A Study of Ocrelizumab in Comparison With Interferon Beta-1a (Rebif) in Participants With Relapsing Multiple Sclerosis

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01247324
• Collaborator: (none)
• Enrollment: 821
• Locations: 141
• Arms: 2
• Anticipated Duration (Months): 147.9
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized, double-blind, double-dummy, parallel-group study will evaluate the efficacy and safety of ocrelizumab in comparison with interferon beta-1a (Rebif) in participants with relapsing multiple sclerosis. Participants will be randomized to receive either ocrelizumab 600 mg or matching placebo intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week; or interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks). Planned duration of double-blind treatment is 96 weeks. Participants who complete the 96-week double-blind treatment will have an option to enter a single-group, active-treatment, open-label extension period, providing they fulfill the eligibility criteria.

Condition or Disease	Intervention/Treatment	Phase
Relapsing Multiple Sclerosis	Drug: Interferon beta-1a; Drug: Ocrelizumab-matching placebo; Drug: Ocrelizumab; Drug: Interferon beta-1a-matching placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 821 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Double-Dummy, Parallel-Group Study To Evaluate the Efficacy and Safety of Ocrelizumab in Comparison to Interferon Beta-1a (Rebif®) in Patients With Relapsing Multiple Sclerosis
• Actual Study Start Date: Aug 31, 2011
• Actual Primary Completion Date: Apr 2, 2015
• Anticipated Study Completion Date: Dec 28, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Interferon beta-1a 44 mcg SC Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Drug: Interferon beta-1a; Other Names: Rebif ; Drug: Ocrelizumab-matching placebo
Experimental: Ocrelizumab Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.	Drug: Ocrelizumab; Other Names: RO4964913 ; Drug: Interferon beta-1a-matching placebo

Outcome Measures

Primary Outcome Measures

1. Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks [Week 96]

   ARR was protocol-defined and calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of exposure to that treatment.

Secondary Outcome Measures

1. Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period [Week 108]

   Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 12 weeks after the initial documentation of neurological worsening. EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.

2. Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double-Blind Treatment [Baseline up to Week 96]

   The total number of T1 gadolinium-enhancing lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96.

3. Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment [Baseline up to Week 96]

   The total number of new and/or enlarging T2 lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96.

4. Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks [Week 96]

   Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of >= 2.0. It was defined as a reduction in EDSS score of: A) >=1.0 from the baseline EDSS score when the baseline score was >=2 and <=5.5 B) >= 0.5 when the baseline EDSS score > 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined.

5. Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks During the Double-Blind Treatment Period [Week 108]

   Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.

6. Number of T1 Hypointense Lesions During the Double-Blind Treatment [Baseline up to Week 96]

   The total number of new T1-Hypo-Intense Lesions (Chronic Black Holes) for all participants in the treatment group was calculated as the sum of the individual number of new lesions at Weeks 24, 48, and 96.

7. Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96 [Baseline, Week 96]

   MSFC score consists of: A) Timed 25-Foot walk; B) 9-Hole Peg Test (9-HPT); and C) Paced Auditory Serial Addition Test (PASAT-3 version). The MSFCS is based on the concept that scores for these three dimensions (arm, leg, and cognitive function) are combined to create a single score (the MSFC) that can be used to detect change over time in a group of participants with MS. Since the three primary measures differ in what they actually measure, a common composite score for the three different measures i.e., Z- score was selected for the purpose. MSFC Score = {Z arm, average + Z leg, average + Z cognitive} / 3.0. The results from each of these three tests are transformed into Z-scores and averaged to yield a composite score for each participant at each time point. A score of +1 indicates that, on average, an individual scored 1 standard deviation (SD) better than the reference population and a score of -1 indicates that an individual scored 1 SD worse than the reference population.

8. Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96 [From Week 24 up to Week 96]

   Brain volume was recorded as an absolute "normalized" value at the baseline visit then recorded at subsequent visits as a percentage change relative to the absolute value at the baseline visit. Therefore, brain volume at Week 24 was calculated as the brain volume at the baseline visit multiplied by 1 + ([percentage change in brain volume from baseline visit to Week 24]/100). Estimates are from analysis based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: Percentage Change = Brain Volume at Week 24 + Geographical Region (US vs. ROW) + Baseline EDSS (< 4.0 vs. >= 4.0) + Week + Treatment + Treatment*Week (repeated values over Week) + Brain Volume at Week 24*Week.

9. Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96 [Baseline, Week 96]

   The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to 2 distinct higher-ordered clusters: the PCS and mental composite t-score (MCS). The range for all 8 domains as well as for the composite t- scores is from 0 to 100 with 100 as best possible health status and 0 as worst health status.

10. Percentage of Participants Who Have No Evidence of Disease Activity (NEDA) up to Week 96 [Week 96]

    NEDA was defined only for participants with a baseline EDSS score >=2.0. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). Participants who completed the 96- week treatment period were considered as having evidence of disease activity if at least one protocol- defined relapse (PDR), a confirmed disability progression (CDP) event or at least one MRI scan showing MRI activity (defined as Gd-enhancing T1 lesions, or new or enlarging T2 lesions) was reported during the 96-week treatment period, otherwise the participant was considered as having NEDA.

11. Number of Participants With Adverse Events (AEs) [Baseline up to Week 96]

    AEs included infusion related reactions (IRRs) and serious MS relapses, but excluded non-serious MS relapses. Serious Adverse Events (SAEs) included serious MS relapses and serious IRRs.

12. Exposure to Ocrelizumab (Area Under the Concentration - Time Curve, AUC) [Pre-infusion at Weeks 1, 24, 48, 72; and 30 minutes post-infusion at Week 72; at any time during Weeks 84 and 96]

    AUC represents total drug exposure for one dosing interval after the 4th dose.

13. Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab [Baseline up to week 96]

    Number of participants positive for anti-drug antibodies (ADAs) to ocrelizumab is the number of post- baseline evaluable participants determined to have treatment-induced ADA or treatment-enhanced ADA during the study period.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of multiple sclerosis, in accordance with the revised McDonald criteria (2010)

• At least 2 documented clinical attacks within the last 2 years prior to screening or one clinical attack in the years prior to screening (but not within 30 days prior to screening)

• Neurologic stability for greater than or equal to (>=) 30 days prior to both screening and baseline

• Expanded Disability Status Scale (EDSS) score 0 to 5.5 inclusive

Exclusion Criteria:

• Primary progressive multiple sclerosis

• Disease duration of more than 10 years in participants with EDSS less than or equal to (<=) 2.0 at screening

• Contraindications for MRI

• Known presence of other neurological disorders which may mimic multiple sclerosis

• Pregnancy or lactation

• Requirement for chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study

• History of or currently active primary or secondary immunodeficiency

• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies

• Active infection, or history of or known presence of recurrent or chronic infection (e.g., hepatitis B or C, human immunodeficiency virus [HIV], syphilis, tuberculosis)

• History of progressive multifocal leukoencephalopathy

• Contraindications to or intolerance of oral or iv corticosteroids

• Contraindications to Rebif or incompatibility with Rebif use

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	21st Century Neurology	Phoenix	Arizona	United States	85004
2	Scripps Clinic	La Jolla	California	United States	92037
3	MS Center of California	Laguna Hills	California	United States	92653
4	Southern California Permanente Medical Group	Los Angeles	California	United States	90027
5	Neuro-Therapeutics Inc.	Pasadena	California	United States	91105
6	Mercy Medical Group	Sacramento	California	United States	95816
7	University of California at San Francisco	San Francisco	California	United States	94115
8	Neurology Associates PA	Maitland	Florida	United States	32751
9	Health First Physicians Inc.	Melbourne	Florida	United States	32901
10	Mercy Research Institute	Miami	Florida	United States	33133
11	Miami Research Associates	South Miami	Florida	United States	33143
12	Axiom Clinical Research of Florida	Tampa	Florida	United States	33609
13	University of South Florida	Tampa	Florida	United States	33613-4706
14	Shepherd Center Inc.	Atlanta	Georgia	United States	30309
15	Emory University; Department of Neurology	Atlanta	Georgia	United States	30322
16	NeuroTrials Research, Inc.	Atlanta	Georgia	United States	30342
17	Northwestern University; Dept. of Neurology	Chicago	Illinois	United States	60611
18	Consultants in Neurology Ltd	Northbrook	Illinois	United States	60062
19	American Health Network Institute, LLC	Avon	Indiana	United States	46123
20	Massachusetts General Hospital.	Boston	Massachusetts	United States	02114
21	Michigan Neurology Associates P.C.	Clinton Township	Michigan	United States	48035
22	Michigan Institute for Neurological Disorders	Farmington Hills	Michigan	United States	48334
23	The Minneapolis Clinic of Neurology	Golden Valley	Minnesota	United States	55422
24	Washington University; Wash Uni. Sch. Of Med	Saint Louis	Missouri	United States	63110
25	The MS Center for Innovations In Care	Saint Louis	Missouri	United States	63131
26	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-0600
27	University of New Mexico	Albuquerque	New Mexico	United States	87131
28	The MS Center; Advance Neurology and Pain	Advance	North Carolina	United States	27006
29	OnSite Clinical Solutions LLC	Charlotte	North Carolina	United States	28203
30	Atrium Health Neurosciences Institute - Charlotte	Charlotte	North Carolina	United States	28204
31	University Neurology Inc.	Cincinnati	Ohio	United States	45219
32	The Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43212
33	Oklahoma Medical Research Foundation	Oklahoma City	Oklahoma	United States	73104
34	Providence Neurological Specialties	Portland	Oregon	United States	97225
35	Albert Einstein Medical Center; Depatment of Neurosensory sciences	Philadelphia	Pennsylvania	United States	19141
36	Magee-Woman's Hospital	Pittsburgh	Pennsylvania	United States	15213
37	Uni of Texas Health Science Center At Houston	Houston	Texas	United States	77030
38	Bhupesh Dihenia M.D. P.A.	Lubbock	Texas	United States	79410
39	Uni of Vermont Medical Center;	Burlington	Vermont	United States	05405
40	Multicare Research Institute; Multicare Neuroscience Center of Washington	Tacoma	Washington	United States	98405
41	Instituto centenario	Buenos Aires		Argentina	C1204AAD
42	Hospital Español	Ciudad Autonoma Bs As		Argentina	C1209AAB
43	Fundacion Rosarina de Neurorehabilitacion	Rosario		Argentina	S2000BZL
44	Royal North Shore Hospital; Department of Neurology	St Leonards	New South Wales	Australia	2065
45	Barmherzige Brueder Konventspital	Linz		Austria	4040
46	AZ Sint Jan	Brugge		Belgium	8000
47	Cliniques Universitaires Saint-Luc; Neurology	Bruxelles		Belgium	1200
48	AZ Delta (Campus Rumbeke)	Roeselare		Belgium	8800
49	Hospital das Clinicas - UFG;Reumatologia	Goiania	GO	Brazil	74653-050
50	IMV Pesquisa Neurológica	Porto Alegre	RS	Brazil	90110-000
51	Clinica Neurologica; Neurocirurgica de Joinville	Joinville	SC	Brazil	89202-190
52	MHAT Avis Medica; Neurology Department	Pleven		Bulgaria	5800
53	MHATNP Sv.Naum EAD; Clinic in neurology diseases for movement disorders	Sofia		Bulgaria	1113
54	First MHAT; Clinic of Neurology	Sofia		Bulgaria	1142
55	ACIBADEM CITY CLINIC TOKUDA HOSPITAL EAD; Clinic of Neurology and Sleep Medicine	Sofia		Bulgaria	1407
56	Military Medical Academy; Neurology	Sofia		Bulgaria	1606
57	Hospital Carlos Van Buren	Valparaiso		Chile	2340000
58	Fakultni nemocnice u sv. Anny; Neurologicka klinika	Brno		Czechia	656 91
59	Fakultni nemocnice Hradec Kralove	Hradec Kralove		Czechia	500 05
60	Nemocnice Jihlava; NEU-Neurologicke oddeleni	Jihlava		Czechia	58633
61	Krajska Nemocnice Pardubice Neurologicka Klinika	Pardubice		Czechia	532 03
62	VFN Praha Poliklinika Rs Centrum - Budova A	Prague		Czechia	12808
63	Krajska zdravotni, a. s. - Nemocnice Teplice, o. z.; Neurologicke oddeleni	Teplice		Czechia	415 29
64	West Tallinn Central Hospital	Tallinn		Estonia	10617
65	Tartu University Hospital	Tartu		Estonia	51014
66	FinnMedi Oy	Tampere		Finland	33520
67	Groupe Hospitalier Pellegrin	Bordeaux		France	33000
68	CHU Hopital Gabriel Montpied; Service de Neurologie	Clermont Ferrand		France	63003
69	Hopital Central; Neurologie	Nancy		France	54035
70	CHU de Nîmes Hopital Caremeau; Service de Neurologie	Nimes		France	30900
71	Hopital Hautepierre - CHU Strasbourg; Service de Neurologie	Strasbourg		France	67098
72	Charité Universitaetsmedizin Berlin, Campus Charité Mitte	Berlin		Germany	10117
73	Universitätsklinikum "Carl Gustav Carus"; MS Center Dresden	Dresden		Germany	01307
74	Asklepiosklinik Barmbek; Abteilung Neurologie	Hamburg		Germany	22291
75	Diakoniekrankenhaus Henriettenstiftung gGMBH; Klinik für Neurologie und klinische Neurophysiologie	Hannover		Germany	30171
76	Universitaetsklinikum Mainz - PS; Klinik und Poliklinik fuer Neurologie	Mainz		Germany	55131
77	Praxis Dr. med. Mathias Niedhammer, Facharzt für Neurologie	Oldenburg		Germany	26122
78	Neurozentrum Prien Elisabeth Hans-Thümmler Stefan Braune	Prien		Germany	83209
79	Universitätsklinikum Rostock, Zentrum für Nervenheilkunde; Klinik und Poliklinik für Neurologie	Rostock		Germany	18147
80	Universitätsklinikum Tübingen, Zentrum für Neurologie	Tübingen		Germany	72076
81	Studienzentrum Nordwest, Dr. med. Joachim Springub / Herr Wolfgang Schwarz	Westerstede		Germany	26655
82	Semmelweis Egyetem AOK; Neurologiai Klinika	Budapest		Hungary	1083
83	Fovarosi Onkormanyzat Jahn Ferenc Del-Pesti	Budapest		Hungary	1204
84	Szent Borbala Korhaz; Neurology	Tatabánya		Hungary	2800
85	Chaim Sheba Medical Center; Neurology Department	Ramat-Gan		Israel	5262000
86	Azienda Ospedaliera Sant'Andrea	Roma	Lazio	Italy	00189
87	Irccs Ospedale San Raffaele	Milano	Lombardia	Italy	20132
88	Azienda Socio Sanitaria Territoriale della Valle Olona (pres	Gallarate	Valle D'Aosta	Italy	21013
89	Azienda Ospedaliera di Padova; Clinica Neurologica	Padova	Veneto	Italy	35128
90	Maritime Medicine Centre of Latvia Hospital of Vecmilgravis; Department of Neurology	Riga		Latvia	1015
91	P. Stradins Clinical University Hospital; Neurology	Riga		Latvia	LV-1002
92	Kaunas Medical University Hospital	Kaunas		Lithuania	50009
93	Klaipeda University Hospital; Public Institution	Klaipeda		Lithuania	92288
94	Vilnius University Hospital Santariskiu Clinic	Vilnius		Lithuania	08661
95	Grupo Médico Camino S.C.	Ciudad de México	Mexico CITY (federal District)	Mexico	03600
96	Hospital Universitario Dr Jose Eleuterio Gonzalez; Universidad Autónoma de Nuevo León	Monterrey		Mexico	64460
97	St. Antonius Ziekenhuis Nieuwegein	Nieuwegein		Netherlands	3435 CM
98	Policlinico Especializado en Neurologia	Callao		Peru	04
99	Clinica Anglo Americana	Lima		Peru	18
100	Hospital Nacional Dos de Mayo	Lima		Peru
101	Clinica Centenario Peruano Japonesa; Neurology	Pueblo Libre		Peru	Lima 21
102	COPERNICUS Podmiot Leczniczy Sp. z o. o. Szpital im. M. Kopernika; Oddział Neurologiczny	Gdansk		Poland	80-803
103	Specjal. Praktyka Lekarska; Prof. Grzegorz Opala	Katowice		Poland	40-588
104	M.A. - LEK A.M.Maciejowscy SC.	Katowice		Poland	40-595
105	Neurologiczny NZOZ Centrum Leczenia SM; Osrodek Badan Klinicznych	Plewiska		Poland	62-064
106	Hospital de Braga; Servico de Neurologia	Braga		Portugal	4710-243
107	Sverdlovsk Regional Clinical Hospital 1	Ekaterinburg		Russian Federation	620102
108	Kemerovo Regional Clinical Hospital	Kemerovo		Russian Federation	650066
109	Central Clinical Hospital #2 N.A. Semashko OAO RJHD	Moscow		Russian Federation	107150
110	Clinical Hospital #83	Moscow		Russian Federation	115682
111	FSBIH Siberian Regional Medical Centre of FMBA of Russia	Novosibirsk		Russian Federation	630007
112	MRC for Oncology and Neurology Biotherapy	Novosibirsk		Russian Federation	630090
113	Samara State Medical University	Samara		Russian Federation	443099
114	Reg. SI of Health Care Smolensk Regional Clinical Hospital	Smolensk		Russian Federation	214018
115	MMA of Ministry of Defense of Russia named after S.M. Kirov	St. Petersburg		Russian Federation	194044
116	St.-Peterburg State institution of health care City multifield hospital #2	St. Petersburg		Russian Federation	194354
117	Regional Multiple Sclerosis Centre b/o CC ECM "Neftyanik"	Tyumen		Russian Federation	625000
118	Military Medical Academy	Belgrade		Serbia	11040
119	Clinical Center Kragujevac	Kragujevac		Serbia	34000
120	Clinical Center Nis	NIS		Serbia	18000
121	FNsP Bratislava - Nemocnica Stare mesto	Bratislava		Slovakia	813 69
122	FNsP Bratislava, Nemocnica Ruzinov	Bratislava		Slovakia	826 06
123	Univerzitna nemocnica Bratislava Nemocnica sv. Cyrila a Metoda; Nemocnicna lekaren	Bratislava		Slovakia	851 07
124	Fakultna nemocnica s poliklinikou Zilina	Zilina		Slovakia	012 07
125	Dr CC Coetzee Inc	Durban		South Africa	4319
126	Complejo Hospitalario Nuestra Señora de la Candelaria; Servicio de Neurologia	Santa Cruz De Tenerife	Tenerife	Spain	38010
127	Hospital de Basurto	Bilbao	Vizcaya	Spain	48013
128	Hospital Universitario Puerta de Hierro; Servicio de Neurologia	Madrid		Spain	28222
129	Hospital Universitario Virgen Macarena	Sevilla		Spain	41009
130	Universitätsspital Basel Medizin Neurologie; Neurologische Poliklinik	Basel		Switzerland	4031
131	Ospedale Regionale Lugano Civico Medizin Neurologie; Neurologia	Lugano		Switzerland	6900
132	Hopital Razi	Mannouba		Tunisia	2010
133	Hopital Universitaire Fattouma Bourguiba	Monastir		Tunisia	5000
134	Hopital Charles Nicolle	Tunis		Tunisia	1006
135	MMPIDon.Reg.Cl.&Ter.Med.Com.Neur.Dept.DNMU n.a.M.Gorkiy; Ch. of Nervous Diseases and Med. Genetics	Donetsk		Ukraine	83099
136	St.In.Inst. of Neurol.Psych.and Narcol.of the AMSU; Dept. of Neuroinfection and Multiply Sclerosis	Kharkov		Ukraine	61068
137	Kyiv City Cl.Hosp.#4 Depart.of Neurology #2NMU; Department of Neurology	Kyiv		Ukraine	03110
138	Lviv Regional Clinical Hospital; Department of Neurology	Lviv		Ukraine	79010
139	Vin.Reg.Psych.Hosp.N.A Yuschenko O.I., Vnmu N.A. Pyrogov; Department of Nervous Diseases	Vinnytsya		Ukraine	21005
140	Walton Centre NHS Foundation Trust, Neuroscience Research Centre; CLINICAL TRIALS UNIT	Liverpool		United Kingdom	L9 7LJ
141	Royal London Hospital; Neurology	London		United Kingdom	E1 1BD

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01247324
• Other Study ID Numbers: WA21092; 2010-020337-99
• First Posted: Nov 24, 2010
• Last Update Posted: Jul 12, 2022
• Last Verified: Jul 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Interferons; Interferon-beta; Interferon beta-1a; Ocrelizumab

Study Results

Participant Flow

Pre-assignment Detail	A total of 1051 participants were screened for entry into the study. 821 participants were entered into the double-blind treatment period. Participants who completed the 96-week double-blind treatment had an option to enter a single group, active treatment open label extension, providing they fulfilled the eligibility criteria.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Period Title: Overall Study
STARTED	411	410
COMPLETED	340	366
NOT COMPLETED	71	44

Baseline Characteristics

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab	Total
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.	Total of all reporting groups
Overall Participants	411	410	821
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.9 (9.3)	37.1 (9.3)	37.0 (9.3)
Sex: Female, Male (Count of Participants)
Female	272 66.2%	270 65.9%	542 66%
Male	139 33.8%	140 34.1%	279 34%

Outcome Measures

1. Primary Outcome

Title	Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks
Description	ARR was protocol-defined and calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of exposure to that treatment.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all randomized participants in the study.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	411	410
Number (95% Confidence Interval) [relapses/participant year of treatment]	0.292	0.156

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	Adjusted by Geographical Region (US vs. Rest of World) and baseline EDSS (<4.0 vs. >=4.0).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Negative Binomial Model
	Comments
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.536
	Confidence Interval	(2-Sided) 95%; 0.4 to 0.719
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio was calculated as Ocrelizumab ARR/Interferon beta-1a 44 mcg SC ARR.

2. Secondary Outcome

Title	Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period
Description	Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 12 weeks after the initial documentation of neurological worsening. EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.
Time Frame	Week 108

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	411	410
Median (Full Range) [weeks]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	Time to onset CDP at week 12
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0139
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.37 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double-Blind Treatment
Description	The total number of T1 gadolinium-enhancing lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	411	410
Number [lesions]	337	21

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Negative Binomial Model
	Comments
Method of Estimation	Estimation Parameter	Adjusted rate ratio
	Estimated Value	0.058
	Confidence Interval	() 95%; 0.032 to 0.104
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted by baseline T1 Gd lesion (present or not), baseline EDSS (<4.0 vs. >=4.0) and geographical region (US vs. rest-of-world). Adjusted rate ratio was calculated as Ocrelizumab adjusted rate/Interferon beta-1a 44 mcg SC adjusted rate.

4. Secondary Outcome

Title	Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment
Description	The total number of new and/or enlarging T2 lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	411	410
Number [lesions]	1916	430

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Negative Binomial Model
	Comments
Method of Estimation	Estimation Parameter	Adjusted rate ratio
	Estimated Value	0.229
	Confidence Interval	() 95%; 0.174 to 0.300
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted by baseline T2 lesion (present or not), baseline EDSS (<4.0 vs. >=4.0) and geographical region (US vs. rest-of-world). Adjusted rate ratio was calculated as Ocrelizumab adjusted rate/Interferon beta-1a 44 mcg SC adjusted rate.

5. Secondary Outcome

Title	Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks
Description	Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of >= 2.0. It was defined as a reduction in EDSS score of: A) >=1.0 from the baseline EDSS score when the baseline score was >=2 and <=5.5 B) >= 0.5 when the baseline EDSS score > 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study. Here, number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	306	310
Number (95% Confidence Interval) [percentage of participants]	12.42 3%	20.00 4.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0106
	Comments
	Method	CMH Chi-Squared test (stratified)
	Comments	CMH (Cochran-Mantel-Haenszel) Chi-Squared test Stratified by Geographical Region (US vs. Rest of World) and Baseline EDSS (<4.0 vs. >=4.0)
Method of Estimation	Estimation Parameter	Relative risk (stratified)
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; 1.11 to 2.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks During the Double-Blind Treatment Period
Description	Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.
Time Frame	Week 108

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	411	410
Median (Full Range) [weeks]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	Time to onset CDP at week 24
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0278
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.34 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Number of T1 Hypointense Lesions During the Double-Blind Treatment
Description	The total number of new T1-Hypo-Intense Lesions (Chronic Black Holes) for all participants in the treatment group was calculated as the sum of the individual number of new lesions at Weeks 24, 48, and 96.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	411	410
Number [lesions]	1307	564

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Negative Binomial Model
	Comments
Method of Estimation	Estimation Parameter	Adjusted rate ratio
	Estimated Value	0.428
	Confidence Interval	() 95%; 0.328 to 0.557
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted by baseline T1-hypointense lesion count, baseline EDSS (<4.0 vs. >=4.0) and geographical region (US vs. rest-of-world). Adjusted rate ratio was calculated as Ocrelizumab adjusted rate/Interferon beta-1a 44 mcg SC adjusted rate.

8. Secondary Outcome

Title	Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96
Description	MSFC score consists of: A) Timed 25-Foot walk; B) 9-Hole Peg Test (9-HPT); and C) Paced Auditory Serial Addition Test (PASAT-3 version). The MSFCS is based on the concept that scores for these three dimensions (arm, leg, and cognitive function) are combined to create a single score (the MSFC) that can be used to detect change over time in a group of participants with MS. Since the three primary measures differ in what they actually measure, a common composite score for the three different measures i.e., Z- score was selected for the purpose. MSFC Score = {Z arm, average + Z leg, average + Z cognitive} / 3.0. The results from each of these three tests are transformed into Z-scores and averaged to yield a composite score for each participant at each time point. A score of +1 indicates that, on average, an individual scored 1 standard deviation (SD) better than the reference population and a score of -1 indicates that an individual scored 1 SD worse than the reference population.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study. Here, n signifies the number of participants evaluable at specified time points.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	411	410
Unadjusted Baseline mean (n= 359, 360)	0.028 (0.034)	-0.012 (0.040)
Adjusted Week 96 mean (n= 308, 322)	0.174 (0.031)	0.213 (0.031)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	= 0.3261
	Comments
	Method	mixed-effect model of repeated measures
	Comments	Estimates are from analysis based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix.
Method of Estimation	Estimation Parameter	Difference in Adjusted Means
	Estimated Value	0.039
	Confidence Interval	(2-Sided) 95%; -0.039 to 0.116
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.039
	Estimation Comments	Difference in adjusted means was calculated as Ocrelizumab adjusted mean at Week 96/ Interferon beta-1a 44 mcg SC adjusted mean at Week 96.

9. Secondary Outcome

Title	Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96
Description	Brain volume was recorded as an absolute "normalized" value at the baseline visit then recorded at subsequent visits as a percentage change relative to the absolute value at the baseline visit. Therefore, brain volume at Week 24 was calculated as the brain volume at the baseline visit multiplied by 1 + ([percentage change in brain volume from baseline visit to Week 24]/100). Estimates are from analysis based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: Percentage Change = Brain Volume at Week 24 + Geographical Region (US vs. ROW) + Baseline EDSS (< 4.0 vs. >= 4.0) + Week + Treatment + Treatment*Week (repeated values over Week) + Brain Volume at Week 24*Week.
Time Frame	From Week 24 up to Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study. Here, number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	267	281
Mean (Standard Error) [percent change]	-0.741 (0.046)	-0.572 (0.044)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0042
	Comments
	Method	mixed-effect model of repeated measures
	Comments	Estimates are from analysis based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix.
Method of Estimation	Estimation Parameter	Difference in Adjusted Means
	Estimated Value	0.168
	Confidence Interval	(2-Sided) 95%; 0.053 to 0.283
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.058
	Estimation Comments	Difference in the rate of brain volume loss: 22.8%. Difference in adjusted means was calculated as Ocrelizumab adjusted mean at Week 96/ Interferon beta-1a 44 mcg SC adjusted mean at Week 96.

10. Secondary Outcome

Title	Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96
Description	The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to 2 distinct higher-ordered clusters: the PCS and mental composite t-score (MCS). The range for all 8 domains as well as for the composite t- scores is from 0 to 100 with 100 as best possible health status and 0 as worst health status.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Descriptive statistics at baseline include participants with assessment at baseline and at least one post- baseline value. ITT population included all randomized participants in the study. Here, n signifies the number of participants evaluable at specified time points.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	411	410
Unadjusted Baseline mean (n= 338, 357)	45.399 (0.529)	45.065 (0.507)
Adjusted mean change at week 96 (n= 276, 315)	-0.657 (0.475)	0.036 (0.456)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	= 0.2193
	Comments
	Method	mixed-effect model of repeated measures
	Comments	Estimates are from analysis based on mixed-effect model of repeated measures using unstructured covariance matrix.
Method of Estimation	Estimation Parameter	Difference in Adjusted Means
	Estimated Value	0.693
	Confidence Interval	(2-Sided) 95%; -0.414 to 1.800
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.564
	Estimation Comments	Difference in adjusted means was calculated as Ocrelizumab adjusted mean at Week 96/ Interferon beta-1a 44 mcg SC adjusted mean at Week 96.

11. Secondary Outcome

Title	Percentage of Participants Who Have No Evidence of Disease Activity (NEDA) up to Week 96
Description	NEDA was defined only for participants with a baseline EDSS score >=2.0. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). Participants who completed the 96- week treatment period were considered as having evidence of disease activity if at least one protocol- defined relapse (PDR), a confirmed disability progression (CDP) event or at least one MRI scan showing MRI activity (defined as Gd-enhancing T1 lesions, or new or enlarging T2 lesions) was reported during the 96-week treatment period, otherwise the participant was considered as having NEDA.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study. Here, number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	291	289
Number (95% Confidence Interval) [percentage of participants]	27.1 6.6%	47.4 11.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	CMH Chi-Squared test (stratified)
	Comments	Analyzed using CMH test, stratified by Geographical Region (US vs. rest-of-world) and baseline EDSS (<4.0 vs. >=4.0).
Method of Estimation	Estimation Parameter	Relative risk (stratified)
	Estimated Value	1.74
	Confidence Interval	(2-Sided) 95%; 1.39 to 2.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	AEs included infusion related reactions (IRRs) and serious MS relapses, but excluded non-serious MS relapses. Serious Adverse Events (SAEs) included serious MS relapses and serious IRRs.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received any study drug.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	409	408
Number [Participants]	331 80.5%	327 79.8%

13. Secondary Outcome

Title	Exposure to Ocrelizumab (Area Under the Concentration - Time Curve, AUC)
Description	AUC represents total drug exposure for one dosing interval after the 4th dose.
Time Frame	Pre-infusion at Weeks 1, 24, 48, 72; and 30 minutes post-infusion at Week 72; at any time during Weeks 84 and 96

Outcome Measure Data

Analysis Population Description

The pharmacokinetics (PK) population included all participants in the ocrelizumab group who had at least 1 measurable concentration value.

Arm/Group Title	Ocrelizumab
Arm/Group Description	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	393
Mean (Standard Deviation) [micrograms per milliliter*day]	3513 (955)

14. Secondary Outcome

Title	Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab
Description	Number of participants positive for anti-drug antibodies (ADAs) to ocrelizumab is the number of post- baseline evaluable participants determined to have treatment-induced ADA or treatment-enhanced ADA during the study period.
Time Frame	Baseline up to week 96

Outcome Measure Data

Analysis Population Description

Baseline evaluable participants with an ADA assay result from a baseline sample(s). The safety population included all participants who received any study drug. Here, n signifies the number of participants evaluable at the specified time points.

Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Measure Participants	409	408
Positive sample at baseline (n= 397, 396)	2 0.5%	1 0.2%
Positive for ADA post-baseline (n= 401, 402)	2 0.5%	1 0.2%

Adverse Events

Time Frame	Baseline to week 96 (Double Blind Treatment Period)
Arm/Group Title	Interferon Beta-1a 44 mcg SC		Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).		Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
All Cause Mortality
	Interferon Beta-1a 44 mcg SC		Ocrelizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Interferon Beta-1a 44 mcg SC		Ocrelizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/409 (7.8%)		28/408 (6.9%)
Blood and lymphatic system disorders
Leukopenia	1/409 (0.2%)		0/408 (0%)
Cardiac disorders
Atrial flutter	0/409 (0%)		1/408 (0.2%)
Cardiac failure congestive	0/409 (0%)		1/408 (0.2%)
Eye disorders
Retinal artery occlusion	1/409 (0.2%)		0/408 (0%)
Gastrointestinal disorders
Gastritis	0/409 (0%)		1/408 (0.2%)
Pancreatitis	0/409 (0%)		1/408 (0.2%)
Pancreatitis acute	0/409 (0%)		1/408 (0.2%)
General disorders
Chest pain	0/409 (0%)		2/408 (0.5%)
Hepatobiliary disorders
Cholelithiasis	0/409 (0%)		2/408 (0.5%)
Cholecystitis	0/409 (0%)		1/408 (0.2%)
Cholecystitis chronic	0/409 (0%)		1/408 (0.2%)
Immune system disorders
Drug hypersensitivity	1/409 (0.2%)		1/408 (0.2%)
Infections and infestations
Cellulitis	1/409 (0.2%)		2/408 (0.5%)
Abscess limb	2/409 (0.5%)		0/408 (0%)
Appendicitis	2/409 (0.5%)		0/408 (0%)
Acute tonsillitis	1/409 (0.2%)		0/408 (0%)
Biliary sepsis	0/409 (0%)		1/408 (0.2%)
Device related infection	0/409 (0%)		1/408 (0.2%)
Enterocolitis infectious	1/409 (0.2%)		0/408 (0%)
Gastroenteritis	1/409 (0.2%)		0/408 (0%)
Herpes simplex	0/409 (0%)		1/408 (0.2%)
Injection site cellulitis	1/409 (0.2%)		0/408 (0%)
Perirectal abscess	1/409 (0.2%)		0/408 (0%)
Septic arthritis staphylococcal	1/409 (0.2%)		0/408 (0%)
Urinary tract infection	1/409 (0.2%)		0/408 (0%)
Injury, poisoning and procedural complications
Ankle fracture	1/409 (0.2%)		0/408 (0%)
Craniocerebral injury	0/409 (0%)		1/408 (0.2%)
Hand fracture	1/409 (0.2%)		0/408 (0%)
Humerus fracture	0/409 (0%)		1/408 (0.2%)
Infusion related reaction	0/409 (0%)		1/408 (0.2%)
Multiple injuries	1/409 (0.2%)		0/408 (0%)
Overdose	1/409 (0.2%)		0/408 (0%)
Post procedural haematoma	1/409 (0.2%)		0/408 (0%)
Procedural pain	0/409 (0%)		1/408 (0.2%)
Tibia fracture	1/409 (0.2%)		0/408 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms	0/409 (0%)		1/408 (0.2%)
Rheumatoid Arthritis	1/409 (0.2%)		0/408 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma	0/409 (0%)		2/408 (0.5%)
Uterine leiomyoma	2/409 (0.5%)		0/408 (0%)
Mantle cell lymphoma	1/409 (0.2%)		0/408 (0%)
Renal cancer	0/409 (0%)		1/408 (0.2%)
Salivary gland adenoma	1/409 (0.2%)		0/408 (0%)
Nervous system disorders
Multiple sclerosis relapse	3/409 (0.7%)		0/408 (0%)
Epilepsy	1/409 (0.2%)		1/408 (0.2%)
Seizure	0/409 (0%)		2/408 (0.5%)
Aphasia	1/409 (0.2%)		0/408 (0%)
Dizziness	0/409 (0%)		1/408 (0.2%)
Dysarthria	1/409 (0.2%)		0/408 (0%)
Ruptured cerebral aneurysm	1/409 (0.2%)		0/408 (0%)
Sciatica	0/409 (0%)		1/408 (0.2%)
Psychiatric disorders
Depression	0/409 (0%)		2/408 (0.5%)
Anxiety	0/409 (0%)		1/408 (0.2%)
Completed suicide	1/409 (0.2%)		0/408 (0%)
Suicide attempt	0/409 (0%)		1/408 (0.2%)
Reproductive system and breast disorders
Endometriosis	0/409 (0%)		1/408 (0.2%)
Menorrhagia	0/409 (0%)		1/408 (0.2%)
Ovarian cyst	1/409 (0.2%)		0/408 (0%)
Respiratory, thoracic and mediastinal disorders
Hyperventilation	1/409 (0.2%)		0/408 (0%)
Sinus congestion	1/409 (0.2%)		0/408 (0%)
Surgical and medical procedures
Mammoplasty	1/409 (0.2%)		0/408 (0%)
Other (Not Including Serious) Adverse Events
	Interferon Beta-1a 44 mcg SC		Ocrelizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	257/409 (62.8%)		241/408 (59.1%)
General disorders
Influenza like illness	85/409 (20.8%)		15/408 (3.7%)
Injection site erythema	74/409 (18.1%)		0/408 (0%)
Fatigue	28/409 (6.8%)		21/408 (5.1%)
Infections and infestations
Urinary tract infection	56/409 (13.7%)		52/408 (12.7%)
Upper respiratory tract infection	35/409 (8.6%)		59/408 (14.5%)
Nasopharyngitis	43/409 (10.5%)		43/408 (10.5%)
Sinusitis	25/409 (6.1%)		19/408 (4.7%)
Injury, poisoning and procedural complications
Infusion related reaction	30/409 (7.3%)		125/408 (30.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	28/409 (6.8%)		25/408 (6.1%)
Back pain	20/409 (4.9%)		25/408 (6.1%)
Nervous system disorders
Headache	54/409 (13.2%)		33/408 (8.1%)
Psychiatric disorders
Depression	24/409 (5.9%)		28/408 (6.9%)
Insomnia	15/409 (3.7%)		21/408 (5.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.