Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial

Abstract

Objective: No evidence of progression or active disease (NEPAD) is a novel combined endpoint defined by the absence of both progression and inflammatory disease activity in primary progressive multiple sclerosis (PPMS). In the placebo-controlled phase III ORATORIO study (NCT01194570), we investigated the effect of ocrelizumab on this comprehensive outcome and its components in a post-hoc analysis.

Methods: The proportion of patients with NEPAD (no evidence of progression [NEP; no 12-week confirmed progression of ≥1/≥0.5 points on the Expanded Disability Status Scale if the baseline score was ≤5.5/>5.5 points, respectively; no 12-week confirmed progression of ≥20% on the Timed 25-Foot Walk test and 9-Hole Peg Test], no brain magnetic resonance imaging activity [no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions], and no protocol-defined relapse) from baseline to week 120 was determined in ocrelizumab- (600 mg; n = 465) and placebo-treated (n = 234) patients.

Results: The majority of ORATORIO study patients with PPMS experienced clinical progression or evidence of disease activity. From baseline to week 120, 29.9% and 42.7% ocrelizumab-treated compared to 9.4% and 29.1% placebo-treated patients maintained NEPAD (relative risk [95% confidence interval {CI}], 3.15 [2.07-4.79]; p < 0.001) and NEP (relative risk [95% CI], 1.47 [1.17-1.84]; p < 0.001), respectively. Effects on the individual components of both measures were consistent with the compound outcomes.

Interpretation: Compared to placebo, ocrelizumab enhanced 3-fold the proportion of PPMS patients with no evidence of either progression or inflammatory disease activity. NEPAD may represent a sensitive and meaningful comprehensive measure of disease control in patients with PPMS. Ann Neurol 2018;84:527-536.

Figure 1

Clinical and subclinical components of NEPAD. No Evidence of Progression defined as: no 12‐week CDP, as measured by the EDSS; no evidence of 12‐week confirmed ≥ 20% progression on hand/arm function as measured by 9HPT; no evidence of 12‐week confirmed ≥ 20% progression on ambulation as measured by the T25FW test. 9HPT = 9‐Hole Peg Test; CDP = confirmed disability progression; EDSS = Expanded Disability Status Scale; Gd⁺ = gadolinium‐enhancing; MRI = magnetic resonance imaging; NEPAD = no evidence of progression or active disease; T25FW = Timed 25‐Foot Walk.

Figure 2

Schedule of MRI scans and assessment of disability measures in the ORATORIO trial. ^aThe blinded treatment period continued until the last patient completed at least 120 weeks and a target of 253 CDP events was reached. ^bPatients received methylprednisolone before each ocrelizumab infusion or placebo infusion. ^c2:1 ocrelizumab:placebo randomization stratified by age (<45 vs > 45 years) and region (USA vs rest of world). ^dPatients who declined to participate in the OLE entered safety follow‐up. ^eContinued monitoring occurred if B cells were not repleted. BL = baseline; CDP = confirmed disability progression; IV = intravenous; MRI = magnetic resonance imaging; OLE = open‐label extension.

Figure 3

Proportion of patients with NEP from baseline to week 120 in ORATORIO. Venn diagram with approximately surface‐proportional representation. Exploratory analysis; p value from a Cochran–Mantel–Haenszel test stratified by age (≤45 vs > 45 years) and region (USA vs rest of world). NEP analysis population is ITT population excluding patients with missing baseline score for EDSS, T25FW, or 9HPT, or withdrawn for reasons other than efficacy failure or death preceding the week 120 visit, and without evidence of progression (n = 41). Imputation is used for patients withdrawn from the treatment prior to the week 120 visit and who had no event; patients withdrawn because of efficacy failure or death are considered as having an event. Relative risk for ocrelizumab vs placebo. 9HPT = 9‐Hole Peg Test; CI = confidence interval; EDSS = Expanded Disability Status Scale; ITT = intention‐to‐treat; NEP = no evidence of progression; T25FW = Timed 25‐Foot Walk.

Figure 4

Proportion of patients with NEPAD from baseline to week 120 in ORATORIO. Exploratory analysis; the relative risk and p value are from a Cochran–Mantel–Haenszel test stratified by age (≤45 vs > 45 years) and region (USA vs rest of world). NEPAD analysis population is a modified ITT population. Patients who discontinued treatment early with at least one event before discontinuation were considered as having EPAD. Patients with no reported event before early discontinuation were considered as having EPAD if the reason for early treatment discontinuation was reported to be lack of efficacy or death; otherwise, they were excluded from the analysis. In this approximately surface‐proportional Venn diagram representation, the sector including two ocrelizumab patients with protocol‐defined relapse but with no MRI activity and NEP cannot be displayed. Relative risk for ocrelizumab vs placebo. CI = confidence interval; EPAD = evidence of progression or active disease; Gd⁺ = gadolinium‐enhancing; ITT = intention‐to‐treat; MRI = magnetic resonance imaging; NEP = no evidence of progression; NEPAD = no evidence of progression or active disease.

Figure 5

Kaplan–Meier analysis of time to evidence of progression or active disease in the ITT population during the double‐blind controlled period in ORATORIO. Patients are considered as failing NEPAD if one of the following events occurred: protocol‐defined relapse, 12‐week CDP, 12‐week confirmed progression on T25FW or 9HPT, or MRI activity. Hazard ratio estimates are obtained from a Cox model stratified by region (ROW; US) and including age, disease duration from onset, baseline EDSS score, baseline T25FW, and baseline 9HPT. p value is from a log‐rank test stratified by region (ROW; US), age (>45; ≤ 45 years), and baseline EDSS score category (<4; ≥ 4). 9HPT = 9‐Hole Peg Test; CDP = confirmed disability progression; CI = confidence internal; EDSS = Expanded Disability Status Scale; ITT = intention‐to‐treat; MRI = magnetic resonance imaging; NEPAD = no evidence of progression or active disease; ROW = rest of world; T25FW = Timed 25‐Foot Walk.