Subgroup analysis of clinical and MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study
Abstract
Background:
The Phase 3, 96-week ORACLE-MS study evaluated the efficacy of cladribine tablets (10 mg; cumulative doses of 3.5 mg/kg or 5.25 mg/kg over 2 years) in individuals experiencing a first clinical demyelinating event (FCDE). Cladribine significantly reduced the risk of progression to clinically definite multiple sclerosis (CDMS, defined by Poser criteria) and MS according to the 2005 McDonald criteria. It also decreased the number of new or persisting T1 gadolinium-enhancing (Gd+), new or enlarging T2, and combined unique active (CUA) MRI lesions compared to placebo. Since baseline demographics and disease characteristics may influence disease progression, this study examined how these factors affected cladribine’s efficacy in subgroups of ORACLE-MS participants.
Methods:
This retrospective analysis included data from 616 participants in the ORACLE-MS trial (placebo: n=206; cladribine 3.5 mg/kg: n=206; cladribine 5.25 mg/kg: n=204). Subgroups were predefined based on baseline characteristics, including sex, age (<30 vs. ≥30 years), FCDE classification, presence or absence of T1 Gd+ lesions, and number of T2 lesions (<9 vs. ≥9). Key endpoints re-analyzed across these subgroups included time to conversion to CDMS and MS (2005 McDonald criteria). MRI outcomes included cumulative T1 Gd+ and new or enlarging T2 lesions. Cox proportional hazards models were used to assess conversion risk. The analysis focused primarily on the 3.5 mg/kg dose, which is the approved dosage for relapsing forms of MS.
Results:
In the intent-to-treat (ITT) population, cladribine tablets 3.5 mg/kg significantly reduced the risk of conversion to CDMS (HR=0.326; P<0.0001) and MS per the 2005 McDonald criteria (HR=0.485; P<0.0001) versus placebo. Similar risk reductions were observed across the predefined subgroups. Cladribine also significantly reduced the number of cumulative T1 Gd+ lesions (rate ratio range: 0.106–0.399), new or enlarging T2 lesions (range: 0.178–0.485), and CUA lesions (range: 0.154–0.384), all with nominal P-values <0.03. Multivariate analysis identified baseline age (HR=0.577), FCDE classification (HR=0.738), presence of T1 Gd+ lesions (HR=0.554), and T2 lesion count (HR=0.417) as significant predictors of conversion to MS (2005 criteria). No baseline factors were significantly associated with conversion to CDMS.
Conclusion:
This post hoc analysis of the ORACLE-MS study showed that cladribine tablets 3.5 mg/kg reduced the risk of conversion to MS and decreased MRI lesion burden in both the overall population and across subgroups defined by baseline demographic and disease characteristics.