Trial Outcomes & Findings for Study to Assess the Efficacy and Safety of Ublituximab in Participants With Relapsing Forms of Multiple Sclerosis (RMS) ( ULTIMATE 1 ) (NCT NCT03277261)

Last Updated: 2021-12-06

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

549 participants

Primary outcome timeframe

Up to 96 weeks

Results posted on

2021-12-06

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.	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).
Overall Study STARTED	274	275
Overall Study COMPLETED	240	252
Overall Study NOT COMPLETED	34	23

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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).
Overall Study Adverse Event	17	1
Overall Study Participant Withdrawal of Consent	6	15
Overall Study Investigator / Sponsor Decision	4	2
Overall Study Pregnancy	2	0
Overall Study Lost to Follow-up	2	2
Overall Study Lack of Efficacy	2	2
Overall Study Other-Alternative Treatment/Unspecified Reasons	1	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ublituximab + Oral Placebo n=274 Participants 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.	Teriflunomide + IV Placebo n=275 Participants 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 n=549 Participants Total of all reporting groups
Age, Continuous	36.3 years STANDARD_DEVIATION 8.48 • n=5 Participants	37.0 years STANDARD_DEVIATION 9.62 • n=7 Participants	36.7 years STANDARD_DEVIATION 9.07 • n=5 Participants
Sex: Female, Male Female	167 Participants n=5 Participants	180 Participants n=7 Participants	347 Participants n=5 Participants
Sex: Female, Male Male	107 Participants n=5 Participants	95 Participants n=7 Participants	202 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	7 Participants n=5 Participants	2 Participants n=7 Participants	9 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	263 Participants n=5 Participants	267 Participants n=7 Participants	530 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	6 Participants n=7 Participants	10 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black or African American	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	267 Participants n=5 Participants	267 Participants n=7 Participants	534 Participants n=5 Participants
Race/Ethnicity, Customized Race · Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 96 weeks

Population: 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.

Outcome measures

Outcome measures
Measure	Ublituximab + Oral Placebo n=271 Participants 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.	Teriflunomide + IV Placebo n=274 Participants 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).
Annualized Relapse Rate (ARR)	0.076 relapses per participant-years Interval 0.042 to 0.138	0.188 relapses per participant-years Interval 0.124 to 0.283

SECONDARY outcome

Timeframe: Weeks 12, 24, 48, and 96

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Ublituximab + Oral Placebo n=264 Participants 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.	Teriflunomide + IV Placebo n=269 Participants 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 Number of Gadolinium (Gd)-Enhancing T1-Lesions Per Magnetic Resonance Imaging (MRI) Scan Per Participant	0.016 lesions per scan per participant Interval 0.008 to 0.032	0.491 lesions per scan per participant Interval 0.355 to 0.679

SECONDARY outcome

Timeframe: Weeks 24, 48, and 96

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Ublituximab + Oral Placebo n=260 Participants 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.	Teriflunomide + IV Placebo n=267 Participants 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 Number of New and Enlarging T2 Hyperintense Lesions (NELs) Per MRI Scan Per Participant	0.213 lesions per scan per participant Interval 0.144 to 0.316	2.789 lesions per scan per participant Interval 2.136 to 3.643

SECONDARY outcome

Timeframe: Up to Week 96

Population: 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 \[NCT03277248\].

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.

Outcome measures

Outcome measures
Measure	Ublituximab + Oral Placebo n=543 Participants 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.	Teriflunomide + IV Placebo n=546 Participants 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).
Time to Confirmed Disability Progression (CDP) for at Least 12 Weeks	NA weeks Median and Inter Quartile Range was not reached due to the low number of participants with events.	NA weeks Median and Inter Quartile Range was not reached due to the low number of participants with events.

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ublituximab + Oral Placebo n=271 Participants 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.	Teriflunomide + IV Placebo n=274 Participants 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).
Percentage of Participants With No Evidence of Disease Activity (NEDA)	44.6 percentage of participants	15.0 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ublituximab + Oral Placebo n=271 Participants 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.	Teriflunomide + IV Placebo n=274 Participants 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).
Percentage of Participants With Impaired Symbol Digit Modalities Test (SDMT)	29.2 percentage of participants	31.8 percentage of participants

SECONDARY outcome

Timeframe: Baseline up to Week 96

Outcome measures

Outcome measures
Measure	Ublituximab + Oral Placebo n=204 Participants 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.	Teriflunomide + IV Placebo n=207 Participants 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).
Percent Change From Baseline in Brain Volume	-0.197 percent change Interval -0.228 to -0.166	-0.125 percent change Interval -0.155 to -0.095

SECONDARY outcome

Timeframe: From the first dose of study drug through the end of the study (up to approximately 116 weeks)

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

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.

Outcome measures

Outcome measures
Measure	Ublituximab + Oral Placebo n=273 Participants 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.	Teriflunomide + IV Placebo n=275 Participants 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).
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) TEAEs	86.1 percentage of participants	89.1 percentage of participants
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) TESAEs	11.4 percentage of participants	6.9 percentage of participants

Adverse Events

Ublituximab + Oral Placebo

Serious events: 31 serious events

Other events: 197 other events

Deaths: 2 deaths

Teriflunomide + IV Placebo

Serious events: 19 serious events

Other events: 181 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

TG Therapeutics Clinical Support Team

TG Therapeutics

Phone: 1-877-575-8489

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Ublituximab + Oral Placebo n=273 participants at risk 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.	Teriflunomide + IV Placebo n=275 participants at risk 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).
Skin and subcutaneous tissue disorders Alopecia	2.2% 6/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	13.1% 36/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Blood and lymphatic system disorders Lymphopenia	9.9% 27/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	1.5% 4/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Blood and lymphatic system disorders Neutropenia	4.0% 11/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	5.5% 15/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Gastrointestinal disorders Nausea	10.6% 29/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	5.5% 15/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Gastrointestinal disorders Diarrhoea	7.0% 19/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	9.5% 26/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Gastrointestinal disorders Abdominal pain upper	2.6% 7/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	5.1% 14/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
General disorders Pyrexia	15.0% 41/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	4.7% 13/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
General disorders Chills	7.0% 19/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	0.36% 1/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Infections and infestations Nasopharyngitis	12.5% 34/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	16.0% 44/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Infections and infestations Respiratory tract infection viral	7.3% 20/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	2.9% 8/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Infections and infestations Rhinitis	6.6% 18/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	2.9% 8/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Infections and infestations Urinary tract infection	4.0% 11/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	5.8% 16/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Infections and infestations Upper respiratory tract infection	5.9% 16/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	5.5% 15/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Investigations Lymphocyte count decreased	12.1% 33/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	2.9% 8/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Investigations Aspartate aminotransferase increased	5.1% 14/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	1.5% 4/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Investigations Alanine aminotransferase increased	4.4% 12/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	5.8% 16/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Musculoskeletal and connective tissue disorders Back pain	5.9% 16/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	10.9% 30/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Musculoskeletal and connective tissue disorders Pain in extremity	5.5% 15/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	4.4% 12/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Nervous system disorders Headache	30.8% 84/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	21.5% 59/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Vascular disorders Hypertension	4.4% 12/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	8.4% 23/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).
Gastrointestinal disorders Abdominal pain	5.5% 15/273 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).	3.3% 9/275 • From the first dose of study drug through the end of the study (up to approximately 116 weeks) 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).