients had worsened at one year, and as a group these patients worsened substantially on the MSFC, as shown by a change of 0.400. Stable or improved patients, by this definition, also worsened on the composite but to a lesser extent, Dr. Cohen said.

There was a statistically significant correlation between the change in the MSFC and change in the EDSS over 12 months, although the strength of the correlation was modest. As expected, the correlation between change in the timed 25-foot walk and change in the EDSS was strongest, with a weaker correlation with the 9-hole peg test, and essentially no correlation between change in the PASAT and change in the EDSS.

The MSFC provides continuous information about neurologic function not obtained on the ordinal EDSS. This characteristic, plus its reliability (by less variability) should make the MSFC more sensitive to differences than the EDSS, he explained.

While the MSFC was developed as an outcome measure for clinical trials, it can be useful in following individual patients. "We routinely perform tests such as the timed 25-foot walk in our practice," Dr. Cohen added.

Predictive Value of the MS Functional Composite in Relapsing-Remitting MS: Results of a Long-Term Follow-up Study

Richard A. Rudick, MD, Professor of Neurology, Director of the Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Ohio

In relapsing MS patients, the MS Functional Composite (MSFC) has been found to be predictive of EDSS status in the subsequent six to eight years. In fact, results of long-term follow-up of patients in the Phase III interferon beta-1a (Avonex®) trial, showed change on the MSFC to be a better predictor of significant disability than relapse frequency or EDSS change, reported Richard A. Rudick, MD.

The MSFC, which consists of a walking score, an arm function score, and a cognitive score, was recommended as an outcome measure for clinical trials by a task force of the National MS Society. Its long-term predictive value has not been validated in a prospective study until now.

A follow-up assessment was done on 160 relapsing-remitting patients from the Phase III trial. The relationship between Phase III study data and patient status at follow-up 8.1 years later was determined. (The study has not yet evaluated treatment effects, therefore, the current analysis is based on pooled data from both treatment and placebo arms.)

"Most studies test patients over the short term, but we are really interested in the implications of our findings over the long term," Dr. Rudick commented. "This formed the basis of the study. What I am reporting here is what the MSFC during the study tells us about the predictor variables-such as EDSS, relapse number, BPF, T2 and gadolinium-enhancing lesions, and symptom impact profile (SIP) scores-eight years later."

EDSS scores at the beginning of the study ranged from 1.0-3.5, but by the eight-year visit 35 percent of these patients had reached level six or higher. To determine the predictive value of the MSFC, the percentage of cases at EDSS six or higher at year eight was plotted, according to their MSFC score at year zero and the change during the two years of the trial. The baseline MSFC did prove to be predictive, as patients with the best MSFC scores at baseline had an 18 percent chance of being at EDSS six or higher at the eight year follow-up; the second-best quartile also had an 18 percent chance; the third quartile had a 46 percent chance; and the worst MSFC baseline score was associated with a 57 percent chance of being at EDSS six by the study's end, Dr. Rudick reported.

A change in MSFC over time also contributed, so that only ten percent of patients with the least amount of change were at the EDSS six or higher level. This increased to 19 percent in the second quartile, 40 percent in the third quartile, and 65 percent in the highest quartile.

Dr. Rudick also presented the magnitude of difference by absolute MSFC score, in terms of patients who were in the "positive-outcome group" at follow-up (EDSS < 6) versus those in the "negative-outcome group" (EDSS = 6). In the positive-outcome group, baseline MSFC was 0.19 standard deviations; in the negative-outcome group it was -0.35, for a highly significant difference (p < 0.0001). The change in the MSFC from baseline to two years was 0.09 (a slight improvement) in the positive-outcome group, but deteriorated by 0.65 standard deviation units in the negative-outcome group (p = 0.09).

"So the relative risk, in terms of change, was quite substantial," he commented. "Both MSFC at baseline, and the change in MSFC, correlated with the likelihood that a patient would be at the EDSS six or higher level at follow-up."

Compared to patients who had secondary progressive MS at follow-up, patients with relapsing forms had a baseline MSFC of 0.18, versus -0.19 for the progressive group, a statistically significant difference (p < 0.0001). In terms of change, the relapsing-remitting patients improved slightly, whereas the secondary progressive patients had MSFC scores that deteriorated significantly.

BPF at baseline was normally distributed around a mean of 0.83. At follow-up, these patients deteriorated and by eight years later, 42 percent had severe atrophy, indicated by a BPF of less than 0.80. Patients with the least atrophy on follow-up had a mean baseline MSFC of 0.29, while those with the most atrophy had a significantly lower MSFC, 0.25 (p = 0.0001). Based on MSFC change, patients without severe brain atrophy improved slightly on the composite, while those with severe atrophy deteriorated by 0.44 standard deviations (p < 0.01), Dr. Rudick reported.

Dr. Rudick concluded that MSFC score and the two-year MSFC change correlate six to eight years later with EDSS status, the presence of SPMS, the presence of severe brain atrophy, and self-reported quality of life (as presented by Dr. Deborah Miller, PhD). These results further validate the use of the MSFC as an outcome measure in clinical trials.

PATIENT POPULATIONS

Clinical Significance of Quality of Life Measures in MS: Results of a Long-Term Follow-up Study Deborah M. Miller, PhD, The Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Ohio

Long-term follow-up of patients in the Phase III trial of interferon beta-1a (Avonex®) validated the importance of patient-reported quality of life as an endpoint in clinical trials. This study found that the MS Functional Composite (MSFC) best reflects the experience of MS patients, and that the Sickness Impact Profile (SIP) is also a useful way to quantitate health-related quality of life, according to Deborah M. Miller, PhD, who reported on the eight-year follow-up of 134 relapsing-remitting patients.

MSFC data from the two-year study period were analyzed for their relationship to the outcome status at the follow-up assessment eight years later. At follow-up, patients were evaluated by means of the EDSS, MSFC, and SIP.

Little change was found in SIP scores from baseline to year two, with the exception of improvements in sleep and recreation. But between year two and the follow-up, there was significant worsening in SIP in the area of physical function, and though less profound, there were changes in emotional status as well, Dr. Miller reported.

The major factors associated with the overall SIP score at eight years were the change in the MSFC (48.5 percent), and previous SIP score (19.9 percent). The major factors associated with the SIP psychosocial dimension at eight years were the psychosocial score at baseline (35.5 percent) and the change in the MSFC from year two to follow-up (15.5 percent); almost half the contributing factors (47.2 percent) could not be explained, and the EDSS had limited importance in predicting SIP at eight years, she said.

Contributing the most to the physical dimension was change in the MSFC between year two and follow-up (61.8 percent) and baseline SIP physical score (12.2 percent). Change in EDSS or disease duration contributed only marginally (6.6 percent).

Dr. Miller reiterated the findings regarding predictive variables. "The change in the MSFC between two years and follow-up accounted for 62 percent of the findings. A huge proportion of the ultimate quality of life score was accounted for by this factor, whereas baseline SIP accounted for only 12 percent."

"What's interesting is that the change in EDSS from baseline to year two accounted for only 6 percent. The MSFC is clearly more predictive," she said.

Dr. Miller commented that the MSFC has been validated mostly in cross-sectional studies; its predictive value in a longitudinal study is further validation of its importance as an evaluation tool. Many clinicians, she concluded, are now using both instruments.

A Comparison of the MSTRAC and New York State Multiple Sclerosis Consortium Registries

David M. Smith, PhD, Director of Information Systems and Technology, Department of Neurology, Buffalo General Hospital, New York

This poster presentation compared data from two registries that are currently enrolling and evaluating MS patients. MSTRAC, which began in 1998, is a Biogen supported, physician-based registry from across the US, intended to reflect care in the community. The 3,938 patients in this registry, referred from 447 physicians, have relapsing forms of MS. The New York State Multiple Sclerosis Consortium (NYSMSC), which began accrual in 1996, is based on 17 MS centers in New York. Its 4,750 patients primarily (but not exclusively) have relapsing MS.

At a poster presentation, David M. Smith, PhD, reported that the two populations are very similar in terms of a number of patient-related and disease-related characteristics. This is important, he said, because of the need to better describe the natural history of MS and to foster collaborative research. Dr. Smith noted that the NYSMSC collects a broad range of information useful to MS researchers; for instance, it manages a large database on African Americans with MS, gathers familial history of autoimmune diseases, and houses a tissue repository.

It is important for research purposes, he said, to confirm that the NYSMSC is representative of the MS population as a whole.

The key findings in a comparison of the two registries were as follows:

• Relapsing MS populations in both registries were essentially identical, with a mean number of 2.2-2.5 relapses in the past three years and a median number of 2.0.

• About 50 percent of patients in both registries were employed.

• Approximately 90 percent of relapsing-remitting patients in both registries had an EDSS of 0.0-5.5, compared to only 40 percent of patients with progressive forms in the NYSMSC data registry.

• About 60 percent of progressive patients in both registries had an EDSS of 6.0 or higher.

• There was a longer time between symptom onset and MS diagnosis in the NYSMSC patients, 4.2 years versus 2.0 years, which remains unexplained.

• MSTRAC patients were more likely to have been treated with immunomodulating agents (IMAs), 75 percent versus 44 percent.

The investigators noted that the longer duration between symptom onset and diagnosis might be partially due to the fact that the NYSMSC contains patients with somewhat more progressive disease and also contains more referred patients. As for the difference in use of IMAs, the NYSMSC began enrolling in 1996, when the prescribing of IMAs was more limited.

On the other hand, the MSTRAC data more realistically reflect the change in prescribing habits as clinicians become more familiar with the benefits of early treatment, noted co-investigator, Jeffrey I. Greenstein, MD.

Quality of Life of Patients Enrolled in MSTRAC: Impact of Treatment and Disease Progression

Jeffrey I. Greenstein, MD, Matthew T. Moore Professor and Chairman, Department of Neurology, Temple University School of Medicine, Philadelphia, Pennsylvania

Quality of life measures for patients enrolled since 1998 in the nationwide MSTRAC registry were reported by the principal investigator Jeffrey I. Greenstein, MD.

The study documented the significant impact of MS on quality of life. Even patients who had no disability exhibited poorer quality of life than the general US population, the study found.

Patients (n = 2,594) completed the MS Quality of Life Inventory (MSQLI), which includes the Health Status Questionnaire (SF-36), supplemented by nine MS-specific measures. The SF-36 consists of 36 items organized into eight subscales and also contains a Physical Component Summary (PCS) and Mental Component Summary (MCS). Gender, education level, form of relapsing MS, relapse rate, disability status, and IMA use were examined. Disability was assessed using the Disease Steps Scale.

"This finding was an eye-opener," he said. "We have vastly underestimated the effect of MS on the quality of people's lives. We assumed [patients were not] affected until later in the disease, when [they] became disabled. But you see that the quality of life is impacted very early and very significantly."

Overall, disability had a greater effect on physical functioning than on mental functioning. Interestingly, however, patients with severe disabilities actually had higher mean MCS scores than less disabled patients. One reason may be that they have "come to terms with their illness" and relieved themselves of the stress of employment, Dr. Greenstein suggested. "Patients push themselves to keep working, and it becomes frustrating and difficult to maintain. Once they stop working, they become better able to cope with the disease itself." The following findings were also made:

• Physical function was more affected than mental function by the form of MS, disability status, and IMA use.

• Patients with progressive-relapsing MS had significantly lower mean physical component scores than patients with relapsing-remitting MS (p < 0.05).

• A higher relapse rate was associated with significant decreases in scores on both physical and mental components (p < 0.05).

• Mean physical and mental scores were not affected by gender; however, mental component scores were significantly lower in females (p < 0.05).

• Lower physical and mental component scores were more common in less-educated patients.

• Treatment with an IMA was associated with significantly lower mean physical scores, but had no effect on mean mental scores.

This study will track the outcomes of IMA users and never-users over time, and will evaluate the conversion of never-users to users as physicians change their prescribing patterns in favor of earlier treatment, Dr. Greenstein said.

Glatiramer Acetate Treatment in Relapsing-Remitting MS: Quantitative MR Assessment

Yulin Ge, MD, University of Pennsylvania, Philadelphia

Lesion and brain volume quantitation techniques were used to follow the treatment effects of glatiramer acetate and placebo in 27 patients with relapsing-remitting MS. A significant difference was noted between treated and placebo groups with respect to the percent annual change in both brain parenchyma volume and gadolinium-enhancing volume, reported Yulin Ge, MD, at the meeting.

Patients were observed for two years with T2-weighted and gadolinium-enhancing T1-weighted images. The volume of these lesions and the brain parenchyma volume were the primary outcome measures.

Placebo-treated patients had a three-fold greater annual decline in brain parenchymal volume: a decrease of 1.8 in glatiramer acetate recipients versus 0.6 for placebo (p = 0.0078). Percent annual change in gadolinium-enhanced T1-weighted volume was also significantly greater in the placebo recipients (p = 0.003), and there was a trend for fewer numbers of enhanced lesions. Only the placebo patients exhibited a statistically significant yearly increase in gadolinium-enhanced lesions, Dr. Ge reported.

"Copaxone® slowed the progression of brain cell loss and may decrease lesion inflammation and rate of brain atrophy in relapsing-remitting MS," he commented.

But the presentation was challenged by other investigators in the audience, primarily relating to the lack of equality between the treatment groups at baseline.

"The validity of any study results depends on how well matched the groups are. The fact is that the Copaxone® group had a median T2 lesion volume of 3600 cc and the placebo group had 6400 cc [at baseline]," said R. Philip Kinkel, MD, Medical Director of The Mellen Center at the Cleveland Clinic. "Those groups are incredibly mismatched."

"In our work, T2 lesion volume is correlated with the development of cerebral atrophy, so if your placebo group has a much higher volume at baseline, of course this group will have a greater degree of atrophy and this would imply the study results are totally invalid," he remarked.

Another listener added, "If you are making a case about a treatment effect and your two groups are unequal, you introduce too much bias. When you see huge differences in baseline parameters, then the two groups are not equal." Dr. Ge did not reply to either comment.

FOOTNOTES:

1. The US Food and Drug Administration has not approved Rebif® for use in the United States.

(c) 2000 Millennium Medical Communications, Inc.

Multiple Sclerosis Forum Report™ is a product of Millennium Medical Communications, Inc. ("MMC, Inc."), an independent, third-party organization providing educational information concerning current medical data and opinions presented at worldwide medical meetings. The Multiple Sclerosis Forum Report™ is published in accordance with the Guidance for Industry: Industry Supported Scientific and Educational Activities, 62 Fed. Reg. 64,093, 64,096-99 (1997) adopted by the U.S. Department of Health and Human Services Food and Drug Administration. Pursuant to the foregoing standards, MMC, Inc. is solely responsible for selecting the topics discussed herein as well as the guest editor. The ideas and opinions expressed by the guest editor are those solely of the guest editor and do not necessarily reflect the opinions of Millennium Medical Communications, Inc. or any Sponsor hereto. This Multiple Sclerosis Forum Report™ may contain data on products, product uses, indications, and dosages, which are not approved for use in the USA, Canada and the European Union and no endorsement is hereby made or intended by coverage of any unapproved use. The content of this report is intended for educational purposes only, and merely conveys scientific data presented at medical meetings. Approved product labeling should always be consulted for prescribing information. The Multiple Sclerosis Forum Report™ is an independent and non-promotional report intended to provide accurate scientific and medical information for educational purposes. MMC, Inc. is not responsible for errors or omissions in reports. The production of this report was supported by a wholly unrestricted educational grant from Biogen, Inc. Biogen, Inc. maintains no control, direct or indirect, over the content, substance, or distribution of this report.