Study to Assess the Efficacy and Safety of Ublituximab in Participants With Relapsing Forms of Multiple Sclerosis (RMS) ( ULTIMATE 1 )

• Sponsor: TG Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03277261
• Collaborator: (none)
• Enrollment: 549
• Locations: 14
• Arms: 2
• Actual Duration (Months): 37.6
• Patients Per Site: 39.2
• Patients Per Site Per Month: 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: 549 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 I STUDY)
• Actual Study Start Date: Sep 19, 2017
• Actual Primary Completion Date: Jul 23, 2020
• Actual Study Completion Date: Nov 6, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ublituximab + Oral Placebo Participants were administered ublituximab 150 milligrams (mg), intravenous (IV) infusion 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 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 were administered 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 Panel (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) [Week 24 up 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 up 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 from baseline of at least 4 points at any post-baseline assessment up to the Week 96 visit.

6. Percent Change From Baseline in Brain Volume [Baseline up 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. A TEAE is an AE that starts or worsens after receiving 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:

• 18-55 age

• Diagnosis of 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 MS (PPMS)

• Pregnant or nursing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	TG Therapeutics RMS Investigational Trial Site	Carlsbad	California	United States	92001
2	TG Therapeutics RMS Investigational Trial Site	Long Beach	California	United States	90808
3	TG Therapeutics RMS Investigational Trial Site	Pasadena	California	United States	91105
4	TG Therapeutics RMS Investigational Trial Site	Stanford	California	United States	94305
5	TG Therapeutics RMS Investigational Trial Site	Miami	Florida	United States	33136
6	TG Therapeutics RMS Investigational Trial Site	Northbrook	Illinois	United States	60062
7	TG Therapeutics RMS Investigational Trial Site	Kansas City	Kansas	United States	66160
8	TG Therapeutics RMS Investigational Trial Site	Detroit	Michigan	United States	48201
9	TG Therapeutics RMS Investigational Trial Site	Amherst	New York	United States	14226
10	TG Therapeutics RMS Investigational Trial Site	Westerville	Ohio	United States	43081
11	TG Therapeutics RMS Investigational Trial Site	Franklin	Tennessee	United States	37064
12	TG Therapeutics RMS Investigational Trial Site	Knoxville	Tennessee	United States	37922
13	TG Therapeutics RMS Investigational Trial Site	Dallas	Texas	United States	75246
14	TG Therapeutics RMS Investigational Site	Round Rock	Texas	United States	78681

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: NCT03277261
• Other Study ID Numbers: TG1101-RMS301; 2017-000638-75
• 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 549 participants were enrolled across investigative sites in Belarus, Spain, the United Kingdom, Georgia, Poland, Russia, Serbia, Ukraine, and the United States from 19 September 2017 to 6 November 2020.
Pre-assignment Detail	A total of 646 participants were screened and of those, 549 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 were administered ublituximab 150 milligrams (mg), intravenous (IV) infusion 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 once daily (QD) from Day 1 up to the last day of Week 95.	Participants were administered 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	274	275
COMPLETED	240	252
NOT COMPLETED	34	23

Baseline Characteristics

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo	Total
Arm/Group Description	Participants were administered ublituximab 150 mg, IV infusion 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 QD from Day 1 up to the last day of Week 95.	Participants were administered 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	274	275	549
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.3 (8.48)	37.0 (9.62)	36.7 (9.07)
Sex: Female, Male (Count of Participants)
Female	167 60.9%	180 65.5%	347 63.2%
Male	107 39.1%	95 34.5%	202 36.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 2.6%	2 0.7%	9 1.6%
Not Hispanic or Latino	263 96%	267 97.1%	530 96.5%
Unknown or Not Reported	4 1.5%	6 2.2%	10 1.8%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	6 2.2%	6 2.2%	12 2.2%
White	267 97.4%	267 97.1%	534 97.3%
Native Hawaiian or Other Pacific Islander	1 0.4%	0 0%	1 0.2%
Other	0 0%	2 0.7%	2 0.4%

Outcome Measures

1. Primary Outcome

Title	Annualized Relapse Rate (ARR)
Description	ARR is defined as the number of Independent Relapse Adjudication Panel (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 have at least one baseline and post baseline efficacy assessment.

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants were administered ublituximab 150 mg, IV infusion 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 QD from Day 1 up to the last day of Week 95.	Participants were administered 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	271	274
Least Squares Mean (95% Confidence Interval) [relapses per participant-years]	0.076	0.188

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	<0.0001
	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	0.406
	Confidence Interval	(2-Sided) 95%; 0.268 to 0.615
	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- magnetic resonance imaging (MRI) population included participants in mITT population who have baseline and 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 were administered ublituximab 150 mg, IV infusion 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 QD from Day 1 up to the last day of Week 95.	Participants were administered 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	264	269
Least Squares Mean (95% Confidence Interval) [lesions per scan per participant]	0.016	0.491

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	<0.0001
	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	0.033
	Confidence Interval	(2-Sided) 95%; 0.019 to 0.058
	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 included participants in mITT population who have baseline and 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 were administered ublituximab 150 mg, IV infusion 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 QD from Day 1 up to the last day of Week 95.	Participants were administered 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	260	267
Least Squares Mean (95% Confidence Interval) [lesions per scan per participant]	0.213	2.789

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	<0.0001
	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	0.076
	Confidence Interval	(2-Sided) 95%; 0.056 to 0.104
	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 have 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-RMS302 [NCT03277248].

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants were administered ublituximab 150 mg, IV infusion 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 QD from Day 1 up to the last day of Week 95.	Participants were administered 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	Week 24 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 have at least one baseline and post baseline efficacy assessment.

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants were administered ublituximab 150 mg, IV infusion 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 QD from Day 1 up to the last day of Week 95.	Participants were administered 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	271	274
Number [percentage of participants]	44.6 16.3%	15.0 5.5%

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	<0.0001
	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	5.442
	Confidence Interval	(2-Sided) 95%; 3.536 to 8.375
	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 from baseline of at least 4 points at any post-baseline assessment up to the Week 96 visit.
Time Frame	Baseline 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 have at least one baseline and post baseline efficacy assessment.

Arm/Group Title	Ublituximab + Oral Placebo	Teriflunomide + IV Placebo
Arm/Group Description	Participants were administered ublituximab 150 mg, IV infusion 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 QD from Day 1 up to the last day of Week 95.	Participants were administered 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	271	274
Number [percentage of participants]	29.2 10.7%	31.8 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	=0.4669
	Comments	Logistic regression model with treatment, region, baseline EDSS strata, and log-transformed baseline MRI counts (T1 unenhancing, T2, Gd enhancing) as covariates.
	Method	Logistic Regression
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (Ublituximab/Teriflunomide)
	Estimated Value	0.872
	Confidence Interval	(2-Sided) 95%; 0.603 to 1.261
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

mITT- MRI population included participants in mITT population who have baseline and 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 were administered ublituximab 150 mg, IV infusion 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 QD from Day 1 up to the last day of Week 95.	Participants were administered 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	204	207
Least Squares Mean (95% Confidence Interval) [percent change]	-0.197	-0.125

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	<0.0001
	Comments	The 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 (MMRM)
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.072
	Confidence Interval	(2-Sided) 95%; -0.107 to -0.036
	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. A TEAE is an AE that starts or worsens after receiving 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 were administered ublituximab 150 mg, IV infusion 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 QD from Day 1 up to the last day of Week 95.	Participants were administered 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	273	275
TEAEs	86.1 31.4%	89.1 32.4%
TESAEs	11.4 4.2%	6.9 2.5%

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	All-Cause Mortality: All the enrolled participants; Adverse Events: 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 were administered ublituximab 150 mg, IV infusion 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 QD from Day 1 up to the last day of Week 95.		Participants were administered 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	2/274 (0.7%)		0/275 (0%)
Serious Adverse Events
	Ublituximab + Oral Placebo		Teriflunomide + IV Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/273 (11.4%)		19/275 (6.9%)
Blood and lymphatic system disorders
Neutropenia	1/273 (0.4%)		0/275 (0%)
Endocrine disorders
Hyperthyroidism	0/273 (0%)		1/275 (0.4%)
Gastrointestinal disorders
Pancreatitis chronic	1/273 (0.4%)		0/275 (0%)
Oesophageal achalasia	0/273 (0%)		1/275 (0.4%)
General disorders
Asthenia	0/273 (0%)		1/275 (0.4%)
Immune system disorders
Anaphylactic reaction	1/273 (0.4%)		0/275 (0%)
Hypersensitivity	1/273 (0.4%)		0/275 (0%)
Infections and infestations
Pneumonia	3/273 (1.1%)		0/275 (0%)
COVID-19 pneumonia	2/273 (0.7%)		1/275 (0.4%)
Central nervous system enteroviral infection	2/273 (0.7%)		0/275 (0%)
Appendicitis	1/273 (0.4%)		0/275 (0%)
Bullous erysipelas	1/273 (0.4%)		0/275 (0%)
Encephalitis	1/273 (0.4%)		0/275 (0%)
Measles	1/273 (0.4%)		0/275 (0%)
Meningoencephalitis viral	1/273 (0.4%)		0/275 (0%)
Peritonsillar abscess	1/273 (0.4%)		0/275 (0%)
Pulmonary tuberculosis	1/273 (0.4%)		0/275 (0%)
Salpingitis	1/273 (0.4%)		0/275 (0%)
Upper respiratory tract infection	1/273 (0.4%)		0/275 (0%)
Bacterial infection	0/273 (0%)		1/275 (0.4%)
Lyme disease	0/273 (0%)		1/275 (0.4%)
Pyelonephritis acute	0/273 (0%)		1/275 (0.4%)
Urinary tract infection	0/273 (0%)		2/275 (0.7%)
Injury, poisoning and procedural complications
Concussion	1/273 (0.4%)		0/275 (0%)
Femoral neck fracture	1/273 (0.4%)		0/275 (0%)
Infusion related reaction	1/273 (0.4%)		0/275 (0%)
Patella fracture	1/273 (0.4%)		0/275 (0%)
Investigations
Lymphocyte count decreased	1/273 (0.4%)		0/275 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	1/273 (0.4%)		0/275 (0%)
Myalgia	1/273 (0.4%)		0/275 (0%)
Back pain	0/273 (0%)		1/275 (0.4%)
Intervertebral disc disorder	0/273 (0%)		1/275 (0.4%)
Muscular weakness	0/273 (0%)		1/275 (0.4%)
Nervous system disorders
Dizziness	1/273 (0.4%)		0/275 (0%)
Neurological symptom	1/273 (0.4%)		4/275 (1.5%)
Presyncope	1/273 (0.4%)		0/275 (0%)
Acoustic neuritis	0/273 (0%)		1/275 (0.4%)
Pregnancy, puerperium and perinatal conditions
Ectopic pregnancy	1/273 (0.4%)		0/275 (0%)
Psychiatric disorders
Affective disorder	1/273 (0.4%)		0/275 (0%)
Mental disorder	1/273 (0.4%)		0/275 (0%)
Psychotic disorder	0/273 (0%)		1/275 (0.4%)
Renal and urinary disorders
Tubulointerstitial nephritis	1/273 (0.4%)		0/275 (0%)
Reproductive system and breast disorders
Ovarian cyst ruptured	0/273 (0%)		1/275 (0.4%)
Uterine haemorrhage	0/273 (0%)		1/275 (0.4%)
Skin and subcutaneous tissue disorders
Angioedema	0/273 (0%)		1/275 (0.4%)
Rosacea	0/273 (0%)		1/275 (0.4%)
Surgical and medical procedures
Medical device removal	1/273 (0.4%)		0/275 (0%)
Vascular disorders
Varicose vein	1/273 (0.4%)		0/275 (0%)
Other (Not Including Serious) Adverse Events
	Ublituximab + Oral Placebo		Teriflunomide + IV Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	197/273 (72.2%)		181/275 (65.8%)
Blood and lymphatic system disorders
Lymphopenia	27/273 (9.9%)		4/275 (1.5%)
Neutropenia	11/273 (4%)		15/275 (5.5%)
Gastrointestinal disorders
Nausea	29/273 (10.6%)		15/275 (5.5%)
Diarrhoea	19/273 (7%)		26/275 (9.5%)
Abdominal pain upper	7/273 (2.6%)		14/275 (5.1%)
Abdominal pain	15/273 (5.5%)		9/275 (3.3%)
General disorders
Pyrexia	41/273 (15%)		13/275 (4.7%)
Chills	19/273 (7%)		1/275 (0.4%)
Infections and infestations
Nasopharyngitis	34/273 (12.5%)		44/275 (16%)
Respiratory tract infection viral	20/273 (7.3%)		8/275 (2.9%)
Rhinitis	18/273 (6.6%)		8/275 (2.9%)
Urinary tract infection	11/273 (4%)		16/275 (5.8%)
Upper respiratory tract infection	16/273 (5.9%)		15/275 (5.5%)
Investigations
Lymphocyte count decreased	33/273 (12.1%)		8/275 (2.9%)
Aspartate aminotransferase increased	14/273 (5.1%)		4/275 (1.5%)
Alanine aminotransferase increased	12/273 (4.4%)		16/275 (5.8%)
Musculoskeletal and connective tissue disorders
Back pain	16/273 (5.9%)		30/275 (10.9%)
Pain in extremity	15/273 (5.5%)		12/275 (4.4%)
Nervous system disorders
Headache	84/273 (30.8%)		59/275 (21.5%)
Skin and subcutaneous tissue disorders
Alopecia	6/273 (2.2%)		36/275 (13.1%)
Vascular disorders
Hypertension	12/273 (4.4%)		23/275 (8.4%)

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.