Ofatumumab Subcutaneous Administration in Subjects With Relapsing-Remitting Multiple Sclerosis (MIRROR)

• ClinicalTrials.gov Identifier: NCT01457924
• Recruitment Status: Completed
• First Posted: October 24, 2011
• Results First Posted: March 1, 2018
• Last Update Posted: June 6, 2018
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Multiple Sclerosis
• Interventions: Drug: Ofatumumab 3mg; Drug: Ofatumumab 30mg; Drug: Ofatumumab 60mg; Drug: Placebo
• Enrollment: 232

Participant Flow

Recruitment Details	A participant (par.) completed the study if he/she completed all assessments up to and including the 24 Week Follow-up Phase (FUP) (Week 48) without prematurely discontinuing.
Pre-assignment Details	A total of 324 par. with Relapsing-Remitting Multiple Sclerosis (RRMS) were screened and 232 par. were randomized to 24 Week Treatment Phase (Weeks 0-12 were placebo controlled) of the study. A total of 231 par. received at least one dose of double-blind Investigational Product (IP) and were included in the Safety Population.

Arm/Group Title	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description	Par. received ofatumumab matching placebo subcutaneous (SC) injection every 4 weeks (q4w) from Week 0 to Week 20, except on Week 12 participants received 3 milligrams (mg) ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 gram (g) and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection every 12th week (q12w) on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
Period Title: Treatment Phase (Weeks 0-24)
Started	67	34	32	34	64
Completed to Week 12	65	31	30	33	60
Completed	64	29	30	33	58
Not Completed	3	5	2	1	6
Reason Not Completed
Adverse Event	0	4	1	0	2
Physician Decision	0	0	0	0	1
Lack of Efficacy	1	0	0	0	0
Protocol Violation	1	0	1	0	0
Withdrawal by Subject	0	0	0	1	1
Other-Protocol defined stopping criteria	1	1	0	0	2
Period Title: FUP (Weeks 24-48)
Started [1]	66	31	32	33	59
Completed	63	30	30	32	57
Not Completed	3	1	2	1	2
Reason Not Completed
Adverse Event	0	0	1	0	0
Physician Decision	1	0	1	0	0
Lost to Follow-up	0	0	0	1	0
Withdrawal by Subject	2	1	0	0	2
[1] A total of 221 par. entered the FUP, including 7 of the 17 par. who were withdrawn before Week 24.
Period Title: Individualized FUP (Weeks 48+)
Started [1]	16	18	16	20	42
Completed	11	14	12	15	36
Not Completed	5	4	4	5	6
Reason Not Completed
Lost to Follow-up	1	0	1	0	0
Other-Protocol defined stopping criteria	3	4	2	3	5
Withdrawal by Subject	1	0	1	2	1
[1] Par. whose CD19+ B lymphocyte counts had not recovered to lower limit of normal entered IFU phase.

Baseline Characteristics

Arm/Group Title		Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w	Total
Arm/Group Description		Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Total of all reporting groups
Overall Number of Baseline Participants		67	34	32	34	64	231
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	67 participants	34 participants	32 participants	34 participants	64 participants	231 participants
		37.7 (9.38)	38.1 (8.29)	37.2 (10.04)	37.3 (9.67)	36.2 (9.57)	37.2 (9.36)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	67 participants	34 participants	32 participants	34 participants	64 participants	231 participants
	Female	46 68.7%	22 64.7%	24 75.0%	22 64.7%	41 64.1%	155 67.1%
	Male	21 31.3%	12 35.3%	8 25.0%	12 35.3%	23 35.9%	76 32.9%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	67 participants	34 participants	32 participants	34 participants	64 participants	231 participants
African American/African Heritage		1	0	0	0	1	2
Asian - East Asian Heritage		0	0	1	0	0	1
White - White/Caucasian/European Heritage		65	34	31	34	61	225
Mixed Race		1	0	0	0	2	3

Outcome Measures

1. Primary Outcome

Title	Cumulative Number of New Gadolinium-enhancing (GdE) T1 Lesions at Week 12
Description	The cumulative number of new GdE T1 lesion at Week 12 were analyzed from screening based on magnetic resonance imaging (MRI) brain scans at Weeks 4, 8, and 12. The outcome measure was analyzed using an Emax model adjusting for the presence/absence of GdE lesions on the Screening MRI and assuming the number of new lesions followed a negative binomial distribution. Dose was fitted as a continuous variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of new GdE lesions per scan at Week 12 were determined from the model. The all evaluable scans (AES) dataset was used which included all evaluable on-treatment MRI scans for each participant analysed.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population comprised of all randomized par. who received at least one dose of IP and who had at least one post screen MRI assessment. Only those par. available at the specified time points were analyzed. Please see footnote of statistical analysis 1 for discrepancy in analysis population Week 24 and 48.

Arm/Group Title	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description:	Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
Overall Number of Participants Analyzed	67	33	30	33	63
Mean (Standard Deviation); Unit of Measure: Cumulative number of lesions
	4.2 (7.57)	1.7 (3.29)	2.2 (3.41)	2.2 (3.70)	1.2 (2.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 3 mg q12w
	Comments	Note: There is a discrepancy in the number of par. in ITT populations at Wk 24 and Wk 48: 228 and 229 respectively. This resulted from a data issue: one par was incorrectly excluded from ITT pop. at Wk 24, but correctly included in Wk 48. This error affects all source tables, analyses relating to ITT and per protocol populations, primary endpoint and secondary MRI endpoints reported at Wk 24. This discrepancy affects all statistical analyses, but not summary statistics.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Non-Linear Emax Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; 0.221 to 0.548
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 30 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Non-Linear Emax Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; 0.221 to 0.548
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 60 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Non-Linear Emax Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; 0.221 to 0.548
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 60mg q4w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Non-Linear Emax Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; 0.221 to 0.548
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Cumulative Number of New GdE T1 Lesions at Week 24
Description	The cumulative number of new GdE T1 lesion at Week 24 were analyzed from screen based on MRI brain scans at Weeks 4, 8, 12, 16, 20 and 24. Anticipating an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of new GdE T1 lesions per scan at Week 24 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each participant analyzed.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description:	Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
Overall Number of Participants Analyzed	67	33	30	33	63
Mean (Standard Deviation); Unit of Measure: Cumulative number of lesions
	5.6 (9.34)	2.2 (3.80)	2.5 (3.88)	2.2 (3.83)	1.4 (3.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 3 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.003
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.38
	Confidence Interval	(2-Sided) 95%; 0.20 to 0.72
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 30 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.003
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.38
	Confidence Interval	(2-Sided) 95%; 0.20 to 0.72
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 60 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.001
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; 0.19 to 0.65
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 60mg q4w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.23
	Confidence Interval	(2-Sided) 95%; 0.13 to 0.39
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Change From Baseline in Brain Volume at Week 24 and Week 48
Description	Brain volume is a measure of brain size determined by a MRI scan. Baseline is defined as the par. last available assessment prior to initiation of the IP (i.e. Screening). Change from Baseline was calculated by subtracting the Baseline value from the post-Baseline value.
Time Frame	Baseline (Week 0), Week 24 and Week 48

Outcome Measure Data

Analysis Population Description

ITT Population. Only those par. available at the specified time points were analyzed.

Arm/Group Title		Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description:		Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
Overall Number of Participants Analyzed		28	12	16	12	22
Mean (Standard Deviation); Unit of Measure: Cubic centimeters
Week 24	Number Analyzed	25 participants	12 participants	16 participants	12 participants	22 participants
		-13.5 (26.96)	-7.2 (22.26)	-8.4 (26.62)	-13.3 (34.02)	-1.4 (56.42)
Week 48	Number Analyzed	28 participants	12 participants	16 participants	11 participants	19 participants
		-22.0 (38.22)	-12.9 (14.55)	-5.0 (28.84)	-7.3 (29.16)	-11.8 (55.30)

4. Secondary Outcome

Title	Cumulative Number of Persistent GdE Brain Lesions on T1-weighted MRI at Week 12
Description	The cumulative number of persistent GdE T1 lesions at Week 12 were analyzed from screen based on MRI scans at Weeks 4, 8, and 12. The AES dataset was used which included all evaluable on-treatment MRI scans for each par. analyzed.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Only those par. available at the specified time points were analyzed.

Arm/Group Title	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description:	Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
Overall Number of Participants Analyzed	67	34	30	33	63
Mean (Standard Deviation); Unit of Measure: Number of lesions per scan
	3.2 (7.41)	1.2 (1.94)	2.3 (3.94)	1.8 (3.31)	1.8 (4.81)

5. Secondary Outcome

Title	Cumulative Number of All (New Plus Persistent) GdE Brain Lesions on T1-weighted MRI at Week 12
Description	The cumulative number of all (new plus persistent) GdE T1 lesion at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8 and 12. Anticipating an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of all (new plus persistent) GdE T1 lesions per scan at Week 12 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each par. analyzed.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Only those par. available at the specified time points were analyzed.

Arm/Group Title	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description:	Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
Overall Number of Participants Analyzed	67	33	30	33	63
Mean (Standard Deviation); Unit of Measure: Cumulative number of lesions
	7.4 (13.90)	2.9 (4.62)	4.5 (7.09)	4.0 (6.70)	3.1 (6.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 3 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 95%; 0.16 to 0.60
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 30 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.075
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.56
	Confidence Interval	(2-Sided) 95%; 0.29 to 1.06
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 60 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.035
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.27 to 0.95
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 60mg q4w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.32
	Confidence Interval	(2-Sided) 95%; 0.19 to 0.55
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Total Volume of New GdE Brain Lesions on T1-weighted MRI at Week 12
Description	Lesion volume is a measure of lesion size determined by a MRI brain scan. The cumulative volume of new GdE T1 lesions at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8 and 12. Anticipating an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative volume of lesions was fitted as an offset. Estimates of the rate of cumulative volume of new GdE T1 lesions per scan at Week 12 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each par. analyzed.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Only those par. available at the specified time points were analyzed.

Arm/Group Title	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description:	Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
Overall Number of Participants Analyzed	67	34	30	33	63
Mean (Standard Deviation); Unit of Measure: Cubic millimeter (mm^3)
	607.5 (1090.89)	226.5 (449.37)	452.9 (682.33)	248.6 (457.62)	146.6 (304.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 3 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.026
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 95%; 0.06 to 0.84
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 30 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.296
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95%; 0.13 to 1.86
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 60 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.285
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95%; 0.14 to 1.78
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 60mg q4w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.009
	Comments	[Not Specified]
	Method	Non-Linear Emax Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95%; 0.09 to 0.71
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Total Volume of All (New and Persistent) GdE Brain Lesions on T1-weighted MRI at Week 12
Description	Lesion volume is a measure of lesion size determined by a MRI brain scan. The cumulative volume of all (new and persistent) GdE T1 lesions at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8 and 12. The endpoint was analyzed using a generalized linear model assuming an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative volume of lesions was fitted as an offset. Estimates of the rate of cumulative volume of all (new and persistent) GdE T1 lesions per scan at Week 12 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each par. analyzed.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Only those par. available at the specified time points were analyzed.

Arm/Group Title	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description:	Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
Overall Number of Participants Analyzed	67	33	30	33	63
Mean (Standard Deviation); Unit of Measure: mm^3
	1039.6 (1809.97)	386.2 (628.41)	886.2 (1637.47)	426.5 (679.44)	344.4 (735.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 3 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.004
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.18
	Confidence Interval	(2-Sided) 95%; 0.05 to 0.58
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 30 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.248
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95%; 0.15 to 1.63
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 60 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.181
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.15 to 1.43
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 60mg q4w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.003
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; 0.10 to 0.62
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Cumulative Number of New and Newly Enlarging GdE T2 Lesions at Week 12
Description	The cumulative number of new and newly enlarging GdE T2 lesions (NET2L) at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8 and 12. The endpoint was analyzed using a generalized linear model assuming an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of NET2L per scan at Week 12 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each par. analyzed.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Only those par. available at the specified time points were analyzed.

Arm/Group Title	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description:	Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
Overall Number of Participants Analyzed	67	33	30	33	63
Mean (Standard Deviation); Unit of Measure: Cumulative number of lesions
	3.7 (6.72)	1.2 (2.38)	1.6 (2.79)	1.7 (2.67)	0.8 (1.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 3 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; 0.15 to 0.58
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 30 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.002
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.34
	Confidence Interval	(2-Sided) 95%; 0.17 to 0.68
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 60 mg q12w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.006
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; 0.21 to 0.77
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ofatumumab 3 mg, Ofatumumab 60mg q4w
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Generalized Linear Model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; 0.11 to 0.35
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Total Volume of New and/or Newly Enlarging T2 Lesions at Week 12
Description	Lesion volume is a measure of lesion size determined by a MRI brain scan. T2 lesions, are indicative of brain myelin content.The cumulative volume of new and/or newly enlarging T2 lesions at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8, and 12. The AES dataset was used which included all evaluable on-treatment MRI scans for each par.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Only those par. available at the specified time points were analyzed.

Arm/Group Title	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description:	Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
Overall Number of Participants Analyzed	67	34	30	33	63
Mean (Standard Deviation); Unit of Measure: mm^3
	1204.5 (3426.79)	279.9 (695.75)	611.3 (1042.06)	293.8 (576.35)	167.9 (450.65)

10. Secondary Outcome

Title	Cumulative Number of New T1 Hypointense Lesions at Week 24 and Week 48
Description	The cumulative number of new T1 hypointense lesions at week 24 were analyzed from screen based on MRI brain scans at Weeks 4, 8, 12, 16, 20 and 24. The AES dataset was used which included all evaluable on-treatment MRI scans for each par.
Time Frame	Week 24 and Week 48

Outcome Measure Data

Analysis Population Description

ITT Population. Only those par. available at the specified time points were analyzed.

Arm/Group Title		Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description:		Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
Overall Number of Participants Analyzed		67	34	32	33	63
Mean (Standard Deviation); Unit of Measure: Number of lesions
Week 24	Number Analyzed	67 participants	34 participants	30 participants	33 participants	63 participants
		0.4 (0.96)	0.4 (1.26)	0.5 (1.01)	0.5 (1.12)	0.3 (0.78)
Week 48	Number Analyzed	67 participants	34 participants	32 participants	33 participants	63 participants
		0.6 (1.27)	0.5 (1.26)	0.5 (0.98)	0.6 (1.25)	0.3 (0.96)

11. Secondary Outcome

Title	Cumulative Volume of New T1 Hypointense Lesions at Week 24 and Week 48
Description	Lesion volume is a measure of lesion size determined by a MRI brain scan. Baseline is defined as the participant's last available assessment prior to initiation of IP. Change from Baseline was calculated by subtracting the Baseline value from the post-Baseline value. The AES dataset was used which included all evaluable on-treatment MRI scans for each par.
Time Frame	Baseline, Week 24 and Week 48

Outcome Measure Data

Analysis Population Description

ITT Population. Only those par. available at the specified time points were analyzed.

Arm/Group Title		Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description:		Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
Overall Number of Participants Analyzed		67	34	32	33	63
Mean (Standard Deviation); Unit of Measure: mm^3
Week 24	Number Analyzed	67 participants	34 participants	30 participants	33 participants	63 participants
		86.9 (240.40)	43.1 (131.96)	67.4 (147.00)	65.0 (139.14)	42.9 (140.93)
Week 48	Number Analyzed	67 participants	34 participants	32 participants	33 participants	63 participants
		113.6 (270.89)	54.2 (137.74)	63.2 (143.14)	116.3 (370.35)	53.2 (173.62)

Adverse Events

Time Frame	On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 24).
Adverse Event Reporting Description	SAEs and non-serious AEs were reported for members of the safety population, comprised of all par. who were randomized to treatment, and received at least one dose of study medication.
Arm/Group Title	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
Arm/Group Description	Par. received ofatumumab matching placebo SC injection q4w from Week 0 to Week 20, except on Week 12 participants received 3 mg ofatumumab SC injection. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 0, 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 30 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q12w on Week 1 and Week 12. Participants received matching placebo on Weeks 4, 8, 16 and 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.	Par. received ofatumumab 3 mg conditioning dose SC injection or matching placebo on Week 0 and received ofatumumab 60 mg SC injection q4w from Week 1 to Week 20. Participants also received pre-medication of acetaminophen 1 g and antihistamine (cetirizine or equivalent) 10 mg prior to administration of each SC injection of investigational product.
All-Cause Mortality
	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/67 (0.00%)	0/34 (0.00%)	0/32 (0.00%)	0/34 (0.00%)	0/64 (0.00%)
Serious Adverse Events
	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/67 (0.00%)	1/34 (2.94%)	0/32 (0.00%)	1/34 (2.94%)	4/64 (6.25%)
Hepatobiliary disorders
Cholelithiasis † 1	0/67 (0.00%)	0/34 (0.00%)	0/32 (0.00%)	0/34 (0.00%)	1/64 (1.56%)
Immune system disorders
Cytokine release syndrome † 1	0/67 (0.00%)	0/34 (0.00%)	0/32 (0.00%)	1/34 (2.94%)	0/64 (0.00%)
Injury, poisoning and procedural complications
Injection related reaction † 1	0/67 (0.00%)	0/34 (0.00%)	0/32 (0.00%)	0/34 (0.00%)	2/64 (3.13%)
Metabolism and nutrition disorders
Hypokalaemia † 1	0/67 (0.00%)	0/34 (0.00%)	0/32 (0.00%)	0/34 (0.00%)	1/64 (1.56%)
Skin and subcutaneous tissue disorders
Angioedema † 1	0/67 (0.00%)	1/34 (2.94%)	0/32 (0.00%)	0/34 (0.00%)	0/64 (0.00%)
Urticaria † 1	0/67 (0.00%)	1/34 (2.94%)	0/32 (0.00%)	0/34 (0.00%)	0/64 (0.00%)
1 Term from vocabulary, MedDRA 16.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo/Ofatumumab 3 mg	Ofatumumab 3 mg q12w	Ofatumumab 30 mg q12w	Ofatumumab 60 mg q12w	Ofatumumab 60mg q4w
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	41/67 (61.19%)	20/34 (58.82%)	23/32 (71.88%)	22/34 (64.71%)	47/64 (73.44%)
Blood and lymphatic system disorders
Anaemia † 1	1/67 (1.49%)	2/34 (5.88%)	0/32 (0.00%)	1/34 (2.94%)	1/64 (1.56%)
Gastrointestinal disorders
Nausea † 1	4/67 (5.97%)	0/34 (0.00%)	1/32 (3.13%)	1/34 (2.94%)	2/64 (3.13%)
Diarrhoea † 1	4/67 (5.97%)	0/34 (0.00%)	0/32 (0.00%)	0/34 (0.00%)	0/64 (0.00%)
General disorders
Fatigue † 1	8/67 (11.94%)	0/34 (0.00%)	3/32 (9.38%)	2/34 (5.88%)	3/64 (4.69%)
Pyrexia † 1	2/67 (2.99%)	2/34 (5.88%)	2/32 (6.25%)	1/34 (2.94%)	1/64 (1.56%)
Injection site pain † 1	0/67 (0.00%)	2/34 (5.88%)	0/32 (0.00%)	0/34 (0.00%)	1/64 (1.56%)
Infections and infestations
Nasopharyngitis † 1	8/67 (11.94%)	1/34 (2.94%)	4/32 (12.50%)	7/34 (20.59%)	7/64 (10.94%)
Urinary tract infection † 1	4/67 (5.97%)	3/34 (8.82%)	3/32 (9.38%)	2/34 (5.88%)	1/64 (1.56%)
Respiratory tract infection † 1	2/67 (2.99%)	1/34 (2.94%)	0/32 (0.00%)	2/34 (5.88%)	0/64 (0.00%)
Injury, poisoning and procedural complications
Injection related reaction † 1	18/67 (26.87%)	16/34 (47.06%)	13/32 (40.63%)	17/34 (50.00%)	42/64 (65.63%)
Fall † 1	0/67 (0.00%)	2/34 (5.88%)	1/32 (3.13%)	0/34 (0.00%)	2/64 (3.13%)
Investigations
Reticulocyte count decreased † 1	1/67 (1.49%)	0/34 (0.00%)	2/32 (6.25%)	1/34 (2.94%)	1/64 (1.56%)
Blood immunoglobulin G decreased † 1	0/67 (0.00%)	2/34 (5.88%)	0/32 (0.00%)	0/34 (0.00%)	1/64 (1.56%)
Weight decreased † 1	0/67 (0.00%)	0/34 (0.00%)	2/32 (6.25%)	0/34 (0.00%)	0/64 (0.00%)
Musculoskeletal and connective tissue disorders
Back pain † 1	6/67 (8.96%)	1/34 (2.94%)	2/32 (6.25%)	0/34 (0.00%)	1/64 (1.56%)
Arthralgia † 1	2/67 (2.99%)	1/34 (2.94%)	2/32 (6.25%)	1/34 (2.94%)	0/64 (0.00%)
Nervous system disorders
Headache † 1	7/67 (10.45%)	2/34 (5.88%)	2/32 (6.25%)	2/34 (5.88%)	6/64 (9.38%)
Dizziness † 1	0/67 (0.00%)	0/34 (0.00%)	1/32 (3.13%)	0/34 (0.00%)	4/64 (6.25%)
Neuralgia † 1	0/67 (0.00%)	0/34 (0.00%)	2/32 (6.25%)	0/34 (0.00%)	0/64 (0.00%)
Psychiatric disorders
Anxiety † 1	2/67 (2.99%)	1/34 (2.94%)	2/32 (6.25%)	0/34 (0.00%)	0/64 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	2/67 (2.99%)	2/34 (5.88%)	1/32 (3.13%)	0/34 (0.00%)	1/64 (1.56%)
Skin and subcutaneous tissue disorders
Ecchymosis † 1	0/67 (0.00%)	2/34 (5.88%)	0/32 (0.00%)	0/34 (0.00%)	1/64 (1.56%)
1 Term from vocabulary, MedDRA 16.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

The incorrect exclusion of one par. from ITT pop. at Wk 24 was not considered to impact overall interpretation of data: no updates were made to source tables/analyses. This par. had withdrawn early, having never received a dose of active study drug.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

• Name/Title: GSK Response Center
• Organization: GlaxoSmithKline
• Phone: 866-435-7343

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bar-Or A, Grove RA, Austin DJ, Tolson JM, VanMeter SA, Lewis EW, Derosier FJ, Lopez MC, Kavanagh ST, Miller AE, Sorensen PS. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. Neurology. 2018 May 15;90(20):e1805-e1814. doi: 10.1212/WNL.0000000000005516. Epub 2018 Apr 25. Erratum in: Neurology. 2018 Sep 11;91(11):538.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01457924
• Other Study ID Numbers: 112831
• First Submitted: October 20, 2011
• First Posted: October 24, 2011
• Results First Submitted: March 21, 2017
• Results First Posted: March 1, 2018
• Last Update Posted: June 6, 2018