SYNERGY: Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Participants With Relapsing Forms of Multiple Sclerosis When Used Concurrently With Avonex

• Sponsor: Biogen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01864148
• Collaborator: (none)
• Enrollment: 419
• Locations: 72
• Arms: 5
• Duration (Months): 31
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary objective of the study is to evaluate the efficacy of BIIB033 in participants with active relapsing multiple sclerosis (MS) when used concurrently with Avonex.

Secondary objectives of this study in this study population are to assess the safety, tolerability, and population pharmacokinetics of BIIB033 when used concurrently with Avonex.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: BIIB033; Other: Placebo; Drug: Avonex	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 419 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Ranging Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Subjects With Relapsing Forms of Multiple Sclerosis When Used Concurrently With Avonex
• Study Start Date: Aug 1, 2013
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BIIB033, 3 mg/kg BIIB033 3 mg/kg once every 4 weeks intravenous (IV) infusion up to Week 72. Avonex once-weekly intramuscular (IM) injection up to Week 84.	Drug: BIIB033; Other Names: anti-LINGO-1 mAb ; Drug: Avonex; Other Names: interferon beta-1a
Experimental: BIIB033, 10 mg/kg BIIB033 10 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	Drug: BIIB033; Other Names: anti-LINGO-1 mAb ; Drug: Avonex; Other Names: interferon beta-1a
Experimental: BIIB033, 30 mg/kg BIIB033 30 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	Drug: BIIB033; Other Names: anti-LINGO-1 mAb ; Drug: Avonex; Other Names: interferon beta-1a
Experimental: BIIB033, 100 mg/kg BIIB033 100 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	Drug: BIIB033; Other Names: anti-LINGO-1 mAb ; Drug: Avonex; Other Names: interferon beta-1a
Placebo Comparator: Placebo Placebo once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	Other: Placebo; Drug: Avonex; Other Names: interferon beta-1a

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants Confirmed as Improvement Responders for Primary Multicomponent Endpoint [72 weeks]

   Estimated proportion of participants experiencing confirmed improvement in any 1 or more of the following components: a ≥1 point decrease in the Expanded Disability Status Scale (EDSS) score from a baseline score of <=6.0 (decrease sustained for ≥3 months); a ≥15% improvement from baseline in time to complete 9-Hole Peg Test (9HPT) by either hand (improvement sustained for ≥3 months for the same hand), where the time is the average time of 2 trials per hand at the same visit; a ≥15% improvement from baseline in time to complete Timed 25-Foot Walk (T25FW) test (improvement sustained for ≥3 months), where the time is the average time of 2 trials at the same visit; or a ≥15% improvement from baseline 3-Second Paced Auditory Serial Addition Test (PASAT-3) score (improvement sustained for 3 months or greater). Estimated proportion of responders is based on logistic regression adjusted for multiple sclerosis (MS) type, region and baseline component assessments.

Secondary Outcome Measures

1. Proportion of Participants Confirmed as Worsening Responders for Primary Multicomponent Endpoint [72 weeks]

   Estimated proportion of participants experiencing confirmed clinical worsening in 1 or more components of the multicomponent endpoint (EDSS, T25FW, 9HPT, or PASAT-3) over 72 weeks, defined as: a ≥1.0 point increase in EDSS from a baseline score of ≤5.5 or a ≥0.5 point increase from a baseline score equal to 6.0 (increase sustained for 3 months or greater); a ≥15%worsening from baseline in time to complete T25FW test (worsening sustained for 3 months or greater), where the time is the average of 2 trials at the same visit; a ≥15% worsening from baseline in time to complete 9HPT by either hand (worsening sustained for 3 months or greater for the same hand), where the time is the average of 2 trials for each hand at the same visit; a ≥15% worsening from baseline in PASAT-3 score (worsening sustained for 3 months or greater). Estimated proportion of responders is based on logistic regression adjusted for MS type, region and baseline component assessments.

2. Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) and Discontinuations Due to AEs [Up to 84 weeks]

   An AE was any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigators, placed the participant at immediate risk of death (a life-threatening event); however, this did not include an event that, had it occurred in a more severe form, might have caused death; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigators, could have jeopardized the participant or may have required intervention to prevent one of the other outcomes listed in the definition above.

3. Pharmacokinetics: BIIB033 Plasma Concentrations up to Week 84 [Up to 84 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 58 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Diagnosis of relapsing remitting MS (RRMS) or onset of secondary progressive MS (SPMS)

• RRMS and SPMS subjects must have evidence of ongoing disease activity within 12 months of enrollment.

• All male and female subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for at least 6 months after their last dose of study treatment

Key Exclusion Criteria:

• A MS relapse that has occurred within the 90 days prior to Day 1/Baseline and/or the subject has not stabilized from a previous relapse prior to Screening

• Previous history of clinically significant disease.

• Plans to undergo elective major procedures/surgeries at any time during the study.

• Treatment with any investigational MS drugs within 3 weeks or 5 times the half life (whichever is longer) prior to Day 1/Baseline

• RRMS subjects with any history of inadequate response to any approved interferon β preparation

• History of human immunodeficiency virus (HIV), hepatitis C virus antibody, or hepatitis B virus

• History or evidence of drug or alcohol abuse within 2 years prior to randomization

Note: Other protocol defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	North Central Neurology Assoc PC	Cullman	Alabama	United States	35058
2	Phoenix Neurological Associates	Phoenix	Arizona	United States	85018
3	Raleigh Neurology Associates PA	Raleigh	California	United States	27607-6000
4	Stanford University Medical Center	Stanford	California	United States	94305
5	Immunoe International Research Center	Centennial	Colorado	United States	80112
6	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
7	Michigan Institute For Neurological Disorders	Farmington Hills	Michigan	United States	48334
8	Washington University	Saint Louis	Missouri	United States	63110
9	Multiple Sclerosis Center of North Eastern New York	Latham	New York	United States	12110
10	OMRF Multiple Sclerosis Center of Excellence	Oklahoma City	Oklahoma	United States	73104
11	Swedish Medical Center	Seattle	Washington	United States	98122
12	Research Site	Ottowa	Ontario	Canada
13	Research Site	Gatinueau	Quebec	Canada
14	Research Site	Greenfield Park	Quebec	Canada
15	Research Site	Levis	Quebec	Canada
16	Research Site	Montreal	Quebec	Canada
17	London Health Sciences Centre	London		Canada	N6A 5A5
18	Vseobecna Fakultni Nemocnice V Praze	Praha	Hlavní Mesto	Czech Republic	128 08
19	Fakultni Nemocnice Hradec Kralove	Hradec Králové	Královéhradecký kraj	Czech Republic	500 05
20	Nemocnice Jihlava Prispevkova Organizace	Jihlava	Vysocina	Czech Republic	586 33
21	NEUROSPOL Sro	Havirov		Czech Republic	736 01
22	Fakultni nemocnice v Motole	Praha 5		Czech Republic	150 06
23	Krajska Zdravotni a.s. Nemocnice Teplice Oz	Teplice	Ústecký kraj	Czech Republic	415 29
24	Hôpital Guillaume Et René Laënnec	Nantes	Loire-Atlantique	France	44805
25	Hôpital Maison Blanche	Reims	Marne	France	51092
26	Hôpital Roger Salengro	Lille	Nord	France	59000
27	Hôpital Sud	Amiens	Somme	France	80054
28	Hopital Gabriel Montpied	Clermont-Ferrand		France	63003
29	CHRU Nancy	Nancy		France	54000
30	Fondation Rothschild	Paris		France	75019
31	Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ	Szeged	Csongrád	Hungary	6725
32	Uzsoki Utcai Korhaz	Budapest		Hungary	1145
33	Jahn Ferenc Dél-Pesti Kórház és Rendelöintézet	Budapest		Hungary	1204
34	Pécsi Tudományegyetem	Pécs		Hungary	7623
35	Azienda Ospedaliera Universitaria San Martino	Genova	Liguria	Italy	16132
36	Ospedale San Raffaele S.r.l.	Milano	Lombardia	Italy	20127
37	Azienda Ospedaliera Spedali Civili di Brescia - Presidio Ospedaliero di Montichiari	Montichiari	Lombardia	Italy	25018
38	Fondazione Istituto San Raffaele G. Giglio di Cefalù	Cefalù	Palermo	Italy	90015
39	Azienda Ospedaliero Universitaria Policlinico-Vittorio Emanuele	Catania	Sicilia	Italy	95123
40	Azienda Ospedaliera S. Antonio Abate di Gallarate	Gallarate	Varese	Italy	21013
41	Erasmus MC	Rotterdam	Zuid-Holland	Netherlands	3015 CE
42	Zuyderland Medisch Centrum	Sittard-Geleen		Netherlands	6162 BG
43	Centrum Neurologii K. Selmaj	Lódz	Lódzkie	Poland	93-121
44	Wojskowy Instytut Medyczny	Warszawa	Mazowieckie	Poland	00-901
45	Novo-Med Zielinski i wsp. Sp.J.	Katowice	Slaskie	Poland	40-650
46	Pomorskie Centrum Traumatologii im. M. Kopernika w Gdansku	Gdansk		Poland	80-803
47	Regionalny Szpital Specjalistyczny im. dr Wladyslawa Bieganskiego	Grudziądz		Poland	86-300
48	M.A.- Lek A.M.Maciejowscy Spolka Cywilna	Katowice		Poland	40-595
49	Gabriela Klodowska-Duda Neuro-Care NZOZ Site Management Organization	Katowice		Poland	40-749
50	Neurologiczny NZOZ Centrum Leczenia SM Osrodek Badan Klinicznych Dr n. med. Hanka Hertmanowska	Plewiska		Poland	62-064
51	Niepubliczny Zaklad Opieki Zdrowotnej NEURO-KARD Ilkowski i Partnerzy Spolka Partnerska Lekarzy	Poznan		Poland	61-853
52	SPZOZ Wojewodzki Szpital Specjalistyczny w Rybniku	Rybnik		Poland	44-200
53	EUROMEDIS Sp. z o.o.	Szczecin		Poland	70-215
54	Kaluga Regional Hospital	Kaluga		Russian Federation	248007
55	Republican Clinical Hospital For Rehabilitation Treatment	Kazan		Russian Federation	420021
56	Krasnoyarsk State Medical Academy	Krasnoyarsk		Russian Federation	660049
57	Perm State Medical Academy	Perm		Russian Federation	614990
58	City Center of MS Treatment based on Saint-Petersburg City Clinical Hospital #31	Saint-Petersburg		Russian Federation	197110
59	Regional Clinical Hospital #3	Volgograd		Russian Federation	400001
60	Clinical Center of Serbia	Belgrade		Serbia	11000
61	Military Medical Academy	Belgrade		Serbia	11000
62	Clinical Center Kragujevac	Kragujevac		Serbia	34000
63	General Hospital Uzice	Uzice		Serbia	31000
64	Hospital Universitari de Bellvitge	l Hospitalet de Llobregat	Barcelona	Spain	8907
65	Hospital Universitario Vall d'Hebron	Barcelona	Cataluña	Spain	8035
66	Hospital Universitario Reina Sofia	Cordoba	Córdoba	Spain	14008
67	Hospital Clinico San Carlos	Madrid	Madrid, Communidad Delaware	Spain	28040
68	Hospital Universitario Puerta de Hierro Majadahonda	Majadahonda	Madrid	Spain	28222
69	Hospital de Basurto Osakidetza	Bilbao	Vizcaya	Spain	48013
70	Hospital General Carlos Haya	Malaga		Spain	29010
71	Hospital Universitario Virgen Macarena	Sevilla		Spain	41071
72	Queen's Medical Centre	Nottingham	Nottinghamshire	United Kingdom	NG5 1PB

Sponsors and Collaborators

• Biogen

Investigators

• Study Director: Medical Director, Biogen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT01864148
• Other Study ID Numbers: 215MS201; 2011-006262-40
• First Posted: May 29, 2013
• Last Update Posted: May 3, 2017
• Last Verified: Mar 1, 2017

• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Interferons; Interferon-beta; Interferon beta-1a

Study Results

Participant Flow

Pre-assignment Detail	A total of 419 participants were randomized; 1 participant was not dosed.

Arm/Group Title	Placebo	BIIB033, 3 mg/kg	BIIB033, 10 mg/kg	BIIB033, 30 mg/kg	BIIB033, 100 mg/kg
Arm/Group Description	Placebo once every 4 weeks intravenous (IV) infusion up to Week 72. Avonex once-weekly intramuscular (IM) injection up to Week 84.	BIIB033 3 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 10 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 30 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 100 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.
Period Title: Overall Study
STARTED	93	45	95	94	92
Randomized and Dosed	93	45	95	93	92
COMPLETED	73	40	84	68	69
NOT COMPLETED	20	5	11	26	23

Baseline Characteristics

Arm/Group Title	Placebo	BIIB033, 3 mg/kg	BIIB033, 10 mg/kg	BIIB033, 30 mg/kg	BIIB033, 100 mg/kg	Total
Arm/Group Description	Placebo once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 3 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 10 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 30 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 100 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	Total of all reporting groups
Overall Participants	93	45	95	93	92	418
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.5 (9.29)	36.5 (9.47)	40.5 (9.78)	40.9 (9.70)	39.8 (9.10)	39.8 (9.51)
Sex: Female, Male (Count of Participants)
Female	67 72%	24 53.3%	59 62.1%	61 65.6%	66 71.7%	277 66.3%
Male	26 28%	21 46.7%	36 37.9%	32 34.4%	26 28.3%	141 33.7%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants Confirmed as Improvement Responders for Primary Multicomponent Endpoint
Description	Estimated proportion of participants experiencing confirmed improvement in any 1 or more of the following components: a ≥1 point decrease in the Expanded Disability Status Scale (EDSS) score from a baseline score of <=6.0 (decrease sustained for ≥3 months); a ≥15% improvement from baseline in time to complete 9-Hole Peg Test (9HPT) by either hand (improvement sustained for ≥3 months for the same hand), where the time is the average time of 2 trials per hand at the same visit; a ≥15% improvement from baseline in time to complete Timed 25-Foot Walk (T25FW) test (improvement sustained for ≥3 months), where the time is the average time of 2 trials at the same visit; or a ≥15% improvement from baseline 3-Second Paced Auditory Serial Addition Test (PASAT-3) score (improvement sustained for 3 months or greater). Estimated proportion of responders is based on logistic regression adjusted for multiple sclerosis (MS) type, region and baseline component assessments.
Time Frame	72 weeks

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all randomized participants who received at least 1 dose of study treatment and included in the efficacy analysis (6 participants were excluded due to study site Good Clinical Practice deviation).

Arm/Group Title	Placebo	BIIB033, 3 mg/kg	BIIB033, 10 mg/kg	BIIB033, 30 mg/kg	BIIB033, 100 mg/kg
Arm/Group Description	Placebo once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 3 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 10 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 30 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 100 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.
Measure Participants	91	45	94	91	91
Number [proportion of participants]	0.516 0.6%	0.511 1.1%	0.656 0.7%	0.688 0.7%	0.412 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, BIIB033, 3 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9584
	Comments
	Method	Regression, Logistic
	Comments	Odds ratios, 95% CI and p-values are based on logistic regression adjusted for MS type, region and baseline component assessments.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.46 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, BIIB033, 10 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0636
	Comments
	Method	Regression, Logistic
	Comments	Odds ratios, 95% CI and p-values are based on logistic regression adjusted for MS type, region and baseline component assessments.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.79
	Confidence Interval	(2-Sided) 95%; 0.97 to 3.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, BIIB033, 30 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0220
	Comments
	Method	Regression, Logistic
	Comments	Odds ratios, 95% CI and p-values are based on logistic regression adjusted for MS type, region and baseline component assessments.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.06
	Confidence Interval	(2-Sided) 95%; 1.11 to 3.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, BIIB033, 100 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1771
	Comments
	Method	Regression, Logistic
	Comments	Odds ratios, 95% CI and p-values are based on logistic regression adjusted for MS type, region and baseline component assessments.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.36 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, BIIB033, 3 mg/kg, BIIB033, 10 mg/kg, BIIB033, 30 mg/kg, BIIB033, 100 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8931
	Comments
	Method	Trend test
	Comments	Trend test p-value is based on a linear contrast in logistic regression.

2. Secondary Outcome

Title	Proportion of Participants Confirmed as Worsening Responders for Primary Multicomponent Endpoint
Description	Estimated proportion of participants experiencing confirmed clinical worsening in 1 or more components of the multicomponent endpoint (EDSS, T25FW, 9HPT, or PASAT-3) over 72 weeks, defined as: a ≥1.0 point increase in EDSS from a baseline score of ≤5.5 or a ≥0.5 point increase from a baseline score equal to 6.0 (increase sustained for 3 months or greater); a ≥15%worsening from baseline in time to complete T25FW test (worsening sustained for 3 months or greater), where the time is the average of 2 trials at the same visit; a ≥15% worsening from baseline in time to complete 9HPT by either hand (worsening sustained for 3 months or greater for the same hand), where the time is the average of 2 trials for each hand at the same visit; a ≥15% worsening from baseline in PASAT-3 score (worsening sustained for 3 months or greater). Estimated proportion of responders is based on logistic regression adjusted for MS type, region and baseline component assessments.
Time Frame	72 weeks

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all randomized participants who received at least 1 dose of study treatment and included in the efficacy analysis (6 participants were excluded due to study site Good Clinical Practice deviation).

Arm/Group Title	Placebo	BIIB033, 3 mg/kg	BIIB033, 10 mg/kg	BIIB033, 30 mg/kg	BIIB033, 100 mg/kg
Arm/Group Description	Placebo once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 3 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 10 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 30 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 100 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.
Measure Participants	91	45	94	91	91
Number [proportion of participants]	0.403 0.4%	0.304 0.7%	0.509 0.5%	0.489 0.5%	0.369 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, BIIB033, 3 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3058
	Comments
	Method	Regression, Logistic
	Comments	Odds ratios, 95% CI and p-values are based on logistic regression adjusted for MS type, region and baseline component assessments.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.28 to 1.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, BIIB033, 10 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1873
	Comments
	Method	Regression, Logistic
	Comments	Odds ratios, 95% CI and p-values are based on logistic regression adjusted for MS type, region and baseline component assessments.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.53
	Confidence Interval	(2-Sided) 95%; 0.81 to 2.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, BIIB033, 30 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2766
	Comments
	Method	Regression, Logistic
	Comments	Odds ratios, 95% CI and p-values are based on logistic regression adjusted for MS type, region and baseline component assessments.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 95%; 0.76 to 2.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, BIIB033, 100 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6578
	Comments
	Method	Regression, Logistic
	Comments	Odds ratios, 95% CI and p-values are based on logistic regression adjusted for MS type, region and baseline component assessments.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.45 to 1.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, BIIB033, 3 mg/kg, BIIB033, 10 mg/kg, BIIB033, 30 mg/kg, BIIB033, 100 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5255
	Comments
	Method	Trend test
	Comments	Trend test p-value is based on a linear contrast in logistic regression.

3. Secondary Outcome

Title	Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) and Discontinuations Due to AEs
Description	An AE was any untoward medical occurrence that did not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence that at any dose: resulted in death; in the view of the Investigators, placed the participant at immediate risk of death (a life-threatening event); however, this did not include an event that, had it occurred in a more severe form, might have caused death; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigators, could have jeopardized the participant or may have required intervention to prevent one of the other outcomes listed in the definition above.
Time Frame	Up to 84 weeks

Outcome Measure Data

Analysis Population Description

Safety Population: all participants who received at least 1 dose of study treatment.

Arm/Group Title	Placebo	BIIB033, 3 mg/kg	BIIB033, 10 mg/kg	BIIB033, 30 mg/kg	BIIB033, 100 mg/kg	BIIB033 Total
Arm/Group Description	Placebo once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 3 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 10 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 30 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 100 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 3, 10, 30, or 100 mg/kg once every 4 weeks IV infusion
Measure Participants	93	45	95	93	92	325
Any event	79 84.9%	39 86.7%	84 88.4%	79 84.9%	73 79.3%	275 65.8%
Moderate or severe event	59 63.4%	26 57.8%	59 62.1%	59 63.4%	58 63%	202 48.3%
Severe event	7 7.5%	2 4.4%	6 6.3%	6 6.5%	7 7.6%	21 5%
BIIB033/placebo-related event	8 8.6%	8 17.8%	15 15.8%	12 12.9%	16 17.4%	51 12.2%
Avonex-related event	51 54.8%	28 62.2%	58 61.1%	54 58.1%	50 54.3%	190 45.5%
Serious event	13 14%	4 8.9%	11 11.6%	20 21.5%	16 17.4%	51 12.2%
BIIB033/placebo-related serious event	1 1.1%	0 0%	0 0%	1 1.1%	5 5.4%	6 1.4%
Avonex-related serious event	1 1.1%	0 0%	0 0%	2 2.2%	1 1.1%	3 0.7%
Event leading to discontinuation of treatment	4 4.3%	2 4.4%	3 3.2%	7 7.5%	8 8.7%	20 4.8%
Event leading to withdrawal from study	4 4.3%	2 4.4%	4 4.2%	8 8.6%	7 7.6%	21 5%

4. Secondary Outcome

Title	Pharmacokinetics: BIIB033 Plasma Concentrations up to Week 84
Time Frame	Up to 84 weeks

Outcome Measure Data

Analysis Population Description

PK Population: participants who received at least 1 dose of BIIB033 and had at least 1 serum concentration data point on record.

Arm/Group Title	BIIB033, 3 mg/kg	BIIB033, 10 mg/kg	BIIB033, 30 mg/kg	BIIB033, 100 mg/kg
Arm/Group Description	BIIB033 3 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 10 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 30 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.	BIIB033 100 mg/kg once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.
Measure Participants	45	95	92	92
Baseline, predose; n=44, 95, 92, 92	0.00 (0.00)	0.01 (0.13)	7.79 (74.75)	0.42 (4.07)
Baseline, postdose; n=44, 95, 91, 92	66.70 (16.00)	244.76 (77.90)	688.47 (245.73)	2298.20 (712.91)
Week 4, predose; n=45, 93, 91, 88	10.82 (4.11)	46.28 (33.15)	138.54 (92.82)	457.96 (308.09)
Week 4, postdose; n=45, 94, 89, 85	123.96 (315.66)	279.67 (100.01)	784.08 (204.31)	2763.26 (823.42)
Week 8, predose; n=45, 95, 89, 85	23.55 (54.96)	65.48 (52.53)	195.29 (118.24)	603.11 (425.58)
Week 8, postdose; n=44, 94, 88, 79	86.29 (52.74)	294.44 (78.61)	861.60 (274.56)	2751.25 (697.42)
Week 16, predose; n=43, 94, 86, 79	19.96 (9.74)	71.80 (25.13)	231.94 (125.42)	695.11 (438.57)
Week 16, postdose; n=41, 93, 85, 78	85.95 (29.04)	309.38 (83.38)	881.45 (211.32)	2921.09 (1118.88)
Week 24, predose; n=42, 93, 85, 74	36.41 (85.48)	77.88 (33.68)	230.46 (77.40)	699.63 (400.49)
Week 24, postdose; n=42, 92, 82, 76	144.12 (373.36)	318.01 (84.74)	940.29 (231.35)	2870.29 (874.28)
Week 36, predose; n=41, 88, 79, 74	25.33 (18.28)	85.05 (44.67)	238.48 (73.75)	725.22 (344.01)
Week 36, postdose; n=42, 88, 77, 73	94.62 (21.89)	339.17 (88.96)	197.86 (197.96)	3048.66 (989.34)
Week 48, predose; n=39, 85, 74, 70	20.78 (6.26)	80.28 (31.62)	272.88 (167.79)	806.70 (541.78)
Week 48, postdose; n=42, 85, 75, 72	90.07 (23.37)	334.12 (78.43)	955.25 (193.34)	3167.07 (1144.25)
Week 60, predose; n=41, 84, 70, 68	21.29 (12.34)	81.77 (30.24)	243.18 (78.57)	694.12 (200.41)
Week 60, postdose; n=42, 84, 71, 71	93.11 (35.98)	335.10 (93.29)	939.17 (255.64)	3330.70 (1076.88)
Week 72, predose; n=41, 85, 72, 68	19.53 (9.34)	78.94 (29.95)	215.09 (62.98)	819.39 (577.60)
Week 72, postdose; n=38, 84, 69, 68	82.96 (31.84)	313.13 (87.22)	868.39 (231.14)	3145.82 (1233.66)
Week 84; n=40, 81, 69, 69	2.44 (1.25)	12.77 (6.80)	46.16 (31.52)	127.69 (65.46)

Adverse Events

Time Frame	From first dosing of study treatment through end of study (Week 84)
Arm/Group Title	Placebo		BIIB033 3 mg/kg		BIIB033 10 mg/kg		BIIB033 30 mg/kg		BIIB033 100 mg/kg
Arm/Group Description	Placebo once every 4 weeks IV infusion up to Week 72. Avonex once-weekly IM injection up to Week 84.		BIIB033 3 mg/kg once every 4 weeks IV infusion		BIIB033 10 mg/kg once every 4 weeks IV infusion		BIIB033 30 mg/kg once every 4 weeks IV infusion		BIIB033 100 mg/kg once every 4 weeks IV infusion
All Cause Mortality
	Placebo		BIIB033 3 mg/kg		BIIB033 10 mg/kg		BIIB033 30 mg/kg		BIIB033 100 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		BIIB033 3 mg/kg		BIIB033 10 mg/kg		BIIB033 30 mg/kg		BIIB033 100 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/93 (14%)		4/45 (8.9%)		11/95 (11.6%)		20/93 (21.5%)		16/92 (17.4%)
Blood and lymphatic system disorders
Hypochromic anaemia	1/93 (1.1%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		0/92 (0%)
Cardiac disorders
Acute myocardial infarction	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Myocardial infarction	0/93 (0%)		0/45 (0%)		1/95 (1.1%)		0/93 (0%)		0/92 (0%)
Myocardial ischaemia	0/93 (0%)		1/45 (2.2%)		0/95 (0%)		0/93 (0%)		0/92 (0%)
Gastrointestinal disorders
Ileus	0/93 (0%)		0/45 (0%)		1/95 (1.1%)		0/93 (0%)		0/92 (0%)
Pancreatitis	0/93 (0%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		1/92 (1.1%)
Small intestinal obstruction	1/93 (1.1%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		0/92 (0%)
Hepatobiliary disorders
Bile duct stone	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Cholecystitis acute	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Drug-induced liver injury	0/93 (0%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		1/92 (1.1%)
Immune system disorders
Hypersensitivity	0/93 (0%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		4/92 (4.3%)
Infections and infestations
Cystitis	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Urinary tract infection	2/93 (2.2%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		1/92 (1.1%)
Injury, poisoning and procedural complications
Fall	0/93 (0%)		1/45 (2.2%)		0/95 (0%)		0/93 (0%)		0/92 (0%)
Femur fracture	0/93 (0%)		1/45 (2.2%)		0/95 (0%)		0/93 (0%)		0/92 (0%)
Intentional overdose	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Road traffic accident	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Investigations
Hepatic enzyme increased	1/93 (1.1%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		0/92 (0%)
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/93 (1.1%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		0/92 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Malignant melanoma	0/93 (0%)		0/45 (0%)		1/95 (1.1%)		0/93 (0%)		0/92 (0%)
Thyroid adenoma	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Uterine leiomyoma	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Nervous system disorders
Multiple sclerosis	0/93 (0%)		0/45 (0%)		1/95 (1.1%)		0/93 (0%)		0/92 (0%)
Multiple sclerosis relapse	7/93 (7.5%)		2/45 (4.4%)		6/95 (6.3%)		10/93 (10.8%)		6/92 (6.5%)
Radicular syndrome	1/93 (1.1%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		0/92 (0%)
Secondary progressive multiple sclerosis	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Seizure	1/93 (1.1%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		0/92 (0%)
Trigeminal neuralgia	0/93 (0%)		1/45 (2.2%)		0/95 (0%)		0/93 (0%)		0/92 (0%)
Psychiatric disorders
Acute psychosis	0/93 (0%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		1/92 (1.1%)
Anxiety	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Bipolar disorder	0/93 (0%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		1/92 (1.1%)
Bipolar I disorder	0/93 (0%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		1/92 (1.1%)
Suicidal ideation	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/93 (0%)		0/45 (0%)		1/95 (1.1%)		0/93 (0%)		0/92 (0%)
Menorrhagia	0/93 (0%)		0/45 (0%)		0/95 (0%)		1/93 (1.1%)		0/92 (0%)
Metrorrhagia	0/93 (0%)		0/45 (0%)		1/95 (1.1%)		0/93 (0%)		0/92 (0%)
Uterine polyp	0/93 (0%)		0/45 (0%)		0/95 (0%)		0/93 (0%)		1/92 (1.1%)
Other (Not Including Serious) Adverse Events
	Placebo		BIIB033 3 mg/kg		BIIB033 10 mg/kg		BIIB033 30 mg/kg		BIIB033 100 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/93 (79.6%)		38/45 (84.4%)		79/95 (83.2%)		70/93 (75.3%)		67/92 (72.8%)
Gastrointestinal disorders
Diarrhoea	3/93 (3.2%)		5/45 (11.1%)		3/95 (3.2%)		3/93 (3.2%)		3/92 (3.3%)
General disorders
Asthenia	8/93 (8.6%)		1/45 (2.2%)		5/95 (5.3%)		6/93 (6.5%)		3/92 (3.3%)
Chills	5/93 (5.4%)		4/45 (8.9%)		4/95 (4.2%)		8/93 (8.6%)		4/92 (4.3%)
Fatigue	8/93 (8.6%)		6/45 (13.3%)		5/95 (5.3%)		7/93 (7.5%)		7/92 (7.6%)
Influenza like illness	37/93 (39.8%)		17/45 (37.8%)		51/95 (53.7%)		34/93 (36.6%)		38/92 (41.3%)
Pyrexia	7/93 (7.5%)		9/45 (20%)		8/95 (8.4%)		12/93 (12.9%)		11/92 (12%)
Infections and infestations
Influenza	4/93 (4.3%)		3/45 (6.7%)		6/95 (6.3%)		4/93 (4.3%)		6/92 (6.5%)
Nasopharyngitis	16/93 (17.2%)		3/45 (6.7%)		12/95 (12.6%)		8/93 (8.6%)		10/92 (10.9%)
Pharyngitis	2/93 (2.2%)		5/45 (11.1%)		4/95 (4.2%)		3/93 (3.2%)		3/92 (3.3%)
Sinusitis	5/93 (5.4%)		2/45 (4.4%)		2/95 (2.1%)		0/93 (0%)		2/92 (2.2%)
Upper respiratory tract infection	13/93 (14%)		4/45 (8.9%)		21/95 (22.1%)		11/93 (11.8%)		9/92 (9.8%)
Urinary tract infection	12/93 (12.9%)		7/45 (15.6%)		14/95 (14.7%)		9/93 (9.7%)		13/92 (14.1%)
Injury, poisoning and procedural complications
Fall	10/93 (10.8%)		0/45 (0%)		4/95 (4.2%)		8/93 (8.6%)		5/92 (5.4%)
Investigations
Alanine aminotransferase increased	3/93 (3.2%)		2/45 (4.4%)		5/95 (5.3%)		6/93 (6.5%)		7/92 (7.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/93 (3.2%)		2/45 (4.4%)		4/95 (4.2%)		7/93 (7.5%)		3/92 (3.3%)
Back pain	9/93 (9.7%)		3/45 (6.7%)		9/95 (9.5%)		6/93 (6.5%)		6/92 (6.5%)
Muscle spasms	3/93 (3.2%)		3/45 (6.7%)		2/95 (2.1%)		2/93 (2.2%)		1/92 (1.1%)
Musculoskeletal pain	1/93 (1.1%)		3/45 (6.7%)		1/95 (1.1%)		2/93 (2.2%)		2/92 (2.2%)
Myalgia	5/93 (5.4%)		1/45 (2.2%)		5/95 (5.3%)		4/93 (4.3%)		3/92 (3.3%)
Pain in extremity	4/93 (4.3%)		5/45 (11.1%)		5/95 (5.3%)		7/93 (7.5%)		1/92 (1.1%)
Nervous system disorders
Headache	23/93 (24.7%)		8/45 (17.8%)		19/95 (20%)		13/93 (14%)		11/92 (12%)
Multiple sclerosis relapse	30/93 (32.3%)		17/45 (37.8%)		35/95 (36.8%)		36/93 (38.7%)		28/92 (30.4%)
Psychiatric disorders
Anxiety	4/93 (4.3%)		0/45 (0%)		5/95 (5.3%)		2/93 (2.2%)		3/92 (3.3%)
Depressed mood	2/93 (2.2%)		3/45 (6.7%)		1/95 (1.1%)		2/93 (2.2%)		1/92 (1.1%)
Depression	6/93 (6.5%)		2/45 (4.4%)		6/95 (6.3%)		7/93 (7.5%)		2/92 (2.2%)
Insomnia	1/93 (1.1%)		2/45 (4.4%)		4/95 (4.2%)		6/93 (6.5%)		5/92 (5.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.