The Mayo Clinic-Canadian Cooperative Trial Of Sulfasalazine In Active Multiple Sclerosis
Noseworthy JH; OBrien P; Erickson BJ; Lee D; Sneve D; Ebers GC; Rice GP; Auty A; Hader WJ; Kirk A; Duquette P; Carter J; Francis G; Metz L; Shuster E
Neurology, 1998 Nov, 51:5, 1342-52
Mayo Clinic/Mayo Foundation, Rochester, MN 55905, USA
PMID# 9818858; UI# 9818858
To determine whether Sulfasalazine is better than placebo in slowing Disability progression in MS.
In this randomized, double-blind, placebo-controlled phase III trial, 199 patients with active Relapsing/Remitting (n = 151) or Progressive (n = 48) MS were evaluated at 3-month intervals for a minimum of 3 years (94% completed 3 years of follow-up; mean follow-up, 3.7 years).
MRI studies were performed at 6-month intervals on a subset of 89 patients.
Sulfasalazine failed to slow or prevent disability progression as measured by the primary outcome (confirmed worsening of the Expanded Disability Status Scale [EDSS] score by at least 1.0 point on two consecutive 3-month visits).
Sulfasalazine influenced favorably a number of secondary outcomes during the first 18 months of the trial (e.g., annualized relapse rate, proportion of relapse-free patients; Progressive subgroup only: rate of EDSS progression at 1 and 2 years, median time to EDSS progression) but these positive findings were not sustained into the second half of the trial.
Sulfasalazine does not prevent EDSS score progression in the subset of MS patients studied by this protocol.
Treatments may improve relapse-related outcomes in MS, at least temporarily, without providing sustained slowing of EDSS progression. Phase III MS trials should be of sufficient length to determine a meaningful impact on disease course.
Modified Total Lymphoid Irradiation And Low Dose CorticoSteroids In Progressive Multiple Sclerosis
Cook SD; Devereux C; Troiano R; Wolansky L; Guarnaccia J; Haffty B; Bansil S; Goldstein J; Sheffet A; Zito G; Jotkowitz A; Boos J; Dowling P; Rohowsky Kochan C; Volmer T
J Neurol Sci, 1997 Nov, 152:2, 172-81
Univ of Medicine and Dentistry of New Jersey, New Jersey Medical School, Dept of NeuroSciences, Newark 07103, USA
PMID# 9415539; UI# 98076021
In a double-blind prospective randomized trial, we assessed the efficacy and safety of modified Total Lymphoid Irradiation (TLI) plus Low Dose Prednisone (TLI-LDP) as compared to sham TLI plus Identical Prednisone therapy (sham TLI-LDP) in 46 patients with Progressive forms of Multiple Sclerosis (MS).
No significant difference existed between groups at study entry in patient age, sex, duration of MS, or disability status.
However, following treatment, significantly fewer TLI patients showed a sustained one point decline in the Expanded Disability Status Scale, the primary study endpoint, as compared to the sham TLI group using the Kaplan-Meier Product-limit survival analysis, (P<0.005).
Risk for relapse requiring treatment with IntraVenous MethylPrednisolone was reduced by 54% in the TLI-treated group (P<0.05).
Significantly fewer TLI-LDP patients had Gadolinium enhancing plus new T2-weighted lesions (P=0.018) when compared to the sham group post-treatment.
There was also a substantial and significant decrease in blood Lymphocytes in the TLI-LDP group when compared to either pretreatment values or to sham TLI-LDP through at least 12 months post-therapy.
Side effects secondary to TLI were generally mild and well-tolerated. These results further support the hypothesis that TLI and systemic ImmunoSuppression have a beneficial effect in Progressive forms of MS.
Major Histocompatibility Complex Class II Alleles And The Course And Outcome Of MS
A population-based study
Weinshenker BG; Santrach P; Bissonet AS; McDonnell SK; Schaid D; Moore SB; Rodriguez M
Neurology, 1998 Sep, 51:3, 742-7
Mayo Clinic and Mayo Foundation, Dept of Neurology, Rochester, MN 55905, USA
PMID# 9748020; UI# 98418816
The Major Histocompatibility Complex (MHC) has been consistently associated with susceptibility to MS and the course of several other human AutoImmune Diseases.
A putative association between the course and severity of MS and the MHC remains controversial.
DR and DQ Genotyping by either restriction fragment length PolyMorphism or sequence-specific PCR-based typing in 119 patients representing 73.4% of the population with MS evaluated in a cross-sectional Disability survey and 100 healthy controls from Olmsted County, Minnesota.
We found a positive association between MS susceptibility and the DR15-DQ6 and DR13-DQ7 haplotypes, and we found a negative association with the DR1-DQ5 haplotype.
We found a trend to a positive association of Primary/Progressive MS with DR4-DQ8 and DR1-DQ5 and an association of "bout onset" MS with DR17-DQ2. We did not find an association with disease severity, as defined by EDSS/duration.
Lack of consistency between different studies may be due to regional variation in MS and limitations of power but likely indicate a minor effect of MHC Class II Genes on the course and severity of MS.
Interferon-beta-1a In Primary/Progressive MS: An Exploratory, Randomized, Controlled Trial
Leary SM, Miller DH, Stevenson VL, Brex PA, Chard DT, Thompson AJ
Neurology 2003 Jan 14;60(1):44-51
Institute of Neurology, University College London, NMR Research Unit, UK
Patients with Primary/Progressive MS have atypical clinical and MRI characteristics and have been excluded from most therapeutic trials. The authors report a randomized, controlled trial restricted to Primary/Progressive MS.
Fifty subjects were randomized to weekly IM Interferon-ß-1a 30 microg, 60 microg, or placebo for 2 years. The primary endpoint was time to sustained progression in disability.
Secondary outcomes included the Timed 10-Meter Walk, Nine-Hole Peg Test, and on MRI, T2 and T1 Brain lesion loads and Brain and Spinal Cord Atrophy.
The 30- microg dose of Interferon-ß-1a was well tolerated, but the 60- microg dose caused severe Flulike reactions and raised Liver Enzymes. No treatment effect was seen on the primary endpoint.
Subjects on Interferon-ß-1a 30 microg had a lower rate of accumulation of T2 lesion load than controls (p = 0.025); subjects on 60 microg had a greater rate of Ventricular enlargement than controls (p = 0.025).
This study has demonstrated that Interferon-ß-1a 30 microg was well tolerated, identified useful outcome measures, but showed no efficacy on the primary outcome measure or on most of the secondary outcome measures.