ULTIMATE II: Study to Assess the Efficacy and Safety of Ublituximab in Participants With Relapsing Forms of Multiple Sclerosis (RMS)

• Sponsor: TG Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03277248
• Collaborator: (none)
• Enrollment: 545
• Locations: 13
• Arms: 2
• Actual Duration (Months): 38.6
• Patients Per Site: 41.9
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

This study determines the Annualized Relapse Rate (ARR) in participants with RMS after 96 weeks (approximately 2 years) treatment with intravenous (IV) infusion of ublituximab/oral placebo compared to 14 mg oral teriflunomide/IV placebo.

Condition or Disease	Intervention/Treatment	Phase
Relapsing Multiple Sclerosis (RMS)	Biological: Ublituximab; Drug: Teriflunomide; Drug: Oral Placebo; Drug: IV Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 545 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, multi-center, double-blinded, active-controlled studyRandomized, multi-center, double-blinded, active-controlled study
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double-blinded, active-controlled study
• Primary Purpose: Treatment
• Official Title: Phase III: UbLiTuximab in Multiple Sclerosis Treatment Effects (ULTIMATE II STUDY)
• Actual Study Start Date: Aug 25, 2017
• Actual Primary Completion Date: Aug 4, 2020
• Actual Study Completion Date: Nov 12, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ublituximab + Oral Placebo Participants received ublituximab intravenous (IV) infusion, 150 milligrams (mg) over 4 hours (h) on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo tablet, once daily (QD) from Day 1 up to the last day of Week 95.	Biological: Ublituximab; Administered as an IV infusion.; Other Names: TG-1101 ; Drug: Oral Placebo; Administered orally.
Active Comparator: Teriflunomide + IV Placebo Participants received teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).	Drug: Teriflunomide; Film coated tablets administered orally.; Drug: IV Placebo; Administered as an IV Infusion.

Outcome Measures

Primary Outcome Measures

1. Annualized Relapse Rate (ARR) [Up to 96 weeks]

   ARR is defined as the number of Independent Relapse Adjudication Committee (IRAP)-confirmed relapses per participant year. The estimate of ARR for a treatment group is the total number of relapses for participants in the respective treatment group divided by the sum of treatment duration for participants in that specific treatment group.

Secondary Outcome Measures

1. Total Number of Gadolinium (Gd)-Enhancing T1-Lesions Per Magnetic Resonance Imaging (MRI) Scan Per Participant [Weeks 12, 24, 48, and 96]

   The total number of Gd-enhancing T1-lesions were calculated as the sum of the individual number of lesions at Weeks 12, 24, 48, and 96, divided by the total number of MRI scans of the brain.

2. Total Number of New and Enlarging T2 Hyperintense Lesions (NELs) Per MRI Scan Per Participant [Weeks 24, 48, and 96]

   The total number of NELs were calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96, divided by the total number of MRI scans of the brain.

3. Time to Confirmed Disability Progression (CDP) for at Least 12 Weeks [Up to Week 96]

   12-week CDP is defined as an increase in EDSS at least 1 point higher than the baseline EDSS if the baseline EDSS is ≤5.5 or at least 0.5 higher than the baseline EDSS if the baseline EDSS is >5.5. The EDSS is based on a standard neurological examination, (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, and cerebral) and ambulation function system assessments. The EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death) where higher scores indicate disability. The time to onset of 12-week CDP is the time to progression to the EDSS change defined above.

4. Percentage of Participants With No Evidence of Disease Activity (NEDA) [From Week 24 to Week 96]

   A participant with NEDA is defined as a participant without relapses confirmed by the IRAP, without MRI activities (no T1 Gd+ lesions and no new/enlarging T2 lesions), and no 12-week CDP. Any evidence of disease activity from Week 24 to Week 96 was counted as not reaching NEDA. Any evidence of disease activity before Week 24 was not counted.

5. Percentage of Participants With Impaired Symbol Digit Modalities Test (SDMT) [Baseline to Week 96]

   The SDMT involves a simple substitution task using a reference key, the examinee has 90 seconds to pair specific numbers with given geometric figures. Responses are done verbally. The administration time is approximately 5 minutes. The total SDMT score for each visit ranging from 0-110 is defined as the total number of correct answers reported in the case report form (CRF), where high scores indicate better outcome. Impaired SDMT is defined as a decrease of at least 4 points from baseline at any post-baseline assessment up to the Week 96 visit.

6. Percent Change From Baseline in Brain Volume [Baseline to Week 96]

7. Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [From the first dose of study drug through the end of the study (up to approximately 116 weeks)]

   An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious AE is defined as any untoward medical occurrence that: results in death, is immediately life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, and/or causes a congenital anomaly/birth defect. TEAEs are AEs that start or worsen after receiving the study drug.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis of relapsing multiple sclerosis (RMS) (McDonald Criteria 2010)

• Active disease

• Expanded disability status scale (EDSS) 0 - 5.5 (inclusive) at screening

Exclusion Criteria:

• Treatment with prior Anti-cluster of differentiate 20 (CD20) or other B cell directed treatment

• Treatment with the following therapies at any time prior to randomization: alemtuzumab, natalizumab, teriflunomide, leflunomide and Stem cell transplantation

• Diagnosed with primary progressive multiple sclerosis (PPMS)

• Pregnant or nursing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	TG Therapeutics RMS Investigational Trial site	Phoenix	Arizona	United States	58018
2	TG Therapeutics RMS Investigational Trial Site	Aurora	Colorado	United States	80045
3	TG Therapeutics RMS Investigational Trial Site	Tampa	Florida	United States	33612
4	TG Therapeutics RMS Investigational Trial Site	Lexington	Kentucky	United States	40513
5	TG Therapeutics RMS Investigational Trial Site	Chesterfield	Missouri	United States	63017
6	TG Therapeutics RMS Investigational Trial Site	Las Vegas	Nevada	United States	89106
7	TG Therapeutics RMS Investigational Trial Site	Teaneck	New Jersey	United States	07666
8	TG Therapeutics RMS Investigational Trial Site	Albuquerque	New Mexico	United States	87131
9	TG Therapeutics RMS Investigational Trial Site	Patchogue	New York	United States	11772
10	TG Therapeutics RMS Investigational Trial site	Columbus	Ohio	United States	43221
11	TG Therapeutics RMS Investigational Trial Site	Pittsburgh	Pennsylvania	United States	15212
12	TG Therapeutics RMS Investigational Trial site	San Antonio	Texas	United States	78258
13	TG Therapeutics RMS Investigational Trial site	Seattle	Washington	United States	98122

Sponsors and Collaborators

• TG Therapeutics, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Sep 4, 2020
• Statistical Analysis Plan - Sep 4, 2020

More Information

Publications

None provided.

• Responsible Party: TG Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03277248
• Other Study ID Numbers: TG1101-RMS302; 2017-000639-15
• First Posted: Sep 11, 2017
• Last Update Posted: Dec 6, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Teriflunomide

Study Results

Participant Flow

Recruitment Details	A total of 545 participants were enrolled across investigative sites in Belarus, Spain, the United Kingdom, Croatia, Poland, Russia, Ukraine, and the United States from 25 August 2017 to 12 November 2020.
Pre-assignment Detail	A total of 629 participants were screened and of those, 545 were enrolled and randomized to receive either ublituximab/oral placebo or teriflunomide/IV placebo.

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants received ublituximab intravenous (IV) infusion, 150 milligrams (mg) over 4 hours (h) on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo tablet, once daily (QD) from Day 1 up to the last day of Week 95.	Participants received teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).
Period Title: Overall Study
STARTED	272	273
COMPLETED	254	239
NOT COMPLETED	18	34

Baseline Characteristics

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo	Total
Arm/Group Description	Participants received ublituximab IV infusion, 150 mg over 4 h on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo tablet, QD from Day 1 up to the last day of Week 95.	Participants received teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).	Total of all reporting groups
Overall Participants	272	273	545
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.5 (8.76)	36.2 (8.97)	35.3 (8.90)
Sex: Female, Male (Count of Participants)
Female	178 65.4%	176 64.5%	354 65%
Male	94 34.6%	97 35.5%	191 35%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	2 0.7%	3 1.1%	5 0.9%
White	269 98.9%	269 98.5%	538 98.7%
Other	1 0.4%	1 0.4%	2 0.4%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	6 2.2%	3 1.1%	9 1.7%
Not Hispanic or Latino	262 96.3%	263 96.3%	525 96.3%
Not Reported	2 0.7%	2 0.7%	4 0.7%
Unknown	2 0.7%	5 1.8%	7 1.3%
Region of Enrollment (participants) [Number]
Belarus	29 10.7%	35 12.8%	64 11.7%
Spain	6 2.2%	2 0.7%	8 1.5%
United Kingdom	4 1.5%	1 0.4%	5 0.9%
Croatia	25 9.2%	24 8.8%	49 9%
Poland	39 14.3%	38 13.9%	77 14.1%
Russia	78 28.7%	85 31.1%	163 29.9%
Ukraine	74 27.2%	69 25.3%	143 26.2%
United States	17 6.3%	19 7%	36 6.6%

Outcome Measures

1. Primary Outcome

Title	Annualized Relapse Rate (ARR)
Description	ARR is defined as the number of Independent Relapse Adjudication Committee (IRAP)-confirmed relapses per participant year. The estimate of ARR for a treatment group is the total number of relapses for participants in the respective treatment group divided by the sum of treatment duration for participants in that specific treatment group.
Time Frame	Up to 96 weeks

Outcome Measure Data

Analysis Population Description

Modified Intention-to-Treat (mITT) population consisted of all participants in the ITT population who received at least one dose of study medication and had at least one baseline and post baseline efficacy assessment.

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants received ublituximab IV infusion, 150 mg over 4 h on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo tablet, QD from Day 1 up to the last day of Week 95.	Participants received teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).
Measure Participants	272	272
Least Squares Mean (95% Confidence Interval) [relapses per participant-years]	0.091	0.178

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ublituximab + Oral Placebo, Teriflunomide + IV Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments	GEE (Generalized Estimating Equation) model for the relapse count per participant with logarithmic link function, treatment, region, and baseline Expanded Disability Status Scale (EDSS) strata as covariates and log (years of treatment) as offset.
	Method	Negative Binomial Model
	Comments
Method of Estimation	Estimation Parameter	Rate Ratio (Ublituximab / Teriflunomide)
	Estimated Value	0.509
	Confidence Interval	(2-Sided) 95%; 0.330 to 0.784
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Total Number of Gadolinium (Gd)-Enhancing T1-Lesions Per Magnetic Resonance Imaging (MRI) Scan Per Participant
Description	The total number of Gd-enhancing T1-lesions were calculated as the sum of the individual number of lesions at Weeks 12, 24, 48, and 96, divided by the total number of MRI scans of the brain.
Time Frame	Weeks 12, 24, 48, and 96

Outcome Measure Data

Analysis Population Description

mITT-MRI population consisted of participants in the mITT population who had a baseline and at least 1 post-baseline MRI efficacy assessments.

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants received ublituximab IV infusion, 150 mg over 4 h on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo tablet, QD from Day 1 up to the last day of Week 95.	Participants received teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).
Measure Participants	272	267
Least Squares Mean (95% Confidence Interval) [lesions per scan per participant]	0.009	0.250

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ublituximab + Oral Placebo, Teriflunomide + IV Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	GEE model for the relapse count per participant with logarithmic link function, treatment, region, and baseline EDSS strata as covariates and log (years of treatment) as offset.
	Method	Negative Binomial Model
	Comments
Method of Estimation	Estimation Parameter	Rate Ratio (Ublituximab / Teriflunomide)
	Estimated Value	0.035
	Confidence Interval	(2-Sided) 95%; 0.019 to 0.064
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Total Number of New and Enlarging T2 Hyperintense Lesions (NELs) Per MRI Scan Per Participant
Description	The total number of NELs were calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96, divided by the total number of MRI scans of the brain.
Time Frame	Weeks 24, 48, and 96

Outcome Measure Data

Analysis Population Description

mITT-MRI population consisted of participants in the mITT population who had a baseline and at least 1 post-baseline MRI efficacy assessments. Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants received ublituximab IV infusion, 150 mg over 4 h on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo tablet, QD from Day 1 up to the last day of Week 95.	Participants received teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).
Measure Participants	269	259
Least Squares Mean (95% Confidence Interval) [lesions per scan per participant]	0.282	2.831

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ublituximab + Oral Placebo, Teriflunomide + IV Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	GEE model for the relapse count per participant with logarithmic link function, treatment, region, and baseline EDSS strata as covariates and log (years of treatment) as offset.
	Method	Negative Binomial Model
	Comments
Method of Estimation	Estimation Parameter	Rate Ratio (Ublituximab / Teriflunomide)
	Estimated Value	0.100
	Confidence Interval	(2-Sided) 95%; 0.073 to 0.136
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Time to Confirmed Disability Progression (CDP) for at Least 12 Weeks
Description	12-week CDP is defined as an increase in EDSS at least 1 point higher than the baseline EDSS if the baseline EDSS is ≤5.5 or at least 0.5 higher than the baseline EDSS if the baseline EDSS is >5.5. The EDSS is based on a standard neurological examination, (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, and cerebral) and ambulation function system assessments. The EDSS disability scale ranges in 0.5-point steps from 0 (normal) to 10 (death) where higher scores indicate disability. The time to onset of 12-week CDP is the time to progression to the EDSS change defined above.
Time Frame	Up to Week 96

Outcome Measure Data

Analysis Population Description

mITT population consisted of all participants in the ITT population who received at least one dose of study medication and had at least one baseline and post baseline efficacy assessment. As per protocol, data was summarized for the mITT Population using pooled data from participants in this study and TG1101-RMS301 [NCT03277261].

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants received ublituximab IV infusion, 150 mg over 4 h on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo tablet, QD from Day 1 up to the last day of Week 95.	Participants received teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).
Measure Participants	543	546
Median (Inter-Quartile Range) [weeks]	NA	NA

5. Secondary Outcome

Title	Percentage of Participants With No Evidence of Disease Activity (NEDA)
Description	A participant with NEDA is defined as a participant without relapses confirmed by the IRAP, without MRI activities (no T1 Gd+ lesions and no new/enlarging T2 lesions), and no 12-week CDP. Any evidence of disease activity from Week 24 to Week 96 was counted as not reaching NEDA. Any evidence of disease activity before Week 24 was not counted.
Time Frame	From Week 24 to Week 96

Outcome Measure Data

Analysis Population Description

mITT population consisted of all participants in the ITT population who received at least one dose of study medication and had at least one baseline and post baseline efficacy assessment.

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants received ublituximab IV infusion, 150 mg over 4 h on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo tablet, QD from Day 1 up to the last day of Week 95.	Participants received teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).
Measure Participants	272	272
Number [percentage of participants]	43.0 15.8%	11.4 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ublituximab + Oral Placebo, Teriflunomide + IV Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	Logistic regression model with treatment, region, baseline EDSS strata and log transformed baseline MRI lesion counts (T1-unenhancing, T2, Gd-enhancing) as covariates.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (Ublituximab / Teriflunomide)
	Estimated Value	7.946
	Confidence Interval	(2-Sided) 95%; 4.917 to 12.841
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With Impaired Symbol Digit Modalities Test (SDMT)
Description	The SDMT involves a simple substitution task using a reference key, the examinee has 90 seconds to pair specific numbers with given geometric figures. Responses are done verbally. The administration time is approximately 5 minutes. The total SDMT score for each visit ranging from 0-110 is defined as the total number of correct answers reported in the case report form (CRF), where high scores indicate better outcome. Impaired SDMT is defined as a decrease of at least 4 points from baseline at any post-baseline assessment up to the Week 96 visit.
Time Frame	Baseline to Week 96

Outcome Measure Data

Analysis Population Description

mITT population consisted of all participants in the ITT population who received at least one dose of study medication and had at least one baseline and post baseline efficacy assessment.

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants received ublituximab IV infusion, 150 mg over 4 h on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo tablet, QD from Day 1 up to the last day of Week 95.	Participants received teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).
Measure Participants	272	272
Number [percentage of participants]	29.0 10.7%	31.6 11.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ublituximab + Oral Placebo, Teriflunomide + IV Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4290
	Comments	Logistic regression model with treatment, region, baseline EDSS strata and log transformed baseline MRI lesion counts (T1 unenhancing, T2, Gd enhancing) as covariates.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (Ublituximab / Teriflunomide)
	Estimated Value	0.862
	Confidence Interval	(2-Sided) 95%; 0.596 to 1.246
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percent Change From Baseline in Brain Volume
Time Frame	Baseline to Week 96

Outcome Measure Data

Analysis Population Description

mITT-MRI population consisted of participants in the mITT population who had a baseline and at least 1 post-baseline MRI efficacy assessments. Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants received ublituximab IV infusion, 150 mg over 4 h on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo tablet, QD from Day 1 up to the last day of Week 95.	Participants received teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).
Measure Participants	235	224
Least Squares Mean (95% Confidence Interval) [percent change]	-0.194	-0.176

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ublituximab + Oral Placebo, Teriflunomide + IV Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3108
	Comments	Mixed model repeated measures (MMRM) model includes treatment, region, baseline EDSS strata, visit, treatment-by-visit interaction, and baseline volume (cube root transformed) as covariates and an unstructured covariance matrix.
	Method	Mixed Model Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.018
	Confidence Interval	(2-Sided) 95%; -0.053 to 0.017
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
Description	An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious AE is defined as any untoward medical occurrence that: results in death, is immediately life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, and/or causes a congenital anomaly/birth defect. TEAEs are AEs that start or worsen after receiving the study drug.
Time Frame	From the first dose of study drug through the end of the study (up to approximately 116 weeks)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of study drug (ublituximab or teriflunomide, with corresponding placebos).

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants received ublituximab IV infusion, 150 mg over 4 h on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo tablet, QD from Day 1 up to the last day of Week 95.	Participants received teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).
Measure Participants	272	273
TEAEs	92.3 33.9%	93.8 34.4%
TESAEs	10.3 3.8%	7.7 2.8%

Adverse Events

Time Frame	From the first dose of study drug through the end of the study (up to approximately 116 weeks)
Adverse Event Reporting Description	Safety population included all participants who received at least one dose of study drug (ublituximab or teriflunomide, with corresponding placebos).
Arm/Group Title	Ublituximab + Oral Placebo		Teriflunomide + IV Placebo
Arm/Group Description	Participants received ublituximab IV infusion, 150 mg over 4 h on Day 1 followed by 450 mg over 1 h on Days 15, 168, 336 and 504 (Week 72) along with the oral placebo tablet, QD from Day 1 up to the last day of Week 95.		Participants received teriflunomide 14 mg tablet, orally, QD from Day 1 up to the last day of Week 95 along with the placebo IV infusion on Days 1, 15, 168, 336 and 504 (Week 72).
All Cause Mortality
	Ublituximab + Oral Placebo		Teriflunomide + IV Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/272 (0.4%)		0/273 (0%)
Serious Adverse Events
	Ublituximab + Oral Placebo		Teriflunomide + IV Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/272 (10.3%)		21/273 (7.7%)
Blood and lymphatic system disorders
Bone marrow toxicity	1/272 (0.4%)		0/273 (0%)
Febrile neutropenia	1/272 (0.4%)		0/273 (0%)
Eye disorders
Glaucoma	1/272 (0.4%)		0/273 (0%)
Astigmatism	0/272 (0%)		1/273 (0.4%)
Cataract	0/272 (0%)		1/273 (0.4%)
Retinal degeneration	0/272 (0%)		1/273 (0.4%)
Gastrointestinal disorders
Abdominal hernia	1/272 (0.4%)		0/273 (0%)
Pancreatitis acute	0/272 (0%)		1/273 (0.4%)
General disorders
Decreased activity	1/272 (0.4%)		0/273 (0%)
Fatigue	1/272 (0.4%)		0/273 (0%)
Pyrexia	1/272 (0.4%)		0/273 (0%)
Hepatobiliary disorders
Cholecystitis chronic	0/272 (0%)		1/273 (0.4%)
Infections and infestations
Acute sinusitis	3/272 (1.1%)		0/273 (0%)
COVID-19 pneumonia	2/272 (0.7%)		1/273 (0.4%)
Pneumonia	2/272 (0.7%)		2/273 (0.7%)
Appendicitis	1/272 (0.4%)		0/273 (0%)
Chronic hepatitis B	1/272 (0.4%)		0/273 (0%)
Complicated appendicitis	1/272 (0.4%)		1/273 (0.4%)
Epididymitis	1/272 (0.4%)		0/273 (0%)
Gastrointestinal infection	1/272 (0.4%)		0/273 (0%)
Bronchitis	0/272 (0%)		1/273 (0.4%)
Chronic tonsillitis	0/272 (0%)		1/273 (0.4%)
Periodontitis	0/272 (0%)		1/273 (0.4%)
Peritonitis	0/272 (0%)		1/273 (0.4%)
Pilonidal cyst	0/272 (0%)		1/273 (0.4%)
Pyelonephritis acute	0/272 (0%)		2/273 (0.7%)
Pyelonephritis chronic	0/272 (0%)		1/273 (0.4%)
Septic shock	0/272 (0%)		1/273 (0.4%)
Tooth abscess	0/272 (0%)		1/273 (0.4%)
Injury, poisoning and procedural complications
Tibia fracture	1/272 (0.4%)		0/273 (0%)
Concussion	0/272 (0%)		1/273 (0.4%)
Hand fracture	0/272 (0%)		1/273 (0.4%)
Metabolism and nutrition disorders
Hyperkalaemia	1/272 (0.4%)		0/273 (0%)
Musculoskeletal and connective tissue disorders
Muscular weakness	1/272 (0.4%)		1/273 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Desmoid tumour	1/272 (0.4%)		0/273 (0%)
Endometrial stromal sarcoma	1/272 (0.4%)		0/273 (0%)
Uterine cancer	1/272 (0.4%)		0/273 (0%)
Uterine leiomyoma	1/272 (0.4%)		0/273 (0%)
Nervous system disorders
Coordination abnormal	1/272 (0.4%)		0/273 (0%)
Dysaesthesia	1/272 (0.4%)		0/273 (0%)
Cerebral infarction	0/272 (0%)		1/273 (0.4%)
Epilepsy	0/272 (0%)		2/273 (0.7%)
Tremor	0/272 (0%)		1/273 (0.4%)
Renal and urinary disorders
Renal colic	0/272 (0%)		1/273 (0.4%)
Reproductive system and breast disorders
Ovarian cyst	1/272 (0.4%)		0/273 (0%)
Surgical and medical procedures
Ovarian cystectomy	1/272 (0.4%)		0/273 (0%)
Pituitary gland operation	1/272 (0.4%)		0/273 (0%)
Vascular disorders
Deep vein thrombosis	1/272 (0.4%)		0/273 (0%)
Other (Not Including Serious) Adverse Events
	Ublituximab + Oral Placebo		Teriflunomide + IV Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	234/272 (86%)		233/273 (85.3%)
Blood and lymphatic system disorders
Lymphopenia	26/272 (9.6%)		2/273 (0.7%)
Anaemia	9/272 (3.3%)		15/273 (5.5%)
Cardiac disorders
Sinus tachycardia	20/272 (7.4%)		5/273 (1.8%)
Gastrointestinal disorders
Nausea	29/272 (10.7%)		28/273 (10.3%)
Abdominal pain	28/272 (10.3%)		12/273 (4.4%)
Diarrhoea	25/272 (9.2%)		32/273 (11.7%)
Constipation	16/272 (5.9%)		17/273 (6.2%)
Dyspepsia	16/272 (5.9%)		15/273 (5.5%)
Toothache	16/272 (5.9%)		15/273 (5.5%)
Abdominal pain upper	15/272 (5.5%)		9/273 (3.3%)
General disorders
Pyrexia	34/272 (12.5%)		14/273 (5.1%)
Influenza like illness	28/272 (10.3%)		7/273 (2.6%)
Chills	25/272 (9.2%)		3/273 (1.1%)
Hyperthermia	18/272 (6.6%)		4/273 (1.5%)
Asthenia	16/272 (5.9%)		20/273 (7.3%)
Fatigue	15/272 (5.5%)		11/273 (4%)
Infections and infestations
Nasopharyngitis	67/272 (24.6%)		54/273 (19.8%)
Respiratory tract infection	30/272 (11%)		28/273 (10.3%)
Pharyngitis	24/272 (8.8%)		6/273 (2.2%)
Upper respiratory tract infection	24/272 (8.8%)		25/273 (9.2%)
Respiratory tract infection viral	22/272 (8.1%)		23/273 (8.4%)
Cystitis	17/272 (6.3%)		12/273 (4.4%)
Sinusitis	17/272 (6.3%)		13/273 (4.8%)
Oral herpes	14/272 (5.1%)		16/273 (5.9%)
Rhinitis	9/272 (3.3%)		14/273 (5.1%)
Injury, poisoning and procedural complications
Infusion related reaction	19/272 (7%)		2/273 (0.7%)
Investigations
Lymphocyte count decreased	15/272 (5.5%)		2/273 (0.7%)
Musculoskeletal and connective tissue disorders
Back pain	35/272 (12.9%)		23/273 (8.4%)
Arthralgia	17/272 (6.3%)		13/273 (4.8%)
Pain in extremity	16/272 (5.9%)		13/273 (4.8%)
Nervous system disorders
Headache	103/272 (37.9%)		87/273 (31.9%)
Dizziness	16/272 (5.9%)		12/273 (4.4%)
Psychiatric disorders
Insomnia	21/272 (7.7%)		8/273 (2.9%)
Anxiety	16/272 (5.9%)		12/273 (4.4%)
Reproductive system and breast disorders
Dysmenorrhoea	12/272 (4.4%)		15/273 (5.5%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	18/272 (6.6%)		9/273 (3.3%)
Throat irritation	14/272 (5.1%)		1/273 (0.4%)
Skin and subcutaneous tissue disorders
Alopecia	13/272 (4.8%)		48/273 (17.6%)
Vascular disorders
Hypertension	10/272 (3.7%)		15/273 (5.5%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

There is NOT 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.