Clinical trial NCT02738775
Conditions: Multiple Sclerosis
Keywords: multiple sclerosis
Sponsor: TG Therapeutics, Inc.
Start date: 2016-05-27; Completion date: 2018-08-13
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study evaluates the use of single agent ublituximab, a novel monoclonal antibody, in participants with relapsing forms of multiple sclerosis.

Detailed description:

Arms: arm 1: Participant received intravenous (IV) infusion of ublituximab 150 milligrams (mg)/4 hour (hr) on Day 1, 450 mg/3 hr on Day 15 and 450 mg/1.5 hr on Week 24. Some participants initially received placebo IV infusion /4 hr on Day 1 and /3 hr on Day 15 before receiving ublituximab. arm 2: Participant received IV infusion of ublituximab 150 mg/4 hr on Day 1, 450 mg/1.5 hr on Day 15 and 450 mg/1 hr on Week 24. Some participants initially received placebo IV infusion /4 hr on Day 1 and /1.5 hr on Day 15 before receiving ublituximab. arm 3: Participant received IV infusion of ublituximab 150 mg/4 hr on Day 1, 450 mg/1 hr on Day 15 and 600 mg/1 hr on Week 24. Some participants initially received placebo IV infusion /4 hr on Day 1 and /1 hr on Day 15 before receiving ublituximab. arm 4: Participant received IV infusion of ublituximab 150 mg/3 hr on Day 1, 600 mg/1 hr on Day 15 and 600 mg/1 hr on Week 24. Some participants initially received placebo IV infusion /3 hr on Day 1 and /1 hr on Day 15 before receiving ublituximab. arm 5: Participant received IV infusion of ublituximab 150 mg/2 hr on Day 1, 600 mg/1 hr on Day 15 and 600 mg/1 hr on Week 24. Some participants initially received placebo IV infusion /2 hr on Day 1 and /1 hr on Day 15 before receiving ublituximab. arm 6: Participant received IV infusion of ublituximab 150 mg/1 hr on Day 1, 600 mg/1 hr on Day 15 and 600 mg/1 hr on Week 24. Some participants initially received placebo IV infusion /1 hr on Day 1 and /1 hr on Day 15 before receiving ublituximab.
Interventions: intervention 1: Ublituximab intervention 2: Placebo
Intervention descriptions: intervention 1: Administered as an IV infusion. intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Placebo-Controlled Multi-Center Phase IIa Dose Finding Study of 
Ublituximab, a Third-Generation Anti-CD20 Monoclonal Antibody, in 
Patients with Relapsing Forms of Multiple Sclerosis. 
NCT Number: 
NCT02738775 
 
Document Date: 
 
Protocol Version 8.0: 10 October 2017 
 
 
 
 
 
 
 


TG1101-RMS201 
 
 
Dated: 10 October 2017 (Ver. 8.0) 
 
Page 1 of 75 
Protocol version/Date:  
 
Version 8.0 / October 10, 2017 
Local Protocol #: 
 
 
Protocol TG1101-RMS201 
TITLE: 
A Placebo-Controlled Multi-Center Phase IIa Dose Finding Study of Ublituximab, a Third-Generation Anti-
CD20 Monoclonal Antibody, in Patients with Relapsing Forms of Multiple Sclerosis. 
 
Sponsor: 
 
 
TG Therapeutics, Inc. 
 
 
 
 
2 Gansevoort St; 9th Floor 
 
 
 
 
New York, NY 10014 
 
 
 
 
Tel: (212) 554-4484 
 
IND Numbers: 
 
127265 
 
Study Chair:   
 
, MD, PhD  
 
 
 
 
 
 
 
 
 
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:  17 September 2015 
Version:   1.1  
 
 
 
 
 
 
 
Date:  30 October 2015 
Version:  2.0  
 
 
 
 
 
 
 
Date:  22 January 2016 (date on 
approval from CIRBI) 
Version:  2.1  
 
 
 
 
 
 
 
Date:  14 March 2016 
Version: 3.0 
 
 
 
 
 
 
 
 
Date:  23 May 2016 
Version: 4.0 
 
 
 
 
 
 
 
 
Date: 17 June 2016 
Version: 5.0 
 
 
 
 
 
 
 
 
Date: 20 October 2016 
Version: 6.0 
 
 
 
 
 
 
 
 
Date: 13 December 2016 
Version: 7.0 
 
 
 
 
 
 
 
 
Date: 24 April 2017 
Version: 8.0 
 
 
 
 
 
 
 
 
Date: 10 October 2017 
 
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. 
 
 


22Nov2017


TG1101-RMS201 
 
Dated: 10 October 2017 (Ver. 8.0) 
Page 3 of 75 
PROTOCOL ACCEPTANCE FORM
Protocol Title: 
A Placebo-Controlled Multi-Center Phase IIa Dose Finding 
Study of Ublituximab, a Third-Generation Anti-CD20 
Monoclonal Antibody, in Patients with Relapsing Forms of 
Multiple Sclerosis. 
Protocol Number: 
TG1101-RMS201 
Trial Drug: 
Ublituximab (TG-1101) 
IND Numbers: 
127265 
Date FINAL: 
10 October 2017 
I have read the attached protocol and agree that it contains all the necessary details for performing TG1101-
RMS201. 
I will provide copies of the protocol and of the ublituximab Investigators’ Brochure, which were furnished to me by 
TG Therapeutics (Sponsor), 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 and the 
conduct of the study. 
Once the protocol has been approved by the IRB, I will not modify this protocol without obtaining the prior 
approval of TG Therapeutics and of the IRB.  I will submit the protocol modifications and/or any informed consent 
modifications to TG Therapeutics and the IRB, 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 up to and including the Washington 
Clarification (2002). 
Print Name 
Signature 
Date 


TG1101-RMS201 
 
 
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Page 4 of 75 
Version 1.1 (Dated 30 October 2015) of this Protocol is the first amendment to this clinical trial and contains the 
following modifications: 
• 
12 Lead ECG will be performed pre- and post-dose on any day of infusion 
• 
Instead of 1.5T MRI, the study sites can use MRI machines ≥1.5 T 
Version 2.0 (Dated 19 January 2016) of this Protocol is the second amendment to this clinical trial and contains the 
following modifications: 
• 
Relabeled the superscript legend on page 35 to correct a mistake on the prior version for the ECG 
• 
Further defined the unit of B cell count as a percentage of CD19+ 
• 
In synopsis, directed the investigator to section 7.1.1 for complete listing of laboratory assessments 
• 
Further defined PK and anti-drug- antibody (antibodies developed against ublituximab) collection 
instructions in trial synopsis and section 7.1.1, and added analysis time points at weeks 4, 16, and 48 
• 
Quantitative immunoglobulin defined as IgA. IgM, IgG in section 7.1.1 
• 
Treatment and subject enrollment scheme was amended with the addition of a placebo arm during the 
first 28 days.  Following completion of Day 28, all placebo subjects will enter their respective “x” cohort 
and receive active treatment in Table 2 below. Cohort sizes were expanded to include 8 patients, of 
which 2 will be on placebo.  Study title changed to include “Placebo-Controlled” in the title 
• 
Added two additional PK analysis time points at weeks 4 and 25 
• 
Added fibrinogen level testing 
• 
Added a rescue clause in case subjects experience an MS relapse during the study 
• 
Excluded subjects vaccinated with live virus within 2 months of randomization 
• 
Added requirement for skilled personnel and adequate equipment at all sites to provide emergency 
treatment should subjects experience anaphylaxis, hypotension or respiratory distress 
• 
Changed directions for infusion interruptions:  If there is a second interruption of treatment due to IRR 
(infusion related reaction) symptoms, ublituximab infusion must be stopped.  The treating physician 
may decide whether to attempt completion of the infusion on a second day 
• 
The local radiologists will now review all MRI to 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 provide a report of the MRI to the treating physician.  
Further, physicians must obtain expert evaluations of brain MRI images of subjects with suspected 
opportunistic CNS infections including PML 
• 
Formatting and spelling errors were corrected throughout 
• 
Expansion of the rationale section 
• 
Instead of 1.5T MRI, the study sites can use closed MRI machines ≥1.5 T 
• 
Changed Per Protocol (PP) population to modified intent-to-treat population (mITT) 
• 
Change in primary efficacy measure (% B cell depletion) to >95% 
• 
Delete cohort 4  
Possible cohort expansion to include 25 – 900 mg ublituximab 
Version 2.1 (Dated 14 March 2016) of this Protocol is the third amendment to this clinical trial and contains the 
following modifications: 
• 
Change the premedication requirement to the following:  Pre-medicate approximately 30 minutes prior 
to each dose of ublituximab with an antihistamine (diphenhydramine 50 mg or equivalent), and 
corticosteroid (dexamethasone 10-20mg or equivalent).  Oral acetaminophen, 650 mg (or equivalent; 
only used for intervention) should be restricted to patient 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. 


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Page 5 of 75 
Version 3.0 (Dated 23 May 2016) of this protocol is the 4th amendment to this clinical trial and contains the 
following modifications: 
• 
Modifications to EDSS assessment instructions to require the following:  EDSS will be assessed based 
on a slightly modified neurological examination as fatigue will not contribute to the EDSS 
assessment 
• 
Will exclude subjects previously treated with alemtuzumab 
• 
Revised exclusion criteria for subjects previously treated with teriflunomide to the following:  
• 
Patients treated with teriflunomide within 12 months prior to screening. Exceptions will be subjects who 
have undergone accelerated/rapid elimination with oral activated charcoal or oral cholestyramine ≥ 90 
days of screening 
• 
Deleted the section on prophylaxis for pulmonary events as this does not pertain to this study subject 
population or investigational drug 
Version 4.0 (Dated 17 June 2016) of this protocol is the 5th amendment to this clinical trial and contains the 
following modifications:  
• 
Section 8.1.1 was updated to include the most recent adverse event information related to sponsor study 
drugs 
Version 5.0 (Dated 20 October 2016) of this protocol is the 6th amendment to this clinical trial and contains the 
following modifications: 
• 
Added another cohort (cohort 4) to the study  
• 
In the evaluation table: Weeks 8 and beyond, collections/assessments may occur ±2 days from specified 
time points 
Version 6.0 (Dated 13 December 2016) of this protocol is the 7th amendment to this clinical trial and contains the 
following modifications: 
• 
Revised original cohort 4 to smaller number of subjects and after initial infusion time 
• 
Added 2 other cohorts (cohorts 5 and 6) to the study 
Version 7.0 (Dated 24 April 2017) of this protocol is the 8th amendment to this clinical trial and contains the 
following modification: 
• 
Addition of relapse assessment into the study evaluation table in section 7.  This was erroneously left out. 
• 
Added the option for subjects completing the 48 week study, and fulfilling entry criteria, to enter into an 
open label extension study (this will be submitted as separate protocol: TG1101-RMS201E).  This is 
mentioned in Synopsis: Study Duration, Section 4 (Duration of Therapy), Section 7 (Study Evaluation 
Table), and Section 7.1 (Overview). 
Version 8.0 (Dated 10 October 2017) of this protocol is the 9th amendment to this clinical trial and contains the 
following modification: 
• 
Include information regarding a new vial size and concentration for ublituximab 
• 
Minor typographical errors 
 
 
 
 


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Page 6 of 75 
TRIAL SYNOPSIS 
Study Title 
A Placebo-Controlled Multi-Center Phase IIa Dose Finding Study of 
Ublituximab, a Third-Generation Anti-CD20 Monoclonal Antibody, in Patients 
with Relapsing Forms of Multiple Sclerosis. 
 
Study 
Rationale 
Over the past decade, the understanding of the role of B and T cells in autoimmune 
diseases has been of great priority in both pre-clinical and clinical research in 
autoimmune diseases, especially in multiple sclerosis.  In multiple sclerosis, B cells 
can form autoantibodies, which can result in pathological immune complex 
depositions that can activate the complement system as well as initiate acute 
inflammatory cascade by producing pro-inflammatory cytokines and chemokines.  
Further, B cells has been shown to regulate the formation and function of T cells, 
which can aid in the demyelinating events seen with multiple sclerosis.[13] 
Ublituximab (also known as TG-1101) is a monoclonal antibody that specifically 
binds to the trans-membrane antigen CD20 found on B-lymphocytes. The binding of 
ublituximab induces an immune response that causes lysis of B cells.  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).   The CD20 molecule is 
expressed on pre-B cells and throughout the lifecycle of both naïve and memory B 
cells.  It is not expressed on stem cells or pro-B cells at the earliest stages of B cell 
differentiation.  Further, it is not expressed on plasmablasts or terminally 
differentiated plasma cells.[8] Thus, CD20 is an ideal target for B cells targeted 
immunotherapy.  Rituximab was the first anti-CD20 monoclonal antibody (mAb) 
tested in relapsing forms of Multiple Sclerosis (RMS) patients.  More recently, 
ocrelizumab, a humanized anti-CD20 monoclonal antibody has shown promising 
results in its 2 Phase III trials (OPERA I and OPERA II).  In OPERA I and II, patients 
treated with ocrelizumab had significantly lower annualized relapse rates (0.156 and 
0.155, respectively) compared to patients treated with IFNβ-1a 44μg (0.292 and 
0.29, respectively).  Further, in OPERA I and II, patients treated with ocrelizumab 
had 40% reduction in clinical disease progression compared to those treated with 
IFNβ-1a 44μg. [14] 
To date, a B-cell targeted therapy has not been approved for the treatment of RMS.  
Although an ublituximab phase I has been completed in chronic lymphocytic 
leukemia (CLL) and in non-Hodgkin’s lymphoma (NHL) patients with no MTD 
reached up through 1200 mg, a dose ranging study has not been initiated in the MS 
population.  It is important determine the optimal dose of ublituximab use to treat 
MS patients as well as understand the safety and tolerability profile of ublituximab in 
this population.  Thus, the primary purpose of this study is to identify the 
recommended Phase 3 dose and infusion time as well as explore the safety of 
ublituximab in patients with relapsing forms of MS. 
Products 
 
Ublituximab is a recombinant chimeric monoclonal antibody against the CD20 
antigen, available as a 10 mg/mL or 25mg/mL concentrate for solution for infusion, 
supplied by TG Therapeutics, Inc.  


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Page 7 of 75 
Phase 
Phase IIa 
Study 
Sponsor 
TG Therapeutics, Inc. (New York, NY, USA) 
Study Chair 
RMS Group Study Chair 
, MD, PhD 
 
 
 
 
 
Study 
Objectives 
Primary Objectives 
• 
To determine the level of B cell depletion by ublituximab in subjects with RMS 
• 
To determine the optimal dose and infusion time for ublituximab in subjects with 
RMS 
Secondary Objective 
• 
To examine the effect of ublituximab on the development of new Gadolinium- 
(Gd) enhancing lesions and new or enlarging T2 lesions at 24 and 48 weeks  
• 
To evaluate the % of relapses in ublituximab-treated RMS subjects 
• 
To determine immunogenicity 
• 
To evaluate the safety of ublituximab, as determined by adverse events (AEs) 
and serious adverse events (SAEs), including MS worsening 
 
Efficacy 
Endpoints  
 
Efficacy Endpoints 
• 
Responders Rate defined as percent of subjects with ≥95% reduction of B cells 
(CD19+ cells) within 2 weeks after the second infusion (day 15) 
 
Secondary efficacy endpoints 
• 
Number of new Gd-enhancing lesions at 24 and 48 weeks 
• 
Number of new or enlarging T2 lesions at 24 and 48 weeks 
• 
Annualized relapse rate (ARR)  
• 
Relapse rate reduction (RRR) 
• 
Percent of relapse free subjects 
• 
Reduction in B cells (CD19+), memory (CD19+CD27+) and naïve (CD19+CD27-) 
B cells at baseline, day 1 (pre dose), 2, week 2, Day 15 (pre-dose), week 4 and 
every 4 weeks thereafter until the next infusion at weeks 24 (pre-dose and 2 
days post dose) 25, 28, 36, 40, 44 and 48.  
• 
Additional immune profiling (CD4+, CD8+, IL10 and NK cells) at baseline, day 1 
(pre dose), 2, week 3, 15 (pre-dose), week 4 and every 4 weeks thereafter until 
the next infusion at week 24 (pre-dose and 2 dose post-dose) 25, 28, 36, 40, 44 
and 48. 
• 
PK (ADME) profile of ublituximab at day 1 and 15 and weeks 4, 24 and 25 
Safety 
Endpoints 
All AEs will be reported and evaluated during the treatment period using National 
Cancer Institute (NCI) version 4.0 grading system; the number and severity of 
infusion-associated events, defined as AEs reported during or within 24 hours of an 
infusion; the number and severity of infectious AEs; any clinically significant changes 
in laboratory or vital sign measurements; the incidence of anti-drug antibodies 
(antibodies developed against ublituximab) to assess safety over the 52-week trial.   
Study Design 
This is a 52-week, phase IIa, placebo-controlled, multi-center study that is primarily 
designed to assess the optimal dosing, optimal infusion time as well as 
safety/tolerability of ublituximab (TG1101; UTX) in patients with RMS. 


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Page 8 of 75 
 
Subjects may be screened up to 4 weeks before first dosing date.  Qualified subjects 
will receive ublituximab on Days 1, 15, and week 24.  There will be at least four 
treatment cohorts in the study with 8 subjects (2 placebo and 6 ublituximab 
treatment; please see treatment schema) enrolled in each cohort.  Subjects within 
each cohort will receive either placebo or study drug dosing on Days 1 and 15 and 
week 24 per dosing schema (please see table below). Additional dose ranging 
cohorts may be explored and expansion cohorts at selected doses are contemplated.  
 
A Data and Safety Monitoring Board (DSMB) will be established to safe guard the 
wellbeing of the subjects and to advise the Sponsor whether it is appropriate to 
expand the enrollment to a dosing cohort or to initiate next dosing cohort.  The 
DSMB may recommend to the Sponsor to terminate the enrollment to a treatment 
cohort for safety concerns or otherwise.  For example, the DSMB may recommend 
early termination of enrollment to a dosing cohort that is higher than the optimal 
treatment cohort after the optimal dosing is determined or a cohort that is 
considered without meaningful clinical benefit.   
 
Once a subject is qualified, the Site will contact the Sponsor or its designee for cohort 
assignment (treatment assignment).  The Sponsor or its designee will issue the 
cohort assignment for the subject using the following procedures.  If DSMB deems 
that a cohort is not appropriate (e.g., due to safety), enrollment to that cohort and all 
higher cohorts will be terminated and all future subjects will be enrolled to the 
lowest incomplete cohort.  Upon completion of first two patients in each cohort (one 
on placebo and one on study drug) through 21 days, the DSMB will review safety 
data and assuming no safety concern is raised, the remaining qualified subjects will 
be enrolled into such cohort.    
 
MS Relapses during the study: 
Any patient experiencing a multiple sclerosis relapse while on study will be allowed 
rescue therapy with intravenous methylprednisolone 1gm/day for up to 5 
consecutive days.  Subjects requiring rescue therapy will have an MRI scan 10 days 
after completion of treatment with steroids. 
Re-consent criteria 
In case of a confirmed diagnosis of MS relapse (as defined in the protocol, Appendix 
C), or in case of an increase in EDSS of 1.0 points or more, sustained for at least 3 
months, during the study, the following actions will be taken: 
1. 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.  
2. The subject will be requested to re-sign an informed consent form if he/she 
chooses to continue to participate in the study, in the same treatment assignment. 
 
Subjects enrolled into the study will be closely monitored through the study course 
by the Sponsor’s personnel as well as by an external independent data monitoring 
committee (DSMB) in order to ensure subjects’ welfare. 
 
 


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Treatment 
Study Visits 
Ublituximab (or Placebo) Regimen 
 
• 
Ublituximab (IV): Infusions on Days 1 and 15 and week 24 
• 
Placebo (IV): Infusions on Days 1 and 15 
 
Laboratory Assessment Schedule: 
• 
For subjects initially treated with UTX: 
o Blood collection for CBC and serum chemistry at baseline, and day 1 (pre-
dose), 2, 8, 15 (pre-dose), and weeks 4, 8, 12, 16, 20, 24 (pre-dose and 2 
days post-dose), 25, 28, 36, 40, 44 and 48 
o Blood collection for immune profiling at screening, baseline, and day 1 
(pre-dose), 2, 8, 15 (pre-dose), and week 4, 8, 12, 16, 20, 24 (pre-dose 
and 2 days post dose), 25, 28, 36, 40, 44 and 48 
• 
For subjects initially treated with placebo followed by UTX treatment  
o Blood collection for CBC and serum chemistry at baseline, and day 1 (pre-
dose), 2, 8, 15 (pre-dose), and week 4.  Once the subject starts UTX 
treatment, blood collection for CBC and serum chemistry on day 1 (pre-
dose), 2, 8, 15 (pre-dose), and week 4, 8, 12, 16, 20, 24 (pre-dose and 2 
days post-dose), 25, 28, 36, 40, 44 and 48 
o Blood collection for immune profiling at screening, baseline, and day 1 
(pre-dose), 2, 8, 15 (pre-dose), and week 4.  Once the subject starts UTX 
treatment, blood collection for immune profiling will occur on day 1 (pre-
dose), 2, 8, 15 (pre-dose), and week 4, 8, 12, 16, 20, 24 (pre-dose and 2 
days post-dose), 25, 28, 36, 40, 44 and 48 
 
MRI Schedule: Screening, weeks 24 (pre-dose) and 48 
Clinical Assessment Schedule: Screening, baseline, weeks 24 (pre dose), and 48 
Baseline Lab 
Evaluation 
(Local Lab) 
• 
CBC with differential  
• 
Varicella titer 
• 
Serology to rule out active Hep B/C and HIV 
• 
Serum chemistry 
• 
Serum pregnancy test 
• 
B lymphocyte cell counts (% CD19+ B cells) 
• 
See section 7.1.1 for complete listing of laboratory assessments 


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Pharmacokin
etic (PK) 
• 
For subjects treated with UTX, serum samples will be drawn at the Baseline (Day 
1) visit prior to the first infusion of UTX and 30 minutes after the completion of 
the infusion; week 2; Day 15 (prior to the infusion of UTX and 30 minutes after 
the completion of the infusion); week 4; week 24 (prior to the infusion of UTX 
and 30 minutes after the completion of the infusion) and week 25.   
• 
For subjects initially treated with placebo, serum samples will be drawn at 
Baseline (Day 1) visit prior to the first infusion of placebo and 30 minutes after 
the completion of the infusion; week 2; Day 15 (prior to the infusion of UTX and 
30 minutes after the completion of the infusion); week 4.  Upon week 4, placebo 
subjects will start ublituximab treatment and will thus follow the PK analysis 
timeline as UTX subjects starting from Day 1 of UTX treatment 
Instrumental 
Tests 
• 
MRI (≥1.5T; closed MRI only) 
 
 


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Dosing 
Regimen 
Table 1: Ublituximab/Placebo (Dose Range) 
 
 
Randomization 
Treatment Period 
Cohort 
Subjects and 
treatment 
Day 1/ 
infusion time  
Day 15/ 
infusion time  
Week 24/ 
infusion time  
1 
Placebo (n=2)b 
Placebo / 4h 
Placebo / 3h 
- 
UTX (n=6) 
150 mg / 4h 
450 mg / 3h 
450 mg / 1.5h 
2 
Placebo (n=2)b 
Placebo / 4h 
Placebo / 1.5h 
- 
UTX (n=6) 
150 mg / 4h 
450 mg / 1.5h 
450 mg / 1h 
3 
Placebo (n=2)b 
Placebo / 4h 
Placebo / 1h 
- 
UTX (n=6) 
150 mg / 4h 
450 mg / 1h 
600 mg / 1h 
4 
Placebo (n=2)b 
Placebo / 3h 
Placebo / 1h 
- 
UTX (n=6) 
150 mg / 3h 
600 mg / 1h 
600 mg / 1h 
5 
Placebo (n=2)b 
Placebo / 2h 
Placebo / 1h 
- 
UTX (n=6) 
150 mg / 2h 
600 mg / 1h 
600 mg / 1h 
6 
Placebo (n=2)b 
Placebo / 1h 
Placebo / 1h 
- 
UTX (n=6) 
150 mg / 1h 
600 mg / 1h 
600 mg / 1h 
Cohort 
expansiona 
Up to 100 
To be explored at selected doses pending on the 
results of the above doses 
 
a  Additional cohorts may be evaluated at doses ranging from 25 mg up to 900 mg to 
further elucidate the level of B-cell depletion and recovery parameters in subjects 
with RMS 
b Following completion of Day 28, all placebo subjects will enter their respective “a” 
cohort and receive active treatment as described in Table 2 below. Further, the study 
evaluation table (section 7) will be restarted for these patients upon the initiation of 
active treatment with ublituximab 
Table 2: Treatment Schema for Placebo Subjects after Day 28 
Cohort 
Subjects  
Day 1/ infusion 
time  
Day 15/ infusion 
time  
Week 24/ 
infusion time  
1a 
Pbo patients 
from Cohort 1 
150 mg UTX 
/ 4h 
450 mg UTX 
/ 3h 
450 mg UTX 
/ 1.5h 
2a 
Pbo patients 
from Cohort 2 
150 mg UTX 
/ 4h 
450 mg UTX 
/ 1.5h 
450 mg UTX 
/ 1h 
3a 
Pbo patients 
from Cohort 3 
150 mg UTX 
/ 4h 
450 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
4a 
Pbo patients 
from Cohort 4 
150 mg UTX 
/ 3h 
600 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
5a 
Pbo patients 
from Cohort 5 
150 mg UTX 
/ 2h 
600 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
6a 
Pbo patients 
from Cohort 6 
150 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
 
 


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Inclusion 
Criteria  
Patients must meet all of 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. Active disease 
5. EDSS 0-5.5 (inclusive) 
6. B cell counts ≥5% of total lymphocytes 
7. Neurologic stability ≥ 30 days prior to screening and baseline 
8. 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 acceptable method of contraception throughout the study 
period and for 30 days after the last dose of either study drug. 
9. Willingness and ability to comply with trial and follow-up procedures, give 
written consent 
Exclusion 
Criteria 
Patients 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 within last 12 
months   
2. Treated with alemtuzumab  
3. Patients treated with teriflunomide within 12 months prior to screening.  
a. Exceptions to above are patients who have undergone accelerated/rapid 
elimination with oral activated charcoal or oral cholestyramine ≥ 90 days 
of screening 
4. Prior DMT exposure within days of screening 
a. 90 days with fingolimod and natalizumab 
b. 30 days with glatiramer acetate, interferons, dimethyl fumarate, or 
glucocorticoids  
5. Pregnant or nursing 
6. ≥ 10 years disease duration with subjects EDSS ≤ 2.0 
7. Contraindication for MRI and gadolinium  
8. Known presence of other neurologic disorders that may mimic MS 
9. Current evidence or known history of clinically significant infection including: 
a. Chronic or ongoing active 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 HIV 
10. History of clinically significant CNS trauma (e.g. traumatic brain injury, cerebral 
contusion, spinal cord compression)  
11. Past or current history of medically significant adverse effects (including 
allergic reactions) from: 
a. Corticosteroids 


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b. Diphenhydramine 
c. Murine or mouse/human chimeric antibodies 
12. Absolute neutrophil count or platelet count outside of normal range (as per 
reference laboratory) 
13. Absolute lymphocyte counts less than 1000/microliter 
14. 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 >470 msec 
c. Angina not well-controlled by medication 
d. 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 
15. Significant concurrent, uncontrolled medical condition including, but not 
limited to, cardiac, renal, hepatic, hematological, gastrointestinal, endocrine, 
immunodeficiency syndrome, pulmonary, cerebral, 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 
16. Current participation in any other interventional clinical trial.  Participation in 
non-interventional trial requires approval of the protocol by investigator 
17. Inability or unwillingness to comply with study and/or follow-up procedures 
outlined in the protocol 
18. Lack immunity to varicella as determined by screening.  Patient may receive 
vaccine and be rescreened 
19. Vaccination with live virus within 2 months of randomization 
Populations 
Intention-To-Treat (ITT) – all registered subjects who received at least one dose of 
ublituximab  
Modified Intent to Treat (mITT) – all subjects who received UTX and have one 
baseline and post-baseline MRI 
Statistical 
Consideratio
ns 
The primary efficacy analyses will be based on intent-to-treatment (ITT) population 
that will include all subjects who receive any study drugs and provide some post 
baseline efficacy values.  Additional efficacy analyses based on modified intent-to-
treat (mITT) population may also be performed.  mITT are all subjects who received 
UTX and have one baseline and post-baseline MRI.  All safety analyses will be based 
on the safety population that will include all subjects who received any study drugs. 
 
  All efficacy variables will be summarized.  The primary 
efficacy variable, responders rate, will be analyzed for dose response (trend 
analysis).  In this analysis, responders are subjects who have at least 95% reduction 
in B cells (CD19+ cells) within 2 weeks of second dose (day 15) of study drug. 


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Safety profiles will be evaluated based on adverse events and laboratory outcomes.  
More details of efficacy and safety analyses can be found in Statistical Considerations 
sections of the protocol. 
Estimated 
Study 
Duration 
Approximately 52 weeks.  Upon study completion, subjects may have the option of 
entering a 112 week open label extension study, with a continuation of treatment, 
relapse and safety monitoring.   
 
 


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PROTOCOL SCHEMA 
Phase IIa 
Ublituximab / Placebo 
Table 3: Ublituximab/Placebo (Dose Range) 
 
Randomization 
Treatment Period 
Cohort 
Subjects and 
treatment 
Day 1/ infusion 
time  
Day 15/ infusion 
time  
Week 24/ infusion 
time  
1 
Placebo (n=2)b 
Placebo / 4h 
Placebo / 3h 
- 
UTX (n=6) 
150 mg / 4h 
450 mg / 3h 
450 mg / 1.5h 
2 
Placebo (n=2)b 
Placebo / 4h 
Placebo / 1.5h 
- 
UTX (n=6) 
150 mg / 4h 
450 mg / 1.5h 
450 mg / 1h 
3 
Placebo (n=2)b 
Placebo / 4h 
Placebo / 1h 
- 
UTX (n=6) 
150 mg / 4h 
450 mg / 1h 
600 mg / 1h 
4 
Placebo (n=2)b 
Placebo / 3h 
Placebo / 1h 
- 
UTX (n= 6) 
150 mg / 3h 
600 mg / 1h 
600 mg / 1h 
5 
Placebo (n=2)b 
Placebo / 2h 
Placebo / 1h 
- 
UTX (n= 6) 
150 mg / 2h 
600 mg / 1h 
600 mg / 1h 
6 
Placebo (n=2)b 
Placebo / 1h 
Placebo / 1h 
- 
UTX (n= 6) 
150 mg / 1h 
600 mg / 1h 
600 mg / 1h 
Cohort 
expansiona 
Up to 100 
To be explored at selected doses pending on the results of the above 
doses 
 
a  Additional cohorts may be evaluated at doses ranging from 25 mg up to 900 mg to further elucidate the level of B-
cell depletion and recovery parameters in subjects with RMS 
b Following completion of Day 28, all placebo subjects will enter their respective “a” cohort and receive active 
treatment as described in Table 4 below. Further, the study evaluation table (section 7) will be restarted for these 
patients upon the initiation of active treatment with ublituximab 
Table 4: Treatment Schema for Placebo Subjects after Day 28 
Cohort 
Subjects  
Day 1/ infusion time  
Day 15/ infusion 
time  
Week 24/ infusion 
time  
1a 
Pbo patients from Cohort 1 
150 mg UTX 
/ 4h 
450 mg UTX 
/ 3h 
450 mg UTX 
/ 1.5h 
2a 
Pbo patients from Cohort 2 
150 mg UTX 
/ 4h 
450 mg UTX 
/ 1.5h 
450 mg UTX 
/ 1h 
3a 
Pbo patients from Cohort 3 
150 mg UTX 
/ 4h 
450 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
4a 
Pbo patients from Cohort 4 
150 mg UTX/ 3h 
600 mg UTX/ 1h 
600 mg UTX/ 1h 
5a 
Pbo patients from Cohort 5 
150 mg UTX/ 2h 
600 mg UTX/ 1h 
600 mg UTX/ 1h 
6a 
Pbo patients from Cohort 6 
150 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
 


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LIST OF ABBREVIATIONS 
Abbreviations and Definition of Terms 
Ab 
Antibody 
ADCC 
Antibody-Dependent Cellular Cytotoxicity 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase  
ALT 
Alanine aminotransferase 
ARR 
Annualized Relapse Rate 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Class 
AUC 
Area Under the Curve 
BBB 
Blood Brain Barrier 
BM 
Bone Marrow 
Ca  
Calcium 
CAEPRS 
Comprehensive Adverse Events and Potential Risks 
CBC 
Complete Blood cell Count 
CD 
Cluster of Differentiation 
CDC 
Complement-Dependent Cytotoxicity 
Cl 
Clearance 
CLL 
Chronic Lymphocytic Leukemia 
Cmax 
Maximum Concentration 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Curriculum Vitae 
CVA 
Cerebrovascular Accident 
D, d 
Day 
DLT 
Dose Limiting Toxicity 
DMT 
Disease Modifying Therapy 
DOR 
Duration of Response 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDSS 
Expanded Disability Status Scale 
Fc 
Fragment crystallizable (region) 
FL 
Follicular Lymphoma 
FU 
Follow-up 
GCP 
Good Clinical Practice  
GCSF 
Granulocyte Colony Stimulating Factor 
Gd 
Gadolinium 
GLP 
Good Laboratory Practice 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IEC/IRB 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB)  
Ig 
Immunoglobulin 


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Abbreviations and Definition of Terms 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IL 
Interleukin 
IRR 
Infusion Related Reactions 
ITT 
Intent to Treat 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
MCL 
Mantle Cell Lymphoma 
MRI 
Magnetic Resonance Imaging 
MRT 
Mean Residence Time 
mAb 
Monoclonal Antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MS 
Multiple Sclerosis 
NCI 
National Cancer Institute 
NCI-WG 
National Cancer Institute – Working Group 
NK 
Natural Killer 
NHL 
Non-Hodgkin’s Lymphoma 
OS 
Overall survival 
PCR 
Polymerase Chain Reaction  
PFS 
Progression-Free Survival 
PD 
Pharmacodynamic or Progressive Disease 
PHI 
Patient Health Information 
PI 
Primary Investigator 
PK 
Pharmacokinetic 
PML 
Progressive Multifocal Leukoencephalopathy 
PPMS 
Primary Progressive Multiple Sclerosis 
PR 
Partial Response 
PRMS 
Progressive Relapsing Multiple Sclerosis 
PT 
Preferred Term 
R-FC 
Rituximab-Fludarabine, Cyclophosphamide 
RMS 
Relapsing forms of Multiple Sclerosis 
RRMS 
Relapsing Remitting Multiple Sclerosis 
RRR 
Relapse Rate Reduction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease  
SOC 
System Organ Class 
t1/2 
Half-Life of Elimination 
TB 
Tuberculosis 
TEAEs 
Treatment Emergent Adverse Events 
TIA 
Transient Ischemic Attack 
ULN 
Upper Limit of Normal 
V 
Visit 
Vd 
Volume of distribution 
WHO 
World Health Organization 
 
 


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TABLE OF CONTENTS 
1 INTRODUCTION .......................................................................................................................................................... 21 
1.1 Background .................................................................................................................................................................................................. 21 
1.2 Ublituximab ................................................................................................................................................................................................. 21 
1.2.1 Pre-Clinical Evaluations of Ublituximab .......................................................................................................................................................................................... 21 
1.2.2 Clinical Development of Ublituximab ................................................................................................................................................................................................ 22 
1.3 Rationale ....................................................................................................................................................................................................... 23 
1.3.1 Clinical Studies with Rituximab and Ocrelizumab ...................................................................................................................................................................... 23 
1.3.2 Rationale for the trial ................................................................................................................................................................................................................................ 24 
2 OBJECTIVES .................................................................................................................................................................. 25 
2.1 Primary Objectives ................................................................................................................................................................................... 25 
2.2 Secondary Objective................................................................................................................................................................................. 25 
3 TRIAL POPULATION .................................................................................................................................................. 26 
3.1 Inclusion Criteria ....................................................................................................................................................................................... 26 
3.2 Exclusion Criteria ...................................................................................................................................................................................... 26 
3.3 Discontinuation from Trial Treatment ............................................................................................................................................. 27 
3.3.1 Pregnancy ....................................................................................................................................................................................................................................................... 27 
4 REGISTRATION/TREATMENT ASSIGNMENT PROCEDURES ........................................................................ 29 
4.1 Registration Process ................................................................................................................................................................................ 29 
4.2 Treatment Assignment Process .......................................................................................................................................................... 29 
5 TREATMENT PLAN .................................................................................................................................................... 30 
5.1 Dosing Schema ........................................................................................................................................................................................... 30 
5.1.1 Dose-Limiting Toxicity ............................................................................................................................................................................................................................. 31 
5.1.2 Determination of Dose-Limiting Toxicity ........................................................................................................................................................................................ 31 
5.1.3 Stopping Rules .............................................................................................................................................................................................................................................. 31 
5.2 Agent Administration .............................................................................................................................................................................. 32 
5.2.1 Guidelines for Administration of Ublituximab .............................................................................................................................................................................. 32 
5.3 General Concomitant Medication and Supportive Care Guidelines ..................................................................................... 34 
5.4 Duration of Therapy ................................................................................................................................................................................. 35 
5.5 End of study/Open label extension study ....................................................................................................................................... 35 
6 DOSING DELAYS/DOSE MODIFICATION - RECOMMENDATIONS ............................................................... 36 
6.1 Criteria for Ongoing Treatment .......................................................................................................................................................... 36 
6.2 Important Dose Modifications ............................................................................................................................................................. 36 
6.2.1 Dose Modifications of Ublituximab .................................................................................................................................................................................................... 36 
7 Study Evaluation Table ............................................................................................................................................ 39 
7.1 Overview ....................................................................................................................................................................................................... 40 
7.1.1 Laboratory Evaluation .............................................................................................................................................................................................................................. 40 


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7.1.2 Radiological Evaluation ............................................................................................................................................................................................................................ 42 
7.1.3 Neurological Evaluation ........................................................................................................................................................................................................................... 42 
7.1.4 Relapse Assessment ................................................................................................................................................................................................................................... 42 
7.2 Definitions .................................................................................................................................................................................................... 43 
7.3 Disease Parameters .................................................................................................................................................................................. 43 
7.4 Duration of Response .............................................................................................................................................................................. 43 
7.5 Response Review ...................................................................................................................................................................................... 43 
8 PHARMACEUTICAL INFORMATION ..................................................................................................................... 44 
8.1 Ublituximab ................................................................................................................................................................................................. 44 
8.1.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ............................................................................................................................... 45 
8.1.2 Dispensing ...................................................................................................................................................................................................................................................... 45 
8.1.3 Administration ............................................................................................................................................................................................................................................. 47 
8.2 Ordering Investigational Agents ......................................................................................................................................................... 50 
9 STATISTICAL CONSIDERATIONS ........................................................................................................................... 51 
9.1 Sample Size and Power ........................................................................................................................................................................... 51 
9.2 General Analysis Convention ............................................................................................................................................................... 51 
9.3 Analysis Populations................................................................................................................................................................................ 51 
9.4 Subject Disposition ................................................................................................................................................................................... 51 
9.5 Subject Demographics and Baseline Characteristics ................................................................................................................. 52 
9.6 Medical History .......................................................................................................................................................................................... 52 
9.7 Extent of Exposure ................................................................................................................................................................................... 52 
9.8 Efficacy Analyses ....................................................................................................................................................................................... 52 
9.8.1 Primary Efficacy Variable ........................................................................................................................................................................................................................ 52 
9.8.2 Secondary Efficacy Variable ................................................................................................................................................................................................................... 52 
10 SAFETY REPORTING AND ANALYSIS ................................................................................................................. 54 
10.1 Safety Analyses ........................................................................................................................................................................................ 54 
10.2 Adverse Events ........................................................................................................................................................................................ 54 
10.3 Adverse Event Characteristics .......................................................................................................................................................... 54 
10.4 Protocol-Specific Expedited Adverse Event Reporting Exclusions ................................................................................... 54 
10.5 Adverse Events (AE’s) and Treatment Emergent Adverse Events (TEAE’s) ................................................................. 54 
10.6 Definitions of Adverse Events ........................................................................................................................................................... 55 
10.7 Adverse Events / Serious Adverse Event Causality Assessment ........................................................................................ 55 
10.7.1 Recording of Adverse Events .............................................................................................................................................................................................................. 56 
10.7.2 Abnormal Laboratory Values and Vital Signs ............................................................................................................................................................................. 56 
10.7.3 Handling of Adverse Events ................................................................................................................................................................................................................ 56 
10.8 Serious Adverse Events ....................................................................................................................................................................... 57 
10.8.1 Definitions of Serious Adverse Events ........................................................................................................................................................................................... 57 
10.8.2 Serious Adverse Event Reporting by Investigators ................................................................................................................................................................. 58 
10.9 Sponsor SAE Reporting Requirements .......................................................................................................................................... 59 


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10.10 Recording of Adverse Events and Serious Adverse Events ................................................................................................ 59 
10.11 Diagnosis vs. Signs and Symptoms ............................................................................................................................................... 59 
10.11.1 Persistent or Recurrent Adverse Events .................................................................................................................................................................................... 59 
10.11.2 Abnormal Laboratory Values ........................................................................................................................................................................................................... 59 
10.11.3 Deaths.......................................................................................................................................................................................................................................................... 60 
10.11.4 Hospitalization, Prolonged Hospitalization, or Surgery ..................................................................................................................................................... 60 
10.11.5 Pre-Existing Medical Conditions .................................................................................................................................................................................................... 60 
10.11.6 Protocol-Defined Events of Special Interest ............................................................................................................................................................................. 60 
11 STOPPING RULES ..................................................................................................................................................... 61 
11.1.1 Suspension of Patient Enrollment: .................................................................................................................................................................................................. 61 
11.1.2 Lack of Clinical Response ..................................................................................................................................................................................................................... 61 
12 CLINICAL DATA COLLECTION AND MONITORING ........................................................................................ 62 
12.1 Site Monitoring Plan .............................................................................................................................................................................. 62 
13 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ................................................................. 63 
13.1 IRB Approval ............................................................................................................................................................................................ 63 
13.2 Regulatory Approval ............................................................................................................................................................................. 63 
13.3 Insurance and Indemnity .................................................................................................................................................................... 63 
13.4 Informed Consent ................................................................................................................................................................................... 63 
13.5 Confidentiality ......................................................................................................................................................................................... 64 
13.6 Investigator and Staff Information .................................................................................................................................................. 64 
13.7 Financial Information ........................................................................................................................................................................... 65 
14 RECORD RETENTION AND DOCUMENTATION OF THE TRIAL ................................................................. 66 
14.1 Amendments to the Protocol ............................................................................................................................................................. 66 
14.2 Documentation Required to Initiate Trial .................................................................................................................................... 66 
14.3 Trial Documentation and Storage .................................................................................................................................................... 67 
14.4 Data Collection ......................................................................................................................................................................................... 68 
14.5 Trial Monitoring, Auditing, and Inspecting .................................................................................................................................. 68 
14.6 Quality Assurance and Quality Control ......................................................................................................................................... 68 
14.7 Disclosure and Publication Policy ................................................................................................................................................... 69 
15 REFERENCES ............................................................................................................................................................. 70 
16 Appendix A ................................................................................................................................................................ 71 
17 Appendix B ................................................................................................................................................................ 73 
18 Appendix C ................................................................................................................................................................. 74 
 
 


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1 INTRODUCTION 
1.1 BACKGROUND 
Multiple Sclerosis (MS) is a chronic demyelinating 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 higher incidences in females 
versus males.  According to the Multiple Sclerosis Foundation, it estimates that >400,000 people in the United 
States and approximately 2.5 million people worldwide have been diagnosed with the disease.[1]  Previously, MS 
has been classified into four clinical subtypes: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), 
primary progressive MS (PPMS) and progressive relapsing MS (PRMS).[2]  Most recently, 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), RRMS (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 patients 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 6 injectables, 3 orals and 3 infusions.  The main target in the 
majority of these therapies has been on the T cells.  Despite improvements in the available therapies in reducing 
relapses by up to 65% [4] and slowing the progression of the disease, patients continue to experience disease 
relapses and progression.  Recent immunopathologic and clinical studies have demonstrated that B cells also play a 
significant role in the pathogenesis of the disease.  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). 
1.2.1 PRE-CLINICAL EVALUATIONS OF UBLITUXIMAB 
1.2.1.1 IN VITRO ACTIVITY  
In an in-vitro assay using B-CLL cells from patient 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 in 
vitro ADCC against CLL cells, and a higher FcγRIIIA mediated interleukin (IL)-2 production by FcγRIIIA+ Jurkat 
cells (5).  Ublituximab demonstrated high ADCC against both patient-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).  
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-


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related anti-tumor activity with 100% tumor growth inhibition in the FL xenograft at a dose of 100mg/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). 
1.2.2 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.   These 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 patient 
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 5. 
 
Figure 1: Linear mean serum concentration-times profile after the first, the fourth and the eighth infusion of 
ublituximab 
 
 
 


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Table 5: Pharmacokinetic results after the 1st (150 mg), the 4th (450 mg) and the 8th (450 mg) infusion of 
ublituximab 
PK 
Parameters a 
1st Infusion 
150 mg  (Day 1) 
4th Infusion 
450mg  (Day 22) 
8th Infusion 
450 mg  (Day 50) 
N 
12 
11 
11 
Cmax (mg/L) 
23.4 ± 11.2 
168.6 ± 61.8 
220.5 ± 141.9 
tmax (h) 
9.0 (5.0-30.3) 
5.00 (3.1-52.0) 
5.1 (3.1-23.5) 
AUC∞ (mg.h/L) 
732.1 ± 590 
17890 ± 17730* 
50760 ± 74460 
t1/2term (h) 
13.43± 10.2 
80.7 ± 58.5* 
147.8 ± 133.8 
CL (mL/h) 
424.2 ± 389.3 
57.69 ± 42.91 
38.62 ± 26.63 
Vd/Vdss, (L) 
4.8 ± 2.1 
4.9 ± 2.3* 
5.7 ± 3.3 
      a mean ± SD, tmax: median (range) , with respect to the start of infusion                   *Accurate determination not possible 
Concentration was still measurable in at least one patient of the cohort up to day 169. Values for Cmax and AUC 
increased from the first to the eighth infusion whereas t1/2 term decreased.  
1.2.2.2 IMMUNE EFFECTS 
Significant blood lymphocyte depletion was observed in all subjects reflecting the intended biological activity of 
ublituximab.  
 
 Lymphocyte depletion was sustained until 6 months after 
start of therapy for most subjects. 
1.3 RATIONALE 
1.3.1 CLINICAL STUDIES WITH RITUXIMAB AND OCRELIZUMAB 
In vivo and in vitro studies have shown that B cells contribute to tissue damage in MS.  B cells may enhance 
autoimmune processes through the presentation of autoantigens.  Additionally, B cells can modulate the effector 
function of other autoimmune cells by producing soluble inflammatory mediators.  In MS, B cells are believed to 
cross the blood brain barrier (BBB) and undergo stimulation, antigen-driven affinity maturation and clonal 
expansion within the CNS environment.[8]  B cells are the source of differentiating plasma cells which secretes 
autoreactive antibodies, which may contribute to the demyelinating events in the CNS.   
The CD20 molecule is expressed on pre-B cells and throughout the lifecycle of both naïve and memory B cells.  It is 
not expressed on stem cells or pro-B cells at the earliest stages of B cell differentiation.  Further, it is not expressed 
on plasmablasts or terminally differentiated plasma cells.  Thus, CD20 is an ideal target for B cells targeted 
immunotherapy.  Rituximab was the first anti-CD20 monoclonal antibody (mAb) to be tested in RRMS patients.  
The rituximab Phase I trial, a 72 week open-label study consisting of 26 enrolled RRMS patients, demonstrated that 
B-cell depletion was approximately 99.8% depleted by week 2 and sustained through week 48 when patients were 
treated with rituximab (500mg day 1; 500mg day 15).[9]  Further, rituximab showed a 96% reduction in Gd-
enhancing lesions at week 24 with 100% reduction by week 72.  Clinically, the annualized relapse rate (ARR) at 48 
and 72 weeks were 0.25 and 0.22, respectively, which equated to 81% and 83% reduction from baseline, 
respectively.  The phase II (HERMES) study similarly demonstrated significant reduction in MRI and clinical 
activities, 91% reduction in the total number of Gd-enhancing lesions at weeks 12, 16, 20 and 24 compared to 
placebo and 42.3% reduction in relapse rate compare to placebo at 48 weeks.[10] 
The second anti-CD20 mAb tested in RRMS patient was ocrelizumab.  In its phase II study, similar to rituximab, 
there were significant reductions in both radiological and clinical activities.[11]  In patients treated with 
ocrelizumab (600mg), there was an 89% reduction in total number of Gd-enhancing lesions for weeks 12, 16, 20 
and 24 when compared to placebo.  Clinically, ocrelizumab treated patients achieved an 80% reduction in relapse 


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rate when compared to placebo at 24 weeks.  More recently, ocrelizumab demonstrated promising results in its 2 
Phase III trials (OPERA I and OPERA II).  In OPERA I and II, patients treated with ocrelizumab had significantly 
lower annualized relapse rates (0.156 and 0.155, respectively) compared to patients treated with IFN𝛽−
1a 44μg (0.292 and 0.29, respectively).  Further, in OPERA I and II, patients treated with ocrelizumab had 40% 
reduction in clinical disease progression compared to those treated with IFNβ-1a 44μg. [14] 
1.3.2 RATIONALE FOR THE TRIAL 
Although an ublituximab phase I has been completed in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s 
lymphoma (NHL) patients with no MTD reached at doses explored up through 1200 mg, a dose ranging study has 
not been initiated in the MS population.  It is important determine the optimal dose of ublituximab use to treat MS 
patients as well as understand the safety and tolerability profile of ublituximab in this population.  Thus, the 
purpose of this phase IIa study is to explore the safety/tolerability and dose of ublituximab in subjects with 
relapsing forms of MS. 
         
 


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2 OBJECTIVES 
2.1 PRIMARY OBJECTIVES 
• 
To determine the level of B cell depletion by ublituximab in subjects with RMS 
• 
To determine the optimal dose and infusion time for ublituximab in subjects with RMS 
2.2 SECONDARY OBJECTIVE 
• 
To examine the effect of ublituximab on the development of new Gadolinium- (Gd) enhancing lesions and new 
or enlarging T2 lesions at 24 and 48 weeks  
• 
To evaluate the % of relapses in ublituximab-treated RMS subjects 
• 
To determine immunogenicity 
• 
To evaluate the safety of ublituximab, as determined by adverse events (AEs) and serious adverse events 
(SAEs), including MS worsening 


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3 TRIAL POPULATION 
3.1 INCLUSION CRITERIA 
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. Active disease 
5. EDSS 0-5.5 (inclusive) 
6. B cell counts ≥5% of total lymphocytes 
7. Neurologic stability ≥ 30 days prior to screening and baseline 
8. 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 
acceptable method of contraception throughout the study period and for 30 days after the last dose of either 
study drug. 
9. Willingness and ability to comply with trial and follow-up procedures, give written consent   
3.2 EXCLUSION CRITERIA 
1. Treatment with Anti-CD20 or other B cell directed treatment within last 12 months   
2. Treated with alemtuzumab  
3. Subjects treated with teriflunomide within 12 months. 
a. Exceptions to above are patients who have undergone accelerated/rapid elimination with oral activated 
charcoal or oral cholestyramine ≥ 90 days of screening 
4. Prior DMT exposure within days of screening 
a. 90 days with fingolimod and natalizumab 
b. 30 days with glatiramer acetate, interferons, dimethyl fumarate, or glucocorticoids  
5. Pregnant or nursing 
6. ≥ 10 years disease duration with subjects EDSS ≤ 2.0 
7. Contraindication for MRI and gadolinium  
8. Known presence of other neurologic disorders that may mimic MS 
9. Current evidence or known history of clinically significant infection including: 
a. Chronic or ongoing active 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 HIV 
d. Prior history, suspicion, or documented positive TB test 
10. History of clinically significant CNS trauma (e.g. traumatic brain injury, cerebral contusion, spinal cord 
compression)  
11. Past or current history of medically significant adverse effects (including allergic reactions) from: 
a. Corticosteroids 
b. Diphenhydramine 
c. Murine or mouse/human chimeric antibodies 
12. Absolute neutrophil count or platelet count outside of normal range (as per reference laboratory) 


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13. Absolute lymphocyte counts less than 1000/microliter 
14. 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 >470 msec 
c. Angina not well-controlled by medication 
d. 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 
15. Significant concurrent, uncontrolled medical condition including, but not limited to, cardiac, renal, hepatic, 
hematological, gastrointestinal, endocrine, immunodeficiency syndrome, pulmonary, cerebral, 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 
16. Current participation in any other interventional clinical trial.  Participation in non-interventional trial 
requires approval of the protocol by investigator 
17. Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol 
18. Lack immunity to varicella as determined by screening.  Patient may receive vaccine and be rescreened 
19. Vaccination with live virus within 2 months of randomization 
3.3 DISCONTINUATION FROM TRIAL TREATMENT 
Subjects will be discontinued from trial treatment for any of the following reasons: 
• 
Disease progression, defined as 6 month confirmed disability progression (≥ 1 point increase in the EDSS score)   
• 
Irreversible or intolerable toxicity or abnormal laboratory values thought to be related to drug toxicity 
• 
Patient requests to withdraw consent or discontinue treatment 
• 
Pregnancy (see Section 3.3.1) 
• 
Inability of the patient to comply with trial requirements 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Inter-current illness (this will be at the investigator’s discretion) 
• 
Non-compliance/lost to follow-up 
• 
Discontinuation of the study by the Sponsor 
If a patient withdraws from treatment during the first 4 weeks due to any reason other than DLT, that patient will 
be replaced.    
After withdrawal from protocol treatment, subjects must be followed for AEs for 30 calendar days after their last 
dose of the trial drug.  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.  
In this case the investigators 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 CTCAE grade 3 or 4 laboratory abnormalities at the time of withdrawal must be followed until 
the laboratory values have returned to grade 1 or 2, unless it is, in the opinion of the investigator, not likely that 
these values are to improve because of the underlying disease.  In this case, the investigator must record his or her 
reasoning for making this decision in the subjects’ medical records and as a comment on the eCRF. 
3.3.1 PREGNANCY 


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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 treating investigator immediately if they suspect that they may 
be pregnant (a missed or late menstrual period should be reported to the treating investigator).   
If an investigator suspects that a patient may be pregnant prior to administration of trial drug(s), the trial drug(s) 
must be withheld until the result of the pregnancy test is confirmed.  If a pregnancy is confirmed, the patient must 
not receive any trial drug(s), and must be discontinued from the trial.   
If an investigator suspects that a patient may be pregnant after the patient has been receiving trial drug(s), the trial 
drug(s) must immediately be withheld until the result of the pregnancy test is confirmed.  If a pregnancy is confirmed, 
the trial drug(s) must be immediately and permanently stopped, the patient must be discontinued from the trial, and 
the investigator must notify the Study Chair or Medical Monitor as soon as possible.  If a patient becomes pregnant 
while enrolled in the trial, an SAE form should be completed and faxed to the Sponsor expeditiously.  For more details 
regarding handling and reporting of pregnancies that occur during treatment, see Section 10.11.6.  


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4 REGISTRATION/TREATMENT ASSIGNMENT PROCEDURES  
4.1 REGISTRATION PROCESS 
The patient must willingly consent after being informed of the procedures to be followed, the experimental nature 
of the treatment, potential benefits, alternatives, side-effects, risks and discomforts.  IRB approval of this protocol 
and consent form is required.  Eligible subjects who wish to participate in the study will be enrolled into the trial. 
To register a patient, the following documents should be completed by the research coordinator or data manager at 
the clinical trial site and faxed or emailed to the Sponsor (See Study Manual for Registration Information): 
• 
Signed Eligibility Screening Worksheet 
• 
Registration Form 
The Sponsor will then verify eligibility.  To complete the registration process, the Sponsor will: 
• 
Assign a patient study number 
• 
Assign a cohort and dose level for the patient 
• 
Register the patient on the study 
• 
Fax or e-mail the completed patient registration form to the participating site 
• 
Call or email the research coordinator or data manager at the participating site and confirm registration. 
 
4.2 TREATMENT ASSIGNMENT PROCESS 
A DSMB will be established to safe guard the well-being of the subjects and to advise the Sponsor whether it is 
appropriate to expand the enrollment to a dosing cohort or to initiate next dosing cohort.  The DSMB may also 
recommend to the Sponsor to terminate the enrollment to a treatment cohort.  For example, the DSMB may 
recommend early termination of enrollment to a dosing cohort that is higher than the optimal treatment cohort 
after the optimal dosing is determined or a cohort that is considered without meaningful clinical benefit.   
 
Once a subject is qualified, the Site will contact the Sponsor or its designee for cohort assignment (treatment 
assignment).  The Sponsor or its designee will issue the cohort assignment for the subject using the following 
procedures.  If DSMB deems that a cohort is not appropriate (e.g., due to safety), enrollment to that cohort and all 
higher cohorts will be terminated and all future subjects will be enrolled to the lowest incomplete cohort.  Assuming 
that no safety concern is raised after the DSMB has completed its review based on the safety data from the first two 
subjects (one placebo and one UTX treatment) in a cohort, the next qualified subject will be enrolled, if applicable.  
If, however, the new subject is qualified before the DSMB has the opportunity to review the safety data, the new 
subject will be enrolled to the lowest incomplete cohort.   For example, the first two subjects of the study will be 
enrolled to Cohort 1.  If the fourth subject is qualified before the DSMB has the chance to review the safety data from 
the first two subjects, the subject will be enrolled to Cohort 1.   
 
 


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5 TREATMENT PLAN 
5.1 DOSING SCHEMA 
Table 6: Ublituximab/Placebo (Dose Range) 
 
Randomization 
Treatment Period 
Cohort 
Subjects and 
treatment 
Day 1/ infusion 
time  
Day 15/ infusion 
time  
Week 24/ infusion 
time  
1 
Placebo (n=2)b 
Placebo / 4h 
Placebo / 3h 
- 
UTX (n=6) 
150 mg / 4h 
450 mg / 3h 
450 mg / 1.5h 
2 
Placebo (n=2)b 
Placebo / 4h 
Placebo / 1.5h 
- 
UTX (n=6) 
150 mg / 4h 
450 mg / 1.5h 
450 mg / 1h 
3 
Placebo (n=2)b 
Placebo / 4h 
Placebo / 1h 
- 
UTX (n=6) 
150 mg / 4h 
450 mg / 1h 
600 mg /1h 
4 
Placebo (n=2)b 
Placebo / 3h 
Placebo / 1h 
- 
UTX (n=6) 
150 mg / 3h 
600 mg / 1h 
600 mg /1h 
5 
Placebo (n=2)b 
Placebo / 2h 
Placebo / 1h 
- 
UTX (n=6) 
150 mg / 2h 
600 mg / 1h 
600 mg /1h 
6 
Placebo (n=2)b 
Placebo / 1h 
Placebo / 1h 
- 
UTX (n=6) 
150 mg / 1h 
600 mg / 1h 
600 mg /1h 
Cohort 
expansiona 
Up to 100 
To be explored at selected doses pending on the results of the above 
doses 
 
 
a  Additional cohorts may be evaluated at doses ranging from 25 mg up to 900 mg to further elucidate the level of B-
cell depletion and recovery parameters in subjects with RMS 
b Following completion of Day 28, all placebo subjects will enter their respective “a” cohort and receive active 
treatment as described in Table 7 below. Further, the study evaluation table (section 7) will be restarted for these 
patients upon the initiation of active treatment with ublituximab 
 
Table 7: Treatment Schema for Placebo Subjects after Day 28 
Cohort 
Subjects  
Day 1/ infusion time  
Day 15/ infusion time  
Week 24/ infusion 
time  
1a 
Pbo patients from 
Cohort 1 
150 mg UTX 
/ 4h 
450 mg UTX 
/ 3h 
450 mg UTX 
/ 1.5h 
2a 
Pbo patients from 
Cohort 2 
150 mg UTX 
/ 4h 
450 mg UTX 
/ 1.5h 
450 mg UTX 
/ 1h 
3a 
Pbo patients from 
Cohort 3 
150 mg UTX 
/ 4h 
450 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
4a 
Pbo patients from 
Cohort 4 
150 mg UTX 
/ 3h 
600 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
5a 
Pbo patients from 
Cohort 5 
150 mg UTX 
/ 2h 
600 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
6a 
Pbo patients from 
Cohort 6 
150 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
600 mg UTX 
/ 1h 
 


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5.1.1 DOSE-LIMITING TOXICITY  
Toxicity will be assessed utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE).   
Toxicity will be considered dose-limiting if it occurs during the first 4 weeks of treatment and is considered at least 
possibly related to ublituximab.  Any event defined below, unless the investigator considers the event clearly 
unrelated to study drug or due to extraneous causes, will be considered a dose-limiting toxicity.   
Dose-limiting toxicities will be defined as the following: 
• 
Grade 4 anemia; Grade 4 neutropenia or thrombocytopenia lasting >7 days;  Grade ≥3 febrile neutropenia; and 
Grade ≥3 thrombocytopenia with Grade >2 hemorrhage; 
• 
Grade ≥ 3 non-hematologic toxicity unresponsive to standard supportive care measure with the exception of:   
o Grade ≥3 ALT/AST elevation that resolves to ≤ Grade 2 within 7 days; 
o Infusion related reactions (IRR’s) Grade > 3 related to ublituximab occurring at the 1st infusion, which 
does not affect continuation to subsequent infusions  
• 
Treatment delay of ≥14 days due to unresolved toxicity; and  
• 
Non-hematologic toxicity of Grade 2 (at any time during treatment) that, in the judgment of the Investigators, 
Study Chair, and the Medical Monitor, is dose-limiting. 
Adverse events meeting the above definitions but are clearly unrelated to study drug will not be considered DLTs.  
In rare instances an event may fall within the definition of a DLT as defined above but the event may not be 
considered a DLT (i.e., not clinically meaningful/significant).  If this occurs, a meeting with the Investigator(s), the 
Medical Monitor, and the Study Chairs, will take place to thoroughly review the event and supporting data, and the 
reasons for not considering the event a DLT will be clearly documented with supporting rationale.  In addition, 
other events may occur which do not meet the definition of a DLT but are concerning to the Investigator(s), 
Medical Monitor, and Study Chairs, and may be then considered to be DLTs. 
 
5.1.2 DETERMINATION OF DOSE-LIMITING TOXICITY  
The patient population used for determination of DLT will consist of subjects who have met the minimum safety 
evaluation requirements of the study, and/or who have experienced a DLT.  Minimum safety requirements will be 
met if, during the first 4 weeks of treatment of the study, the patient completes all required safety evaluations, and 
is observed for at least 4 weeks following the first dose of ublituximab.  Subjects who experience a DLT will be 
considered evaluable regardless of the number of doses received.  
Subjects who discontinue treatment early due to disease progression or withdrawal will be asked to have all end-
of-treatment safety evaluations performed as described in the protocol.  If a patient withdraws from treatment 
during the first 4 weeks due to any reason other than a DLT, that patient may be replaced. 
5.1.3 STOPPING RULES  
The DSMB (Study Chairs, Medical Monitor and Sponsor Representative) will be in charge of reviewing safety data 
after the first 4 weeks of therapy for the last patient in each cohort, and will decide whether or not it is possible to 
proceed to the next cohort according to the dosing schema described in Section 5.1 These events will be reviewed 
by the DSMB and potentially other study Investigators at the end of each cohort and routinely thereafter during the 
course of the study.  All other serious and non-serious adverse events will be documented, managed including 
possible reductions in dose according to investigator discretion, followed until resolution or stabilization, and will 
also be reviewed by the DSMB at the end of each cohort and routinely thereafter during the course of the study.  


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The Data Review Group will look at the total safety data in determining whether it is possible to proceed to the 
next dose cohort and have discretion to apply the following:  
Suspension of Patient Enrollment: 
In the event of one (1) death attributed to the study drug(s), study accrual will be suspended pending further 
investigation, and will only be resumed at the recommendation of the DSMB and the Investigators.  The DSMB will 
have discretion to terminate the trial if an additional death occurs that can be attributed to either or both of the 
study drugs. 
 
5.2 AGENT ADMINISTRATION 
Treatment will be administered in the MS center. The MS centers must have skilled personnel and adequate 
equipment to provide emergency treatment should the subject experience anaphylaxis, hypotension or respiratory 
distress.  Subjects will be enrolled into a specified cohort. A single dose of 150 mg of ublituximab on Day 1 with an 
infusion rate of 4 hours, 450 or 600 mg on Day 15 at different infusion rates (see dosing scheme), and at week 24, a 
single dose of 450 or 600 mg of ublituximab with different infusion rates will be administered to the respective 
cohorts.  Additionally, 2 subjects in each cohort will be randomized to a placebo group.  On day 28, the placebo 
subjects will begin active treatment with ublituximab in its respective cohort (see dosing scheme).  Administration 
of ublituximab and placebo will be under the direction of the study investigators.  Additional dosing cohorts may 
be explored. 
It is required the absolute neutrophil counts and the platelet count should be within normal range before the 
infusion of ublituximab. 
If the liver enzymes (ALT and/or AST) are > 5 times the upper limit of normal (ULN) of the normal range, or if the 
neutrophil count and platelets counts are below acceptable levels as described, the dose of ublituximab will be held 
for up to 48 hours until the laboratory values return to within acceptable range. If all labs above do not return to 
within the acceptable range within 48 hours, the subject will not receive the ublituximab infusion and will be 
withdrawn from the study. Subjects who are withdrawn will be asked to enter the follow-up evaluation period of the 
study. 
 
 
5.2.1 GUIDELINES FOR ADMINISTRATION OF UBLITUXIMAB 
• 
Necessity of MS Center: Center must have personnel and equipment necessary to provide adequate 
emergency treatment for anaphylaxis, hypotension and respiratory distress. 
• 
Method of Administration: Ublituximab must be administered as an intravenous infusion through a dedicated 
intravenous line and will be done under the supervision of the study investigator 
• 
Potential Drug Interactions:  No drug interactions have been reported to date. 
• 
Pre-medications: Pre-medicate approximately 30 minutes prior to each dose of ublituximab with an 
antihistamine (diphenhydramine 50 mg or equivalent), and corticosteroid (dexamethasone 10-20mg or 
equivalent).  Oral acetaminophen, 650 mg (or equivalent; only used for intervention) should be restricted 
to patient 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. 


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• 
Hypersensitivity and Infusion Reaction Precautions: Medication and resuscitation equipment utilized by a 
trained personnel must be available per institutional guidelines prior to ublituximab administration for the 
emergency management of potential anaphylactic reactions   
• 
Subject Care Implications:   
o Ublituximab should not be administered as an IV push or bolus. 
o Ublituximab should only be diluted in 0.9% NaCl. 
o Diluted ublituximab should be checked before administration for cloudiness, color, or deposits.  
Ublituximab 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 be administered immediately after dilution. 
o No other treatment may be co-administered with ublituximab (other than for immediate intervention for 
adverse event). 
 
5.2.1.1 INFUSION RELATED REACTIONS AND INFUSION RATE GUIDANCE 
Infusion related reactions, including severe reactions, have been reported with ublituximab administration in 
subjects with CLL and NHL.  Guidelines are provided below for subjects who experience such reactions.  
Symptomatic infusion reactions, despite premedication, may be treated at the discretion of the Principal 
Investigators using the following or other appropriate treatments: oral acetaminophen 650 mg, corticosteroids, 
antihistamines, oxygen, and bronchodilators.   
The following are recommended infusion rate reduction/delay guidelines for subjects who experience severe 
Infusion Related Reactions (IRR’s) that require treatment interruption. The final decision for the infusion rate 
reduction/delay or discontinuation resides with the treating investigator. Infusion rates should be considered 
targets for each respective cohort.  If the treating investigator decides to interrupt the infusion or slow the infusion 
rate, then the reduction/delay and the reason for it must be noted on the eCRF and infusion log. 
 
 
Infusion Interruption: 
• 
Stop the infusion, and closely monitor the subject. Institute symptomatic medical management until 
resolution of IRR symptoms. 
• 
Following the judgment of the investigator and provided the subject is stable, the infusion may be resumed 
at no more than half the previous rate. 
If the subject does not experience any further IRR symptoms, the infusion may be resumed at the increments and 
intervals as appropriate for the treatment dose. 
 
If there is a second interruption of treatment due to IRR symptoms, ublituximab infusion must be stopped.  The 
treating physician may decide whether to attempt completion of the infusion on a second day. 
 
5.2.1.2 DISPENSING OF UBLITUXIMAB 
Before dispensing, the site pharmacist or his/her representative must check that the ublituximab product received 
is in accordance with the product specifications and the re-test/expiration date.   
The exact dose, date and time of administration of ublituximab must be recorded within the CRF, the subject’s 
medical records and/or in the drug accountability records. 


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The pharmacist or his/her representative should complete the accountability forms with information concerning 
the dispensation of ublituximab. Preparation should be done by the pharmacist or his/her representative 
according to instructions for sterile dilution provided below.   
The pharmacist or his/her representative should record the date dispensed and the subject’s study identification 
number and initials, as well as complete the accountability forms with information concerning the dispensation of 
ublituximab. Preparation should be done by the pharmacist or his/her representative according to instructions for 
sterile dilution. 
 
 
5.3 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
The following treatments are prohibited while on clinical trial:  other investigational drug treatments or study 
participation, other DMTs used to treat MS, radiation therapy, hormonal therapy for cancer, cancer immunotherapy 
or other biologic therapy excluding trial drugs. 
• 
No glucocorticoids may be administered outside of protocol requirements for premedication or AE 
management, except low doses of steroids stabilized at < 10 mg per day of prednisone or equivalent, and 
started at least 7 days prior to study entry. 
Neutropenia: Granulocyte colony stimulating factor (G-CSF; filgrastim or pegfilgrastim) may be used during the 
course of the study after the first 28 days during the dose-escalation portion, at the investigator discretion.  The 
drug(s) should be used at a dose/schedule specified in the package insert.  During the cohort expansion, GCSF may 
be used at the discretion of the investigator. 
Antiemetics: Ublituximab is considered to be of low emetogenic potential that may be adequately prevented with 
prochlorperazine.  Other antiemetics may be used at the discretion of the treating physician if nausea and/or 
vomiting is not adequately controlled/prevented.  
Infusion Reactions with ublituximab: Infusion related reactions have been reported with ublituximab, more 
profound in patients with hematologic malignancies.  All subjects treated with ublituximab require pre-medication 
approximately 30 minutes prior to each dose of ublituximab with an antihistamine (diphenhydramine 50 mg or 
equivalent), and a corticosteroid (dexamethasone 10-20 mg or equivalent).  Symptomatic infusion reactions despite 
premedication, 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. 
 
MS Relapses during the study: 
Any patient experiencing a multiple sclerosis relapse while on study will be allowed rescue therapy with 
intravenous methylprednisolone 1gm/day for up to 5 consecutive days.  Subjects requiring rescue therapy will 
have an MRI scan 10 days after completion of treatment with steroids. 
Re-consent criteria 
In case of a confirmed diagnosis of MS relapse (as defined in the protocol, Appendix C), or in case of an increase in 
EDSS of 1.0 points or more, sustained for at least 3 months, during the study, the following actions will be taken: 
1. 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.  
2. The subject will be requested to re-sign an informed consent form if he/she chooses to continue to participate in 
the study, in the same treatment assignment. 
Subjects enrolled into the study will be closely monitored through the study course by the Sponsor’s personnel as 
well as by an external independent data monitoring committee (DSMB) in order to ensure subjects’ welfare. 


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5.4 DURATION OF THERAPY 
In the absence of treatment delays due to adverse event(s), treatment should continue through first 24 weeks and 
beyond unless one of the following criteria applies: 
• 
Disease progression or inter-current illness that prevents further treatment, 
• 
Patient decides to withdraw from the study, or changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
The first efficacy assessment should be approximately 24 weeks after Day 1 (± 7 days) and approximately another 
24 weeks thereafter (± 7 days) through the first 48 weeks following initiation of therapy. 
The reason for study removal and the date the patient was removed must be documented in the Case Report Form. 
Subjects who discontinue therapy due to an adverse event should be followed until disease progression. 
 
5.5 END OF STUDY/OPEN LABEL EXTENSION STUDY 
Subjects who are in good health with stable disease and has completed the treatments and scheduled assessments 
through the final study visit may have the option of entering a 112 week open label extension study, with a 
continuation of treatment, and relapse and safety monitoring.  The criteria for entering the open label extension 
study will be clearly stated in a separate protocol (TG1101-RMS201E). 
 


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6 DOSING DELAYS/DOSE MODIFICATION - RECOMMENDATIONS 
Subjects 
should 
be 
assessed 
clinically 
for 
toxicity 
at 
each 
visit 
using 
the 
NCI 
CTCAE 
v4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE) grading scale. 
Dosing will occur only if a patient’s clinical assessment and laboratory test values are acceptable.   
Dose modification and or intervention with supportive care recommendations for ublituximab is  provided below, 
however final discretion lies with the treating investigator in regards to more or less aggressive intervention, if the 
investigational agent needs to be reduced, and actual dose reductions, as well as the number of dose reductions. 
6.1 CRITERIA FOR ONGOING TREATMENT 
Repeat treatment should be administered per protocol provided that: 
• 
Renal function should continually be assessed, with appropriate dose modifications as needed 
• 
Recovered from grade 3-4 non-hematologic toxicity to grade 2 or less.  
• 
Treatment may be delayed to recover from toxicity or per investigator discretion.  
• 
No clinical or radiographic evidence of disease progression.  
6.2 IMPORTANT DOSE MODIFICATIONS 
For RMS subjects, the hematologic dose modifications are graded by the CTCAE v4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE). 
6.2.1 DOSE MODIFICATIONS OF UBLITUXIMAB 
If toxicity, in the opinion of the investigator, is attributable to ublituximab, the following guidelines for 
neutropenia, thrombocytopenia, anemia, and elevated liver enzymes are recommended below (for Infusion Related 
Reactions, see Section 6.2.1.2).  Final discretion lies with the treating investigator in regards to more or less 
aggressive dose reductions, as well as the number of dose reductions. 
6.2.1.1 LAB ABNORMALITIES 
If cytopenias are deemed related to the underlying disease rather than ublituximab, dose reductions are 
not required, or are per investigator discretion. 
Worst CTCAE 
Grade Toxicity 
Action to be Taken 
Neutropenia 
Grade 
Management 
≤ Grade 1 
No action required. 
Grade 2 
No action required; consider growth factor support. 
Grade 3 or 4 
1st Occurrence 
Hold until < Grade 3.  Consider growth factor support per protocol 
requirement.  Resume ublituximab at current dose cohort. Hold until < Grade 
3.  Consider growth factor support per protocol requirement.  Resume 
ublituximab at current dose cohort. 
Grade 3 or 4 
subsequent 
Occurrences 
Hold until < Grade 3.  Consider growth factor support.  Resume ublituximab at 
current dose cohort. 
Management of neutropenia are per institution guidelines and if in the opinion of treating 
investigator, are appropriate for patient care. 


TG1101-RMS201 
 
 
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Worst CTCAE 
Grade Toxicity 
Action to be Taken 
Thrombocytopenia or Anemia 
Grade 
Management 
≤ Grade 1 
No action required. 
Grade 2 
No action required. 
Grade 3 or 4 
1st Occurrence 
Hold until < Grade 3, or at subjects previous baseline. Resume ublituximab at 
current dose cohort. 
Grade 3 or 4 
subsequent 
Occurrences 
Hold until < Grade 3, or at subjects previous baseline.  Resume ublituximab at 
current dose cohort. 
Management of thrombocytopenia and anemia are per institution guidelines and if in the opinion 
of treating investigator, are appropriate for patient care. 
 
Worst CTCAE 
Grade Toxicity 
Action to be Taken 
Elevated Liver Enzymes 
Grade 
Management 
≤ Grade 1 
No action required. 
Grade 2 
No action required. 
Grade 3 or 4 
1st Occurrence 
Hold until < Grade 1, or at subjects previous baseline. Resume ublituximab at 
current dose cohort. 
Grade 3 or 4 
subsequent 
Occurrences 
Hold until < Grade 3, or at subjects previous baseline.  Resume ublituximab at 
current dose cohort. 
Management of elevated liver enzymes are at the discretion of the investigator and should be 
discussed with TG Therapeutics. 
 
6.2.1.2 INFUSION RELATED REACTIONS 
Infusion related reactions have been reported with ublituximab.  All subjects treated with ublituximab require pre-
medication approximately 30 minutes prior to each dose of ublituximab or placebo with an antihistamine 
(diphenhydramine 50 mg or equivalent), and a corticosteroid (dexamethasone 10-20 mg or equivalent).  
Symptomatic infusion reactions, despite premedication, may be treated at the discretion of the treating physician, 
including but not limited to: oral acetaminophen 650 mg (or equivalent), corticosteroids, antihistamines, oxygen and 
bronchodilators. 
6.2.1.2.1 INFUSION RATE REDUCTIONS DUE TO INFUSION RELATED REACTIONS 
The following are recommended infusion rate reduction/delay guidelines for subjects who experience severe 
Infusion Related Reactions (IRR’s) in which treatment must be interrupted.  Infusion rates should be considered 
targets for each respective cohort.  If the treating investigator decides to interrupt the infusion or slow the infusion 
rate, then the reduction/delay and the reason for it must be noted on the eCRF and infusion log. 
1st Dose Interruption: 
• 
The patient must be closely monitored until resolution of symptoms.  
• 
Following the judgment of the Investigator, and provided vital signs are stable and normal saline has infused 
for at least 30 minutes, the infusion may be resumed at maximum 50% of previous rate. 
• 
The rate should be increased by 50% every 30 minutes to the max rate of 100 mL/hr as long as tolerated. 
2nd Dose Interruption (same day): 


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• 
Wait approximately 2 hours.  The patient should be closely monitored until resolution of symptoms. 
If there is a second interruption of treatment due to IRR symptoms, ublituximab infusion must be stopped.  The 
treating physician may decide whether to attempt completion of the infusion on a second day. 
 
• 
If the dose discontinued is the Day 1 infusion, administration of the remainder of the dose on Day 2 is 
permitted as follows:   
o On Day 2, if patient symptoms have resolved, estimate remaining dose needed and prepare 
accordingly for infusion. 
o Begin infusion of remaining dose according to the infusion rate guidelines presented above for the 
first infusion of ublituximab.   
If the patient has a dose interruption on Day 2, discontinue the infusion.  The patient should again be monitored for 
all symptom resolution prior to release from trial site.  The patient should start their next scheduled infusion at the 
protocol specific dose (Day 15) and infusion rate.   If infusion rate reductions should be needed for the Day 15 
infusion, please refer to the above recommendations.  Final decision for infusion rate or discontinuation resides with 
the treating investigator. 
 


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7 STUDY EVALUATION TABLE 
Baseline evaluations / laboratory tests are to be conducted within 28 days prior to Day 1.  MRI scans used to 
identify measurable/evaluable disease are required to be done within 30 days prior to Day 1.  In the event that the 
patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of 
the next infusion. 
 
 
Screen-
ing 
 
Baseline 
 
 
 
 
 
 
 
 
 
 
                          Study End 
Procedure 
 
W1 
W1 
W2 
W3 
W4 
W8 
W12 
W16 
W20 
W24 
W24 
W25 
W28 
W36 
W40 
W44 
W48 
 
D (-28 
to 0 
D1 
D2 
 
D15 
 
 
 
 
 
 
 (2 
days 
post 
week 
24 
dose) 
 
 
 
 
 
 
Patient 
consent 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X12 
Medical 
history 
Х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
Pregnancy 
test1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
Pregnancy 
Test5 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
EDSS and 
Neurological 
Assessment4,1
1 
Х 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Physical 
exam8 & Vital 
signs (pulse  
rate, BP, 
temperature)
3,4 
Х 
X 
X 
X 
X 
X 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Relapse 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRI4 
Х 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
12 Lead ECG9 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Blood 
collection for 
CBC and 
serum 
chemistry3,4 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
collection for 
Immunologic
al  analyses3,4 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fibrinogen 4,5 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK analysis 4, 
6 
 
X 
 
X 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
Ublituximab 
Dose 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serology: 
HIV, HCV, 
HBV, 
varicella2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-drug 
Abs3,7, 10,4 
 
X 
 
 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
PT/INR 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative 
Immunoglob
ulin3,4 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Adverse 
events (CTC 
v4.0)4 
 
X 
X 
X 
X 
X 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication4 
X 
X 
X 
X 
X 
X 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


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1 For women of child bearing potential completed within 5 days prior to Day 1 
2 To confirm negative HIV 1 and 2, HBV and HCV 
3 Pre-dose on any day of infusion  
4 Weeks 8 and beyond, collections/assessments may occur ±2 days from specified time points  
5Prior to each dosing  
6 Prior to and 15-30 minutes after each dosing on UTX treatment days; for non-treatment days, 1 PK sample should be obtained 
7 To confirm potential development of human anti-chimeric antibodies 
8 Physical exam will occur on all visits except Days 2 and 15 and weeks 2, 24 and 25 
9 Pre-dose and post-dose on any day of infusion 
10 Anti-drug antibodies are antibodies developed against ublituximab 
11 EDSS Assessment will be assessed based on a slightly modified neurological examination as fatigue will not contribute to the EDSS assessment 
12 Consent for open label extension study 
7.1 OVERVIEW 
All subjects should visit the study center on the days specified within this protocol.  The complete schedule of 
assessments is shown in Section 7.  The baseline physical examination with vital signs, medical history, evaluation 
of concomitant medications, EDSS (will be assessed based on a slightly modified neurological examination as 
fatigue will not contribute to the EDSS assessment), complete blood count/full blood count (3 part differential 
accepted), serum chemistry, and a baseline ECG should be done within 28 days prior to initiation of treatment.  For 
women of child bearing potential, a serum pregnancy test should be completed within 5 days prior to Day 1.  MRI 
scans should be performed ≤30 days prior to initiation of treatment.  In the event that the patient’s condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next infusion. 
Subjects who are in good health with stable disease and has completed the treatments and scheduled assessments 
through the final study visit may have the option of entering a 112 week open label extension study, with a 
continuation of treatment, and relapse and safety monitoring. Entry into the open label extension will require patient 
consent and fulfillment of entry criteria per the TG1101-RMS201E open label extension protocol.    
 
7.1.1 LABORATORY EVALUATION 
1. Hematologic profile: CBC/FBC with differential and platelet count should be obtained at: 
a. For subjects initially treated with UTX: 
i. Blood collection for CBC and serum chemistry at baseline, and day 1 (pre-dose), 2, 8, 15 
(pre-dose), and week 4, 8, 12, 16, 20, 24 (pre-dose and 2 days post-dose), 25, 28, 36, 40, 44 
and 48 
b. For subjects initially treated with placebo followed by UTX treatment  
i. Blood collection for CBC and serum chemistry at baseline, and day 1 (pre-dose), 2, 8, 15 
(pre-dose), and week 4.  Once the subject starts UTX treatment, blood collection for CBC and 
serum chemistry on day 1 (pre-dose), 2, 8, 15 (pre-dose), and week 4, 8, 12, 16, 20, 24 (pre-
dose and 2 days post dose), 25, 28, 36, 40, 44 and 48 
 
2. Serum chemistry should be obtained at the same schedule for hematologic profile (outlined above) 
Serum Chemistry 
Albumin 
Creatinine 
SGOT [AST] 
Alkaline phosphatase 
Glucose 
SGPT [ALT] 
Bicarbonate 
LDH 
Sodium 
BUN 
Magnesium 
Total bilirubin 
Calcium 
Phosphorus 
Total Protein 


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Chloride 
Potassium 
Uric acid 
 
3. Serum pregnancy test should be obtained within 5 days prior to the initiation of therapy for women of 
childbearing potential. 
4. PT/INR should be drawn on Day 1 prior to administration. 
5. Quantitative immunoglobulin (IgG, IgM, IgA) test should be analyzed by a local laboratory on Day 1 (pre-
dose), week 12, week 24 (pre-dose), and weeks 36 and 48. 
6. Coagulant (Fibrinogen) tests will be obtained at the same schedule for hematologic profile (outlined above) 
 
 
a. Samples will be drawn from all subjects at Baseline (Day 1) prior to the first infusion of UTX and 
15-30 minutes after the completion of the infusion; on Day 15 prior to the infusion of UTX and 15-
30  minutes after the completion of the infusion; on Day 180  (week 24) prior to the infusion of UTX 
and 15-30 minutes after the completion of the infusion;  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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7.1.2 RADIOLOGICAL EVALUATION 
Assessment of effect on Gd enhancing lesion and new and enlarging T2 lesions will be evaluated as outlined in the 
schedule of events.  For subjects initially treated with placebo, they will obtain a MRI at baseline and on week 4 
(prior to start of UTX treatment). 
Additionally, all study MRIs will undergo safety review by the site radiologist to 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 provide a report of the MRI to the treating physician. 
7.1.3 NEUROLOGICAL EVALUATION 
Assessment of effect on relapse rate will be evaluated as outlined in the schedule of events.  For subjects initially 
treated with placebo, they will obtain a neurological evaluation at baseline and on week 4 (prior to start of UTX 
treatment).  EDSS will be assessed based on a slightly modified neurological examination as fatigue will not 
contribute to the EDSS assessment. 
7.1.4 RELAPSE ASSESSMENT 
Relapses are defined as the occurrence of new or worsening neurological symptoms attributable to MS, and 
immediately preceded by a stable or improving neurological state of at least 30 days.  Symptoms that persists for 
more than 24 hrs in the absence of fever and be accompanied by objective neurological worsening consistent with 
an increase ≥0.5 on the EDSS (subjects with baseline EDSS of >1.0) or an increase ≥1.0 on the EDSS (subjects with 
baseline EDSS=0). 


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Subjects will be assessed for relapse by the treating investigator at each study visit as outlined in the study 
evaluations table and, if necessary, at unscheduled visits.  If a protocol defined relapse does occur, it will be 
documented in the eDC. 
MS Relapses during the study: 
Any patient experiencing a multiple sclerosis relapse while on study will be allowed rescue therapy with 
intravenous methylprednisolone 1gm/day for up to 5 consecutive days.  Subjects requiring rescue therapy will 
have an MRI scan 10 days after completion of treatment with steroids. 
Re-consent criteria 
In case of a confirmed diagnosis of MS relapse (as defined in the protocol, Appendix C), or in case of an increase in 
EDSS of 1.0 points or more, sustained for at least 3 months, during the study, the following actions will be taken: 
3. 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.  
4. The subject will be requested to re-sign an informed consent form if he/she chooses to continue to participate in 
the study, in the same treatment assignment. 
7.2 DEFINITIONS 
Evaluable for toxicity.  All subjects will be evaluable for toxicity from the time of their first treatment on 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. 
7.3 DISEASE PARAMETERS 
Measurable disease:  Diagnosis of RMS will be based on the 2010 McDonald’s criteria (Appendix C). 
7.4 DURATION OF RESPONSE 
Duration of stable disease: 
Stable disease is measured from the start of the treatment 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.  
7.5 RESPONSE REVIEW 
Subjects will be assessed for relapse by the treating investigator at each study visit as outlined in the study 
evaluations table and, if necessary, at unscheduled visits.   
Relapses are defined as the occurrence of new or worsening neurological symptoms attributable to MS, and 
immediately preceded by a stable or improving neurological state of at least 30 days.  Symptoms that persists for 
more than 24 hrs in the absence of fever and be accompanied by objective neurological worsening consistent with 
an increase ≥0.5 on the EDSS (subjects with baseline EDSS of >1.0) or an increase ≥1.0 on the EDSS (subjects with 
baseline EDSS=0). 
 
 


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8 PHARMACEUTICAL INFORMATION 
8.1 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 () heavy chains and two kappa () 
light chains linked by disulfide bridges. It is composed of a murine variable region (37.2% of 
total amino acids) fused onto human constant regions. 
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.  Ublituximab must not be frozen. 
Stability: 
Once a vial of ublituximab has been opened and/or diluted it must 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 24 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 
• 
Unit kit of 6 vials per kit with each vial 15 mL 
OR 
• 
Six 6 mL vial containing 25 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 6 mL is a type I glass vial closed by a 
siliconized chlorobutyl rubber stopper sealed with an aqua plastic aluminum cap. 


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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 a white plastic and 
aluminum cap. 
Availability: 
 
Ublituximab is available from TG Therapeutics. 
 
8.1.1 COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS) 
The following adverse events were observed in subjects treated with single agent ublituximab and were considered 
at least possibly related to study medication.  See the ublituximab investigator brochure for a complete list of all 
adverse events reported regardless of causality. 
8.1.1.1 COMMON (>20%) 
• 
Blood and lymphatic system disorders:  Neutropenia, Thrombocytopenia 
• 
General disorders and administration site conditions: Infusion-related reaction, Pyrexia, Chills 
• 
Nervous system disorders:  Headache 
 
8.1.1.2 LESS COMMON (10-20%) 
• 
Blood and lymphatic system disorders:  Anaemia 
• 
Gastrointestinal disorders: Diarrhoea, Nausea, Abdominal Pain Upper 
• 
General disorders and administration site conditions:  Fatigue, Asthenia 
 
8.1.1.3 UNCOMMON (ADVERSE EVENTS REPORTED IN AT LEAST 2 PATIENTS BUT < 10%) 
• 
Blood and lymphatic system disorders:  Febrile neutropenia, Pancytopenia 
• 
General disorders and administration site conditions:  Pain 
• 
Infections and infestation:  Bronchitis 
• 
Investigations: Blood bilirubin increase, Alanine aminotransferase increased, Aspartate aminotransferase 
increased, Gamma-glutamyltransferase increased, Elevated liver enzymes 
• 
Musculoskeletal and connective tissue disorders:  Muscle weakness 
• 
Nervous system disorders: Dysgeusia 
• 
Respiratory, thoracic and mediastinal disorders:  Throat irritation/tightness, Dyspnea 
• 
Skin and subcutaneous tissue disorders: Pruritus 
• 
Vascular disorders: Hypertension 
8.1.2 DISPENSING 
Before dispensing, the site pharmacist or his/her representative must check that ublituximab is in accordance with 
the product specifications and the validity is within the re-test and expiry date. 
The exact dose and the date and time of administration of ublituximab must be recorded within the CRF, patient’s 
medical records, and/or in the drug accountability records. 
The Pharmacist or his/her representative should record the date dispensed and patient’s number and initials on 
the labels. He/she should complete the accountability forms with information concerning the dispensation of 
ublituximab. Preparation should be done by the Pharmacist or his/her representative according to instructions for 
sterile dilution included within the unit boxes of ublituximab.  Dilution for ublituximab is as follows: 
8.1.2.1 DILUTIONS OF UBLITUXIMAB 


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Ublituximab must not be mixed with other medicinal products.  Ublituximab should only be diluted in 0.9% NaCl 
before use.  No data are available for other solutions such as 5% dextrose and 5% mannitol. 


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Ublituximab or IV placebo must not be mixed with other medicinal products.  
 
 
 
 
Dose of 
ublituximab for 
infusion 
150 mg 
450 mg 
600 mg 
 
 
 
Dose of 
ublituximab for 
infusion 
150 mg 
450 mg 
600 mg 
8.1.3 ADMINISTRATION 
• 
IV administration only.  Ublituximab should not be administered as an IV push or bolus. 
• 
Ublituximab must be checked before being administered for cloudiness, color, soapy aspect, or deposits. 
• 
Ublituximab must not be administered if does not conform to the specifications. The Investigator or his/her 
representative must immediately inform the Monitor/Sponsor. 
• 
In accordance with Section 5.3, a list of pre-medication will be administered before infusion of ublituximab.  
• 
Since infusion-related hypotension may occur, antihypertensive medications should be withheld 24 
hours prior to and throughout infusion of ublituximab 
• 
No other treatment may be co-administered with ublituximab (other than for immediate intervention for 
adverse event). 
• 
It is recommended that ublituximab be administered immediately after dilution. 
 
Ublituximab should be administered only by slow infusion via intravenous route as a single administration as 
described below:  
• 
1st infusion  in approximately 4 hours 
• 
2nd and 3rd infusion  in approximately 1 to 3 hours, depending on the cohort 
The flow rate is specified in the tables below. 
 
8.1.3.1 FLOW RATE RECOMMENDATIONS FOR UBLITUXIMAB ADMINISTRATION 
1st infusion over 4 hours for all cohorts 


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1ST INFUSION OF UBLITUXIMAB OR PLACEBO 
Cohorts 
Ublituximab 
Dose 
Total volume 
to be infused 
Infusion rate 
T0 to T30’ 
T30' to T1H 
T1H to T2H 
T2H to T4H 
1-3 
150 mg 
250 mL 
10 mL/H 
20 mL/H 
35 mL/H 
100 mL/H 
 
Cohorts 
Ublituximab 
Dose 
Total volume 
to be infused 
Infusion rate 
T0 to T30’ 
T30' to T1H 
T1H to T2H 
T2H to T3H 
4 
150 mg 
250 mL 
10 mL/H 
20 mL/H 
85 mL/H 
150 mL/H 
 
Cohorts 
Ublituximab 
Dose 
Total volume 
to be infused 
Infusion rate 
T0 to T30’ 
T30' to T1H 
T1H to T2H 
5 
150 mg 
250 mL 
10 mL/H 
40 mL/H 
225 mL/H 
 
Cohorts 
Ublituximab 
Dose 
Total volume 
to be infused 
Infusion rate 
T0 to T30’ 
T30' to T1H 
6 
150 mg 
250 mL 
50 mL/H 
450 mL/H 
 
 


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2nd infusion  
2ND INFUSION OF UBLITUXIMAB OR PLACEBO 
Cohort 
Ublituximab Dose 
Total volume to be infused 
Infusion rate 
T0 to T1H 
T1H to T2H 
T2H to T3H 
1 
450  
250 mL 
25 mL/H 
75 mL/H 
150 mL/H 
 
Cohort 
Ublituximab Dose 
Total volume to be infused 
Infusion rate 
T0 to T30 min 
T30 min to T90min 
2 
450  
250 mL 
100 mL/H 
200 mL/H 
 
Cohort 
Ublituximab Dose 
Total volume to be infused 
Infusion rate 
T0 to T30min 
T30min to T60min 
3 
450 mg 
250 mL 
100 mL/H 
400 mL/H 
 
Cohort 
Ublituximab Dose 
Total volume to be infused 
Infusion rate 
T0 to T30min 
T30min to T60min 
4-6 
600 mg 
250 mL 
100 mL/H 
400 mL/H 
 
3rd infusion  
3RD INFUSION OF UBLITUXIMAB 
Cohort 
Ublituximab Dose 
Total volume to be infused 
Infusion rate 
T0 to T30min 
T30min to T90min 
1 
450  
250 mL 
100 mL/H 
200 mL/H 
 
Cohort 
Ublituximab Dose 
Total volume to be infused 
Infusion rate 
T0 to T30min 
T30min to T60min 
2 
450  
250 mL 
100 mL/H 
400 mL/H 
 
Cohorts 
Ublituximab Dose 
Total volume to be infused 
Infusion rate 
T0 to T30min 
T30min to T60min 
3 -6 
600mg 
250 mL 
100 mL/H 
400 mL/H 
 
 
8.1.3.2 AGENT HYPERSENSITIVITY 
Ublituximab Hypersensitivity and Infusion Reactions:  Available at the bedside prior to ublituximab 
administration will be medications and resuscitation equipment for the emergency management of anaphylactic 
reactions per institution guidelines.  Ublituximab should be administered intravenously through a dedicated line. 
 
 
8.1.3.3 INFUSION RATE REDUCTIONS DUE TO INFUSION RELATED REACTIONS 
The following are recommended infusion rate reduction/delay guidelines for subjects who experience severe 
Infusion Related Reactions (IRR’s) in which treatment must be interrupted. The final decision for the infusion rate 


TG1101-RMS201 
 
 
Dated: 10 October 2017 (Ver. 8.0) 
 
Page 50 of 75 
reduction/delay or discontinuation resides with the treating investigator. Infusion rates should be considered 
targets for each respective cohort.  If the treating investigator decides to interrupt the infusion or slow the infusion 
rate, then the reduction/delay and the reason for it must be noted on the eCRF and infusion log. 
1st Dose Interruption: 
• 
The patient must be closely monitored until complete disappearance of symptoms.  
• 
Following the judgment of the Investigator, and provided vital signs are stable and normal saline has 
infused for at least 30 minutes, the infusion may or may not be resumed at maximum 50% of previous rate. 
• 
The rate should be increased by 50% every 30 minutes to the max rate of 100 mL/hr as long as tolerated. 
 
2nd Dose Interruption (same day): 
• 
Wait a minimum of 2 hours 
• 
After 2 hours, the patient must again be closely monitored until complete disappearance of symptoms. 
• 
Following the judgment of the Investigator, and provided vital signs are stable and normal saline has 
infused for at least 30 minutes, the infusion may or may not be resumed at maximum 50% of previous rate. 
• 
The rate should be increased by 50% every 30 minutes to the max rate of 100 mL/hr as long as tolerated. 
 
If there is a second interruption of treatment due to IRR symptoms, ublituximab infusion must be stopped.  The 
treating physician may decide whether to attempt completion of the infusion on a second day.  Clinical 
investigators and clinical monitors familiar with the clinical course of MS must use their judgement and determine 
the tolerability of a given dose of ublituximab. 
• 
If the dose is discontinued on Day 1, administration of the remainder of the dose on Day 2 is permitted as 
follows:   
o On Day 2, if patient symptoms have resolved, estimate remaining dose needed and prepare 
accordingly for infusion. 
o Begin infusion of remaining dose according to the infusion rate guidelines presented above for the 
first infusion of ublituximab.   
If the patient has a dose interruption on Day 2, discontinue the infusion.  The patient should again be monitored for 
all symptom resolution prior to release from trial site.  The patient should start their next scheduled weekly 
infusion at the protocol specific dose (Day 15), at the infusion rate indicated in Section 8.1.3.1 for 2nd and 3rd 
infusions.   If infusion rate reductions should be needed for the week 24 infusion, please refer to the above 
recommendations.  Final decision for infusion rate reduction/delay or discontinuation resides with the treating 
investigator.  Clinical investigators and clinical monitors familiar with the clinical course of MS must use their 
judgement and determine the tolerability of a given dose of ublituximab. 
8.2 ORDERING INVESTIGATIONAL AGENTS 
Once the clinical trial site receives regulatory approval (IRB/IEB), and the Sponsor and/or Sponsor designee 
performs the Site Initiation Visit and inspection of pharmacy, and determines the site to be officially open for 
enrollment, an automatic shipment of pre-determined quantity of both drugs will be shipped to the clinical trial 
site. 
Upon receipt of treatment supplies, the Pharmacist or the appropriate person of the site should update the 
accountability forms. 
If any abnormality on the supplied boxes is observed, the Pharmacist or the appropriate person must document 
that on the acknowledgement of receipt and contact that Sponsor and/or Sponsor designee. 
 


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9 STATISTICAL CONSIDERATIONS 
This section describes the statistical methods to be used to analyze the efficacy and safety endpoints.  A formal 
statistical analysis plan (SAP), which must be finalized before database lock, will provide additional details for data 
handling procedures, statistical methods, and data presentations (e.g., table, listing, and figure shells). The final 
clinical study report will describe deviations from the SAP, if any. 
9.1 SAMPLE SIZE AND POWER 
   
9.2 GENERAL ANALYSIS CONVENTION 
Unless otherwise stated, all analyses will be performed using SAS Version 9.2 or higher and all hypothesis tests will 
be conducted at a two-sided significance level of 0.05.  P-values will be presented with 3 decimals and p-values that 
are less than 0.001 will be presented as <0.001. 
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.  In 
general, mean, standard deviation, median, 25th and 75th percentiles, minimum, maximum, and percentages will 
be presented with one decimal.  
9.3 ANALYSIS POPULATIONS 
The Intent-to-Treat (ITT) population will consist of all subjects who receive at least one dose of study drug and 
provide some efficacy values.  The primary efficacy analyses will be performed based on the ITT population. 
The Safety Population will include all subjects who receive at least one dose of study drug.  All safety assessments 
including toxicity will be performed on the Safety Population. 
The modified intent-to-treat Population (mITT) will consist of all subjects who have received UTX and have one 
baseline and post-baseline MRI without a major protocol deviation. The criteria for a major protocol deviation will 
be determined and documented prior to data base lock.  Subject exclusion from the mITT population will also be 
determined and documented prior to database lock.  Supportive analyses may be performed based on the mITT 
population. 
9.4 SUBJECT DISPOSITION 
The disposition of subjects includes the number and percentage of subjects for the following categories: subjects 
enrolled, subjects treated (safety population), subjects in the ITT population, Subjects in the mITT population, if 
applicable, subjects completed, and subjects discontinued from the study.  The reasons for study discontinuation 
will also be summarized in this table.  Only one primary reason for study discontinuation will be reported in the 
summary.  However, all reasons will be presented in the listing. 
A listing will present data concerning subject disposition. 
 


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9.5 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 ITT Population.   
9.6 MEDICAL HISTORY 
Medical history will be captured at the Screening visit.  Medical history will be coded using MedDRA and will be 
listed and may be summarized by MedDRA system organ class and preferred term for the Safety population, if 
deem necessary. 
9.7 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.  The number and percentage of subjects whose dose is 
modified at any time will be summarized by infusions and overall.  The proportion of subjects completing each 
infusion of treatment will be summarized. 
9.8 EFFICACY ANALYSES   
The study is not designed (powered) to detect treatment differences.  All efficacy variables will be summarized at 
all-time scheduled points where they are assessed.  If appropriate, dose response or treatment differences may be 
analyzed.  If p-values are presented, they will be nominal p-values without adjustment for multiple tests. 
9.8.1 PRIMARY EFFICACY VARIABLE 
The primary efficacy variable will be responder rate at week 4 (2 weeks after the second infusion (day 15)), where 
responders are subjects who have reduced B-cell depletion by ≥95%.    The percentages of the responders will be 
presented.  The 95% confidence intervals of the percentages may be presented, if appropriate, using exact method 
due to small sample size.   Logistic analysis may be used to perform trend tests to assess dose response.   
9.8.2 SECONDARY EFFICACY VARIABLE 
The secondary efficacy variables include: 
• 
Number of new Gd-enhancing lesions at 24 and 48 weeks 
• 
Number of new or enlarging T2 lesions at 24 and 48 weeks 
• 
Annualized relapse rate (ARR)  
• 
Relapse rate reduction (RRR) 
• 
Percent of relapse free subjects 
• 
Reduction in B cells (CD19+), memory (CD19+CD27+) and naïve (CD19+CD27-) B cells at baseline, day 1 
(pre dose)and 2; week 2; Day15 (pre-dose); week 4 and every 4 weeks thereafter until the next infusion at 
week 24 (pre-dose and 2 days post-dose) 25, 28, 36, 40, 44 and 48 
• 
To examine sustained B cell reduction during the first and third infusions 
• 
Additional immune profiling (CD4+, CD8+, IL10 and NK cells) at baseline, day 1 (pre dose) and 2; week 2, 
Day 15 (pre-dose); week 4 and every 4 weeks thereafter until the next infusion at week 24 (pre-dose and 2 
days post dose) 25, 28, 36, 40, 44 and 48 
• 
PK (ADME) profile of ublituximab at day 1 (pre-dose); week 2; day 15 (pre-dose); weeks 4, 24 (pre-dose) 
and 25 


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All these variables will be summarized.  Dose response and treatment difference may be analyzed as appropriate.  
Additional efficacy variables may be included as appropriate.  


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10 SAFETY REPORTING AND ANALYSIS 
10.1 SAFETY ANALYSES 
Safety evaluations will be based on the incidence, intensity, and type of adverse events, as well as on clinically 
significant changes in the patient’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 the dose of 
ublituximab 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. 
10.2 ADVERSE EVENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list of AEs and 
the characteristics of an observed AE (Section 8.1.1) will determine whether the event requires expedited 
reporting in addition to routine reporting.   
10.3 ADVERSE EVENT CHARACTERISTICS  
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.     
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting purposes only.  
10.4 PROTOCOL-SPECIFIC EXPEDITED ADVERSE EVENT REPORTING EXCLUSIONS 
For this protocol only, certain AEs/grades are exceptions to the Expedited Reporting Guidelines and do not 
require expedited reporting (i.e., MedWatch).  The following AEs are considered expected and do not require 
expedited reporting.  
CTCAE 
Category 
Adverse Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Blood/bone 
marrow 
Neutropenia <7 days without 
fever 
4 
No 
Yes 
Blood/bone 
marrow 
Thrombocytopenia <7 days 
without bleeding 
4 
No 
Yes 
10.5 ADVERSE EVENTS (AE’S) AND TREATMENT EMERGENT ADVERSE EVENTS (TEAE’S) 
All AEs and SAEs occurring on study will be listed by patient.  The frequency and percentages of subjects with 
treatment-emergent adverse events (TEAEs) will be tabulated by system organ class (SOC) and PT, where 
treatment-emergent is defined as any AE that: 
• 
Occurs after first dosing of study medication and through the end of the study or up through 30 days after 
the last dose of study treatment, or 


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• 
Is considered treatment-related regardless of the start date of the event, or  
• 
Is present before first dosing of study medication but worsens in intensity or the investigator subsequently 
considers treatment-related.  
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. 
AEs that occur after informed consent but before first dosing of study medication will not be summarized but will 
be listed.   
At each level of summarization, a patient will be counted only once for each AE, SOC, or PT experienced within that 
level.  In the summation for AE severity, within each level of AE, SOC, or PT experienced, the one with the highest 
severity will be included.  In the summation for AE’s relationship to the study drug, within each level of AE, SOC, or 
PT experienced, the one with the closest relationship to the study drug will be included. 
10.6 DEFINITIONS OF ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation patient 
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. 
In clinical studies, an AE can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no trial treatment has been administered.  The NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v4.0 is to be used for the grading of severity of symptoms and abnormal findings.  For 
adverse events not covered by the NCI-CTCAE Version 4.0 grading system, the following definitions will be used: 
• 
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. 
10.7 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 drug but a definite 
cause cannot be ascertained. 
3. Possible: There is still a reasonable possibility that the cause of the event was the study drug but there 
exists a more likely cause of the event such as complications of progressive disease. 


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4. Probable: The most likely cause of the event is the study drug but other causes cannot be completely 
excluded. 
5. Definite: Clear cut temporal and/or mechanistic relation to the study drug.  All other causes have been 
eliminated.  Events classified as definite will often be confirmed by documenting resolution on 
discontinuation of the study drug and recurrence upon resumption. 
In the summary of drug related AEs, Categories 1 and 2 will be considered as “Not Drug Related” and all other 
categories, including missing, will be considered as “Drug Related.” 
10.7.1 RECORDING OF ADVERSE EVENTS 
All adverse events of any patient during the course of the trial will be reported on the case report 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).  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 treatment spanning from Day 1 until 30 calendar 
days after discontinuation or completion of either protocol-specific treatment as defined by the protocol for that 
patient, are to be recorded on the CRF.  
10.7.2 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 patient 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 
or prolong inpatient 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 
4.0 when applicable.  Patient incidence of laboratory toxicity will be summarized by treatment group and 
maximum grade for each laboratory test. 
10.7.3 HANDLING OF ADVERSE EVENTS 
All adverse events resulting in discontinuation from the trial should be followed until resolution or stabilization.  
Subjects must be followed for AEs for 30 calendar days 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.  In this case, 
the investigators must record his or her reasoning for this decision in the patient’s medical record and as a 
comment on the CRF.  After 30 days, only AEs, SAEs, or deaths assessed by the investigator as treatment related are 
to be reported. 


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MS Relapses during the study:  For subjects having MS disease activity including relapses (protocol defined or 
otherwise): 
Any patient experiencing a multiple sclerosis relapse while on study will be allowed rescue therapy with 
intravenous methylprednisolone 1gm/day for up to 5 consecutive days.  Subjects requiring rescue therapy will 
have an MRI scan 10 days after completion of treatment with steroids. 
Re-consent criteria 
In case of a confirmed diagnosis of MS relapse (as defined in the protocol,  Appendix C), or in case of an increase in 
EDSS of 1.0 points or more, sustained for at least 3 months, during the study,  the following actions will be taken: 
1. 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.  
2. The subject will be requested to re-sign an informed consent form if he/she chooses to continue to participate in 
the study, in the same treatment assignment. 
Subjects enrolled into the study will be closely monitored through the study course by the Sponsor’s personnel as 
well as by an external independent data monitoring committee (DSMB) in order to ensure subjects’ welfare. 
 
Investigators must obtain expert evaluations of brain MRI images of subjects with suspected opportunistic CNS 
infections including PML. 
10.8 SERIOUS ADVERSE EVENTS 
10.8.1 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 at least a 24-hour 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 patient 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 
• 
Outpatient or same-day surgery units 


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• 
Observation or short-stay unit 
• 
Rehabilitation facility 
• 
Hospice or skilled nursing facility 
• 
Nursing homes, Custodial care or Respite care facility 
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. 
10.8.2 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 CRF. 
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 30-day 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 CRF page. 
All SAEs and medically confirmed deaths (regardless of causality assessment) occurring on trial treatment or 
within 30 days of last trial treatment must be reported to the sponsor as SAEs within the CRF and followed until 
resolution (with autopsy report if applicable). 
Deaths occurring within 30 days after last trial treatment that are deemed ‘possibly’ or ‘probably’ related to 
ublituximab must be reported as SAEs within the CRF (with an autopsy report if available). 
Deaths occurring within 30 days after last trial treatment and not attributed to trial treatment (e.g., disease 
progression) need not be reported in an expeditious manner to the Sponsor, but can simply be captured on the 
appropriate CRF as an SAE (death). 
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 CRF 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 CRF.  
The detailed SAE reporting process will be provided to the sites in the Safety Monitoring Plan. 
Investigators must report SAEs and follow-up information to their responsible Institutional Review Board 
(IRBs)/Independent Ethics Committee according to the policies of the responsible IRB (Research Ethics 
Committee). 
 


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10.9  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 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 but unexpected SAEs including non-death/non-life-
threatening related but unexpected SAEs associated with the use of the trial medications to the FDA, investigators, 
and central IRBs by a written safety report within 15 calendar days of notification.  Investigators using local IRBs 
are responsible for sending written safety reports for these events to their IRBs within 15 calendar days.  
10.10 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 CRF.  Avoid colloquialisms and abbreviations. 
All AEs, including those that meet SAE reporting criteria, should be recorded on the AE CRF; AEs that meet the 
definition of an SAE should additionally be reported. 
10.11 DIAGNOSIS VS. SIGNS AND SYMPTOMS 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the opinion of the 
Principal Investigator or designated physician, 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 CRF).  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. 
10.11.1 PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution, between patient evaluation time points.  Such 
events should only be recorded once on the SAE Report Form and/or the AE CRF.    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 CRF.   
A recurrent AE is one that occurs and resolves between patient evaluation time points, and subsequently recurs.  
All recurrent AEs should be recorded on an SAE Report Form and/or AE CRF for each recurrence. 
10.11.2 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 inpatient 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. 


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10.11.3 DEATHS 
All on-trial deaths, regardless of attribution, will be recorded on an SAE Report Form 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 
CRF.  If the cause of death is unknown and cannot be ascertained at the time of reporting, record “Death NOS” on 
the CRF Adverse Event page. 
10.11.4 HOSPITALIZATION, PROLONGED HOSPITALIZATION, OR SURGERY 
Any AE that results in hospitalization of >24 hours 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 Section 10.8).   
10.11.5 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 CRF.  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 CRF, it is important to convey the concept that the pre-
existing condition has changed by including applicable descriptors. 
10.11.6 PROTOCOL-DEFINED EVENTS OF SPECIAL INTEREST 
The following are events of special interest, and will need to be reported expeditiously: 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
If a patient becomes pregnant while enrolled in the trial, an SAE form should be completed and faxed/emailed to 
the Sponsor.  Sponsor should be notified expeditiously, irrespective of whether or not it meets the criteria for 
expedited reporting.  Abortions (spontaneous, accidental, or therapeutic) must also be reported to the Sponsor. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be expeditiously reported as an 
SAE, using the previously described process for SAE reporting. 
Trial Drug Overdose 
Symptomatic and non-symptomatic overdose must be reported in the CRF.  Any accidental or intentional overdose 
with the trial treatment that is symptomatic, even if not fulfilling a seriousness criterion, is to be reported to the 
Sponsor immediately (within 24 hours) using the corresponding CRF page, and following the same process 
described for SAEs (see Section 10).  If a trial drug overdose occurs, subjects should stop trial drug dosing and be 
clinically monitored as appropriate. 
Malignancies 
Malignancies must be reported via a MedWatch expedited report (in addition to your routine AE reporting 
mechanisms).  Any malignancy possibly related to treatment (including AML/MDS) should also be reported via the 
routine reporting mechanisms outlined in the protocol. 


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11 STOPPING RULES 
An independent DSMB (data safety monitoring board) will be in charge of reviewing safety data. In order to ensure 
safety and limit toxicity for enrolled subjects, the DSMB will meet (by phone) at least once (prior to subject 
enrollment (organizational meeting)), after first two subjects have completed infusion (one with placebo and the 
other with ublituximab) in each cohort during the treatment phase of the study and at end of the completion of the 
infusion of ublituximab for the eighth subject in each cohort. The independent DSMB may meet more frequently at 
their discretion depending on the safety and/or efficacy data presented and may stop the study at any time for 
safety or any other reason after discussing their findings with the Principal Investigator. The independent DSMB 
will be comprised of at least three MDs, with one being a neurologist and one with experience in the use of anti-
CD20 mAb. 
11.1.1 SUSPENSION OF PATIENT ENROLLMENT: 
In the event of one (1) death attributed to the study drug, study accrual will be suspended pending further 
investigation, and will only be resumed at the recommendation of the DSMB.  The DSMB will have discretion to 
terminate the trial if an additional death occurs that can be attributed to the study drug.   
11.1.2 LACK OF CLINICAL RESPONSE 
The DSMB may recommend to the Sponsor early termination of a study group if the MRI at 24-weeks demonstrates 
disease worsening. 


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12 CLINICAL DATA COLLECTION AND MONITORING 
12.1 SITE MONITORING PLAN 
A Sponsor representative or designee will have made a site visit to each institution within 6 months prior to 
initiating the protocol to inspect the drug storage area, and fully inform the Investigator of his/her responsibilities 
for studies and the procedures for assuring adequate and correct documentation.  A study initiation site visit or a 
teleconference will be performed to review investigator responsibilities, the protocol, and its requirements with 
the Investigator(s).  During the initiation, the case report forms (CRFs)/ eCRF’s and other pertinent study materials 
will be reviewed with the investigator’s research staff.  During the course of the study, the Sponsor will make visits 
to the sites as necessary in order to review protocol compliance, examine CRFs, and individual subject medical 
records, and ensure that the study is being conducted according to the protocol and pertinent regulatory 
requirements.  Selected CRF entries will be verified with source documentation.  The review of medical records 
will be done in a manner to assure that patient confidentiality is maintained. 
Site monitoring shall be conducted to ensure the human subject protection, trial procedures, laboratory, trial 
intervention administration, and data collection processes are of high quality and meet the Sponsor, GCP/ICH and, 
when appropriate, regulatory guidelines.  The Site Monitoring Plan shall define aspects of the monitoring process. 


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13 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).  
13.1 IRB APPROVAL 
The trial protocol, ICF, IB, available safety information, patient documents (e.g., trial diary), patient 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 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 trial 
review. The PI/Sponsor (as appropriate) must submit and, where necessary, obtain approval from the IRB 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. 
If applicable, the PI will notify the IRB within 90 days of the end of the trial, or if the trial terminates early, the PI 
must notify the IRB 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. 
13.2 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 will be prepared by the Sponsor (or its representative), as required, for submission 
to the relevant regulatory authority.   
13.3 INSURANCE AND INDEMNITY 
Details of insurance and/or indemnity will be contained within the written agreement between the PI or site and 
the Sponsor. 
13.4 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. 
The ICF will be submitted for approval to the IRB 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. 


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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 patient’s medical record.  A copy of the informed consent form, 
including the patient’s signature, will be provided by the investigator to the patient.   
If an amendment to the protocol substantially alters the trial design or the potential risks to the subjects, the 
patient’s consent to continue participation in the trial must be obtained. 
13.5 CONFIDENTIALITY 
Patient Confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA), and national data protection laws. HIPAA regulations require that, in order to 
participate in the trial, a patient 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 patient’s medical records, 
but the patient 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 patient to revoke his or her authorization.  
In the event that a patient 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 patient 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 patient is alive) at the end of their scheduled trial period. 
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 direct access 
to review the patient’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 initials will identify subjects on the CRF 
or other documents submitted to the Sponsor. This information, together with the patient’s date of birth, will be 
used in the database for patient identification. Patient names or addresses will not be entered in the CRF or 
database. No material bearing a patient’s name will be kept on file by the Sponsor. Subjects will be informed of 
their rights within the ICF. 
13.6 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 


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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. 
13.7 FINANCIAL INFORMATION  
The finances for this trial will be subject to a separate written agreement between the Sponsor and applicable 
parties.  Any Investigator financial disclosures as applicable to 21CFR Part 54 shall be appropriately provided. 


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14 RECORD RETENTION AND DOCUMENTATION OF THE TRIAL 
14.1 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 and the Principal Investigator supporting the trial.  
The written amendment must be reviewed and approved by the Sponsor, and submitted to the IRB at the 
investigator’s facility for the board’s approval. 
Amendments specifically involving change to trial design, risk to patient, increase to dosing or exposure, subject 
number increase, addition or removal of new tests or procedures, shall be reviewed and approved by the IRB at the 
Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the Sponsor as applicable, 
and specifically when an increase to dosing or patient exposure and/or subject number has been proposed; or, 
when the addition or removal of an Investigator is necessitated. 
Items requiring a protocol amendment with IRB and REC and/or FDA and Competent Authority approval include, 
but are not limited to, the following: 
• 
Change to trial design  
• 
Risk to patient 
• 
Increase to dose or patient 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. 
14.2 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. 
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 approval of the trial and the IRB members list; 
• 
Current Curricula Vita for the principal investigator and any associate investigator(s) who will be involved 
in the trial; 
• 
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; 


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• 
A copy of the IRB-approved consent form containing permission for audit by representatives of the 
Sponsor, the IRB, and the FDA;  
• 
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. 
14.3 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 CRFs are to be included on this document. All entries in the 
patient’s CRF 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 patient’s CRF 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 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 CRFs, IRB approval documents, Financial Disclosure forms, patient 
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 drug shipped/received, date, quantity and batch/code, or lot 
number for identity of each shipment.  In addition, all original source documents supporting entries in the CRF 
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 shall maintain adequate documentation / records of IRB 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 


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Page 68 of 75 
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 
CRFs, 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. 
14.4 DATA COLLECTION 
The trial CRF is the primary data collection instrument for the trial. A case report form (CRF/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 trial number, patient number, initials and date of birth will identify the 
patient in the CRF.  If the patient’s name 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 
patient number and patient’s initials.  The investigator will maintain a personal patient identification list (patient 
numbers with corresponding patient identifiers) to enable records to be identified and verified as authentic. 
Patient data/information will be kept confidential, and will be managed according to applicable local, state, and 
federal regulations. 
14.5 TRIAL MONITORING, AUDITING, AND INSPECTING 
The investigator will permit trial-related monitoring, quality audits, and inspections by the sponsor, government 
regulatory authorities, the Sponsor or its representative(s) of all trial-related documents (e.g., source documents, 
regulatory documents, data collection instruments, 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. 
14.6 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 


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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 Standard Operating Procedures (SOP’s) to define and ensure quality 
assurance/control processes for trial conduct, data generation & collection, recording of data/documentation and 
reporting according to the protocol, GCP and any applicable local, national or international regulations. 
14.7 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 trial report will be prepared upon completion of the study.  The Sponsor will disclose the trial results, in 
the form of a clinical trial 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 trial report and its addendum will comply 
with ICH E3 guidelines for structure and content of a clinical trial report. 
The financial disclosure information will be provided to the Sponsor prior to trial participation from all PIs and 
Sub-Investigators who are involved in the trial and named on the FDA 1572 form. 
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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15 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. 
 


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16 APPENDIX A 
Contraceptive Guidelines and 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 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. 
Contraceptive Guidelines for Women of Child-Bearing Potential: 
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use 
highly effective contraception during the study and for 30 days after stopping treatment. The highly effective 
contraception is defined as either: 
1. True abstinence: When this is in line with the preferred and usual lifestyle of the patient. 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 six 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 patient. 
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 at baseline and a 
negative urine pregnancy test prior to each dosing. 
Fertile Males: 
Fertile males, defined as all males physiologically capable of conceiving offspring must use condom 
during treatment, and for an additional 4 weeks after study drug discontinuation, and should not 
father a child in this period.   
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to TG 
Therapeutics Inc. within 24 hours of learning of its occurrence. The pregnancy should be followed 
up for 3 months after the termination of the pregnancy 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. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the investigator 
to TG Therapeutics Inc.  Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the study drug 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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17 APPENDIX B 
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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18 APPENDIX C 
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 
 

SAP_001.pdf: 
 
Official Title: 
A Placebo-Controlled Multi-Center Phase IIa Dose Finding Study of 
Ublituximab, a Third-Generation Anti-CD20 Monoclonal Antibody, in 
Patients with Relapsing Forms of Multiple Sclerosis. 
NCT Number: 
NCT02738775 
 
Document Date: 
 
SAP Version 1.0: 03 February 2021 
 
 
 
 
 
 
 


1 
TG Therapeutics - 
 
 
SAP Version/Date: 
Version 1.0 / 3 February 2021 
Related to Local Protocol #: 
Protocol TG1101-RMS201 
Protocol Title: 
A Placebo-Controlled Multi-Center Phase IIa Dose Finding Study of Ublituximab, a Third- 
Generation Anti-CD20 Monoclonal Antibody, in Patients with Relapsing Forms of Multiple 
Sclerosis. 
 
Sponsor: 
TG Therapeutics, Inc. 
2 Gansevoort St; 9th Floor 
New York, NY 10014 
Tel: (212) 554-4484 
IND Number: 
127265 
 
Biostatistician: 
, PhD 
 
TG Therapeutics, Inc. 
2 Gansevoort St; 9th Floor 
New York, NY 10014 
 
 
Study Coordination: 
TG Therapeutics, Inc. 
2 Gansevoort St; 9th Floor 
New York, NY 10014 
Tel: (212) 554-4484 
 
Version: 1.0 
Date: 3 February 2021 
 
 
 
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. 


2 
TG Therapeutics - 
 
 
SPONSOR APPROVAL 
The undersigned have reviewed and approved the format and content of this statistical analysis plan for 
Protocol TG1101-RMS201. 
Protocol Title: 
A Placebo-Controlled Multi-Center Phase IIa Dose Finding Study of 
Ublituximab, a Third-Generation Anti-CD20 Monoclonal Antibody, 
in Patients with Relapsing Forms of Multiple Sclerosis. 
 
 
Protocol Number: 
TG1101-RMS201 
 
Trial Drug: 
Ublituximab (TG-1101) 
IND Numbers: 
127265 
Date FINAL: 
3 February 2021 
SPONSOR CONTACTS, TG Therapeutics, Inc. 
  
, MS, MSF 
 
  
   
 
Print Name 
Signature 
Date 
STATISTICIAN, TG Therapeutics, Inc. 
  
, Ph.D. 
 
  
   
 
Print Name 
Signature 
Date 


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List of Abbreviations and Definitions of Terms 
ADA 
Anti-drug antibody 
ADME 
Absorption, Distribution, Metabolism, Excretion 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ARR 
Annualized relapse rate 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical Classification 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
CSR 
Clinical study report 
DILI 
Drug-induced liver injury 
DSMB 
Data Safety Monitoring Board 
DLT 
Dose-limiting toxicity 
ECG 
electrocardiogram 
eDISH 
Evaluations of drug-induced serious hepatotoxicity 
EDSS 
Expanded Disability Status Scale 
Gd 
gadolinium 
GGT 
Gamma glutamyl transferase 
INR 
International normalization ratio 
ITT 
Intent-to-treat 
MDRD 
Modification of diet in renal disease formula 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-to-Treat 
MRI 
Magnetic resonance imaging or magnetic resonance image 
MS 
Multiple sclerosis 
NEDA 
No evidence of disease activity 
PK 
Pharmacokinetic 
PT 
Preferred term 
QTcF 
QT Interval Corrected Using Fridericia's Formula 
RMS 
Relapsing forms of Multiple Sclerosis 
RRR 
Relapse rate reduction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SGOT/AST 
Serum glutamic oxaloacetic transaminase/aspartate aminotransferase 
SGPT/ALT 
Serum glutamic pyruvic transaminase/alanine aminotransferase 
SIB 
Suicidal ideation and Behavior 
SMQ 
Standardized MedDRA Queries 


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SOC 
System Organ Class 
TBL 
Total bilirubin 
TEAE 
Treatment emergent adverse event 
UTX 
Ublituximab 
WHO-DD 
World health organization drug dictionary 


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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 
1.3 
Determination of Sample Size ............................................................................................................ 8 
1.4 
Study Plan ........................................................................................................................................... 8 
2 
Statistical and Analytical Procedures .................................................................................................. 8 
2.1 
Analysis Variables ............................................................................................................................... 8 
2.1.1 
Demographics and Baseline Characteristics .............................................................................. 9 
2.1.2 
Study Treatment Exposure ....................................................................................................... 10 
2.1.3 
Efficacy Variables ..................................................................................................................... 10 
2.1.4 
Safety Variables ....................................................................................................................... 11 
2.1.5 
Pharmacokinetic Variables ...................................................................................................... 13 
2.1.6 
Other Variables ........................................................................................................................ 13 
2.2 
Analysis Populations ......................................................................................................................... 13 
2.2.1 
Safety Population .................................................................................................................... 13 
2.2.2 
Intent-to-Treat (ITT) ................................................................................................................ 14 
2.2.3 
Modified Intent-to-Treat (mITT) Population ........................................................................... 14 
2.2.4 
Other Analysis Population ....................................................................................................... 14 
2.3 
Disposition of Subjects .................................................................................................................... 14 
2.4 
Statistical Methods ........................................................................................................................... 14 
2.4.1 Demographics and Baseline Characteristics ................................................................................... 15 
2.4.2 Primary Efficacy Variable ................................................................................................................. 16 
2.4.3 Secondary Endpoints ....................................................................................................................... 16 
2.4.4 Exploratory Endpoints ..................................................................................................................... 17 
2.4.5 Analyses of Safety Data ................................................................................................................... 17 
2.4.6 Study Treatment Exposure and Compliance ................................................................................... 21 
2.4.7 Analyses of Pharmacokinetics ......................................................................................................... 21 
2.4.8 Analyses of Anti-Drug Antibody (ADA) ............................................................................................ 22 
2.4.9 Analyses of Immunoglobulins ......................................................................................................... 22 
2.5 
Data Handling Conventions .............................................................................................................. 22 


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2.5.1 
Missing Data ............................................................................................................................ 22 
2.5.2 
Windows for Time Points ........................................................................................................ 25 
2.5.3 
Unscheduled Visits .................................................................................................................. 25 
3 
Interim Analysis ................................................................................................................................. 26 
 


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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-RMS201” protocol Version 8.0 dated 10 October 2017. The goal of the SAP is to 
specify the statistical approaches to the analysis of study data. 
 
1.1 
Study Design and Randomization 
 
This is a 52-week, phase IIa, placebo-controlled, multi-center study that is primarily designed to 
assess the optimal dosing, optimal infusion time as well as safety/tolerability of ublituximab 
(TG1101; UTX) in patients with RMS. 
 
Subjects may be screened up to 4 weeks before first dosing date. Qualified subjects will receive 
ublituximab on Days 1, 15, and week 24. There will be at least four treatment cohorts in the study 
with 8 subjects (2 placebo and 6 ublituximab treatment; please see treatment schema) enrolled in 
each cohort. 
 
A Data and Safety Monitoring Board (DSMB) will be established to safeguard the wellbeing of 
the subjects and to advise the Sponsor whether it is appropriate to expand the enrollment to a dosing 
cohort or to initiate next dosing cohort. Once a subject is qualified, the Site will contact the 
Sponsor or its designee for cohort assignment (treatment assignment). The Sponsor or its designee 
will issue the cohort assignment for the subject using the following procedures. If DSMB deems 
that a cohort is not appropriate (e.g., due to safety), enrollment to that cohort and all higher cohorts 
will be terminated and all future subjects will be enrolled to the lowest incomplete cohort. Upon 
completion of first two patients in each cohort (one on placebo and one on study drug) through 21 
days, the DSMB will review safety data and assuming no safety concern is raised, the remaining 
qualified subjects will be enrolled into such cohort. 
 
 
1.2 
Objectives 
 
1.2.1 
Primary Objective 
 
• 
To determine the level of B cell depletion by ublituximab in subjects with RMS 
• 
To determine the optimal dose and infusion time for ublituximab in subjects with RMS 
 
1.2.2 
Secondary Objectives 
 
• 
To examine the effect of ublituximab on the development of new Gadolinium- (Gd) enhancing 
lesions and new or enlarging T2 lesions at 24 and 48 weeks 
• 
To evaluate the % of relapses in ublituximab-treated RMS subjects 


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• 
To determine immunogenicity 
• 
To evaluate the safety of ublituximab, as determined by adverse events (AEs) and serious adverse 
events (SAEs), including MS worsening 
 
 
1.3 
Determination of Sample Size 
 
 
1.4 
Study Plan 
 
Refer to the study protocol for TG1101-RMS201 for study schedule for analysis variables. 
 
• 
Ublituximab (IV): Infusions on Days 1 and 15 and week 24 
• 
Placebo (IV): Infusions on Days 1 and 15 
 
 
2 
Statistical and Analytical Procedures 
2.1 Analysis Variables 
 
Baseline for both efficacy and safety variables are defined as the last non-missing value on or 
before the first dose of Ublituximab. 


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2.1.1 Demographics and Baseline Characteristics 
 
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) and Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not 
Reported, Unknown) 
 
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 
23.0. 
 
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) 
• Prior Treatments for Current Diagnosis 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, 
≥30) calculated from weight and height. 


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Concomitant medications 
All concomitant medications or concomitant medications (extension) are reported in the case 
report forms (CRF). 
 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD). 
• 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. 
 
• Concomitant medications (extension) are those taken at any time between last study 
treatment and end of extension. 
 
Technical details related to calculating dates, imputation for missing dates, etc. are described in 
Section 2.5. 
 
2.1.2 Study Treatment Exposure 
 
Treatment exposure for ublituximab/placebo is summarized with following variables: 
• The total number of infusions of placebo 
• The total number of infusions of ublituximab received over the 3 expected 
infusions. 
• The overall number of infusions of ublituximab, number and percentage (based on 
all infusions) of infusions completed with/without interruption and infusions not 
completed. 
• The number and percentage of patients (based on all patients with at least one 
infusion) with and without any infusion complication (interruption or stop). 
• The percentage of planned total infusion received. 
 
2.1.3 
Efficacy Variables 
 
2.1.3.1 
Primary Efficacy Variable 
 
The primary efficacy variable will be responder rate at week 4 (2 weeks after W3D15, the second 
scheduled infusion of ublituximab), where responders are subjects who have reduced B-cell 
depletion by ≥95%. 
 
2.1.3.2 
Secondary Efficacy Variables 
The secondary efficacy variables are as follows: 
• Number of new Gd-enhancing lesions at 24 and 48 weeks 
• Number of new or enlarging T2 lesions at 24 and 48 weeks 
• Annualized relapse rate (ARR) 
• Relapse rate reduction (RRR) 
• Percent of relapse free subjects 


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• Reduction in B cells (CD19+), memory (CD19+CD27+) and naïve (CD19+CD27-) B cells 
at baseline, day 1 (pre dose) and 2; week 2; Day15 (pre-dose); week 4 and every 4 weeks 
thereafter until the next infusion at week 24 (pre-dose and 2 days post-dose) 25, 28, 36, 40, 
44 and 48 
• To examine sustained B cell reduction during the first and third infusions 
• Additional immune profiling (CD4+, CD8+, IL10 and NK cells) at baseline, day 1 (pre 
dose) and 2; week 2, Day 15 (pre-dose); week 4 and every 4 weeks thereafter until the next 
infusion at week 24 (pre-dose and 2 days post dose) 25, 28, 36, 40, 44 and 48 
• PK (ADME) profile of ublituximab at day 1 (pre-dose); week 2; day 15 (pre-dose); weeks 
4, 24 (pre-dose) and 25 
 
2.1.3.3 Exploratory Endpoints 
• The proportion of subjects with confirmed disability progression/improvement for at least 24 
weeks 
 
Confirmed disability progression was defined as an initial increase of ⩾1.0 point from the baseline 
EDSS score (not attributable to another etiology, concurrent illness, or concomitant medication) 
when the baseline score was ⩽5.5, and of ⩾0.5 point when the baseline score was >5.5, confirmed 
in a subsequent EDSS assessment 24 weeks later. Confirmed disability improvement followed the 
same criteria, but with a sustained decrease of ⩾1.0 EDSS point from baseline. 
 
• No evidence of disease activity (NEDA) 
 
No evidence of disease activity (NEDA) was defined as no evidence of clinical (relapse, confirmed 
disability progression for 24 weeks) or MRI (T1-weighted gadolinium-enhancing or new/enlarging 
T2 lesions) disease activity. 
 
2.1.4 
Safety Variables 
 
The safety analysis will be based on the reported DLTs, AEs and other safety information, such as 
clinical laboratory data, electrocardiogram (ECG), physical examination, and vital signs. 
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. The MedDRA terms selected 
for AESI analysis will be provided in the Clinical Study Report (CSR). 


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Suicidal ideation and behavior will be identified by the AE preferred terms included in MedDRA 
SMQ “Suicide/self-injury”. 
 
2.1.4.2 
Laboratory Safety Variables 
 
Clinical laboratory data consist of hematology, serum chemistry and coagulation. Clinical 
laboratory values will be analyzed after conversion into standard international units. International 
units will be used in all listings and tables. 
 
The laboratory parameters will be classified as follows: 
Hematology 
Hematology and differential panel: hemoglobin, hematocrit, red blood cell count, mean 
corpuscular hemoglobin, white blood cell count, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, and platelets 
 
Serum chemistry/ Pancreatic enzyme panel 
The serum chemistry to be analyzed are presented in the table below. 
 
Serum Chemistry 
Albumin 
Creatinine 
SGOT [AST] 
Alkaline phosphatase 
Glucose 
SGPT [ALT] 
Bicarbonate 
LDH 
Sodium 
BUN 
Magnesium 
Total bilirubin 
Calcium 
Phosphorus 
Total Protein 
Chloride 
Potassium 
Uric acid 
 
Coagulation 
PT/INR and Fibrinogen 
 
All observations of these tests including unscheduled measurements will be assigned to the 
appropriate safety analysis visit window, as defined in Section 2.5.3. In the presence of multiple 
measurements of the same laboratory test in the same window, the one closest to the targeted visit 
date will be used for the by-visit summaries. In case of equal distance, the later observation will 
be selected. All other lab results will only be listed. 
 
2.1.4.3 
Vital Signs 
 
The following vital sign parameters will be analyzed: 
• Systolic and diastolic blood pressures (mmHg) 
• Heart Rate (beats/min) 
• Weight (kg) 
• Body Temperature (All results will be converted to Celsius) 


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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) and QTcF interval will be collected by visit and - where 
applicable - time point (pre-/post-dose). 
 
 
2.1.5 
Pharmacokinetic Variables 
 
To characterize population PK of ublituximab, blood samples will be drawn from all subjects at 
pre-infusion and 15-30 minutes after the completion of the infusion on Day 1 and 15 and 180 
(week 24); three additional sample will be taken at week 2, 4 and 25. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2 Analysis Populations 
 
2.2.1 
Safety Population 
 
The Safety Population will include all subjects who receive at least one dose of Ublituximab. All 
safety assessments for Ublituximab including toxicity will be performed on the Safety Population. 
The Placebo Safety Population will include all subjects who receive at least one dose of Placebo. 
All safety assessments for Placebo including toxicity will be performed on the Placebo Safety 
Population. 


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2.2.2 
Intent-to-Treat (ITT) 
 
The Intent-to-Treat (ITT) population will consist of all subjects who receive at least one dose of 
Ublituximab. The primary efficacy analyses will be performed based on the ITT population. 
 
 
2.2.3 
Modified Intent-to-Treat (mITT) Population 
 
The modified intent-to-treat Population (mITT) will consist of all subjects who have received 
ublituximab and have one baseline and post-baseline MRI. 
 
 
2.2.4 
Other Analysis Population 
 
The PK Population will be a subset of the Safety Population containing subjects who participate 
in the population PK subset and have at least one baseline and one post-baseline PK sample 
taken. 
 
 
2.3 
Disposition of Subjects 
Subject disposition will be tabulated as follows: 
• Screened subjects defined as subjects who signed the informed consent; 
• Screened but not randomized subjects and reasons for not randomized (screen failure etc.); 
• Randomized subjects and corresponding treatment; 
• Subjects who completed the 48-week study treatment period 
• Subjects who discontinued study treatment and reasons for discontinuation but continue to 
allow assessments in the study after stopping study medication; 
 
For all categories of subjects (except for the screened and non-randomized categories) 
percentages will be calculated using the number of randomized subjects per cohort as the 
denominator. 
 
Additionally, the analysis populations for safety, ITT and mITT will be summarized in a table 
by subject counts on the randomized population. 
 
2.4 Statistical Methods 
 
Unless otherwise stated, all analyses will be performed using SAS Version 9.2 or higher. All 
hypothesis tests will be descriptive and conducted at a two-sided significance level of 0.05; no 


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multiplicity adjustment will be done. P-values will be presented with 3 decimals and p-values that 
are less than 0.001 will be presented as <0.001. 
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 population. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics as described in Section 2.1.1 will be summarized by 
treatment cohort 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 cohort. The table will be 
sorted alphabetically by SOC and by decreasing frequency in the total column. 
 
Concomitant/follow-up medications 
The concomitant and follow-up medications will be presented on the safety population. 
 
Medications will be summarized by treatment cohort, 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 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 total 
column. In case of equal frequency regarding anatomic categories or therapeutic categories, 
alphabetical order will be used. 
 
Previous MS treatment 
 
Variables related to previous MS treatment will be summarized per treatment cohort. 
No statistical tests will be performed on demographic and baseline characteristic data. 


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2.4.2 Primary Efficacy Variable 
The primary efficacy variable will be responder rate of B-cell depletion at week 4, which is the 
proportion of subjects who have reduced B-cell depletion at week 4 (2 weeks after W3D15 
administration of ublituximab) in the ITT population. The percentages of the responders and its 
95% confidence intervals will be presented by cohort and total, if appropriate, using exact method 
due to small sample size. The B-cell count in % and its change from baseline will be summarized 
by visit. Logistic analysis may be used to perform trend tests to assess dose response. 
 
2.4.3 Secondary Endpoints 
 
MRI count variables: 
• Number of new Gd-enhancing lesions at 24 and 48 weeks 
• Number of new or enlarging T2 lesions at 24 and 48 weeks 
 
The MRI count variables will be summarized by visit (baseline, 24 and 48 weeks) using 
descriptive statistics. 
 
The Volume of Gd-enhancing lesions and T2 lesions at 24 and 48 weeks and the change from 
baseline will be summarized using descriptive statistics. 
 
• Annualized relapse rate (ARR) 
• Relapse rate reduction (RRR) 
• Percent of relapse free subjects 
 
ARR at week 48 is calculated as the ratio of the sum of all patients’ confirmed relapse counts 
divided by the sum of all patients’ treatment duration (in years). The confirmed relapses count 
includes the confirmed relapses starting (Start Date of Suspected Relapse Symptoms) on or after 
the day of first dose date of ublituximab and up to date of Week 48 visit or the early withdraw 
date, whichever occurs earlier. 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). ARR will be summarized by cohorts and total in 
ITT population. 
 
Years under treatment will be derived as: 
Treatment years = (date of Week 48 visit or early withdraw date – date of first dose of ublituximab 
+ 1) / 365.25. 
 
RRR will be calculated as the percentage reduction from baseline ARR to ARR at week 48. 
Baseline ARR will be the sum of (Total # of Relapses Within 1 Year Prior to Screening collected 
from CRF) divided by the number of subjects. 


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The percent and its 95% CI of relapse free subjects during the treatment period in ITT population 
will be presented. 
 
• Reduction in B cells (CD19+), memory (CD19+CD27+) and naïve (CD19+CD27-) B cells at 
baseline, day 1 (pre dose) and 2; week 2; Day15 (pre-dose); week 4 and every 4 weeks 
thereafter until the next infusion at week 24 (pre-dose and 2 days post-dose) 25, 28, 36, 40, 44 
and 48 
• To examine sustained B cell reduction during the first and third infusions 
 
The reduction in B cells (%) will be summarized and plotted by visit using descriptive statistics. 
 
• Additional immune profiling (CD4+, CD8+, IL10 and NK cells) at baseline, day 1 (pre dose) 
and 2; week 2, Day 15 (pre-dose); week 4 and every 4 weeks thereafter until the next infusion 
at week 24 (pre-dose and 2 days post dose) 25, 28, 36, 40, 44 and 48 
 
Descriptive statistics will be presented by visit. 
 
 
2.4.4 Exploratory Endpoints 
 
• The proportion of subjects with confirmed disability progression/improvement at 48 weeks 
 
The EDSS score will be summarized by visit using descriptive statistics. The proportion of subjects 
with confirmed disability progression or improvement at 48 weeks will be presented. 
 
• No evidence of disease activity (NEDA) 
 
The proportion of subjects who have no evidence of disease activity, no evidence of clinical and 
no evidence of MRI disease activity will be reported. 
 
2.4.5 Analyses of Safety Data 
 
Safety results will be summarized and presented by cohort and total in safety population. 
 
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 cohort 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. 


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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. 
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 
 
The Treatment-Emergent Adverse Events (TEAE) is defined as any AE that: 
• Occurs after first dosing of study medication and through the end of the study or up through 
30 days after the last dose of study treatment, or 
• Is considered treatment-related regardless of the start date of the event, or 
• Is present before first dosing of study medication but worsens in intensity or the investigator 
subsequently considers treatment related. 
 
Dose-limiting toxicity (DLT) is defined in protocol section 5.1.1 and collected in eCRF. 
 
Adverse event incidence tables will be presented by cohort and total, the number (n) and 
percentage (%) of subjects experiencing an AE. 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 cohort. 
 
Not treatment emergent AE(s) summary: 
• 
Listing of (not treatment emergent) AEs showing cohort, 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 
- 
DLT 
- 
(related/all) TEAE leading to death 
- 
(related/all) TEAE of grade 3 or higher 
- 
(related/all) TEAE leading to drug interruption 
- 
(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 total 
column. This sorting order will be applied to all other tables, unless otherwise specified. 
 
• 
TEAEs by PT, sorted by decreasing frequency in the total column. 
• 
All at least possibly drug related 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. 
 
DLT summaries: 
• 
DLTs by SOC and PT, showing number (%) of subjects with at least one DLT, sorted by 
sorting order defined above. 
 
• 
Listing of DLTs showing cohort, 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 category and PT, showing number (%) of subjects with at least 
one TEAE, sorted alphabetically by category and decreasing incidence of PTs within category 
for the total column. This sorting order will be applied to all other tables, unless otherwise 
specified. 
 
• 
Listing of treatment-emergent AESI showing cohort, subject identifier, category, 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: 


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• 
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 ublituximab 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. 
 
• 
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: 
 
• 
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 presented by cohort and total. 
• 
All TEAEs leading to death, by primary SOC and PT, showing number (%) of subjects sorted 
by sorting order defined above. 
• 
Listings of deaths showing cohort, subject identifier, gender, race, age, date of death (if 
relevant), study day relative to first dose date, primary cause of the death 
 
2.4.5.2 Analysis of Laboratory Variables 
 
Clinical laboratory variables that will be analyzed include hematology tests, serum chemistry tests 
and coagulation tests (see Section 2.1.4.2 for the complete list of parameters). 
 
Laboratory data for hematology and serum chemistry tests will be reported in summary tables 
and listings. Laboratory data for coagulation and serology tests will be presented in listings. 
Individual values outside the laboratory reference ranges will be identified (by “H” for high 
and “L” for low) in the data listings displaying the absolute values for each subject. 
 
Continuous laboratory test results will be summarized descriptively by cohort for actual values 
and for changes from baseline. Number and percentage of subjects with laboratory 
abnormalities (H/L) will be presented. Visits to be summarized include all scheduled post- 
baseline visits. 


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Shift table from baseline to the worst post-baseline tests will be presented based on laboratory 
abnormalities (H/L). Laboratory tests that have high and low abnormalities will be summarized 
separately for each direction (e.g., hypocalcemia and hypercalcemia). 
 
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. 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. 
Similarly, a graph for ALT vs. TBL and a graph for AST vs. TBL will be provided. 
 
2.4.5.3 Analyses of Vital Sign Variables 
 
Summary tables of vital signs and change from baseline will be presented for all scheduled 
visits where vital signs were assessed. All recorded vital sign data will be listed. 
 
2.4.5.4 Analysis of Physical Examination Variables 
 
Physical examination data will be presented in a data listing. 
 
2.4.5.5 Analysis of Electrocardiogram Variables 
 
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 Study Treatment Exposure and Compliance 
 
Treatment exposure and compliance variables 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 cohort. 
 
 
2.4.7 Analyses of Pharmacokinetics 
 
Pharmacokinetics for ublituximab 
An independent SAP will be issued to detail the conduct of population PK and exposure-response 
analyses. 


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2.4.8 Analyses of Anti-Drug Antibody (ADA) 
 
The percentage of subjects developing ADA will be summarized by cohort. A listing will be 
provided for ADA data. 
 
2.4.9 Analyses of Immunoglobulins 
 
The descriptive summary and change from baseline of Immunoglobulins will be summarized by 
cohort. A listing will be provided for Immunoglobulins data. 
 
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. Additionally, 
eGFR based on MDRD will be calculated. 
 
 
2.5.1 
Missing Data 


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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 
 
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 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 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. 


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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. 
 
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 
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. 
 
2.5.1.3 Prior and concomitant medication date 
 
Medication start and end date will be used for prior, concomitant and follow up medication 
classification and potential analysis for specific medications. 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. 
 
Prior/Concomitant medication start date 
 
If start day is missing, and start month and year are not missing: Impute the start day using the first 
day of the month. Imputation flag is ‘D’. 
 
If start month is missing, and start year is not missing: Impute the start day using 1 January. Imputation 
flag is ‘M’. 


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If start year is missing: No imputation will be done. 
 
Prior/Concomitant 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 date, 
use end of study 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 date, use the end of study date instead. Imputation flag is ‘M’. 
 
If end year is missing: 
Impute date using the end of study date. Imputation flag is ‘Y’. 
 
 
 
2.5.2 
Windows for Time Points 
 
MRIs 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 dose as documented in 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 within a window have the same target distance, the later one will be used for 
analysis. The following windows will be used: 


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Week of study 
Target day 
Minimal days 
Maximum days 
1 (day 1) 
1 
1 
1 
1 (day 2) 
2 
2 
4 
2 
8 
5 
W3-1 (11) 
3 
15 
W3 (12) 
W3 +6 (21) 
4 
28 
W3+7 (22) 
42 
8 
56 
43 
70 
12 
84 
71 
98 
16 
112 
99 
126 
20 
140 
127 
W24-1 (154) 
24 
168 
W24 (155) 
W24+6 (172) 
2 days after w24 
170 
W24+2 (NA) 
W24+4 (NA) 
25 
175 
W24+5 (173) 
W24+17 (185) 
28 
196 
W24+18 (186) 
224 
36 
252 
225 
294 
48 
336 
295 
378 
 
Note: w3 and w24 refer to the actual date of 2nd and 3rd administration of ublituximab; the days 
in () are the alternative window if there is no 2nd or 3rd administration of ublituximab. 
 
3 
Interim Analysis 
 
There are no interim efficacy analyses planned for this study.