Sunday, February 03, 2008

Rating the main MS studies (the classics)

from Neurology suppl 59;S3 2002
CHAMPS Avonex v. Solumedrol/placebo Outcome point CDMS NOT disability, relapse, brain atrophy. NTT 6.7 to prevent one conversion to CDMS over 3 years. Class I Category A trial

Beta1a v. placebo. Primary endpoint was confimred EDSS progression between treatment group and controls. Relpase rate was a secondary endpoint. EDSS 1-3.5 at entry, 2 relapses in 3 years. Only 57 % of patients completed 2 years. Proportion with a one point increase in EDSS was 21.9 v. 34.9 % in treated/control groups, respectively. (p=0.02). Relapse rate improved by 18 %. Among the subgroup that completed 2 years of treatment there was a 31 % reduction of relapses. There was a 50 % reduction of Gad+ lesions but only 165/301 patients were included in this analysis. There wa no effect on T2 burden. NAbs were seen in 22 % by week 104. NTT to prevent one point increase in EDSS was 7.7. Class I Category A. However, it was short study was stopped early , studied a restricted population (mild entry EDSS 1-3.5) and showed decreased disability but no effect on T2 burden .

ETOMS Rebif 22 sq/per week v. placebo . Unlike CHAMPS, no steroids given in placebo group. No change in EDSS seen. MRI showed a benefit. NTT 9.1 to prevent one CDMS in 2 years. Class I Category A trial

PRISMS patients with 2 relapses in 2 years with EDSS 0-5.0 were reandomized to Rebif 22, Rebif 44 or placebo. Active treatment increased the time to progression of disability and reduced the probability of progression, and reduced the median integrated Disabiliyt status Scale score (area under the curve) mean increase in EDSS and mean increase in Ambulation Index. It reduced relapses, reduced moderate and severe relapses, number of steroid courses, and number of hospitalizations. It increased the number of relapse free patients. T2 burden increased by 10 % inplacebo and decreased with both treatment arms. Number of active lesions also was significantly reduced. 90 % completed 2 years and 95 % were followed for two years. NTT (high and low dose Rebif) to prevent one relapse per year, was 2.4, and 2.7, to render one patient relapse free for one year, 4.3 and 6.7; to render one patient relapse free for two years, 6.3 and 9.1; to prevent one moderate to severe relapse over two years, 2.7 and 3.6; and to prevent onepoint progression in EDSS, 9 and 12. Class I Category A. Rebif prevents progression of disability and reduces relapses in MS.

PRISMS 4-- extension of trial to four years. primary endpoint was relapse rate, with main comparison high dose angainst placebo. Original placebo patients were rerandomized to high or low dose. A dose effect relationship for disability was seen in years 3 and 4. Relapse rate was better with treatment but not with high dose treatment. The higher dose was significantly more effective for time to second relapse and the need for steroids. MRI was always better in the earlier treated patients. 20 % + of patients switching from placebo to drug developed NAbs. NTT not calculated. Class I, Category A. The trial established that Rebif 22 or 44 was effective in reducing relapses, delaying disability, improving MRI markers(t2 burden and no of new T2 lesions per scan) but no difference between high and low doses.

Interferon B1b in RRMS EDSS 0-5.5. gave betaseron 1.6 or 8 miu sq qod. Not well blinded, but randomized. No beneficial effect of EDSS found. Significant effect found on time to first relapse, proportion of patients relapse free, relapse rate, , number of moderate or severe relapses, and need for hospitalization over two years. MRI lesion burden increased by 20 % in placebo group, 10.5 % in low dose group, and decreased by 0.1 % in high dose group. NTT was 2.3 patients to prevent one relapse per year in this actively relapsing group. NTT 5.6 patients to keep one patient relapse free for two years, and 4.5 to prevent one moderate or severe relapse in one year. Class I category A

Extension study of Beta ib. Primary outcome measures were time to sustained worsening by one point on EDSS and mean change in each group from baseline. Not blinded. Study showed a trend (p=0.096) on time to sustained disability over five years with NO DATA GIVEN on other stated endpoint of mean change in EDSS. Both doses led to better relapse data for whole five year period. Rate of moderate and severe attacks was lower in both groups. Less patients completed years 3-5. MRI was beneficial for treated group although numbers were small at this point of study. There were 154 dropoutsby then en d of the study. NTT not calculated. Class II Category B, shows an effect for relapses only.

Copolymer (glatiramer acetate) GA v. placebo baseline EDSS of 0-5.5 . There was no effect of EDSS. Relapses were reduced 29 % over two years. MRI data not presented. NTT was 2.7 to prevent one relapse over two years. Class I Category A study for relapses.

Open label extension trial. Disability data gleaned against natural history data. Annual relapse rate of 0.42 over both phases of trial was stated as 72 % reduction over 2 years before study entry is misleading as it only was calculated with 83 patients and no account was made for regression to the mean. No MRI data exist. Injection site reactions were reported as 2.4 %. There was 27 % dropout. Class II Category C.

IVIG-- insufficient quality to be evaluated

Mitoxantrone randomized MRI blinded patients with aggressive MS EDSS <> 1.0. Entry 2 relapses in 2 years. EDSS outcome was better in treatment group (7 % progresses v. 37 % changed by one point over two years; however there was no change in MEAN change in EDSS score. Relapse outcome over 2 years was .89 v. 2.62. Percent relapse free was 63 v. 21 % all significant. NTT was 3.3. Class II/III Category C study due to trouble blinding.

MIMS MTX in SPMS bseline EDSS 4.5-7 with one point deterioration in year prior to entry. Primary endpoint was a composite of EDSS, Ambulation Index, number of relapses requiring steroids, and Standard Neurologic Status. The result was highly significant p<0.0001). There was a difference in groups on EDSS progression, at 6 months, mean number of treated relapses, time to first treated relapse, percentage of patients without a relapse, totoal number of relapses, and number of hospitalizations. Class II Category B. Key point is that it was ana actively relapsing group in the two years before study entry.

Secondary progressive MS:
Interferon B1b (European) entry 3-6.5 EDSS 70 % of patients had relapses in 2 years before study entry. Progression of disability was 49.7 % v. 38.9 % p=0.0048, also less patients became wheelchair bound. Relapses were reduced by about 30 %. No treatment effects in patients with baseline EDSS 6.0 or 6.5. Decreased T2 burden. NTT was 9.2 patients for 3 years to prevent one point EDSS increase. Class I Category A. Difference with SPECTRIMS (North American study) might be due to less pre treatment relapses in N American group.

Head to Head
INCOMIN Beta 1b v. Beta 1a (Betaseron v. Avonex) 2 year trial, primary endpoint was no of relapse free patients, and number of patients with no new T2 lesions on their MRI. Entry 2 relapses in 2 years, EDSS 1-3.5. EDSS progression of one point was 13 % over 2 years with Betaseron, 30 % with Avonex. T2 lesion burden showed o new lesions in 55 %with Betaseron, 26 % of those with placebo. NTT to make a patient relapse free for 2 years was 7 for betaseron v. avonex. Class I for MRI, Class III for clinical outcomes (unblinded)

EVIDENCE Rebif v. Avonex. primary endpoint was proportion of patients who were relapse free at 24 weeks. entry edss 0-5.5, pastients who got Rebif received 44 mcg tiw dose. Evaluating neurologists were blinded. There was no change in disability. Relapse free patients favored Rebif (74.9 v. 63.3 %, odds ratio 1.9, p=0.0005). Combined unique active lesions on MRI favored Rebif. NTT was 9 at 24 weeks and 10 at 48 weeks. Class I study.

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