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Clinical Trial
. 2018 Dec;24(14):1862-1870.
doi: 10.1177/1352458518808189. Epub 2018 Nov 12.

Ocrelizumab reduces progression of upper extremity impairment in patients with primary progressive multiple sclerosis: Findings from the phase III randomized ORATORIO trial

Edward J Fox  1 , Clyde Markowitz  2 , Angela Applebee  3 , Xavier Montalban  4 , Jerry S Wolinsky  5 , Shibeshih Belachew  6 , Damian Fiore  7 , Jinglan Pei  7 , Bruno Musch  7 , Gavin Giovannoni  8
Affiliations
Clinical Trial

Ocrelizumab reduces progression of upper extremity impairment in patients with primary progressive multiple sclerosis: Findings from the phase III randomized ORATORIO trial

Edward J Fox et al. Mult Scler. 2018 Dec.

Abstract

Background: Upper extremity (UE) impairment is common with primary progressive multiple sclerosis (PPMS).

Objective: This exploratory analysis examined the effects of ocrelizumab on confirmed progression (CP) and confirmed improvement (CI) in UE impairment in patients from ORATORIO.

Methods: Patients with PPMS received ocrelizumab 600 mg or placebo every 24 weeks for ⩾120 weeks. The Nine-Hole Peg Test (9HPT) was administered at baseline (BL) and every 12 weeks thereafter. Prespecified exploratory endpoints included change in 9HPT time and proportion of patients with CP of ⩾20% in 9HPT. Analysis populations included intention-to-treat (ITT) patients and subgroups stratified by BL 9HPT time and Expanded Disability Status Scale. Post hoc analyses included the proportion of patients achieving more severe thresholds of CP and the proportion achieving CI in 9HPT.

Results: Among ITT patients, ocrelizumab significantly reduced the change in 9HPT time over 120 weeks, the risk of CP of ⩾20% in 9HPT time for both hands and the risk of more severe 9HPT progression versus placebo. Numerical trends also favoured ocrelizumab versus placebo with respect to achieving CI. Consistent directional trends were observed in subgroup analyses.

Conclusion: Ocrelizumab reduces the risk of UE disability progression and may increase the possibility of improvement versus placebo in PPMS.

Trial registration: ClinicalTrials.gov NCT01194570.

Keywords: Multiple sclerosis; disease progression; disease-modifying therapies; ocrelizumab; progressive; upper extremity impairment.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.J.F. has received speaker honoraria and travel expense reimbursement from, participated in clinical research or speakers bureaus for, or served on advisory/consulting/steering committees for AbbVie, Acorda, Allergan, Bayer, Biogen, Celgene, Chugai, EMD Serono, F. Hoffmann-La Roche Ltd, Mallinckrodt, MedDay, Novartis, Sanofi Genzyme, Teva Pharmaceuticals, and TG Therapeutics. C.M. has served as a consultant for Bayer HealthCare, Biogen, F. Hoffmann-La Roche Ltd and Genentech, Inc., Mallinckrodt, Merck Serono, Mylan, Novartis, Sanofi Genzyme, and Teva Pharmaceuticals. A.A. has served on advisory boards, received speaker honoraria, or participated in clinical trials for Acorda Therapeutics, Actelion Pharmaceuticals, Biogen, F. Hoffmann-La Roche Ltd and Genentech, Inc., Novartis Pharmaceuticals, Opexa Therapeutics, Sanofi Genzyme, and Teva Pharmaceuticals. X.M. has received speaker honoraria and travel expense reimbursement for participation in scientific meetings and has been a steering committee member of clinical trials or served on advisory boards of clinical trials for Actelion, Almirall, Bayer, Biogen, F. Hoffmann-La Roche Ltd, Genzyme, Merck, Novartis, Octapharma, Receptos, Sanofi, Teva Pharmaceuticals, and Trophos. J.S.W. has served on advisory boards and data monitoring or steering committees, has consulting agreements, or received speaker honoraria from the following entities: AbbVie, Actelion, Alkermes, Bayer HealthCare, Biogen, Bionest, Celgene, Clene Nanomedicine, EMD Serono, Forward Pharma A/S, MedDay Pharmaceuticals, Novartis Pharmaceuticals, Otsuka, PTC Therapeutics, Roche Genentech, Sanofi Genzyme, Strategic Consultants International, Takeda, and Teva Pharmaceuticals; royalties are received for out licenced monoclonal antibodies through UTHealth from Millipore Corporation. S.B. is an employee and shareholder of F. Hoffmann-La Roche Ltd. D.F. is an employee of Genentech, Inc., and a shareholder of F. Hoffmann-La Roche Ltd. J.P. is an employee of Genentech, Inc. B.M. is an employee of Genentech, Inc., and a shareholder of F. Hoffmann-La Roche Ltd. G.G. has received honoraria from AbbVie, Atara Biotherapeutics, Bayer HealthCare, Biogen, Canbex Therapeutics, F. Hoffmann-La Roche Ltd, Five Prime Therapeutics, Genzyme, GlaxoSmithKline, GW Pharmaceuticals, Merck, Merck Serono, Novartis, Protein Discovery Laboratories, Synthon, Teva Pharmaceuticals, UCB, and Vertex; has received research grant support from Biogen, Ironwood, Merck Serono, Merz, and Novartis; and has received compensation from Elsevier.

Figures

Figure 1.
Figure 1.
Time to 24-week CP (⩾20% increase) in 9HPT time in the ITT population and subgroups of patients with abnormal/normal 9HPT times at baseline, and patients with baseline EDSS <6 and ⩾6. HR derived from a Cox proportional hazards model stratified by region (USA vs rest of world) and age (⩽45, >45 years). 9HPT: Nine-Hole Peg Test; BL: baseline; CP: confirmed progression; EDSS: Expanded Disability Status Scale; HR: hazard ratio; ITT: intention-to-treat; OCR: ocrelizumab; PBO: placebo.
Figure 2.
Figure 2.
Time to more severe 24-week CP (⩾25%, ⩾30% and ⩾35% increase) in 9HPT time in the ITT population. HR derived from a Cox proportional hazards model stratified by region (USA vs rest of world) and age (⩽45, >45 years). No adjustments were made to account for multiplicity of testing. 9HPT: Nine-Hole Peg Test; BL: baseline; CP: confirmed progression; EDSS: Expanded Disability Status Scale; HR: hazard ratio; ITT: intention-to-treat; OCR: ocrelizumab; PBO: placebo.
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