Dataset Information

Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

ABSTRACT:

Background

In the Phase 3, 96-week ORACLE-MS study, cladribine tablets 10?mg (3.5 or 5.25?mg/kg cumulative dosage over two years) significantly reduced lesions associated with multiple sclerosis versus placebo in participants following a first clinical demyelinating event (FCDE).

Objective

To determine the timing of effects of cladribine tablets on lesion activity assessed by magnetic resonance imaging (MRI).

Methods

This post hoc analysis assessed the effect of cladribine tablets versus placebo in ORACLE-MS on secondary MRI endpoints including T1 gadolinium-enhancing (Gd+), new or enlarging T2 lesions, and combined unique active lesions assessed on MRI scans performed at screening and every 3?months thereafter.

Results

Compared to placebo, cladribine tablets 3.5?mg/kg treatment appeared to lead to a trend of reductions in the mean number of T1 Gd+ lesions by Week 13 (first post-baseline scan: 0.37 vs. 1.00), new or enlarging T2 (0.20 vs. 1.01) and combined unique active (0.29 vs. 1.91) lesions by Week 24. Low lesion counts were maintained with cladribine tablets throughout 96?weeks. Similar results were observed with the 5.25?mg/kg dosage.

Conclusion

In participants with an FCDE, cladribine tablets appeared to reduce lesion numbers within 13?weeks (time of first evaluation).

SUBMITTER: Freedman MS

PROVIDER: S-EPMC7925953 | biostudies-literature | 2021 Jan-Mar

REPOSITORIES: biostudies-literature

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Publications

Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

Freedman Mark S MS Coyle Patricia K PK Comi Giancarlo G L Scarberry Susan S Damian Doris D Hyvert Yann Y Dangond Fernando F Galazka Andrew A Jack Dominic D Lebson Lori A LA Leist Thomas P TP

Multiple sclerosis journal - experimental, translational and clinical 20210101 1

<h4>Background</h4>In the Phase 3, 96-week ORACLE-MS study, cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dosage over two years) significantly reduced lesions associated with multiple sclerosis versus placebo in participants following a first clinical demyelinating event (FCDE).<h4>Objective</h4>To determine the timing of effects of cladribine tablets on lesion activity assessed by magnetic resonance imaging (MRI).<h4>Methods</h4>This <i>post hoc</i> analysis assessed the effect of clad ...[more]

PMID: 33717501

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Project description:Understanding the predictors of progression from a first to a second demyelinating event (and formerly, a diagnosis of clinically definite multiple sclerosis) is important clinically. Previous studies have focused on predictors within a single domain, e.g. radiological, lacking prospective data across multiple domains. We tested a comprehensive set of personal, environmental, neurological, MRI and genetic characteristics, considered together, as predictors of progression from a first demyelinating event to clinically definite multiple sclerosis. Participants were aged 18-59 years and had a first demyelinating event during the study recruitment period (1 November 2003-31 December 2006) for the Ausimmune Study (n = 216) and had follow-up data to 2-3 years post-initial interview. Detailed baseline data were available on a broad range of demographic and environmental factors, MRI, and genetic and viral studies. Follow-up data included confirmation of clinically definite multiple sclerosis (or not) and changes in environmental exposures during the follow-up period. We used multivariable logistic regression and Cox proportional hazards regression modelling to test predictors of, and time to, conversion to clinically definite multiple sclerosis. On review, one participant had an undiagnosed event prior to study recruitment and was excluded (n = 215). Data on progression to clinically definite multiple sclerosis were available for 91.2% (n = 196); 77% were diagnosed as clinically definite multiple sclerosis at follow-up. Mean (standard deviation) duration of follow-up was 2.7 (0.7) years. The set of predictors retained in the best predictive model for progression from a first demyelinating event to clinically definite multiple sclerosis were as follows: younger age at first demyelinating event [adjusted odds ratio (aOR) = 0.92, 95% confidence interval (CI) = 0.87-0.97, per additional year of age); being a smoker at baseline (versus not) (aOR = 2.55, 95% CI 0.85-7.69); lower sun exposure at age 6-18 years (aOR = 0.86, 95% CI 0.74-1.00, per 100 kJ/m2 increment in ultraviolet radiation dose), presence (versus absence) of infratentorial lesions on baseline magnetic resonance imaging (aOR = 7.41, 95% CI 2.08-26.41); and single nucleotide polymorphisms in human leukocyte antigen (HLA)-B (rs2523393, aOR = 0.25, 95% CI 0.09-0.68, for any G versus A:A), TNFRSF1A (rs1800693, aOR = 5.82, 95% CI 2.10-16.12, for any C versus T:T), and a vitamin D-binding protein gene (rs7041, aOR = 3.76, 95% CI 1.41-9.99, for any A versus C:C). The final model explained 36% of the variance. Predictors of more rapid progression to clinically definite multiple sclerosis (Cox proportional hazards regression) were similar. Genetic and magnetic resonance imaging characteristics as well as demographic and environmental factors predicted progression, and more rapid progression, from a first demyelinating event to a second event and clinically definite multiple sclerosis.

Project description:ImportanceThe value of serum neurofilament light chain (sNfL) levels for predicting long-term disability in patients with multiple sclerosis (MS) remains controversial.ObjectiveTo assess whether high sNfL values are associated with disability worsening in patients who underwent their first demyelinating MS event.Design, setting, and participantsThis multicenter cohort study included patients who underwent their first demyelinating event suggestive of MS at Hospital Universitario Ramón y Cajal (development cohort; June 1, 1994, to September 31, 2021, with follow-up until August 31, 2022) and 8 Spanish hospitals (validation cohort; October 1, 1995, to August 4, 2020, with follow-up until August 16, 2022).ExposuresClinical evaluations at least every 6 months.Main outcomes and measuresThe main outcomes were 6-month confirmed disability worsening (CDW) and an Expanded Disability Status Scale (EDSS) score of 3. Levels of sNfL were measured in blood samples obtained within 12 months after disease onset using a single molecule array kit. The cutoffs used were sNfL level of 10 pg/mL and a standardized score (z score) of 1.5. Multivariable Cox proportional hazards regression models were used to evaluate outcomes.ResultsOf the 578 patients included in the study, 327 were in the development cohort (median age at sNfL analysis, 34.1 years [IQR, 27.2-42.7 years]; 226 female [69.1%]) and 251 patients were in the validation cohort (median age at sNfL analysis, 33.3 years [IQR, 27.4-41.5 years]; 184 female [73.3%]). The median follow-up was 7.10 years (IQR, 4.18-10.0 years). Levels of sNfL greater than 10 pg/mL were independently associated with higher risk of 6-month CDW and an EDSS of 3 in the development cohort (6-month CDW: hazard ratio [HR], 2.39; 95% CI, 1.39-4.12; P = .002; EDSS of 3: HR, 4.12; 95% CI, 2.18-7.77; P < .001) and the validation cohort (6-month CDW: HR, 1.61; 95% CI, 1.07-2.42; P = .02; EDSS of 3: HR, 2.03; 95% CI, 1.23-3.33; P = .005). Highly effective disease-modifying treatments were associated with lower risks of 6-month CDW and an EDSS of 3 in patients with high baseline sNfL values.Conclusions and relevanceThis cohort study found that high sNfL values obtained within the first year of disease were associated with long-term disability worsening in MS, suggesting that sNfL level measurement may help identify optimal candidates for highly effective disease-modifying treatments.

Dataset Information

Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

Background

Objective

Methods

Results

Conclusion

Publications

Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

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