Conditions: Relapsing Multiple Sclerosis (RMS)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 545
Healthy volunteers: no

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.

Detailed description:

Arms:
arm 1: 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. arm 2: 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).

Interventions: intervention 1: Ublituximab intervention 2: Teriflunomide intervention 3: Oral Placebo intervention 4: IV Placebo
Intervention descriptions: intervention 1: Administered as an IV infusion. intervention 2: Film coated tablets administered orally. intervention 3: Administered orally. intervention 4: Administered as an IV Infusion.

Protocol document:
Prot_000.pdf: 


TG1101-RMS302 
 
 
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Page 1 of 140 
Protocol version/Date:  
 
Version 5.0 / September 4, 2020 
Local Protocol #: 
 
 
Protocol TG1101-RMS302 
TITLE: 
Phase III: UbLiTuximab In Multiple Sclerosis Treatment Effects (ULTIMATE II STUDY). 
 
Sponsor: 
 
 
TG Therapeutics, Inc. 
 
 
 
 
2 Gansevoort St; 9th Floor 
 
 
 
 
New York, NY 10014 
 
 
 
 
Tel: (212) 554-4484 
 
IND Number:  
 
127265 
EudraCT Number: 
 
2017-000639-15 
 
Study Chair:   
 
, MD 
 
  
 
 
 
 
 
 
 
 
Medical Monitor: 
 
, MD 
 
 
 
 
 
Tel: 
 
 
 
Study Coordination:  
TG Therapeutics, Inc. 
 
 
 
 
2 Gansevoort St; 9th Floor 
 
 
 
 
New York, NY 10014 
 
 
 
 
Tel: (212) 554-4484 
 
Version: 1.0 
 
 
 
 
 
 
 
 
Date: 14 April 2017 
Version: 2.0 
 
 
 
 
 
 
 
 
Date: 7 June 2017 
Version: 2.1 
 
 
 
 
 
 
 
 
Date: 26 July 2017 
Version: 3.0 
 
 
 
 
 
 
 
 
Date: 03 August 2017 
Version: 3.1 
 
 
 
 
 
 
 
 
Date: 20 October 2017 
Version: 3.2, Ukraine  
 
 
 
 
 
 
Date: 09 February 2018 
Version: 4.0 
 
 
 
 
 
 
 
 
Date: 17 January 2020 
Version: 5.0 
 
 
 
 
 
 
 
 
Date: 04 September 2020 
 
 
This document is a confidential communication of TG Therapeutics, Inc. Acceptance of this document constitutes 
agreement by the recipient that no unpublished information contained herein shall be published or disclosed without 
prior written approval, except that this document may be disclosed to the appropriate Institutional Review Boards/ 
Independent Ethics Committees under the condition that they keep it confidential. 
 
 




TG1101-RMS302 
 
 
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Page 2 of 140 
SPONSOR APPROVAL 
The undersigned have reviewed the format and content of this protocol and have approved Protocol TG1101-
RMS302 for issuance. 
Protocol Title: 
Phase III: UbLiTuximab In Multiple Sclerosis Treatment Effects 
(ULTIMATE II STUDY). 
Protocol Number: 
TG1101-RMS302 
Trial Drug: 
Ublituximab (TG-1101)  
IND Number: 
EudraCT Number: 
127265 
2017-000639-15 
 
 
 
Date FINAL: 
04 September 2020  
MEDICAL MONITOR, 
  
, MD 
 
 
 
 
Print Name 
 
Signature 
 
Date 
STUDY CHAIR  
, MD 
 
 
 
Print Name 
 
Signature 
 
Date 
SPONSOR CONTACTS, TG Therapeutics, Inc. 
, PhD 
 
 
 
 
Print Name 
 
Signature 
 
Date 
STATISTICIAN, TG Therapeutics, Inc. 
 
 
 
 
 
Print Name 
 
Signature 
 
Date 
 
 
September 15, 2020




TG1101-RMS302 
 
 
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Page 3 of 140 
PROTOCOL ACCEPTANCE FORM 
Protocol Title: 
Phase III: UbLiTuximab In Multiple Sclerosis Treatment 
Effects (ULTIMATE II STUDY). 
Protocol Number: 
TG1101-RMS302 
Trial Drug: 
Ublituximab (TG-1101)  
IND Number: 
EudraCT Number: 
127265 
2017-000639-15 
 
Date FINAL: 
04 September 2020 
I have read the attached protocol and agree that it contains all the necessary details for performing TG1101-
RMS302. 
I will provide copies of the protocol and of the ublituximab and teriflunomide Investigator Brochures, which were 
furnished to me by TG Therapeutics (Sponsor) or its representative, to all members of the study team for whom I 
am responsible and who participate in the study.  I will discuss this material with them to ensure that they are fully 
informed regarding ublituximab, teriflunomide and the conduct of the study. 
Once the protocol has been approved by the IRB/EC, I will not modify this protocol without obtaining the prior 
approval of TG Therapeutics and of the IRB/EC.  I will submit the protocol modifications and/or any informed 
consent modifications to TG Therapeutics and the IRB/EC, and approval will be obtained before any modifications 
are implemented. 
I understand the protocol and will work according to it, the principles of Good Clinical Practice (current ICH 
guidelines), and the Declaration of Helsinki (2013) including all amendments. 
 
 
 
 
 
 
 
Print Name 
 
Signature 
 
Date 
 
 
 










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Page 7 of 140 
 
An independent Data Safety Monitoring Board (DSMB) will be established to advise 
the Sponsor on safety and ethical issues of the study.  The DSMB and Study Chair, 
Medical Monitor and Sponsor Representative will be in charge of reviewing safety 
data. The independent DSMB will be comprised of a total of five members with at least 
three MDs, a biostatistician and the DSMB chair.  The DSMB will meet periodically to 
discuss procedures and review unblinded data related to study status and enrollment, 
adverse events, previous/concomitant medications, hematology, blood pressure, 
relapses and the EDSS scores.  All other serious and non-serious adverse events will 
be documented, managed for each subject including review of the safety data by the 
DSMB and possible study participation termination at the investigator’s discretion.  
Information on these meetings will be provided per the DSMB Charter. Statistical 
analyses required for planned DSMB meetings will be prepared and disseminated to 
the DSMB members. The committee will receive unblinded safety data to allow review 
and assessment by treatment group. In addition, the committee will receive unblinded 
efficacy data to perform benefit/risk ratio assessment. Based on their reviews and 
analyses of safety and efficacy data, the committee shall have the right to advise the 
sponsor to stop the study after any meeting. 
 
MS Relapses During the Study 
Subjects enrolled into the study will be closely monitored through the study course by 
the Site and Sponsor’s personnel as well as by an external independent Data Safety 
Monitoring Board (DSMB) to ensure subjects’ welfare. 
 
Relapses that occur after study drugs are withdrawn will be assessed over the 
remainder of the study period and this data will be utilized as part of additional 
sensitivity analysis (described in the statistical plan) as long as the subject has not 
withdrawn their consent to be in the trial.  
 
The confirmation of a protocol-defined relapse will be determined by the Independent 
Relapse Adjudication Committee (IRAP). The steps for confirming a relapse are as 
follows: 
 
1. Subject Reported Relapse  
Subjects who experience new or worsening neurologic symptoms are instructed to 
contact the Treating Neurologist within 48 hours of symptom onset. All new or 
worsening neurological events, reported at a visit or over the phone, consistent with 
MS representing a clinical relapse as assessed by the subject will be initially reported 
to the Treating Neurologist. In parallel, the Examining Neurologist will also be notified 
to perform additional assessments. Upon the notification to the Treating Neurologist, 
the time and date of suspected subject reported relapse will be documented in the 
dedicated page eCRF (subject reported) by the Treating Neurologist or designee. 
 
The following should be recorded in the eCRF (subject reported) by the Treating 
Neurologist or designee: 
• 
Date and time of symptom onset as reported by the subject  
• 
Symptoms and events reported by the subject (both neurological and non-
neurological) 
• 
Date of initial contact by subject 
• 
Time of initial contact by subject 
 


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Within 7 days of the subject reporting the suspected relapse to the Treating 
Neurologist, the subject will be scheduled and assessed by both the Treating and 
Examining Neurologist independently.  
 
2. Initial Assessment of Relapse by Treating Neurologist and Examining 
Neurologist 
 
The Treating Neurologist will perform a neurological and physical examination and 
safety assessment. The Treating Neurologist or designee will document in the eCRF 
the following:  
• 
Time and date of neurological and physical examination 
• 
Clinical findings of neurological and physical examination 
• 
Review of previously documented concomitant medications and medical 
history 
• 
Safety assessment, including vital signs, CBC, B-cell count, lymphocyte counts, 
fibrinogen, quantitative immunoglobulin  
 
Subjects with suspected clinical relapses reported to the Treating Neurologist or 
designee will be referred to the blinded Examining Neurologist who will use 
Neurostatus to assess the EDSS independently of the Treating Neurologist.   
 
The Examining Neurologist or designee will document in the eCRF the following: 
• 
Date and time of assessment 
• 
EDSS score  
• 
FS Scores 
 
In addition, subjects may not begin IV methylprednisolone (IVMP) treatment of a 
relapse until the Examining Neurologist has completed his/her examination.  
 
Treatment of relapses may proceed at the discretion of the Treating Neurologist 
only after the Examining Neurologist has completed his/her exam. The Treating 
Neurologist will not know the results of the EDSS assessment. When making 
determination to treat a potential acute relapse the Treating Neurologist can use IVMP 
(1.0 g/day for at least 3 days and can be extended to 5 days) and will not affect the 
subject eligibility to continue in the study.   
 
The subject must re-consent at the time of each IRAP-confirmed or Treating 
Neurologist medically confirmed relapse to continue. 
 
The findings from either the Treating Neurologist and Examining Neurologist will not 
be shared. The Examining Neurologist must be blinded to the Treating Neurologist’s 
assessment and vice versa. 
 
Following the completion of assessments by the Treating and Examining Neurologists 
these results will be sent independently to the IRAP.  
 
3. Confirmation of Relapse by IRAP 
All assessments entered into the eCRF from both the Treating Neurologist and the 
blinded Examining Neurologist, will be sent to an Independent Relapse Adjudication 
Panel (IRAP). IRAP adjudicates each case based on all available data provided for that 
case and members are not permitted to contact the site or the sponsor for additional 


TG1101-RMS302 
 
 
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Page 9 of 140 
information. The IRAP will, in turn, make the final determination of whether the 
neurological events meet the criteria for a protocol-defined relapse. 
 
Each episode of relapse must be confirmed by the IRAP, based on the neurological 
assessments performed independently by the Treating and/or Examining Neurologist 
by documenting either of the following: 
 
• 
≥ 2 points increase on one of the appropriate FS or 1 point on two or more of 
the appropriate FS.  The change must affect the selected FS (i.e., pyramidal, 
ambulation, cerebellar, brainstem, sensory or visual).  Note, the change in FS 
scores should correspond to the patient’s symptoms (e.g., patient reported 
change in visual acuity should correspond to a change in the vision FS score). 
Episodic spasm, sexual dysfunction, fatigue, mood change or bladder or bowel 
urgency or incontinence will not suffice to establish a relapse; 
• 
An increase of ≥0.5 points in the EDSS score (unless EDSS score = 0, then an 
increase of at least 1.0 points is required) from the previous clinically stable 
assessment. 
 
MS relapses are defined as a new or worsening neurological symptoms lasting 
≥24 hours with the absence of fever, injury, infection or adverse reactions to 
medications and accompanied by new neurological findings upon examination by the 
Examining Neurologist.  The symptoms are attributed to MS and are preceded by 
30 days of stability or improvement in neurological state. The change in EDSS score as 
assessed by the Examining Neurologist is ≥ 0.5 increase or ≥ 2 points increase on one 
of the appropriate FS or 1 point on two or more of the appropriate FS.  The change 
must affect the selected FS (i.e., pyramidal, ambulation, cerebellar, brainstem, sensory 
or visual).  Note, the change in FS scale scores should correspond to the patient’s 
symptoms (e.g., patient reported change in visual acuity should correspond to a 
change in the vision FS score).  Episodic spasm, sexual dysfunction, fatigue, mood 
change or bladder or bowel urgency or incontinence will not suffice to establish a 
relapse.  Please note: sexual dysfunction and fatigue will not be scored.  If the 
symptoms occur less than 30 days following the onset of a protocol-defined relapse, it 
should be considered part of the same relapse and would not be treated with IVMP 
within the protocol.  New or recurrent neurologic symptoms that evolve gradually 
over months should be considered disability progression, not an acute relapse and 
should not be treated with steroids.   
 
The suspected relapse must be reviewed and confirmed by the IRAP; Appendix D. The 
IRAP will then notify the CRO and Treating Neurologist of the results of its review.  
Treating Neurologist/designee will enter into the eCRF whether the neurological 
symptoms identified were a result of an IRAP-confirmed relapse. 
IRAP-confirmed relapses are the sole confirmation of a protocol-defined relapse. 
However, for instances where IRAP-confirmed relapses may not be feasible, 
provisions are provided within Section 4.4.2 (Treating Neurologist medically 
confirmed relapse). 
The subject must re-consent at the time of each IRAP-confirmed or  Treating 
Neurologist medically confirmed relapse to continue. 
 
Signing the informed consent form for re-consent (if the subject has a confirmed 
relapse), to proceed with the study at the next scheduled office visit should be within 
6 weeks after first reporting of relapse.  


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Re-consent criteria after relapse 
In case of an IRAP-confirmed MS relapse (as defined in the protocol, Appendix C) or 
Treating Neurologist medically confirmed relapse during the study, the following 
actions will be taken: 
• 
The subject will be reminded of the current approved MS medications/treatments 
and the opportunity to terminate the study and be treated with an approved MS 
medication.  
• 
The subject will be requested to re-sign an informed consent form within 6 weeks 
after first reporting of the suspected relapse if he/she chooses to continue to 
participate in the study, in the same treatment assignment. 
 
Disability Progression 
The method of disability progression calculation will be different than that of the 
relapse confirmation. The EDSS score will be used to assess disability progression. 
EDSS assessment will be performed by the Examining Neurologist. The Examining 
Neurologist must not share the EDSS score with the Treating Neurologist. The EDSS 
assessment for disability progression will be performed at screening and on Week 1 
Day 1 (prior to randomization) and Weeks 12, 24, 36, 48, 60, 72, 84 and 96.  To clarify, 
disability progression is not calculated by the Examining Neurologist (disability 
progression is a post hoc analysis based on the EDSS scores). 
 
Disability progression is defined as an increase of ≥1.0 point from the baseline EDSS 
score that is not attributable to another etiology (e.g., fever, concurrent illness, or 
concomitant medication) when the baseline score is 5.5 or less, and ≥0.5 when the 
baseline score is above 5.5.  Disability progression is considered confirmed when the 
increase in the EDSS is confirmed at regularly scheduled visits at least 12 or 24 weeks 
after the initial documentation of neurological worsening. 
 
 
 








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infection, chronic chest infection with bronchiectasis, tuberculosis (TB), or 
active hepatitis C  
b. Previous serious opportunistic or atypical infections 
c. History of positive serology for hepatitis B or hepatitis C or HIV 
12. History of clinically significant CNS trauma (e.g., traumatic brain injury, cerebral 
contusion, spinal cord compression)  
13. History of liver disease, including but not limited to:  
a. Known history of active hepatitis B or C any time prior to randomization or 
known history of active hepatitis A within 3 years prior to randomization 
b. Presence of clinically significant chronic liver or biliary disease 
c. Moderate or severe hepatic impairment defined as Child Pugh Score B or C, 
respectively, based on measurement of total bilirubin, serum albumin, 
International Normalized Ratio (INR) and as well as on presence /absence and 
severity of ascites and hepatic encephalopathy 
d. Any of the following abnormal laboratory values at screening or first infusion: 
• 
ALT/SGPT>2X the Upper Limit of Normal (ULN) 
• 
AST/SGOT>2X ULN 
14. Previous diagnosis with a congenital or acquired immunodeficiency (AIDS) 
15. History of renal impairment, including, but not limited to:  
a. Hypoproteinemia (e.g., in case of severe renal disease or nephrotic syndrome) 
with serum albumin <3.0 g/dL 
b. Severe renal insufficiency requiring renal dialysis 
16. Past or current history of medically significant adverse effects (including allergic 
reactions) from: 
a. Corticosteroids 
b. Diphenhydramine 
c. Murine or mouse/human chimeric antibodies  
17. Subjects with significantly impaired bone marrow function or significant anemia, 
leukopenia, or thrombocytopenia 
a. Hematocrit <24% and/or 
b. Absolute white blood cell count <4,000 cells/mm3 and/or 
c. Platelet count <150,000 cells/mm3 and/or 
d. Absolute neutrophil ≤ 1,500 cells/mm3 
18. Absolute lymphocyte counts less than 1000/microliter 
19. Any severe and/or uncontrolled medical conditions or other conditions that could affect 
their participation in the study such as: 
a. Symptomatic, or history of documented congestive heart failure (New York Heart 
Association functional classification III-IV [see Appendix B] 
b. QTcF: Female >450 msec; male > 430 msec Angina not well-controlled by 
medication 
c. Poorly controlled or clinically significant atherosclerotic vascular disease 
including cerebrovascular accident (CVA), transient ischemic attack (TIA), 
angioplasty, cardiac or vascular stenting in the past 6 months prior to screening 














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TABLE OF CONTENTS 
1 INTRODUCTION .......................................................................................................................................................... 29 
1.1 Background .................................................................................................................................................................................................. 29 
1.2 Ublituximab ................................................................................................................................................................................................. 29 
 Pre-Clinical Evaluations of Ublituximab .......................................................................................................................................................................................... 29 
 Clinical Development of Ublituximab ................................................................................................................................................................................................ 30 
1.3 Rationale ....................................................................................................................................................................................................... 31 
 Clinical Studies with Rituximab and Ocrelizumab ...................................................................................................................................................................... 31 
 Rationale for the Trial ............................................................................................................................................................................................................................... 32 
2 Endpoints ...................................................................................................................................................................... 33 
2.1 Primary Endpoint...................................................................................................................................................................................... 33 
2.2 Secondary Endpoints ............................................................................................................................................................................... 33 
2.3 Tertiary Endpoints ................................................................................................................................................................................... 33 
3 STUDY POPULATION................................................................................................................................................. 34 
3.1 Inclusion Criteria ....................................................................................................................................................................................... 34 
3.2 Exclusion Criteria ...................................................................................................................................................................................... 34 
3.3 Discontinuation from STUDY Treatment ........................................................................................................................................ 36 
 Pregnancy ....................................................................................................................................................................................................................................................... 36 
4 TREATMENT PLAN .................................................................................................................................................... 38 
4.1 Definition of Study Staff .......................................................................................................................................................................... 38 
 At the Study Site ........................................................................................................................................................................................................................................... 38 
 Principal Investigator ................................................................................................................................................................................................................................ 38 
 Treating Neurologist ................................................................................................................................................................................................................................. 38 
 Examining Neurologist (Evaluating Neurologist) ....................................................................................................................................................................... 38 
 MRI Staff .......................................................................................................................................................................................................................................................... 39 
 Clinical Coordinator ................................................................................................................................................................................................................................... 39 
4.2 Study Committees ..................................................................................................................................................................................... 39 
 Data Safety Monitoring Board (DSMB) ............................................................................................................................................................................................. 39 
 Steering Committee.................................................................................................................................................................................................................................... 40 
 Independent Relapse Adjudication Panel (IRAP) ........................................................................................................................................................................ 40 
 Blinded Assessment Relapse Team (BART) ................................................................................................................................................................................... 40 
4.3 Dosing Schema ........................................................................................................................................................................................... 40 
 Stopping Rules .............................................................................................................................................................................................................................................. 40 
4.4 General Concomitant Medication and Supportive Care Guidelines ..................................................................................... 40 
 MS Relapse During the Study ................................................................................................................................................................................................................ 41 
 Treating Neurologist Medically Confirmed Relapse .................................................................................................................................................................. 43 
 Re-consent Criteria After Relapsing ................................................................................................................................................................................................... 43 
 Disability Progression ............................................................................................................................................................................................................................... 43 


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4.5 Duration of Therapy ................................................................................................................................................................................. 44 
4.6 Subject Retention Strategies ................................................................................................................................................................ 44 
5 DOSING DELAYS .......................................................................................................................................................... 46 
5.1 Criteria for Ongoing Treatment .......................................................................................................................................................... 46 
5.2 Guidance for Suspected Relapse ......................................................................................................................................................... 46 
5.3 Guidance for Laboratory Abnormalities .......................................................................................................................................... 47 
6 Schedule of Assessments and Procedures ........................................................................................................ 49 
6.1 Overview ....................................................................................................................................................................................................... 55 
6.2 Laboratory Evaluation ............................................................................................................................................................................ 55 
6.3 Clinical Assessment and Procedures................................................................................................................................................. 58 
 Assessment of Relapse.............................................................................................................................................................................................................................. 58 
 Disability Evaluation ................................................................................................................................................................................................................................. 61 
 Radiological Evaluation ............................................................................................................................................................................................................................ 62 
 Neurological Evaluation ........................................................................................................................................................................................................................... 63 
 Cognition Assessment ............................................................................................................................................................................................................................... 63 
 Subject Reported Outcomes ................................................................................................................................................................................................................... 63 
 Safety Data ...................................................................................................................................................................................................................................................... 64 
6.4 Replacement Policy .................................................................................................................................................................................. 65 
6.5 Definitions .................................................................................................................................................................................................... 65 
6.6 Disease Parameters .................................................................................................................................................................................. 65 
6.7 Duration of Response .............................................................................................................................................................................. 65 
6.8 Response Review ...................................................................................................................................................................................... 65 
6.9 Re-Screening Procedures ....................................................................................................................................................................... 65 
6.10 End of Study Follow-Up ....................................................................................................................................................................... 66 
 Accelerated Teriflunomide Elimination Procedure ................................................................................................................................................................. 67 
7 Pharmaceutical Information ................................................................................................................................. 69 
7.1 Teriflunomide ............................................................................................................................................................................................. 69 
 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) for Teriflunomide ........................................................................................ 70 
7.2 Ublituximab ................................................................................................................................................................................................. 70 
 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) for ublituximab ............................................................................................. 71 
7.3 Ordering Study Medications ................................................................................................................................................................. 72 
7.4 Blinding, Packaging and Labeling ....................................................................................................................................................... 72 
 Teriflunomide or Oral Placebo ............................................................................................................................................................................................................. 72 
 Ublituximab or IV Placebo ...................................................................................................................................................................................................................... 73 
7.5 Dispensing and Administration .......................................................................................................................................................... 73 
 Dispensing and Administration of Teriflunomide or Oral Placebo..................................................................................................................................... 73 
 Dispensing and Administration of Ublituximab or iV Placebo .............................................................................................................................................. 74 
 Co-Administration for Ublituximab/oral Placebo and Teriflunomide/IV Placebo on Ublituximab/Placebo on infusion days ............ 79 
8 STATISTICAL CONSIDERATIONS ........................................................................................................................... 80 


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8.1 Sample Size and Power ........................................................................................................................................................................... 80 
8.2 General Analysis Convention ............................................................................................................................................................... 80 
8.3 Statistical analyses will be described in detail in the statistical analysis plan completed prior to final data 
lock.Analysis Populations ............................................................................................................................................................................. 80 
 Safety population ........................................................................................................................................................................................................................................ 81 
 Intention-to-Treat (ITT) .......................................................................................................................................................................................................................... 81 
 Modified Intention-to-Treat (mITT) .................................................................................................................................................................................................. 81 
 Per-Protocol Group (PP) .......................................................................................................................................................................................................................... 81 
8.4 Subject Disposition ................................................................................................................................................................................... 81 
 Screening and Enrollment ...................................................................................................................................................................................................................... 81 
 Disposition...................................................................................................................................................................................................................................................... 81 
8.5 Subject Demographics and Baseline Characteristics ................................................................................................................. 82 
8.6 Medical History .......................................................................................................................................................................................... 82 
8.7 Extent of Exposure ................................................................................................................................................................................... 82 
8.8 Interim Sample Size Reassessment ................................................................................................................................................... 82 
8.9 Efficacy Analyses ....................................................................................................................................................................................... 84 
 Primary Efficacy Variable ........................................................................................................................................................................................................................ 84 
 Secondary Efficacy Variables ................................................................................................................................................................................................................. 85 
 Sensitivity analyses .................................................................................................................................................................................................................................... 86 
 Tertiary Efficacy and Other Variables ............................................................................................................................................................................................... 87 
 88 
8.9.6 Anti-Drug Antibody (ADA) Analysis .................................................................................................................................................................................................. 89 
9 SAFETY REPORTING AND ANALYSIS ................................................................................................................... 90 
9.1 Safety Analyses........................................................................................................................................................................................... 90 
9.2 Adverse Events ........................................................................................................................................................................................... 90 
9.3 Adverse Event Characteristics ............................................................................................................................................................. 90 
9.4 Adverse Event Expectedness ............................................................................................................................................................... 91 
9.5 Treatment Emergent Adverse Events (TEAE’s) ........................................................................................................................... 91 
9.6 Adverse Events / Serious Adverse Event Causality Assessment .......................................................................................... 91 
 Recording of Adverse Events ................................................................................................................................................................................................................. 92 
 Abnormal Laboratory Values and Vital Signs ................................................................................................................................................................................ 92 
 Handling of Adverse Events ................................................................................................................................................................................................................... 92 
9.7 Serious Adverse Events .......................................................................................................................................................................... 93 
 Definitions of Serious Adverse Events .............................................................................................................................................................................................. 93 
 Serious Adverse Event Reporting by Investigators .................................................................................................................................................................... 94 
9.8 Sponsor SAE Reporting Requirements ............................................................................................................................................ 95 
9.9 Recording of Adverse Events and Serious Adverse Events ..................................................................................................... 95 
9.10 Diagnosis vs. Signs and Symptoms .................................................................................................................................................. 95 
 Persistent or Recurrent Adverse Events ....................................................................................................................................................................................... 95 
 Abnormal Laboratory Values ............................................................................................................................................................................................................. 96 


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 Deaths ............................................................................................................................................................................................................................................................ 96 
 Hospitalization, Prolonged Hospitalization, or Surgery ........................................................................................................................................................ 96 
 Pre-Existing Medical Conditions ....................................................................................................................................................................................................... 96 
 Protocol-Defined Events of Special Interest ................................................................................................................................................................................ 96 
10 STOPPING RULES ..................................................................................................................................................... 98 
11 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ................................................................. 99 
11.1 IRB/EC Approval .................................................................................................................................................................................... 99 
11.2 Regulatory Approval ............................................................................................................................................................................. 99 
11.3 Insurance and Indemnity .................................................................................................................................................................... 99 
11.4 Informed Consent ................................................................................................................................................................................... 99 
11.5 Confidentiality ...................................................................................................................................................................................... 100 
11.6 Investigator and Staff Information ............................................................................................................................................... 101 
11.7 Financial Information ........................................................................................................................................................................ 101 
12 RECORD RETENTION AND DOCUMENTATION OF THE TRIAL .............................................................. 102 
12.1 Amendments to the Protocol .......................................................................................................................................................... 102 
12.2 Documentation Required to Initiate Trial ................................................................................................................................. 102 
12.3 Trial Documentation and Storage ................................................................................................................................................. 103 
12.4 Data Collection ...................................................................................................................................................................................... 104 
12.5 Trial Monitoring, Auditing, and Inspecting ............................................................................................................................... 105 
12.6 Quality Assurance and Quality Control ...................................................................................................................................... 105 
12.7 Disclosure and Publication Policy ................................................................................................................................................ 105 
13 REFERENCES .......................................................................................................................................................... 107 
14 Appendix A; Pregnancy ...................................................................................................................................... 109 
15 Appendix B; NYHA Classifications .................................................................................................................. 111 
16 Appendix C; 2010 McDonald Diagnostic Criteria for MS ........................................................................ 112 
17 Appendix D; Independent Relapse Adjudication Panel (IRAP) ........................................................... 114 
18 Appendix E: Evaluation Procedure for Subject Reported Relapses ................................................... 116 
19 Appendix F: Per Visit Procedure ..................................................................................................................... 117 
 
 


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Summary of Changes 
Version 2.0 (dated 7 June 2017) is the first amendment to this protocol and contains the following updates: 
• 
A sentence was added to include additional analysis of relapses from a more specific timeframe. The sentence 
reads as follows: “Relapses that occur after study drugs are withdrawn will be assessed over the remainder 
of the study period and this data will be utilized as part of additional sensitivity analysis (described in the 
statistical plan) as long as the subject has not withdrawn their consent to be in the trial.”, 
• 
The interface between IRAP and the study sites have been updated to as follows: “IRAP adjudicates each case 
based on all available data provided for that case and members are not permitted to contact the site or the 
sponsor for additional information.”,  
• 
The change in EDSS score for defining progression of disability has been updated to state as follows: “…if a 
subject experiences at least 1.0 point increase on the EDSS when a baseline score is < 5.5…”,  
• 
The assessment tables now stipulates EDSS must be assessed 1 day prior to randomization,  
• 
Intent to treat definition was updated in the body of the protocol 
• 
Now included is a hierarchy analysis, sensitivity analysis for secondary endpoints and subjects who 
withdraw from study  
• 
The timeframe of relapse assessment was further defined 
• 
Interim sample size reassessment for relapses was further defined  
• 
Minor typographical errors 
Version 2.1 (dated 26 July 2017) is the second amendment to this protocol and contains the following updates: 
• 
Endpoints are now numbered instead of bulleted 
• 
Examining and Treating Neurologists will act independently. Any scores from evaluations performed by 
either the Examining or Treating Neurologist will not be shared.  
Version 3.0 (dated 03 August 2017) is the third amendment to this protocol and contains the following updates: 
• 
Include information regarding a new vial size for ublituximab 
• 
Update Sections 7.2.1.3 and 7.2.1.4 to reflect changes in adverse events as reported in the revised 
Investigator Brochure (Version 5.0; dated 01 August 2017) 
• 
Minor typographical errors 
Version 3.1 (dated 20 October 2017) is the fourth amendment to this protocol and contains the following updates: 
• 
Minor administrative updates and typographical errors were corrected throughout  
• 
Adverse Events will be reported using version 4.03 of the NCI grading system 
• 
FS scale scores should be correspond to patient’s symptoms 
• 
For relapses, patients must re-consent only if they have a confirmed relapse 
• 
Re-consenting criteria will based on the Treating Neurologists discretions and the criteria in Appendix C 
• 
Treatment Schema has been updated to reflect additional MRI scan at Week 12 
• 
Malignancy has been added to the list of discontinuation reasons 
• 
All subjects at Week 116 will be counseled by the treating team to have their teriflunomide plasma 
concentration re-measured prior to attempting to become pregnant or trying to impregnate their female 
partner.  
• 
The Treating Neurologist will perform MSFC and SDMT assessments 
• 
Blinded Assessment Relapse Team (BART) will reassess sample size when 210 out of 220 patients in each 
arm have been randomized 
• 
The use of medical equivalents when those listed in Section 4.4 and Sections 7.5.2.1 are not available can be 
used at the Investigator’s Discretion for Supportive Care Guidelines  
• 
Section 5.2.1 actions taken per Grade have been updated 


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• 
EDSS scores assessed by the Examining Neurologist is not to be shared with the Treating Neurologist and 
the Principal Investigator, if they act as the Treating Neurologist 
• 
Section 7.1 has been updated to provide storage conditions for the United States and Europe 
• 
Section 7.2 has been updated to reflect the increased shelf life of ublituximab (36 months) 
• 
Teriflunomide may be taken with or without breakfast 
• 
Liver enzymes will be recorded using a Grading System 
• 
Section 7.5.2.4 now describes updated information regarding second infusion interruptions 
• 
Adverse Events, including pregnancies and medically confirmed deaths, will be following beginning from 
the day the consent form is signed until 20 weeks after discontinuation 
• 
Protocol-defined events of special interest (Section 9.10.6) have been updated 
• 
The Data Safety Monitoring Board (DSMB) will be comprised of at least addition three MDs not including 
the chair  
• 
Appendix A has been updated to reflect the following: pregnancies are to be followed for 20 weeks after the 
last study drug was administered, women of child-bearing potential must have a negative serum pregnancy 
test within 5 days prior to initiating treatment, males must not donate sperm for 20 weeks following the 
last study drug administered, the pregnant subject/male subject’s partner will be asked to provide consent 
to allow the pregnancy to be followed up for the full duration (or until termination) and 6 most post birth.  
• 
Appendix F has been updated to reflect newly provided time 
 
Version 3.2 (dated 09 February 2018) is the Ukraine specific amendment to this protocol containing the following 
updates: 
• 
Clarification of the exclusion criteria to avoid potential misinterpretation 
• 
Clarification regarding the active comparator to confirm bioequivalent teriflunomide product is used in the 
study 
• 
Clarification on MRI and Pharmacokinetic (PK) windows 
• 
Minor administrative revisions to remove inconsistencies 
 
Version 4.0 (dated 17 January 2020) is the next amendment to this global protocol which now includes the Ukraine 
specific changes and additional following updates: 
• 
Clarification of the exclusion criteria to avoid potential misinterpretation 
• 
Clarification regarding the active comparator to confirm bioequivalent teriflunomide product is used in the 
study 
• 
Clarification on MRI and Pharmacokinetic (PK) windows 
• 
Minor administrative revisions to remove inconsistencies 
• 
Advise subjects to seek immediate medical help and inform the investigator if they experience signs or 
symptoms of an infection 
• 
Provide information on TG1101-RMS303 which is the Open Label Extension of TG1101-RMS301 and 
TG1101-RMS302 
Version 5.0  (dated 04 September 2020) is the next amendment to this protocol and contains the following 
updates: 
• 
Amended list of abbreviations 
• 
Updated Secondary Endpoints 
• 
Updated Tertiary Endpoints 
• 
Provided clarification/correction for Exclusion Criteria 13b, 15, 21  
• 
Specified timing of teriflunomide elimination procedure post discontinuation from study treatment 
• 
Clarified subjects that early terminate can enter 20-week Follow-Up Period but must sign Early 
Termination ICF 
• 
Refined procedures for pregnancy confirmation and added wording regarding counselling regarding 
teratogenicity 


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• 
Added reference to pharmacists as site team members 
• 
Clarified site team roles and responsibilities including Treating Neurologist, Examining Neurologist, 
Radiologist, and Clinical Coordinator 
• 
Updated DSMB composition and review procedures 
• 
Clarified teriflunomide alternative dosing times are allowed if necessary 
• 
Clarified time window for administration of pre-medication on infusion days 
• 
Defined Treating Neurologist Medically Confirmed relapses  
• 
Added requirement to re-consent patients upon Treating Neurologist medically confirmed relapse 
• 
Updated reference timepoint for patients re-consenting after confirmed relapse 
• 
Clarified the definition of disability progression  
• 
Clarified disability is a post-hoc analysis 
• 
Clarified AE follow-up if subject discontinues from study 
• 
Added guidance to assessments during dosing delay due to lab abnormalities and suspected relapse 
• 
Further defined procedure timing in Schedule of Assessments in tables 5, 6, 7 
• 
Clarified urine pregnancy is required in 20-week Follow-up Period 
• 
Clarified window for PK sampling 
• 
Clarified requirement to collect blood sample for teriflunomide concentration at Early Withdrawal from 
Treatment Visit 
• 
Clarified requirement to collect urine sample at Early Withdrawal from Treatment Visit and Unscheduled 
Relapse Visit 
• 
Clarified requirement to draw blood sample for B-lymphocyte cell count at Early Withdrawal from 
Treatment Visit and Unscheduled Relapse Visit 
• 
Clarified MRI window if early withdrawal from study 
• 
Clarified that MRI reports with only non-MS pathology will be provided to Treating Neurologist after 
randomization 
• 
Clarified subject reported outcomes (FIS, MSQoL) are done at Early Withdrawal from Treatment Visit 
• 
Clarified time windows for recording of ECG and vital signs pre- and post-infusion 
• 
Clarified starting time for teriflunomide elimination procedure for subjects who withdraw from treatment 
• 
Reiterated that no Disease Modifying Therapy is permitted during the 20-week Follow-up Period 
• 
Clarified PK analysis 
• 
Clarified that urine pregnancy testing is mandatory for female subjects of childbearing potential at each 
visit during the follow-up period 
• 
Clarified that teriflunomide drug concentration testing is performed at Week 116 but not shared with sites 
and subjects 
• 
Clarified ublituximab vial cap colors 
• 
Updated the CAEPRS profile of teriflunomide and ublituximab 
• 
Clarified timing of teriflunomide concentration, includes early withdrawal from treatment visit and Week 
116 
• 
Provided definition of Infusion Related Reaction and that they will be analyzed separately 
• 
Updated ublituximab/IV placebo infusion interruption procedure 
• 
Clarified infusion delay process due to relapse 
• 
Updated general analysis will be presented with P values with 4 decimals 
• 
Updated definitions of ITT, mITT,  and PP populations 
• 
Clarified definition of ublituximab/IV placebo treatment exposure 
• 
Specified that primary statistical analysis will be done once all subjects have completed Week 96 
• 
Listed and clarified all pooled analysis 
• 
Provided further statistical analysis details 
• 
Further defined Treatment Emergent Adverse Events 
• 
Clarified that hospitalizations due to the underlying disease (MS disease progression) and due to relapse do 
not have to be reported as SAE 
• 
Replaced protocol list of Adverse Events of Special Interest with reference to valid IB 


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• 
Further defined the definition of overdose  
• 
Updated the requirement for sites to have procedures in place to ensure study conduct 
• 
Specified pregnancy does not require a report on study medication relatedness 
• 
Defined female patients with hysterectomy as not considered women of childbearing potential  
• 
Administrative revisions to Per Visit Procedures in Appendix F 
 
 
 


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1 INTRODUCTION 
1.1 BACKGROUND 
Multiple Sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system (CNS).  
Although it can occur at any age, it is often seen in young adults between the ages of 20 to 40 with a higher incidence 
in females versus males.  According to the Multiple Sclerosis Foundation, over 400,000 people in the United States 
and approximately 2.5 million people worldwide have been diagnosed with the disease.[1]  Prior to 2014, MS had 
been classified into four clinical subtypes: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), 
primary progressive MS (PPMS) and progressive relapsing MS (PRMS).[2]  In 2014, the International Advisory 
Committee on Clinical Trials of MS revised the MS phenotypes to the following disease modifier phenotypes: 
Clinically Isolated Syndrome (CIS; not active or active), RMS (not active or active), progressive disease (active and 
with progression; active but without progression; not active with progression; not active and without 
progression).[3]  The progression, severity and specific symptoms of MS vary amongst each subjects and are 
unpredictable.  Since 1993, twelve disease modifying therapies (DMTs) have been approved by the Food and Drug 
Administration (FDA) to treat MS.  These include 7 injectable agents, 3 orals and 3 infusions.  The main target in the 
majority of these therapies has been T cells.  Despite improvements in the available therapies in reducing relapses 
by up to 65% [4] and slowing the progression of the disease, subjects continue to experience disease relapses and 
progression.  Furthermore, some of the T cell directed therapies have shown safety issues that have challenged their 
more widespread use.  Recent immunopathologic and clinical studies have demonstrated that B cells also play a 
central role in the pathogenesis of the disease, perhaps upstream of the T cell mediated pathology.  As such, targeting 
aberrant autoimmune activity in B cells in MS may represent the next leap forward in treating MS.   Phase 2 and 3 
studies with anti-CD20 antibodies, which selectively deplete B cells, have shown robust efficacy over both placebo 
and B-interferon. To date, B cell targeted therapies have not been approved for the treatment of relapsing and 
progressive forms of MS.  Thus, there is a pressing need for new, innovative, B cell targeted therapies for the 
treatment of this heterogeneous disease.   
1.2 UBLITUXIMAB 
Ublituximab is a novel third generation chimeric anti-CD20 monoclonal antibody bioengineered for potent activity, 
exhibiting a unique glycosylation profile with a low fucose content, designed to introduce superior antibody-
dependent cytotoxicity (ADCC).  Ublituximab has maintained competitive complement-dependent cytotoxicity 
(CDC) and has also demonstrated to induce programmed cell death (PCD) upon binding to the CD20 antigen on B-
lymphocytes.  Ublituximab has a unique protein sequence, and targets epitopes on CD20 not targeted by rituximab 
or ofatumumab, both currently approved anti-CD20 antibodies in oncologic diseases and rheumatoid arthritis 
(rituximab only). 
 PRE-CLINICAL EVALUATIONS OF UBLITUXIMAB 
1.2.1.1 IN VITRO ACTIVITY  
In an in-vitro assay using B-CLL cells from subject donors, ublituximab demonstrated an enhanced ability to kill CLL 
cells compared to rituximab.  Ublituximab demonstrated improved Fcγ receptor IIIA (FcγRIIIA)/CD16 binding and 
FcγRIIIA dependent effector functions compared to rituximab.  Additionally, ublituximab induced higher ADCC 
against CLL cells, and a higher FcγRIIIA mediated interleukin (IL)-2 production by FcγRIIIA+ Jurkat cells (5).  
Ublituximab demonstrated high ADCC against both subject-derived CLL cells and NHL cell lines. Against the NHL cell 
line Ramos, ublituximab was observed to inhibit the constitutively active NF-κB survival pathway and induce the 
expression of PTEN along with inhibition of the PI3K-AKT pathway.  Ublituximab also induced the expression of pro-
apoptotic factors, sensitizing Ramos cells to TRAIL mediated apoptosis (6).  


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1.2.1.2 IN VIVO ACTIVITY 
The antitumor effect of ublituximab was compared to that of rituximab with chemotherapy in follicular lymphoma 
(FL), and mantle cell lymphoma (MCL) xenograft murine models.  Single agent ublituximab demonstrated dose-
related anti-tumor activity with 100% tumor growth inhibition in the FL xenograft at a dose of 100 mg/kg, and a 
superior tumor growth delay (21 days) compared to rituximab. Ublituximab also demonstrated superior anti-tumor 
activity compared to rituximab against MCL xenografts at all dose levels (7).  
1.2.1.3 TOXICOLOGY 
In single-dose and repeat dose toxicology studies performed under GLP, ublituximab displayed a safety profile 
similar to what might be expected for anti-CD20 monoclonal antibodies. Single administration of up to 100 mg/kg 
ublituximab in cynomolgus monkeys was well tolerated, with no local irritation with intravenous administration.  
Genotoxicity studies (Ames test) showed that ublituximab was not mutagenic.  Monkeys that received a single 
injection of 0.3 mg/kg of ublituximab developed an anti-ublituximab response, whereas anti-ublituximab antibodies 
were not detected in the animals which received 10 or 100 mg/kg (see Ublituximab Investigator Brochure). 
 CLINICAL DEVELOPMENT OF UBLITUXIMAB  
1.2.2.1 PHARMACOKINETICS 
After infusion of ublituximab (previously known as LFB-R603) at 150 mg dose followed by seven weekly infusions 
at 450 mg, results suggested non-linear pharmacokinetics with respect to dose (450 mg vs. 150 mg) and time (Week 
4 vs. Week 8); and more than proportional increase of Cmax and AUC∞ due to a clearance decrease.  The volume of 
distribution at steady state was small (~5 L), approximately equal to blood volume.  This non-linear 
pharmacokinetics may be explained by binding of ublituximab to its target, with a large component of target-
mediated elimination after the first dose that is decreased after subsequent infusions due to a reduction in the 
available target.  However, limited data for each dose level cohort and considerable variability in baseline subject 
characteristics, particularly in terms of tumor burden, make firm conclusions difficult. 
The linear mean serum concentration-times profile after the first, the fourth and the eight infusion of ublituximab 
are presented in Figure 1.  A summary of non-compartmental PK parameters after the first, the fourth and the eighth 
infusion of ublituximab are presented in Table 2. 
Figure 1: Linear mean serum concentration-times profile after the first, the fourth and the eighth infusion 
of ublituximab 
 
 
 




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compared to placebo at 24 weeks.  More recently, ocrelizumab demonstrated promising results in its 2 Phase III 
trials (OPERA I and OPERA II) [20].  In OPERA I and II, subjects treated with ocrelizumab had significantly lower 
Annualized Relapse Rates (0.156 and 0.155, respectively) compared to subjects treated with IFNβ-1a, 44µg (0.292 
and 0.29, respectively).  Further, in OPERA I and II, subjects treated with ocrelizumab had approximately 46% 
reduction in ARR as compared to those treated with IFNβ-1a 44μg; TG Therapeutics is powering this study for a 40% 
reduction in ARR. [14] 
 RATIONALE FOR THE TRIAL 
Ublituximab has been studied extensively in the treatment of B-cell malignancies and has been shown to be a potent 
B-cell depleting agent.  Based on the success of other CD20s in the treatment of RMS, ublituximab is being studied in 
RMS.  
TG Therapeutics has performed a phase 2a clinical trial using ublituximab as a single agent to examine the level of B 
cell depletion by ublituximab as well as determine the optimal dose and infusion time for ublituximab in subjects 
with RMS.  Based on the results of the Phase 2a study with a dosing of 150 mg (infused for 4 hours) on Week 1 Day 1 
and a dosing of 450 mg (infused for 1 hour) on Week 3 Day 15, a median of >99% B cell depletion was achieved on 
Week 4 and sustained until Week 24.  The dosing regimen was well tolerated by the subjects with Infusion Related 
Reactions (grade 1 and 2) being the commonly reported adverse event.  
TG Therapeutics also performed a phase 1 clinical study using ublituximab as a single agent to examine the safety 
and tolerability of a single dose ublituximab at 450 mg in subjects diagnosed with acute Neuromyelitis Optica 
relapse.  Although the single dose of 450 mg ublituximab infused for 4 hours was safe and well tolerated, the study 
demonstrated that after 3 months, B cells started to replete after being deplete for >99% upon the initial 
administration of ublituximab on Week 1 Day 1. 
In examining the results from both the Phase 2a RMS and Phase 1 acute NMO clinical studies, it is believed that a 
higher dose of ublituximab will be needed during the initial 6 months of treatment in RMS subjects.  With enhanced 
potency over first generation anti-CD20s due to its glycoengineering, we believe we may be able to optimize the 
therapeutic window and/or safely decrease infusion times, offering subjects comparable efficacy with a more 
convenient infusion. 
         


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2 ENDPOINTS 
2.1 PRIMARY ENDPOINT 
The primary efficacy endpoint is ARR defined as the number of IRAP-confirmed relapsed per-subject year. The 
estimate of ARR for a treatment group will be the total number of relapses for subjects in the respective treatment 
group divided by the sum of treatment duration for subjects in that specific treatment group. Subjects will be treated 
up to 96 weeks.  
2.2 SECONDARY ENDPOINTS 
The key secondary outcomes will be tested using a hierarchical approach with the order specified below using a 
step-down procedure where each test is at a Type I error 0.05. If any endpoint fails to reach significance, then formal 
testing of significance of the subsequent secondary outcomes will not be performed. The hierarchical analyses of the 
key secondary endpoints are as follows:  
 
1. Total number of gadolinium enhancing (Gd-enhancing) T1-lesions per MRI scan by Week 96.     
2. Total number of new and enlarging T2 hyperintense lesions (NELs) per MRI scan by Week 96. 
3. Time to Confirmed Disability Progression (CDP) for at least 12 weeks occurring during the 96-week double-blind 
treatment period. * 
4. Proportion of subjects with No Evidence of Disease Activity (NEDA) from Week 24 to Week 96.   
5. Proportion of subjects reaching impaired SDMT (Symbol Digit Modalities Test) from baseline to Week 96.   
6. Percentage change in Brain Volume from baseline to Week 96.   
* Confirmed Disability Progression for at least 12 weeks during the 96-week treatment period will be analyzed 
using pooled data from the two identical studies TG1101-RMS301 and TG1101-RMS302. 
2.3 TERTIARY ENDPOINTS 
1. Change in MSFC score from baseline to Week 96 
2. Time to Confirmed Disability Progression (CDP) for at least 24 weeks 
3. Time to Confirmed Disability Improvement (CDI) for at least 12 weeks 
4. Time to Confirmed Disability Improvement (CDI) for at least 24 weeks 
5. Health outcomes (MSQoL-54 (inclusive of SF36); FIS, hospitalization, steroid use, time out of work) 
6. Total volume of Gd enhancing T1 lesions per MRI scan over the treatment period 
7. Volume of T2 lesions  
8. Volume of hypointense T1 lesion component (black holes) 
9. Proportion of subjects free of disability progression at 24 weeks, 48 weeks, and 96 weeks 
10. Proportion of subjects with a relapse 
11. Time to first confirmed relapse 


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3 STUDY POPULATION 
3.1 INCLUSION CRITERIA 
Subjects must meet the following inclusion criteria to be eligible for participation in this study: 
1. 18-55 age 
2. Diagnosis of RMS (McDonald criteria 2010; Appendix C)  
3. ≥ 2 relapses in prior 2 years or 1 relapse in the year prior to screening and/or ≥1 Gd enhancing lesion 
4. Documented MRI of brain with abnormalities consistent with MS 
5. Active disease 
6. EDSS 0-5.5 (inclusive) at screening 
7. B cell counts ≥5% of total lymphocytes 
8. Neurologic stability ≥ 30 days prior to screening and baseline 
9. Female subjects who are not of child-bearing potential, have documented surgical sterilization (see Appendix 
A), and female subjects of child-bearing potential who have a negative serum pregnancy test at baseline.  
Female subjects of child-bearing potential (see Appendix A), and all male partners must consent to use a 
medically/clinically acceptable method of contraception throughout the treatment period and for 20 weeks 
after the cessation of active treatment.   Female subjects of child-bearing potential (see Appendix A) must agree 
to undertake urine pregnancy tests every 4 weeks during active treatment and the follow up period. 
10. Fertile male subjects participating in the study who are sexually active with women of child bearing potential, 
must agree to use a condom during the treatment period and for an additional 20 weeks after cessation of 
active treatment. Agree to use an accelerated elimination procedure after the last dose of study medications or 
early termination from the study (see Section 6.10.1) 
11. Willingness and ability to comply with trial and follow-up procedures, give written consent  
3.2 EXCLUSION CRITERIA 
Subjects who meet any of the following exclusion criteria are not to be enrolled to this study: 
1. Treatment with Anti-CD20 or other B cell directed treatment  
2. Treatment with the following therapies at any time prior to randomization: 
• 
Alemtuzumab 
• 
Natalizumab, 
• 
Teriflunomide,  
• 
Leflunomide, and  
• 
Stem cell transplantation 
3. Contraindications to teriflunomide or incompatibility with use of teriflunomide. 
4. Therapies that are disallowed (minimum of 4 weeks prior to randomization): phenytoin, warfarin, tolbutamide, 
St John’s Wort or cholestyramine 
5. Prior DMT exposure within months of screening: 
a. 24 months with cladribine 
b. 6 months with daclizumab, azathioprine, methotrexate, or cyclophosphamide 
c. 90 days with fingolimod, or experimental S1P modulators, IV immunoglobulin, and plasmapheresis 
d. 30 days with glatiramer acetate, interferons, dimethyl fumarate, laquinimod or glucocorticoids  
6. Diagnosed with Primary Progressive MS (PPMS) 
7. Pregnant or nursing 
8. ≥ 10 years disease duration from onset with subjects EDSS ≤ 2.0 
9. Contraindication for MRI and/or gadolinium  


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10. Known presence of other neurologic disorders that may mimic MS 
11. Current evidence or known history of clinically significant infection including: 
a. Chronic or ongoing active viral, bacterial, or fungal infectious disease requiring long term systemic 
treatment such as, but not limited to: PML, chronic renal infection, chronic chest infection with 
bronchiectasis, tuberculosis (TB), or active hepatitis C  
b. Previous serious opportunistic or atypical infections 
c. History of positive serology for hepatitis B or hepatitis C or HIV 
12. History of clinically significant CNS trauma (e.g., traumatic brain injury, cerebral contusion, spinal cord 
compression)  
13. History of liver disease, including but not limited to:  
a. Known history of active hepatitis B or C any time prior to randomization or known history of active 
hepatitis A within 3 years prior to randomization 
b. Presence of clinically significant chronic liver or biliary disease 
c. Moderate or severe hepatic impairment defined as Child Pugh Score B or C, respectively, based on 
measurement of total bilirubin, serum albumin, International Normalized Ratio (INR) and as well as on 
presence /absence and severity of ascites and hepatic encephalopathy 
d. Any of the following abnormal laboratory values at screening or first infusion: 
• 
ALT/SGPT>2X the Upper Limit of Normal (ULN) 
• 
AST/SGOT>2X ULN 
14. Previous diagnosis with a congenital or acquired immunodeficiency (AIDS) 
15. History of renal impairment, including, but not limited to:  
a. Hypoproteinemia (e.g., in case of severe renal disease or nephrotic syndrome) with serum albumin <3.0 
g/dL 
b. Severe renal insufficiency requiring renal dialysis 
16. Past or current history of medically significant adverse effects (including allergic reactions) from: 
a. Corticosteroids 
b. Diphenhydramine 
c. Murine or mouse/human chimeric antibodies  
17. Subjects with significantly impaired bone marrow function or significant anemia, leukopenia, or 
thrombocytopenia 
a. Hematocrit <24% and/or 
b. Absolute white blood cell count <4,000 cells/mm3 and/or 
c. Platelet count <150,000 cells/mm3 and/or 
d. Absolute neutrophil ≤ 1,500 cells/mm3 
18. Absolute lymphocyte counts less than 1000/microliter 
19. Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in 
the study such as: 
a. Symptomatic, or history of documented congestive heart failure (New York Heart Association functional 
classification III-IV [see Appendix B] 
b. QTcF: Female >450 msec; male > 430 msec Angina not well-controlled by medication 
c. Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular 
accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting in the past 6 
months prior to screening 
20. Other significant concurrent, uncontrolled medical condition including, but not limited to, cardiac, renal, 
hepatic, hematological, gastrointestinal, endocrine, immunodeficiency syndrome, pulmonary, cerebral, 


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psychiatric, or neurological disease which could affect the subject’s safety, impair the subject’s reliable 
participation in the trial, impair the evaluation of endpoints, or necessitate the use of medication not allowed 
by the protocol, as determined by the PI of the trial 
21. Current participation in any other interventional clinical trial.  Participation in non-interventional trial requires 
approval by the Sponsor 
22. Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol 
23. Lack of immunity to varicella as determined by screening based on the level of VZV IgG.  Subject may receive 
vaccine and be rescreened 
24. Vaccination with live virus within 2 months of randomization 
25. History or presence of malignancy (except for surgically excised basal or squamous cell skin lesions), 
lymphoproliferative disease, or history of total lymphoid irradiation or bone marrow transplantation 
3.3 DISCONTINUATION FROM STUDY TREATMENT 
Subjects will be discontinued from trial treatment or withdrawn from the study for any of the following reasons: 
• 
Irreversible or intolerable toxicity or abnormal laboratory values thought to be related to drug toxicity 
• 
Subject requests to withdraw consent or discontinue treatment 
• 
Pregnancy (see Section 3.3.1) 
• 
Inability of the subject to comply with trial requirements 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Inter-current illness (this will be at the Principal Investigator and/or Treating Neurologist discretion) 
• 
Malignancy 
• 
Discontinuation of the study by the Sponsor 
After discontinuation from protocol treatment all subjects (other than those who withdraw consent and refuse to 
enter into the 20 week Follow-up Period) should undergo an accelerated teriflunomide elimination procedure with 
either oral cholestyramine or oral activated charcoal and be followed for safety for 20 weeks after their last dose of 
ublituximab/oral placebo or teriflunomide/IV placebo.  All new AEs occurring during this period must be reported 
and followed until resolution, unless, in the opinion of the PI and/or Treating Neurologist, these values are not likely 
to improve because of the underlying disease.  In this case the PI and/or Treating Neurologist must record his or her 
reasoning for this decision in the subjects’ medical records and as a comment on the electronic Case Report Form 
(eCRF). 
All subjects who have Common Terminology Criteria for Adverse Events (CTCAE; Ver 4.03) grade 3 or 4 laboratory 
abnormalities at the time of discontinuation from protocol treatment must be followed until the laboratory values 
have returned to grade 1 or 2, unless it is, in the opinion of the PI and/or Treating Neurologist, not likely that these 
values are to improve because of the underlying disease.  In this case, the PI or Treating Neurologist must record his 
or her reasoning for making this decision in the subjects’ medical records and as a comment on the eCRF. 
Any subject that withdraws their consent to participate in the study will have all data collection stop on that day and 
will not be followed-up on. These subjects, however, could be followed further if they agree to sign the Early 
Termination ICF and enter the 20 week Follow-up Period. 
 PREGNANCY 
During the course of the trial, all female subjects of childbearing potential (the definitions of “women of childbearing 
potential” are listed in Appendix A) must contact the PI and/or Treating Neurologist immediately if they suspect that 
they may be pregnant (a missed or late menstrual period should also be reported to the PI and/or Treating 
Neurologist).   


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If an investigator suspects that a subject may be pregnant during the study, the trial drugs must be withheld 
immediately, until the result of the pregnancy test is confirmed. Subjects will proceed with a urine pregnancy test 
immediately. If the urine pregnancy test is positive, the subject should be informed of the potential teratogenic 
effects, therefore consideration to withhold further teriflunomide/oral placebo dosing should be made and follow-
up appointment should be scheduled as soon as possible where a serum pregnancy test will be performed for 
confirmation. 
If a pregnancy is confirmed via serum pregnancy test, the trial drugs must be stopped immediately and permanently. 
The subject will complete the Withdrawal from Treatment Visit as soon as possible and will then enter the 20-week 
Follow-up Period inclusive of accelerated teriflunomide elimination procedure with either oral cholestyramine or 
oral activated charcoal.  The subject will be expected to complete the full Follow-up Period regardless of the outcome 
of the pregnancy.  The investigator must record the pregnancy on a Pregnancy Report Form within 24 hours of 
learning of its occurrence (see Section 9.10.6 for more details on pregnancy reporting).  
Additionally, if a pregnancy is confirmed, the subject will be asked to sign an informed consent form to allow the 
collection of medical information of both the subject and her baby throughout the pregnancy and until 6 months 
after the baby is born, as permitted by local regulations.  Where required by local regulations, the consent of the 
father will also be obtained. 
If a male subject’s female partner becomes pregnant and the male subject has taken at least one dose of study 
medications (ublituximab/oral placebo or teriflunomide/IV placebo), the pregnancy and newborn will also be 
followed.  In this case, the subject’s partner will be asked to sign an informed consent form to allow the collection of 
medical information of both the mother and baby throughout the pregnancy and until 6 months after the baby is 
born, as permitted by local regulations.  Where required by local regulations, the consent of the male subject will 
also be obtained. If the mother is younger than legal age, her parent(s)/guardian(s) will also need to give consent, as 
required by local regulations.  
Prior to discharge from the study, all subjects will be counseled by the treating team to have their teriflunomide 
plasma concentration re-measured prior to attempting to become pregnant or trying to impregnate their female 
partner.   
Confirmed pregnancy must be reported to pharmacovigilance.  


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4 TREATMENT PLAN 
4.1 DEFINITION OF STUDY STAFF 
 AT THE STUDY SITE 
At each study center the staff will consist of a minimum of two neurologists. One neurologist will be the Treating 
Neurologist and one will be the Examining Neurologist for a given subject throughout the study. An MRI radiologist 
and technologist, and a clinical coordinator, and a pharmacist (or another authorized staff member) must also be 
members of the study staff at each center. A technician/staff nurse qualified to perform MSQoL54 (inclusive of SF36) 
and FIS must also be a member of the study staff at each center. When performing a relapse assessment or disability 
progression, the results from the Treating and Examining Neurologist will not be shared.  
 PRINCIPAL INVESTIGATOR 
At each investigational center, a neurologist will be appointed to serve as a Principal Investigator and will have 
overall responsibility to lead the site study team (neurologists, radiologists, technicians, staff nurses, pharmacists 
and clinical coordinators) in all aspects of the study. The Principal Investigator will oversee the recruitment and 
accrual of appropriate subjects, the conduct of the study according to the study protocol, and the collection of 
required study data and regulatory requirements including timely reporting of all SAEs. The Principal Investigator 
may be the Treating Neurologist for a given subject but cannot be the Examining Neurologist (see Sections 4.1.3 and 
4.1.4 for the roles and responsibilities of the Treating Neurologist and Examining Neurologist, respectively). 
 TREATING NEUROLOGIST 
The Treating Neurologist will be responsible for subjects’ care, eligibility evaluation, supervision of study medication 
administration, recording and treating of adverse events, serious adverse events and assessing and treating of MS 
relapses, performing neurological examinations and monitoring of safety assessments, including routine laboratory 
results and concomitant medications. The Treating Neurologist will provide no information to the Examining 
Neurologist. The MSFC and SDMT assessments may be performed by the Treating Neurologist, or may be delegated 
to another qualified team member, but must not be performed by the Examining Neurologist. The Treating 
Neurologist (who does not perform the EDSS assessment), other investigative site staff and subject should not have 
access to Examining Neurologist’s EDSS scores. It is encouraged that the same physician maintain the role of Treating 
Neurologist for a given subject throughout the study.   
 EXAMINING NEUROLOGIST (EVALUATING NEUROLOGIST) 
The Examining Neurologist (EDSS Rater) will be responsible for conducting and documenting all EDSS assessments. 
The Examining Neurologist will not share the findings of the EDSS assessment when evaluating relapses with the 
Treating Neurologist. The Examining Neurologist must possess current EDSS rater certification (Level C).  
Throughout the study, the Examining Neurologist is blinded to all subject information collected by the Treating 
Neurologist which includes adverse events, concomitant medications, laboratory results, and any clinical MS 
examination for enrolled subjects. Additionally, the Examining Neurologist should not have access to any prior EDSS 
scores from any time throughout the study or any clinical information when performing their examination. 
 
The Examining Neurologist will also be responsible for entering the EDSS assessment data into the electronic Case 
Report Form (eCRF). The entry of EDSS assessment data into eCRF may be delegated to another staff member, 
provided that the staff member has been trained in the eCRF, maintains the same level of blinding as that of the 
Examining Neurologist and is not involved in any other study-related activities, other than EDSS assessments. 
 


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Every effort should be made to ensure that there is no change in the EDSS Rater throughout the course of the study 
for any individual subject.  Whenever possible, the same person should perform the examination for the full study 
duration. All members of the study staff at the clinical site and the subject should not discuss safety issues with the 
Examining Neurologist.  Subjects will be instructed not to discuss any clinical symptoms or experiences while on 
trial with the Examining Neurologist. The Examining Neurologist should remind the subject at the start of the 
examination to not discuss any clinical symptoms or experiences while on trial. 
 
In exceptional cases, where a site clinical research nurse or a clinical coordinator has neurostatus EDSS rater 
certification level C and extensive experience with EDSS assessments in clinical trials, they may be delegated the 
responsibilities of the Examining Neurologist provided the required level of blinding is maintained.  Additionally, TG 
Therapeutics’ written approval will be required in advance of such a delegation. 
 
The Treating Neurologist and the Examining Neurologist will NOT be allowed to switch roles. 
 MRI STAFF 
The MRI staff will be responsible for performing the MRI according to the protocol and MRI manual. They will also 
prepare adequate electronic material according to the MRI manual for transfer of images to the central MRI reader. 
The MRI manual will provide instructions for storage of the primary data at the site. 
 
Radiologist will review MRI scans locally for non-MS pathology and will provide reports to the Treating Neurologist. 
Local MRI reports after randomization must not contain details of the MS pathology, MRI scans will be read centrally 
for MS pathology by the central MRI reader. 
 CLINICAL COORDINATOR 
The clinical coordinator will be responsible for coordinating and assisting all study site staff, including subject 
scheduling and completion and monitoring of all subjects’ electronic Case Report Forms. He/she will instruct the 
subjects on proper study medication administration, subject diary adherence, obtain vital signs, collect, process, and 
send all blood and urine samples and requests to the central laboratory.  Additionally, he/she will be responsible for 
administering the subject-reported questionnaires (MSQoL-54 and FIS) and coordinating subject’s appointment 
with other departments, e.g.., imaging facility etc. Some or all of these study-related activities may instead be 
performed by the Treating Neurologist or a qualified technician/staff nurse. 
4.2 STUDY COMMITTEES 
 DATA SAFETY MONITORING BOARD (DSMB) 
The DSMB will be an independent group of individuals not involved in the study or study sites or have other conflicts 
of interest with the study and are charged with reviewing safety data and conduct of the trial. The independent DSMB 
will be comprised of five members with at least three MDs, a biostatistician, and the DSMB chair.  The responsibilities 
of the DSMB will be described in a DSMB Charter.  The committee will meet periodically, but at least annually to fulfill 
the duties and obligations outlined in the DSMB Charter.  Minutes of these meetings will be prepared as specified in 
the DSMB Charter.  There will be minutes from both an open session which will be transmitted to the Sponsor and 
CRO and minutes of the closed session maintained by an unblinded DSMB Coordinator from CRO until the study is 
complete, at which point they will be transmitted to the Sponsor and CRO. Statistical analyses required for the 
planned DSMB meetings will be prepared and disseminated to the DSMB members. The committee will receive 
unblinded safety data to allow review and assessment by treatment group. In addition, the committee will receive 
unblinded efficacy data to perform benefit/risk ratio assessment. On the basis of their reviews and analyses of safety 
and efficacy data, the committee shall have the right to advise the sponsor to stop the study after any meeting for 
efficacy or detrimental effects or futility.  The process and options will be specified in the Charter. 




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Antiemetic for Ublituximab or IV placebo: Ublituximab or IV placebo is considered to be of low emetogenic 
potential that may be adequately prevented with prochlorperazine.  Other antiemetic may be used at the discretion 
of the Treating Neurologist/PI if nausea and/or vomiting is not adequately controlled/prevented. 
Pre-medication prior to infusion with ublituximab or IV placebo: Infusion Related Reactions have been reported 
with ublituximab or IV placebo with more profound reactions in subjects with hematologic malignancies.  All 
subjects treated with ublituximab or IV placebo require pre-medication 30–60 minutes prior to each dose of 
ublituximab or IV placebo with an antihistamine (diphenhydramine 50 mg or equivalent; administered orally), and 
a corticosteroid (dexamethasone 10-20 mg or equivalent; administered orally).  
Treatment of IRR: Symptomatic infusion reactions despite pre-medication, may be treated at the discretion of the 
treating physician, including but not limited to: oral acetaminophen 650 mg (only used for intervention), 
corticosteroids, antihistamines, oxygen and bronchodilators.  
Note: In case the above referenced medications are not available, equivalents can be used at the investigator’s 
discretion. If medications are given intravenously, the IV line used for ublituximab/IV placebo should not be used. If 
needed, please consult the Medical Monitor. 
Antihypertensive Medications: Since infusion related hypotension may occur, the investigator should carefully 
consider withholding anti-hypertensive medication during the 24 hours prior to, and throughout the IV infusion of 
ublituximab or placebo. 
 MS RELAPSE DURING THE STUDY 
MS Relapses During the Study 
Subjects enrolled into the study will be closely monitored through the study course by the Site and Sponsor’s 
personnel as well as by an external independent Data Safety Monitoring Board (DSMB) to ensure subjects’ welfare. 
 
Relapses that occur after study drugs are withdrawn will be assessed over the remainder of the study period and 
this data will be utilized as part of additional sensitivity analysis (described in the statistical plan) as long as the 
subject has not withdrawn their consent to be in the trial.  
 
The confirmation of a protocol-defined relapse will be determined by the Independent Relapse Adjudication 
Committee (IRAP). The steps for confirming a relapse are as follows: 
 
1. Subject Reported Relapse  
Subjects who experience new or worsening neurologic symptoms are instructed to contact the Treating Neurologist 
within 48 hours of symptom onset. All new or worsening neurological events, reported at a visit or over the phone, 
consistent with MS representing a clinical relapse as assessed by the subject will be initially reported to the Treating 
Neurologist. In parallel, the Examining Neurologist will also be notified to perform additional assessments. Upon the 
notification to the Treating Neurologist, the time and date of suspected subject reported relapse will be documented 
in the dedicated page eCRF (subject reported) by the Treating Neurologist or designee. 
 
The following should be recorded in the eCRF (subject reported) by the Treating Neurologist or designee: 
• 
Date and time of symptom onset as reported by the subject  
• 
Symptoms and events reported by the subject (both neurological and non-neurological) 
• 
Date of initial contact by subject 
• 
Time of initial contact by subject 
 
Within 7 days of the subject reporting the suspected relapse to the Treating Neurologist, the subject will be scheduled 
and assessed by both the Treating and Examining Neurologist independently.  
 
2. Initial Assessment of Relapse by Treating Neurologist and Examining Neurologist 
 


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The Treating Neurologist will perform a neurological and physical examination and safety assessment. The Treating 
Neurologist or designee will document in the eCRF the following:  
• 
Time and date of neurological and physical examination 
• 
Clinical findings of neurological and physical examination 
• 
Review of previously documented concomitant medications and medical history 
• 
Safety assessment, including vital signs, CBC, B-cell count, lymphocyte counts, fibrinogen, quantitative 
immunoglobulin  
 
Subjects with suspected clinical relapses reported to the Treating Neurologist or designee will be referred to the 
blinded Examining Neurologist who will use Neurostatus to assess the EDSS independently of the Treating 
Neurologist.   
 
The Examining Neurologist or designee will document in the eCRF the following: 
• 
Date and time of assessment 
• 
EDSS score  
• 
FS Scores 
 
In addition, subjects may not begin IV methylprednisolone (IVMP) treatment of a relapse until the Examining 
Neurologist has completed his/her examination.  
 
Treatment of relapses may proceed at the discretion of the Treating Neurologist only after the Examining 
Neurologist has completed his/her exam. The Treating Neurologist will not know the results of the EDSS 
assessment. When making determination to treat a potential acute relapse the Treating Neurologist can use IVMP 
(1.0 g/day for at least 3 days and can be extended to 5 days) and will not affect the subject eligibility to continue in 
the study.   
 
The subject must re-consent at the time of each IRAP-confirmed or  Treating Neurologist medically 
confirmed relapse to continue. 
 
The findings from either the Treating Neurologist and Examining Neurologist will not be shared. The Examining 
Neurologist must be blinded to the Treating Neurologist’s assessment and vice versa. 
 
Following the completion of assessments by the Treating and Examining Neurologists these results will be sent 
independently to the IRAP.  
 
3. Confirmation of Relapse by IRAP 
All assessments entered into the eCRF from both the Treating Neurologist and the blinded Examining Neurologist, 
will be sent to an Independent Relapse Adjudication Panel (IRAP). IRAP adjudicates each case based on all available 
data provided for that case and members are not permitted to contact the site or the sponsor for additional 
information. The IRAP will, in turn, make the final determination of whether the neurological events meet the criteria 
for a protocol-defined relapse. 
 
Each episode of relapse must be confirmed by the IRAP, based on the neurological assessments performed by the 
Treating and/or Examining Neurologist independently by documenting either of the following: 
 
• 
≥ 2 points increase on one of the appropriate FS or 1 point on two or more of the appropriate FS.  The change 
must affect the selected FS (i.e., pyramidal, ambulation, cerebellar, brainstem, sensory or visual).   Note, the 
change in FS scores should correspond to the patient’s symptoms (e.g., patient reported change in visual 
acuity should correspond to a change in the vision FS score).  Episodic spasm, sexual dysfunction, fatigue, 
mood change or bladder or bowel urgency or incontinence will not suffice to establish a relapse; 
• 
An increase of ≥0.5 points in the EDSS score (unless EDSS score = 0, then an increase of at least 1.0 points is 
required) from the previous clinically stable assessment. 


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MS relapses are defined as a new or worsening neurological symptoms lasting ≥24 hours with the absence of fever, 
injury, infection or adverse reactions to medications and accompanied by new neurological findings upon 
examination by the Examining Neurologist.  The symptoms are attributed to MS and are preceded by 30 days of 
stability or improvement in neurological state. The change in EDSS score as assessed by the Examining Neurologist 
is ≥ 0.5 increase or ≥ 2 points increase on one of the appropriate FS or 1 point on two or more of the appropriate FS.  
The change must affect the selected FS (i.e., pyramidal, ambulation, cerebellar, brainstem, sensory or visual).  Note, 
the change in FS scale scores should correspond to the patient’s symptoms (e.g., patient reported change in visual 
acuity should correspond to a change in the vision FS score).   Episodic spasm, sexual dysfunction, fatigue, mood 
change or bladder or bowel urgency or incontinence will not suffice to establish a relapse.  Please note: sexual 
dysfunction and fatigue will not be scored.  If the symptoms occur less than 30 days following the onset of a protocol 
defined relapse, it should be considered part of the same relapse and would not be treated with IVMP within the 
protocol.  New or recurrent neurologic symptoms that evolve gradually over months should be considered disability 
progression, not an acute relapse and should not be treated with steroids.   
 
The suspected relapse must be reviewed and confirmed by the IRAP; Appendix D. The IRAP will then notify the CRO 
and Treating Neurologist of the results of its review.  
Treating Neurologist or designee will enter into the eCRF whether the neurological symptoms identified were a 
result of an IRAP-confirmed relapse. 
IRAP-confirmed relapses are the sole confirmation of a protocol-defined relapse. However, for instances where 
IRAP-confirmed relapses may not be feasible, provisions are provided within Section 4.4.2 (Treating Neurologist 
medically confirmed relapse).  
The subject must re-consent at the time of each IRAP-confirmed or Treating Neurologist medically 
confirmed relapse to continue. 
 
Signing the informed consent form for re-consent (if the subject has a confirmed relapse), to proceed with the study 
at the next scheduled office visit should be within 6 weeks after first reporting of relapse.  
 TREATING NEUROLOGIST MEDICALLY CONFIRMED RELAPSE 
In suspected relapse events for which IRAP confirmation is pending, may not be logistically possible, and/or 
complete case profiles for IRAP review are not available, the Treating Neurologist will medically evaluate the 
suspected relapse event.   In these cases, all information from the Treating Neurologist’s medical evaluation should 
still be entered into the eCRF and provided to the IRAP for adjudication.  This is to ensure each suspected relapse is 
documented.  Treating Neurologist medically confirmed relapses will not be included in the ARR calculation for the 
primary endpoint. For any relapse that is Treating Neurologist medically confirmed, subjects should re-consent to 
continue participation in the trial.   
 RE-CONSENT CRITERIA AFTER RELAPSING 
If a relapse is confirmed by IRAP and/or deemed a Treating Neurologist medically confirmed relapse, the following 
actions will be taken: 
• 
The subject will be reminded of the current approved MS medications/treatments and the opportunity to 
terminate the study and be treated with an approved MS medication.  
• 
The subject will be requested to re-sign an informed consent form within 6 weeks after first reporting of the 
suspected relapse if he/she chooses to continue to participate in the study, in the same treatment assignment. 
 DISABILITY PROGRESSION 




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Obtain and update contact information 
(routine) 
Discuss potential or anticipated barriers to 
attending appointments (routine) 
Provide travel/meal reimbursement for 
study visits, in accordance with local 
regulation (routine) 
Medium 
Concerns about the study medication, 
behavioral treatment, or procedures 
Concern that current condition or 
circumstances could interfere with 
fulfilling study requirements  
Reluctant to schedule follow-up 
appointments due to aforementioned 
concerns about treatments, 
circumstances, or conditions 
Normalize and accept concerns about the 
study (routine)  
Continue to provide education/communicate 
on the disease and treatments to the subject 
(routine) 
Remind subject about rationale for study 
involvement (routine)  
Provide a range of options to facilitate 
involvement (non-routine) 
High 
Cancels appointments frequently 
without rebooking, regular no-show, 
and is unresponsive to contacts for 
rescheduling appointments  
Reveals a desire to drop out of the trial 
Conduct an adherence assessment; that is, 
learn the participant’s explanation for 
nonattendance or wish to drop out (non-
routine) 
Obtain consensus about risk factors 
associated with nonadherence (non-routine)  
Establish priorities for attending to risk 
factors (non-routine) 
Identify a range of options for addressing 
nonadherence (non-routine) 
Send out letters or emails to participants who 
are unresponsive to personal contact (non-
routine) 
Delay decision making about dropping out 
(non-routine)  
Accept a “no” as temporary and obtain 
permission to re-contact at a later time (non-
routine) 








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6 SCHEDULE OF ASSESSMENTS AND PROCEDURES 
Individual trial procedures are detailed in Tables 5-7. It may be necessary to perform these procedures at 
unscheduled time points if deemed clinically necessary by the Treating and Examining Neurologists.  
Additional evaluations/testing may be deemed necessary by the Treating Neurologist and/or the Sponsor for 
reasons related to subject safety. 










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1 For women of child bearing potential 
2 To confirm negative HIV 1 and 2, Hepatitis B Virus, Hepatitis C Virus and varicella 
3 Labs drawn pre-infusion on any infusion days  
4 Weeks 8 and beyond, collections/assessments may occur ±5 days from specified time points, except for MRI scans, which can occur ±7days on 
Weeks 12 and 96 and must be performed pre-infusion on infusion days (- 7 days) on Weeks 24 and 48. MRI scan at Early Withdrawal from Treatment 
Visit should be performed within 4 weeks after withdrawing from the study.   
5Prior to each infusion except PT/INR which is completed at baseline. Urine Pregnancy Test on non-infusion days subjects will test upon arrival at 
the site  
6 Prior to infusion and 30 minutes +/- 15 minutes post-infusion on infusion days. For non-infusion days, one PK sample should be obtained 
7 Anti-Drug Antibodies are antibodies developed against ublituximab 
8 Physical examination will occur on all visits except Week 1 Day 2 and Week 2 Day 8  
9 Within 2 hours pre-infusion and 60 minutes +/- 15 minutes post-infusion on any infusion day  
10 Re-consent following a suspected relapse is required if the relapse is confirmed by IRAP or by the Treating Neurologist (Treating Neurologist 
medically confirmed relapse), whichever comes first. Re-consent must occur within 6 weeks after first reporting of relapse. Re-consent may occur 
at the next schedule office visit but may require an unscheduled visit if the relapse occurs between Weeks 24 and 96 (where the frequency of 
scheduled visits is every 12 weeks). 
11 Serum pregnancy test must be completed within 5 days prior to Week 1 Day 1 
12 Obtain blood sample for teriflunomide drug concentration test prior to first dose of accelerated teriflunomide elimination procedure 
13 Prior to each infusion 
14 The Unscheduled Relapse Visit will be conducted if a possible relapse is reported by the subject. The visit is to be planned as soon as possible, 
within 7 days from subject notification of the relapse to the site. Infusion visit is delayed until relapse is back to baseline, or Treating Neurologist/PI 
does not expect any improvements.  
 
 
 
16 Teriflunomide/oral placebo administration shall be taken in the morning until the last day of Week 95. Alternative dosing times are allowed if 
necessary. 
17 Sample for teriflunomide concentration to be collected before the first oral dose of teriflunomide/oral placebo 
18 For Unscheduled Relapse Visit, EDSS assessment (by Examining Neurologist) and neurological examination (by Treating Neurologist) will be 
performed independently 
19Acknowledge completion of 11-day accelerated teriflunomide elimination procedure started at week 100 
20 If the subject experiences neutropenia, thrombocytopenia, anemia, or elevated liver enzymes, follow guidelines and procedures on laboratory 
retests and study treatment per Section 5.2.   
21 Post Week 24 (including during the Follow-Up Period), urine pregnancy test will be administered every 4 weeks (+/- 5 days).  On days when there 
is not a study visit, the subject will need to perform the test at home and contact the study site to provide the outcome  
22 Week 1/Day 1 EDSS must be assessed within 1 day prior to randomization (i.e., on the day before randomization or on the day of randomization 
but before randomization occurs)  
23 Start 11-day accelerated teriflunomide elimination procedure the day after the early withdraw from treatment visit is completed 
24 Pre-medicate 30-60 minutes prior to each infusion of ublituximab/IV placebo with an anti-histamine (diphenhydramine 50 mg or equivalent) and 
corticosteroid (dexamethasone 10-20 mg or equivalent) 
 
 
 
 




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obtained if a female subject of childbearing potential withdraws from treatment early or has 
an Unscheduled Relapse Visit. Serum pregnancy test may be performed at any time during 
the study in case of a missed or late menstrual cycle. 
4. Urine pregnancy test will be performed on a monthly basis, inclusive of the 20 week Follow-
up Period. During study visits urine pregnancy tests will be performed at the site and on days 
of ublituximab or IV placebo infusion urine pregnancy tests will be performed prior to 
infusion. Post Week 24, urine pregnancy test will be administered every 4 weeks (+/- 5 days), 
unless serum testing is conducted instead. On days when there is not a study visit, the subject 
will need to perform at home and provide the outcome to the study staff at the study site. If a 
urine pregnancy test is positive, the subject should be informed of the potential teratogenic 
effects, therefore consideration to withhold further teriflunomide/oral placebo dosing 
should be made and a follow-up appointment should be scheduled as soon as possible where 
a serum pregnant test will be performed for confirmation.   
5. PT/INR should be drawn on Week 1 Day 1 prior to study medications administration. This is 
the only time PT/INR will be drawn. 
6. Quantitative immunoglobulin (IgG, IgM, IgA) test should be analyzed on Week 1 Day 1 (pre-
dose) and Week 3 Day 15 (pre-dose), Weeks 24 (pre-dose), 48 (pre-dose), 72 (pre-dose) and 
96.  Additionally, quantitative immunoglobulin (IgG, IgM, IgA) test will be analyzed for 
subjects who withdraw from treatment early or have an Unscheduled Relapse Visit. 
7. Fibrinogen tests  
a. All subjects will have 5 serum samples taken prior to the infusions on Week 1 Day 1, 
Week 3 Day 15 and Weeks 24, 48, and 72. Additionally, fibrinogen will be analyzed 
for subjects who withdraw from treatment early or have an Unscheduled Relapse 
Visit. 
8. Anti-Drug Antibody (antibodies developed against ublituximab; Central Lab) 
a. All subjects will have 6 serum samples taken to assess for the presence of ADA prior 
to the infusions on Week 1 Day 1, Week 3 Day 15 and Weeks 24, 48, and 72. In 
addition, a serum sample will be taken at Week 96.  
 
a. Serum samples will be drawn from all subjects pre-infusion any time on infusion days 
of ublituximab or IV placebo and at 30 minutes +/- 15 minutes post infusion on 
infusion days  (Week 1 Day 1, Week 3 Day 15, Weeks 24, 48, and 72). One additional 
serum sample will be taken on Week 96.
 
 
 
  
 
 
 
 
 
 


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10. Plasma concentration for teriflunomide 
a. In order to assess teriflunomide compliance, four plasma samples will be taken from 
all subjects. The first sample will be taken prior to oral administration of 
teriflunomide or oral placebo on Week 1 Day 1. The second sample will be taken prior 
to infusion of ublituximab or IV placebo on Week 48. The third sample will be taken 
at Week 96, prior to first dose of accelerated teriflunomide elimination procedure 
which begins at Week 100. The last plasma sample for teriflunomide will be taken at 
Week 116 following the accelerated teriflunomide elimination procedure with either 
active charcoal or cholestyramine. For subjects who withdraw from treatment early, 
a blood sample will be collected at the Early Withdrawal from Treatment Visit prior 
to first dose of accelerated teriflunomide elimination procedure.  
b. Only plasma samples from subjects treated with teriflunomide will be analyzed for 
plasma teriflunomide concentrations. See the Laboratory Manual for PK collection 
and processing instructions. 
11. Liver function panel: SGOT/AST, SGPT/ALT, serum gamma-glutamyl transferase (SGGT), 
total bilirubin, direct/indirect bilirubin.  Samples will be taken for analysis as directed in the 
schedule of assessment (Tables 5, 6, and 7) and as shown in bullet number 2 (Serum 
Chemistry) 
12. Pancreatic enzyme panel: serum amylase and lipase. Samples will be taken for analysis as 
directed in the schedule of assessment (Tables 5, 6, and 7) and as shown in bullet number 2 
(Serum Chemistry) 
13. Urinalysis panel for routine safety will be sampled as follows at screening, and Week 1 Day 1 
(pre-dose), Day 2, Day 8, Week 3 Day 15 (pre-dose), and Weeks 4, 8, 12, 16, 20, 24 (pre-dose), 
36, 48 (pre-dose) 60, 72 (pre-dose), 84, 96, 100 and 104. The urine is to be analyzed for the 
following pH, ketones, protein, glucose, blood, urobilinogen, bilirubin, microscopic sediment, 
specific gravity and leucocyte esterase. Additionally, a sample should be obtained for subjects 
who withdraw from treatment early or have an Unscheduled Relapse Visit. 
14. B lymphocyte cell counts (% CD19+ B cells).  Samples will be taken for analysis at screening, 
and Week 1 Day 1 (pre-dose), Day 2, Day 8, Week 3 Day 15 (pre-dose), and Weeks 4, 8, 12, 
16, 20, 24 (pre-dose), 36, 48 (pre-dose) 60, 72 (pre-dose), 84, 96, 100 and 104. Additionally, 
B lymphocyte cell counts will be analyzed for subjects who withdraw from treatment early 
or have an Unscheduled Relapse Visit. 
15. At screening the following assessments will be performed: HIV, HCV, HBV, Varicella 
 
 
 
 


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Note, the study site staff will remain blinded to the results of the PK, ADA and teriflunomide 
concentration analysis for all subjects. The study site staff will also remain blinded to the results 
of the B lymphocyte cell counts (% CD19+ B cells) from Week 1 Day 1 onwards. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 CLINICAL ASSESSMENT AND PROCEDURES 
In addition to being a double-blind, double-dummy study, this study is also an assessor blinded study.  
Each site will have 2 neurologists: Treating Neurologist (can be the PI) and an Examining Neurologist.  
Please refer to Section 4.1 for definition and responsibility for each neurologist. The Examining 
Neurologist will be blinded to subject randomization.  
 ASSESSMENT OF RELAPSE 
MS Relapses During the Study 
Subjects enrolled into the study will be closely monitored through the study course by the Site and 
Sponsor’s personnel as well as by an external independent Data Safety Monitoring Board (DSMB) to 
ensure subjects’ welfare. 
 
Relapses that occur after study drugs are withdrawn will be assessed over the remainder of the 
study period and this data will be utilized as part of additional sensitivity analysis (described in 
the statistical plan) as long as the subject has not withdrawn their consent to be in the trial.  
 
The confirmation of a protocol-defined relapse will be determined by the Independent Relapse 
Adjudication Committee (IRAP). The steps for confirming a relapse are as follows: 
 
1. Subject Reported Relapse  
Subjects who experience new or worsening neurologic symptoms are instructed to contact the 
Treating Neurologist within 48 hours of symptom onset. All new or worsening neurological events, 


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reported at a visit or over the phone, consistent with MS representing a clinical relapse as assessed 
by the subject will be initially reported to the Treating Neurologist. In parallel, the Examining 
Neurologist will also be notified to perform additional assessments. Upon the notification to the 
Treating Neurologist; the time and date of suspected subject reported relapse will be documented in 
the dedicated page eCRF (subject reported) by the Treating Neurologist or designee. 
 
The following should be recorded in the eCRF (subject reported) by the Treating Neurologist or 
designee: 
• 
Date and time of symptom onset as reported by the subject  
• 
Symptoms and events reported by the subject (both neurological and non-neurological) 
• 
Date of initial contact by subject 
• 
Time of initial contact by subject. 
 
Within 7 days of the subject reporting the suspected relapse to the Treating Neurologist, the subject 
will be scheduled and assessed by both the Treating and Examining Neurologist independently.  
 
2. Initial Assessment of Relapse by Treating Neurologist and Examining Neurologist 
 
The Treating Neurologist will perform a neurological and physical examination and safety 
assessment. The Treating Neurologist or designee will document in the eCRF the following:  
• 
Time and date of neurological and physical examination 
• 
Clinical findings of neurological and physical examination 
• 
Review of previously documented concomitant medications and medical history 
• 
Safety assessment, including vital signs, CBC, B-cell count, lymphocyte counts, fibrinogen, 
quantitative immunoglobulin.  
 
Subjects with suspected clinical relapses reported to the Treating Neurologist or designee will be 
referred to the blinded Examining Neurologist who will use Neurostatus to assess the EDSS 
independently of the Treating Neurologist.   
 
The Examining Neurologist or designee will document in the eCRF the following: 
• 
Date and time of assessment 
• 
EDSS score  
• 
FS Scores. 
 
In addition, subjects may not begin IV methylprednisolone (IVMP) treatment of a relapse until the 
Examining Neurologist has completed his/her examination.  
 
Treatment of relapses may proceed at the discretion of the Treating Neurologist only after the 
Examining Neurologist has completed his/her exam. The Treating Neurologist will not know 
the results of the EDSS assessment. When making determination to treat a potential acute relapse 
the Treating Neurologist can use IVMP (1.0 g/day for at least 3 days and can be extended to 5 days) 
and will not affect the subject eligibility to continue in the study.   
 
The subject must re-consent at the time of each IRAP-confirmed or Treating Neurologist 
medically confirmed relapse to continue. 
 
The findings from either the Treating Neurologist and Examining Neurologist will not be shared. The 
Examining Neurologist must be blinded to the Treating Neurologist’s assessment and vice versa. 


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Following the completion of assessments by the Treating and Examining Neurologists these results 
will be sent independently to the IRAP.  
 
3. Confirmation of Relapse by IRAP 
All assessments entered into the eCRF from both the Treating Neurologist and the blinded Examining 
Neurologist, will be sent to an Independent Relapse Adjudication Panel (IRAP). IRAP adjudicates each 
case based on all available data provided for that case and members are not permitted to contact the 
site or the sponsor for additional information.  The IRAP will, in turn, make the final determination 
of whether the neurological events meet the criteria for a protocol-defined relapse. 
 
Each episode of relapse must be confirmed by the IRAP, based on the neurological assessments 
performed by the Treating and/or Examining Neurologist independently by documenting either of 
the following: 
 
• 
≥ 2 points increase on one of the appropriate FS or 1 point on two or more of the appropriate 
FS.  The change must affect the selected FS (i.e., pyramidal, ambulation, cerebellar, brainstem, 
sensory or visual).   Note, the change in FS scores should correspond to the patient’s 
symptoms (e.g., patient reported change in visual acuity should correspond to a change in the 
vision FS score).  Episodic spasm, sexual dysfunction, fatigue, mood change or bladder or 
bowel urgency or incontinence will not suffice to establish a relapse; 
• 
An increase of ≥0.5 points in the EDSS score (unless EDSS score = 0, then an increase of at 
least 1.0 points is required) from the previous clinically stable assessment. 
 
MS relapses are defined as a new or worsening neurological symptoms lasting ≥24 hours with the 
absence of fever, injury, infection or adverse reactions to medications and accompanied by new 
neurological findings upon examination by the Examining Neurologist.  The symptoms are attributed 
to MS and are preceded by 30 days of stability or improvement in neurological state. The change in 
EDSS score as assessed by the Examining Neurologist is ≥ 0.5 increase or ≥ 2 points increase on one 
of the appropriate FS or 1 point on two or more of the appropriate FS.  The change must affect the 
selected FS (i.e., pyramidal, ambulation, cerebellar, brainstem, sensory or visual).  Note, the change 
in FS scores should correspond to the patient’s symptoms (e.g., patient reported change in visual 
acuity should correspond to a change in the vision FS score).  Episodic spasm, sexual dysfunction, 
fatigue, mood change or bladder or bowel urgency or incontinence will not suffice to establish a 
relapse.  Please note: sexual dysfunction and fatigue will not be scored.  If the symptoms occur less 
than 30 days following the onset of a protocol defined relapse, it should be considered part of the 
same relapse and would not be treated with IVMP within the protocol.  New or recurrent neurologic 
symptoms that evolve gradually over months should be considered disability progression, not an 
acute relapse and should not be treated with steroids.   
 
The suspected relapse must be reviewed and confirmed by the IRAP; Appendix D. The IRAP will then 
notify the CRO and Treating Neurologist of the results of its review.  
Treating Neurologist/designee will enter into the eCRF whether the neurological symptoms 
identified were a result of an IRAP-confirmed relapse. 
IRAP-confirmed relapses are the sole confirmation of a protocol-defined relapse. However, for 
instances where IRAP-confirmed relapses may not be feasible, provisions are provided within 
Section 4.4.2 (Treating Neurologist medically confirmed relapse). 


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The subject must re-consent at the time of each IRAP-confirmed or Treating Neurologist 
medically confirmed relapse to continue. 
 
Signing the informed consent form for re-consent (if the subject has a confirmed relapse), to proceed 
with the study at the next scheduled office visit should be within 6 weeks after first reporting of 
relapse.  
 
Treating Neurologist Medically Reported Relapse 
In suspected relapse events for which IRAP confirmation is pending, may not be logistically possible 
and/or complete case profiles for IRAP review are not available, the Treating Neurologist will 
medically evaluate the relapse event.  In these cases, all information from the Treating Neurologist’s 
medical evaluation should still be entered into the eCRF and provided to the IRAP for adjudication.  
This is to ensure each suspected relapse is documented.  Treating Neurologist medically confirmed 
relapses will not be included in the ARR  calculation for the primary endpoint. 
For any relapse that is Treating Neurologist medically confirmed, subjects should re-consent to 
continue participation in the trial.  
Re-consent criteria 
In case of an IRAP-confirmed relapse (as defined in the protocol, Appendix C) or  Treating Neurologist 
medically confirmed relapse during the study, the following actions will be taken: 
• 
The subject will be reminded of the current approved MS medications/treatments and the 
opportunity to terminate the study and be treated with an approved MS medication.  
• 
The subject will be requested to re-sign an informed consent form within 6 weeks of first 
reporting of the suspected relapse if he/she chooses to continue to participate in the study, in the 
same treatment assignment. 
 
Re-consenting may occur at the next scheduled office visit, but may require an unscheduled visit if 
the relapse occurs between Weeks 24 and 96 (where the frequency of scheduled visits is every 12 
weeks).  
 DISABILITY EVALUATION 
Disability Progression 
The method of disability progression calculation will be different than that of the relapsed 
confirmation. The EDSS score will be used to assess disability progression. EDSS assessment will be 
performed by the Examining Neurologist. The Examining Neurologist must not share the EDSS score 
with the Treating Neurologist. The EDSS assessment for disability progression will be performed at 
screening and on Week 1 Day 1 (prior to randomization) and Weeks 12, 24, 36, 48, 60, 72, 84 and 96. 
Disability progression is a post hoc analysis only and will not be calculated by the Evaluating 
Neurologist or other study staff. 
The EDSS is based on a standard neurological examination, incorporating the following function 
systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, and cerebral) and 
ambulation rated and scores as function system scores (FS).  Each FS score is an ordinal clinical rating 
scale ranging from 0 to 5 or 6.  These ratings are then used in conjunction with observations and 
information concerning ambulation and used of assistive devices to determine the EDSS score.  The 
EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). 


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The randomization process must ensure that the baseline EDSS is assessed for the subject by the 
Examining Neurologist and is documented before treatment is assigned. 
Disability progression can only be assessed from the EDSS scores performed at baseline and on Week 
1 Day 1 and Weeks 12, 24, 36, 48, 60, 72, 84 and 96. 
 
Disability progression is defined as an increase of ≥1.0 point from the baseline EDSS score that is not 
attributable to another etiology (e.g., fever, concurrent illness, or concomitant medication) when the 
baseline score is 5.5 or less, and ≥0.5 when the baseline score is above 5.5.   
Disability progression is considered confirmed when the increase in the EDSS score is confirmed at 
regularly scheduled visits at least 12 or 24 weeks after the initial documentation of neurological 
worsening.  
 
 RADIOLOGICAL EVALUATION 
Magnetic Resonance Imaging (MRI) is a useful tool for monitoring CNS lesions in MS.  Different MRI 
derived parameters have been related to clinical activity and T1 weighted gadolinium-enhancing 
lesions or new and/or enlarging hyperintense T2 lesions have been related to relapses.  It is 
hypothesized that changes in brain volume may reflect brain atrophy as a result of MS-related tissue 
loss and may thereby correlate with long-term clinical outcomes in RMS subjects. 
Brain MRI scans will be obtained in all subjects as detailed in the Schedule of Assessments in Section 
6. In addition, brain MRI scans will be obtained in subjects who had withdrawn from the trial.  Scans 
will be performed by trained and certified MRI technicians.  
Assessment of effect on Gd enhancing lesion and new, enlarging T2 lesions, brain volume, T1 
hypointense will be evaluated as outlined in the schedule of events by a central reader.  The following 
time windows apply: 
• 
“Baseline” MRI should be performed after informed consent is obtained, but preferably 10 days 
prior to the Week 1 Day 1 visit. 
• 
MRI are scheduled as follows: Weeks 12 (+/- 7 days), 24 (pre-dose; - 7 days), 48 (pre-dose; - 7 
days) and 96 (+/- 7 days)  
• 
MRI scans may be performed on the day of withdrawal or within 4 weeks after withdrawing from 
the study. 
o The MRI may not be needed if an MRI was obtained within 30 days prior to withdrawal 
from the trial.  
If subjects receive corticosteroids for a relapse, every effort should be made to obtain the scan prior 
to the first steroid dose if the pre-steroid scan is within 1 week of the scheduled visit.  In subjects 
receiving corticosteroids, there should be an interval of at least 30 days between the last dose of 
corticosteroids and the scan. 
At each time point, the MRI will include acquisition of scans with and without intravenously 
administered gadolinium contrast enhancement. 


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MRI scans will be read by a centralized reading center located in Montreal, Canada for efficacy 
endpoints.  The centralized reading center is blinded to the treatment assignment and the reading is 
performed in the absence of clinical information.  Additional details on scanning acquisition 
sequences, methods, handling and transmission of the scans, certification of site MRI 
radiologists/technicians, and the procedure for the blinded analysis of the scans at the central 
reading center will be described in a separate MRI Manual. 
All MRI scans will also be reviewed locally by a radiologist for safety (identify any new clinical 
relevant abnormal MRI findings that are not consistent with the diagnosis of MS, with particular 
attention to the possibility of progressive multifocal leukoencephalopathy) and the MRI report  will 
be provided to the Treating Neurologist/PI.  After randomization, the MRI reports provided to the 
Treating Neurologist/PI will contain only non-MS pathology.  At the investigational site, only the 
local radiologist/technician assigned to this study may have access to the MRI scan post-
randomization; the Treating Neurologist should not review the MRI scans unless a safety 
concern arises.   
 NEUROLOGICAL EVALUATION 
Assessment of effect on relapse rate will be evaluated as outlined in the schedule of events (see Study 
Evaluation Tables 5, 6, and 7 and Appendix F).  EDSS score will be calculated via Neurostatus as stated 
in Sections 6.3.1. and 6.3.2. 
Multiple Sclerosis Functional Composite (MSFC) score will be assessed as outlined in the schedule of 
events (see Study Evaluation Tables 5, 6, and 7 and Appendix F).  The MSFC consists of three 
subscales, including the 9-hole-peg test, Paced Auditory Serial Addition Test (PASAT) and Timed 25-
Foot Walk (T25FW), which provide a global quantitative estimate of MS progression. The MSFC 
assessments may be performed by the Treating Neurologist, or may be delegated to another qualified 
team member, but must not be performed by the Examining Neurologist. 
EDSS will be assessed by the Examining Neurologist. The results of the EDSS assessment by the 
Examining Neurologist will not be shared with the Treating Neurologist and the PI. 
 
 COGNITION ASSESSMENT 
The Symbol Digit Modality Test (SDMT) has demonstrated sensitivity in detecting not only the 
presence of cognitive impairment, but also changes in cognitive functioning over time and in 
response to treatment.  The SDMT is brief, easy to administer verbally and involves a simple 
substitution task that normal children and adults can perform.  Using a reference key, the examinee 
has 90 seconds to pair specific numbers with given geometric figures.  Responses will be done 
verbally.  The administration time is approximately 5 minutes. 
The SDMT will be administered verbally by the Treating Neurologist at the time points indicated in 
the Study Evaluation Tables 5, 6, and 7 and Appendix F. The SDMT assessments may be delegated to 
another qualified team member, but must not be performed by the Examining Neurologist. 
 SUBJECT REPORTED OUTCOMES 


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Assessment of effect on MSQoL54 (inclusive of SF36) and FIS will be evaluated as outlined in the 
Study Evaluation Tables 5, 6, and 7 and Appendix F by a qualified coordinator or member of the study 
site.  This will be done prior to each infusion. 
 
MSQoL54 (inclusive of SF36) is a multidimensional health-related quality of life measurement that 
combined generic and MS specific items into a single assessment.  The 54-item instrument generates 
12 subscales along with 2 summary scores and 2 additional single-item measures.  The subscales are 
physical function, role limitations-physical, role limitations-emotional, pain, emotional well-being, 
energy, health perceptions, social function, cognitive function, health distress, overall quality of life 
and sexual function.  The summary score as are the physical health composite and mental health 
composite.  The single item measure is satisfaction with sexual function and change in health.  The 
MSQoL54 will be performed at Week 1 Day 1 (prior to dosing of study medications), Weeks 24 (pre-
dose), 48 (pre-dose) and 96 or Early Withdrawal from Treatment Visit. 
The Fatigue Impact Scale (FIS) is a detailed tool, which takes ~ 3 minutes to complete.  The subject 
completes the tool personally, rather than having an interview.  The score reflects functional 
limitation due to fatigue experienced within the previous assessment rather than a measure of the 
level of fatigue.  There are 40 items, each of which is scored 0 (no problem) to 4 (extreme problem), 
providing a continuous scale of 0 – 160.  It is composed of three subscales that describe how fatigue 
impacts cognition, physicality and psychosocial functions.  The cognitive function includes 
concentration, memory, thinking and organization of thoughts.  Physical function reflects motivation, 
effort, stamina and coordination.  Psychosocial function includes the impact of fatigue on isolation, 
emotions, workload and coping. The FIS assessment will be performed at Week 1 Day 1 (prior to 
dosing of study medications), Weeks 24 (pre-dose), 48 (pre-dose) and 96 or Early Withdrawal from 
Treatment Visit. 
  SAFETY DATA 
Subject safety will be evaluated throughout the study during the following assessments:  
• 
Adverse events 
• 
Physical examination: cardiovascular system, chest and lungs, thyroid, abdomen, nervous 
system, skin and mucosae, and musculoskeletal system, eyes, ears, nose, mouth, throat, spine, 
lymph nodes, extremities, genitourinary, weight 
• 
Hematology and differential panel: hemoglobin, hematocrit, red blood cell count, mean 
corpuscular hemoglobin, white blood cell count, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, and platelets 
• 
Fibrinogen 
• 
Pregnancy testing (serum or urine levels of β-human chorionic gonadotrophin (HCG)) in 
women of childbearing potential). In addition, pregnancy test should be conducted in case of 
an unexpected delay of menorrhea 
• 
ECG (within 2 hours pre-infusion and 60 minutes +/- 15 minutes post-infusion on days of 
infusion; for non-infusion days one ECG assessment should be performed) 
• 
Blood chemistry panel: Albumin, Alkaline Phosphatase, BUN, Calcium, Chloride, Creatinine, 
Glucose, LDH, Magnesium, Phosphate, Potassium, SGOT (AST), SGOT (ALT), Sodium, Total 
Bilirubin, Total Protein, Uric Acid, and direct/ indirect bilirubin 
• 
Liver function panel: SGOT/AST, SGPT/ALT, serum gamma-glutamyl transferase (SGGT), 
total bilirubin, direct/indirect bilirubin. 
• 
Pancreatic enzyme panel: serum amylase and lipase 


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• 
Urinalysis panel for routine safety: pH, ketones, protein, glucose, blood, urobilinogen, 
bilirubin, microscopic sediment, specific gravity and leucocyte esterase. 
• 
Vital signs: (within 2 hours pre-infusion and 60 minutes +/- 15 minutes post-infusion on days 
of infusion) systolic and diastolic blood pressure, heart rate, body temperature, and weight  
6.4 REPLACEMENT POLICY 
Subjects who discontinue and/or withdraw from the study for any reason will not be replaced. 
6.5 DEFINITIONS 
Evaluable for toxicity.  All subjects will be evaluable for toxicity from the time of their first treatment 
on Week 1 Day 1. 
Evaluable for radiological and neurological response.  Only those subjects who have had a pre-
treatment baseline efficacy evaluation and at least one post-treatment efficacy evaluation will be 
considered evaluable for response.  These subjects will have their response classified according to 
the definitions stated below. 
6.6 DISEASE PARAMETERS 
Measurable disease:  Diagnosis of RMS will be based on the 2010 McDonald’s criteria (Appendix C). 
6.7 DURATION OF RESPONSE 
Duration of stable disease: 
Stable disease is measured from the start of the treatment (Week 1 Day 1) until the criteria for relapse 
or progression of disease are met or there is evidence of new radiological activity as assessed by MRI, 
taking as reference the smallest measurements recorded since the treatment started, including the 
baseline measurements.  
6.8 RESPONSE REVIEW 
Subjects will be assessed for relapse by the Treating Neurologist at screening, baseline (pre-dose), 
and all scheduled visits and, if necessary, at unscheduled visits.  If a relapse is suspected, the Treating 
Neurologist and Examining Neurologist will follow the procedures as outlined in Section 6.3.1. 
MS relapses are defined as new or worsening neurological symptoms lasting ≥24 hours with the 
absence of fever, injury, infection or adverse reactions to medications. The symptoms are attributed 
to MS and are preceded by 30 days of stability. The change in EDSS score as assessed by the 
Examining Neurologist is ≥ 0.5 increase from prior visit or ≥ 2 points increase on one of the 
appropriate FS or 1 point on two or more of the appropriate FS.   
6.9 RE-SCREENING PROCEDURES 


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Subjects may be re-screened under the following conditions: 
 
• 
After a relapse recovery (see Section 4.4.1) and upon re-consent 
• 
Varicella titer does not indicate immunity at initial screening and subject is re-immunized 
(see Section 3.2) 
• 
He/she, at initial screening, is not eligible to participate in the study based on 
inclusion/exclusion criteria (Sections 3.1 and 3.2) and wishes to re-assess eligibility after a 
waiting period deemed sufficient by the site investigator. 
• 
The subject was determined eligible, but 28 days or more has elapsed between the initial 
screen and the first infusion (Week 1 Day 1). 
 
Re-screening procedures are identical to initial screening procedures (Appendix F), but with the 
following modifications: 
• 
Medical history does not need to be taken again. 
• 
Screening MRI may not need to be repeated if there was one obtained within 30 days prior to 
this screening 
6.10 END OF STUDY FOLLOW-UP 
After early termination of trial or at the end of study visit at Week 96, subjects will enter a 20-week 
Follow-up Period inclusive of the accelerated elimination of teriflunomide.  The 11-day elimination 
procedure will commence at Week 100 for all subjects who completed all study visits including Week 
96.  For those subjects who had terminated early (discontinued or withdrawn from the study), the 
11-day elimination procedure will commence the day after the Early Withdrawal from Treatment 
Visit.  The follow up period will include visits at Weeks 100, 104, and 116.  Weeks 108 and 112 will 
be performed via a phone call.   
 
For subjects who withdraw their consent to participate in the study, the site should inform these 
subjects of the 20-week Follow-up Period inclusive of the accelerated teriflunomide elimination 
procedure and document this in the eCRF. Participation in the 20-week Follow-up Period inclusive 
of the accelerated teriflunomide elimination procedure for subjects who withdraw early is left to the 
discretion of the subject. If he/she elects not to participate in the 20-week Follow-up inclusive of the 
accelerated teriflunomide elimination procedure, after withdrawing consent and after discussion 
with the site, it should be documented in the eCRF.  
 
For subjects who will participate in the 20-week Follow-up Period inclusive of the accelerated 
teriflunomide elimination procedure after withdrawing consent for this study, a new consent form 
to participate in the 20-week Follow-up Period inclusive of the accelerated teriflunomide elimination 
procedure will need to be signed. If he/she re-consents, the sites will complete the eCRF for Weeks 
100, 104, 108, 112, and 116, accordingly.  
 
The purpose of this follow-up is to monitor safety and relapses after the discontinuation of study 
medications and to eliminate residual teriflunomide from the study subjects.  Because blinding is 
maintained until the data from the treatment period (through Week 96) is locked, all subjects will 
undergo the accelerated teriflunomide elimination procedure regardless of whether they were 
randomized to ublituximab/oral placebo or teriflunomide/IV placebo.  Study subjects that enter the 
Follow-up Period of TG1101-RMS302 (post-Week 96 to Week 116) are not allowed to receive DMTs.  
Please refer to the exclusion criteria of the protocol for a list of MS therapies (Section 3.2).  It should 
be noted that use of systemic corticosteroids for the treatment of a relapse is allowed.  When deciding 


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to treat a potential acute relapse the Treating Neurologist can use IVMP (1.0 g/day for at least 3 days 
and can be extended to 5 days). 
 
 
The procedures of each visit are below: 
 
Week 100 Visit: 
• 
Physical examination and vital signs 
• 
Urine pregnancy test 
• 
Report concomitant medications and Adverse Events  
• 
Initiate rapid teriflunomide elimination program (Section 6.10.1 below) 
• 
Hematology and serum chemistry, urinalysis, and B cell assays (as per Section 6) 
 
Week 104 Visit: 
 
• 
Physical examination and vital signs 
• 
Urine pregnancy test 
• 
Report concomitant medications and Adverse Events  
• 
Hematology and serum chemistry, urinalysis, and B cell assays (as per Section 6) 
• 
Acknowledgment of the completion of teriflunomide rapid elimination program by the site 
on eCRF 
 
Week 108 and 112 (Phone Call): 
• 
Follow-up phone call to subject to collect information on concomitant medications, Adverse 
Events and urine pregnancy test outcomes  
 
Week 116 Visit (Final Visit): 
• 
Physical examination and vital signs 
• 
Urine pregnancy test 
• 
Report concomitant medications and Adverse Events  
• 
Teriflunomide drug concentration test: Draw blood to test teriflunomide plasma 
concentration 
 
TG1101-RMS303 is a 172-week open label extension (OLE) trial. Subjects completing 96-weeks of 
treatment in TG1101-RMS301 or TG1101-RMS302 trials in United States, Croatia, Ukraine, Russia, 
Republic of Belarus, Serbia, Poland, and Georgia may be eligible to participate.  Regardless of which 
treatment group the subject was assigned to in the core study, all subjects enrolled in the OLE will 
receive ublituximab on the following schedule:  Week 1 Day 1, Week 3 Day 15, and Weeks 24, 48, 72, 
96, 120, 144, and 168 or until physician or subject decision to withdraw prior to this time.  Subjects 
will have final assessments done at Week 172. TG1101-RMS302 is considered a core study protocol 
for OLE. The TG1101-RMS303 subjects, sponsor and investigators will not know TG1101-RMS301 
and TG1101-RMS302 treatment assignments until these studies are unblinded. 
 ACCELERATED TERIFLUNOMIDE ELIMINATION PROCEDURE 
All subjects should undergo the 11-day accelerated teriflunomide elimination procedure during the 
Follow-up Period: Oral cholestyramine 8 g is administered three times per day for 11 days.  If subjects 
do not tolerate this regimen, then the dosage may be reduced to 4 g three times per day.   
 


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If tolerability issues persist, cholestyramine administration does not need to occur on consecutive 
days unless there is an acute need to lower teriflunomide levels.   
 
As an alternative to cholestyramine, oral activated charcoal administered as 50 g twice a day for 11 
days may be used.  
 
It needs to be documented in the eCRF which elimination treatment was used.  
 
Plasma will be drawn at Week 116 to determine the concentration of teriflunomide. However, 
results will not be shared with the site or subject to maintain blinding.  Prior to discharge from the 
study, all subjects will be counseled by the treating team to have their teriflunomide plasma 
concentration re-measured prior to attempting to become pregnant or trying to impregnate a 
female partner. 


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7 PHARMACEUTICAL INFORMATION 
7.1 TERIFLUNOMIDE 
Chemical Name: 
Teriflunomide  
Other Names:    
None 
Classification:    
Oral de novo pyrimidine synthesis inhibitor of the DHO-DH enzyme 
Formulation: 
Teriflunomide is formulated as film-coated tablets for oral 
administration. Teriflunomide tablets contain 14 mg of teriflunomide 
and the following inactive ingredients: lactose monohydrate, corn starch, 
hydroxypropylcellulose, microcrystalline cellulose, sodium starch 
glycolate, and magnesium stearate. The film coating for the 14 mg tablet 
is made of hypromellose, titanium dioxide, talc, polyethylene glycol and 
indigo carmine aluminum lake.  
Mode of Action: 
De novo pyrimidine synthesis inhibitor of the DHO-DH enzyme 
 
Description: 
Teriflunomide is an oral de novo pyrimidine synthesis inhibitor of the 
DHO-DH enzyme, with the chemical name (Z)-2-Cyano-3-hydroxy-but-2-
enoic acid-(4trifluoromethylphenyl)-amide. Its molecular weight is 
270.21, and the empirical formula is C12 H9F3N2O2 with the following 
chemical structure:  
 
 
 
How Supplied: 
The 14 mg tablet is white to off white, round film-coated tablet with the 
dose strength “14” engraved on one side and engraved with a “B” on the 
other side 
Each tablet contains 14 mg of teriflunomide. 
 
Storage: 
United States: Store at 68°F to 77°F (20°C to 25°C) with excursions 
permitted between 59°F and 86°F (15°C and 30°C). 
Europe: Store below 25°C. Do not refrigerate or freeze. 


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Route of  
Administration: 
Oral  
Packaging: 
Box of 28 tablets containing 1 wallet composed of 2 folded blister cards 
of 14 tablets per blister card with one wallet package in a box. Four (4) 
box will be supplied to the subject at a time.   
Availability: 
Bioequivalent teriflunomide product (currently non-marketed) is used in 
the study, and is available from TG Therapeutics. 
 COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS) FOR 
TERIFLUNOMIDE 
The following adverse events were observed in subjects treated with teriflunomide [15, 16, 17] and 
were considered at least possibly related to study medication.  Please see the latest teriflunomide 
Investigator Brochure for a complete list of all adverse events reported regardless of causality. 
7.1.1.1 VERY COMMON (≥10%) 
• 
Gastrointestinal Disorders: Diarrhea, Nausea 
• 
Hepatic Disorders:  Elevated Alanine Aminotransferase Level 
• 
Nervous System Disorders: Headache 
• 
Skin and Subcutaneous Tissue Disorders: Hair Loss 
 
7.1.1.2 COMMON (≥<10-%) 
• 
Blood And Lymphatic System Disorders:  Neutropenia 
• 
Musculoskeletal and Connective Tissue Disorders: Joint Pain  
• 
Nervous System Disorders: Numbness 
• 
Vascular Disorders: Hypertension 
7.2 UBLITUXIMAB 
Chemical Name: 
Ublituximab 
 
Other Names:    
TG-1101 
Classification:    
Recombinant chimeric anti-CD20 monoclonal antibody 
Formulation: 
 
See Investigator Brochure 
 
Mode of Action: 
Targets CD20 antigen on B-cells 
 
Description: 
Ublituximab is a genetically engineered chimeric murine/human mAb 
directed against the CD20 antigen found on the surface of B lymphocytes.  
Ublituximab displays the typical structure of immunoglobulins, consisting of 
two gamma (γ) heavy chains and two kappa (κ) light chains linked by 
disulfide bridges. It is composed of a murine variable region (37.2% of total 
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How Supplied:  
Concentration of 10 mg/mL in 15 mL (150 mg) single-use glass vials.  
OR 
 
 
 
Concentration of 25 mg/mL in 6 mL (150 mg) single-use glass vials. 
Storage: 
Ublituximab must be stored in a secured limited-access area at a 
temperature ranging +2°C / + 8°C (36°F to 46°F).  Ublituximab must not be 
frozen. 
Stability: 
Once a vial of ublituximab has been opened and/or diluted it is highly 
recommended that it be used immediately.  After dilution, ublituximab is 
stable in static conditions for 24 hours at 25°C, and in dynamic conditions it 
is stable for 8 hours at 25°C. 
Ublituximab has a shelf-life of 36 months if stored between +2°C / + 8°C, 
based on stability data 
Route of  
Administration: 
Intravenous 
Packaging: 
 
Ublituximab is packed in unit boxes. Each of the unit boxes contains:  
• 
One 15 mL vial containing 10 mg/mL solution of ublituximab 
OR 
• 
One 6 mL vial containing 25 mg/mL solution of ublituximab 
The container closure system for the vials containing 15 mL is a type I glass 
vial closed by a siliconized chlorobutyl rubber stopper sealed with a white 
plastic and aluminum cap. 
The container closure system for the vials containing 6 mL is a Type I plus 
borosilicate vial closed by a siliconized bromobutyl rubber stopper sealed 
with an aqua plastic and aluminum cap. 
Availability: 
 
Ublituximab is available from TG Therapeutics, Inc. 
 COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS) FOR 
UBLITUXIMAB 
The following adverse events were observed in subjects treated with single agent ublituximab and 
were considered at least possibly related to study medication. Please see the ublituximab 
Investigator Brochure for a complete list of all adverse events reported regardless of causality. 
7.2.1.1 VERY COMMON (≥10%) 
• 
Blood and Lymphatic System Disorders: Neutropenia, Thrombocytopenia 
• 
General Disorders and Administration Site Conditions: Pyrexia 
• 
Injury, Poisoning and Procedural Complications: Infusion Related Reaction 


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• 
Nervous System Disorders: Headache 
 
7.2.1.2 COMMON (≥2-<10%) 
• 
Blood and Lymphatic System Disorders: Anemia, Pancytopenia 
• 
Musculoskeletal and Connective Tissue Disorders: Muscular Weakness 
• 
Nervous System Disorders: Dysgeusia 
• 
Vascular Disorders: Hypertension 
• 
Gastrointestinal Disorders:  Diarrhea, Nausea, Abdominal Pain, Oral Pruritus 
• 
General Disorders and Administration Site Conditions: Fatigue, Asthenia, Chills, Edema 
Peripheral, Pain 
• 
Hepatobiliary Disorders: Cytolytic Hepatitis 
• 
Infection and Infestations: Herpes Zoster 
• 
Investigations: Aspartate Aminotransferase Increased, Blood Bilirubin Increased, Gamma-
glutamyltransferase Increased 
• 
Respiratory, Thoracic and Mediastinal Disorders: Throat Irritation, Throat Tightness 
• 
Skin and Subcutaneous Tissue Disorders:  Pruritus, Hyperhidrosis 
 
 
7.3 ORDERING STUDY MEDICATIONS 
Once the clinical trial site receives both IRB/EC and Regulatory Authorities approval, the Sponsor’s 
or its designee will perform the Site Initiation Visit and inspection of pharmacy. Following completion 
of these tasks the site can then be officially open and an automatic shipment of pre-determined 
quantity of all study medication (ublituximab, teriflunomide, IV placebo and oral placebo) and 
treatment supplies (i.e., normal saline, infusion kit, cholestyramine, activated charcoal) will be 
shipped to the clinical trial site, accordingly.  A separate Drug Distribution Plan will detail country 
variances and specifics. 
Upon receipt of study medication and treatment supplies, the Pharmacist or the appropriate person 
of the site should update the accountability forms. 
If any abnormality on the shipment invoice compared to what was actually shipped is observed, the 
Pharmacist or the appropriate person must document that on the acknowledgement of receipt and 
contact the CRO. 
7.4 BLINDING, PACKAGING AND LABELING 
 TERIFLUNOMIDE OR ORAL PLACEBO 
Each tablet of teriflunomide (14 mg) or oral placebo is a white to off white, round-film-coated tablet 
with the dose strength “14” engraved on one side and engraved with a “B” on the other side.  
 
Teriflunomide or oral placebo will be supplied to the subject in a box containing 28 tablets (composed 
of 2 folded blister cards of 14 tablets per blister card as a wallet). Four (4) boxes will be supplied to 


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the subject every 12 weeks. The packaging of the teriflunomide or oral placebo in the blister pack 
will be child resistant. 
 
Therefore, to assist in drug accountability for the site, the subjects over 12 weeks should have 
received 112 tablets and when returning back to the sites in approximately 12 weeks; approximately 
84 tablets should have been taken and approximately 28 tablets should be returned to the site. 
Approximately every 12 weeks, the site must collect all unused teriflunomide or oral placebo tablets.  
 
New boxes of teriflunomide or oral placebo will be provided to the subject. The study side will not 
re-dispense previously unused tablets back to the subject. These tablets should be quarantined until 
the study monitor can inventory them and instruct the site on destruction of them.  
 
The box of teriflunomide or oral placebo dispensed to the subject will be labeled in compliance with 
the applicable regulatory regulations in that country.  
 UBLITUXIMAB OR IV PLACEBO 
Ublituximab or IV placebo is provided to the study site in unit boxes. Each unit box contains one 15 
mL vial (10 mg/mL) or one 6 mL vial (25 mg/mL) solution of ublituximab or IV placebo. The 
container closure system for the vials containing 15 mL is a Type I plus borosilicate vial closed by a 
siliconized bromobutyl rubber stopper sealed with an aqua plastic and aluminum cap and the 
container closure system for the vials containing 6 mL is a type I glass vial closed by a siliconized 
chlorobutyl rubber stopper sealed with a white plastic and aluminum cap. 
The empty vials should be maintained until the study monitor performs reconciliation.  
The box of ublituximab or IV placebo provided to the study site will be labeled in compliance with 
the applicable regulatory regulations in that country.  
7.5 DISPENSING AND ADMINISTRATION 
The exact dose and the date and time of administration of ublituximab/oral placebo or 
teriflunomide/IV placebo must be recorded within the eCRF, subject’s medical records, and in the 
drug accountability records. 
The Pharmacist or his/her representative should record the date dispensed and subject’s number 
and initials on the labels. He/she should complete the accountability forms with information 
concerning the dispensation of ublituximab/oral placebo and teriflunomide/IV placebo.  
 DISPENSING AND ADMINISTRATION OF TERIFLUNOMIDE OR ORAL PLACEBO 
Teriflunomide or oral placebo will be dispensed every 12 weeks to the subject (see Section 7.3 for 
further details).  
7.5.1.1 GUIDELINES FOR ORAL TREATMENT OF TERIFLUNOMIDE OR ORAL PLACEBO 
• 
Necessity of MS Center/Neurology Department: Center must have personnel and equipment 
necessary to provide adequate emergency treatment. 


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• 
Subjects who withdraw from treatment should be followed up for 20 weeks inclusive of the 
11-day accelerated teriflunomide elimination procedure, during which they receive 
cholestyramine or activated charcoal. 
• 
If a pregnancy is confirmed, the trial drug(s) must be immediately and permanently stopped, 
the subject must be discontinued from the trial, and the Treating Neurologist must report this 
to pharmacoviligance as soon as possible.  Further, the subject needs to undergo immediate 
accelerated washout with either oral cholestyramine or oral activated charcoal and be 
followed for AEs for 20 weeks after their last dose of the trial drug (please see Section 6.10.1). 
• 
Teriflunomide or oral placebo shall be taken each in the morning daily until the last day of 
Week 95. Alternative dosing times are allowed if necessary.  
o On Week 1 Day 1, teriflunomide or oral placebo dosing should occur upon completion of 
infusion.  If vomiting occurs during the infusion of ublituximab or IV placebo, refrain from 
administering teriflunomide or oral placebo on Week 1 Day 1. The first dose of 
teriflunomide or oral placebo will be administered on Week 1 Day 2. 
• 
Compliance to administration of teriflunomide or oral placebo 
o Plasma samples to determine the concentration of teriflunomide will be obtained 
from all subjects at the following time-points: Week 1 Day 1 and Week 48 (pre-
infusion of ublituximab or IV placebo), and Week 96 or Early Withdrawal from 
Treatment Visit and Week 116. 
o The study sites will instruct the subjects enrolled into the study to return with their 
used and unused teriflunomide or oral placebo blister packs to the investigation site 
during every visit as shown in the Schedule of Assessments in Section 6 as part of the 
teriflunomide or oral placebo drug accountability assessment program. Compliance 
with teriflunomide or oral placebo administration will be reviewed with all subjects 
during those times by the study site and documented on the eCRF by the study site.  
A comment will be entered into the subject’s subject diary and on the accountability 
log for any variation from the prescribed dosing schedule, such as additional or 
missed doses. 
o Compliance will also be assessed by inspection of the blister packs and counting of 
the used and unused tablets at each visit by the study site. Details of teriflunomide or 
oral placebo (date and time of first dose, last dose prior to visit, number of tablets 
dispensed and number of returned tablets) will be recorded in the eCRF. 
 DISPENSING AND ADMINISTRATION OF UBLITUXIMAB OR IV PLACEBO 
Subjects in the United States (US) during 2017 will initially receive ublituximab at a 
concentration of 10 mg/mL and will be switched to the higher concentration (25 mg/mL) in 
January 2018. All US based subjects enrolled in the study after December 2017, will begin the 
study using 25 mg/mL. All subjects in Europe will begin and complete the study with the 
higher concentration (25 mg/mL). 
Ublituximab or IV placebo will be administered in the MS center/neurology department/ infusion 
center associated with MS center or neurology department. The MS centers/neurology department 


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must have skilled personnel and adequate equipment to provide emergency treatment should the 
subject experience IRR, anaphylaxis, hypotension and/or respiratory distress.   
If randomized to ublituximab, each subject will receive ublituximab, a single dose of 150 mg of 
ublituximab on Week 1 Day 1 with an infusion rate of 4 hours for a total volume of 250 mL to be 
infused. Subjects will receive 450 mg of ublituximab on Week 3 Day 15, Weeks 24, 48, and 72 with 
an infusion rate of 1 hour for a total volume of 250 mL. Subjects receiving IV placebo will receive the 
same infusion volume and infusion rate as those subjects receiving ublituximab. Please see Sections 
7.5.2.2 (dilution of ublituximab or IV placebo) and 7.5.2.3 (administration) for further details.   
If the liver enzymes (ALT and/or AST) are Grade 2 or higher, or if the neutrophil count or platelets 
counts are Grade 3 or 4, the dosing of ublituximab or IV placebo will be withheld.  A re-test will occur 
within 14 days after the initial test.  Ublituximab or IV placebo infusion can occur once the liver 
enzymes are less than Grade 2, and if the neutrophil count or platelets counts are less than Grade 3.  
Please see Section 5.2 (Guidance for Laboratory Abnormalities) for further details. 
 
7.5.2.1 GUIDELINES FOR INFUSION TREATMENT OF UBLITUXIMAB OR IV PLACEBO 
• 
Necessity of MS Center/Neurology Department: Center must have personnel and equipment 
necessary to provide adequate emergency treatment for anaphylaxis, hypotension and 
respiratory distress. 
• 
Method of Administration: Ublituximab or IV placebo must be administered as an intravenous 
infusion through a dedicated intravenous line and will be done under the supervision of the 
study investigator or a designee 
• 
Potential Drug Interactions:  No drug interactions have been reported to date. 
• 
Pre-medications: Pre-medicate 30-60 minutes prior to each dose of ublituximab or IV placebo 
with an antihistamine (diphenhydramine 50 mg or equivalent), and corticosteroid 
(dexamethasone 10-20 mg or equivalent).  Oral acetaminophen, 650 mg (or equivalent; only 
used for intervention) should be restricted to subject who experience fever or pyrexia after 
Week 1 dose, or as clinically warranted and additional medication (which needs to be 
documented) may be used at discretion of the physician if adverse reactions occur. 
Note: In case the above referenced medications are not available, equivalents can be used at 
the Investigator’s discretion. If medications are given intravenously, the IV line used for 
ublituximab/IV placebo should not be used. If needed, please consult the Medical Monitor. 
• 
Subject Care Implications:   
o Ublituximab or IV placebo should not be administered as an IV push or bolus. 
o Ublituximab or IV placebo should only be diluted in 0.9% NaCl. 
o Diluted ublituximab or IV placebo should be checked before administration for 
cloudiness, color, or deposits.  Ublituximab or IV placebo should not be administered if it 
does not conform to the manufacturer’s specifications. The Monitor/Sponsor must be 
informed immediately of any quality concerns or questions about the product. 
o It is recommended that ublituximab or IV placebo be administered immediately after 
dilution within 24 hours. 








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o Subsequent Doses of 450mg ublituximab/IV placebo (Week 3 Day 15, Weeks 
24, 48, and 72): 
 
The suggested initial rate of infusion should be 100 mL/hr. If 100 mL/hr is 
tolerated for 30 minutes, then the remainder of the infusion can be completed 
based on Treating Neurologist/PI discretion (rates of 100 mL/hr up to a 
maximum of 400 mL/hr). 
 
At Treating Neurologist/PI discretion, subjects may receive ublituximab/IV 
placebo at even slower rates, as long as the known stability profile of diluted 
ublituximab is not violated (see ublituximab IB). An example of such an 
infusion scheme is 25 mL/hr for 30 minutes, increasing to 50 mL/hr after 30 
minutes, then 75 mL/hr after 30 minutes, concluding at 100 mL/hr for 1 hour 
and 45 minutes. 
 
If there are any questions about a particular infusion scheme, please contact 
the CRO or Sponsor. 
 
If there is a second interruption of the infusion on the same infusion day due to IRR symptoms, the 
infusion of ublituximab or IV placebo must be stopped and the subject should be scheduled for the 
next day. IRR is not a reason to discontinue a subject from the study or future infusions. 
 
Infusion Delays due to Relapse 
For subjects reporting a suspected relapse the Treating Neurologist should perform an Unscheduled 
Relapse Visit. The next scheduled infusion visit is postponed until the subject is back to baseline or 
PI/Treating Neurologist does not expect any improvement.  
 CO-ADMINISTRATION FOR UBLITUXIMAB/ORAL PLACEBO AND 
TERIFLUNOMIDE/IV PLACEBO ON UBLITUXIMAB/PLACEBO ON INFUSION DAYS   
Ublituximab or IV placebo infusion days are defined as Week 1 Day 1, Week 3 Day 15 and Weeks 24, 
48, and 72. On those infusion days teriflunomide or oral placebo should be administered after 
completion of the IV infusion. 
On Week 1 Day 1, if vomiting occurs during the ublituximab or IV placebo infusion, do not administer 
teriflunomide or oral placebo on Week 1 Day 1.  The first dose of teriflunomide or oral placebo will 
occur on Week 1 Day2. On other ublituximab or IV placebo infusion days, if vomiting occurs during 
infusion, do not administer teriflunomide or oral placebo on that day.  Resume administration of 
teriflunomide or oral placebo the next day.  
 
 


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8 STATISTICAL CONSIDERATIONS 
This section describes the statistical methods to be used to analyze the efficacy and safety 
endpoints.  Safety related analyses are described in Section 9. Full details will be provided in a 
formal statistical analysis plan (SAP).  The final Clinical Study Report will describe deviations from 
the SAP, if any.   
The statistical analyses will be done once all subjects have completed Week 96 (Week 96 visit or 
earlier if withdrawn).  
8.1 SAMPLE SIZE AND POWER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 this required sample size is 
increased to 220 per group or a total randomized of 440. 
8.2 GENERAL ANALYSIS CONVENTION 
Unless otherwise stated, all analyses will be performed using SAS Version 9.4 or higher and the 
primary hypothesis test on relapses will be conducted at the two-sided type I error set to 0.05.  All 
tertiary hypotheses will be conducted at a two-sided significance level of 0.05.  P-values will be 
presented with 4 decimals and p-values that are less than 0.0001 will be presented as <0.0001. 
Continuous (non-survival related) data will be summarized using descriptive statistics: number of 
observations (n), mean, standard deviation (SD), median, 25th and 75th percentiles, minimum, and 
maximum.  Frequencies and percentages will be used to summarize categorical (discrete) data.  
Presentations of categorical data will generally suppress percentages for items where the count is 
zero in order to draw attention to the nonzero counts.  
8.3 STATISTICAL ANALYSES WILL BE DESCRIBED IN DETAIL IN THE 
STATISTICAL ANALYSIS PLAN COMPLETED PRIOR TO FINAL 
DATA LOCK.ANALYSIS POPULATIONS 


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 SAFETY POPULATION 
The Safety Population will include all subjects who receive at least one dose of study drug 
(ublituximab or teriflunomide, with corresponding placebos).  All safety assessments including 
toxicity will be performed on the Safety Population by treatment actually received. 
 INTENTION-TO-TREAT (ITT) 
The Intention-to-Treat (ITT) population will consist of all randomized subjects. Subjects will be 
analyzed by randomized treatment group. Analyses of key efficacy endpoints based on ITT 
population will serve as sensitivity analyses.  
 MODIFIED INTENTION-TO-TREAT (MITT) 
The modified Intention-to-Treat (mITT) population will consist of all subjects in the ITT population 
who received at least one dose of study medication and have at least one baseline and post baseline 
efficacy assessment.  The primary efficacy analyses will be performed based on the mITT population. 
The MRI analyses will be based on the subset of subjects in the mITT population who have one 
baseline and post-baseline MRI efficacy assessment. 
Subjects will be analyzed by randomized treatment group. 
 PER-PROTOCOL GROUP (PP) 
The Per-Protocol (PP) population will consist of all subjects in the mITT group who were treated 
for at least 1.75 years and do not have a major protocol deviation that might impact efficacy 
analysis. The Per-Protocol population will only be used for sensitivity analysis of the primary 
efficacy and key secondary variables. Subjects will be analyzed by randomized treatment group. 
8.4 SUBJECT DISPOSITION 
 SCREENING AND ENROLLMENT 
Enrollment will be summarized by treatment group. A table will present the number and percentages 
of subjects by treatment group. Details include number of subjects screened, number of screening 
failures with reason and number of subjects enrolled.  
 DISPOSITION 
The disposition of subjects (number randomized, treated, study medications exposure, duration of 
follow-up, subjects’ allocation by country & region) will be tabulated by treatment group.  
Discontinuation of study medications prior to the end of study will be summarized by treatment 
group and reason for discontinuation will be displayed. Drug discontinuation and termination from 
study prior to the end of the study will be summarized by treatment group and reason for 
discontinuation and/or withdrawal (termination) will be displayed. Listings will present time to and 


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reason for discontinuation or termination by treatment group and subject. In addition, a table of 
major protocol deviations will be presented by group. 
8.5 SUBJECT DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Baseline demographic and clinical characteristics will be summarized as percentages for categorical 
variables and as mean, standard deviation, median, minimum and maximum for continuous 
measures. The analyses of baseline characteristics will be presented for the Safety, ITT, mITT, and PP 
Populations by treatment group.   
8.6 MEDICAL HISTORY 
Medical history will be captured at the Screening visit.  Medical history will be coded using MedDRA 
and will be listed and summarized by MedDRA system organ class and preferred term for the Safety 
population. 
All prior and concomitant medications and procedures will be classified by preferred terms 
according to the  World Health Organization (WHO) Drug Dictionary and will be summarized by the 
number and percentage of subjects by preferred term. Prior medications and procedures are those 
which have a stop date prior to the randomization date, and concomitant medications and 
procedures are those which have a stop date after treatment start  date or are ongoing. Concomitant 
medications will be assessed at both scheduled and unscheduled visits.  
8.7 EXTENT OF EXPOSURE 
The dose (mg) of study drugs administered, the total number of doses of study drugs, and the 
duration of treatment will be summarized with descriptive statistics.   
For ublituximab or IV placebo infusions,  treatment exposure is summarized as the total 
number of infusions (greater than 50% complete) received over the 5 expected infusions.  
Furthermore, the overall number of infusions, number and percentage (based on all 
infusions) of infusions completed with/without interruption and infusions not completed 
will be calculated per arm.  The number and percentage of patients (based on all patients 
with at least one infusion) with and without any infusion complication (interruption or stop) 
per arm will be presented as well.  The percentage of planned total infusion received will also 
be calculated. 
 
For teriflunomide or oral placebo, the proportion of at least 80 percent of taken oral medication will 
be calculated.  These proportions will be summarized by treatment group. 
8.8 INTERIM SAMPLE SIZE REASSESSMENT 
An independent committee, Blinded Assessment Relapse Team (BART), reporting to TG 
Therapeutics, and the DSMB will reassess the sample size for the study when 210 of the 220 
participants have been randomized.  Assuming a uniform rate of recruitment, we need an estimate 
as to how many person years of exposure will occur before an interim adjustment occurs.  If 


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recruitment is going to be accomplished in 8 to 10 months, the average exposure time when 210 
subjects per group are recruited would experience half of the recruitment period or 9/2=4.5 
months. We can use all of the data available at that time and thus will have approximately 4.5 x 210 
= 945 person months or approximately 43 person years of observation (the denominator to compute 
the ARR).   
The Table below provides the sample sizes (total adjusted sample sizes) needed per group per study 
based on the findings at the interim (Columns of the Table) for reductions in the ARR of teriflunomide 
by 40%.  As an example, if the estimated ARR in the pooled population is 0.20 and we are assuming 
an hypothesized 40% reduction in the ARR rate by ublituximab, then the ARR in the individual groups 
(red numbers in the table below) can be derived by solving a simple equation; (NU*0.6 PT + NT*PT)/( 
NU + NT)=0.20 where PT is the ARR in the teriflunomide group and NT and NU are the sample sizes, 
assumed to be equal.  Thus, if the combined ARR=0.20, then this equation under the hypothesized 
reduction of 40% yields an estimated ARR of 0.25 in teriflunomide and 0.15 in ublituximab.  
Calculating the required sample size using a negative binomial comparison with 1.75 years of 
observation overall, results in an updated sample size of 219 per group.  Thus, the original sample 
size of N=200 would be adjusted upward by adding 19 participants per treatment group, plus the 
10% for dropouts yielding a total of 241 subjects per group or 21 additional participants. 
In the Table below, which can guide the interim sample size reassessment, we see two color blocks 
in the table.  The green area shows results that have two (2) characteristics - one, they require smaller 
sample sizes and two, they are unlikely to occur because the ARR rate in the teriflunomide group 
would have to exceed 0.31 (arbitrarily chosen, but some level is reasonable as an upper limit on what 
the rate is likely to be).  Either way, if the blinded ARR falls in the green area or above, the sample 
size will not be reduced since we do not plan to reduce the sample size and 210 participants per 
group will have already been enrolled. The yellow area is the range for the combined total rates. If 
the overall ARR =0.19 then the estimated teriflunomide rate would be estimated at 0.2375 and 
ublituximab would be estimated at 0.1425 and the sample size required would be 233 per group.  
Thus, a rate <= 0.19, the sample size will be increased by 30 per treatment group in each study, but 
no more.  Such observed relapse rates are quite low and unexpected, so that further adjustments are 
probably not warranted.    
Recruitment will continue while the interim analysis is ongoing and if the participants recruited 
beyond the 220 per group will be used in the final analyses if the sample size is not increased and 
will count toward the additional sample size if warranted. 




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Relapses that occur after study drugs are withdrawn will be assessed over the remainder of the 
study period and this data will be utilized as part of additional sensitivity analysis (described in the 
statistical plan) as long as the subject has not withdrawn their consent to be in the trial.  
 
The treatment group will have 2 levels (teriflunomide/ IV placebo or ublituximab/oral placebo).  In 
order to account for different treatment durations among subjects, the log-transformed 
standardized treatment duration (randomization to date last treatment before early withdrawal or 
completion of Week 96 assessment) will be included in the model as an “offset” variable for 
appropriate computation of the Annualized Relapse Rate.  
 will be used to assess 
the overall model with subjects in a repeated statement using a Generalized Estimating Equation 
(GEE) approach. 
 
Two-sided 95% confidence intervals of the rate ratio will be provided for the comparisons of 
Ublituximab/oral placebo versus teriflunomide/IV placebo.  The estimated relapse rate and its 2-
sided 95% confidence intervals will be provided for each treatment group. 
 SECONDARY EFFICACY VARIABLES 
The key secondary outcomes will be tested using a hierarchical approach with the order specified  
below using a step-down procedure where each test is at a Type I error 0.05. If any endpoints fail to 
reach significance, then formal testing of significance of the subsequent secondary outcomes will not 
be performed.  
1. Total number of gadolinium enhancing (Gd-enhancing) T1-lesions per MRI scan by Week 96.     
2. Total number of new and enlarging T2 hyperintense lesions (NELs) per MRI scan by Week 
96. 
3. Time to Confirmed Disability Progression (CDP) for at least 12 weeks occurring during the 
96-week, double-blind treatment period. *   
4. Proportion of subjects with No Evidence of Disease Activity (NEDA) from Week 24 to Week 
96.   
5. Proportion of subjects reaching impaired SDMT (Symbol Digit Modalities Test) from baseline 
to Week 96.   
6. Percentage change in Brain Volume from baseline to Week 96. 
 
* Confirmed Disability Progression for at least 12 weeks during the 96-week treatment period will 
be analyzed using pooled data from the two identical studies TG1101-RMS301 and TG1101-
RMS302. 
The total number of gadolinium enhancing (Gd-enhancing) T1-lesions will be 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.  The total number of new and enlarging T2 hyperintense lesions will be 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.  The MRI count variables will be assessed for differences between the 
treatment groups using negative binomial regression with an offset based on time on study and 
covariates, region, baseline EDSS strata, and baseline MRI counts.   Percent brain volume change will 
be assessed between the two groups using linear mixed effects models 
 with 
covariates region, baseline EDSS strata, and baseline brain volume.   
 


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Disability progression is defined as an increase of ≥1.0 point from the baseline EDSS score that is not 
attributable to another etiology (e.g., fever, concurrent illness, or concomitant medication) when the 
baseline score is 5.5 or less, and ≥0.5 when the baseline score is above 5.5.  Disability progression is 
considered confirmed when the increase in the EDSS score is confirmed at regularly scheduled visits 
at least 12 or 24 weeks after the initial documentation of neurological worsening. 
Please note that Confirmed Disability Progression for at least 12 weeks during the 96-week 
treatment period will be analyzed using pooled data from the two identical studies TG1101-
RMS301 and TG1101-RMS302.  With the exception of this endpoint (CDP), which will be analyzed 
at the pooled level, all other secondary efficacy endpoints will be tested if and only if the individual 
study secondary endpoint listed ahead of it has reached the significance level at 0.05.    
All pre-specified pooled analyses are listed below.  However, only CDP for at least 12 weeks is part 
of the secondary analysis and the remainder are included in the tertiary analysis. 
1. Time to Confirmed Disability Progression for at least 12 weeks (secondary analysis) 
2. Time to Confirmed Disability Progression for at least 24 weeks (tertiary analysis) 
3. Time to Confirmed Disability Improvement for at least 12 weeks (tertiary analysis) 
4. Time to Confirmed Disability Improvement for at least 24 weeks (tertiary analysis) 
 
 
Summary tables of progression to CDP will present the proportion who achieved CDP at Week 96 and 
associated 95% CIs for each treatment group. The median time-to-event with 2-sided 95% CIs as well 
as the proportion of subjects remaining event-free at times of interest will be estimated using Kaplan-
Meier methods implemented with 
.  All time to CDP (and CDI) endpoints will 
be analyzed similarly. 
 
 
The proportion of subjects with No Evidence of Disease Activity (NEDA) will be calculated at Week 
96. A subject with NEDA is defined as a subject without relapses confirmed by the IRAP, without MRI 
activities (no T1 Gd+ lesions and no new/enlarging T2 lesions), and no 12-week Confirmed Disability 
Progression. Any evidence of disease activity from Week 24 to Week 96 will be counted as not 
reaching NEDA.  Any evidence of disease activity before Week 24 will not count.  NEDA rates will be 
compared using logistic regression 
 with baseline adjustments the same as 
used in the primary analysis plus baseline MRI counts and without an offset to take into account time 
on study.    
 
Change in cognition (SDMT) will be assessed using the total score at each SDMT visit which is defined 
as the total number of correct answers reported in the CRF.  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.  The 
proportion of impaired SDMT will be analyzed in all subjects in the mITT population.  SDMT rates 
will be compared using logistic regression 
 with baseline adjustments the 
same as used in the primary endpoint analysis, without treatment duration offset, but including log-
transformed baseline MRI counts (T1 unenhancing, T2, Gad enhancing).  To avoid zero values for the 
log transformation of MRI counts, 1 will be added to each observation before transforming. 
 SENSITIVITY ANALYSES 


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Sensitivity Analysis 
1.  The primary analysis will be repeated based on all reported MS relapses (rather than just 
confirmed ones). 
2.  A time to relapses analysis using Cox proportional hazards model with first IRAP-confirmed 
relapse as the primary event will be conducted to compare with the primary analysis in a negative 
binomial model. The Cox proportional hazards model will be specified with treatment, region, 
number of relapses in previous year, baseline EDSS score, baseline number of T1 Gd-enhancing 
lesions sex and the subject’s age at baseline as covariates. 
3.  To assess the effects of treatment withdrawals, the primary analysis will be repeated using the 
information on relapses which occur during the period following drug withdrawal to the end of the 
study period regardless of whether additional treatment were utilized.  Relapses which occurred 
after permanent discontinuation of study medication will be included and natural log (time on study 
in years) rather than the natural log (time on study drug in years) will be used as the offset variable 
in the negative binomial model, which is the primary analysis. 
4. We will examine the dropouts from the trial using all participants who provided withdrawal of 
consent excluding deaths.  Multiple imputation will be used to impute the expected number of 
relapses a participant would have had if they had continued to participate in the trial.  To perform 
the imputation, 10 replicates will be used since a relapse on treatment is relatively low frequency 
event.   The covariates used to model and predict the imputations will include: treatment, region, 
number of relapses in previous year, baseline EDSS score, baseline number of T1 Gd-enhancing 
lesions sex and the subject’s age at baseline as covariates. 
5.  For secondary outcomes T1 Gd enhancing, T2 NELs, and 12 week CDP, the effects of dropouts and 
study discontinuations will be similarly evaluated as number 4 above.  
6.  Additional sensitivity analyses may be defined in the analysis plan prior to database lock. 
 
 TERTIARY EFFICACY AND OTHER VARIABLES 
All tertiary analyses will be assessed at a Type I error of 0.05 with no adjustment for multiplicity.   
1. Change in MSFC score from baseline to Week 96 
2. Time to Confirmed Disability Progression (CDP) for at least 24 weeks 
3. Time to Confirmed Disability Improvement (CDI) for at least 12 weeks 
4. Time to Confirmed Disability Improvement (CDI) for at least 24 weeks 
5. Health outcomes (MSQoL-54 (inclusive of SF36); FIS, hospitalization, steroid use, time out of 
work) 
6. Total volume of Gd enhancing T1 lesions per MRI scan over the treatment period 
7. Volume of T2 lesions  
8. Volume of hypointense T1 lesion component (black holes) 
9. Proportion of subjects free of disability progression at Weeks 24, 48 and 96.   
10. Proportion of subjects with a relapse 
11. Time to first confirmed relapse 
 


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Change in MSFC and Health Outomes (MSQoL-54 (inclusive of SF36), FIS), will be analyzed using 
linear Mixed Models.  including results with baseline as a covariate along with region and other 
covariates if used in the primary analyses.   
 
The analysis of CDI at 12 and 24 weeks will utilize the same approach as that used for CDP.     12 Week 
Confirmed Disability Improvement (12 Week CDI) is defined as a reduction from the baseline EDSS 
score of at least 1.0 point (or 0.5 points if the baseline EDSS score was >5.5) that was sustained and 
confirmed at the next scheduled visit at least 12 weeks after the initial documentation of neurological 
improvement.  Similarly, 24-week Confirmed Disability Improvement (24 Week CDI) requires an 
initial reduction from baseline EDSS score and a subsequent confirmation of the reduction at all 
regular scheduled visits for at least 24 Weeks after the initial documentation of neurological 
worsening 
 
Hospitalization, Steroid Use, and Time Out of Work will be summarized by descriptive statistics as 
well as frequency and percentage.  For Time Out of Work, percentages of missed work hours will be 
compared between arms using Wilcoxon rank sum tests.   For Steroid Use, the number of IRAP 
confirmed relapses treated with steroid will be analyzed the same way as the primary endpoint. 
For analysis of lesion volume related variables (Total volume of Gd enhancing T1 lesions per MRI 
scan over the treatment period, Volume of T2 lesions, Volume of hypointense T1 lesion component 
(black holes)) Mixed Model Repeated Measures (MMRM) analyses will be implemented via 
 
 
Time to first confirmed relapse is defined as (date of relapse onset – date of randomization + 1) and 
will be regarded as censored at the end of treatment. The analysis will be similar to the one of time 
to confirmed disability progression. The proportions of subjects with a relapse and subjects free of 
disability progression at different time points will be estimated using the Kaplan-Meier method. 
 
  
 
 
 
 
 
  
 
 
 
     
 
 
 
 
 
 
 


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8.9.6 ANTI-DRUG ANTIBODY (ADA) ANALYSIS 
Immunogenicity results will be reported based on all subjects in the safety population. The 
percentage of subjects developing ADA will be summarized.  .  


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9 SAFETY REPORTING AND ANALYSIS 
9.1 SAFETY ANALYSES 
To evaluate the safety of ublituximab/placebo and teriflunomide/oral placebo, as determined by 
adverse events (AEs) and serious adverse events (SAEs), including MS worsening.   
Safety will be tabulated as described below in the safety section.  Tables will summarize the 
proportion of subjects ever experiencing a particular AE, and in select tables will also include the 
number of times a particular AE occurs.  
Safety evaluations will be based on the incidence, intensity, and type of adverse events, as well as on 
clinically significant changes in the subject’s physical examination, vital signs, and clinical laboratory 
results.  Safety analyses will be performed using the safety population.  Safety variables will be 
tabulated and presented by treatment actually received.  Exposure to study treatment and reasons 
for discontinuation of study treatment will also be tabulated.  Must obtain expert evaluations of brain 
MRI images of subjects with suspected opportunistic CNS infections including PML.  
For select laboratory values, box plots of the values over time will be used for displays of these 
parameters. In the event of higher than expected incidence rates of abnormalities, further exploration 
of combinations of events, such as Hy’s law, will be examined. 
9.2 ADVERSE EVENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product. An AE does not necessarily have to have a causal 
relationship with this treatment.   An adverse event (AE) can therefore be 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. This includes any occurrence that is new in onset or aggravated in severity or 
frequency from the baseline condition. 
9.3 ADVERSE EVENT CHARACTERISTICS  
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.03.  A copy of the CTCAE version 4.03 can 
be 
downloaded 
from 
the 
following 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.     
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03 is to be used for the 
grading of severity of symptoms and abnormal findings.  For adverse events not covered by the NCI-
CTCAE Version 4.03 grading system, the following definitions will be used: 


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• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated. 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated. 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5: Death related to AE. 
9.4 ADVERSE EVENT EXPECTEDNESS  
AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting purposes only. Expected AEs are those 
listed in the Investigator Brochures for either ublituximab or teriflunomide. 
9.5 TREATMENT EMERGENT ADVERSE EVENTS (TEAE’S) 
The frequency and percentages of subjects with treatment-emergent adverse events (TEAEs) will be 
tabulated by system organ class (SOC) and preferred term (PT), where treatment-emergent is 
defined as any AE with an onset on or after the first dose of study medication and through 30 days 
after the last dose of study medication or with an onset prior to the first dose of study medication 
that increases in severity on, or after the first dose of study medication and through 30 days after the 
last dose of study medication. 
In addition, TEAEs that are considered at least possibly related to study treatment will be tabulated 
as well as deaths, SAEs, and events resulting in treatment discontinuation or termination. 
Additionally, the subset of events which occurred after the last study drug administration will be 
summarized.  
9.6 ADVERSE EVENTS / SERIOUS ADVERSE EVENT CAUSALITY ASSESSMENT 
The Investigator must also assess the relationship of any adverse event to the use of study drug, 
(whether none, one, or all) based on available information, using the following guidelines: 
1. Not Related: Clear-cut temporal and/or mechanistic relation to a cause other than the 
study drug. 
2. Doubtful: There is no reasonable possibility that the event is related to the study 
medications but a definite cause cannot be ascertained. 
3. Possible: There is still a reasonable possibility that the cause of the event was the study 
medications but there exists a more likely cause of the event such as complications of 
progressive disease. 
4. Probable: The most likely cause of the event is the study medications but other causes 
cannot be completely excluded. 
5. Definite: Clear cut temporal and/or mechanistic relation to the study medications.  All 
other causes have been eliminated.  Events classified as definite will often be confirmed 


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by documenting resolution on discontinuation of the study medications and recurrence 
upon resumption. 
In the summary of drug related AEs, “Not Related” and “Doubtful” will be considered as “Not Drug 
Related” and “Possible”, “Probable”, and “Definite” will be considered as “Drug Related.”  In the event 
that causality is missing for an AE, it will be considered as “Drug Related.” 
 RECORDING OF ADVERSE EVENTS 
All adverse events of any subject during the course of the trial will be reported on the electronic 
CaseRreport Form, and the investigator will give his or her opinion as to the relationship of the 
adverse event to trial drug treatment (i.e., whether the event is related or unrelated to trial drug 
administration –ublituximab/IV placebo or teriflunomide/oral placebo).  If the adverse event is 
serious, it should be reported as soon as possible and no greater than 24 hours to the sponsor or 
designee.  Other untoward events occurring in the framework of a clinical trial are also to be recorded 
as AEs (i.e., AEs that occur prior to assignment of trial treatment that are related to a protocol-
mandated intervention, including invasive procedures such as biopsies, medication washout, or no 
treatment run-in). 
All AEs regardless of seriousness or relationship to ublituximab/IV placebo and/or 
teriflunomide/oral placebo treatment, as well as all pregnancies, spanning from the signing of the 
informed consent and until 20 weeks after discontinuation or completion of either protocol-specific 
treatment as defined by the protocol for that subject, are to be recorded on the eCRF/Pregnancy 
Report Form.  
 ABNORMAL LABORATORY VALUES AND VITAL SIGNS 
The reporting of abnormalities of vital signs as adverse events should be avoided.  Abnormalities of 
vital signs should not be reported unless any criterion for an SAE is fulfilled, the vital signs 
abnormalities cause the subject to discontinue trial treatment, or the investigator insists that the 
abnormality should be reported as an AE.  Abnormal laboratory results should be noted in the eCRF 
as an adverse event if they are associated with an overdose, require prolong in-patient 
hospitalization, or are otherwise considered clinically significant by the investigator. If an abnormal 
laboratory value or vital sign is associated with clinical signs and/or symptoms, the sign or symptom 
should be reported as an AE, and the associated laboratory value or vital sign should be considered 
additional information that must be collected in the relevant eCRF.  If the laboratory abnormality is 
a sign of a disease or syndrome, only the diagnosis needs to be recorded on the SAE Report Form or 
AE eCRF. 
Clinical Laboratory Results will be summarized.  Summary statistics for actual values and for changes 
from baseline will be tabulated for laboratory results by scheduled visit.  Subjects with laboratory 
values outside of the normal reference range at any post-baseline assessment will be summarized, 
and graded per NCI CTCAE Version 4.03 when applicable.  Subject incidence of laboratory toxicity 
will be summarized by treatment group and maximum grade for each laboratory test. 
 HANDLING OF ADVERSE EVENTS 


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All adverse events resulting in discontinuation from the trial should be followed until resolution or 
stabilization.  Subjects must be followed for AEs for 20 weeks after discontinuation or completion of 
protocol-specific treatment.  All new AEs occurring during this period must be reported and followed 
until resolution unless, in the opinion of the investigator, these values are not likely to improve 
because of the underlying disease or the subject is lost to follow up.  In this case, the investigators 
must record his or her reasoning for this decision in the subject’s medical record and as a comment 
on the eCRF.  After 20 weeks, only AEs, SAEs, or deaths assessed by the investigator as treatment 
related are to be reported. 
9.7 SERIOUS ADVERSE EVENTS 
 DEFINITIONS OF SERIOUS ADVERSE EVENTS 
The definitions of serious adverse events (SAEs) are given below.  The Principal Investigator is 
responsible for ensuring that all staff involved in the trial are familiar with the content of this section. 
An SAE or reaction 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. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the previous definition.  These should also 
usually be considered serious.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
A SUSAR is defined as a suspected unexpected SAE, and SUSAR reporting is encompassed within SAE 
reporting guidelines as defined in this section. 
Treatment within or admission to the following facilities is not considered to meet the criteria of “in-
patient hospitalization” (although if any other SAE criteria are met, the event must still be treated as 
an SAE and immediately reported): 
• 
Emergency Department or Emergency Room 
• 
Out-patient or same-day surgery units 
• 
Observation or short-stay unit 
• 
Rehabilitation facility 
• 
Hospice or skilled nursing facility 
• 
Nursing homes, Custodial care or Respite care facility 


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Hospitalization due to MS relapse does not need to be reported to the Sponsor as an SAE if the 
Treating Neurologist medically confirms the relapse.  The subsequent IRAP adjudication will not 
impact the reporting status of the SAE. 
Events related to underlying MS disease (i.e., MS progression) also do not require reporting as an 
SAE. 
Hospitalization during the trial for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the trial), does not require reporting as a serious adverse event to the 
Sponsor. 
 SERIOUS ADVERSE EVENT REPORTING BY INVESTIGATORS 
It is important to distinguish between “serious” and “severe” adverse events, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  For example, nausea which persists for several hours may be 
considered severe nausea, but may not be considered an SAE.  On the other hand, a stroke which 
results in a limited degree of disability may be considered only a mild stroke, but would be considered 
an SAE.  Severity and seriousness should be independently assessed when recording AEs and SAEs 
on the eCRF. 
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to the Sponsor in order to comply with regulatory requirements.  Serious adverse events 
may occur at any time from the signing of the informed consent form through the 20-week Follow-
up Period after the last trial treatment.  Sponsor or designee must be notified of all SAEs, regardless 
of causality, within 24 hours of the first knowledge of the event by the treating physician or research 
personnel.   
To report an SAE, see the appropriate SAE eCRF page. 
All SAEs and medically confirmed deaths (regardless of causality assessment) spanning from the 
signing of the informed consent and until 20 weeks of last trial treatment must be expeditiously 
reported to the sponsor as SAEs within the eCRF and followed until resolution (with autopsy report 
if applicable). 
The investigator must review and sign off on the SAE data on the SAE report.  The SAE will be 
reported to the Sponsor (or Sponsor designee) as outlined in the Safety Monitoring Plan.   
If an SAE is reported to the sponsor or designee via fax, the same information must be entered on the 
eCRF within 24 hours (1 business day).  The SAE transmission should be confirmed by the site 
personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should also 
be reported to the sponsor or designee as soon as it is available; these reports should be submitted 
using the appropriate eCRF.  The detailed SAE reporting process will be provided to the sites in the 
Investigator Study Guide. 


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Investigators must report SAEs and follow-up information to their responsible Institutional Review 
Board (IRBs/EC)/Independent Ethics Committee according to the policies of the responsible IRB or 
Ethics Committee. 
9.8  SPONSOR SAE REPORTING REQUIREMENTS 
Sponsor is responsible for reporting relevant SAEs to the Competent Authority, other applicable 
Regulatory Authorities, and participating investigators, in accordance with ICH guidelines, FDA 
regulations, and/or local regulatory requirements. 
Sponsor is responsible for reporting related, unexpected fatal or life-threatening events associated 
with the use of the trial drugs to the regulatory agencies and competent authorities via telephone or 
fax within 7 calendar days after being notified of the event.  The Sponsor will report all related, 
unexpected SAEs including non-death/non-life-threatening SAEs associated with the use of the trial 
medications to the applicable Regulatory Authorities, investigators, and central IRBs or EC by a 
written safety report within 15 calendar days of notification.  Investigators using local IRBs or EC are 
responsible for sending written safety reports for these events to their IRBs or EC within 15 calendar 
days or accordingly to the timelines outlined in the policies of the responsible IRB or EC.  
9.9 RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on the 
SAE Report Forms and AE eCRF.  Avoid colloquialisms and abbreviations. 
All AEs, including those that meet SAE reporting criteria, should be recorded on the AE eCRF; AEs 
that meet the definition of an SAE should additionally be reported. 
9.10 DIAGNOSIS VS. SIGNS AND SYMPTOMS 
All AEs should be recorded individually in the subject’s own words (verbatim) unless, in the opinion 
of the PI and/or Treating Neurologist, the AEs constitute components of a recognized condition, 
disease, or syndrome.  In the latter case, the condition, disease, or syndrome should be named rather 
than each individual sign or symptom.  If a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each individual 
event should be recorded as an AE or SAE as appropriate on the relevant form(s) (SAE Report Form 
and/or AE eCRF).  If a diagnosis is subsequently established, it should be reported, as follow-up 
information is available.  If a diagnosis is determined subsequent to the reporting of the constellation 
of symptoms, the signs/symptoms should be updated to reflect the diagnosis. 
 PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution, between subject evaluation time 
points.  Such events should only be recorded once on the SAE Report Form and/or the AE eCRF.    If 
a persistent AE becomes more severe (changes from a Grade 1 or 2 AE to a Grade 3 or 4 AE) or lessens 
in severity (changes from a Grade 3 or 4 AE to a Grade 1 or 2 AE), it should be recorded on a separate 
SAE Report Form and/or AE eCRF.   


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A recurrent AE is one that occurs and resolves between subject evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or AE eCRF 
for each recurrence. 
 ABNORMAL LABORATORY VALUES 
Abnormal laboratory results should be noted in the eCRF as an adverse event if they are associated 
with an overdose, require or prolong in-patient hospitalization, or are otherwise considered 
clinically significant by the investigator. If an abnormal laboratory value or vital sign is associated 
with clinical signs and/or symptoms, the sign or symptom should be reported as an AE, and the 
associated laboratory value or vital sign should be considered additional information that must be 
collected in the relevant eCRF.  If the laboratory abnormality is a sign of a disease or syndrome, only 
the diagnosis needs to be recorded on the SAE Report Form or AE eCRF. 
 DEATHS 
All medically confirmed deaths, regardless of attribution, spanning from the signing of the informed 
consent and until 20 weeks after discontinuation or completion of either protocol-specific treatment 
will be recorded within the eCRF and expeditiously reported to the Sponsor. 
When recording a serious adverse event with an outcome of death, the event or condition that caused 
or contributed to the fatal outcome should be recorded as the single medical concept on the Adverse 
Event page of the eCRF.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, record “Death NOS” on the eCRF Adverse Event page. 
 HOSPITALIZATION, PROLONGED HOSPITALIZATION, OR SURGERY 
Any AE that results in in-patient hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol.  There are some 
hospitalization scenarios that do not require reporting as an SAE when there is no occurrence of an 
AE (refer to Sections 9.7.1 and 9.7.2).   
 PRE-EXISTING MEDICAL CONDITIONS 
A pre-existing relevant medical condition is one that is present at the start of the trial.  Such 
conditions should be recorded on the study’s appropriate medical history eCRF.  A pre-existing 
medical condition should be recorded as an AE or SAE only if the frequency, severity, or character of 
the condition worsens during the trial.  When recording such events on the appropriate SAE Report 
Form and/or AE eCRF, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 
 PROTOCOL-DEFINED EVENTS OF SPECIAL INTEREST 
Reference the ublituximab Investigator Brochure for Adverse Events of Special Interest (AESI). AEs 
that are considered AESIs are to be reported in the appropriate eCRF. SAEs that are considered 
AESIs should be reported following the timeline and reporting process outlined in Section 9.7.2. 
 


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Pregnancy: 
Since pregnancy as such is not considered to be an adverse event, it does not need to be reported as 
an AESI.  However, if pregnancy is associated with adverse events, it is these adverse events that 
need to be reported in eCRF.  Pregnancy reporting requirements outlined in Appendix A must be 
followed. 
Overdose: 
All instances of overdose, whether symptomatic or asymptomatic, of either ublituximab/IV placebo 
or Teriflunomide/oral placebo must be reported in eCRF on the Overdose form.  Anything over the 
prescribed daily dose is considered an overdose.  
If an overdose is associated with adverse events, it is these adverse events that need to be reported 
in eCRF.  If an adverse event associated with an overdose meets a seriousness criterion, it must be 
expeditiously reported as an SAE. 
Suicidal ideation and behavior will be identified by the AE preferred terms included in MedDRA SMQ 
“Suicide/self-injury”.  
 


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10 STOPPING RULES 
The DSMB (Study Chairs, Medical Monitor and Sponsor Representative) will be in charge of reviewing 
safety data. These events will be reviewed by the DSMB and potentially other study investigators 
during the course of the study.  All other serious and non-serious adverse events will be documented, 
managed for each subject including review of the safety data by the DSMB and possible study 
participation termination at the investigator and DSMB discretion.  The independent DSMB will be 
comprised of a total of 5 members with at least 3 MDs, a biostatistician and the DSMB chair. 
The DSMB may stop the study due to safety reasons after reviewing the safety data.  


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11 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This trial will be conducted according to the standards of Good Clinical Practice outlined in the ICH 
E6 Tripartite Guideline and CFR Title 21 part 312, applicable government regulations, institutional 
research policies and procedures and any other local applicable regulatory requirement(s).  
11.1 IRB/EC APPROVAL 
The trial protocol, ICF, IBs, available safety information, subject documents (e.g., trial diary), subject 
recruitment procedures (e.g., advertisements), information about payments (i.e., PI payments) and 
compensation available to the subjects and documentation evidencing the PI’s qualifications must be 
submitted to the IRB/EC for ethical review and approval prior to the trial start.   
The PI/Sponsor and/or designee will follow all necessary regulations to ensure initial and ongoing, 
IRB/EC trial review. The PI/Sponsor and/or designee (as appropriate) must submit and, where 
necessary, obtain approval from the IRB/EC for all subsequent protocol amendments and changes to 
the informed consent document.  Investigators will be advised by the sponsor or designee whether 
an amendment is considered substantial or non-substantial and whether it requires submission for 
approval or notification only to an IRB/EC. 
If applicable, the PI will notify the IRB/EC within 90 days of the end of the trial, or if the trial 
terminates early, the PI must notify the IRB/EC within 15 days of the termination.  A reason for the 
early termination must be provided (as defined in Directive 2001/20/EC). The Sponsor will either 
prepare or review all submission documents prior to submission to the IRB/EC. 
11.2 REGULATORY APPROVAL 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and approval 
of the appropriate regulatory bodies obtained, prior to trial initiation. If required, the Sponsor will 
also ensure that the implementation of substantial amendment to the protocol and other relevant 
trial documents happen only after approval by the relevant Regulatory Authorities. 
Safety updates for ublituximab/IV placebo and teriflunomide/oral placebo will be prepared by the 
Sponsor (or its representative), as required, for submission to the relevant Regulatory Authority.   
11.3 INSURANCE AND INDEMNITY 
Details of insurance and/or indemnity will be contained within the written agreement between the 
PI or site and the Sponsor. 
11.4 INFORMED CONSENT 
Informed consent is a process by which a subject voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the subject's decision to participate.  Informed consent is documented by means of a written, 
signed and dated informed consent form. 


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The ICF will be submitted for approval to the IRB/EC that is responsible for review and approval of 
the trial.  Each consent form must include all of the relevant elements currently required by the 
responsible Regulatory Authority, as well as local county authority or state regulations and national 
requirements. 
Before recruitment and enrollment into the trial, each prospective candidate will be given a full 
explanation of the trial.  Once the essential information has been provided to the prospective 
candidate, and the investigator is sure that the individual candidate understands the implications of 
participating in this trial, the candidate will be asked to give consent to participate in the trial by 
signing an informed consent form.  A notation that written informed consent has been obtained will 
be made in the subject’s medical record.  A copy of the informed consent form, including the subject’s 
signature, will be provided by the investigator to the subject.   
If an amendment to the protocol substantially alters the trial design or the potential risks to the 
subjects, the subject’s consent to continue participation in the trial must be obtained.  Additionally, 
upon either IRAP-confirmed or  Treating Neurologist medically confirmed relapse, subjects should 
re-consent to continue participation in the trial.  
11.5 CONFIDENTIALITY 
Subject Confidentiality 
Confidentiality of subject’s personal data will be protected in accordance with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA; for USA only), and national data protection laws. 
HIPAA regulations require that, in order to participate in the trial, a subject must sign an 
authorization from the trial that he or she has been informed of following: 
• 
What protected health information (PHI) will be collected from subjects in this trial; 
• 
Who will have access to that information and why; 
• 
Who will use or disclose that information;  
• 
That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal or 
state privacy laws;  
• 
The information collected about the research trial will be kept separate from the subject’s 
medical records, but the subject will be able to obtain the research records after the 
conclusion of the trial; 
• 
Whether the authorization contains an expiration date; and 
• 
The rights of a research subject to revoke his or her authorization.  
In the event that a subject revokes authorization to collect or use his or her PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should be 
made to obtain permission to collect at least vital status (i.e., that the subject is alive) at the end of 
their scheduled trial period. 


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In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that the 
investigator and institution permit authorized representatives of the Sponsor, the Regulatory 
Authorities and the IRB/EC direct access to review the subject’s original medical records at the site 
for verification of trial-related procedures and data.  
Measures to protect confidentiality include: only a unique trial number and year of birth will identify 
subjects on the eCRF or other documents submitted to the Sponsor. This information will be used in 
the database for subject identification. Subject names, addresses or birthdate/month will not be 
entered in the eCRF or database. No material bearing a subject’s name will be kept on file by the 
Sponsor. Subjects will be informed of their rights within the ICF. 
11.6 INVESTIGATOR AND STAFF INFORMATION 
Personal data of the investigators and sub-investigators may be included in the Sponsor database, 
and shall be treated in compliance with all applicable laws and regulations.  When archiving or 
processing personal data pertaining to the investigator or sub-investigator, the Sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized party. 
11.7 FINANCIAL INFORMATION  
The finances for this trial will be subject to a separate written agreement between the Sponsor 
and/or designee and applicable parties.  Any Investigator financial disclosures as applicable to 21CFR 
Part 54 shall be appropriately provided. 


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12 RECORD RETENTION AND DOCUMENTATION OF THE TRIAL 
12.1 AMENDMENTS TO THE PROTOCOL 
Amendments to the protocol shall be planned, documented and signature authorized prior to 
implementation.   
If an amendment to the protocol is required, the amendment will be originated and documented by 
the Sponsor.  All amendments require review and approval of the Sponsor.  The written amendment 
must be reviewed and approved by the Sponsor, and submitted to the IRB/EC at the investigator’s 
facility for the board’s approval. 
Amendments specifically involving change to trial design, risk to subject, increase to dosing or 
exposure, subject number increase, addition or removal of new tests or procedures, shall be reviewed 
and approved by the IRB/EC at the Investigator’s facility. 
The amendment will be submitted to Regulatory Authorities by the Sponsor or designee as 
applicable, and specifically when an increase to dosing or subject exposure and/or subject number 
has been proposed. 
Items requiring a protocol amendment with IRB/EC and Regulatory Authority approval include, but 
are not limited to, the following: 
• 
Change to trial design  
• 
Risk to subject 
• 
Increase to dose or subject exposure to drug  
• 
Subject number increase of more than 20% 
• 
Addition or removal of tests and / or procedures  
• 
Addition/removal of a new Investigator  
It should be further noted that, if an amendment to the protocol substantially alters the trial design 
or the potential risks to the subjects, their consent to continue participation in the trial should be 
obtained. 
12.2 DOCUMENTATION REQUIRED TO INITIATE TRIAL 
Before the trial may begin, documentation required by FDA regulations must be provided by the 
Investigator.  The required documentation should be submitted to the Sponsor or designee. 
Documents at a minimum required to begin the trial include, but are not limited to, the following: 
• 
A signature-authorized protocol and contract; 
• 
A copy of the official IRB/EC approval of the trial and the IRB/EC members list; 
• 
Current Curricula Vitae for the Principal Investigator and any associate investigator(s) who 
will be involved in the trial; 


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• 
Indication of appropriate accreditation for any laboratories to be used in the trial and a copy 
of the normal ranges for tests to be performed by that laboratory; 
• 
Original Form FDA 1572 (Statement of Investigator), appropriately completed and signed; 
• 
A copy of the IRB/EC-approved consent form containing permission for audit by 
representatives of the Sponsor, the IRB/EC, the FDA, and other applicable regulatory 
agencies;  
• 
Financial disclosure forms for all investigators listed on Form FDA 1572; 
• 
GCP Certificate for trial training; 
• 
Site qualification reports, where applicable; 
• 
Verification of Principal Investigator acceptability from local and/or national debarment 
list(s). 
The Sponsor/Sponsor designee will ensure that all documentation that is required to be in place 
before the trial may start, in accordance with ICH E6 and Sponsor SOPs, will be available before any 
trial sites are initiated. 
12.3 TRIAL DOCUMENTATION AND STORAGE 
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated trial 
duties and should ensure that all persons assisting in the conduct of the trial are informed of their 
obligations. All persons authorized to make entries and/or corrections on the eCRFs are to be 
included on this document. All entries in the subject’s eCRF are to be supported by source 
documentation where appropriate. 
Source documents are the original documents, data, records and certified copies of original records 
of clinical findings, observations and activities from which the subject’s eCRF data are obtained. 
These can include, but are not limited to, hospital records, clinical and office charts, laboratory, 
medico-technical department and pharmacy records, diaries, microfiches, EKG traces, copies or 
transcriptions certified after verification as being accurate and complete, photographic negatives, 
microfilm or magnetic media, X-rays, and correspondence. 
The PI and trial staff are responsible for maintaining a comprehensive and centralized filing system 
(Site Trial File/SSF or ISF) of all trial-related (essential) documentation, suitable for inspection at any 
time by representatives from the Sponsor or designee and/or applicable Regulatory Authorities.  The 
ISF/SSF must consist of those documents that individually or collectively permit evaluation of the 
conduct of the trial and the quality of the data produced.  The ISF/SSF should contain as a minimum 
all relevant documents and correspondence as outlined in ICH GCP Section 13 and 21 CFR Part 
312.57, including key documents such as the IB and any amendments, protocol and any amendments, 
signed ICFs, copies of completed eCRFs, IRB/EC approval documents, Financial Disclosure forms, 
subject identification lists, enrollment logs, delegation of authority log, staff qualification documents, 
laboratory normal ranges, records relating to the trial drug including accountability records.  Drug 
accountability records should, at a minimum, contain information regarding receipt, shipment, and 
disposition.  Each form of drug accountability record, at a minimum, should contain PI name, date 
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In addition, all original source documents supporting entries in the eCRF must be maintained and be 
readily available. 
The Sponsor shall maintain adequate investigational product records and financial interest records 
as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing application 
has been approved by FDA; or, in the event that the marketing application has not been approved by 
FDA, for no less than 2 years after the last shipment / delivery of the drug for investigational use is 
discontinued and FDA has been notified of the discontinuation. 
The IRB/EC shall maintain adequate documentation / records of IRB/EC activities as per 21CFR 
Part 56.115 for at least 3 years after completion of the research. 
The Investigator shall maintain adequate records of drug disposition, case histories and any other 
trial-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not been 
approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
To enable evaluations and/or audits from Regulatory Authorities or from the Sponsor or its 
representative, the investigator additionally agrees to keep records, including the identity of all 
participating subjects (sufficient information to link records e.g., medical records), all original, signed 
informed consent forms, and copies of all eCRFs, SAE Reporting forms, source documents, detailed 
records of treatment disposition, and related essential regulatory documents.  The documents listed 
above must be retained by the investigator for as long as needed to comply with national and 
international regulations (generally 2 years after discontinuing clinical development or after the last 
marketing approval).  The Sponsor or its representative will notify the investigator(s)/institutions(s) 
when the trial-related records are no longer required.   
If the investigator relocates, retires, or for any reason withdraws from the trial, the sponsor and/or 
its representative should be prospectively notified.  The trial records must be transferred to an 
acceptable designee, such as another investigator, another institution, or to sponsor.  The 
investigator must obtain the sponsor written permission before disposing of any records, even if 
retention requirements have been met.  All trial files will be maintained by the Sponsor or its 
representative throughout the trial, and will be transferred to the Sponsor at the conclusion of the 
trial. 
12.4 DATA COLLECTION 
The trial eCRF is the primary data collection instrument for the trial. An electronic Case Report Form 
(eCRF) will be utilized for the collection of all data and all data will be entered using the English 
language and should be kept current to enable the monitor to review the subjects’ status throughout 
the course of the trial. 
In order to maintain confidentiality, only subject number and year of birth will identify the subject in 
the eCRF.  If the subject’s name or full date of birth appears on any other document (e.g., laboratory 
report), it must be obliterated on the copy of the document to be supplied to the investigator site and 
replaced instead with the subject number and subject’s year of birth.  The investigator will maintain 
a personal subject identification list (subject numbers with corresponding subject identifiers) to 


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enable records to be identified and verified as authentic. Subject data/information will be kept 
confidential, and will be managed according to applicable local, state, and federal regulations. 
12.5 TRIAL MONITORING, AUDITING, AND INSPECTING 
The investigator will permit trial-related monitoring, quality audits, and inspections by the 
government Regulatory Authorities, the Sponsor or its representative(s) of all trial-related 
documents (e.g., source documents, regulatory documents, data collection instruments, electronic 
Case Report Forms).  The investigator will ensure the capability for inspections of applicable trial-
related facilities.  The investigator will ensure that the trial monitor or any other compliance or QA 
reviewer is given access to all trial-related documents and trial-related facilities.   
Participation as an investigator in this trial implies the acceptance of potential inspection by 
government Regulatory Authorities, the sponsor or its representative(s).  
At the Sponsor’s discretion Source Document Verification (SDV) may be performed on all data items 
or a percentage thereof. 
12.6 QUALITY ASSURANCE AND QUALITY CONTROL 
In addition to the Clinical Monitoring component of this protocol, the Sponsor’s Quality Assurance 
(QA) department shall establish an Auditing Plan document separate from the protocol to establish 
the criteria by which independent auditing shall be conducted during the conduct of the trial to assess 
compliance with GCP and applicable regulatory requirements.  Data or documentation audited shall 
be assessed for compliance to the protocol, accuracy in relation to source documents and compliance 
to applicable regulations. 
Each trial site shall be required to have processes and/or procedures in place that will ensure the 
study is conducted according to the protocol, GCP and any applicable local, national or international 
regulations. 
12.7 DISCLOSURE AND PUBLICATION POLICY 
All information provided regarding the trial, as well as all information collected/documented during 
the course of the trial, will be regarded as confidential.  The Sponsor reserves the right to release 
literature publications based on the results of the trial. 
A Clinical Study Report will be prepared upon completion of the study.  The Sponsor will disclose the 
trial results, in the form of a clinical study report synopsis, to the IEC and the applicable Regulatory 
Authorities within one year of the end of the trial.  The format of this synopsis and that of the Clinical 
Study Report and its addendum will comply with ICH E3 guidelines for structure and content of a 
Clinical Study Report. 
The financial disclosure information will be provided to the Sponsor or designee prior to trial 
participation from all PIs and Sub-Investigators who are involved in the trial and named on the FDA 
1572 form. 


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By conducting this study, the Investigator affirms to the Sponsor that he or she will maintain, in strict 
confidence, information furnished by the Sponsor including data generated from this study and 
preliminary laboratory results, except as exempted for regulatory purposes.  
All data generated during the conduct of this study is owned by the Sponsor and may not be used by 
the Investigator or affiliates without the expressed written consent of the Sponsor. 
All manuscripts, abstracts, or other presentation materials generated by site investigators must be 
reviewed and approved by the Sponsor prior to submission. 


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13 REFERENCES 
1. 
http://www.healthline.com/health/multiple-sclerosis/facts-statistics-infographic 
(Assessed June 11, 2015) 
2. 
Lublin FD et al.  Neurology.  1996 ;46 :907-911. 
3. 
Lublin FD et al. Neurology. 2014 ; 83 :278-286. 
 
4. 
Polman C et al.  NEJM. 2006 ; 354(9) :889-910. 
5. 
de Romeuf C, Dutertre CA, Le Garff-Tavernier M, Fournier N, Gaucher C, Glacet A, et al. 
Chronic lymphocytic leukaemia cells are efficiently killed by an anti-CD20 monoclonal antibody 
selected for improved engagement of FcgammaRIIIA/CD16. British journal of haematology. 
2008;140(6):635-43. 
6. 
Baritaki S, Militello L, Malaponte G, Spandidos DA, Salcedo M, Bonavida B. The anti-CD20 
mAb ublituximab interrupts the dysregulated NF-kappaB/Snail/RKIP/PTEN resistance loop in B-
NHL cells: role in sensitization to TRAIL apoptosis. Int J Oncol. 2011;38(6):1683-94. 
7. 
Esteves I, Dumontet C, Herveau S et al.  ublituximab a Third Generation Monoclonal Anti-
CD20 Antibody Displays an Additive Antitumor Activity with Antileukemic Chemotherapeutic 
Agents in Mouse Xenograft Models.  American Society of Clinical Oncology 2011 Poster 
Presentation. 
8. 
Hauser SL.  Multi Scler.  2015 ; 21(1) :8-21. 
 
9. 
Bar-Or A et al.  Ann Neurol. 2008 ; 63 :395-400. 
 
10. 
Hauser SL et al. NEJM. 2008 ; 358 ;676-688. 
 
11. 
Kappos L et al.  Lancet. 2011 ; 378 :1779-1787. 
 
12.
 
http://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures
/Paper-TipSheet_-2010-Revisions-to-the-McDonald-Criteria-for-the-Diagnosis-of-MS.pdf (assessed 
July 1, 2015) 
13. 
Kauser F et al. Expert Opin Drug Evaluations. 2009; 9(7):889-895. 
14. 
Hauser S et al. Presented at the 2015 European Committee for Treatment and Research in 
Multiple Sclerosis Meeting, Barcelona, Spain. October 7-10. Mult Scler. 2015; 21(11 Suppl):Parallel 
session 190. 
15. 
Teriflunomide (Abagio®) Product Information 
16. 
O'Connor, P et al.  NEJM.  2011; 365:1293-1303. 
17 
Confavreux C et al.  Lancet Neurol.  2014; 13:247-256. 
18. 
Zweben A et al.  Drugs Info J.  2009; 43(4) 


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19.  
https://www.aubagio.com/media/pdf/Guide to Accelerated Elimination Procedure for AUBAGIO
(R)(teriflunomide).pdf 
20.  
Hauser, SL. et al. NEJM. 2017 ; 366(3): 221-234 
21. 
O’Connor P et al.  NEJM. 2011; 365: 1293 – 1303 
22.  
Vermersch et al. MSJ. 2014; 6(6): 705 – 716  


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14 APPENDIX A; PREGNANCY 
Women Not of Childbearing Potential are Defined as Follows: 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea (based on 
the subject’s medical history) with serum FSH levels > 40 mIU/mL [for US only: and estradiol 
< 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy) at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment is she considered not of child bearing 
potential.  In addition, female patients with hysterectomy but with available ovaries are not 
considered WOCBP because of their belonging to surgically sterile category of patients. 
Contraceptive Guidelines for Women of Child-Bearing Potential: 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use effective contraception during the study and for 20 weeks after the last study 
drug was administered. The effective contraception is defined as either: 
1. True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
2. Sterilization:  have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least 6 weeks ago.  In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment. 
3. Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female subjects on the study, the vasectomised male 
partner should be the sole partner for that subject. 
4. Oral contraception, injected or implanted hormonal methods. 
5. Use of a combination of any two of the following (a+b): 
a. Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
The following are unacceptable forms of contraception for women of childbearing potential:  
• 
Female condom  
• 
Natural family planning (rhythm method) or breastfeeding  
• 
Fertility awareness  
• 
Withdrawal  
• 
Cervical shield 


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Women of child-bearing potential must have a negative serum pregnancy test within 5 days prior to 
initiating treatment. 
Fertile Males: 
Fertile males, defined as all males physiologically capable of conceiving offspring must use condom 
during treatment, and for an additional 20 weeks after the last study drug was administered, and 
should not father a child in this period. Male subjects must also not donate sperm during active 
treatment and for 20 weeks following the last study drug administered. 
Female partners of fertile male participants must also use effective measures of contraceptives as 
described above for females. 
Pregnancies 
To ensure subject safety, each pregnancy in a subject on study treatment must be reported to TG 
Therapeutics Inc. within 24 hours of learning of its occurrence. The pregnant subject/male subject’s 
partner will be asked to provide informed consent to allow the pregnancy to be followed up for the 
full duration (or until termination) to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications.  Additionally, medical information will 
be collected on the newborn for 6 months after birth, as permitted by local regulations.  
Pregnancy should be recorded on a Pregnancy Report Form and reported by the investigator to TG 
Therapeutics Inc.  Pregnancy follow-up should be recorded on the same form and reported by the 
investigator to TG Therapeutics Inc.  Any SAE experienced during pregnancy must be reported on 
the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 


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15 APPENDIX B; NYHA CLASSIFICATIONS 
New York Heart Association (NYHA) Classifications  
Class 
Functional Capacity 
Objective Assessment 
I 
Subjects with cardiac disease but without resulting 
limitations of physical activity.  Ordinary physical 
activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Subjects with cardiac disease resulting in slight 
limitation of physical activity.  They are comfortable at 
rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Subjects with cardiac disease resulting in marked 
limitation of physical activity.  They are comfortable at 
rest.  Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Subjects with cardiac disease resulting in inability to 
carry on any physical activity without discomfort.  
Symptoms of heart failure or the anginal syndrome 
may be present even at rest.  If any physical activity is 
undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 
1994:253-256. 


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16 APPENDIX C; 2010 MCDONALD DIAGNOSTIC CRITERIA FOR MS 
2010 Revised McDonald Diagnostic Criteria for MS [12] 
Clinical (Attacks) 
Lesions 
Additional Criteria to Make 
Diagnosis 
≥ 2 
Objective clinical evidence of ≥ 2 
lesions or objective clinical 
evidence of 1 lesion with 
reasonable historical evidence of 
a prior attack 
None.  Clinical evidence alone will 
suffice; additional evidence 
desirable but must be consistent 
with MS 
≥ 2 
Objective clinical evidence of 1 
lesion 
Dissemination in time, 
demonstrated by: 
• 
≥1 T2 lesion in ≥ 2 MS typical 
CNS regions (periventricular, 
juxtacortical, infratentorial, 
spinal cord); OR  
• 
Await further clinical attack 
implicating a different CNS 
site 
1 
Objective clinical evidence of ≥2 
lesions 
Dissemination in time, 
demonstrated by: 
• 
Simultaneous asymptomatic 
contrast-enhancing and non-
enhancing lesions at any 
time; OR 
• 
A new T2 and/or contrast-
enhancing lesions(s) on 
follow-up MRI, irrespective 
of its timing; OR 
• 
Await a second clinical 
attack 
1  
Objective clinical evidence of 1 
lesion 
Dissemination in space, 
demonstrated by 
• 
≥1T2 lesion in at least 2 MS 
typical CNS regions 
(periventricular, 
juxtacortical, infratentorial, 
spinal cord); OR 
• 
Await further clinical attack 
implicating a different CNS 
site AND 
Dissemination in time, 
demonstrated by 
• 
Simultaneous asymptomatic 
contrast-enhancing and non-
enhancing lesions at any 
time; OR 


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• 
A new T2 and/or contrast-
enhancing lesions(s) on 
follow-up MRI, irrespective 
of its timing; OR 
• 
Aware a second clinical 
attack 
 
0 (Progression from 
onset) 
 
One year of disease progression 
(retrospective or prospective) AND 
≥ 2 out of 3 criteria: 
• 
Dissemination in space in the 
brain based on ≥1 T2 lesion 
in periventricular, 
juxtacortical or infratentorial 
regions; 
• 
Dissemination in space in the 
spinal cord based on ≥2 T2 
lesions; OR 
• 
Positive CSF 
 
What is an attack? 
• 
Neurological disturbance of kind seen in MS 
• 
Subjective report or objective observation 
• 
≥ 24 Hours duration in the absence of fever or infection 
• 
Excludes pseudo-attacks, single paroxysmal symptoms (multiple episodes of paroxysmal 
symptoms occurring over 24 hours or more are acceptable as evidence) 
• 
Some historical events with symptoms and pattern typical for MS can provide reasonable 
evidence of previous demyelinating event(s), even in the absence of objective findings 
Determining Time Between Attacks: 30 days between onset of event 1 and onset of event 2 
Provides Evidence for Dissemination in Space (DIS)? 
• 
≥1 T2 lesion in at least 2 out of four areas of the CNS: periventricular, juxtacortical, 
infratentorial or spinal cord 
• 
Gd enhancement of lesions is not required for DIS 
• 
If a subject has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded and 
do not contribute to lesion count 
What provides MRI Evidence of Dissemination in Time (DIT)? 
• 
A new T2 and/or Gd-enhancing lesion(s) on follow-up MRI, with reference to a baseline scan, 
irrespective of the timing of the baseline MRI OR 
• 
Simultaneous presence of asymptomatic Gd-enhancing and non-enhancing lesions at any time 
What is Positive CSF: Oligoclonal IgG bands in CSF (and not serum) or elevated IgG index 
 
 


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17 APPENDIX D; INDEPENDENT RELAPSE ADJUDICATION PANEL 
(IRAP) 
Independent Relapse Adjudication Panel (IRAP) 
The Phase III study includes an objective definition of relapse and a standardized procedure for 
assessment of all suspected relapses as described in Section 4.4.1.  As outlined in this section, the 
Treating Neurologist will, within these guidelines, exercise his or her best clinical judgement in 
treating the suspected relapse.  However, neither the Treating Neurologist nor the blinded 
rater/Examining Neurologist will make the final determination of whether a suspected event is 
counted as a relapse for the purpose of calculating the primary study outcome of Annualized Relapse 
Rate (ARR). Instead, an independent, blinded IRAP will make all relapse determinations in the Phase 
III study.  The purpose of the IRAP is to ensure that relapses are scored in a manner that is consistent 
and objective as possible, and to minimize the variability between sites.  
The IRAP will review all subject records pertaining to suspected on-study relapses (i.e., new or 
worsening neurological symptoms of acute onset) that occur outside the scheduled study visits and 
are reported by the subject within 48 hours.  Upon receiving the report by the subject, of a suspected 
relapse/acute neurological event, the Treating Neurologist and Examining Neurologists will in an 
independent manner, and blinded to the results of their separate examinations follow the procedures 
and timelines as described below and outlined in Appendix E.  All suspected relapses initially 
reported by the subject are evaluated by the IRAP regardless of whether the Treating Neurologist 
considered the subject’s symptoms to be the result of a relapse. 
The IRAP comprises of 6 independent neurologists with expertise in MS clinical research who are not 
investigators in any other TG Therapeutics-sponsored studies with ublituximab.  The IRAP members 
are trained on study procedures by the Sponsor and an independent Contract Research Organization 
(CRO) who manages all IRAP activities throughout the study.  IRAP members are required to review 
trial data and perform adjudications in accordance with the protocol- specified definition (Section 
4.4.1).     
The CRO transfers blinded data that are relevant to assessment of relapses (entered into the eCRF by 
both the Treating Neurologist and the Examining Neurologist) and prepares blinded case dossiers to 
be reviewed by the IRAP via a secure electronic portal.  The dossiers include a standardized listing 
for each suspected relapse that specified onset date, type and severity of reported symptoms, 
whether the event had disqualifying characteristics (e.g., lasted less than 24 hours, or symptoms not 
MS-related), and whether event has been treated with methylprednisolone.  The dossiers also include 
vital signs, AEs related to the potential relapse, physical examinations, and EDSS scores with all 
supporting data from the standardized Neurostatus exam; values from baseline and the most recent 
prior quarterly assessment are provided as context for values from the relapse evaluation visit.  
Medical/surgical history and clinical episode history are also provided.  In order to minimize the 
potential for inclusion of data which can potentially unblind an individual case under review (e.g., 
inclusion of adverse event with details that could suggest a treatment assignment), the CRO will 
perform additional programmatic checks on text fields pertaining to Adverse Events and physical 
examination findings for data points that are part of the relapse case listing. 
Each potential relapse is reviewed by 2 IRAP members who have worked and entered their 
evaluations independently, on cases randomly assigned to them by the CRO.  The IRAP adjudicates 


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each case based on all available data provided for that case and members are not permitted to contact 
the site or the sponsor for additional information.    If 2 IRAP reviewers reached the same decision as 
to whether an episode constitutes a relapse, the decision is recorded by the CRO.  If the 2 reviewers 
provide a conflicting assessment, a third IRAP member will review the case so that a majority vote 
can be obtained.  The majority vote of up to 3 IRAP members serves as the final determination as to 
whether an event meets criteria for an on-study protocol defined relapse.   
Relapse determinations by the IRAP are communicated to the Treating Neurologist, who will in turn, 
notify the subject and update the eCRF accordingly.  The IRAP has no involvement in subsequent 
subject management decisions.  In order to maintain independence and blinding, the Examining 
Neurologist will not receive this report.  Furthermore, neither the Treating Neurologist nor the 
subject may disclose the IRAP decision to the Examining Neurologist. The Treating Neurologist, upon 
receiving the IRAP decision, will counsel the subject per Section 4.4.1.  The subject will need to give 
her/his consent to continue study participation.   
For the Phase III study, the results of IRAP adjudications are transferred to the Sponsor only after the 
last subject completes the study. The Sponsor has no knowledge of  IRAP adjudications while the 
study is ongoing. 


















































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Timing and 
Sequence 
Considerations: 
Once signed consent is obtained, procedures can be scheduled for the day at 
Investigator and subject convenience.  
 
 

SAP_001.pdf: 




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List of Abbreviations and Definitions of Terms 
 
9-HPT 
9 Hole Peg Test 
 
ACTH 
Adrenocorticotrophic hormone 
 
ADA 
Anti-drug antibody 
 
ADME 
Absorption, Distribution, Metabolism, Excretion 
 
AE 
Adverse event 
 
AESI 
Adverse event of special interest 
 
ALT 
Alanine aminotransferase 
 
ANCOVA 
Analysis of covariance 
 
aPTT 
Activated partial thromboplastin time 
 
ARR 
Annualized relapse rate 
 
AST 
Aspartate aminotransferase 
 
ATC 
Anatomic Therapeutic Chemical Classification 
 
BART 
Blinded Assessment Relapse Team 
 
BMI 
Body mass index 
 
BOD 
Burden of disease 
 
BP 
Blood pressure 
 
BPF 
Brain parenchymal fraction 
 
BUN 
Blood urea nitrogen  
CNS 
Central nervous system 
CrCl 
Creatinine clearance  
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
 
CSR 
Clinical study report 
 
DILI 
Drug-induced liver injury 
 
DMC 
Data Monitoring Committee 
 
DSMB 
Data Safety Monitoring Board 
 
EAE 
Experimental allergic encephalomyelitis 
 
ECG 
electrocardiogram 
 
EDSS 
Expanded Disability Status Scale 
 
EOPII 
End of Phase II 
 
EPTD 
Early permanent treatment discontinuation 
 
EQ-5D 
EuroQoL (quality of life scale) 
 


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FIS 
Fatigue Impact Scale 
 
FS 
Functional System 
 
FSH 
Follicle stimulating hormone 
 
GCP 
Good clinical practice 
 
Gd 
gadolinium 
GEE 
Generalized estimating equation 
GGT 
Gamma glutamyl transferase 
Hb 
hemoglobin 
HCG 
Human chorionic gonadotrophin 
HIV 
Human immunodeficiency virus 
HLGT 
High Level Group Term 
HLT 
High Level Term 
 
HMR1726 
Teriflunomide 
 
ICH 
International Council for Harmonisation 
 
ICU 
Intensive care unit 
 
INR 
International normalization ratio 
 
IP 
Investigational product 
 
IRAP 
Independent Relapse Adjudication Committee  
 
ITT 
Intent-to-treat 
 
IVRS 
Interactive voice response system 
 
LOCF 
Last observation carried forward 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
mITT 
modified Intent-to-Treat 
 
MMRM 
Mixed-effect model with repeated measures 
 
MRI 
Magnetic resonance imaging or magnetic resonance image 
 
MRI-AC 
MRI analysis center 
 
MS 
Multiple sclerosis 
 
MSFC 
Multiple Sclerosis Functional Composite 
 
MSQoL-54 
Multiple Sclerosis Quality of Life-54 
 
NEDA 
No evidence of disease activity 
 
PASAT 
Paced Auditory Serial Addition Test 
PCA 
Predefined change abnormal 
PK 
Pharmacokinetic 
 


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PK/PD 
Population pharmacokinetic/pharmacodynamic 
 
PML 
Progressive Multifocal Leukoencephalopathy 
 
PP 
Per Protocol 
 
PR 
Pulse rate 
 
PS-MS 
Performance Scales–Multiple Sclerosis 
 
PT 
Preferred term 
 
RMS 
Relapsing forms of Multiple Sclerosis 
 
SAE 
Serious adverse event 
 
SAP 
Statistical analysis plan 
 
SD 
Standard deviation 
 
SDMT 
Symbol Digit Modalities Test 
SF-36 
Short Form generic health survey (36 items) 
SGGT 
Serum gamma-glutamyl transferase 
SGOT/AST 
Serum glutamic oxaloacetic transaminase/aspartate aminotransferase 
 
SGPT/ALT 
Serum glutamic pyruvic transaminase/alanine aminotransferase 
 
SMQ 
Standardized MedDRA Queries 
 
SOC 
System Organ Class 
 
T25-FW 
Timed 25-Foot Walk 
 
TEAE 
Treatment emergent adverse event 
 
VAS 
Visual Analogue Scale 
 
WBC 
White blood cells 
 
WHO-DD 
World health organization drug dictionary 
 
WPAI 
Work productivity and activity impairment 
 
 


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Contents 
1 
Overview and Investigational Plan ...................................................................................................... 7 
1.1 
Study Design and Randomization....................................................................................................... 7 
1.2 
Objectives ........................................................................................................................................... 7 
1.2.1 
Primary Objective ....................................................................................................................... 7 
1.2.2 
Secondary Objectives ................................................................................................................. 7 
1.2.3 
Tertiary Objectives ..................................................................................................................... 7 
1.3 
Determination of Sample Size ............................................................................................................ 8 
1.3.1 
Interim Sample Size Reassessment ............................................................................................. 8 
1.4 
Study Plan ........................................................................................................................................... 9 
2  
Statistical and Analytical Procedures ................................................................................................ 10 
2.1  
Analysis Variables ............................................................................................................................. 10 
2.1.1  
Demographics and Baseline Characteristics ............................................................................ 10 
2.1.2  
Duration of Study Treatment Exposure and Compliance ........................................................ 12 
2.1.3  
 Efficacy Variables ..................................................................................................................... 13 
2.1.4  
 Safety Variables ....................................................................................................................... 17 
2.1.5  
 Pharmacokinetic Variables ...................................................................................................... 19 
2.1.6  
 Other Variables ........................................................................................................................ 19 
2.2  
Analysis Populations ......................................................................................................................... 19 
2.2.1  
 Safety Population .................................................................................................................... 19 
2.2.2  
 Intention-to-Treat (ITT) ........................................................................................................... 20 
2.2.3  
 Modified Intention-to-Treat (mITT) Population ...................................................................... 20 
2.2.4  
 Per-Protocol (PP) Population ................................................................................................... 20 
  
 
 21 
2.3  
 Disposition of Subjects .................................................................................................................... 21 
2.4  
Statistical Methods ........................................................................................................................... 21 
2.4.1 Demographics and Baseline Characteristics ................................................................................... 22 
2.4.2 Primary Efficacy Variable ................................................................................................................. 22 
2.4.3  
 Secondary Endpoints ............................................................................................................... 25 
2.4.4   
 Tertiary Endpoints ................................................................................................................... 29 
2.4.5 Analyses of Safety Data ................................................................................................................... 33 
2.4.6 Duration of Study Treatment Exposure and Compliance ............................................................... 38 


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2.4.7  
 Analyses of Pharmacokinetics ................................................................................................. 38 
2.4.8  
 Analyses of Anti-Drug Antibody (ADA) .................................................................................... 39 
2.4.9  
 Analysis of Pharmacodynamics ............................................................................................... 40 
2.5  
Data Handling Conventions .............................................................................................................. 40 
2.5.1  
 Missing Data ............................................................................................................................ 40 
2.5.2  
 Windows for Time Points ........................................................................................................ 44 
2.5.3  
 Unscheduled Visits .................................................................................................................. 44 
2.5.4  
 Pooling of Centers for Statistical Analyses .............................................................................. 45 
3  
Interim Analysis ................................................................................................................................. 45 
4  
Software Documentation .................................................................................................................. 45 
5  
Revisions of the SAP .......................................................................................................................... 46 
6  
References ......................................................................................................................................... 48 
Appendix A: ............................................................................................................................................... 49 
Appendix B: ............................................................................................................................................... 51 
 
 
 


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1   
Overview and Investigational Plan 
 
This statistical analysis plan (SAP) provides a detailed description of the statistical strategy for the 
“TG1101-RMS302” protocol Version 5.0 dated 04 September 2020.  The goal of the SAP is to pre-
specify the statistical approaches to the analysis of study data prior to study initiation. It has been 
revised before database lock to cover protocol amendments and all technical aspects of the planned 
statistical analysis. Significant revisions and the corresponding rationale are summarized in Section 
5 of this document. 
 
1.1  
Study Design and Randomization 
 
This is a 120 week, Phase 3, randomized, multi-center, double-blinded, double-dummy, 
active-controlled study that is primarily designed to assess the annualized relapse rate (ARR) and 
safety/tolerability of ublituximab (TG‐1101; UTX)/oral placebo as compared to teriflunomide/IV 
placebo in subjects with relapsing forms of Multiple Sclerosis (RMS).  
 
After early termination of trial or at the end of study visit at Week 96, subjects will enter a 20 week 
follow-up program inclusive of the accelerated elimination of teriflunomide. 
 
 
1.2  
Objectives 
 
1.2.1   
Primary Objective 
 
To determine the annualized relapse rate (ARR) in subjects with RMS after 96 weeks (approximately 
2 years with a year is equal to 365.25 days) treatment with IV infusion of ublituximab/oral placebo 
compared to 14 mg oral teriflunomide/IV placebo. 
 
1.2.2   
Secondary Objectives  
 
The secondary objectives are to examine the effects of ublituximab/oral placebo as compared to 
teriflunomide/IV placebo as follows: 
 
1. On MRI parameters, 
2. Confirmed Disability Progression (CDP),  
3. No Evidence of Disease Activity (NEDA),  
4. Symbol Digit Modality Test (SDMT) 
5.    To evaluate the safety of ublituximab/oral placebo, as determined by adverse events (AEs) and serious 
adverse event (SAEs), including MS worsening. 
 
1.2.3 Tertiary Objectives 
 






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Refer to the study protocol for TG1101-RMS302 for study schedule for analysis variables.  
 
2  
Statistical and Analytical Procedures  
2.1  Analysis Variables 
2.1.1  Demographics and Baseline Characteristics 
 
 
All baseline safety and efficacy parameters (apart from the one listed below) are presented along 
with the summary statistics in the safety and efficacy sections (Section 2.4). 
 
Demographic and other baseline characteristics 
 
Demographic variables are gender (Male, Female), race (White, Black or African American, 
Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, Other, or 
Not Applicable due to country’s legislation), age in years (quantitative and categorical variable:  
<38, and ≥38 years), Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, 
Unknown), country and region.  
Regions are defined as follows: 
• USA and Western Europe: USA, Spain, United Kingdom 
• Eastern Europe: all other countries 
 
Other baseline characteristics: 
• 
Baseline hepatic function (normal, mild, moderate, or severe impairment) 
• 
Baseline renal function (normal, mild, moderate, or severe impairment) 
 
Classification of hepatic impairment per NCI-ODWG Criteria 
 
 
Category  
NCI-ODWG 
Total Bilirubin 
ALT or AST 
Mild 
B1: ≤ULN 
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B2: >1-1.5x ULN 
B2: Any 
Moderate 
>1.5-3x ULN 
Any 
Severe 
>3x ULN 
Any 
 
Classification of renal impairment per EMA Guidance   
 
 
 
Medical and surgical history 
 
Medical history data will be coded to “Preferred Term (PT)” and associated primary “System Organ 
Class (SOC)” using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.0. 
Dictionary upgrades are not planned during the course of the study. 
 
Disease characteristics at baseline 
 
• Number of relapses experienced within past 1 year and 2 years (0, 1, 2, 3, and 
≥4), respectively 
• 
Time since first diagnosis of MS (in years) to be derived as  
(Day of randomization – Day of first MS diagnosis) / 365.25 
• Time since first symptoms of MS (in years) to be derived as 
(Day of randomization – day of first symptoms of MS) / 365.25 
• Time since most recent relapse onset (in months) to be derived as 
(Day of randomization – day of most recent relapse onset) / (365.25 / 12)  
• Baseline EDSS score 
• Baseline EDSS (≤3.5, >3.5) 
• Number of baseline Gadolinium (Gd)-enhancing lesions (0, ≥1) 
• Baseline T2 lesion count 
• Baseline T2 lesion Volume 
• Baseline brain volume 
 
Multiple Sclerosis treatment history 
• Received any MS therapy for at least 1 month (30 days) prior to enrollment (Yes, No) 
• MS therapy in the previous 5 years by Preferred Name 
• Previous corticosteroid treatment for relapse 
• Time since last corticosteroid treatment for relapse (months) 
 
Vital signs and height 
 
Vital signs are variables: weight in kg (quantitative variable and categorical variable: 
<50, ≥50 - <100, ≥100), height (m) and Body Mass Index (BMI) in weight[kg]/height[m²] (<30, 
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Prior or concomitant medications or Follow-Up Medications 
 
All medications taken within 3 months (5 years for previous MS treatments) before randomization 
and until the end of the study are reported in the case report forms (CRF). 
 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD). 
 
• Prior medications are those taken prior to first dose of treatment, either stopped before study 
treatment start or continuing. 
 
• Concomitant medications are those taken at any time during the study treatment period, from 
the first study treatment use to the day of last study drug treatment, started before or during 
study treatment.   
 
• Follow-up medications are those taken at any time between last study treatment and end of 
follow-up, 
 
Technical details related to calculating dates, imputation for missing dates, etc. are described in 
Section 2.5. 
 
2.1.2  Duration of Study Treatment Exposure and Compliance 
 
Duration of oral study treatment exposure 
 
Duration of treatment exposure (to oral study treatment teriflunomide/placebo) will be derived as: 
 
 (Date of Last oral Study Treatment - Date of First oral Study Treatment + 1). 
 
In addition, duration of treatment exposure will also be categorized using the following intervals: 
 
• 
0 < Duration ≤4 weeks 
• 
4 < Duration ≤12 weeks 
• 
12 < Duration ≤24 weeks 
• 
24 < Duration ≤48 weeks 
• 
48 < Duration ≤72 weeks 
• 
72 < Duration <96 weeks 
• 
Duration ≥96 weeks. 
 
Treatment compliance 
 
Treatment compliance for ublituximab/ IV placebo is summarized as the total number of 
infusions received over the 5 expected infusions. Each infusion must be greater than 50% 
complete. 
Furthermore, the overall number of infusions, number and percentage (based on all infusions) 
of infusions completed with/without interruption and infusions not completed will be 
calculated per arm. 
The number and percentage of patients (based on all patients with at least one infusion) with 
and without any infusion complication (interruption or stop) per arm will be presented as well. 


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The percentage of planned total infusion received will also be calculated. 
 
Treatment compliance for teriflunomide/oral placebo is summarized as the percentage of 
actual drug taken over the exposure duration. It is calculated according to the following 
formula: 
 
Treatment compliance =100% x (total number tablets taken) / oral treatment exposure duration 
(days). 
 
2.1.3   
Efficacy Variables  
 
Evaluation schedule for efficacy variables are presented in TG1101-RMS302 protocol.  
 
Baseline is defined as the last non-missing value on or before the date of randomization. For subjects 
who have no value on or before randomization date, the last non-missing value on or before the date 
of first dose will be used as baseline. Baseline MRIs delayed due to scheduling problems or 
re-testing, a window of up to 30 days will be allowed for use of the baseline MRI value. 
 
2.1.3.1  
Primary Efficacy Variable 
 
The primary efficacy variable (per patient) is the number of IRAP-confirmed relapses (recorded in 
the eCRF as “Was the relapse adjudicated as protocol defined relapse by IRAP?”=Yes) which started 
(Start Date of Suspected Relapse Symptoms) on or after the day of randomization and up to the day 
of last study treatment. If the exact start date of relapse symptoms is unknown, the relapse will be 
assumed to have started during this period unless sufficient information is available to conclude that 
the symptoms started before or after (e.g. in case of missing start day, the symptoms start month is 
after the month of treatment end). 
 
Annualized Relapse Rate will be summarized within treatment group as the ratio of the sum of all 
patients’ relapse counts divided by the sum of all patients’ treatment duration (in years). Years under 
treatment will be derived as: 
 
Treatment years = (date of last treatment intake (oral or IV) – date of randomization + 1) / 365.25. 
 
The statistical testing approach is described in section 2.4.3.1. 
 
Please see below for the assessment process of suspected relapses.  
 
MS Relapses During the Study 
Subjects enrolled into the study will be closely monitored through the study course by the Site and 
Sponsor’s personnel as well as by an external Independent Data Safety Monitoring Board (DSMB) to 
ensure subjects’ welfare. 
 
Relapses that occur after study drugs are withdrawn will be assessed over the remainder of the study 
period and this data will be utilized as part of additional sensitivity analysis (described in the statistical 
plan) as long as the subject has not withdrawn their consent to be in the trial.  
 


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The confirmation of a relapse will be determined by the Independent Relapse Adjudication 
Committee (IRAP). The steps for confirming a relapse are as follows: 
 
1. Subject Reported Relapse  
Subjects who experience new or worsening neurologic symptoms are instructed to contact the 
Treating Neurologist within 48 hours of symptom onset. All new or worsening neurological events, 
reported at a visit or over the phone, consistent with MS representing a clinical relapse as assessed by 
the subject will be initially reported to the Treating Neurologist. In parallel, the Examining 
Neurologist will also be notified to perform additional assessments. Upon the notification to the 
Treating Neurologist; the time and date of suspected subject reported relapse will be documented in 
the dedicated page eCRF (subject reported) by the Treating Neurologist or designee. 
 
The following should be recorded in the eCRF (subject reported) by the Treating Neurologist or 
designee: 
• Date and time of symptom onset as reported by the subject  
• Symptoms and events reported by the subject (both neurological and non-neurological) 
• Date of initial contact by subject 
• Time of initial contact by subject 
 
Within 7 days of the subject reporting the suspected relapse to the Treating Neurologist, the subject 
will be scheduled and assessed by both the Treating and Examining Neurologist independently.  
 
2. Initial Assessment of Relapse by Treating Neurologist and Examining Neurologist 
 
The Treating Neurologist will perform a neurological and physical examination and safety 
assessment. The Treating Neurologist or designee will document in the eCRF the following:  
• Time and date of neurological and physical examination 
• Clinical findings of neurological and physical examination 
• Review of previously documented concomitant medications and medical history 
• Safety assessment, including vital signs, CBC, B-cell count, lymphocyte counts, fibrinogen, 
quantitative immunoglobulin  
 
Subjects with suspected clinical relapses reported to the Treating Neurologist or designee will be 
referred to the blinded Examining Neurologist who will use Neurostatus to assess the EDSS 
independently of the Treating Neurologist.   
 
The Examining Neurologist or designee will document in the eCRF the following: 
• Date and time of assessment 
• EDSS score  
• FS Scores 
 
In addition, subjects may not begin IV methylprednisolone (IVMP) treatment of a relapse until the 
Examining Neurologist has completed his/her examination.  
 
Treatment of relapses may proceed at the discretion of the Treating Neurologist only after the 
Examining Neurologist has completed his/her exam. The Treating Neurologist will not know 
the results of the EDSS assessment. When making determination to treat a potential acute relapse 


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the Treating Neurologist can use IVMP (1.0 g/day for at least 3 days and can be extended to 5 days) 
and will not affect the subject eligibility to continue in the study.   
 
The findings from either the Treating Neurologist and Examining Neurologist will not be shared. The 
Examining Neurologist must be blinded to the Treating Neurologist’s assessment and vice versa. 
 
Following the completion of assessments by the Treating and Examining Neurologists these results 
will be sent independently to the IRAP.  
 
3. Confirmation of Relapse by IRAP 
All assessments entered into the eCRF from both the Treating Neurologist and the blinded Examining 
Neurologist, will be sent to an IRAP. The IRAP adjudicates each case based on all available data 
provided for that case and members are not permitted to contact the site or the sponsor for additional 
information. The IRAP will, in turn, make the final determination of whether the neurological events 
meet the criteria for a protocol-defined relapse. 
 
Each episode of relapse must be confirmed by the IRAP, based on the neurological assessments 
performed by the Treating and/or Examining Neurologist independently by documenting either of the 
following: 
 
• ≥ 2 points increase on one of the appropriate FS or 1 point on two or more of the appropriate 
FS.  The change must affect the selected FS (i.e., pyramidal, ambulation, cerebellar, brainstem, 
sensory or visual).   Note, the change in FS scores should correspond to the patient’s symptoms 
(e.g., patient reported change in visual acuity should correspond to a change in the vision FS 
score). Episodic spasm, sexual dysfunction, fatigue, mood change or ladder or bowel urgency 
or incontinence will not suffice to establish a relapse; 
• An increase of ≥0.5 points in the EDSS score (unless EDSS score = 0, then an increase of at 
least 1.0 points is required) from the previous clinically stable assessment. 
 
MS relapses are defined as a new or worsening neurological symptoms lasting ≥24 hours with the 
absence of fever, injury, infection or adverse reactions to medications and accompanied by new 
neurological findings upon examination by the Examining Neurologist. The symptoms are attributed 
to MS and are preceded by 30 days of stability or improvement in neurological state. The change in 
EDSS score as assessed by the Examining Neurologist is ≥ 0.5 increase or ≥ 2 points increase on one 
of the appropriate FS or 1 point on two or more of the appropriate FS.  The change must affect the 
selected FS (i.e. pyramidal, ambulation, cerebellar, brainstem, sensory or visual).   Note, the change 
in FS scale scores should correspond to the patient’s symptoms (e.g., patient reported change in visual 
acuity should correspond to a change in the vision FS score). Episodic spasm, sexual dysfunction, 
fatigue, mood change or ladder or bowel urgency or incontinence will not suffice to establish a 
relapse.  Please note: sexual dysfunction and fatigue will not be scored.  If the symptoms occur less 
than 30 days following the onset of a protocol defined relapse, it should be considered part of the 
same relapse and would not be treated with IVMP within the protocol. New or recurrent neurologic 
symptoms that evolve gradually over months should be considered disability progression, not an acute 
relapse and should not be treated with steroids.  
 




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1. 
Change in MSFC score from baseline to Week 96 
2. 
Time to Confirmed Disability Progression (CDP) for at least 24 weeks 
3. 
Time to Confirmed Disability Improvement (CDI) for at least 12 weeks 
4. 
Time to Confirmed Disability Improvement (CDI) for at least 24 weeks 
5. 
Health outcomes (MSQoL-54 (inclusive of SF36); FIS, hospitalization, steroid use, time 
out of work) 
6. 
Total volume of Gd enhancing T1 lesions per MRI scan over the treatment period 
7. 
Volume of T2 lesions  
8. 
Volume of hypointense T1 lesion component (black holes) 
9. 
Proportion of subjects free of disability progression at 24 weeks, 48 weeks, and 96 weeks 
10. 
The Proportion of subjects with a relapse 
11. 
Time to first confirmed relapse 
 
 
2.1.4   
Safety Variables 
 
The safety analysis will be based on the reported AEs and other safety information, such as clinical 
laboratory data, electrocardiogram (ECG), physical examination, and vital signs.  
Baseline for non-efficacy variables is defined as last non-missing value before the first dose of study 
medication (teriflunomide/IV placebo or ublituximab/oral placebo). If the time of first dose intake 
or safety variables is missing and only date part is present, then the baseline will be the last non-
missing value on or before the date of first dose date, unless the safety variable value is collected 
clearly after the administration of first dose. 
 
2.1.4.1  
Adverse Events 
 
Adverse events will be coded and classified according to the System Organ Class (SOC) and Preferred 
Term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA). 
The occurrence of AEs (including SAEs and adverse events of special interest [AESIs]) will be 
captured from the time the informed consent is obtained until the participant terminates participation 
in the study.  
AESI will be categorized using a grouped set of MedDRA terms based on Standardized MedDRA 
Queries (SMQs) and clinical concept, as determined by the Sponsor prior to database lock. The 
MedDRA terms selected for AESI analysis will be provided in the Clinical Study Report (CSR). 
Suicidal ideation and behavior will be identified by the AE preferred terms included in MedDRA SMQ 
“Suicide/self-injury”. SMQ version 20 includes the following preferred terms: Assisted suicide, 
Columbia suicide severity rating scale abnormal, Completed suicide, Depression suicidal, Intentional 
overdose, Intentional self-injury, Poisoning deliberate, Self-injurious ideation, Suicidal behavior, 
Suicidal ideation, Suicide attempt, Suicide threat.  
 




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• Heart Rate (beats/min) 
• Weight (kg) 
• Body Temperature (All results will be converted to Celsius) 
 
2.1.4.4  
Physical Examination 
 
Physical examination is assessed per visit and body system, with possible outcomes normal and 
abnormal (plus free text for specification if abnormal).  
 
2.1.4.5  
ECG 
ECG interpretation (normal/abnormal) will be collected by visit and - where applicable - time point 
(pre-/post-dose). 
 
2.1.5   
Pharmacokinetic Variables 
 
To characterize population PK of ublituximab, serum samples will be drawn from all subjects pre-
infusion any time on infusion days of ublituximab or IV placebo and at approximately 30 minutes 
+/- 15 minutes post infusion on infusion days (Week 1 Day 1, Week 3 Day 15, Weeks 24, 48, and 
72). One additional serum sample will be taken on Week 96. 
 
 
 
  
 
  
2.1.6   
Other Variables 
• Immunogenicity-absence or presence of ADA to ublituximab (Anti-Drug Antibody; ADA) 
• Pharmacodynamic parameter (% CD19+ B cells) 
2.2  Analysis Populations 
 
Randomized subjects are all subjects allocated based on the randomization process and recorded in 
the database.  Subjects will be randomly assigned in a 1:1 ratio to either active teriflunomide or active 
ublituximab. Randomization will be generated by the IWRS.  
 
 
2.2.1   
Safety Population 
 
The Safety Population will include all subjects who receive at least one dose of study drug 
(ublituximab or teriflunomide, with corresponding placebos). All safety assessments including 
toxicity and anti-drug antibodies will be performed on the Safety Population by the first treatment 
actually received.  


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2.2.2   
Intention-to-Treat (ITT) 
 
The Intention-to-Treat (ITT) population will consist of all randomized subjects. Subjects will be 
analyzed by randomized treatment group. Sensitivity analyses of key efficacy endpoints will be 
performed based on ITT population.  
 
2.2.3   
Modified Intention-to-Treat (mITT) Population 
 
The modified Intention-to-Treat (mITT) population will consist of all subjects in the ITT population 
who received at least one dose of study medication and have at least one baseline and post baseline 
efficacy assessment. The primary efficacy analyses (of primary, secondary and tertiary efficacy 
endpoints, except MRI related) will be performed based on the mITT population. 
The MRI related efficacy analyses will be performed on the subjects in mITT population who have 
baseline and post-baseline MRI efficacy assessments (mITT-MRI).  
Subjects will be analyzed by randomized treatment group.  
2.2.4   
Per-Protocol (PP) Population 
 
The Per-Protocol (PP) population will consist of all subject in the mITT group who were treated 
for at least 1.75 years and do not have a major protocol deviation that might impact efficacy 
analysis. The PP population will only be used for sensitivity analysis of the primary efficacy and 
key secondary variables. Subjects will be analyzed by randomized treatment group.   
 
MRI related efficacy analyses will be repeated on the subjects in the PP population who have baseline 
and post-baseline MRI efficacy assessments (PP-MRI).  
 
All reported protocol deviations will be reviewed and assessed for their potential impact on the 
efficacy analyses before database lock and unblinding. Subjects with one or more major protocol 
deviation that might impact the efficacy analysis will be excluded from the per-protocol 
population.  Details will also be given in the protocol deviation plan. 
 
Major efficacy-related protocol deviations include, but not limited to, the following:   
• EDSS score >5.5 at screening 
• Subjects with less than 2 clinical relapses in the last 2 years and less than 1 clinical 
relapse in last 1 year prior to screening and no Gd-enhancing lesion in the screening MRI 
• Subject randomized more than once 
• Compliance <80% (see Section 2.4.2) 
• Subjects taking prohibited medication which are approved disease modified MS drugs 
during the study 
• Non-randomized subject received double-blind study medication 
• Screen failure subject randomized 




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All statistical analyses will be performed at the 2-sided 0.05 level of significance, except as otherwise 
noted.  
2.4.1 Demographics and Baseline Characteristics 
 
Continuous data will be summarized using number with available data: mean, standard deviation 
(SD), median, minimum, and maximum, and 1st and 3rd quartile for each treatment group. 
Categorical or ordinal data will be summarized using the number and percentage of subjects within 
each treatment group. Summaries will be presented for the ITT, mITT and Safety population. 
 
Demographics and Baseline Characteristics  
 
Demographic and baseline characteristics as described in Section 2.1.1 will be summarized by 
treatment group and overall using descriptive statistics. 
 
 
Medical and surgical history 
 
Medical history and concurrent medical conditions (ongoing at screening) will be summarized by 
primary system organ class (SOC) and preferred term for each treatment group. The table will be 
sorted alphabetically by SOC and by decreasing frequency in the ublituximab column.  
 
 
Prior/concomitant/follow-up medications 
 
The prior, concomitant and follow-up medications will be presented on the safety population. 
 
Medications will be summarized by treatment group, according to the international classification 
of medicines (WHO-DD dictionary), using the terms corresponding to the ATC class level 4 and 
Preferred Name. All ATC codes corresponding to a medication will be summarized. Subjects will 
be counted once in each ATC categories (anatomic or therapeutic) linked to the medication.  
 
The tables for prior, concomitant and follow-up medications will be sorted by decreasing frequency 
of anatomic category followed by all other therapeutic classes based on the incidence in the 
Ublituximab group. In case of equal frequency regarding anatomic categories or therapeutic 
categories, alphabetical order will be used. 
 
In addition, number and percentage of confirmed relapses requiring steroid treatment will be 
presented. 
 
Previous MS treatment 
 
Variables related to previous MS treatment will be summarized per treatment group.  
 
No statistical tests will be performed on demographic and baseline characteristic data. 
2.4.2 Primary Efficacy Variable 
 
Main statistical model and adjustment for covariates 
 




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Subgroup analyses will be performed for the primary efficacy variable by: 
 
• Gender 
 
• Race 
 
• Age category (<38, ≥38) 
 
o Age of 38 is expected to be close to the median age of all randomized subjects 
 
• Regions as defined in 2.1.1 
 
• Baseline EDSS strata (<3.5, ≥3.5) 
 
• Number of relapses experienced in the 2 years prior to study start (≤1, 2, 3, and ≥4) 
 
• Received approved disease modifying MS drug prior to enrollment (Yes, No) 
 
• Number of baseline Gd-enhancing lesions (0, ≥1) 
 
The GEE method will be used to assess consistency of treatment effects across the subgroup levels, 
utilizing a treatment-by-subgroup interactions test at significance level of 0.05, and forest plots of the 
group comparisons of ARR and their confidence intervals. Each subgroup factor will be assessed 
separately. The model will include treatment, EDSS strata, region, subgroup, and treatment-by-
subgroup interaction as fixed effects, log-transformed standardized treatment duration as an offset 
variable. In addition, summary statistics of relapse rates will be provided for each subgroup, based 
on the model for each subgroup, including treatment, EDSS strata and region as covariates. 
 
Sensitivity Analysis 
1. The primary analysis will be repeated based on all reported MS relapses (rather than just confirmed 
ones). 
2. A time to relapses analysis using Cox proportional hazards model with first IRAP-confirmed 
relapse as the primary event will be conducted to compare with the primary analysis in a negative 
binomial model. The Cox proportional hazards model will be specified with treatment, region, number 
of relapses in previous year, baseline EDSS score strata (<3.5, ≥3.5), baseline number of T1 Gd-
enhancing lesions, sex, and the subject’s age at baseline as covariates. 
3. To assess the effects of treatment withdrawals, the primary analysis will be repeated using the 
information on relapses which occur during the period following drug withdrawal to the end of the 
study period regardless of whether additional treatment were utilized. Relapses which occurred after 
permanent discontinuation of study medication will be included and natural log (time on study in 
years) rather than the natural log (time on study drug in years) will be used as the offset variable in 
the negative binomial model, which is the primary analysis. 
4. We will examine the dropouts from the trial using all participants who provided withdrawal of 
consent excluding deaths. Multiple imputation will be used to impute the expected number of relapses 
a participant would have had if they had continued to participate in the trial. To perform the imputation, 
10 replicates will be used since a relapse on treatment is relatively low frequency event. The covariates 
used to model and predict the imputations will include: treatment, region, number of relapses in 
previous year, baseline EDSS score strata (<3.5, ≥3.5), baseline number of T1 Gd-enhancing lesions, 
sex and the subject’s age at baseline as covariates. 


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5. For secondary outcomes T1 Gd enhancing, T2 NELs, and 12 week CDP, the effects of dropouts 
and study discontinuations will be similarly evaluated as number 4 above. 
6. Additional sensitivity analyses may be conducted as needed  
 
 
 2.4.3   
Secondary Endpoints 
 
2.4.3.1 Statistical testing Strategy 
 
Once the null hypothesis of the primary analysis has been rejected, the key secondary outcomes will 
be tested using a hierarchical approach with the order specified below using a step-down procedure 
where each test is at a Type I error 0.05. If any endpoint fails to reach significance, then formal testing 
of significance of the subsequent secondary outcomes will not be performed. All p-values will be 
reported and will be interpreted as either confirmatory or non-confirmatory (i.e., descriptive only).  
 
1. Total number of gadolinium enhancing (Gd-enhancing) T1-lesions per MRI scan by Week 96.     
2. Total number of new and enlarging T2 hyperintense lesions (NELs) per MRI scan by Week 
96  
3. Time to confirmed disability progression (CDP) for at least 12 weeks occurring during the 96-
week, double-blind, treatment period (pooled analysis with Study TG1101-RMS302). * 
4. Proportion of subjects with no evidence of disease activity (NEDA) from Week 24 to Week 
96.   
5. Proportion of subjects reaching impaired SDMT (Symbol Digit Modalities Test) from baseline 
to Week 96.   
6. Percentage change in Brain Volume from baseline to Week 96. 
 
* Confirmed Disability Progression for at least 12 weeks during the 96-week treatment period will be analyzed 
using pooled data from the two identical studies TG1101-RMS301 and TG1101-RMS302. 
For all tests other than #3 (12-week CDP), the testing will be based on Study ULTIMATE II 
individually, at alpha=0.05.   
For #3, 12-week CDP endpoint, the testing will be based on pooled data from both Studies 
ULTIMATE I and ULTIMATE II achieve sufficient statistical power to detect relevant treatment 
differences. Therefore, this test will not be performed until data from both studies are available. 
Specifically, this test is considered confirmatory only if all tests for the primary endpoint and all 
secondary endpoints before this test (i.e. #1 & #2) are statistically significant at alpha=0.05 level in 
both studies. Once this test is statistically significant, all subsequent tests (#4-6) will continue at 
alpha=0.05 level within each individual study.  
The statistical testing sequence is illustrated below. 




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Gad Enhancing Lesion Volume 
X 
  
X 
X 
X 
X 
 
The analysis endpoints will be derived as follows: 
Protocol endpoint 
MRI test result to be used 
Derivation 
total number of gadolinium 
enhancing (Gd-enhancing) 
T1-lesions per MRI scan by 
Week 96 
Gad Enhancing Lesion Count 
(GADCNT) 
  
[GADCNT(w12)+GADCNT(w24)+GADCNT(w48)+GADCNT(w96)]/[number 
of MRIs available (w12/w24/w48/w96)] 
Note: the division by the number of MRIs will be accomplished by an offset in 
the negative binomial regression 
Total number of new and 
enlarging T2 hyperintense 
lesions (NELs) per MRI scan 
by Week 96 
New Enlarging T2 Lesion 
Count (NEWT2CNT) 
[NEWT2CNT(w24)+ NEWT2CNT(w48)+ NEWT2CNT(w96)]/ [number of 
MRIs available (w24/w48/w96)] 
Note: the division by the number of MRIs will be accomplished by an offset in 
the negative binomial regression 
Volume of hypointense T1 
lesion component (black 
holes) 
T1 Unenhancing Lesion 
Volume (T1UNVOL) 
 T1UNVOL (w24) , T1UNVOL (w48) ,T1UNVOL (w96)  
Volume of T2 lesion 
T2 Lesion Volume (T2VOL) 
T2VOL(w24), T2VOL(w48),T2VOL(w96) 
MRI part of NEDA 
definition (no T1 Gd+ 
lesions and no new/enlarging 
T2 lesions) 
Gad Enhancing Lesion Count 
(GADCNT), 
New Enlarging T2 Lesion 
Count (NEWT2CNT) 
All values , GADCNT(w24), GADCNT(w48), GADCNT(w96), 
NEWT2CNT(w24), NEWT2CNT(w48), NEWT2CNT(w96) need to be zero 
Percent change in brain 
volume as detected by MRI 
compare to baseline 
 
Brain Volume (BV) 
(BV(w24) – NBV(baseline))/NBV(baseline)*100 
(BV(w48) – NBV(baseline))/NBV(baseline)*100 
(BV(w96) – NBV(baseline))/NBV(baseline)*100 
Total volume of 
Gd-enhancing T1 lesions per 
MRI scan over the treatment 
period 
Gad Enhancing Lesion 
Volume (GADVOL) 
[Sum of all post-baseline GADVOL(w24/w48/w96)] / [number of MRIs 
available (w24/w48/w96)] 
 
MRI data will only be used for analysis if not rejected or invalid, e.g. due to change of scanner, 
indicated as comments from the central lab. 
MRIs will also be excluded from analysis if corticosteroids (ATC level 2 = “CORTICOSTEROIDS 
FOR SYSTEMIC USE”) were dosed within 30 days prior to the scan. 
The MRI count variables (Total Number of gadolinium enhancing (Gd-enhancing) T1-lesions per 
MRI scan at Weeks 12 (where applicable), 24, 48, and 96, Total number of new and enlarging T2 
hyperintense lesions (NELs) per MRI scan at Weeks 24, 48, and 96) will be assessed for differences 
between the treatment groups using negative binomial regression with an offset based on the log-
transformed number of post-baseline MRI scans and covariates region, baseline EDSS strata, and 
corresponding baseline lesion count.  
 
For analysis of percent brain volume change from baseline, a Mixed Model Repeated Measures 
(MMRM) analysis will be implemented via 
 by fitting percent change from 
baseline values on the cube root transformed volume from all visits after baseline  in the treatment 
period with scheduled assessments of brain volume. The models will include factors (fixed effects) 
for treatment, region, baseline EDSS strata, visit, treatment-by-visit interaction, and baseline value of 


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the brain volume (cubic root transformed). The factor, visit, with nominal visits to avoid undue 
reliance on a linear in time effect will have 3 levels (Week 24, Week 48 and Week 96). An 
unstructured correlation matrix will be used to model the within-patient errors. Parameters will be 
estimated using restricted maximum likelihood method with the Newton-Raphson algorithm. 
Denominator degrees of freedom will be estimated using Satterthwaite’s approximation.  
2.4.3.3 NEDA 
The proportion of subjects with no evidence of disease activity (NEDA) will be calculated at Week 
96. A subject with NEDA is defined as a subject without evidence of disease activity, which is defined 
as a subject without relapses confirmed by the IRAP, without MRI activities (no T1 Gd+ lesions and 
no new/enlarging T2 lesions), and no 12-week Confirmed Disability Progression.  
 
1. Any evidence of disease activity from Week 24 to Week 96 will be counted as not reaching 
NEDA.  Any evidence of disease activity before Week 24 will not count. 
2. In the case of early termination at any time point (including before Week 24), even if an 
event was not reported before early discontinuation, the subject will be considered as not 
reaching NEDA. 
  
NEDA rates will be compared using logistic regression 
 with baseline 
adjustments the same as used in the primary endpoint analysis, without treatment duration offset, but 
including log-transformed baseline MRI counts (T1 unenhancing, T2, Gad enhancing).  
To avoid zero values for the log transformation of MRI counts, 1 will be added to each observation 
before transforming. 
 
2.4.3.4 SDMT 
The total score at one visit is defined as the total number of correct answers reported in the CRF.  
Impaired SDMT is defined as a decrease from baseline of at least four points at any post-baseline 
SDMT assessment up to the Week 96 visit.  The proportion of impaired SDMT will be analyzed in 
all subjects within the modified intention to treat (mITT) population. 
SDMT rates will be compared using logistic regression 
 with baseline 
adjustments the same as used in the primary endpoint analysis, without treatment duration offset, but 
including log-transformed baseline MRI counts (T1 unenhancing, T2, Gad enhancing).  To avoid zero 
values for the log transformation of MRI counts, 1 will be added to each observation before 
transforming 
. 
2.4.3.5 EDSS/Disability 
12 week Confirmed Disability Progression (CDP) is defined as an increase in EDSS 
• at least 1 point higher than the baseline EDSS if the baseline EDSS is ≤5.5 
• at least 0.5 higher than the baseline EDSS if the baseline EDSS is >5.5 
Disability progression is considered confirmed (CDP) when the increase in the EDSS is confirmed 
(same criteria) at a regularly scheduled visit 12 weeks after the initial documentation of neurological 
worsening  (does not include unscheduled visits). 
 


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The time to onset of 12 week confirmed disability progression (CDP) will be the time to progression 
to the EDSS change defined above. For each of these events, the time from randomization to the date 
of the first measurement of the increased EDSS as required is the “time to event”. If no event occurs, 
the time to CDP is regarded as censored at the last scheduled EDSS assessment. Summary tables of 
progression to CDP will present the proportion of subjects who suffered CDP during the study at 2 
years and associated 95% CIs for each treatment group. The median time-to-event with 2-sided 95% 
CIs as well as the proportion of subjects remaining event-free at times of interest will be estimated 
using Kaplan-Meier methods implemented with 
. The proportion of subjects 
with 12-week confirmed disability progression will be summarized. 
EDSS results will be summarized as continuous and categorical variables by scheduled assessment 
time point and treatment group. All data collected for assessment of EDSS will be listed.  
 
 
 
 
2.4.4    
Tertiary Endpoints 
 
All tertiary analyses will be assessed at a Type I error of 0.05 with no adjustment for 
multiplicity
.  
1. Change in MSFC score from baseline to Week 96 
2. Time to Confirmed Disability Progression (CDP) for at least 24 weeks 
3. Time to Confirmed Disability Improvement (CDI) for at least 12 weeks 
4. Time to Confirmed Disability Improvement (CDI) for at least 24 weeks 
5. Health outcomes (MSQoL-54 (inclusive of SF36); FIS, hospitalization, steroid use, time out of 
work) 
6. Total volume of Gd enhancing T1 lesions per MRI scan over the treatment period 
7. Volume of T2 lesions  
8. Volume of hypointense T1 lesion component (black holes) 
9. Proportion of subjects free of disability progression at 24 weeks, 48 weeks, and 96 weeks  
10. Proportion of subjects with a relapse 
11. Time to first confirmed relapse 
 
 
2.4.4.1 MSFC 
Items collected per visit 
 
 
 
Timed 25-Foot Walk 
Time for Trial 1 (sec) 
TW1(visit) 
 
Time for Trial 2 (sec) 
TW2(visit) 
9-Hole Peg Test 
Dominant Hand: Time for Trial 1 (sec) 
PTD1(visit) 
 
Dominant Hand: Time for Trial 2 (sec) 
PTD2(visit) 
 
Non-Dominant Hand: Time for Trial 1 (sec) 
PTN1(visit) 
 
Non-Dominant Hand: Time for Trial 2 (sec) 
PTN2(visit) 
PASAT 3 seconds 
PASAT 3'' Total Score 
PAS(visit) 
 
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Average 25-Foot Walk 
(summarizing the two 
trials of one assessment) 
TW(visit) = Mean(TW1(visit), 
TW2(visit)) 
If one of the two (TW1, TW2) 
is missing at a visit, use the 
available value for TW 
If both are missing, use 
instructions in the next row.  
Z-score leg 
Zleg,average(visit) = - (TW(visit) – 
mean(TW(baseline, all subjects in 
analysis population))/SD(TW(baseline, 
all subjects in the analysis population))) 
Note: The leftmost minus sign 
is intended to assign the same 
direction (higher=better) as for 
PASAT 
If subject’s input TW(visit) is 
not available, the Z-score is set 
to -13.7. 
Average 9-Hole Peg Test 
(summarizing the 4 trials 
– two of each hand) 
PT(visit) =  
mean( (1/mean(PTD1(visit), 
PTD2(visit)), 1/mean(PTN1(visit), 
PTN2(visit)) ) 
Note: means are inverted to 
assign the same direction 
(higher=better) as for PASAT. 
If one of the two (PTx1, PTx2) 
is missing at a visit, use the 
available value. 
If both are missing for a hand, 
use 777 for this hand. 
Z-score arm 
Zarm,average(visit) = (PT(visit) – 
mean(PT(baseline, all subjects in 
analysis population))/SD(PT(baseline, all 
subject in analysis population))) 
 
Z-score cognitive 
Zcognitive = (PAS(visit) – 
mean(PAS(baseline, all subjects in 
analysis population)))/SD(PAS(baseline, 
all subjects in analysis population)) 
 
MSFC score 
MSFC(visit) = Zleg,average(visit) + 
Zarm,average(visit) + Zcognitive 
 
 
Change in MSFC will be tested using linear Mixed Models including all scheduled assessment time 
points with baseline as a covariate along with the other covariates as used in the primary analysis. 
2.4.4.2 Disability endpoints 
24 week Confirmed Disability Progression (24 Week CDP) is defined as an increase of ≥ 1.0 point from the 
baseline EDSS score that is not attributable to another etiology (e.g., fever, concurrent illness, or concomitant 
medication – this information will be reflected in the assessments documented by the investigator. In the 
statistical analysis no further checks are necessary.) when the baseline score is 5.5 or less, and ≥ 0.5 when the 
baseline score is above 5.5.  Disability progression is considered confirmed when the increase in the EDSS 
is confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological 
worsening. 
12 Week Confirmed Disability Improvement (12 Week CDI) is defined as a reduction from the baseline 
EDSS score of at least 1.0 point (or 0.5 points if the baseline EDSS score was >5.5) that was sustained and 
confirmed at the next scheduled visit at least 12 weeks after the initial documentation of neurological 
improvement. Similarly, 24-week Confirmed Disability Improvement (24 Week CDI) requires an initial 
reduction from baseline EDSS score and a subsequent confirmation of the reduction at all regular scheduled 
visits for at least 24 Weeks after the initial documentation of neurological worsening. 


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The analysis of the time to 24-week CDP and CDI at 12 and 24 weeks will utilize the same approach 
as that used for 12-week CDP (including subject proportions). 
2.4.4.3 Fatigue Impact Scale 
The FIS is composed of 40 items that assess the individual’s attribution of functional limitations to 
their subjective experience of fatigue in 3 dimensions. 
• 0 - “No problem” 
• 1 - “Small problem” 
• 2 - “Moderate problem” 
• 3 - “Big problem” 
• 4 - “Extreme problem” 
(Lower score = Less fatigue impact) 
Cognitive Dimension Score = sum of items 1; 5; 6; 11; 18; 21; 26; 30; 34; 35 
Physical Dimension Score = sum of items 10; 13; 14; 17; 23; 24; 31; 32; 37; 38 
Social Dimension Score = sum of items 2; 3; 4; 7; 8; 9, 12; 15; 16, 19; 20; 22; 25; 27; 28; 29; 33; 
36; 39; 40 
Total Score = sum of all items (1-40) 
 
If up to four items are missing within one questionnaire, these items will be imputed with the median 
of the available observations of the same questionnaire for the Total Score derivation. If more than 
four items are missing, the Total Score will be regarded as missing. The dimension scores will only 
be calculated if all included items are available. 
Change in FIS will be tested using linear Mixed Models including all scheduled assessment time 
points with baseline as a covariate along with the other covariates as used in the primary analysis 
 
2.4.4.4 MSQOL-54 
The available software will be used to summarize the questionnaire data. In a first step, SDTM 
datasets containing response items will be transformed into a file format appropriate to input to the 
scoring software. The output data of the scoring software will be transformed into ADaM format for 
statistical analysis. 
Change in MSQoL-54 will be tested using linear Mixed Models including all scheduled assessment 
time points with baseline as a covariate along with the other covariates as used in the primary analysis 
 
2.4.4.5 Time out of work 
Diaries will be summarized for periods of approximately 48 weeks and the overall treatment period, 
calculating, per period: 
• Sum of hours worked (not tabulated) 




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(black holes)) Mixed Model Repeated Measures (MMRM) analyses will be implemented via 
 
 
For every valid MRI, cubic root transformed volumes will be used for analysis. For each time point, 
the sum of these values for all scheduled post-baseline MRIs, divided by the number of MRIs 
contributing to this sum will be used as the analysis value. Change from baseline in these cubic root 
transformed, cumulative values will be analyzed. The descriptive analysis will use the untransformed 
data. 
The models will include factors (fixed effects) for treatment, region, baseline EDSS strata, visit, 
treatment-by-visit interaction, and baseline value (cubic root transformed). The factor, visit, with 
nominal visits to avoid undue reliance on a linear in time effect will have 3/4 levels (Week 12 – where 
applicable - , Week 24, Week 48, and Week 96). An unstructured correlation matrix will be used to 
model the within-patient errors. Parameters will be estimated using restricted maximum likelihood 
method with the Newton-Raphson algorithm. Denominator degrees of freedom will be estimated 
using Satterthwaite’s approximation.  
Time to first confirmed relapse is defined as (date of relapse onset – date of randomization + 1) and 
will be regarded as censored at the end of treatment. The analysis will be similar to the one of time to 
confirmed disability progression. The Nelson–Aalen estimator is a non-parametric estimator of the 
cumulative hazard rate function in case of censored data or incomplete data and will be provided for 
descriptive purposes. 
 
The proportions of subjects with a relapse and subjects free of disability progression at different time points 
will be estimated using the Kaplan-Meier method. 
2.4.5 Analyses of Safety Data 
 
Safety results will be summarized and presented by treatment group. 
 
Observation period 
 
The observation period is defined as the time from first dose of study medication up to 20 weeks 
after the last dose of study medication or until the final subject completes the Week 96 assessment. 
 
General common rules 
 
All safety analyses will be performed on the Safety Population as defined in Section 2.2.1, unless 
otherwise specified, using the following common rules: 
 
1. For quantitative safety parameters based on central laboratory/ reading measurements, visit and 
treatment group will use descriptive statistics to summarize results and change from baseline 
values. Summaries will include the value and/or the worst value of the observation period.  
 
2. All of the values including unscheduled measurements will be assigned to the appropriate safety 
analysis visit window. The safety analysis visit window is defined in Section 2.5.2. In the 
presence of multiple measurements of the same test in the same window, the one closest to the 
targeted visit date will be used for the by-visit summaries. 
 


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3. The analysis of the safety variables will in general be descriptive and no systematic statistical 
testing is planned.  
 
2.4.5.1  
Analysis of Adverse Events 
 
Adverse event classification: 
 
1. Pre-existing AEs are defined as adverse events that started prior to treatment start and are 
ongoing at the time of treatment start. After treatment start, if these adverse events worsened 
during the treatment period these will be considered as treatment-emergent adverse events 
(TEAEs). 
 
2. TEAEs are defined as AEs with an onset on, or after the first dose of study medication and 
through 30 days after the last dose of study medication or with an onset prior to the first dose of 
study medication that increases in severity on, or after the first dose of study medication and 
through 30 days after the last dose of study medication.  
 
3. Post-treatment AEs are defined as AEs that developed or worsened during the post treatment 
period after stopping study medication. As an example, AEs occurring during the 20-week 
follow-up involving rapid teriflunomide/oral placebo elimination would be considered a 
post-treatment AE.  
 
Data will be analyzed as available in the database as not all subjects are expected to be followed 
up for the full period e.g. due to switch to the open-label extension. 
Adverse event incidence tables will be presented by treatment group, the number (n) and 
percentage (%) of subjects experiencing an AE. The incidence of events will be presented: A 
subject will only be counted once in the tables within a treatment phase. In a subset of tables, also 
all occurrences will be counted providing a severity of occurrence of the AE. The denominator 
for computation of percentages is the Safety Population within each treatment group. 
 
Not treatment emergent AE(s) summary: 
• 
Listing of (not treatment emergent) AEs showing treatment group, subject identifier, SOC, PT, 
verbatim term, date and day of onset, end date/time, duration, outcome, severity, date of death 
(if relevant), relationship to study treatment, action taken, AE seriousness and criteria. 
 
 
TEAE(s) summaries: 
 
The following TEAE summaries will be generated for the Safety Population. 
 
Overview of TEAEs, summarizing number (%) of subjects with any 
 
- 
(related/all) TEAE  
- 
(related/all) Serious TEAE 
- 
(related/all) TEAE leading to death 
- 
(related/all) TEAE of grade 3 or higher 
- 
(related/all) TEAE leading to drug interruption 
- 
(related/all) TEAE leading to study discontinuation 
- 
(related/all) TEAE of special interest (AESI) 
- 
(related/all) TEAE leading to permanent discontinuation 
  


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• 
TEAEs by primary SOC and PT, showing number (%) of subjects with at least one TEAE, sorted 
alphabetically by SOC and decreasing incidence of PTs within SOC for the ublituximab arm. 
This sorting order will be applied to all other tables, unless otherwise specified.  
• 
TEAEs by PT, sorted by decreasing frequency in the ublituximab arm  
 
• 
Common TEAEs (incidence ≥ 2% in any treatment group for PT) by primary SOC and PT, 
showing number (%) of subjects with at least one common TEAE. 
 
• 
All at least possibly drug related (to IV and/or oral study treatment) TEAEs by primary SOC 
and PT, showing number (%) of subjects with at least one possibly related TEAE, sorted by 
sorting order defined above. 
 
• 
All TEAEs by maximal severity, presented by primary SOC and PT, showing number (%) of 
subjects with at least one TEAE by severity (ie, mild, moderate, or severe), sorted by sorting 
order defined above. 
 
• 
Listing of TEAEs showing treatment group, subject identifier, SOC, PT, verbatim term, date 
and day of onset, end date/time, duration, outcome, severity, date of death (if relevant), 
relationship to study treatment, action taken, AE seriousness and criteria. 
AESI summaries: 
• 
Treatment-emergent AESI by primary SOC and PT, showing number (%) of subjects with at least 
one TEAE, sorted alphabetically by SOC and decreasing incidence of PTs within SOC for the 
Ublituximab arm. This sorting order will be applied to all other tables, unless otherwise specified.  
 
• 
Listing of treatment-emergent AESI showing treatment group, subject identifier, SOC, PT, 
verbatim term, date and day of onset, end date/time, duration, outcome, severity, date of death 
(if relevant), relationship to study treatment, action taken, AE seriousness and criteria. 
 
Treatment-Emergent Suicidal Ideation and Behavior (SIB) 
• 
Treatment-emergent SIB events will be summarized by treatment group, showing number (%) 
of subjects with at least one TEAE of suicidal ideation and behavior, and number (%) of subjects 
for each PT.   
• 
A listing of suicidal ideations and behaviors will also be presented. 
• 
Additional SIB analyses may be conducted as needed, such as follow-up time adjusted 
incidence rates of SIB event. 
 
Serious TEAE(s) summaries: 
  
• 
All serious TEAEs by primary SOC and PT, showing number (%) of subjects with at least one 
serious TEAE, sorted by sorting order defined above. 
 
• 
All at least possibly related (to IV and/or oral study treatment) serious TEAEs by primary SOC 
and PT, showing number (%) of subjects with at least one possibly related serious TEAE, sorted 
by sorting order defined above. 
 
• 
All serious TEAEs by seriousness criteria, presented by primary SOC and PT, showing 
number (%) of subjects with at least one serious TEAE by seriousness criteria. 
 


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• 
Listings of SAEs showing treatment group, subject identifier, SOC, PT, verbatim term, date and 
day of onset, end date/time, duration, outcome, severity, date of death (if relevant), relationship 
to study treatment, action taken, AE seriousness and criteria. 
 
TEAE(s) leading to treatment discontinuation summaries: 
 
These events will be selected by the eCRF variables “Action taken with IV study treatment” and/or 
“Action taken with Oral study treatment” = “Permanently discontinued”. 
 
• 
All TEAEs leading to treatment discontinuation, by primary SOC and PT, showing number 
(%) of subjects with at least one TEAE sorted by sorting order defined above. 
• 
 
 
• 
Listings of TEAEs leading to treatment discontinuation showing treatment group, subject 
identifier, SOC, PT, verbatim term, date and day of onset, end date/time, duration, outcome, 
severity, date of death (if relevant), relationship to study treatment, action taken, AE seriousness 
and criteria. 
 
Deaths summaries: 
 
• 
Number (%) of subjects who died during the study period will be shown by treatment group.  
 
• 
Death in non-randomized subjects or randomized but not treated subjects will be listed. 
 
• 
All TEAEs leading to death, by primary SOC and PT, showing number (%) of subjects sorted 
by sorting order defined above. 
 
• 
Listings of deaths showing treatment group, subject identifier, gender, race, age, duration of 
exposure, date of death (if relevant), causes and circumstances surrounding the death 
 
2.4.5.2  Analysis of Laboratory Variables 
 
Clinical laboratory variables that will be analyzed include hematology tests, serum chemistry tests, 
pancreatic enzymes, a coagulation test, and urinalysis (see Section 2.1.4.2 for the complete list of 
parameters).  
 
Summary statistics (including mean, SD, median, Q1, Q3, minimum and maximum) of all laboratory 
variables (raw data and changes from baseline) will be calculated for each visit. Mean changes from 
baseline with the corresponding standard deviation will be plotted over time (at same time points) in 
each treatment group for selected parameters using box plots, which include hemoglobin, 
lymphocytes, neutrophils, platelets, ALT, AST, TBL, and serum creatinine (and CrCL). 
 
Subjects with laboratory values outside of the normal reference range at any post-baseline assessment 
will be summarized and graded per NCI CTCAE Version 4.03 when applicable. Subject incidence 
of laboratory toxicity will be summarized by treatment group and maximum grade for each laboratory 
test. Shift tables between baseline and worst post-baseline results will also be presented. 
 
A listing of subjects with at least one post-baseline abnormal lab test will be provided and will 
display the complete profile over time of all values of corresponding test. In this listing, baseline, 
endpoint value and individual values will be flagged when lower or higher than the lower or upper 
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Drug-Induced Liver Injury (DILI) 
 
The liver function tests, namely AST, ALT, total bilirubin (TBL), and alkaline phosphatase are 
used to assess possible drug induced liver injury. The proportion of subjects with abnormal values 
at any post-baseline visit by baseline status will be displayed by treatment group for each 
parameter. The proportion of subjects with abnormal values at any post baseline visit will also be 
displayed by duration of exposure for each treatment group. 
 
Time to onset of the initial ALT and AST elevation (>3x ULN) and total Bilirubin elevation (>2x 
ULN) will be analyzed using Kaplan-Meier estimates, presented by treatment group. Evaluations 
of drug-induced serious hepatotoxicity (eDISH) plot (Hy’s Law graphs) of distribution of peak 
values of ALT, AST and the maximum of ALT and AST versus peak values of total bilirubin will 
also be presented. Note that the ALT/AST and Total bilirubin values will be presented on a 
logarithmic scale. The eDISH plots will be divided into 4 quadrants with a vertical line 
corresponding to 3x ULN for ALT and/or AST and a horizontal line corresponding to 2x ULN for 
total bilirubin. Similarly, a graph for ALT vs. TBL and a graph for AST vs. TBL will be provided. 
 
The normalization (to ≤1 ULN) of elevated liver function tests will be summarized by categories of 
elevation (≥3x, ≥5x, ≥8x, ≥10x, ≥20x ULN for ALT, AST, ALT or AST, ≥1.5x, ≥2x ULN for 
alkaline phosphatase, and ≥1.5x, ≥2x ULN for total bilirubin), with following categories of 
normalization: not normalized, normalized after temporary discontinuation of study medications, 
normalized after permanent discontinuation of study medications. Note that a subject will be 
counted only under the maximum elevation category. 
 
2.4.5.3  Analyses of Vital Sign Variables  
 
The summary statistics (including mean, SD, median, Q1, Q3, minimum and maximum) of all 
vital signs variables (raw data and changes from baseline) will be calculated for each visit by 
treatment group and presented. Mean changes from baseline with the corresponding standard 
deviations will be plotted over time (at same time points) in each treatment group. 
 
The incidence of abnormal vital signs at any time during the observation period will be summarized 
by treatment group. A shift table from baseline to worst vital sign status during the observation 
period will be presented. 
A listing of subjects with at least one post-baseline abnormal vital signs observation will be 
provided and will display the whole profile over time of all parameters. 
 
2.4.5.4  Analysis of Physical Examination Variables 
The incidence of abnormal findings per body system will be tabulated by visit and for the whole post-
baseline observation period. Free text specifications will be listed. 
 
2.4.5.5  Analysis of Electrocardiogram Variables 
 


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ECG interpretation will be tabulated as frequencies by visit and time point, and in a shift table of 
baseline vs. worst post-baseline observation. Results per time point and free-text specifications of 
abnormalities will be listed.  
 
 
 
2.4.6 Duration of Study Treatment Exposure and Compliance 
 
The duration of study treatment exposure and compliance will be summarized by actual 
treatment within the safety population as continuous and categorical variables. 
 
 
Duration of oral study treatment exposure 
 
 
Duration of exposure (to oral study treatment/placebo) will be summarized descriptively as a 
quantitative variable (N, mean, SD, median, Q1, Q3, minimum, and maximum).  
 
The cumulative duration of treatment exposure, defined as the sum of subjects’ duration of 
treatment exposure in subject years, will be summarized by treatment group. 
 
Treatment compliance / Exposure to IV study treatment 
 
Treatment compliance for both ublituximab/IV placebo and teriflunomide/oral placebo will be 
summarized as quantitative variables (N, mean, SD, median, Q1, Q3, minimum, and maximum). The 
percentage of subjects who have a compliance of <80%, 80% to <100%, and >=100% will be 
tabulated by treatment group.  
Furthermore, for teriflunomide or oral placebo, the proportion of months on at least 80 percent of 
prescribed oral medication will be calculated with the following algorithm: 
1. 
For every period between a dispensation of tablets and the succeeding dispensation (or the last 
return), the ratio #tablets taken/#duration or the period in days is calculated 
 2. 
This calculated ratio is assigned to each day of the containing period 
3. 
For each full 28 day period starting on the first day of oral treatment (or the potentially shorter 
last period) the fractions are added and divided by the number of days in this period. This result is 
compared with the defined threshold (0.8 / 80%), and for each subject the percentage of periods 
reaching the threshold will be calculated and summarized. 
 
 
2.4.7   
Analyses of Pharmacokinetics 
 
Pharmacokinetics for ublituximab 
Population PK (nonlinear mixed effect modeling) analyses will be performed by an independent 
vendor and reported separately. This analysis will assess dose- and time-dependent kinetics as well 




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subjects developing ADA will be summarized by actual treatment group. A listing will be provided 
for ADA data. 
 
2.4.9   
Analysis of Pharmacodynamics 
B lymphocyte cell counts (% CD19+ B cells) will be tabulated per scheduled time point together with 
absolute and percentage changes from baseline. 
 
2.5  Data Handling Conventions 
Data handling discussions for the primary efficacy is included in Section 1.2.1. The further 
discussion for the data handling conventions for other variables will be included in this section. 
 
General conventions 
 
The following formulas will be used for computations of parameters. 
Demographic formulas: 
The age variable recorded in the eCRF will be used for analysis, no derived age variable is planned 
as only the year of birth is reported. 
 
 
Renal function formulas: 
 
Creatinine clearance value will be derived using the equation of Cockroft and Gault. The calculation 
requires body weight and age. The last weight measurement on or before the visit of the creatinine 
measurement will be used. If available, the age used by central lab at the visit will also be used for 
this derivation, otherwise the age at informed consent will be used. 
 
2.5.1   
Missing Data 
 
For categorical variables, subjects with missing data are not included in calculations of percentages 
unless otherwise specified. The number of subjects with missing data will be presented. 
 
For data listings, the character date will always be used to present the date collected in the eCRF, 
which allows the actual recorded date to be shown if elements are unknown/missing. 
 
2.5.1.1 Multiple sclerosis medical history variables 
 


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If the date of first MS diagnosis, first symptoms of MS, most recent relapse onset or start and end of 
previous MS treatments are incomplete, (i.e., month is unknown or day is unknown), unknown 
month/day will be set to July 1st,  an unknown day will be set to the 15th. 
  
2.5.1.2 Date of first and last treatment intake 
 
For all treated subjects, first treatment date is the date recorded on the baseline CRF.  
 
If first dose day is missing and first dose month and year are not missing: 
Impute first dose date using the first day of the month. If this leads to a date before first drug 
dispense date, use the first drug dispense date instead. Imputation flag is ‘D’. 
 
 
If first dose month is missing and first dose year is not missing: 
Impute first dose date using 1 January as the day and month. If this leads to a date before first drug 
dispense date, use the first drug dispense date instead. Imputation flag is ‘M’. 
 
If first dose year is missing: 
Impute first dose date using the first drug dispensing date if the subject did not return all 
medication. Imputation flag is ‘Y’; 
 
Last treatment intake date is collected on eCRF page. For treated subjects, if the date is 
incomplete, 
 
If last dose day is missing, and last dose month and year are not missing: 
Impute last dose date using the last day of the month. If this leads to a date after study 
completion/discontinuation date, use study completion/discontinuation date instead. Imputation flag 
is ‘D’. 
 
If last dose month is missing, and last dose year is not missing: 
Impute last dose date using 31 December as the day and month. If this leads to a date after study 
completion/discontinuation date, use study completion/discontinuation date instead. Imputation flag 
is ‘M’ 
 
If last dose year is missing: 
Impute last dose date using study completion/discontinuation date. Imputation flag is ‘Y’. 
  
2.5.1.3 Adverse event information 
 
Adverse event start date 
AE start date will be used for AE classification and analysis. If AE start date is not complete, then 
the character variable will keep the original incomplete date, the numerical date variable will be 
imputed and an imputation flag will indicate which date component is missing. 
 
If AE start day is missing, and AE start month and year are not missing: 
If AE start year is the same as first dose year and the AE start month is the same as the first dose 
month) then impute AE start day using the day of first dose. If this leads to a date after the AE end 
date, use AE end date instead. Otherwise (AE start year is not the same as first dose year and/or AE 
start month is not the same as the first dose month) impute the AE start day using the first day of the 


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month. If this leads to a date before informed consent, the informed consent date will be used. 
Imputation flag is ‘D’. 
 
If AE start month is missing, and AE start year is not missing: 
If AE start year is less than the first dose year, use the informed consent day and month. If AE 
start year is equal to the first dose year, use the first dose day and month. If this leads to a date 
after the AE end date, use AE end date instead. If AE start year is after the first dose year, use 1 
January. Imputation flag is ‘M’.  
 
If AE start year is missing: 
Impute AE start date using the day of first dose. If this leads to a date after the AE end date, use 
AE end date instead. Imputation flag is ‘Y’. 
 
 
Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for AE starting date imputation, In order to carry through the logic for programming, the 
following intermediate step will be used. Afterwards, the original character/numeric date recorded 
in CRF and supportive imputed end date will be kept in the final analysis dataset. 
 
If AE end day is missing, and AE end month and year are not missing: 
Impute AE end date using the last day of the month. If this leads to a date after end of follow-
up date, use end of follow-up date instead. 
 
If AE end month is missing, and AE end year is not missing: 
Impute AE end date using 31 December as the day and month. If this leads to a date after end of 
follow-up date, use the end of follow-up date instead. 
 
If AE end year is missing: 
Impute AE end date using the end of follow-up date. 
 
Adverse event relationship and severity 
Missing AE relationship and severity will be imputed according to the rules below at the data 
level using “analysis” variables. The original variables will also be included in the analysis 
datasets. 
 
Severity of adverse event 
 
If the severity is missing for one of the treatment emergent occurrences of an AE (the same 
SOC/PT), the maximal severity on the remaining occurrences will be considered. If the severity is 
missing for all the occurrences a “missing” category will be added in summary table. 
 
Relationship to investigational product 
 
If the assessment of the relationship to investigational product is missing, then the relationship to 
investigational product has to be assumed as related and the AE considered as such in the derived 
analysis variable. 
 
Adverse event Listings 
 


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For date variables, only character date variables will be presented, and no imputed dates will be 
printed in the listings. If the AE start date is imputed, then the onset relative day will be empty; if 
the AE start date or end date is imputed, then AE duration will be empty. 
  
22.5.1.4 Prior and concomitant medication (other than MS treatment) date 
 
Medication start and end date will be used for prior, concomitant and follow up medication 
classification and potential analysis for specific medications. In addition, the start and stop date for 
concomitant systemic corticosteroid will also be used to identify valid MRI scans (after a minimum 
of 30 days following the completion of a course of corticosteroid) for analysis, therefore different 
imputation rules will be used for end date of systemic corticosteroid to avoid excluding too many 
MRI scans (details can be found below). To keep the data integrity, if the date is not complete, 
then the character variable will keep the original incomplete date, the numerical date variable will 
be imputed (impute the end date first) and an imputation flag will indicate which date component 
is missing. Only the character variable will be used in data listing. 
 
As prior and concomitant medications are flagged using the recorded start and end dates, it is not possible 
to apply different imputation rules based on the prior/concomitant status of a record. So the same 
algorithm will be used for all records made in the “prior/concomitant medication” section of the eCRF. 
The only distinction is made between systemic corticosteroid treatments and all other treatments. 
Systemic corticosteroid treatment is defined as ATC level 2 = “CORTICOSTEROIDS FOR 
SYSTEMIC USE”. 
 
 
Prior/Concomitant medication start date 
 
The imputation rule for concomitant medication start date is the same as AE start date. 
 
Prior/Concomitant medication end date 
 
 
Imputation of non-systemic corticosteroid medication end date 
 
 
If end day is missing, and end month and year are not missing: 
Impute end date using the last day of the month. If this leads to a date after end of study follow up 
date, use end of follow up date instead. Imputation flag is ‘D’. 
 
If end month is missing, and end year is not missing: 
Impute end date using 31 December as the day and month. If this leads to a date after end of 
study follow up date, use the end of follow up date instead. Imputation flag is ‘M’. 
 
If end year is missing: 
Impute date using the end of follow up date. Imputation flag is ‘Y’. 
 
Systemic corticosteroid medication end date 
 
According to the protocol, the preferred corticosteroids treatment in protocol is methylprednisolone 
sodium succinate 1 g, intravenously daily for 3-5 days. To avoid excluding too many MRI scans due 


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to the incomplete date, the end date of corticosteroid will be imputed by the date closest to 5 days 
after the start. Details are described as below: 
 
If end day is missing and end month and year are not missing: 
If the end month and year are the same as start date + 5, then impute the end date using start date 
+5; If the month and year are earlier than start date + 5, then impute the day using the last day of 
the month; If the month and year are later than start date + 5, then impute the day using the first 
day of the month. If this leads to a date after end of study follow up date, use the end of follow up   
date instead. Imputation flag is ‘D’. 
 
If end month is missing and year is not missing: 
If the end year are the same as start date + 5, then impute the end date using start date +5; If the 
year are earlier than start date + 5, then impute the month and day using December 31; If the year 
are later than start date + 5, then impute the month and day using June 15. If this leads to a date 
after end of study follow up date, use the end of follow up date instead. Imputation flag is ‘M’. 
 
If end year is missing: 
Impute the end date using start date +5. If this leads to a date after end of study follow up date, 
use the end of follow up date instead. Imputation flag is ‘Y’. 
 
A special note, for subjects with incomplete systemic corticosteroid start date, the rule of 5 days 
after the start would not apply for the initial imputation. Thus for these cases, after imputation of 
start date, the end date will be re-imputed by repeating the above rules. 
 
 
2.5.2   
Windows for Time Points 
 
MRIs (including repeat imaging in case of QC rejections) are linked to specific visits, so it is not 
necessary to assign visits based on relative timing. 
Other efficacy assessments will be summarized by the nominal visit as well and no visit window 
will be defined. 
 
For safety assessments, the reference date for the derivation of relative days of events or findings 
will be the date of first drug intake as documented in the study medications administration page of 
the eCRF. All available values obtained between 2 visits including unscheduled measurements will 
be assigned to the appropriate visit window as specified in section 2.5.3. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will be 
used for the by-visit summary, in case of equal distance the later observation will be selected. For 
further details please see the section “Unscheduled Visits” as well. 
 
2.5.3   
Unscheduled Visits 
 
Only scheduled visit efficacy measurements will be used for analyses visit to exclude the temporary 
fluctuations in the clinical status that may occur with a relapse. 
 
Safety data from unscheduled visits will be used in in all safety analyses. The unscheduled visits will 
be assigned to the appropriate analysis time window. The one closest to the targeted visit date will 
be used in the presence of multiple measurements within the same time window. If two observations 


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within a window have the same target distance, the later one will be used for analysis. The following 
windows will be used: 
 
Week of study 
Target day 
Minimal days 
Maximum days 
1 (day 1) 
1 
1 
1 
1 (day 2) 
2 
2 
4 
2 
8 
5 
11 
3 
15 
12 
21 
4 
28 
22 
42 
8 
56 
43 
70 
12 
84 
71 
98 
16 
112 
99 
126 
20 
140 
127 
154 
 
24 
 
168 
155 
210 
36 
252 
211 
294 
48 
336 
295 
378 
60 
420 
379 
462 
72 
504 
463 
546 
84 
588 
547 
630 
96 
672 
631 
686 
100 
700 
687 
714 
104 
728 
715 
770 
116 
812 
771 
 
 
 
2.5.4   
Pooling of Centers for Statistical Analyses 
  
Due the small sample size in some centers/countries, the centers will be pooled to regions for 
statistical analysis. Please refer to section 2.1.1 for the definition of regions. 
 
3  
Interim Analysis 
 
There are no interim efficacy analyses planned for this study. 
A preplanned interim analysis for sample size reassessment will be performed by BART. 
4  
Software Documentation 
 
All summaries and statistical analyses will be generated using SAS® version 9.4 or higher (Cary, 
NC). 
 
 


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5  
Revisions of the SAP 
 
Version 3.0 (dated 04 September 2020) contains the following updates 
Section 
Modification 
Rationale 
Cover letter 
Updated personnel 
 
Terms 
Added abbreviations and definitions of terms 
Terms added to SAP 
1.1 
Clarified follow-up period after week 96 or 
early termination 
To correspond with protocol 
1.2 
Updated study objectives 
To correspond with protocol 
1.3 
Additional sample size details provided 
To correspond with the 
protocol  
 
 
 
1.4 
Schedule of Assessments refer to protocol 
To correspond with protocol 
2.1.1 
Demography categories updated  
To correspond to CRF 
2.1.1 
Disease characteristics variables updated 
To use a similar derivation 
approach as for other duration 
variables 
2.1.2 
Treatment exposure and compliance updated 
To correspond with protocol 
2.1.3 
Updated primary, secondary and tertiary 
efficacy variables 
To correspond with protocol 
2.1.3 
Relapse re-consent criteria 
Includes Treating Neurologist 
medically confirmed relapse 
2.1.4. 
ECG and physical examination added 
To mention all relevant safety 
assessments 
2.1.4.1 
AESI and Suicidal ideation language updated 
To mention all relevant safety 
assessments 
2.1.5 
PK variables added 
 
2.1.4.2 
Lab tests updated 
To correspond with 
parameters provided by the 
central lab 
2.2 
Definitions of analysis populations  
To reflect the study protocol  
 
Procedures for protocol deviations 
To reflect Protocol Deviation 
Plan 
2.3 
Clarified disposition of subjects 
To correspond with protocol 
2.4 
Update various statistical methods including 
demographics and baseline characteristics, 
duration of oral study treatment exposure, 
primary efficacy, secondary endpoints, tertiary 
endpoints, analyses of safety data, analyses of 
pharmacokinetics, analyses of ADA, and 
analysis of pharmacodynamics 
To correspond with protocol 
2.5 
Data handling conventions for general 
conventions, missing data, date of first and last 
treatment, adverse event information, windows 
for time points, unscheduled visits, pooling of 
centers 
To be consistent with protocol 


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Appendix B 
Re-consent can occur with Treating Neurologist 
medically confirmed relapse 
To be consistent with protocol 


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6  
References 
 
1 Li D, Held U, Petkau J, Daumer M, Barkhof F, Fazekas F et al. MRI T2 lesion burden in 
multiple sclerosis: a plateauing relationship with clinical disability Neurology 2006; 66: 
1384 – 1389. 
 
2 Hochberg (1988) A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika 75(4):800-802 
 
3 Jill Fisher, et al. Multiple sclerosis functional composite (MSFC) administration and 
scoring manual. Revised, October 2001. 
  
4 The EuroQol Group. EuroQol- a new facility for the measurement of health-related quality 
oflife. Health Policy 1990; 16(3): 199-208. 
 
5 Dolan P. Modeling valuations for EuroQol health states. Medical Care Vol 35, No. 11, 
pp.1095-1108. 1997 
 
6.   Liang, K-Y, and Zeger, S. L., Longitudinal data analysis using generalized linear models. 
Biometrika 1986; 73: 13-2 
 
7.   Hauser, SL. et al. NEJM. 2017 ; 366(3): 221-234 
 
8.   O’Connor P et al. NEJM. 2011; 365: 1293 – 1303 
 
9.   Vermersch et al. MSJ. 2014; 6(6): 705 – 716 
 
 


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Appendix A: 
 
Independent Relapse Adjudication Panel (IRAP) 
The Phase III study includes an objective definition of relapse and a standardized procedure for 
assessment of all suspected relapses as described in Section 4.4.1 of the protocol (TG1101-
RMS302). As outlined in this section, the Treating Neurologist will, within these guidelines, 
exercise his or her best clinical judgement in treating the suspected relapse. However, neither the 
Treating Neurologist nor the blinded rater/Examining Neurologist will make the final 
determination of whether a suspected event is counted as a relapse for the purpose of calculating 
the primary study outcome of Annualized Relapse Rate (ARR). Instead, an independent, blinded 
IRAP will make all relapse determinations in the Phase III study. The purpose of the IRAP is to 
ensure that relapses are scored in a manner that is consistent and objective as possible, and to 
minimize the variability between sites.  
The IRAP will review all subject records pertaining to suspected on-study relapses (i.e., new or 
worsening neurological symptoms of acute onset) that occur outside the scheduled study visits and 
are reported by the subject within 48 hours. Upon receiving the report by the subject, of a suspected 
relapse/acute neurological event, the Treating Neurologist and Examining Neurologists will in an 
independent manner, and blinded to the results of their separate examinations follow the 
procedures and timelines as described below and outlined in Appendix B (Appendix E of 
TG1101-RMS302). All suspected relapses initially reported by the subject are evaluated by the 
IRAP regardless of whether the Treating Neurologist considered the subject’s symptoms to be the 
result of a relapse. 
The IRAP comprises of 6 independent neurologists with expertise in MS clinical research who are 
not investigators in any other TG Therapeutics-sponsored studies with ublituximab. The IRAP 
members are trained on study procedures by the Sponsor and an independent Contract Research 
Organization (CRO) who manages all IRAP activities throughout the study. IRAP members are 
required to review trial data and perform adjudications in accordance with the protocol- specified 
definition (section 4.4.1 of the protocol (TG1101-RMS302).   
The CRO transfers blinded data that are relevant to assessment of relapses (entered into the eCRF 
by both the Treating Neurologist and the Examining Neurologist) and prepares blinded case 
dossiers to be reviewed by the IRAP via a secure electronic portal. The dossiers include a 
standardized listing for each suspected relapse that specified onset date, type and severity of 
reported symptoms, whether the event had disqualifying characteristics (e.g., lasted ≥24 hours, or 
symptoms not MS-related), and whether event has been treated with methylprednisolone. The 
dossiers also include vital signs, AEs related to the potential relapse, physical examinations, and 
EDSS scores with all supporting data from the standardized Neurostatus exam; values from 
baseline and the most recent prior quarterly assessment are provided as context for values from 
the relapse evaluation visit. Medical/surgical history and clinical episode history are also provided. 
In order to minimize the potential for inclusion of data which can potentially unblind an individual 
case under review (e.g. inclusion of AE with details that could suggest a treatment assignment), 


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Statistical Analysis Plan ULTIMATE II                                                                                      04 Sept 
2020 
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the CRO will perform additional programmatic checks on text fields pertaining to AEs and 
Physical Examination findings for data points that are part of the relapse case listing. 
Each potential relapse is reviewed by 2 IRAP members who have worked and entered their 
evaluations independently, on cases randomly assigned to them by the CRO. The IRAP adjudicates 
each case based on all available data provided for that case and members are not permitted to 
contact the site or the sponsor for additional information. If 2 IRAP reviewers reached the same 
decision as to whether an episode constitutes a relapse, the decision is recorded by the CRO. If the 
2 reviewers provide a conflicting assessment, a third IRAP member will review the case so that a 
majority vote can be obtained. The majority vote of up to 3 IRAP members serves as the final 
determination as to whether an event meets criteria for an on-study protocol defined relapse.  
Relapse determinations by the IRAP are communicated to the Treating Neurologist, who will in 
turn, notify the subject and update the eCRF accordingly. The IRAP has no involvement in 
subsequent subject management decisions. In order to maintain independence and blinding, the 
Examining Neurologist will not receive this report. Furthermore, neither the Treating Neurologist 
nor the subject may disclose the IRAP decision to the Examining Neurologist. The Treating 
Neurologist, upon receiving the IRAP decision, will counsel the subject per Section 4.4.1 of the 
protocol (TG1101-RMS302). The subject will need to give her/his consent to continue the 
treatment phase of the trial.  
For the Phase III study, the results of IRAP adjudications are transferred to the Sponsor only after 
the last subject completes the study. The Sponsor is blinded to the outcome of the IRAP 
adjudications while the study is ongoing.