Ocrelizumab treatment effect on upper limb function in PPMS patients with disability: Subgroup results of the ORATORIO study to inform the ORATORIO-HAND study design

Background: It is critically important, for independent daily living, to preserve upper limb function in patients with primary progressive multiple sclerosis (PPMS), especially among those with advanced disability. In the Phase III ORATORIO study (NCT01194570), ocrelizumab (OCR) demonstrated efficacy vs placebo (PBO) in reducing upper limb dysfunction, assessed by 9‐Hole Peg Test (9HPT) in PPMS patients with Expanded Disability Status Scale (EDSS) ≤6.5. An important unmet need would be addressed if OCR benefited upper limb function in more disabled PPMS patients ineligible for inclusion in ORATORIO who are more representative of real‐world clinical settings. Objective: To assess the effect of OCR on upper limb function in subgroups of more disabled/older patients in ORATORIO, and thereby to inform the design of ORATORIO‐HAND, a Phase IIIb, randomised, double‐blind, placebo‐controlled study in PPMS. Methods: In ORATORIO, PPMS patients (N=732) with EDSS 3.0‐6.5, aged 18‐55 years were randomised (2:1) to OCR or PBO for ≥120 weeks and until a pre‐specified number of EDSS progression events (primary endpoint) occurred. Efficacy of OCR in preventing confirmed 20% worsening in 9HPT was investigated in pre‐specified baseline (BL) subgroups of EDSS ≥6.0 and age >45 years, and in an additional subgroup with 9HPT times >25 seconds (s). Results: Subgroup analyses indicate that OCR reduces progression of upper limb disability in more disabled/older PPMS patients: relative risk reduction with OCR vs PBO in 12‐week confirmed 9HPT was similar in patients with BL EDSS < 6.0 and ≥6.0 (40% vs 38%, interaction p=0.9187). It was also similar in patients with BL 9HPT ≤25s and >25s (49% vs 44%, interaction p=0.8221); however, 9HPT progression events mainly occurred in patients with 9HPT >25s vs ≤25s (PBO: 34.3% vs 17.8%; OCR: 21.5% vs 9.9%). In patients ≤45 years, OCR showed a weak trend for greater risk reduction for 9HPT progression than those >45 years (52% vs 33%, interaction p=0.2854). Conclusions: Based in part on the observed encouraging treatment effect of OCR on upper limb function, the ORATORIOHAND study has been designed to further investigate the efficacy of OCR on upper limb function in a rigorous, controlled manner. Eligible patients will be randomised (1:1) to OCR or PBO for â‰��120 weeks and until a pre‐specified number of confirmed 9HPT progression events (primary endpoint) occur. Key entry criteria include EDSS 3.0‐8.0, age 18‐65 years, 9HPT >25s. Screening will begin Q4 2018.