A Single Blind, Randomised, Placebo Controlled, Repeat Dose, Dose Escalating Study Investigating Safety, Tolerability Pharmacokinetics, Pharmacodynamics and the Beta-Cell Preserving Effect of Otelixizumab in New-Onset, Autoimmune Type 1 Diabetes Mellitus Patients
Phase: PHASE1
Conditions: Diabetes Mellitus, Type 1
Sponsor: GlaxoSmithKline

2011N129686_09 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
OTX116505 
 
1 
 
TITLE PAGE 
Division: Worldwide Development 
Information Type: Protocol Amendment 
Title: 
A Single Blind, Randomised, Placebo Controlled, Repeat Dose, 
Dose Escalating Study Investigating Safety, Tolerability 
pharmacokinetics, Pharmacodynamics and the Beta-Cell 
Preserving Effect of Otelixizumab in New-Onset, Autoimmune 
Type 1 Diabetes Mellitus Patients 
Compound Number: GSK2136525 
Development Phase: 
II 
Effective Date: 
26-OCT-2017 
Protocol Amendment Number:  08 
Author (s):
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
PPD

2011N129686_09 
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OTX116505 
 
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Revision Chronology 
GlaxoSmithKline 
Document Number 
Date 
Version 
2011N129686_00 
2013-SEP-05 
Original 
2011N129686_01 
2014-FEB-27 
Amendment No. 1 
Addition of unblinded Pharmacy Monitor to table summarising blinding status of 
personnel; endpoint in table updated to include insulin measurement for 7 days before all 
outpatient visits; endpoint of glucose added when performing MMTT and clamp 
procedures; clarification of time period for collecting information in the screening period;  
removal of TCR complexes and clarification of CD3 requirements throughout protocol; 
change of volume required to purge the IV infusion line and total volume filled into 
syringe, and removal of “micopore” from description; the following changes to the Time 
and Events Tables: clarification that insulin should be recorded for 7 days before all 
outpatient visits; addition of Day 6 to footnote 18; clarification that glucose will be 
collected in addition to C-peptide during the hyperglycaemic clamp procedure (Section 
6.2.2); addition of ECGs at 6 hours post start of infusion (Section 6.2.3) clarification of 
which ECGs will be triplicate or single measures; addition of TCR deep sequencing at 24 
months to Biomarker Assay Table; clarification that MMTT will be at least 7 days prior 
to the first dose of study drug; clarification that c-peptide and glucose samples will be 
shipped within 3 weeks of collection; clarification that the hyperglycaemic range of 180-
240mg/dL during 140 minutes for consistency with blood sampling time points. 
2011N129686_02 
2014-APR-02 
Amendment No. 2 
Hyperglycaemic events is included in the follow up endpoints and the Time and Events 
table to be consistent with the applicable secondary objective; rephrased “Immuno-Assay 
for syphilis test” in order to allow for different types of tests; increased the overage 
volume required to remain in the syringe for infusion; clarified the start of AE recording. 
2011N129686_03 
2014-JUN-18 
Amendment No. 3 
The third medical monitor has changed, therefore contact information for the replacement 
is included. The eligibility inclusion criterion was changed from two to one positive 
autoantibody associated with TIDM. 
2011N129686_04 
2014-JUL-28 
Republishing-Amendment 
No. 3 
Clarified that within each cohort administration of study treatment for the first three 
patients will be staggered by at least three days across each centre. 
2011N129686_05 
2015-FEB-11 
Amendment No. 4 
To increase flexibility for patients, dosing on Day 4, 5 & 6 may be performed on an out-
patient basis if the Investigator is satisfied with the clinical status of the patient; 
clarification that if the infusion needs to be reduced or temporarily stopped the 
Investigator should first consult with the Medical Monitor who will consult the Sponsor, 
unless there is an immediate safety hazard, in this case the Investigator can inform the 
Medical Monitor afterwards;  clarified that insulin use is to be recorded prior to each visit 
and phone call; clarification that the decision to replace a patient is to be based on the 

2011N129686_09 
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OTX116505 
 
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reason for withdrawal; inclusion criteria # 3 amended; screen failure data are to be 
collected; assessments following patient withdrawal clarified; clarified that infusion kits 
are supplied to sites; assessment of EBV reactivation now conducted at 6 weeks after the 
first active dose (reduced from 12 weeks); blinding status amended to clarify that only the 
patient is blinded and not site staff; requirement for pharmacy staff to document that 
investigational product shipping conditions were 2-8°C included; anti-emetic added as a 
permitted concomitant medication, window of ± 1 day added to Day 14 and 21 visits and 
Week 4 telephone call; Section 6.2.2 amended to include a phone call at Week 4 to 
discuss AEs with patient and addition of assessments at Week 6; endpoints amended to 
reflect the change to visits at Week 4 and Week 6; Section 6.2.3 amended to include ECG 
at 3 hours and to clarify that assessments may stop at 3 hours post dose; clarification of 
cytokine release syndrome adverse events grading system and stopping criteria in Section 
7.1.5; clarification on requirements for bilirubin samples included; CRO responsibilities 
clarified and supply of Ensure powder by CRO/GSK included. 
2011N129686_06 
2015-AUG-18 
Amendment No. 5 
The assay for screening EBV IgG and IgM assessment was clarified in exclusion 
criterion number 18 and in Table 2 in the Risk Management section; exclusion criterion 
18 was split into two exclusion criteria (18 and 19) to clarify EBV IgM, IgG and Viral 
load requirements for the interpretation of the results: a footnote was added to Table 6 
(Stopping Criteria for CRS-Adverse Events) to provide further clarification regarding 
when individual stopping criteria are met; the dose preparation section was updated to 
clarify that an additional maximum of 30 minutes is allowed for dose preparation tasks 
and that if 6 hours is exceeded, the syringe and  infusion materials must be replaced; 
EBV serology samples to assess IgG and IgM included for Day -1 in the Time and Events 
Table (Table 6.2.2 Dosing and Follow-Up).  
2011N129686_07 
2016-SEP-12 
Amendment No. 6 
Clarifications were made to the exploratory biomarker objectives and endpoints. 
Significant changes were: the addition of Th17 cells to the objective to assess the effect 
of otelixizumab on circulating lymphocytes; the addition of viral antigens to the 
endpoints to assess the effect of otelixizumab on the frequency of cytokine-producing 
antigen specific T cells; the addition of transcriptomic gene expression changes to the 
objective to assess the effect of otelixizumab on the clonal repertoire of circulating T cell 
populations; and clarification that the suppression activity of circulating T lymphocytes 
may be further evaluated by adapting assay conditions, possibly through adding and/or 
blocking of stimuli.  
The Time and Events table was updated to show requirement for telephone calls at Month 
36, 48 and 60. 
Month 24 exploratory biomarkers are now being routinely collected and are not subject to 
the results of Month 12 biomarker analysis. In addition, it was clarified that Month 24 
exploratory biomarker samples will be collected and only analysed after review of safety 
endpoints from Month 12 and not efficacy endpoints as previously stated. 
 Minor clarifications related to the Month 12 Interim Analyses were included. 
The name Quest was amended to Q2 Solutions and Study Procedures Manual was 
changed to Study Reference Manual. 

2011N129686_09 
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OTX116505 
 
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2011N129686_08 
2017-SEP-11 
Amendment No. 7 
All details of how the currently used Ensure powder (Abbott) is prepared has been 
removed from the Mixed Meal Tolerance Test (Appendix 5). This has been amended 
because the manufacturer (Abbott) has discontinued the currently used powder and the 
new product has a slightly different formulation. The details for each of the products will 
now be detailed in the Study Reference Manual. 
2011N129686_09 
2017-OCT-26 
Amendment No. 8 
Data which emerged from an interim analysis carried out in this study showed a prompt 
regain of immune competence observed in treated subjects and consequent rapid 
resolution of EBV reactivation, both clinically and virologically. The long term EBV 
related PTLD risk, as observed in solid organ transplant on a chronic immune 
suppression therapy, is negligible. 
Therefore, all references to month 48 and 60 have been removed as no patient currently 
enrolled in the study has reached month 48 of follow up. For the patients who have yet to 
complete their 24 month visit, this visit will be treated as a final visit and for those who 
have gone past month 24, they will be followed up with a final communication or visit 
(final follow up) upon approval of this protocol amendment.  
Data from the literature identified a causal relationship between the degree of 
immunosuppression and an increased incidence of EBV related Post Transplant 
Lymphoprolerative Disorders (PTLD) and for this reason a long-term follow-up was 
implemented at the start of the study.  
 
 

PPD
PPD

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SPONSOR/MEDICAL MONITOR INFORMATION PAGE 
Medical Monitor and Sponsor Contact Information: 
Role 
Name 
Day 
Time 
Phone 
Number 
After-
hours 
Phone/ 
Cell 
Number 
Fax Number / 
e-mail address 
Address 
Primary 
Medical 
Monitor 
(CRO) 
PAREXEL International 
He 
rman Heijermansweg 20   
1077 WL Amsterdam  
The Netherlands 
Secondary 
Medical 
Monitor 
(GSK) 
Experimental Medicine 
Unit, Immuno-
inflammation Therapy 
Unit 
GlaxoSmithKline 
Medicines  
Stevenage Hertfordshire  
SG1 2NY, UK  
Third 
Medical 
Monitor 
(GSK) 
Experimental Medicine 
Unit, Immuno-
inflammation Therapy 
Unit 
GlaxoSmithKline 
Medicines  
Stevenage Hertfordshire  
SG1 2NY, UK 
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
PPD

2011N129686_09 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
For protocol number OTX116505 
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment. 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study.  
Investigator Name: 
 
Investigator Address: 
 
 
Investigator Phone Number: 
 
 
 
Investigator Signature 
Date 
 

2011N129686_09 
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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS ........................................................................................... 12 
1. 
INTRODUCTION .................................................................................................... 14 
1.1. 
Study Rationale .......................................................................................... 14 
1.2. 
Brief Background ........................................................................................ 16 
1.2.1. 
Tolerance induction by targeting the TCR/CD3 complex .............. 16 
1.2.2. 
Type 1 Diabetes Mellitus (T1DM) ................................................. 16 
1.2.3. 
Otelixizumab (GSK2136525) is a non-mitogenic, non-
depleting anti-CD3 monoclonal antibody (mAb) ........................... 18 
1.2.4. 
Previous human experience with GSK2136525 and other 
anti-CD3 antigen binding therapeutic antibodies .......................... 19 
1.2.5. 
Anti-CD3 treatment in autoimmune (Type 1) Diabetes 
Mellitus (T1DM) ........................................................................... 19 
1.2.5.1. 
GSK2136525 (Otelixizumab) ...................................... 19 
2. 
OBJECTIVES AND ENDPOINTS ........................................................................... 21 
3. 
STUDY DESIGN .................................................................................................... 24 
3.1. 
Study Design Detail .................................................................................... 24 
3.2. 
Study Schematics ....................................................................................... 25 
3.3. 
Discussion of Study Design ........................................................................ 26 
3.3.1. 
Design Rationale ......................................................................... 26 
3.3.1.1. 
Study Population ........................................................ 26 
3.3.1.2. 
Study Duration ............................................................ 26 
3.3.1.3. 
Measurement of beta cell mass and function, 
disease progression and predictive biomarkers .......... 27 
3.3.2. 
Dose Rationale ............................................................................ 27 
3.4. 
Risk Management ....................................................................................... 29 
4. 
STUDY POPULATION ........................................................................................... 34 
4.1. 
Number of Subjects .................................................................................... 34 
4.2. 
Eligibility Criteria ......................................................................................... 34 
4.2.1. 
Inclusion Criteria .......................................................................... 34 
4.2.2. 
Exclusion Criteria ......................................................................... 35 
4.3. 
Lifestyle and/or Dietary Restrictions ............................................................ 38 
4.3.1. 
Contraception Requirements ....................................................... 38 
4.3.1.1. 
Female Subjects ......................................................... 38 
4.3.1.2. 
Male Subjects ............................................................. 38 
4.3.2. 
Meals and Dietary Restrictions .................................................... 39 
4.3.2.1. 
Alcohol ....................................................................... 39 
4.3.2.2. 
Activity ........................................................................ 39 
4.3.2.3. 
Travel ......................................................................... 39 
4.4. 
Screen and Baseline Failures ..................................................................... 39 
4.5. 
Withdrawal Criteria and Procedures ............................................................ 39 
4.6. 
Patient Completion ..................................................................................... 40 
5. 
STUDY TREATMENT ............................................................................................ 41 
5.1. 
Investigational Product and Other Study Treatment .................................... 41 

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5.2. 
Treatment Assignment ................................................................................ 41 
5.3. 
Patient Specific and Dose Escalation Stopping Criteria .............................. 42 
5.3.1. 
Cytokine Release Syndrome Stopping Criteria ............................ 42 
5.3.2. 
EBV Stopping Criteria .................................................................. 44 
5.3.3. 
Assessment of Cytokine Release Syndrome & EBV 
Stopping Criteria .......................................................................... 46 
5.3.4. 
Liver Chemistry Stopping Criteria ................................................ 46 
5.3.5. 
QTc Withdrawal Criteria ............................................................... 47 
5.3.6. 
Lymphopenia ............................................................................... 47 
5.3.7. 
Hypersensitivity Reaction ............................................................. 47 
5.3.8. 
Other Stopping Safety Criteria ..................................................... 48 
5.4. 
Blinding ....................................................................................................... 48 
5.5. 
Packaging and Labelling ............................................................................. 48 
5.6. 
Preparation/Handling/Storage/Accountability .............................................. 48 
5.6.1. 
Study Medication Storage and Handling ...................................... 49 
5.6.2. 
Study Medication Preparation ...................................................... 49 
5.6.3. 
Study Medication Administration .................................................. 52 
5.7. 
Assessment of Compliance ........................................................................ 52 
5.8. 
Treatment of Study Treatment Overdose .................................................... 53 
5.9. 
Treatment after the End of the Study .......................................................... 53 
5.10. 
Permitted Concomitant Medications and Non-Drug Therapies .................... 53 
5.10.1. 
Prophylaxis and Treatment of Cytokine Release 
Symptoms .................................................................................... 53 
5.10.1.1. Prophylaxis ................................................................. 54 
5.10.1.2. Treatment ................................................................... 54 
5.11. 
Prohibited Concomitant Medications and Non-Drug Therapies ................... 55 
6. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 55 
6.1. 
Visit Windows ............................................................................................. 55 
6.2. 
Time and Events Tables ............................................................................. 57 
6.2.1. 
Screening .................................................................................... 57 
6.2.2. 
Dosing and Follow-Up.................................................................. 58 
6.2.3. 
Detail for Vitals, ECG and Pharmacokinetic and 
Pharmacodynamic Monitoring over the Infusion Period 
(Cohorts 1-4) ............................................................................... 61 
6.3. 
Demographic/Medical History Assessments ............................................... 63 
6.4. 
Safety ......................................................................................................... 63 
6.4.1. 
Physical Exams ........................................................................... 63 
6.4.2. 
Vital Signs .................................................................................... 63 
6.4.3. 
Electrocardiogram (ECG) ............................................................. 63 
6.4.4. 
Clinical Laboratory Assessments ................................................. 63 
6.4.4.1. 
Haematology .............................................................. 64 
6.4.4.2. 
Clinical Chemistry ....................................................... 64 
6.4.4.3. 
Serology ..................................................................... 65 
6.4.5. 
Tuberculosis ................................................................................ 65 
6.4.6. 
EBV Viral Load Detection (PCR) .................................................. 65 
6.5. 
Pharmacokinetics ....................................................................................... 65 
6.5.1. 
Blood Sample Collection .............................................................. 65 
6.5.2. 
Sample Analysis .......................................................................... 65 
6.6. 
Biomarker(s)/Pharmacodynamic Markers ................................................... 66 
6.6.1. 
Anti-Otelixizumab Antibodies ....................................................... 66 
6.6.2. 
TIDM Auto-antibodies .................................................................. 66 

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6.6.3. 
CD4+, CD8+ Levels and CD3. Free CD3 and bound 
otelixizumab on CD4 and CD8+ Cells .......................................... 66 
6.6.4. 
Exploratory Biomarkers ................................................................ 66 
6.7. 
Efficacy ....................................................................................................... 67 
6.7.1. 
Mixed Meal Tolerance Test, (C-Peptide Unstimulated, 
Serum Stimulated C-Peptide Peak Levels and C-Peptide 
AUC) ............................................................................................ 67 
6.7.2. 
Hyperglycaemic Clamp Serum Stimulated C-Peptide 
Levels and C-Peptide AUC .......................................................... 68 
6.7.3. 
Daily Insulin Use .......................................................................... 68 
6.7.4. 
Glycosylated Haemoglobin, HbA1c .............................................. 69 
6.8. 
Pharmacogenetics ...................................................................................... 69 
7. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND PREGNANCY ............ 69 
7.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) ......................... 69 
7.1.1. 
Time Period for Collecting AE and SAE Information .................... 69 
7.1.2. 
Method of Detecting AEs and SAEs ............................................. 70 
7.1.3. 
Definition of Adverse Events ........................................................ 70 
7.1.4. 
Definition of Serious Adverse Events ........................................... 71 
7.1.5. 
Cytokine Release Syndrome Adverse Events .............................. 72 
7.1.6. 
Cardiovascular Events ................................................................. 73 
7.1.7. 
Death Events ............................................................................... 73 
7.1.8. 
Prompt Reporting of SAEs to GSK............................................... 73 
7.1.9. 
Regulatory Reporting Requirements for SAEs ............................. 74 
7.2. 
Pregnancy .................................................................................................. 74 
7.2.1. 
Time Period for Collecting Pregnancy Information ....................... 74 
7.2.2. 
Action to be taken if pregnancy occurs ........................................ 74 
7.2.3. 
Action to be taken if pregnancy occurs in a female partner 
of a male study patient ................................................................. 75 
8. 
DATA MANAGEMENT ........................................................................................... 75 
9. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................... 75 
9.1. 
Hypotheses and Treatment Comparisons ................................................... 75 
9.2. 
Sample Size Considerations ....................................................................... 76 
9.2.1. 
Sample Size Assumptions ........................................................... 76 
9.2.2. 
Sample Size Sensitivity ................................................................ 77 
9.2.3. 
Sample Size Re-estimation .......................................................... 77 
9.3. 
Data Analysis Considerations ..................................................................... 78 
9.3.1. 
Interim Analyses .......................................................................... 78 
9.3.1.1. 
During the Study ......................................................... 78 
9.3.1.2. 
Dose Escalation ......................................................... 78 
9.3.1.3. 
Interim Analyses (12 Months) ..................................... 78 
9.3.2. 
Final Analyses ............................................................................. 79 
9.3.2.1. 
Final Analyses (24 Months) ........................................ 79 
9.3.3. 
Safety Analyses ........................................................................... 79 
9.3.4. 
Pharmacokinetic Analyses ........................................................... 79 
9.3.5. 
Efficacy Analyses ......................................................................... 80 
9.3.6. 
Pharmacodynamic/Biomarker Analyses ....................................... 80 
9.3.7. 
Pharmacokinetic/Pharmacodynamic Analyses ............................. 80 
9.3.8. 
Exploratory Biomarker(s) Analyses .............................................. 80 

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10. STUDY GOVERNANCE CONSIDERATIONS ........................................................ 81 
10.1. 
Posting of Information on Publicly Available Clinical Trial Registers ............ 81 
10.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................ 81 
10.2.1. 
Urgent Safety Measures .............................................................. 81 
10.3. 
Quality Control (Study Monitoring) .............................................................. 81 
10.4. 
Quality Assurance ....................................................................................... 82 
10.5. 
Study and Site Closure ............................................................................... 82 
10.6. 
Records Retention ...................................................................................... 83 
10.7. 
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ................. 83 
11. REFERENCES ....................................................................................................... 85 
12. APPENDICES ........................................................................................................ 90 
12.1. 
Appendix 1: Liver Safety Process ............................................................... 90 
12.2. 
Appendix 2: Pharmacogenetic research ..................................................... 94 
12.3. 
Appendix 3: Country Specific Requirements ............................................... 99 
12.4. 
Appendix 4: Procedures for Detection, Evaluation, Follow-Up and 
Reporting of Adverse Events .................................................................... 100 
12.5. 
Appendix 5: Mixed Meal Tolerance Test (MMTT) ...................................... 102 
12.6. 
Appendix 6: Hyperglycaemic Clamp Procedure ........................................ 104 
12.7. 
Appendix 7: ADA Classification ................................................................. 108 
12.8. 
Appendix 8: Protocol Amendment Changes .............................................. 109 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ADA 
American Diabetes Association 
Anti GAD 
Antibody to Glutamic Acid Decarboxylase 
Anti IA2 
Antibody to Protein Tyrosine Phosphatase-like Protein 
ALT 
Alanine aminotransferase (SGPT) 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area Under the Curve 
BDR 
Belgian Diabetes Registry 
CMV 
Cytomegalovirus 
CRO 
Contract Research Organisation 
CRS 
Cytokine Release Syndrome 
CTL 
Cytotoxic T-Lymphocyte 
DM 
Diabetes Mellitus 
EBNA 
Epstein-Barr Nuclear Antigen 
EBV 
Epstein Barr Virus 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Forms 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
h 
Hour 
IAA 
 Insulin Antibodies 
ICA 
Antibody to Islet-Cell Antigen 
IB 
Investigator Brochure 
INS 
Insulin 
ISR 
Insulin Secretion Rate 
i.v. 
Intravenous 
LFT 
Liver Function Tests 
mAb 
Monoclonal Antibody 
mg 
Microgram 
mL 
Millilitre 
MMTT 
Mixed Meal Tolerance test 
NOD 
Non Obese Diabetes 
NOT1DM 
New Onset Type 1 Diabetes Mellitus 
NSAID 
Non Steroidal Anti-Inflammatory Drug 
PBMC 
Peripheral Blood Mononuclear Cell 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PTLD 
Post-Transplant Lymphoproliferative Disorder 
qPCR 
Quantitative Polymerase Chain Reaction 
QTcB 
QT duration corrected for heart rate by Bazett’s formula 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
RBC 
Red Blood Cells 
RT-PCR 
Reverse Transcription-Polymerase Chain Reaction 

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SAE 
Serious Adverse Event 
SOI 
Start of Infusion 
SRM 
Study Reference Manual 
TB 
Tuberculosis 
TCR 
T Cell Receptor 
TTEDD 
Therapeutic Evaluation of Different Multi-Dose Regimens in Type 1 
Diabetes Mellitus 
T1DM 
Type 1 Diabetes Mellitus 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
WHO 
World Health Organisation 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
Abbott 
 
 
Clozaril 
 
 
Macrogenics 
 
 
Orthoclone 
 
 
PAXgene 
 
 
Risperdal 
 
 
SAS 
 
 
Seroquel 
 
 
WinNonlin 
 

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1. 
INTRODUCTION 
1.1. 
Study Rationale 
The aim of this Phase I/IIa study is to identify a safe and tolerable dosage regimen of 
intravenously administered otelixizumab.  In addition, the C-peptide decline in new onset 
type 1 diabetes mellitus (NOT1DM) patients and possible immunological mechanisms 
will be investigated with a view to identifying trends and early immunological 
biomarkers which could predict response in halting/slowing β-cell destruction in this 
patient population. 
This exploratory study will explore the safety and tolerability between the well tolerated 
but non-efficacious cumulative dose of 3.1 mg (in previously completed Phase III 
studies) and a cumulative dose of 48 mg (in a previously completed Phase II study) at 
which efficacy based on C-peptide analysis was demonstrated, albeit with evidence of 
Epstein Barr Virus (EBV) reactivation and Cytokine Release Syndrome (CRS).  
Exploration of the tolerability dose response is considered a necessary first step to 
determining the therapeutic index of otelixizumab. 
It has been shown that treatment with non-mitogenic anti-CD3 monoclonal antibodies 
(mAbs) can achieve some degree of immuno-modulation in NOT1DM patients resulting 
in halting the decline of stimulated C-peptide secretion (a validated surrogate of  
pancreatic β-cell function) for up to 12 months post-treatment (teplizumab - Herold study 
[Herold, 2005] and otelixizumab BDR study [Keymeulen, 2005]). This effect translated 
to a reduction of insulin requirements with no loss of glycaemic control  up to 18 months 
post-treatment [Keymeulen, 2005].  The relatively high dose regimens investigated in 
these studies, were estimated to have reduced circulating free CD3 levels to less than 
10% of pre-treatment levels throughout the dosing period (6 and 14 days, for 
otelixizumab (cumulative dose 48-64 mg) and teplizumab (cumulative dose 34.9 mg) 
respectively, see Figure 1). However, infusion reactions typical of CRS were consistently 
observed following administration of both molecules, and in the case of otelixizumab, 
reactivation of latent EBV occurred in most subjects, accompanied by symptoms of 
mononucleosis.   
In contrast, in two Phase III trials (DEFEND 1&2, respectively), where a substantially 
reduced dosage regimen of otelixizumab was investigated (total dose of 3.1 mg vs. 48-64 
mg in the BDR proof-of-concept study), no effect on C-peptide or any key secondary or 
exploratory endpoints were observed. Likewise, in the Phase III trial Protégé, lower doses 
of teplizumab relative to the proof-of-concept study (0.1, 0.2, 0.4, 0.8, 10 X 1.6 mg per 
day, 17.5 mg cumulative dose compared to 34.9 mg in the Herold study) failed to 
demonstrate a statistically significant treatment effect on a range of metabolic endpoints. 
However, although some trends were observed with respect to C-peptide and insulin 
requirements, the duration of apparent efficacy was reduced (6 months vs. 12 months). 
Thus, the relationship between dose, duration of treatment, and magnitude and duration 
of efficacy has not been fully elucidated with any anti-CD3 antibody. However, the 
current weight of clinical evidence suggests that a high and sustained degree of blockade 
of CD3 is required during the dosing period to achieve a clinically relevant and durable 
response in halting the disease progression of NOT1DM patients. 

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In addition to dose, several post-hoc analyses (BDR, Herold and Protégé studies [Sherry, 
2011; Herold, 2005]) have suggested that time to treat following disease diagnosis and 
age of the patient are key determinants of treatment response, with teplizumab preserving 
C-peptide secretion only in T1DM patients treated within 6 weeks from the diagnosis 
[Sherry, 2011; Herold, 2005]. 
Therefore, the efficacy measured on the degree of β-cell preservation efficacy seems to 
be strictly dose and time from diagnosis dependent, with the younger population (<27 
years old) being more responsive (BDR and Protégé studies). 
It is anticipated that the therapeutic window for anti-CD3 therapy is fairly narrow with 
the immediate risk of tolerability related to increased severity of cytokine release 
syndrome (CRS) at higher doses and the longer-term risk related to EBV reactivation.  
Therefore, the aims of this study are to explore the safety, tolerability, pharmacokinetics, 
pharmacodynamics, efficacy and immunological profile of escalating repeat doses of 
intravenously administered otelixizumab in NOT1DM patients. The data obtained from 
this study will inform the design of subsequent efficacy studies.   
Figure 1 
Predicted Dose Response for Human CD3 Antigen Occupancy on 
CD4+ T cells for Various Clinical Studies in NOT1DM Patients with 
Anti-CD3 Monoclonal Antibodies 
NB: DEFEND 1 &2 and BDR studies (otelixizumab), Herold and Protégé (teplizumab). Based on in vitro 
characterization and limited clinical data otelixizumab and teplizumab assumed the same potency and 
pharmacokinetics. 

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1.2. 
Brief Background 
1.2.1. 
Tolerance induction by targeting the TCR/CD3 complex 
The CD3 complex is a group of cell surface molecules associated with the T-cell antigen 
receptor, constituting the T Cell Receptor (TCR) complex which, when activated, induces 
a signalling transduction cascade [Kuhns, 2006].  The CD3 complex is expressed on the 
surface of thymocytes and mature lymphocytes expressing either alpha-beta or gamma-
delta TCR.  Multiple effects of anti-CD3 treatment have been demonstrated in vitro and 
in vivo including internalization of the TCR-CD3 complex (which renders cells blind to 
the antigen), stimulation of cytokine release, triggering of apoptosis, induction of T cell 
anergy, transient lymphopenia/redistribution and eventual expansion of regulatory T cell 
numbers.  In animal models of diabetes [Herold, 1992; Chatenoud, 1994 and Chatenoud, 
1997; Belghith, 2003; Li, 2006; Mehta, 2010; Nishio, 2010] autoimmune arthritis 
[Hughes, 1994; Notley, 2010] and multiple sclerosis [Tran, 2001; Kohm, 2005; Chao, 
2009; Belmar, 2009], the collective effects of anti-CD3 treatment appear to modify the 
immune system to produce “tolerance”, leading to sustained remission without 
continuing anti-CD3 treatment.  However, the precise mechanism by which anti-CD3 
treatment induces tolerance is not understood.  Regulatory/suppressor cells are key to 
peripheral control of potential autoreactive T lymphocytes which escape thymic deletion 
[Van Kaer, 2010; Tsai, 2011] and it is assumed that persisting tolerance after anti-CD3 
treatment is dependent upon increased regulatory/suppressor activity.  Increased numbers 
of CD4+ and CD8+ regulatory cells have been reported in animals and T1DM patients 
after anti-CD3 treatment [Nishio, 2010; Waldron-Lynch, 2012; Esplugues, 2011; 
Bisikirska, 2005]. 
1.2.2. 
Type 1 Diabetes Mellitus (T1DM) 
Diabetes mellitus (DM) is a metabolic disorder characterised by chronic hyperglycaemia 
due to deficient production of/or response to insulin.  A classification system developed 
by an international Expert Committee on the Diagnosis and Classification of DM 
working under the sponsorship of the American Diabetes Association (ADA) recognises 
four types of diabetes mellitus (Expert Committee on the Diagnosis and Classification of 
Diabetes Mellitus (2003)).  Type 1 Diabetes Mellitus (T1DM) has been described as 
diabetes characterized primarily by an absolute deficiency of insulin.  Patients with 
T1DM represent approximately 5% to 10% of all patients with DM. 
Type 1 diabetes becomes clinically apparent after a preclinical period of varying length, 
during which progressive loss of β-cells in the pancreatic islets impairs the ability to 
maintain blood glucose levels within a physiologic range [Rowe, 2011].  The disease is 
classified in two subtypes: 1A, which includes the common, immune-mediated forms of 
the disease; and 1B, which includes non-immune forms [Concannon, 2009].  In 
autoimmune T1DM, roles for both the innate and adaptive arms of the immune system in 
the pathogenesis have been postulated, though most recent work has focused on the role 
of cytotoxic T cells [Coppieters, 2012].   
The events triggering the development of an autoimmune attack on the β-cell are unclear. 
Type 1 diabetes mellitus occurs most often in children, adolescents, and young adults, but 

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can present at any age. It has been reported that the age of onset is decreasing as cases are 
doubling for children under five years of age [Patterson, 2009]. Although T1DM 
aggregates in some families, it does not segregate with any clear mode of inheritance 
reflecting a complex interaction between environment and inheritance in determining 
individual risk of developing T1DM. Common viral infections may be a trigger in 
susceptible individuals [Van Belle, 2011; Coppieters, 2011].   
The histological hall mark of the pancreas in T1DM is a loss of β-cells. Analyses of 
pancreatic islets obtained post-mortem from recent onset T1DM patients suggest a 
defined sequence of insulitis (with mononuclear inflammatory cell infiltrate around and 
within islets) accompanied by morphologic changes in β -cells indicative of 
compensatory mechanism (hypertrophy) to maintain insulin secretion, followed by an 
absolute loss of β-cells [Rowe, 2011; Willcox, 2009].  In humans, in contrast to rodents, 
there is limited potential for expansion of β cell numbers in post-neonatal life, either from 
replication of existing cells or neogenesis from stem cells in the ductal epithelium [Cnop, 
2011].   
Autoantibodies against GAD, IA 2, IA 2β, and/or insulin are detectable in approximately 
85% to 90% of patients with T1DM [Vermeulen, 2011]. Positive serology is a risk factor 
for progression to T1DM in first degree relatives of affected probands [Alves, 2012; 
Seidel, 1996].  Autoreactive CD8+ and CD4+ T lymphocytes can be detected in 
peripheral circulation and are directed to many of the same epitopes [Velthuis, 2010; 
Unger, 2011]. In diseased islets, cytotoxic CD8+ T cells are the most abundant 
population of immune cells at all stages of the insulitis. Macrophages (CD68+) are also 
present during both early and later stages of the insulitis, although in fewer numbers.  
CD20+ B cells are present in only small numbers in early insulitis and become more 
numerous as β cell death progresses [Rowe, 2011; Willcox, 2009].   
Therefore, the net effect of autoimmune destruction of β cells coupled with little or no 
regeneration marks a progressive deterioration of glucose homeostasis, culminating in an 
absolute dependence on exogenous insulin replacement therapy.  It is estimated that only 
10-20% of β-cells are still functioning at the time of clinical diagnosis [Knip, 2002].  The 
rate of progression from normo-glycaemia, through pre-clinical impairment of glucose 
handling to insulin dependence is variable.  Indeed, even 1-5 years after diagnosis, about 
50% of T1DM show clinically meaningful β-cell function [Palmer, 2009].   
The destruction process of β-cells is not a continuous phenomenon and it has been argued 
that T1DM is a relapsing-remitting disease [Von Herrath, 2007] as longitudinal studies 
suggested that the decline in β-cell function follows a saw-tooth profile (Figure 2). 
 

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Figure 2 
Timelines for Type 1 Diabetes 
 
 [Van Belle, 2011] 
There are currently no curative treatments for T1DM. Current management of T1DM is 
by lifelong insulin replacement. Clearly safe, well-tolerated strategies to identify and 
intervene on the autoimmune process involving the destruction of the pancreatic islets 
represent a major unmet clinical need. Immuno-modulation coupled with other 
therapeutic strategies such antigen tolerizing approach/regenerative medicine might offer 
a radical change in the management of new onset T1DM.  
1.2.3. 
Otelixizumab (GSK2136525) is a non-mitogenic, non-depleting 
anti-CD3 monoclonal antibody (mAb) 
Otelixizumab is a humanized, Fc-modified, non-mitogenic anti-CD3 monoclonal 
antibody (mAb) directed against the ε domain of the human lymphocyte antigen CD3. 
Otelixizumab has the same amino acid sequence as ChAglyCD3, an anti-human CD3 
monoclonal antibody derived from the rat anti-human CD3 mAb YTH12.5. ChAglyCD3 
features a mutation of the human IgG1 constant region to remove the only attachment site 
for N-linked carbohydrate (N297A). This aglycosyl mutation appears to eliminate 
mitogenicity in the presence of human serum. Studies of the biochemical and biological 
properties of ChAglyCD3 and otelixizumab have shown that they are analytically 
comparable and functionally indiscriminate. It has been postulated that otelixizumab may 

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have a dual mechanism of action. First, activated pathogenic T cells are eliminated or 
inhibited by redistribution, depletion, or down modulation of the CD3/T cell receptor 
(TCR) complex. Second, “operational” tolerance is established by the generation and/or 
expansion of T regulatory cells that actively control the pathogenic autoimmune 
response. 
1.2.4. 
Previous human experience with GSK2136525 and other anti-CD3 
antigen binding therapeutic antibodies 
A murine monoclonal IgG2a antibody against CD3ε (Orthoclone, OKT3) has been in 
clinical use since 1986 for the treatment of acute, glucocorticoid resistant rejection of 
allogenic renal, heart and liver transplants. OKT3 is associated with infusion reactions 
and the formation of neutralising auto-drug antibodies which have limited its clinical use 
and investigation beyond transplantation. The ability of CD3-specific antibodies to 
induce T-cell proliferation and cytokine production in vitro is closely tied to their cross-
linking ability to bind to FcRs on monocyte ⁄ macrophages and natural killer cells 
[Nepom, 2011]. A number of second generation anti-CD3 antibodies were developed in 
an attempt to reduce the immunogenicity and infusion reactions: visilizumab (Hu 291), 
teplizumab (hOKT31(Ala-Ala)) and otelixizumab (ChAglyCD3) [Kaufman, 2009].  
Numerous clinical trials have been conducted with these agents in a variety of 
autoimmune diseases including ulcerative colitis (visilizumab), [Sandborn, 2010], new 
onset type 1 diabetes (otelixizumab [Keymeulen, 2005], teplizumab [Herold, 2005; 
Sherry, 2011], psoriasis [Wiczling, 2010]) and rheumatoid and psoriatic arthritis 
(otelixizumab and teplizumab) [Utset, 2002].  
1.2.5. 
Anti-CD3 treatment in autoimmune (Type 1) Diabetes Mellitus 
(T1DM) 
1.2.5.1. 
GSK2136525 (Otelixizumab) 
In a randomised placebo-controlled academic-led Phase II proof-of-concept study (BDR 
study), investigating otelixizumab administered as 6 short daily intravenous infusions of 
8 mg per day, the decline in stimulated C-peptide, a validated marker of functioning 
insulin-producing β -cells in the pancreatic insulae was observed for a period of up to 1 
year in NOT1DM patients [Keymeulen, 2005]. In a follow-up, post-hoc analysis, the 
observed reduction in daily insulin dose in the treated group was maintained for up to 4 
years in a subset of patients [Keymeulen, 2010]. However, this regimen was associated 
with consistent first-dose infusion reactions typical of CRS and EBV reactivation as 
measured by significant increased viral load (21 out of 22 subjects had evaluable 
samples) accompanied by clinical symptoms of mononucleosis in 75% of patients dosed 
with otelixizumab. In contrast, an 8-day intravenous short infusion regimen consisting of 
much reduced daily doses 0.1, 0.2, 0.3 mg respectively, followed by 5 daily doses of 0.5 
mg of otelixizumab, failed to show any efficacy in a similar patient group in the Phase III 
study DEFEND-1. As a consequence, the replicate Phase III study DEFEND-2 was 
stopped for futility and terminated.  In these latter studies symptoms related to CRS were 
generally mild and well tolerated and no clinical symptoms of mononucleosis or 
increases in EBV viral load were observed in either study. In addition, the acute 
tolerability of various intravenous infusion regimens of otelixizumab in T1DM patients 
were investigated in the RT4 and Therapeutic Evaluation of Different Multi-Dose 

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Regimens in Type 1 Diabetes Mellitus (TTEDD) studies. Further details of the individual 
studies can be found in the Investigators Brochure [GlaxoSmithKline Document Number 
RM2008/00587/05].  
Efficacy in NOT1DM patients has been demonstrated with another therapeutic antibody, 
teplizumab, (Macrogenics), (hu OKT3y1ala-ala) fully humanised monoclonal Ab also 
targeting human CD3ε with similar potency. In a randomised, controlled but open-label 
study investigating a 14-day regimen of teplizumab consisting of nominal (per 70 kg) 
daily short infusions of 0.1, 0.4, 0.8, and 1.6 mg respectively, followed by 10 daily short 
infusions of 3.2 mg (cumulative nominal dose of 34.9 mg), the decline in stimulated C-
peptide, was similarly halted for a period of up to 1 year in NOT1DM patients. A 
treatment difference was maintained for up to 2 years, although C-peptide appeared to be 
declining at the same rate in the treated and placebo group at this time [Herold, 2005]. 
While consistent, but manageable first dose reactions were observed, no EBV 
reactivation has been reported. In a subsequent Phase III randomised placebo-controlled 
study in a similar population, lower dose regimens were investigated. Doses up to a 
nominal daily dosage regimen of 0.1, 0.2, 0.4, 0.8 mg respectively, followed 10 daily 
infusions of 1.6 mg (cumulative nominal dose of 17.5 mg), failed to show a statistically 
significant change in HbA1c, insulin dose, or stimulated C-peptide [Sherry, 2011]. 
Exploratory post-hoc analysis revealed some trends in slowing C-peptide decline and 5% 
of patients in the teplizumab treated groups were completely off insulin at one year, 
compared with none in the placebo group (p=0.03). Furthermore, a greater proportion of 
those in the highest dose group had better β-cell preservation as measured by an increase 
in the area under the curve (AUC) for stimulated C-peptide levels compared with placebo 
(40% versus 28%, P=0.046). β-cell preservation was observed to be improved in patients 
of age 8-11 years old. Efficacy benefit was also greater for those patients who started on 
treatment sooner after their diagnosis (within six weeks of the reported date of T1DM 
diagnosis). CRS symptoms were classified as mild and no EBV reactivation was 
reported. 

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2. 
OBJECTIVES AND ENDPOINTS 
Primary Objectives (Safety) 
Primary Endpoints (Safety) 
• 
To assess the effect of a single course of 
otelixizumab treatment on the acute and 
long term safety and tolerability of 
otelixizumab in NOT1DM patients.  
 
• 
Incidence of adverse events (AEs) 
particularly those related to Cytokine 
release syndrome (CRS).  
• 
Epstein-Barr virus (EBV) reactivation over 
Day 21 to Month24.  
• 
Changes in laboratory values, 
electrocardiograms (ECGs) and vital signs 
over Day 14 to Month 24. 
Secondary Objectives (Pharmacokinetic) 
Secondary Endpoints (Pharmacokinetic) 
• 
To assess the pharmacokinetics of repeat 
dose administration of otelixizumab over 
14 days in NOT1DM patients. 
• 
Free serum otelixizumab concentrations 
over Days 1-14 and summary PK 
parameters. 
Secondary Objectives (Efficacy) 
Secondary Endpoints (Efficacy) 
• 
To assess the effect of a single course of 
otelixizumab treatment on the rate of 
decline of pancreatic β-cell function over 
24 months in NOT1DM patients.  
• 
Change from baseline in C-peptide and 
glucose AUC (0-120) after a Mixed Meal 
Tolerance Test at Month 3, 6, 12, 18 and 
24. 
 
• 
To assess the effect of a single course of 
otelixizumab treatment on the rate of 
decline of C-peptide response and insulin 
sensitivity of β-cell function determined 
after a hyperglycemic clamp over 24 
months in NOT1DM patients. 
• 
Change from baseline in C-Peptide and 
glucose AUC hyperglycemic phase [H60 to 
H140 minutes] and insulin sensitivity (IS) 
index after a hyperglycemic clamp at 
Months 6 and 24.  
 
• 
To assess the effect of a single course of 
otelixizumab treatment on exogenous 
insulin use for otelixizumab over 24 
months in NOT1DM patients.  
• 
Change from baseline in mean daily insulin 
use over 7 consecutive days during the 
week preceding all visits and phone calls.  
• 
To assess the effect of a single course of 
otelixizumab treatment on glycaemic 
control over 24 months in NOT1DM 
patients.   
• 
Change from baseline in HbA1c level.  
• 
Body weight Day -1, Months 12-24.  
• 
Hypoglycemic and hyperglycemic events 
over Months 1-24.  

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Secondary Objectives (Pharmacodynamic) 
Secondary Endpoints (Pharmacodynamic) 
• 
To assess the effect of a single course of 
otelixizumab treatment on the time course 
and magnitude of CD4 + and CD8+ cells 
and CD3 binding and saturation on all 
these cells during repeat dose 
administration of otelixizumab over 14 
days in NOT1DM patients. 
• 
Relative change from baseline (%) in 
CD4+ and CD8+ cells, free CD3 and 
bound otelixizumab on CD4+ and CD8+ 
cells on Days 1 through 14. 
• 
To assess the effect of a single course of 
otelixizumab treatment on the 
immunogenicity of otelixizumab in 
NOT1DM patients. 
• 
Change from baseline in anti-drug antibody 
levels at Months 3 and 6.  
Exploratory Objectives* 
Exploratory Endpoints* 
• 
To assess the effect of a single course of 
otelixizumab treatment on circulating 
lymphocyte populations over 24 months in 
NOT1DM patients. 
• 
Change from baseline in absolute 
lymphocyte counts and ratios in some or 
all, but not limited to subsets (CD3+ 
CD4+, CD3+ CD8+, and CD19+ cells) and 
phenotype (eg effector, memory, regulatory 
T cells, eg CD45RA, CCR7+) over Week 6 
to Month 24. 
• 
To assess the effect of a single course of 
otelixizumab treatment on circulating 
lymphocytes such as regulatory T cell 
numbers (as quantified by CD3 and  
demethylated FoxP3 expression) and Th17 
cells over 24 months in NOT1DM patients. 
• 
Change from baseline in cell-type specific 
methylation marker expression in some or 
all, but not limited to CD3, FoxP3 and 
Th17 in whole blood over Week 6 to 
Month 24. 
• 
To assess the effect of a single course of 
otelixizumab treatment on absolute 
numbers and ratios of circulating antigen 
specificCD8+ T cells over 24 months in 
HLA-A2+ NOT1DM patients. 
• 
Change from baseline in absolute numbers 
and ratios of HLA-A2-restricted CD8 T 
lymphocytes reactive to specific auto-
antigens (by multimer) over Week 6 to 
Month 24. 
• 
To assess the effect of a single course of 
otelixizumab treatment on frequency of 
cytokine-producing antigen specific T cells 
over 24 months in NOT1DM patients. 
• 
Change from baseline in frequency of 
cytokine producing cells following in vitro 
stimulation with auto-antigens and viral 
antigens (by ELISPOT) over Week 6 to 
Month 24. 
• 
To assess the effect of a single course of 
otelixizumab treatment on serum auto-
antibodies titers and serum analytes 
associated with treatment or autoimmune 
pathology over 24 months in NOT1DM 
patients.  
• 
Change from baseline in auto-antibody 
titres (using a panel of common auto-
antibodies associated with T1DM antigens 
and possibly other auto-antigens) and 
serum analytes (such as cytokines/ 
chemokines) during the first 14 days of 
treatment and over Week 6 to Month 24.  

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Exploratory Objectives* 
Exploratory Endpoints* 
• 
To assess the effect of a single course of 
otelixizumab treatment on clonal repertoire 
of circulating T cell populations and/or 
transcriptomic gene expression changes 
over 24 months in NOT1DM patients. 
• 
Change from baseline in T cell clonal 
repertoire by TCR deep sequencing over 
Day 6 to Month 24.  
• 
Change from baseline in transcriptomic 
gene expression profile(s) by micro-
array and/or alternative equivalent 
technologies including RNA 
sequencing at selected timepoint(s) post 
dosing. 
• 
To assess the effect of a single course of 
otelixizumab treatment on β-cell death 
over 24 months in NOT1DM patients.  
• 
Change from baseline in serum by 
measuring relative levels of unmethylated 
INS DNA and/or other biomarkers for β-
cell death in serum over Week 6 to Month 
24.  
• 
To assess the effect of a single course of 
otelixizumab treatment on suppression 
activity of circulating T lymphocytes over 
24 months in NOT1DM patients. 
• 
Change from baseline in relative levels of 
T lymphocyte suppression using micro 
suppression assay over Week 6 to Month 
24. Suppression activity may be further 
evaluated by adapting assay conditions 
possibly through adding and/or blocking of 
stimuli. 
Follow up Objectives  
Follow up Endpoints - Data from month 36 
(if available) or final follow-up. This will 
only be applicable for patients past month 
24 
• 
To assess long term safety follow-up with 
otelixizumab treatment. 
• 
Significant adverse events.  
• 
Severe (as per ADA classification, 
Appendix 7) hypoglycemic events which 
occurred following Month 24 visit (if 
available) until final follow-up.   
• 
Severe hyperglycemic events which 
occurred following Month 24 visit (if 
available) until final follow up. 
• 
Mean daily insulin use over 7 consecutive 
days preceding the call.  
• 
HbA1c results around time of the phone 
call. 
*Samples will be collected and only analysed after review of safety endpoints 

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3. 
STUDY DESIGN 
3.1. 
Study Design Detail 
The study is a multi-centre, single-blind (see Section 5.4), randomised, placebo-
controlled 6 day repeat dose study to investigate the safety, tolerability, 
pharmacokinetics, pharmacodynamics, efficacy and immunological profile of 
intravenously administered otelixizumab in New Onset Type 1 Diabetes Mellitus 
patients. 
Approximately 40 patients will be dosed, in a dose escalation design exploring 4 dose 
cohorts (4 dose levels and placebo). At each dose cohort 8 patients will be randomised to 
otelixizumab and 2 patients to placebo. 
Screening Period: Patients will be dosed within approximately 28 days of diagnosis (not 
more than 32 days). Insulin usage will be documented for approximately 7 days prior to 
Day -1. There will be a 7 - 21-day period from screening to admission to the clinic on 
Day -2 for the first overnight stay of the in-patient period, this time period will ensure 
appropriate time to review laboratory results prior to randomisation.  During the 
screening period, total lymphocytes will be quantified on two occasions at least 3 days 
apart (one of the assessments may be performed on Day -1); lymphocytes must be 
confirmed as being within normal limits before administration of the first dose. All 
screening procedures are outlined in the Time and Events Table in Section 6.2. 
Pre-Treatment Period: On Day -1 safety assessments will be performed as outlined in 
the Time and Events Table in Section 6.2. If the investigator is satisfied that the patient 
still meets the entry criteria they will be randomized to treatment and the hyperglycemic 
clamp procedure performed.   
Treatment Period: Dosing will start on Day 1 and patients will remain in the unit as an 
in-patient for Days 1, 2 and 3 for intravenous dosing of study treatment.   
 Patients will be given the following flexible options for dosing on Days 4, 5 and 6: 
• Option 1:  Receive study treatment on an out-patient basis on any of Days 4, 5 or 6, if 
the Investigator is satisfied with the clinical condition of the patient. For these 
patients, safety monitoring will continue up to a minimum of 3 hours post-dose.  
• Option 2: Patients will remain in the unit if there are any concerns about their clinical 
status, or if the patient prefers to remain in the unit for logistical reasons.  Patients 
will be fully discharged from the hospital unit on Day 6 after completion of dosing 
and all study procedures. If the investigator considers additional safety monitoring is 
necessary, the patient will be asked to stay in the unit after Day 6 until they are in a 
satisfactory condition to be discharged.  
CRS experienced from dosing to the resolution of symptoms and EBV clinical 
reactivation will be monitored in all the patients dosed and specific decision criteria will 
be used for dose escalation based on these assessments.  

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Within each cohort administration of study treatment for the first three patients will be 
staggered by at least three days across each centre. 
Patients will continue to receive their usual standard of care including insulin while 
participating in the study. 
Figure 3 shows a schematic of the overall study design. 
Figure 4 shows a schematic of the study screening, dosing and follow up phases for all 
study patients.  
3.2. 
Study Schematics 
Figure 3 
Overall Study Design 
Cohort  1 
(9 mg) 
and 
Placebo
Cohort 2 
(18 mg) 
and 
Placebo
Cohort 3 
(27 mg) 
and 
Placebo
DE*
DE*
*See  section 5.3 for details of dose escalation (DE) criteria
•Doses shown  are cumulative doses, dosed over 6 days 
Cohort 4 
(36 mg) 
and 
Placebo
DE*
 
 

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Figure 4 
Study Visits Schematic 
For study assessments see the Time and Events tables in Section 6.2 
 
Note: Dosing on Days 4-6 inclusive may be performed on an out-patient basis, if judged 
acceptable on the basis of the clinical condition of the patient by the Investigator.  
3.3. 
Discussion of Study Design 
3.3.1. 
Design Rationale 
3.3.1.1. 
Study Population 
The study population is chosen to replicate the demographics of patients who showed 
least decline in β-cell function based on post hoc sub-group analyses in Phase II (BDR) 
and Phase III (Defend 1 & 2) studies with otelixizumab. See Section 4.2.1 for full 
inclusion criteria. Patients of paediatric age (16 and 17 years old) will be included as 
there is a high prevalence of the disease in this age group. 
3.3.1.2. 
Study Duration 
Data from the literature at the origin of the study design identified a causal relationship 
between the degree of immunosuppression and an increased incidence of EBV related 
Post Transplant Lymphoprolerative Disorders (PTLD) and for this reason a long-term 
follow-up (60 months) was implemented at the start of the study. The interim analysis 
data which emerged from this study showed a prompt regain of immune competence 
observed in treated subjects and consequent rapid resolution of EBV reactivation, both 
clinically and virologically. The long term EBV related PTLD risk, as observed in solid 
organ transplant on a chronic immune suppression therapy, is negligible. As a result, the 
overall study duration for each subject will be 24 months, except for those patients who 
have already passed the 24 month or 36 month follow up, in which case they will have a 
final follow up communication (telephone call or visit) as soon as possible following 
approval of this amendment 08 of the protocol. Further details are provided in the Study 
Reference Manual (SRM). If further follow up is required, the Investigator will request 
that the patient visits the site. See Section 9.3 for a description of analysis considerations. 

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3.3.1.3. 
Measurement of beta cell mass and function, disease progression and 
predictive biomarkers 
The assessment of the number and function of β-cells in vivo is necessarily indirect and 
based on static or dynamic measures of the concentration of β-cell products in the 
peripheral circulation.  An international D-Cure workshop in 2007 recommended the 
measurement of stimulated C-peptide under standardised conditions, and particularly the 
2-h area under the curve (AUC) during a mixed meal tolerance test (MMTT) as the 
primary endpoint in interventional trials evaluating therapies aimed at preserving or 
improving β-cell function in T1DM [Cernea, 2009].  The MMTT test has been validated 
to assess β-cell function by measuring residual C-peptide secretion as an appropriate 
outcome for therapeutic trials in early T1D [Greenbaum, 2008]. Validated measures of β-
cell function from the MMTT test include fasting and 2-h insulin and C-peptide levels, 
and the calculated AUC for each analyte during the test.  Further parameters are 
generated by a mathematical model of β-cell function and insulin secretion rate (ISR) 
calculated by deconvolution analysis of C-peptide levels, and β-cell glucose sensitivity 
[Mari, 2008].  Both peak C-peptide response and the C-peptide AUC during the MMTT 
test are highly reproducible and validated against the Glucagon Test [Greenbaum, 2008].   
By assessing β-cell function after MMTT, some estimate of the rate of decline of β-cell 
mass can be made.  The majority of the data have been derived from the control/placebo 
arm of interventional  studies and likely reflects disease progression in patients whose 
insulin therapy has been optimized.  Recent studies employing MMTT at baseline, 3, 6, 9 
and 12 months post randomization in patients recruited within 3 months of diagnosis 
report an approximate linear decline in C-peptide AUC over the period from 3-12 months 
[Herold, 2002, Herold, 2005, Sherry, 2011].  In some of these studies, the initial rate of 
decline of β-cell loss in these studies (over the period from baseline to 3 months) is 
reduced in the control patients (or even increased above baseline) and this has been 
attributed to the effects of tighter glycaemic control reducing the possible toxic effects of 
hyperglycaemia and dyslipidaemia on β-cell function. 
A two-phase glucose-clamp procedure will be also performed at baseline and 6 and 24 
months post-treatment (-180 to 0 minutes), when euglycemia (60-90 mg/dl) will be 
maintained by intravenous insulin infusion to keep low endogenous insulin secretion and 
during the second phase (0 to 140 minutes), blood glucose levels will be increased and 
maintained between 180-240 mg/dl in order to test and stimulate the endogenous residual 
β-cell secretory capacity. This methodology which has been used in previous studies 
[Keymeulen, 2005] should allow us to characterize the second phase of insulin secretion 
(+60/+140 min post start of Hyperglycaemic Phase) with a lower degree of intra and 
inter-individual variability in comparison with the MMTT. 
3.3.2. 
Dose Rationale 
The proposed daily and cumulative doses and duration of treatment in this study are 
supported by the existing clinical safety data obtained in the original proof of concept 
study in NOT1DM patients (BDR study), where 6 day regimens of short daily infusions 
of 8 mg, and individual daily doses of up to 24 mg, were investigated (cumulative dose 
48-64 mg). 

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The mechanism of action of anti-CD3 mAb therapy and the degree and duration of 
pharmacology necessary for clinical benefit is not fully understood.  However, the weight 
of clinical evidence obtained in NOT1DM patients, based on the cumulative experience 
with otelixizumab and teplizumab (see Section 1.2), suggests a high degree of CD3 target 
engagement and thus a relatively low level of free CD3 antigen on peripheral blood T-
lymphocytes (<10%) during the dosing period may be required to achieve a demonstrable 
effect on stimulated C-peptide secretion and insulin production. In addition, this level of 
blockade was required for effective inhibition of a range of human lymphocyte 
proliferative responses in vitro - see the Investigators Brochure. The lowest proposed 
dosage regimen (9 mg total dose) is anticipated to maintain an average of ~ 10% free 
CD3 antigen on peripheral blood T-lymphocytes during the dosing interval. Higher doses 
are anticipated to reduce free CD3 to less than 10% for the entire dosing period. A 6 day 
dosing regimen, as used in the BDR study where efficacy was demonstrated, was also 
chosen for this study.  
The majority of all reactions, and all severe infusion-reactions with otelixizumab in the 
BDR study occurred during the first 3 days of treatment [Keymeulen, 2005]. In the 
TTEDD study, when the infusion time was reduced from 2 hours to 30 or 15 mins, there 
was a corresponding increase in both peak serum cytokine levels and the incidence of 
CRS-related adverse events.  
An overview of the regimens proposed for each cohort is presented below in Table 1. The 
slow infusions for the first three days of treatment are anticipated to improve the 
tolerability associated with administration of otelixizumab relative to the short infusion 
regimens investigated in previous studies.  
Table 1 
Dosage Cohorts 
Cohort 
Cumulative 
Dose 
(mg) 
Day 1 
Day 2 
Day 3 
Days 4-6 
D 
(mg) 
R 
(mg/h) 
T. 
(h) 
D 
(mg) 
R 
(mg/h) 
T. 
(h) 
D 
(mg) 
R 
(mg/h) 
T. 
(h) 
D 
(mg) 
R 
(mg/h) 
T. 
(h) 
1 
9 
1.5 
0.167 
9* 
1.5 
0.25 
6 
1.5 
0.5 
3 
1.5 
1.5 
1 
2 
18 
3 
0.25 
12 
3 
0.5 
6 
3 
1 
3 
3 
3 
1 
3 
27 
4.5 
0.375 
12 
4.5 
0.75 
6 
4.5 
1.5 
3 
4.5 
4.5 
1 
4 
36 
6 
0.5 
12 
6 
1.2 
6 
6 
2 
3 
6 
6 
1 
NB: D = daily dose, R = rate of infusion, T = infusion time or duration 
* The 9mg (Cohort 1) infusion time will be 9 hours on Day 1 
If there is any need to reduce the infusion rate or temporarily stop the infusion, the 
Investigator should first consult with the Medical Monitor who will consult with the 
Sponsor.  However, the Investigator has the flexibility to reduce or temporarily stop the 
infusion immediately (with no prior consultation with the Medical Monitor), if there are 
any immediate safety/tolerability concerns. In this case the Investigator must inform the 
Medical Monitor as soon as possible after reducing or stopping the dosing.  
 

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3.4. 
Risk Management 
Table 2 
Summary of Key Issues, their Impact and Strategy to Mitigate Risk 
Potential Risk 
Summary of Data 
Impact- Eligibility Criteria 
Strategy-Monitoring/Stopping Criteria 
Cytokine Release 
Syndrome (CRS) 
(chills/rigors, 
fever, nausea, 
vomiting, 
diarrhoea, 
arthralgia, 
myalgia, 
hypotension, 
headache) 
• 
CRS is a well-known consequence of anti-CD3 therapy when administered 
via intravenous injection or infusion.   
• 
Additionally, with high doses of otelixizumab (e.g. 48-64mg cumulative 
tested in the BDR study), liver enzyme elevations occurred and were 
considered to be possibly associated with CRS.   
 
Patients with on-going 
pyrexial infections and with 
history of significant 
systemic infection during 
the 6 weeks prior to the first 
dose of study drug will not 
be enrolled. 
 
Only patients with normal 
liver function will be 
included, defined as AST or 
ALT >2.0 ULN 
• 
Slow infusion; The infusion of the first 
dose in each cohort will be conducted 
over 12 hours. (except for cohort 1 which 
will last 9 hours). The reduction of the 
infusion time will be staged.  
• 
Inpatient clinical observation; at a 
minimum, patients will be in-house for the 
first 3 days of the infusion period. Days 4, 
5 & 6 may be on an out-patient basis with 
safety monitoring for at least 3 hours post 
dose. Patients will be discharged only 
after Investigator clinical approval. The 
facilities will be located within a hospital 
with provision for Intensive Care facilities 
and with immediate access to 
resuscitation and emergency care.  
• 
Prophylaxis CRS; prophylaxis (see 
Section 5.10.1) will be administered in 
conjunction with adequate oral hydration 
prior to and during dosing with 
otelixizumab  
• 
Withdrawal and stopping criteria; 
Individual withdrawal criteria are in place 
(see Section 5.3). 
• 
Dose Escalation: dose escalation is 
based on a strict CRS AE criteria (see 
Section 5.3)  

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Potential Risk 
Summary of Data 
Impact- Eligibility Criteria 
Strategy-Monitoring/Stopping Criteria 
Allergic 
hypersensitivity 
reactions 
• 
Allergic hypersensitivity reactions to biologics are relatively common and in 
practice may be difficult to differentiate from CRS.   
• 
Allergic/hypersensitivity reactions may include the following: flushing, 
pruritus, rash, hives, bronchospasm, dyspnea, diaphoresis, abdominal 
cramping.   
• 
Angiodema, rash, including urticaria, was seen in otelixizumab studies in 
patients with T1DM.  No anaphylaxis or anaphylactoid reactions have been 
seen to date.   
Patients with prior allergic 
reaction, including 
anaphylaxis, to any human, 
humanised, chimeric, or 
rodent antibody will not be 
enrolled. 
• 
An anti-histamine given as part of CRS 
prophylaxis may decrease the occurrence 
of rash. 
• 
Medical management of more severe 
allergic reactions as per local clinical 
guidelines 
• 
Individual withdrawal criteria and Study 
stopping criteria are in place (see Section 
5.3)  

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Potential Risk 
Summary of Data 
Impact- Eligibility Criteria 
Strategy-Monitoring/Stopping Criteria 
Epstein-Barr virus 
(EBV) 
• 
Epstein-Barr virus (EBV) is a widespread human gamma herpes-virus.   
• 
Primary infection with EBV usually occurs asymptomatically, where after the 
virus persists for life in a latent form in B lymphocytes.   
• 
The initial expansion and reactivation of these latently infected B 
lymphocytes is controlled by specific CD8+ major cytotoxic T-lymphocyte 
(CTL) responses. 
• 
EBV reactivation is accompanied by one or more of the following: rash; 
elevated liver function tests, other signs and symptoms consistent with 
acute infectious mononucleosis (pharyngo-laryngeal pain, acute tonsillitis, 
lymphadenopathy, fever).   
• 
The most sensitive confirmation of EBV reactivation is by detecting an 
increase in viral copy number (by RT-PCR).   
• 
In patients on chronic immune-suppression persisting EBV reactivation can 
be detected.  Chronic EBV reactivation is thought to be causal for early 
post-transplant lymphoproliferative disorder (PTLD) which may occur in up 
to 30-40% of patients chronically maintained on high dose 
immunosuppression.   
• 
In studies with otelixizumab in patients with NOT1DM an increased 
incidence of transient EBV reactivation with regimens employing higher 
daily doses has been observed (i.e. 48-64mg cumulative tested in the BDR 
study).  Rapid immune response was evident and full immunity to EBV was 
restored with no evidence of recurring viremia.  Maximum EBV levels 
occurred around Week 3 and decreased to baseline around Month 3.   
• 
As daily dose increases, so the degree of lymphopenia increases and 
TCR/CD3 surface expression declines, resulting in approximately 90% 
reduction in surface expression of TCR/CD3 of 90% sustained.   
Patients within 3 months of 
evidence of acute/active 
EBV infection (e.g)  
• 
Symptomatic 
• 
Positive EBV 
capsid Ab IgM in 
absence of a 
positive EBV 
EBNA Ab IgG  
• 
EBV viral load of 
>10,000 copies 
per 106 
lymphocytes  
will not be enrolled in the 
study. 
• 
Patients with previous history of 
immunosuppression and/or on active 
immunosuppressant therapy will be 
excluded from this study 
• 
Patients will be monitored for clinical 
symptoms of mononucleosis and changes 
in EBV viral load. 

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Potential Risk 
Summary of Data 
Impact- Eligibility Criteria 
Strategy-Monitoring/Stopping Criteria 
Abnormal Liver 
Chemistry 
• 
In the Belgian Diabetes Registry study, administration of high cumulative 
doses of otelixizumab (48-64mg) have been temporally associated with 
abnormal liver chemistry thought to be due to increased cytokine release.  
In subsequent dose-finding studies conducted at lower doses, no trends 
with respect to changes in liver chemistry were observed. 
Patients with history of liver 
diseases and/or persistent  
AST or ALT >2.0 ULN will 
not be included 
Liver chemistry will be monitored daily for the 
duration of treatment to detect any 
unanticipated liver event. 
Liver chemistry individual withdrawal and study 
stopping criteria and follow-up are in place 
(Section 5.3). 
Progressive 
Disease 
 
 
Intensive monitoring and care will be provided 
according to current standards of care for 
patients with type 1 diabetes. Diabetes care 
will be at the discretion of the investigator and 
may include consultations with a nutritionist or 
dietician and/or a diabetes educator according 
to the local institution’s guidelines for 
NOT1DM. Study centres are expected to work 
with each subject to optimize glycaemic control 
as per standard of care, with a target HbA1c 
less than 7% (53 mmol/mol). HbA1c will not be 
communicated to the trial centre by BDR 
unless HbA1c  is ≥ 7% .  Diabetes 
management will be directed towards helping 
each subject reach this target or come as close 
to it as possible.  
Preterm birth 
• 
Preclinically, GLP reproductive toxicity studies have not been completed, 
however; [Gomez-Lopez N , 2016] reported that pregnant B6 mice dosed 
with an antimouse CD3 monoclonal antibody (mAb) on Gestation Day 16.5 
(late gestation) led to an increased frequency of preterm birth and increased 
pup mortality thought to be due to T-cell activation, however, no data to 
demonstrate pharmacology was provided. 
 
Clinically, one subject in a GSK clinical trial (RAO112438) was exposed to the 
investigational product before conception and during the first trimester of 
pregnancy. One hundred ninety nine (199) days after the last dose of IP, the 
subject developed Grade 2 or moderate impending parturition prematurus and 
Grade 2 or moderate hematemesis. The investigator considered that there was 
no reasonable possibility that the uterine  contractions during pregnancy and 
hematemesis may have been caused by investigational product. After 37 weeks 
Eligibility criteria includes 
contraception requirements 
for female subjects and 
male subjects with female 
partners of child-bearing 
potential.  
Pregnancy will be monitored 
with serum pregnancy tests at all 
assessments. 

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Potential Risk 
Summary of Data 
Impact- Eligibility Criteria 
Strategy-Monitoring/Stopping Criteria 
and six days gestation, the subject gave birth to a female live infant. There were 
no birth defects. 
Opportunistic 
Infections 
• 
Mild to severe infections that generally respond to customary treatment 
have occurred in otelixizumab-treated subjects. There have been no 
opportunistic infections reported with otelixizumab in subjects with T1DM. 
Patients who are 
immunocompromised (e.g. 
HIV positive patients) or 
those on 
immunosuppressive 
medications may be at 
higher risk of infections are 
excluded from the clinical 
study with otelixizumab in 
T1DM. 
 
All safety data will be reviewed by the Safety 
Review Team per current practices. 
JC Virus (JCV) 
• 
JCV reactivation has not been observed with other anti-CD3 MAbs; 
however, this has been an area of interest with other types of monoclonal 
antibodies.  
Patients with previous 
history of 
immunosuppression and/or 
on active 
immunosuppressant 
therapy are excluded from 
the study. 
 
 

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4. 
STUDY POPULATION 
4.1. 
Number of Subjects 
Approximately 40 subjects will be enrolled into the study in order to have 10 patients 
complete dosing on all four cohorts (stopping criteria permitting). Ten (10) subjects will 
be enrolled in each cohort, 8 on otelixizumab and 2 on placebo (4:1 ratio). Each cohort 
will comprise a new set of subjects.  
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment at the discretion of the Sponsor 
in consultation with the Investigator.  
The decision whether to replace the patient will be based on the reason for premature 
discontinuation (see Section 4.5 for further information). 
Replacement subject numbers will be assigned to the additional subjects. 
4.2. 
Eligibility Criteria 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the Investigator Brochure. 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
4.2.1. 
Inclusion Criteria 
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply: 
1. Male or female aged between 16 and 27 years of age inclusive, at the time of signing 
the informed consent.  
NOTE: Subjects aged 16 to 17 years must be Tanner Stage ≥2 (see SRM). All 
subjects must weigh at least 31 kg. 
2. Diagnosis of diabetes mellitus according to ADA and WHO criteria and consistent 
with Type 1a (autoimmune) DM, with an interval of approximately 28 days (not 
more than 32 days) between the initial diagnosis and the first dose of study drug). 
Written documentation of the diagnosis of DM, including the date of diagnosis, must 
be obtained from the diagnosing physician. 
3. Currently requires insulin treatment for T1DM and has received insulin therapy for 
at least 7 days prior to screening. 
4. Positive for at least one autoantibody associated with T1DM: antibody to glutamic 
acid decarboxylase (anti GAD), antibody to protein tyrosine phosphatase-like protein 
(anti IA 2), antibody to islet-cell antigen (ICA) or ZnT8 Autoantibody. 

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5. Evidence of residual functioning β cells as measured by mixed meal stimulated C- 
peptide peak level ≥ 0.2 nmol/L.  
6. A female subject is eligible to participate if she has a negative pregnancy test as 
determined by a serum hCG test at screening or prior to dosing AND 
• 
Agrees to use one of the contraception methods listed in Section 4.3.1. Female 
subjects must agree to use contraception for 2 weeks prior to dosing and for 60 
days after the last dose of study drug. 
• 
OR has only same-sex partners (refrains from heterosexual intercourse), when 
this is her preferred and usual lifestyle. 
7. Male subjects with female partners of child-bearing potential must agree to use one 
of the contraception methods listed in Section 4.3.1.  This criterion must be followed 
from 2 weeks prior to dosing and for 60 days after the last dose of study drug. 
8. Willing to follow the procedures outlined in the protocol. 
9. AST and ALT <2xULN; alkaline phosphatase and bilirubin ≤1.5xULN (isolated 
bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin 
<35%).  
10. Subjects eligible for enrolment in the study must meet all of the following criteria: 
• QTc <450msec or  
• QTc <480msec for patients with bundle branch block 
The QTc is the QT interval corrected for heart rate according to either Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), or another method, machine or manual overread.  
• For subject eligibility and withdrawal, QTcF will be used. 
• For purposes of data analysis, QTcF will be used as primary. 
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms (ECGs) obtained over a brief recording period. 
11. Screening total lymphocyte counts within the normal range in two separate samples 
taken at least three days apart (eg screening and Day -1). 
12. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form. In the case of minors (under 
18 years) written informed consent must also be obtained from a parent or Legally 
Acceptable Representative (LAR). 
4.2.2. 
Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
1. A positive pre-study Hepatitis B surface antigen or core antibody or positive 
Hepatitis C antibody result within 3 months of screening.  

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2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
3. A positive test for HIV 1 and/or 2 antibody. 
4. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer). 
5. Exposure to more than four new investigational drugs within 12 months prior to the 
first dosing day. 
6. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or CRO/GSK 
Medical Monitor, contraindicates their participation.  
7. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within a 3 month period. 
8. Lactating females. 
9. Subject is mentally or legally incapacitated. 
10. History of thrombocytopenia. 
11. The subject has received immunization with a vaccine within 4 weeks before the first 
dose of study drug or requires a vaccine within 30 days after the last dose of study 
drug 
12. The subject has had significant systemic infection during the 6 weeks before the first 
dose of study drug (e.g., infection requiring hospitalisation, major surgery, or i.v. 
antibiotics to resolve; other infections, e.g., bronchitis, sinusitis, localised cellulitis, 
candidiasis, or urinary tract infections, must be assessed on a case-by-case basis by 
the investigator regarding whether they are serious enough to warrant exclusion). 
13. Current or prior malignancy, other than non-melanoma skin cancer. 
14. Patient has undergone a splenectomy 
15. Radiological evidence of active tuberculosis (TB).   
16. Significant and/or active disease in any body system likely to increase the risk to the 
subject or interfere with the subject’s participation in or completion of the study. 
Examples of significant diseases include, but are not limited to, coronary artery 
disease, congestive heart failure, uncontrolled hypertension, renal failure, 
emphysema, history of bleeding peptic ulcers, history of seizure(s), addiction to 
illicit drugs, and alcohol abuse. 
17. Clinically significant (based on Investigator’s discretion in consultation with the 
Medical Monitor if second opinion required) abnormal laboratory values during the 
screening period, other than those due to T1DM.  A clinically significant abnormal 
value will not result in exclusion if, upon retest, the abnormality is resolved or 
becomes clinically insignificant. 
18. Positive EBV capsid Ab IgM in absence of a positive EBV EBNA Ab IgG  

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19. EBV viral load of >10,000 copies per 106 peripheral blood mononuclear cells 
(PBMCs) as determined by quantitative polymerase chain reaction (qPCR).. 
20. IgG negative for EBV. 
21. A positive result on a test for syphilis; and if result of the first test is positive, then a 
confirmatory test using another method will be performed. 
22. Have used any atypical antipsychotic drug (e.g., risperidone [Risperdal], quetiapine 
[Seroquel], or clozapine [Clozaril]) within the 30 days before signing the ICF. 
23. Have previously received otelixizumab or any other anti CD3 monoclonal antibody, 
e.g., OKT3 (muromonab or Orthoclone), ChAglyCD3, or hOKT3γ1 (ala ala), and are 
not willing to refrain from using any such antibody for the planned duration of study 
participation (2 years after the last dose of study drug). 
24. Previous or current exposure to biologic cell-depleting therapies (e.g. anti-CD11a, 
anti-CD22, anti-CD20, anti-BLyS/BAFF, anti-CD3, anti-CD5, anti-CD52) including 
investigational agents, and planning to use any such antibody for the planned 
duration of study participation (2 years after the last dose of study drug).  
25. Predisposition to thromboembolic disease, or thromboembolic event (excluding 
superficial) in the past 12 months.  
26. Is currently receiving corticoid treatment or has received systemic corticoid 
treatment within a month of screening.  
27. History of Graves disease 
28. Prior allergic reaction, including anaphylaxis, to any human, humanised, chimeric, or 
rodent antibody. 
29. Have undergone any major surgical procedure within 30 days before the first dose of 
study drug, and/or planning to undergo any such surgery within 3 months after the 
last dose of study drug. 
30. Any condition or situation that, in the investigator’s judgment, is likely to cause the 
subject to be unable or unwilling to participate in study procedures or to complete all 
scheduled assessments. 

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4.3. 
Lifestyle and/or Dietary Restrictions 
4.3.1. 
Contraception Requirements 
4.3.1.1. 
Female Subjects 
Female subjects must not become pregnant for 2 weeks prior to dosing and for 60 days 
after and so must be sexually inactive by abstinence or use contraceptive methods with a 
failure rate of <1%.  Female subjects with same sex partners (when this is their preferred 
and usual lifestyle) are not required to be abstinent or to use contraception. 
Abstinence 
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception.  
Contraceptive Methods with a Failure Rate of <1% 
• 
Oral contraceptive, either combined or progestogen alone 
• 
Injectable progestogen  
• 
Implants of etonogestrel or levonorgestrel 
• 
Estrogenic vaginal ring 
• 
Percutaneous contraceptive patches 
• 
Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure 
rate as stated in the product label 
• 
Documented male partner sterilization prior to the female subject's entry into the 
study, and this male is the sole partner for that subject.  For this definition, 
“documented” refers to the outcome of the investigator's/designee’s review of the 
subject's medical history for study eligibility, as obtained via a verbal interview with 
the subject or from the subject’s medical records. 
• 
Male condom combined with a female diaphragm, either with or without a vaginal 
spermicide (foam, gel, cream or suppository). 
 
NOTE: These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label.  The investigator is 
responsible for ensuring subjects understand how to properly use these methods of 
contraception. 
4.3.1.2. 
Male Subjects 
Male subjects with female partners of child-bearing potential must use one of the 
following contraceptive methods for 2 weeks prior to dosing and for 60 days after the last 
dose of study treatment: 

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• 
Condom plus partner use of a highly effective contraceptive (see list in Section 
4.3.1.1).  
• 
Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the subject.  Periodic abstinence (e.g. calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception 
4.3.2. 
Meals and Dietary Restrictions 
4.3.2.1. 
Alcohol 
• 
During the dosing session, patients will abstain from alcohol for 24 hours prior to the 
start of dosing until collection of the final pharmacokinetic and or pharmacodynamic 
sample during the dosing session and around each visit.  
4.3.2.2. 
Activity 
Patients will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests.  Patients may participate in light recreational activities during 
study visits (e.g., watch television, read). 
4.3.2.3. 
Travel 
Patients will also be advised to refrain from travelling to countries where there is a high 
incidence of infectious diseases within the first six months from start of treatment. 
4.4. 
Screen and Baseline Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are not subsequently randomized. To ensure transparent reporting of screen 
failure data (in order to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements), and respond to queries from Regulatory 
authorities, a minimal set of screen failure information is required including:   
• Demography,  
• Reason for screen failure,  
• Eligibility criteria,  
• Serious adverse events. 
 
4.5. 
Withdrawal Criteria and Procedures 
A patient may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. Subjects who withdraw may be replaced to ensure that data on 40 
subjects are obtained.   
The decision on whether to replace the patient will be based on the reason for premature 
discontinuation, as described in Table 3. 

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Table 3 
Patient replacement 
Patients will be 
replaced if: 
• The reason for withdrawal was not treatment related (e.g. 
patient withdrew consent for personal reasons). 
• Adverse event judged unrelated to treatment  
Patients will not be 
replaced if: 
• There is a lack of tolerability to treatment. 
• Individual or group stopping criteria are met. 
• Significant changes in any of the safety assessments (e.g. 
ECG, vital signs, laboratory tests, etc). 
 Decisions regarding patient replacement will be made in consultation with the Medical 
Monitor who will discuss with GSK. 
Subjects that have received treatment and who withdraw should continue to undergo all 
safety assessments as per protocol including PK sampling, if possible. However, efficacy 
(hyperglycaemic clamp and MMTT) pharmacodynamic (PD) assessments may not 
always be performed. The need to perform PD assessments will be agreed on a case-by-
case basis. The date of withdrawal must be recorded in the eCRF. If the patient agrees 
they will follow the original scheduled visit plan after withdrawal. 
Refer to Section 5.3.1 for dose adjustment/stopping criteria.  
Liver chemistry threshold stopping criteria have been designed to assure patient safety 
and to evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance). See Section 5.3.4 for details. 
4.6. 
Patient Completion 
A completed patient is one who has completed Month 24. 
The end of the study is defined as the last patient’s last visit Month 24 or at final follow-
up. 

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5. 
STUDY TREATMENT 
5.1. 
Investigational Product and Other Study Treatment 
 
Study Treatment 
Product name: 
GSK2136525: Otelixizumab 
Concentrated Solution for Infusion, 
5 mg/mL 
Placebo (0.9% w/v Sodium Chloride) 
 
Dosage form: 
Concentrated Solution for Infusion 
Solution for Injection 
Unit dose 
strength(s)/Dosage 
level(s): 
Unit dose strength: 5 mg/mL 
provided as 1 mL solution per vial 
to be diluted to 0.1 mg/mL in 0.9% 
sodium chloride 
Dosage levels: variable 
0.9% w/v Sodium Chloride/ Placebo 
level variable 
Route/ 
Administration/ 
Duration: 
Intravenous infusion via syringe 
pump; using only the infusion kits 
supplied by CRO/GSK, 
administration duration varies  
 
Intravenous infusion via syringe 
pump; using only the infusion kits 
supplied by CRO/GSK, 
administration duration varies  
Dosing 
instructions: 
Study medication will be diluted to 
0.1 mg/mL in 0.9% w/v sodium 
chloride to prepare otelixizumab 
solution for Infusion, 0.1 mg/mL.  
The 0.1 mg/mL solution is 
administered by intravenous 
infusion using a syringe pump and 
an in-line 0.2 micron filter by study 
personnel following specified 
regimens 
0.9% w/v sodium chloride 
administered by intravenous infusion 
in the same manner as the active by 
study personnel following specified 
regimens 
Manufacturer/ 
source of 
procurement: 
Study medication supplied by GSK 
0.9% w/v sodium chloride sourced 
locally by site 
0.9% w/v sodium chloride sourced 
locally by site 
5.2. 
Treatment Assignment 
Patients will be assigned to receive either otelixizumab or matching placebo (4:1 ratio), 
prior to the start of dosing in each cohort by utilizing RAMOS (GSK’s Registration and 
Ordering System).  The randomization schedule utilized by RAMOS will be provided by 
Clinical Statistics (CS), using internal validated software. Once a randomisation number 
has been assigned it must not be re-assigned.  
A description of each regimen is provided in Table 4: 

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Table 4 
Treatment Assignment 
Treatment 
Cohort 
Treatment Description 
Daily Dose of Otelixizumab (mg) 
A 
1 
Otelixizumab 9 mg 
1.5 
B 
2 
Otelixizumab 18 mg 
3 
C 
3 
Otelixizumab 27 mg 
4.5 
D 
4 
Otelixizumab 36 mg 
6 
P 
1-4 
Placebo 
N/A 
5.3. 
Patient Specific and Dose Escalation Stopping Criteria 
5.3.1. 
Cytokine Release Syndrome Stopping Criteria 
Cytokine Release Syndrome (CRS) experienced during the 6 days of dosing will be 
monitored specifically by the investigator according to the grading system presented in 
Table 5 and Section 7.1.5.  In-stream real time data review will be utilised, so as to limit 
patient exposure unnecessarily, if stopping criteria are met. 
Table 5 
CRS AE Grading System 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Headache 
Mild pain 
Moderate pain; 
limiting instrumental 
ADL 
Severe pain; limiting 
self care ADL 
- 
- 
Fever 
38.0 - 39.0 degrees 
C   
>39.0 - 40.0 degrees 
C  
>40.0 degrees C  for 
<=24 hrs 
>40.0 degrees 
C for >24 hrs 
Death 
Vomiting 
1 - 2 episodes 
(separated by 5 
minutes) in 24 hrs 
3 - 5 episodes 
(separated by 5 
minutes) in 24 hrs 
>=6 episodes 
(separated by 5 
minutes) in 24 hrs  
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Diarrhoea 
Increase of <4 
stools per day over 
baseline. 
Increase of 4 - 6 
stools per day over 
baseline. 
Increase of >=7 stools 
per day over baseline; 
incontinence; limiting 
self care ADL 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Hypotension 
Asymptomatic, 
intervention not 
indicated 
Non-urgent medical 
intervention indicated 
Urgent medical 
intervention indicated 
Life-
threatening 
and urgent 
intervention 
indicated 
Death 
Chills 
Mild sensation of 
cold; shivering; 
chattering of teeth 
Moderate tremor of 
the entire body; 
narcotics indicated 
Severe or prolonged, 
not responsive to 
narcotics 
- 
- 
Nausea 
Loss of appetite 
without alteration in 
eating habits 
Oral intake 
decreased without 
significant weight 
loss, dehydration or 
malnutrition 
Inadequate oral 
caloric or fluid intake. 
- 
- 

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Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Arthralgia 
Mild pain 
Moderate pain; 
limiting instrumental 
ADL 
Severe pain; limiting 
self care ADL 
- 
- 
Myalgia 
Mild pain 
Moderate pain; 
limiting instrumental 
ADL 
Severe pain; limiting 
self care ADL 
- 
- 
ADL= Activities of daily living 
Pre-specified CRS individual patient and study dosing stopping criteria are presented in 
Table 6 and should be followed by the Investigator.  
• If individual patient criteria are met: Treatment for that patient will be stopped 
immediately, will not be restarted, and the patient will be followed up as per protocol.  
• If study dosing stopping criteria are met:  In addition to the individual patient 
instruction above, no further patients will be dosed within the cohort currently being 
investigated and no further dose escalation will occur;  patients who have been dosed 
will be followed up as per protocol. 
The symptoms in Table 6 have been classified as objective and subjective endpoints as 
follows: 
Objective Endpoints: Fever, Diarrhoea, Vomiting, Hypotension 
Subjective Endpoints: Headache, Chills, Nausea, Arthralgia, Myalgia 
Based on the above classification four possible outcomes have been defined where dosing 
would be stopped, as described in Table 6: 

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Table 6 
Stopping Criteria for CRS-Adverse Events 
Scenario NCI-CTC Scores 
Individual Subject Criteria 
I 
2 objective endpoints ≥ grade 2 
                 OR 
Fever, vomiting, or diarrhoea ≥ grade 2 
persisting >48 hours despite treatment 
Stop treatment  
II 
1 objective endpoint ≥ grade 2  
                 AND  
• 2 subjective endpoints (except chills) ≥ 
grade 3 
                OR 
• 1 subjective endpoint ≥ grade 3 and 
Chills ≥ grade 2 
Stop treatment 
III 
Three subjective endpoints ≥ grade 3 (except if 
one subjective endpoint is Chills, which only 
needs to be ≥ grade 2)              
Stop treatment 
IV 
1 objective endpoint ≥ grade 4 
Stop treatment 
Study Dosing Stopping Criteria:  
 
• If ≥3 subjects on otelixizumab treatment within a cohort meet individual Stopping 
Criteria I-III detailed above. 
 
Or 
 
• If 1 subject on otelixizumab treatment within a cohort meet individual Stopping 
Criteria IV. 
 
 
Note: in order to meet individual stopping criteria, the reported objective or 
subjective endpoints must be of different types during one 24 hour dosing period for 
any of the scenarios involving more than one endpoint. 
5.3.2. 
EBV Stopping Criteria 
Three parameters as described in Table 7 will be used to assess EBV reactivation at a 
patient level to determine dose escalation: 

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Table 7 
Parameters used to Assess EBV Reactivation 
Parameter 
Criteria 
Clinical Symptoms of Mononucleosis 
Fever, fatigue, malaise, myalgia, pharyngodynia, 
lymphadenopathy 
Change in Viral Load 
EBV by PCR more than 10,000 copies per 106 
peripheral blood mononuclear cells 
Change in Serology 
Emergence of IgM for EBV on otherwise EBV-IgG 
positive patients 
Table 8 shows the possible combinations of the three EBV parameters that will be used to 
assess whether the patient has clinical EBV reactivation for the purpose of the stopping 
criteria. The assessment will be conducted for each subject at approximately 6 weeks post 
first active dose. 
Table 8 
Assessment of EBV Reactivation 
Clinical Signs of 
Mononucleosis 
Serology 
Virology 
EBV Reactivation 
+ 
- 
- 
NO* 
+ 
+ 
+ 
YES 
+ 
+ 
- 
YES 
+ 
- 
+ 
YES 
- 
- 
- 
NO 
- 
+ 
+ 
NO 
- 
+ 
- 
NO 
- 
- 
+ 
NO 
*Other causes of mononucleosis should be checked 
 
There will be ongoing reviews of safety data throughout the trial progression and on 
completion of each cohort.  
If  ≥ 3/8 patients on active treatment within a cohort develop symptoms of clinical EBV 
reactivation as described above, the dosing will be stopped and no further dosing will be 
carried out on any other patients; patients who have been dosed will be followed up as 
per protocol.  
Patient history will be assessed for symptoms of infectious mononucleosis, and 
spontaneous AE reporting will be implemented for assessing clinical EBV reactivation.  

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5.3.3. 
Assessment of Cytokine Release Syndrome & EBV Stopping 
Criteria 
A summary schematic for dose escalation criteria based on CRS & EBV (refer to sub-
Sections in Section 5.3 for criteria) are presented in Figure 5: 
 
Figure 5 
Dose Escalation Schematic 
 
1: As defined in Table 6 
2: As defined in Table 7  
5.3.4. 
Liver Chemistry Stopping Criteria 
Liver chemistry threshold stopping criteria have been designed to assure patient safety 
and to evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance).  
Study treatment will be stopped for a patient if the following liver chemistry stopping 
criteria is met:  
1. ALT ≥ 3xULN and bilirubin ≥ 2xULN  
NOTE: serum bilirubin fractionation should be performed if testing is available.  If 
fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a 
measurement of direct bilirubin, which would suggest liver injury). 

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2. ALT ≥ 5xULN. 
3. ALT ≥ 3xULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness or jaundice) or believed to be related to hypersensitivity (such as fever, 
rash or eosinophilia). 
4. ALT ≥ 3xULN persists for ≥ 4 weeks. 
5. ALT ≥ 3xULN and cannot be monitored weekly for 4 weeks. 
Subjects with ALT ≥ 3xULN and <5xULN and bilirubin <2xULN, who do not exhibit 
hepatitis symptoms or rash, can continue study treatment as long as they can be 
monitored weekly for 4 weeks.   
NOTE: Refer to Appendix 1, for details of the required assessments if a subject meets 
any of the above criteria. 
5.3.5. 
QTc Withdrawal Criteria 
• 
A patient that meets any of the criteria below will be withdrawn from the 
study.  The same QT correction formula should be used to determine 
inclusion and discontinuation for any individual patient throughout the study. 
• QTc >500 msec or uncorrected QT >600 msec, or 
• Change from baseline:  QTc >60 msec 
If a patient has underlying bundle branch block the following withdrawal criteria should 
be used instead. 
Baseline QTc value (with  
underlying bundle branch) 
QTc withdrawal 
criteria 
<450 msec 
>500 msec 
450-480 msec 
≥530 msec 
Withdrawal of patients is to be based on an average QTc value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief period of 
time and then use the averaged QTc values of the 3 ECGs to determine whether the 
patient should be discontinued from the study. 
5.3.6. 
Lymphopenia 
If a single patient’s lymphocyte count does not return to normal 28 days after dosing, the 
study team will review all available data. The patient will be monitored by bi- monthly 
blood counts until resolution and clinical assessments will address any evidence of 
infection. 
5.3.7. 
Hypersensitivity Reaction 
If a single patient develops an episode of angioedema or anaphylaxis, or three patients 
develop the same adverse event of severe urticaria (without angioedema, bronchospasm, 

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hypotension) the study team will review all available data and determine whether or not 
to continue the dosing regimen. 
5.3.8. 
Other Stopping Safety Criteria 
For an individual study participant, other stopping criteria include, but are not limited 
to: 
Severe signs or symptoms, or significant changes in any of the safety assessments, that 
put the safety of the individual at risk (e.g. ECG, vital signs, laboratory tests, etc), as 
judged by the Principal Investigator in consultation with the Medical Monitor if 
necessary. 
5.4. 
Blinding 
This will be a single blind study where the patients will not be aware of the treatment 
they receive. All staff including site personnel, CRO and sponsor team members will be 
unblinded. However, the randomisation code will be restricted to the pharmacist 
preparing the infusions. 
5.5. 
Packaging and Labelling 
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
5.6. 
Preparation/Handling/Storage/Accountability 
A description of the methods and materials required for preparation of otelixizumab are 
provided below.  Additional details are provided in the SRM. 
Study treatment must be dispensed or administered according to procedures described 
herein:   
• Only subjects enrolled in the study may receive study treatment.   
• Only authorized site staff may supply or administer study treatment.   
• All study treatment must be stored in a secure area with access limited to the 
investigator and authorized site staff.   
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for investigational product accountability, reconciliation, and record 
maintenance. The investigator or the head of the medical institution (where applicable), 
or designated site staff (e.g., storage manager, where applicable) must maintain 
investigational product accountability records throughout the course of the study.  The 
responsible person(s) will document the amount of study medication received from GSK, 
document that it was shipped at 2-8°C by checking the temperature monitor, document 
the amount destroyed at end of study and the amount administered to subjects.  The 
required accountability unit for this study will be vials.  Discrepancies are to be 

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reconciled or resolved.  Procedures for final disposition of unused study medication are 
listed in the SRM. 
Study medication is not expected to pose significant occupational safety risk to site staff 
under normal conditions of use and administration.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, medical monitor and/or study 
manager.  A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be provided to 
the investigator, where this is required by local laws, or is available upon request from 
GSK. 
Precaution will be taken to avoid direct contact with the study medication.   
5.6.1. 
Study Medication Storage and Handling 
Otelixizumab Concentrated Solution for Infusion, 5 mg/mL must be stored refrigerated at 
2-8ºC, protected from light. Maintenance of a temperature log (manual or automated) is 
required. All otelixizumab solutions (i.e., drug product and solutions for infusion) must 
not be frozen.  Solutions exposed to temperatures in excess of 25°C must be discarded.   
Otelixizumab Solution for Infusion, 0.1 mg/mL must be prepared on the day of 
administration, as close to dosing as possible, i.e., within 6 hours of dosing, to ensure 
product quality.   
Vigorous shaking of all otelixizumab solutions must be avoided.   
5.6.2. 
Study Medication Preparation 
Otelixizumab 
Otelixizumab Concentrated Solution for Infusion, 5 mg/mL (1.0 mL vial) must be diluted 
in Sterile 0.9% Sodium Chloride in an empty 150 mL intravenous bag (Baxter Intravia) 
to prepare Otelixizumab Solution for Infusion, 0.1 mg/mL.   
• Otelixizumab Solution for Infusion, 0.1 mg/mL is prepared by adding 49.0 mL of 
Sterile 0.9 % Sodium Chloride to the 150 mL empty bag followed by the addition 
of 1.0 mL of Otelixizumab Concentrated Solution for Infusion, 5 mg/mL (total 
50.0 mL).   
• Otelixizumab Solution for Infusion, 0.1 mg/mL is stable when stored in the 
Baxter Intravia bag for 6 hours at up to 25°C. 
 Important Note: When drawn into the syringe for administration to the 
patient it must be administered within 6 hours If needed an additional 
maximum of 30 minutes is allowed for tasks such as connection of line 
and filter, pump set up and priming and purging the lines. However, every 
attempt should be made not to exceed a total time of 6 hours if 
possible.  

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 Important Note: If the infusion period will exceed 6 hours, then the 
syringe and  infusion materials (IV line, stopcock and PES filter) must be 
discarded and a new syringe of dose and infusion materials used. 
Preparation of syringes(s) must be recorded on the Test Article 
Administration Form. 
• The dose will be drawn from a fresh bag of 0.1 mg/mL Otelixizumab 
solution.  
• The pharmacist should allow sufficient time to prepare the final solution 
and must ensure that infusion components are changed at the appropriate 
times.  
• The temperature must be controlled and should not exceed 25°C.  
• The temperature will be recorded at the pharmacy (when the IV bag is 
ready to be transferred to the dosing unit) and at the dosing unit (upon 
receipt). 
•  The required volume of Otelixizumab Solution for Infusion, 0.1 mg/mL (varies 
depending on target dose) and includes an excess of approximately 8 mL volume 
to account for prime/purge (6 mLs – see Section 5.6.3) plus an additional 2 mLs 
(or more if required) as an overage volume required for the syringe pump to 
deliver the exact volume to the patient as specified in Table 9 column 7. The 
additional overage must not be administered to the patient. The required volume 
must be withdrawn into a suitable size polypropylene syringe as close to the time 
of the start of the infusion as possible, to ensure product quality. 
• For infusion periods that exceed 6 hours or infusion volumes exceeding 55 mL, a 
second syringe must be prepared and the infusion period divided across two 
separate syringes.   
Placebo 
• 0.9 % Sodium Chloride will be administered by intravenous infusion in the same 
manner as the active by study personnel following specified regimens. The same 
volume of placebo solution must be withdrawn into the same size polypropylene 
syringe as the corresponding active regimen. 
Table 9 shows dose preparation. 

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Table 9 
Study Medication Dose Preparation 
Treat-
ment 
Regimen 
(cohort) 
Cumul-
ative 
Dose 
(mg) 
Dose per 
day (mg) 
Day of 
Dosing 
Period 
of 
Dosing 
(hours) 
# of 
Syringes 
Total Dosing 
Solution 
Volume to be 
Infused 
Total Vol. Filled into 
Syringe, Includes  
Approximately *8 mL 
Fill Overage (Vol. not 
Infused) 
A (1) 
9 
1.5 
Day 1 
9 
2 
15 mL (7.5 mL 
x 2 syringes)  
15.5 mL x 2 syringes 
Day 2 
6 
1 
15 mL 
23 mL 
Day 3 
3 
1 
15 mL 
23 mL 
Day 4-6 
1 
1 
15 mL 
23 mL 
B (2) 
18 
3 
Day 1 
12 
2 
30 mL (15 mL 
x 2 syringes) 
23 mL x 2 syringes 
Day 2 
6 
1 
30 mL 
38 mL 
Day 3 
3 
1 
30 mL 
38 mL 
Day 4-6 
1 
1 
30 mL 
38 mL 
C (3) 
27 
4.5 
Day 1 
12 
2 
45 mL 
(22.5 mL x 2 
syringes) 
30.5 mL x 2 syringes 
Day 2 
6 
1 
45 mL 
53 mL 
Day 3 
3 
1 
45 mL 
53 mL 
Day 4-6 
1 
1 
45 mL 
53 mL 
D (4) 
36 
6 
Day 1 
12 
2 
60 mL (30 mL 
x 2 syringes) 
38 mL x 2 syringes 
Day 2 
6 
2 
60 mL (30 mL 
x 2 syringes) 
38 mL x 2 syringes 
Day 3 
3 
2 
60 mL (30 mL 
x 2 syringes) 
38 mL x 2 syringes  
Day 4-6 
1 
2 
60 mL (30 mL 
x 2 syringes) 
38 mL x 2 syringes  
P 
0 
0 
0.9% w/v sodium chloride administered by intravenous infusion in the same 
manner as the active by study personnel following specified regimens 
*Overage volume may be adjusted to ensure optimal efficiency of syringe pump to 
deliver the exact dosing volume to be infused. Note the overage volume must NOT be 
delivered to the patient but remain in the syringe and discarded. 

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5.6.3. 
Study Medication Administration 
Using the information given in Table 9: 
• Withdraw the total required volume of Otelixizumab Solution for Infusion, 
0.1 mg/mL or 0.9% Sodium Chloride for the placebo, using the syringe(s) that 
will be used for administration with the infusion pump (see Section 5.6.2 
regarding stability time and time allowed for preparation).   
• Connect a polyethylene intravenous line with an in-line 0.2 µm polyethersulfone 
(PES) filter to the syringe.  If a second syringe is needed to provide the dose, a 
separate infusion line with 0.2 µm PES filter is required.   
• The prime volume of the intravenous line and filter must not exceed a total of 
3 mL.  The approximate 8 mL excess solution in the syringe(s) must be 
primed/purged (3 mL to waste, about 3 mL fills the IV line); target a 
priming/purging rate of 1 mL/min or lower.  Purging 3 ml to waste is required to 
account for protein loss due to binding and to ensure that the full dose is 
administered. The additional 2 mLs (or more if required) should remain as 
overage in the syringe and must not be administered to the patient.   
• After the priming/purging procedure, the syringe(s) contains the volume of 
Otelixizumab Solution for Infusion, 0.1 mg/mL, or 0.9% Sodium Chloride in the 
case of placebo, needed to provide the clinical dose and is ready to be connected 
to the subject for dose delivery.   
• Securely connect the infusion line to the patient cannula.   
• Set the syringe pump to provide the syringe volume for the duration provided in 
Table 9 according to Cohort, Day and Dose to be delivered. 
• Note that the solution remaining in the IV lines must not be administered to the 
patient.    
If there is any need to reduce the infusion rate or temporarily stop the infusion, the 
Investigator should first consult with the Medical Monitor who will consult with the 
Sponsor.  However, the Investigator has the flexibility to reduce or temporarily stop the 
infusion immediately (with no prior consultation with the Medical Monitor), if there are 
any immediate safety/tolerability concerns. In this case the Investigator must inform the 
Medical Monitor as soon as possible after reducing or stopping the dosing. 
5.7. 
Assessment of Compliance 
Patients will be dosed at the study site and they will receive study treatment directly from 
the investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents and eCRF.  The dose 
of study treatment and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
treatment.   

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5.8. 
Treatment of Study Treatment Overdose 
In the event of an overdose (defined as administration of more than the protocol-specified 
dose of otelixizumab, the investigator should: 
• Contact the GSK and CRO Medical Monitor immediately 
• Closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until otelixizumab can no longer be detected 
systemically (at least 7.5 days) for otelixizumab. 
• Additional plasma samples for pharmacokinetic (PK) analysis may be requested 
by the GSK Medical Monitor within 30 days of the last dose, determined on a 
case-by-case basis. 
• Document the quantity of the excess dose as well as the duration of the 
overdosing in the electronic case report form (eCRF). 
• Decisions regarding dose interruptions or modifications will be made by the 
investigator in consultation with the Medical Monitor based on the clinical 
evaluation of the subject. 
5.9. 
Treatment after the End of the Study 
Patients will not receive any additional treatment from GSK after completion of the study 
because other treatment options are available. 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition. 
5.10. 
Permitted Concomitant Medications and Non-Drug 
Therapies 
All concomitants medications required for the management of the underlying disease will 
be permitted and must be recorded in the eCRF. 
Paracetamol at doses of ≤2grams/day and NSAIDs at the suggested clinical dose are 
permitted for use from Day 7 onwards. All medications required for the Standard of Care 
of T1DM will be permitted. 
Other concomitant medication will be considered on a case by case basis by the 
investigator in consultation with the CRO/GSK Medical Monitor. 
5.10.1. 
Prophylaxis and Treatment of Cytokine Release Symptoms 
All medications and fluids used as prophylaxis or treatment for cytokine release 
syndrome (CRS) will be recorded in the eCRF as concomitant medications. 

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5.10.1.1. 
Prophylaxis 
Prophylaxis for CRS will be administered to each patient on each dosing day. 
Medications will be administered according to the investigator’s clinical judgment; but 
the following guidelines are recommended: 
 
NSAID Ibuprofen orally as follows: 800 mg 2 hours before start of infusion (SOI),  
800 mg 6 hours after SOI, and 400 mg at bedtime for the first 3 days of infusion. 
The total dose administered as prophylaxis should not exceed 2400 mg in any 24-hour 
period.  
 
Alternatives to ibuprofen are naproxen and ketoprofen at the recommended clinical 
dosage as per package dosage inserts. 
 
If the patient is intolerant of ibuprofen or if ibuprofen is contraindicated, paracetamol 
may be used in place of ibuprofen. Paracetamol doses should be in accordance with 
current local recommendations for over-the counter dosing and must not exceed 1000 mg 
per 6 hours or 4000 mg per day during in-patient visit. 
 
To avoid exceeding the maximum daily amount of either ibuprofen or paracetamol, 
alternance of the two drugs is suggested. Paracetamol doses must be separated by at least 
6 hours. 
 
A non-sedating antihistamine (e.g., cetirizine) should be administered approximately 
1 hour prior to each infusion of study drug. The recommended initial dose of cetirizine 
is 5 mg or 10 mg per day orally in adults and children aged 12 years and 
older. Other antihistamines of this same class (e.g., loratidine) may be substituted as 
clinically indicated and administered according to manufacturer's instructions.  
Isotonic saline solution (ISS) (0.90% w/v of NaCl ) administered i.v. if needed to 
maintain hydration. 
Observations from previous studies suggest that inadequate hydration may increase the 
risk of hypotension in patients receiving otelixizumab, while excessive hydration may 
increase the risk of some AEs (such as headache) if cytokine release occurs. Subjects 
should receive adequate oral hydration whenever possible. Investigators should use their 
clinical judgment to determine whether to administer i.v. ISS, and on the quantity and 
rate of i.v. ISS infusion. This judgment should be based on the patient’s ability to 
maintain adequate hydration by oral intake and on the patient’s volume status, which 
should be assessed by physical examination and other relevant parameters on each dosing 
day.  
5.10.1.2. 
Treatment 
If cytokine release symptoms persist despite the prophylactic treatment, additional 
treatment may be given at the discretion of the investigator, including more potent 
analgesics (e.g., opioids, such as acetaminophen with codeine, and/or triptans, for 
headache. An anti-emetic such as ondansetron may be given for nausea and/or vomiting). 
However, use of systemic corticosteroids should be avoided unless such treatment is 

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medically necessary and alternative treatments are not considered safe or effective. The 
medical monitor must be notified of the administration of systemic corticosteroids. 
NSAID Ibuprofen Additional ibuprofen may be used if, in the Investigator’s clinical 
judgment, this would be appropriate treatment for an AE. The total dose administered as 
prophylaxis or therapy should not exceed 2400 mg in any 24-hour period. 
Antihistamine Additional doses of antihistamine may be administered as clinically 
indicated and according to manufacturer's instructions. 
5.11. 
Prohibited Concomitant Medications and Non-Drug 
Therapies 
Patients should NOT receive potent immunosuppressive agents (e.g., systemic high-dose 
corticosteroids on a chronic basis, methotrexate, cyclosporine, anti-TNF agents, etc.) 
during the study. Additionally, patients should not receive such agents within 24 months. 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 6.2. 
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: PK, safety blood samples, 
ECG, vital signs, and PD samples. 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
The timing and number of planned study assessments, including: safety, 
pharmacokinetic, pharmacodynamic, biomarker or other assessments may be altered 
during the course of the study based on newly available data (e.g. to obtain data closer to 
the time of peak plasma concentrations) to ensure appropriate monitoring. The change in 
timing or addition of time points for any planned study assessments must be approved 
and documented by GSK, but this will not constitute a protocol amendment. The 
IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme.  
No more than approximately 500 mL of blood will be collected over the first 3 month 
period, including any extra assessments that may be required.  The volume of blood 
collected after the first 3 months will be lower, eg less than 200 mL. 
6.1. 
Visit Windows 
The following visit windows will be allowed to provide flexibility. Visits completed 
within the windows will not constitute a protocol deviation:  
• A ± 1 day window is permitted for the Day 14 and Day 21 visits and Week 4 
telephone call. 

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• Visits from Week 6 to Month 3 inclusive are permitted a ± 3 day window 
• Visits from Month 6 to Month 24 inclusive are permitted a ± 7 day window 
• Telephone calls/visits in the follow-up period at Month 36 and final-up are 
permitted a ±14 day window 
 

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6.2. 
Time and Events Tables 
6.2.1. 
Screening 
 
*Two Total lymphocyte counts within normal range must be obtained prior to dose administration (counts from screening and Day-1, 
must be at least 3 days apart) 
 

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6.2.2. 
Dosing and Follow-Up 
  
  
  
Day 
Month 
  
-2 
-1 
1 
2 
3 
4 
5 
6 
14 
21 
 
 
Week 
4 
Week 
6 
2 
3 
6 
9 
12 
18 
24 
36 
month 
(if 
applicab
le) 
and/or 
final 
follow 
up  
Patient admitted to unit1 
X 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
In Patient 
  
X 
X 
X 
X 
X2 
X2 
X2 
  
  
 
  
  
  
  
  
  
  
  
Prophylaxis (Section 5.10) then  IV Dosing of 
study treatment 
  
  
X 
X 
X 
X 
X 
X 
 
 
Patient Discharged2 
X 
 
 
Out Patient# 
  
  
  
  
  
X  
 X 
 X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone call or out-patient visit to collect 
AEs, hypoglycemic and hyperglycemic events 
and concomitant 
 medication use 
X 
 
X 
Brief Physical Examination  
  
X 
X3 
X3 
X3 
X3 
X3 
X3 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
12 lead ECG4,6 
  
X 
X 
X 
X 
X 
X 
 X 
X 
 
X 
X 
Vital Signs5,6 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Test  
  
X 
  
  
  
  
  
  
  
  
 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol & drugs of abuse test  
  
X 
  
  
  
  
  
  
  
  
 
  
  
 
Haematology7  
  
X 
  
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry7  
  
X 
X 
X 
X 
X 
X 
X8 
X 
  
 
X 
  
X 
X 
X 
X 
X 
X 
HSV-1 & HSV-2 IgG & IgM9 
X 
 
 
EBV Viral Load (PCR)7 
  
X 
  
  
  
  
  
X 
  
 X 
 
X 
X 
X 
X10 
  
  
  
 X 
EBV Serology  - IgG and IgM 7 
  
X 
  
  
  
  
X 
X 
 
X 
X 
X 
X 
X 
  
X 

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Day 
Month 
  
-2 
-1 
1 
2 
3 
4 
5 
6 
14 
21 
 
 
Week 
4 
Week 
6 
2 
3 
6 
9 
12 
18 
24 
36 
month 
(if 
applicab
le) 
and/or 
final 
follow 
up  
CMV  Serology  - IgG and IgM7  
X 
X 
 
X 
X 
X 
X 
X 
X 
PK Blood Sample6 
X 
X 
X 
X 
X 
X 
X11 
 
 
CD3 Saturation, free CD3 bound otelixizumab 
/CD4+/CD8+ Blood Sample6 
X 
X 
X 
X 
X 
X 
X11 
 
 
Record insulin usage for 7 days before visit / 
call 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 
  
  
<---------------------------------------------------------------------------------------------------------------------------------------------------------> 
Concomitant Medication Review 
  
  
<---------------------------------------------------------------------------------------------------------------------------------------------------------> 
Hypoglycaemic / Hyperglycaemic Events 
<--------------------------------------------------------------------------------------------------------------------------------------------------> 
Anti-GAD, anti-IA2, antibody to islet-cell 
antigen (ICA), anti-ZnT8 & Insulin-antibodies 
(IAA) 
X 
 
 
Anti-otelixizumab antibodies Blood Sample  
  
X 
  
  
  
  
  
  
  
  
 
  
  
X 
X 
  
 
Mixed Meal Stimulated C-peptide (MMTT)12 
  
  
  
  
  
  
  
  
  
  
 
  
  
X 
X14 
  
X 
X 
X14 
Beta Cell Function by Hyperglycaemic Clamp13 
  
X 
  
  
  
  
  
  
  
  
 
  
  
  
X14 
  
  
  
X14 
HbA1c 
X 
 
X 
X 
X 
X15 
Bodyweight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Various Blood samples for Exploratory 
Biomarkers 
  
X 
  
  
  
  
  
X16 
  
  
 
X 
  
X 
X 
  
X 
  
X17 
Saliva sample for Pharmacogenetics (PGx)18 
<----------------------------------> 
 
 
#Patients will record insulin usage for 7 days prior to out-patient visits (up to Month 24) and before telephone call/visit in Month 36 (if applicable) or final follow up.  
Significant AEs including hypoglycaemic (≤3.9 mmol/L; ≤70 mg dL) and hyperglycaemic (>13.9 mmol/L; >250 mg/dL) events will be recorded in a diary whenever they 
occur, to include start and stop dates. 

2011N129686_09 
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1. Patient admitted evening of Day -2 
2. Discharged on Day 6 if health considered satisfactory by the investigator. Dosing Day 4-6 may be performed on out-patient basis (see Section 3.1) 
3. Physical exam performed to monitor for changes in clinical status 
4. ECG pre-dose (in triplicate), at the end of the infusion and 6 hours post start infusion (if infusion <6 hours) 
5. Vital signs include temperature, blood pressure and pulse rate (in triplicate), and respiration rate 
6. See Section 6.2.3 for timings  
7. Pre-dose on dosing days 
8. If LFTs have shown an upward trend continue to monitor daily after day 6 
9. HSV-1 & HSV-2 IgG & IgM will be measured at Day -1 and during the study if clinically indicated 
10.  If still positive at 6 months EBV viral load will be monitored every 3 months until month 24 
11. One sample during visit 
12. Blood samples for C-peptide and glucose levels collected at -10, 0, 15, 30, 60, 90 and 120 minutes 
13. Plasma C-peptide and glucose levels will be measured during the hyperglycaemic clamp procedure at the following time points: L150, L165 and L180 minutes [during the 
euglycaemic (L)ow phase], H0, H60, H90, H120 and H140 minutes [during the hyperglycaemic (H)igh phase] 
14. Mixed Meal and Glucose Clamp must be separated by at least 4 days 
15. Patients will be asked to report verbally their HbA1c at Month 36 (if applicable) and/or final follow-up; followed eventually (if available) by a printed result via regular mail (or scan 
electronically). 
16. Limited biomarkers on Day 6 pre-dose  
17. Blood samples for exploratory biomarkers will only be analysed at Month 24 if indicated based on Month 12 results 
18. One PGx (DNA) saliva sample taken between Day 1 and 6 

2011N129686_09 
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6.2.3. 
Detail for Vitals, ECG and Pharmacokinetic and Pharmacodynamic Monitoring over the Infusion Period 
(Cohorts 1-4) 
Day 
Cohort 
Assessment 
Pre 
Dose 
0 H 
30 M 
1 H 
2 H 
3 H 
4 H 
5 H 
6 H 
7 H 
8 H 
9 H 
10 H 
11 H 
12 H 
13 H 
14 H 
15 H 
16 H 
1 
C1 
Dosing 
  
  
  
  
  
  
  
  
  
VItals1,2 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
X 
ECG 
X 
  
  
  
  
  
  
  
X 
  
  
X 
  
  
  
  
  
  
  
PK/CD3 Saturation 
 X 
  
X 
X 
X 
  
X 
  
X 
  
X 
X 
  
  
  
  
  
  
X 
C2-C4 
Dosing 
  
  
  
  
  
  
Vitals1,2 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
PK/CD3 Saturation 
 X 
  
X 
X 
X 
  
X 
  
X 
  
X 
  
  
  
X 
  
  
  
X 
2 
C1-C4 
Dosing 
  
  
  
  
  
  
  
  
  
  
  
  
Vitals1,2 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
  
  
X 
ECG 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
PK/CD3 Saturation 
X 
  
  
  
  
  
  
  
  
  
3 
C1-C4 
Dosing 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vitals1,2 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
ECG 
X 
  
  
  
  
X 
  
  
X  
  
  
  
  
  
  
  
  
  
  
PK/CD3 Saturation 
X 
  
  
  
  
  
  
  
  
  
  
  
  

2011N129686_09 
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Day 
Cohort 
Assessment 
Pre 
Dose 
0 H 
30 M 
1 H 
2 H 
3 H 
4 H 
5 H 
6 H 
7 H 
8 H 
9 H 
10 H 
11 H 
12 H 
13 H 
14 H 
15 H 
16 H 
4 
C1-C4 
Dosing 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vitals1,2 
X 
X 
  
X 
X 
X3 
  
  
  
  
  
  
  
  
ECG 
X 
  
  
X 
  
 X3 
  
  
  
  
  
  
  
  
  
  
  
  
  
PK/CD3 Saturation 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
5 
C1-C4 
Dosing 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vitals1,2 
X 
X 
  
X 
X 
X3 
  
  
  
  
  
  
  
  
ECG 
X 
  
  
X 
  
 X3 
  
  
  
  
  
  
  
  
  
  
  
  
  
PK/CD3 Saturation 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6 
C1-C4 
Dosing 
Vitals1,2 
X 
X 
  
X 
X 
X3 
  
  
  
  
  
  
  
  
ECG 
X 
  
  
X 
  
 X3 
  
  
  
  
  
  
  
  
  
  
  
  
PK/CD3 Saturation 
X 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
1. Blood pressure to be taken in triplicate at Pre-dose 
2.  Vitals to be repeated at 30 min intervals should there be any safety concern 
3. If patients are dosed on an out-patient basis on Day 4, 5 and 6, vital signs and ECGs will stop after the 3 hour post dose time point (if the Investigator is satisfied with the clinical 
status of the patient), if there are any concerns then vital signs and ECGs may be continued as judged necessary by the investigator until the investigator is satisfied 
 
Day 
14 
Cohort 
C1-C4 
Assessment 
Preferably within first hour of visit, time to be recorded in eCRF 
PK/CD3 Saturation 
 
                X 
 

2011N129686_09 
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6.3. 
Demographic/Medical History Assessments 
The following demographic parameters will be captured: year of birth, gender, race and 
ethnicity. 
Medical/medication/drug and alcohol history will be assessed as related to the eligibility 
criteria listed in Section 4.2.  Cardiovascular medical history/risk factors including 
height, weight, blood pressure, smoking history, medical conditions will also be assessed 
at baseline. 
6.4. 
Safety 
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 6.2).  Additional time points for safety tests such as vital signs, physical exams 
and laboratory tests may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring. 
6.4.1. 
Physical Exams 
• 
A complete physical examination will include assessments of the head, eyes, ears, 
nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and 
spleen), lymph nodes and extremities.  Height and weight will also be measured and 
recorded. 
• 
A brief physical examination will include assessments of the skin, lungs, 
cardiovascular system, extremities and abdomen (liver and spleen). 
6.4.2. 
Vital Signs 
Vital sign measurements will be measured in a semi-supine position after 5 minutes rest 
(before the first measurement) and will include systolic and diastolic blood pressure and 
pulse rate (triplicate measures, the average will be recorded in the eCRF), respiratory rate 
and temperature. 
6.4.3. 
Electrocardiogram (ECG) 
12-lead ECGs will be obtained in the semi-supine position after the subject has been 
resting in the semi-supine position for at least 5 minutes at each time point during the 
study using an ECG machine that automatically calculates the heart rate and measures 
PR, RR, QRS, QT, and QTc intervals (QTcB and F).  At screening, baseline (Day -1) and 
pre-dose on dosing days, ECG assessments will be performed in triplicate (5 minutes 
apart) to obtain an average, single ECGs will be performed at other timepoints. Refer to 
Section 5.3.5 for QTc withdrawal criteria, which requires triplicate ECGs to assess QTc. 
6.4.4. 
Clinical Laboratory Assessments 
Haematology, clinical chemistry, and additional parameters to be tested are listed below.  
Details for the preparation and shipment of samples will be provided by the testing 
laboratory.  Reference ranges for all safety parameters will be provided to the site by the 
laboratory. 

2011N129686_09 
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If additional non-protocol specified laboratory assessments are performed at the site’s 
local laboratory and result in a change in patient management, or are considered clinically 
significant by the investigator (for example SAE or AE or dose modification) the results 
must be captured in the eCRF and the Medical Monitor notified.  
6.4.4.1. 
Haematology 
Platelet Count  
RBC Indices: 
Automated WBC Differential: 
RBC Count 
MCV 
Neutrophils 
WBC Count (absolute)  
MCH 
Lymphocytes (see Section 6.6) 
Reticulocyte Count 
MCHC 
Monocytes 
Hemoglobin 
 
Eosinophils 
Hematocrit 
 
Basophils 
 
6.4.4.2. 
Clinical Chemistry 
BUN 
Potassium 
AST (SGOT) 
Total and direct bilirubin* 
Creatinine 
Chloride 
ALT (SGPT) 
Uric Acid 
Glucose, fasting 
Total CO2 
GGT 
Albumin 
Sodium 
Calcium 
Alkaline phosphatase 
Total Protein 
To include CRP (Day -1 only) 
• 
It is not mandatory to measure fractionated bilirubin if total bilirubin is not above the 
normal range. 
NOTE: Details of Liver Chemistry Stopping Criteria and Follow-Up Procedures are 
given in Section 5.3.4 
Other 
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines). 
Pregnancy (Serum test) 
 

2011N129686_09 
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6.4.4.3. 
Serology 
Serology tests for the following will be performed at the time points indicated in the 
Time and Events Table  
• 
Hepatitis B surface antigen and for antibodies to Hepatitis B core antigen, 
Hepatitis C, HIV I and II, IgG and IgM antibodies to EBV and cytomegalovirus 
(CMV). In addition, IgG and IgM antibodies to HSV-1 and HSV-2 will be 
measured on Day -1 and during the study if clinically indicated. 
6.4.5. 
Tuberculosis 
All patients will have a chest x-ray at the screening visit to rule out active tuberculosis. 
6.4.6. 
EBV Viral Load Detection (PCR) 
Blood samples will be drawn for EBV viral load detection by PCR at the timepoints 
indicated in the Time and Events Table. 
6.5. 
Pharmacokinetics 
6.5.1. 
Blood Sample Collection 
Blood samples of approximately 2.5 mL for pharmacokinetic analysis of serum free 
otelixizumab will be collected at the time points indicated in Section 6.2, Time and 
Events Table.  The actual date and time of each blood sample collection will be recorded.  
The timing of PK samples may be altered and/or PK samples may be obtained at 
additional time points to ensure thorough PK monitoring. This will not constitute a 
protocol amendment 
The total volume will not exceed approximately 500 mL during the first 3 months then 
approximately 200 mL or less at each visit until month 24 inclusive. Processing, storage 
and shipping procedures are provided in the Study Reference Manual (SRM). 
6.5.2. 
Sample Analysis 
Serum analysis will be performed by or under the auspices of Bioanalytical Science and 
Toxicokinetics, DMPK, GlaxoSmithKline.  Concentrations of free otelixizumab will be 
determined in serum using the currently approved bioanalytical methodology.  Raw data 
will be stored in the GLP Archives. 

2011N129686_09 
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6.6. 
Biomarker(s)/Pharmacodynamic Markers 
6.6.1. 
Anti-Otelixizumab Antibodies 
Blood samples will be taken at the time points specified in the Time and Events Table 
(Section 6.2) to assess the immunogenicity of otelixizumab. 
Samples will be analyzed for the presence of anti-otelixizumab antibodies using a 
validated immunoelectrochemiluminescent (ECL) assay. Samples testing positive for 
anti-otelixizumab binding may be further characterized. 
Details of blood sample collection (including volume to be collected), processing, storage 
and shipping procedures are provided in the Study Reference Manual (SRM). 
6.6.2. 
TIDM Auto-antibodies 
Tests for antibodies associated with TIDM will be performed at screening and baseline 
(Day -1). At screening tests for anti-GAD, anti-IA2, antibody to islet cell antigen (ICA) 
and anti-ZnT8will be performed. The same tests will be performed at Day -1 together 
with a test for insulin antibodies (IAA).   
6.6.3. 
CD4+, CD8+ Levels and CD3. Free CD3 and bound otelixizumab 
on CD4 and CD8+ Cells 
Whole blood samples will be drawn, as detailed on the Time and Events Table, for 
determining CD4+ and CD8+ levels, together with CD3, free CD3 and bound 
otelixizumab on CD4 and CD8+ cells, respectively. The samples will be analysed by 
flow cytometry. 
6.6.4. 
Exploratory Biomarkers 
Blood samples for exploratory biomarkers will be collected at the time points indicated in 
the Time and Event Table (Section 6.2). Exploratory samples will only be analysed after 
review of safety endpoints. Month 24 blood samples for exploratory biomarkers will only 
be analysed if indicated based on results from Month 12 biomarker analyses. Full details 
on sample collection, processing and shipment will be provided in the SRM/Q2 Solutions 
manual. Below is a table with details on the exploratory biomarker assays under 
consideration to address the exploratory objectives and endpoints as outlined in Section 
2. As new data emerge, it may also be possible to probe novel aspects of the biology of 
T1D, as well as the biological and clinical responses to otelixizumab. If relevant, this 
approach will be extended to include the identification of biomarkers associated with 
adverse events. 

2011N129686_09 
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Biomarker Assay 
Sample Type D -1  D6 M1.5M3 M6 M12 M24* 
CD8+ Multimer analysis 
PBMC 
X 
 
X 
X 
X 
X 
X 
Whole Blood Absolute Lymphocyte Count + 
CD3+ CD4+, CD3+ CD8+, CD19+ 
BCT CytoChex 
X 
 
X 
X 
X 
X 
X 
Antigen-specific ex vivo ELISPOT responses PBMC 
X 
 
X 
X 
X 
X 
X 
Demethylated FoxP3/CD3/Th17  analysis 
BD Vacutainer 
Plus 2mL 
lavender/EDTA 
with Hemogard 
– part number 
368841 
X 
 
X 
X 
X 
X 
X 
Exploratory Lymphocyte Sub-set phenotyping  
of CD3+ T (eg effector, memory, regulatory T 
cells using cell surface markers such as 
CD45RA, CCR7) and CD19+ B cells 
PBMC 
X 
 
X 
X 
X 
X 
X 
Auto-antibody (+ serum analytes) analysis 
Serum 
X 
 
X 
X 
X 
X 
X 
TCR deep sequencing2  
PAXgene 
Blood RNA 
Tube 
X 
X1 
X 
X 
X 
X 
X 
Beta cell death biomarker analysis 
Serum 
X 
 
X 
X 
X 
X 
X 
T lymphocyte suppression assay 
PBMC 
X 
 
X 
X 
X 
X 
X 
1Sample taken pre-dose 
2 Similar additional transcriptomics analysis may be performed using micro-array and/or 
alternative equivalent technologies including RNA sequencing 
* Blood samples for exploratory biomarkers will only be analysed at Month 24 if 
indicated based on Month 12 results 
6.7. 
Efficacy 
6.7.1. 
Mixed Meal Tolerance Test, (C-Peptide Unstimulated, Serum 
Stimulated C-Peptide Peak Levels and C-Peptide AUC) 
The Mixed Meal Stimulated C-peptide and C-peptide unstimulated will be performed 
using the MMTT as shown in Section 6.2 Time and Events Table.   See Appendix 5 for 
the procedure that must be followed for the MMTT. Glucose will also be measured with 
C-Peptide at all timepoints. 
An MMTT test will be performed in the screening period, at least 7 days before the first 
dose of study medication is given. 
Levels of glucose and C-peptide will be assessed from blood samples taken 10 minutes 
before and immediately before Time 0 and at 15, 30, 60, 90, and 120 minutes after 
Time 0. See Appendix 5. 

2011N129686_09 
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Mixed meal-stimulated C-peptide AUC will be the area under the C-peptide/time curve 
from Time 0 to 120 minutes, calculated using the trapezoidal rule. This AUC will be 
normalised for time interval by dividing it by the number of minutes over which it was 
determined (expected to be 120 minutes, but may vary in some cases). This normalised 
AUC will be calculated for each patient at baseline (screening) and Months 3, 6, 12, 18 
and 24. 
6.7.2. 
Hyperglycaemic Clamp Serum Stimulated C-Peptide Levels and 
C-Peptide AUC 
Plasma C-peptide and glucose levels will be measured during the hyperglycaemic clamp 
procedure at the following time points: L150, L165 and L180 minutes [during the 
euglycaemic (L)ow phase], H0, H60, H90, H120 and H140 minutes [during the 
hyperglycaemic (H)igh phase].  C-peptide AUC will be the area under the C-peptide/time 
curve from Time H60 to H140 minutes (Figure 6). AUC will be expressed as value per 
minute for each period. This value will be calculated at baseline, 6 and 24 months. 
Figure 6 
Schematic showing the Euglycaemic and Hyperglycaemic phases of 
the Clamp Procedure 
 
See Appendix 6 for the procedure that must be followed for the hyperglycaemic clamp 
test. 
NB. The MMTT and hyperglycemic clamp test must be separated by at least 4 days 
6.7.3. 
Daily Insulin Use 
Patients will be asked to record their daily insulin usage thoroughly and accurately for 
7 consecutive days in a diary during the week before all outpatient visits or phone calls, 
ie, at Baseline, Day 14 and 21, Week 4 and 6 and Months 2, 3, 6, 9, 12, 18, 24, 36 (if 
applicable) and final follow up (if applicable). Information on insulin usage will be 
transcribed from diaries into the eCRF. 

2011N129686_09 
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Mean daily insulin use over the 7 consecutive days (in units of IU per kg body weight per 
day) will be calculated for each patient at the timepoints described above. 
Long acting and short acting insulin should be reported separately. The delivery device 
will also be recorded. 
6.7.4. 
Glycosylated Haemoglobin, HbA1c 
HbA1c will be recorded at visits as shown in the Time and Events Table. Patients will be 
asked to report verbally their HbA1c (if available) around the time of month 36 (if 
applicable) and/or final follow-up; followed eventually by a printed result via regular 
mail (or scan electronically) if available. HbA1c values will be captured in the eCRF.  
HbA1c up to Month 24 will be analysed by BDR. 
6.8. 
Pharmacogenetics 
A saliva sample will be collected for pharmacogenetic (DNA) analysis on Day – 1 (after 
randomisation) or any other visit up to month 24. 
Information regarding pharmacogenetic (PGx) research is included in Appendix 2.  The 
IRB/IEC and, where required, the applicable regulatory agency must approve the PGx 
assessments before these can be conducted at the site. 
7. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND 
PREGNANCY 
7.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) 
The investigator or site staff are responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
7.1.1. 
Time Period for Collecting AE and SAE Information 
AEs will be collected from signing the Informed Consent Form until the follow-up 
contact, approximately 2 years post last dose.   
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a GSK product will be recorded 
from the time a patient consents to participate in the study up to and including any 
follow-up contact.  All SAEs will be recorded and reported to the Medical Monitor and 
GSK within 24 hours, as indicated in Appendix 4. 
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
patient has been discharged from the study, and he/she considers the event reasonably 
related to the study treatment or study participation, the investigator would promptly 
notify the Medical Monitor and GSK. 

2011N129686_09 
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NOTE: The method of detecting, recording, evaluating and follow-up of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to the Medical Monitor and 
GSK are provided in Appendix 4. 
7.1.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include: 
• 
“How are you feeling?”  
• 
“Have you had any (other) medical problems since your last visit/contact?”  
• 
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”  
7.1.3. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
NOTE: An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.   
Events meeting the definition of an AE include: 
• 
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae). 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE. 

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• 
The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE. 
Events that do not meet the definition of an AE include: 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the patient’s condition. 
• 
The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the patient’s 
condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
7.1.4. 
Definition of Serious Adverse Events 
If an event is not an AE per Section 7.1.3, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc). 
An SAE is any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. Is life-threatening 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the patient was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE:  In general, hospitalization signifies that the patient has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfils any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in disability/incapacity, or 

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NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which 
may interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. 
Is a congenital anomaly/birth defect. 
f. 
Medical or scientific judgment should be exercised in deciding whether 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 medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, 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. 
g. Is associated with liver injury and impaired liver function defined as: 
• ALT ≥ 3xULN and total bilirubin* ≥ 2xULN (>35% direct), or  
* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick.  If fractionation is unavailable 
and ALT ≥ 3xULN and total bilirubin ≥ 2xULN, then the event is still to be reported 
as an SAE. 
** INR testing not required per protocol and the threshold value does not apply to 
patients receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form. 
7.1.5. 
Cytokine Release Syndrome Adverse Events 
CRS is a well-known consequence of anti-CD3 therapy when administered via 
intravenous injection or infusion and therefore any CRS AEs experienced during the 
dosing period will be assessed against the grading system shown in Table 5. This grading 
system has been developed using NCI Common Terminology Criteria for Adverse Events 
(CTCAE) v.4 (Table 5) by selecting AEs that are specifically thought to be associated 
with cytokine release syndrome. Pre-specified CRS individual patient and study dosing 
stopping criteria are shown in Table 6. The symptoms in Table 6 have been classified as 
objective and subjective endpoints as follows: 
• Objective Endpoints: Fever, Diarrhoea, Vomiting, Hypotension 
• Subjective Endpoints: Headache, Chills, Nausea, Arthralgia, Myalgia 
 

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7.1.6. 
Cardiovascular Events 
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:   
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thrombosis 
• Deep Venous Thrombosis 
• Revascularization 
This information should be recorded within one week of when the AE/SAE(s) are first 
reported. 
7.1.7. 
Death Events 
In addition, all deaths will require a specific death data collection tool to be completed.  
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and non- cardiovascular death. 
This information should be recorded within one week of when the death is first reported. 
7.1.8. 
Prompt Reporting of SAEs to GSK 
Once the investigator determines that an event meets the protocol definition of an SAE, 
the SAE will be reported to the Medical Monitor and GSK within 24 hours.  Any follow-
up information on a previously reported SAE will also be reported to the Medical 
Monitor and GSK within 24 hours. 
If the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying the Medical Monitor and GSK of the 
event and completing the appropriate data collection tool.  The investigator will always 
provide an assessment of causality at the time of the initial report as described in 
Appendix 4. 

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7.1.9. 
Regulatory Reporting Requirements for SAEs 
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of patients are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. CRO/GSK 
will comply with country specific regulatory requirements relating to safety reporting to 
regulatory authorities, IRBs/IECs and investigators.   
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.  An investigator who receives an investigator safety report 
describing an SAE(s) or other specific safety information (e.g., summary or listing of 
SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
7.2. 
Pregnancy 
7.2.1. 
Time Period for Collecting Pregnancy Information 
All pregnancy information in female subjects and/or female partners of male subjects will 
be collected after the start of dosing until 24 months after the last dose of study drug. 
7.2.2. 
Action to be taken if pregnancy occurs 
Patients must not receive study drug until a negative pregnancy result has been obtained. 
If a female patient becomes pregnant during the follow-up period (up to 24 months post 
dose), the investigator will record pregnancy information on the appropriate form and 
submit it to CRO (who will notify GSK) within 2 weeks of learning of a patient's 
pregnancy.  The subject will be asked to remain in the study and attend all scheduled 
visits for collection of safety data; no MMTT (or other PD or efficacy assessments) will 
be performed if the patient is pregnant. The patient will be followed to learn the outcome 
of the pregnancy. Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. The investigator will notify the CRO/Sponsor if the pregnancy is 
terminated. If the subject gives birth, information on the health status of the mother and 
child will be forwarded to the CRO/Sponsor. At visits that take place after the birth, 
information on the health status of the child will be recorded. Three months after the 
birth, the subject will be asked to resume her regular schedule of MMTTs and other PD 
and efficacy assessments. 
If a male subject’s partner becomes pregnant, she will be asked to consent to collection of 
data on her health status and the outcome of the pregnancy. If she consents, she will be 
followed to learn the outcome of the pregnancy. The investigator will notify the 
CRO/Sponsor if the pregnancy is terminated. If the subject’s partner gives birth, 
information on the health status of the mother and child will be forwarded to the 
CRO/Sponsor. Pregnancy, childbirth, and elective termination of pregnancy are not 
necessarily considered AEs. Complications of pregnancy or childbirth, spontaneous 
abortions, and termination of pregnancy for medical reasons are AEs; they will be 
considered serious if they meet the definition of an SAE in Section 7.1.4. A spontaneous 
abortion will be considered an SAE if required by the regulations of the country in which 
it occurs. 

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7.2.3. 
Action to be taken if pregnancy occurs in a female partner of a 
male study patient 
The investigator will attempt to collect pregnancy information on any female partner of a 
male study patient who becomes pregnant while participating in this study.  This applies 
only to patients who are randomised to receive study medication. After obtaining the 
necessary written informed consent from the female partner directly, the investigator will 
record pregnancy information on the appropriate form and submit it to the CRO within 
2 weeks of learning of the partner’s pregnancy.  The partner will also be followed to 
determine the outcome of the pregnancy.  Information on the status of the mother and 
child will be forwarded to the CRO.  Generally, follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any premature termination of the 
pregnancy will be reported. 
8. 
DATA MANAGEMENT 
For this study patient data will be entered into GSK approved electronic case report forms 
(eCRFs), combined with data provided from other sources in a validated data system and 
transmitted electronically to the CRO. 
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data. Adverse events and concomitant medications terms 
will be coded using MedDRA (Medical Dictionary for Regulatory Activities) and an 
internal validated medication dictionary, GSKDrug. eCRFs (including queries and audit 
trails) will be retained by GSK, and copies will be sent to the investigator to maintain as 
the investigator copy.  Patient’s PII (Personal identifiable information) including a full 
date of birth and initials will not be collected or transmitted to CRO/GSK according to 
CRO/GSK policy. 
9. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
9.1. 
Hypotheses and Treatment Comparisons 
As the primary objective is to assess the safety, tolerability and maximum tolerated dose 
of Otelixizumab in subjects with NOT1DM patients, there are no formal hypotheses 
being tested in the study, instead an estimation and inference approach will be adopted to 
evaluate the objectives.  
If data permits, a model-based approach will be used to characterise and assess any 
evidence of dose response relationships with endpoints of interest. 

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9.2. 
Sample Size Considerations 
9.2.1. 
Sample Size Assumptions 
There are no formal calculations of power or sample size for this study. The sample sizes 
have been chosen based on feasibility, to primarily allow characterization of safety and 
tolerability of ascending doses of otelixizumab, in T1DM patients. 
A total of 40 patients will be recruited into the study and for each cohort, 8 patients will 
be randomized to otelixizumab and 2 patients to placebo.   
The primary objective of the study is based on safety and tolerability, where safety events 
are of interest, particularly those related to CRS and EBV reactivation which have 
associated defined stopping criteria. From a expected benefit : risk perspective it would 
be unacceptable to continue dosing patients within a cohort or subsequent cohorts, if ≥ 3 
subjects met the defined CRS or EBV stopping criteria described in Section 5.3 Patient 
Specific and Dose Escalation Stopping Criteria.   
 
Assuming we were to observe a number of events out of the 8, then in Table 10, the 
following are estimated for various numbers of observed responders:  
[1] 95% credible intervals for proportion of responders 
[2] Probability of response rate >0.375, derived within a Bayesian framework with a non 
informative conjugate prior distribution, Beta (1, 1), for the response rate. 
 
Table 10 
Estimated 95% Credible Intervals for Proportion of Responders & 
Probability of Response Rate >0.375 
Total No. of 
Subjects          
Per Cohort 
Observed No. of 
Responders 
 
95% Credible Interval for 
Proportion of Responders, 
Given Observed Data 
Probability of Response 
Rate >0.375 (3/8),           
Given Observed Data 
8 
0 
 (0.00 , 0.34) 
0.01 
8 
1 
 (0.03 , 0.48) 
0.09 
8 
2 
 (0.07 , 0.60) 
0.28 
8 
3 
 (0.14 , 0.70) 
0.55 
8 
4 
 (0.21, 0.79) 
0.78 
8 
5 
 (0.30 , 0.86) 
0.93 
8 
6 
 (0.40, 0.93) 
0.98 
8 
7 
 (0.52 , 0.97) 
0.99 
8 
8 
 (0.66 , 1.00) 
1.00 
 
If we were to observe 0 out of 8 subjects with a given CRS or EBV event, the estimated 
95% credible interval for the proportion of responders is (0.00, 0.34) and there would be 
a very low probability (0.01) of the true response rate being greater than 0.375.  

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However, if we were to observe 3 out of 8 subjects with a given CRS or EBV event, the 
estimated 95% credible interval for the proportion of responders is (0.14, 0.70) and there 
would be a 0.55 probability of the true response rate being greater than 0.375. 
In the above scenario where 3 out 8 subjects have a given CRS or EBV event: 
• Treatment for individual patients will be stopped immediately, will not be restarted, 
and the patients will be followed up as per protocol. 
• No further patients will be dosed within the cohort currently being investigated and 
no further dose escalation will occur. 
9.2.2. 
Sample Size Sensitivity 
A sensitivity analyses was conducted on the primary endpoint based on safety events of 
interest, particularly those related to CRS and EBV reactivation. Table 11, provides 
further estimates of the 95% credible interval for the proportion of responders based on 
various accumulated number of subjects within a cohort. 
Table 11 
Estimated 95% Credible Intervals for Proportion of Responders 
Total No. of Subjects      
Observed No. of 
Responders 
95% Credible Interval for Proportion of 
Responders, Given Observed Data 
1 
0 
(0.01, 0.84) 
1 
(0.16, 0.99) 
2 
0 
(0.01, 0.71) 
1 
(0.09, 0.91) 
2 
(0.23, 0.99) 
3 
0 
(0.01, 0.60) 
1 
(0.07, 0.81) 
2 
(0.19, 0.93) 
3 
(0.40, 0.99) 
 
If we were to observe 2 out of 2 subjects with a given CRS or EBV event, the estimated 
95% credible interval for the proportion of responders is (0.23, 0.99). 
9.2.3. 
Sample Size Re-estimation 
No sample size re-estimation will be performed. 
No sample size re-estimation is currently planned for this study. However, if during the 
course of the study, new information becomes available about safety events, clinically 
meaningful differences or variability estimates, a sample size re-estimation may be 
conducted. Full details of the procedure used would be specified in the analysis and 
reporting plan (RAP), and any subsequent change to the target sample size would be 
documented in a protocol amendment. 

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9.3. 
Data Analysis Considerations 
9.3.1. 
Interim Analyses 
9.3.1.1. 
During the Study 
There will be ongoing data reviews conducted by the study team of the unblinded safety 
and efficacy data, and any available pharmacokinetic and pharmacodynamic data 
throughout the trial progression.   
9.3.1.2. 
Dose Escalation 
Further unblinded data reviews of safety data will be performed to support whether to 
dose escalate to the next cohort. If deemed appropriate, the review may also include 
supportive pharmacokinetic, biomarker or pharmacodynamic data if available. Details are 
provided below:  
• Data will be reviewed after 10 patients have been dosed in cohort 1 (8 patients on 
otelixizumab 9 mg and 2 patients on placebo) and have completed approximately 6 
weeks of the study after the first active dose, and required data is available.  
• If required, data reviews prior to 6 weeks may also be conducted to facilitate dose 
escalation to the next cohort.   
• It is not expected that this review will occur on a fully cleaned data. 
• Further data reviews based on criteria provided for cohort 1, will be performed for 
subsequent cohorts, including an overall review of accumulated data across the 
cohorts.  
• Core members of the dose escalation review team will include the Principal 
Investigator, Medical Monitor, GCSP, Clinical Pharmacologist and Statistician. Other 
GSK/CRO study team members may also be included as required.    
9.3.1.3. 
Interim Analyses (12 Months) 
Formal unblinded interim analyses are also planned:  
• The first interim will occur when all patients in cohorts 1 and 2 have completed 
12 months study duration, but may also include any available data from subsequent 
cohorts 3 and 4 as appropriate.   
• The second interim analysis will occur when all patients from the last fully enrolled 
cohort (i.e. not stopped due to safety / tolerability) have completed 12 months study 
duration. 
 
• The purpose of these interim analyses is to provide the project team and GSK 
stakeholders with key data to inform internal decision making, in order to plan future 
studies within the clinical development for the asset. 
• There are no planned implications for the conduct of the study. 

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• Appropriate data summaries will be at the treatment group level for key endpoints of 
interest and the circulation of results will be restricted to selected members of the 
project team and key GSK stakeholders. Results or discussions will not be circulated 
to staff involved in the conduct of the study at the sites.  
• Full details of planned interim analyses will be included in the reporting and analysis 
plan (RAP). 
9.3.2. 
Final Analyses 
Data will be summarized and analysed according to the GSK reporting standards, where 
applicable.  Complete details will be documented in the RAP.  Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP and final study report. 
9.3.2.1. 
Final Analyses (24 Months) 
The final analysis will occur when the last planned cohort (i.e. based on the dose 
escalation criteria) have completed 24 months study duration or have had a final follow-
up for subjects who, at the time of the implementation of Amendment 08 of the protocol, 
will have already reached months 24.  
9.3.3. 
Safety Analyses 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards. 
Further details, regarding specific analyses of safety endpoints (e.g. Cytokine Release 
Syndrome and Epstein-Barr Virus) will be further detailed and included in the RAP. 
9.3.4. 
Pharmacokinetic Analyses 
All free serum otelixizumab concentration data will be graphically represented, 
descriptively summarised and listed appropriately. 
Free serum otelixizumab concentration time data will be analyzed by non-compartmental 
methods with WinNonlin Version 6.1 or higher. Calculations will be based on the 
nominal sampling times recorded during the study.  From the serum concentration-time 
data, the following pharmacokinetic parameters may be determined, as data permit: 
maximum observed plasma concentration (Cmax), time to Cmax (tmax), area under the 
plasma concentration-time curve [AUC(0-t) and AUC(0- τ], and apparent terminal phase 
half-life (t1/2).  Additional parameters may be included as required. 
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D. 

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9.3.5. 
Efficacy Analyses 
Descriptive statistics of both raw and change from baseline data, where appropriate, (i.e. 
n, arithmetic mean, standard deviation, minimum, median and maximum) will be 
calculated for efficacy endpoints and summarized across cohorts. Graphical displays will 
be produced over time if deemed appropriate. All data will be listed. 
If data permits, formal statistical analyses of efficacy endpoints may be conducted, if 
deemed appropriate and full details will be provided in the RAP. Based on the specified 
statistical analyses, estimates of the differences between doses of otelixizumab and 
placebo will be calculated and appropriate statistical inferences based on these results 
will be made. Distributional assumptions underlying the analyses will be assessed as 
appropriate. If these assumptions are strongly violated, appropriate transformations will 
be investigated and if required alternative statistical analyses considered. 
9.3.6. 
Pharmacodynamic/Biomarker Analyses 
Descriptive statistics of both raw and change from baseline data, where appropriate, (i.e. 
n, arithmetic mean, standard deviation, minimum, median and maximum) will be 
calculated for pharmacodynamic/biomarker endpoints and summarized across cohorts. 
Graphical displays will be produced over time if deemed appropriate. All data will be 
listed. 
If data permits, formal statistical analyses of efficacy endpoints may be conducted, if 
deemed appropriate and full details will be provided in the RAP. Based on the specified 
statistical analyses, estimates of the differences between doses of otelixizumab and 
placebo will be calculated and appropriate statistical inferences based on these results 
will be made. Distributional assumptions underlying the analyses will be assessed as 
appropriate. If these assumptions are strongly violated, appropriate transformations will 
be investigated and if required alternative statistical analyses considered. 
9.3.7. 
Pharmacokinetic/Pharmacodynamic Analyses 
The relationship between dose, free serum otelixizumab concentration and 
pharmacodynamic endpoints including free CD3 or bound otelixizumab on CD4+ and 
CD8+ cells may be investigated first by exploratory graphical analysis and then by non-
linear mixed effects modelling. Further details of model terms and possible covariates 
will be included in the RAP. 
9.3.8. 
Exploratory Biomarker(s) Analyses 
The results of these exploratory biomarker investigations may be reported separately 
from the main clinical study report. All endpoints of interest from all comparisons will be 
descriptively and/or graphically summarized as appropriate to the data. 
Additional exploratory analyses may be performed to further characterize the exploratory 
biomarker. 

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10. 
STUDY GOVERNANCE CONSIDERATIONS 
10.1. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of patients begins. 
10.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements. 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and, the guiding principles of the 2008 
Declaration of Helsinki.  This includes, but is not limited to, the following: 
• 
IRB/IEC review and favorable opinion/approval to conduct the study and of any 
subsequent relevant amended documents 
• 
Written informed consent (and any amendments) to be obtained for each patient 
before participation in the study 
• 
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC) 
Written informed consent must be obtained from each patient prior to participation in the 
study. 
10.2.1. 
Urgent Safety Measures 
If an event occurs that is related to the conduct of the study or the development of the 
study treatment, and this new event is likely to affect the safety of patients the Sponsor 
and the investigator will take appropriate urgent safety measures to protect patients 
against any immediate hazard. 
The sponsor or designee will work with the investigator to ensure the IEC/IRB is 
notified. 
10.3. 
Quality Control (Study Monitoring) 
In accordance with applicable regulations including GCP, and GSK procedures, GSK or 
CRO monitors will contact the site prior to the start of the study to review with the site 
staff the protocol, study requirements, and their responsibilities to satisfy regulatory, 
ethical, and GSK requirements.  When reviewing data collection procedures, the 

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discussion will also include identification, agreement and documentation of data items for 
which the CRF or eCRF will serve as the source document. 
GSK or the CRO will monitor the study and site activity to verify that the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of patients are being protected. 
• 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
10.4. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified. 
10.5. 
Study and Site Closure 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations including GCP, and GSK procedures. 
In addition, GSK reserves the right to temporarily suspend or prematurely discontinue 
this study at any time for reasons including, but not limited to, safety or ethical issues or 
severe non-compliance. For multicenter studies, this can occur at one or more or at all 
sites. If GSK determines such action is needed, CRO/GSK will discuss this with the 
investigator or the head of the medical institution (where applicable), including the 
reasons for taking such action.  When feasible, CRO/GSK will provide advance 
notification to the investigator or the head of the medical institution, where applicable, of 
the impending action prior to it taking effect. 
If the study is suspended or prematurely discontinued for safety reasons, CRO/GSK will 
promptly inform investigators or the head of the medical institution (where applicable) 
and the regulatory authorities of the suspension or premature discontinuation of the study 
and the reason(s) for the action.  If required by applicable regulations, the investigator or 
the head of the medical institution (where applicable) must inform the IRB/IEC promptly 
and provide the reason for the suspension or premature discontinuation. 

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10.6. 
Records Retention 
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records, except for those required by local 
regulations to be maintained by someone else, in a safe and secure location.  The records 
must be maintained to allow easy and timely retrieval, when needed (e.g., audit or 
inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and staff.  Where 
permitted by local laws/regulations or institutional policy, some or all of these records 
can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  The 
investigator must assure that all reproductions are legible and are a true and accurate copy 
of the original, and meet accessibility and retrieval standards, including re-generating a 
hard copy, if required.  Furthermore, the investigator must ensure there is an acceptable 
back-up of these reproductions and that an acceptable quality control process exists for 
making these reproductions. 
The CRO on behalf of GSK will inform the investigator of the time period for retaining 
these records to comply with all applicable regulatory requirements.  The minimum 
retention time will meet the strictest standard applicable to that site for the study, as 
dictated by any institutional requirements or local laws or regulations, or GSK 
standards/procedures; otherwise, the retention period will default to 15 years. 
The investigator must notify the CRO of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership of the 
records in the event the investigator leaves the site. 
10.7. 
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study patients, as 
appropriate. 
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis. 
The results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final patient was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome. In addition, a manuscript will be submitted to a peer reviewed journal 

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for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing. 
The results summary for an approved GSK medicinal product will be posted to the 
Clinical Study Register no later than 12 months after the last subject’s last visit (LSLV) 
or sooner if required by legal agreement, local law or regulation.  In addition, a 
manuscript will be submitted to a peer-reviewed journal for publication within 18 months 
of LSLV.  When manuscript publication in a peer reviewed journal is not feasible, further 
study information is posted to the GSK Clinical Study Register to supplement the results 
summary. 
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge. 
 

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von Herrath MG. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions 
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Coppieters KT, von Herrath MG. Viruses and cytotoxic T lymphocytes in type 1 
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F, et.al.. In vivo T-cell activation by a monoclonal αCD3ε antibody induces preterm labor 
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trials in type 1 diabetes.Diabetes Care.2008;31:1966-1971. 
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Prevention of autoimmune diabetes with nonactivating anti-CD3 monoclonal antibody. 
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K, Diamond B, Harlan DM, Bluestone JA. A single course of anti-CD3 monoclonal 
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SE, Harlan DM, Xu D, Zivin RA, and Bluestone JA. Anti-CD3 Monoclonal Antibody in 
New-Onset Type 1 Diabetes Mellitus. N Engl J Med.2002;346:1692-1698 
Hughes C, Wolos JA, Giannini EH, Hirsch R. Induction of T helper cell 
hyporesponsiveness in an experimental model of autoimmunity by using nonmitogenic 
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James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos.2009; 37:1779-1784. 
Kaufman A, Herold KC. Anti-CD3 mAbs for treatment of type 1 diabetes. Diabetes 
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Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, 
Gorus F, Goldman M, Walter M, Candon S, Schandene L, Crenier L, De Block C, 
Seigneurin JM, De Pauw P, Pierard D, Weets I, Rebello P, Bird P, Berrie E, Frewin M, 
Waldmann H, Bach JF, Pipeleers D, Chatenoud L. Insulin needs after CD3-antibody 
therapy in new-onset type 1 diabetes. N Engl J Med.2005; 23;352(25):2598-608. 
Keymeulen B, Walter M, Mathieu C, Kaufman L, Gorus F, Hilbrands R, 
Vandemeulebroucke E, Van de Velde U, Crenier L, De Block C, Candon S, Waldmann 
H, Ziegler AG, Chatenoud L, Pipeleers D. Four-year metabolic outcome of a randomised 
controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their 
age and baseline residual beta cell mass. Diabetologia.2010; 53(4):614-23. 
Knip M. Natural Course of Preclinical Type 1 Diabetes. Horm Res.2002;57 (Suppl 1); 6-
11. 
Kohm, A. P., J. S. Williams, A. L. Bickford, J. S. McMahon, L. Chatenoud, J. F. Bach, J. 
A. Bluestone, and S. D. Miller. Treatment with Nonmitogenic Anti-CD3 Monoclonal 
Antibody Induces CD4+ T Cell Unresponsiveness and Functional Reversal of 
Established Experimental Autoimmune Encephalomyelitis. J Immunol.2005; 174:4525-
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Kuhns MS, Davis MM, Garcia KC. 2006 Deconstructing the form and function of the 
TCR/CD3 complex. Immunity.2006;24(2):133-9. 
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Zimmerman M, Griswold DE, Li L. Modulation of antigen-specific T cell response by a 
non-mitogenic anti-CD3 antibody. Int Immunopharmacol.2006;(6):880-91. 
Mari A, Ferrannini E. Beta-cell function assessment from modeling of oral tests: an 
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Mehta DS, Christmas RA, Waldmann H, Rosenzweig M. Partial and transient modulation 
of the CD3-T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-
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Nishio J, Feuerer M, Wong J, Mathis D, Benoist C. Anti-CD3 therapy permits regulatory 
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Patterson CC, Dahlquist GG, Gyürüs E, Green A, Soltész G; EURODIAB Study Group. 
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Sandborn WJ, Colombel JF, Frankel M, Hommes D, Lowder JN, Mayer L, Plevy S, 
Stokkers P, Travis S, Van Assche G, Baumgart DC, Targan SR. Anti-CD3 antibody 
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Seidel D, Ziegler AG. Prediction of type 1 diabetes. Horm Res.1996;45 Suppl 1:36-9. 
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S, Holland C, Carlin D, King KL, Wilder RL, Pillemer S, Bonvini E, Johnson S, Stein 
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controlled trial. The Lancet.2011;378 (9760): 487-97. 
Tran, G. T., N. Carter, X. Y. He, T. S. Spicer, K. M. Plain, M. Nicolls, B. M. Hall, and S. 
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Tsai S, Clemente-Casares X, Santamaria P. 2010. CD8+ Tregs in autoimmunity: learning 
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Van Belle TL, Coppieters KT, Von Herrath MG.  Type 1 Diabetes: Etiology, 
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12. 
APPENDICES 
12.1. 
Appendix 1: Liver Safety Process 
The procedures listed below are to be followed if a patient meets any of the liver 
chemistry stopping criteria defined in Section 5.3.4 
• 
Immediately withdraw the patient from study treatment if the 6 day treatment period 
has not been completed. Patients will continue to be monitored for safety as per 
protocol 
• 
Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
confirm the patient’s study treatment cessation and follow-up. 
• 
Complete the “Safety Follow-Up Procedures” listed below. 
• 
Complete the liver event case report forms.  If the event also meets the criteria of an 
SAE (see Section 7.1.4), the SAE data collection tool will be completed separately 
with the relevant details. 
• 
Upon completion of the safety follow-up withdraw the patient from the study unless 
further safety follow up is required. 
• 
Do not re-challenge with investigational product 
 
Safety Follow-Up Procedures for patients with ALT ≥3xULN and bilirubin  
≥2xULN (>35% direct); or ALT ≥3xULN and INR1 >1.5 [Stopping Criteria #1]: 
• 
This event is considered an SAE (see Section 7.1.4).  Serum bilirubin fractionation 
should be performed if testing is available. If fractionation is unavailable, urinary 
bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury). 
• 
Make every reasonable attempt to have the patients return to the clinic (within 
24 hours) for repeat liver chemistries, additional testing and to be monitored closely 
(with specialist or hepatology consultation recommended). 
• 
Monitor patients twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
Safety Follow-Up Procedures for patients with ALT ≥5xULN or ALT ≥3xULN who 
have hepatitis symptoms or rash, can’t be monitored for 4 weeks or have elevations 
that persist ≥4 weeks [Stopping Criteria #2 - #5]: 
• 
Make every reasonable attempt to have the patient return to the clinic within 24-72 
hrs for repeat liver chemistries and additional testing. 
                                                 
1 INR testing not required per protocol and the threshold value does not apply to subjects receiving 
anticoagulants. 

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• 
Monitor patients weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values.  
Safety Follow-Up Procedures for patients with ALT ≥ 3xULN and <5xULN and 
bilirubin <2xULN, who do not exhibit hepatitis symptoms or rash: 
• 
Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss patient safety. 
• 
Patient can continue study treatment if liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) can be monitored weekly for up to 4 weeks.   
• 
If at any point these patients meet the liver chemistry stopping criteria (outlined in 
Section 5.3.4), immediately withdraw study treatment, perform additional testing and 
continue safety follow-up until liver chemistries resolve, stabilize or return to 
baseline values.  
• 
After 4 weeks of monitoring, if ALT <3xULN and bilirubin <2xULN, patients must 
be monitored twice monthly until liver chemistries normalize or return to within 
baseline values. 
Additional Follow-Up Procedures for patients who meet any of the stopping criteria: 
• 
Viral hepatitis serology including: 
• 
Hepatitis A IgM antibody; 
• 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);  
• 
Hepatitis C RNA;  
• 
Cytomegalovirus IgM antibody;   
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);   
• 
Hepatitis E IgM antibody. 
• Blood sample for pharmacokinetic (PK) analysis, obtained within 7 days of last dose. 
Record the date/time of the PK blood sample draw and the date/time of the last dose 
of study treatment prior to blood sample draw on the eCRF.  If the date or time of the 
last dose is unclear, provide the patients’s best approximation.  If the date/time of the 
last dose can not be approximated OR a PK sample can not be collected in the time 
period indicated above, do not obtain a PK sample.  Instructions for sample 
handling and shipping are included in the SRM. 
• 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• 
Fractionate bilirubin, if total bilirubin ≥ 2xULN. 
• 
Assess eosinophilia 
• 
Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or 
eosinophilia) as relevant on the AE eCRF 

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• 
Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins on the Concomitant Medications 
eCRF. 
• 
Record alcohol use on the Liver Events eCRF. 
The following are required for patients with ALT ≥ 3xULN and bilirubin ≥ 2xULN 
(>35% direct) but are optional for other abnormal liver chemistries: 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins). 
• 
Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in patients with definite or likely acetaminophen use in 
the preceding week [James, 2009]). 
• 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease. 
• 
The Liver Imaging and/or Liver Biopsy eCRFs are also to be completed if these tests 
are performed. 
 

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Refer to the diagram below for a visual presentation of the procedures listed above. 
ALT≥3xULN ?
Plus Bilirubin ≥ 2xULN
(or INR >1.5 if 
measured)* ?
No
Yes
Yes
Instruct subject to stop IP 
Notify GSK + arrange clinical followup within 24-72h
Obtain weekly liver chemistries (*if possible) until 
resolved, stabilized or returned to baseline values
Perform liver event follow up assessments (serology, 
PK sample, etc as in protocol) 
Complete liver event CRF & if appropriate liver 
imaging and biopsy CRFs (if these tests performed)
Withdraw subject from study after liver chemistry
monitoring complete + do not rechallenge with 
study medication
Instruct subject to stop investigational product (IP)
Notify GSK and arrange clinical followup within 24 hrs
Perform liver event f/u assessments (serology, PK, etc)
Report as an SAE (exc. hepatic impairment or cirrhosis    
studies); complete SAE & liver event CRF + 
liver imaging and biopsy CRFs (if tests performed).
Obtain twice weekly liver chemistries until resolved, 
stabilized or returned to baseline values 
Consultation with hepatologist/specialist recommended
Withdraw subject from study after liver chemistry 
monitoring complete + do not re-challenge with IP
ALT≥5xULN ?
Hepatitis 
symptoms
or rash ? 
No
Able to 
monitor weekly                       
for 4 wks ?
No
Notify GSK within 24 hrs
Continue IP
Check liver chem weekly 
for 4 wks
No
No*
Yes
Yes
Yes
Yes
ALT≥3xULN or 
bilirubin ≥ 2xULN 
after 4 weeks?
Continue IP
Monitor liver chemistries 
2X/month until values normalize 
or return to baseline
*INR threshold does not apply to 
subjects receiving anticoagulants.
 
 

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12.2. 
Appendix 2: Pharmacogenetic research 
Pharmacogenetics – Background 
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations.  There is increasing evidence that an individual's genetic 
background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
PGx associations with safety/adverse events include: 
Drug 
Disease 
Gene 
Variant 
Outcome 
Abacavir 
HIV 
[Hetherington, 2002; 
Mallal, 2002; 
Mallal, 2008] 
HLA-B* 
57:01 
(Human 
Leukocyte 
Antigen B) 
Carriage of the HLA-B*57:01 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir.  
Prospective HLA-B*57:01 screening and 
exclusion of HLA-B*57:01 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity.  Treatment guidelines and 
abacavir product labeling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*57:01 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity.  HLA-B*57:01 
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity. 
Carbamaze
pine 
Seizure, Bipolar 
disorders & 
Analgesia [Chung, 
2010; Ferrell, 2008] 
HLA-
B*15:02 
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02 
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis.  
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*15:02 prior to initiating 
treatment with carbamazepine. 

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Drug 
Disease 
Gene 
Variant 
Outcome 
Irinotecan 
Cancer [Innocenti, 
2004; Liu, 2008; 
Schulz, 2009] 
UGT1A1*
28 
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of 
the drug and a higher risk of side effects. A 
dose of irinotecan that is safe for one patient 
with a particular UGT1A1 gene variation might 
be too high for another patient without this 
variation, raising the risk of certain side-effects 
that include neutropenia following initiation of 
Irinotecan treatment.  The irinotecan drug 
label indicates that individuals who have two 
copies of the UGT1A1*28 variant are at 
increased risk of neutropenia.  A genetic blood 
test is available that can detect variations in 
the gene.     
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies. 
Collection of whole blood samples or saliva samples, even when no a priori hypothesis 
has been identified, may enable PGx analysis to be conducted if at any time it appears 
that there is a potential unexpected or unexplained variation in response to otelixizumab.  
Pharmacogenetic Research Objectives 
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to 
otelixizumab.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with otelixizumab, the following objectives 
may be investigated – the relationship between genetic variants and study treatment with 
respect to: 
• 
Pharmacokinetics and/or pharmacodynamics of study treatment 
• 
Safety and/or tolerability  
• 
Efficacy 
Study Population 
Any subject who is enrolled in the clinical study, can participate in PGx research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the PGx research. 
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study or result in any penalty or loss of benefits to 
which the subject would otherwise be entitled. 

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Study Assessments and Procedures 
Saliva samples will be taken for Deoxyribonucleic acid (DNA) extraction and used in 
PGx assessments. 
Saliva (2mL) is collected into the DNA self-collection kit. A single sample will be taken 
but can be duplicated if the first sample is unusable. It is recommended that the saliva 
sample be collected between Day 1 and 6.   
• 
The PGx sample is labelled (or “coded”) with a study specific number that can be 
traced or linked back to the subject by the investigator or site staff.  Coded samples 
do not carry personal identifiers (such as name or social security number).  The 
saliva sample is taken on a single occasion unless a duplicate sample is required due 
to inability to utilize the original sample.   
The DNA extracted from the saliva sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed. 
The need to conduct PGx analysis may be identified after a study (or a set of studies) of 
otelixizumab has been completed and the clinical study data reviewed.  In some cases, the 
samples may not be studied. e.g., no questions are raised about how people respond to 
otelixizumab. 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.   
Subjects can request their sample to be destroyed at any time. 
Subject Withdrawal from Study 
If a subject who has consented to participate in PGx research withdraws from the clinical 
study for any reason other than being lost to follow-up, the subject will be given a choice 
of one of the following options concerning the PGx sample, if already collected: 
• 
Continue to participate in the PGx research with the PGx sample retained for 
analysis  
• 
Withdraw from the PGx research and destroy the PGx sample  
If a subject withdraws consent for PGx research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. The investigator should forward the Pharmacogenetic Sample 
Destruction Request Form to GSK as directed on the form. This can be done at any time 
when a subject wishes to withdraw from the PGx research or have their sample destroyed 
whether during the study or during the retention period following close of the main study. 

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Screen and Baseline Failures 
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant that their PGx sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent 
and sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files. 
Pharmacogenetics Analyses 
Pharmacogenetics Analyses 
Specific genes may be studied that encode the drug targets, or drug mechanism of action 
pathways, drug metabolizing enzymes, drug transporters or which may underpin adverse 
events, disease risk or drug response. These candidate genes may include a common set 
of ADME (Absorption, Distribution, Metabolism and Excretion) genes that are studied to 
determine the relationship between gene variants or treatment response and/or tolerance.  
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to otelixizumab.  The genes that may code for 
these proteins may also be studied. 
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with a 
candidate gene, may be studied to determine the relationship between genetic variants 
and treatment response or tolerance. This approach is often employed when a definitive 
candidate gene(s) does not exist and/or the potential genetic effects are not well 
understood.  
If applicable and PGx research is conducted, appropriate statistical analysis methods will 
be used to evaluate pharmacogenetic data in the context of the other clinical data. Results 
of PGx investigations will be reported either as part of the main clinical study report or as 
a separate report. Endpoints of interest from all comparisons will be descriptively and/or 
graphically summarized as appropriate to the data.  A detailed description of the analysis 
to be performed will be documented in the study reporting and analysis plan (RAP) or in 
a separate pharmacogenetics RAP, as appropriate.   
Informed Consent 
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study.  PGx informed consent must be obtained prior to any saliva being taken for 
PGx research. 
Provision of Study Results and Confidentiality of Subject’s PGx Data 
GSK may summarize the PGx research results in the clinical study report, or separately, 
or may publish the results in scientific journals.  

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GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, insurers, or employers) of individual 
genotyping results that are not known to be relevant to the subject’s medical care at the 
time of the study, unless required by law. This is due to the fact that the information 
generated from PGx studies is generally preliminary in nature, and therefore the 
significance and scientific validity of the results are undetermined. 
References 
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21. 
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-46. 
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-2. 
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388. 
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-40. 
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-32. 
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-78 
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-66. 

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12.3. 
Appendix 3: Country Specific Requirements 
There are no country specific requirements. 
 

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12.4. 
Appendix 4: Procedures for Detection, Evaluation, Follow-
Up and Reporting of Adverse Events 
Recording of AEs and SAEs 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative 
to the event.  The investigator will then record all relevant information regarding an 
AE/SAE in the appropriate data collection tool.  
It is not acceptable for the investigator to send photocopies of the patients’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE data collection tool.  
However, there may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all patient identifiers, with the exception of the 
patient number, will be blinded on the copies of the medical records prior to submission 
of to GSK. 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms. 
Evaluating AEs and SAEs 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories: 
Mild:  An event that is easily tolerated by the patient, causing minimal discomfort and not 
interfering with everyday activities. 
Moderate:  An event that is sufficiently discomforting to interfere with normal everyday 
activities. 
Severe:  An event that prevents normal everyday activities. 
An AE that is assessed as severe will not be confused with an SAE.  Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.  An event is defined as ‘serious’ when it meets at least one of the pre-
defined outcomes as described in the definition of an SAE. 
Assessment of Causality 
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE.  A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship 
cannot be ruled out.  The investigator will use clinical judgment to determine the 
relationship.  Alternative causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 

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study treatment will be considered and investigated.  The investigator will also consult 
the Investigator Brochure (IB) and/or Product Information, for marketed products, in the 
determination of his/her assessment. 
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that 
the investigator always make an assessment of causality for every event prior to the 
initial transmission of the SAE data to the CRO Medical Monitor and GSK.  The 
investigator may change his/her opinion of causality in light of follow-up information, 
amending the SAE data collection tool accordingly.  The causality assessment is one of 
the criteria used when determining regulatory reporting requirements. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
patient at subsequent visits/contacts.  All AEs and SAEs will be followed until resolution, 
until the condition stabilizes, until the event is otherwise explained, or until the patient is 
lost to follow-up. 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.   The 
investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.  If a subject dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any post-mortem 
findings, including histopathology.  
New or updated information will be recorded in the originally completed data collection 
tool.  The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames. 
Reporting of SAEs to GSK 
Electronic Facsimile and/or e-mail transmission of the paper SAE data collection form is 
the preferred method to transmit this information to the CRO and GSK Medical 
Monitors.  In rare circumstances and in the absence of facsimile equipment, notification 
by telephone is acceptable, with a copy of the SAE data collection form sent by overnight 
mail.  Initial notification via the telephone does not replace the need for the investigator 
to complete and sign the paper SAE data collection form within the designated reporting 
time frames. 
CRO and GSK contacts for SAE receipt can be found at this beginning of the protocol on 
the Sponsor/Medical Monitor Contact Information page. 

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12.5. 
Appendix 5: Mixed Meal Tolerance Test (MMTT) 
The Mixed Meal Stimulated C-peptide and C-peptide unstimulated will be performed as 
shown in the protocol Section 6.2 Time and Events Table 
On the evening before the C-peptide analysis, subjects should eat a full, standard meal. 
They must fast from 12 PM the evening before the test until the test is completed. They 
should remain hydrated and may consume water, black coffee, or black tea (with no sugar 
or artificial sweeteners) during the fast and test. 
Subjects will start the C-peptide analysis in the morning. The time at which the test is 
started should be kept as consistent as possible. Before the test is started, blood glucose 
will be measured using a finger-stick test. The Mixed Meal Stimulated C-peptide may be 
performed only if the blood glucose level is above 70 mg/dL and no higher than 200 
mg/dL. Documentation that the glucose is in this range will be required. If the glucose is 
outside this range, this test must be rescheduled. 
On the morning of the test, subjects will modify their insulin regimen as follows: 
• 
For subjects who do not use an insulin pump: withhold the morning dose of 
long- or intermediate-acting insulin. No regular insulin for at least 6 hours 
before the test; no very short-acting insulin for at least 2 hours before the test.  
• 
For subjects who use an insulin pump: continue the basal insulin rate until the 
start of the test, then stop the pump. No regular insulin boluses for at least 
6 hours before the test; no short-acting insulin boluses for at least 2 hours before 
the test. 
When both unstimulated and Mixed Meal stimulated C-peptide analysis should be done, 
each subject will consume a standardized amount of Ensure Powder (Abbott) drink 
supplied by the CRO/GSK. Further details on this product are provided in the study 
reference manual. 
The time when the subject starts drinking the Ensure will be defined as Time 0. The 
subject will drink the Ensure powder solution within 5 minutes or less.  Blood samples 
will be taken 10 minutes before and immediately before the subject starts drinking the 
Ensure drink at Time 0. These 2 blood samplings belong to the unstimulated C-peptide 
analysis. For the Mixed Meal stimulated C-peptide analysis, blood sampling will be done 
at 15, 30, 60, 90, and 120 minutes after Time 0. The subject may consume water or 
unsweetened black coffee or tea during this period. 
If only the unstimulated C-peptide analysis should be performed (Protocol Section 6.2 
Time and Events Table), 1 blood sample is sufficient. 
A snack appropriate for a subject with diabetes will be available immediately after the 
120-minute blood draw. Glucose will be measured by finger stick; insulin and/or a snack 
will be given as indicated. As soon as feasible after completing the C-peptide analysis 
test, subjects will resume their usual insulin and diet regimens.   

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The tubes with the blood samples will be kept on ice during collection, until centrifuged 
for 15 min at 1530 x g and 4°C.  The plasma will be harvested into 2 green cap transfer 
vials 2.0 mL and stored at <-15°C until shipment (within 3 weeks of collection).   The 
tubes must be shipped on dry ice and remain frozen until analysis.  Further details will be 
provided in the SRM. 
 

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12.6. 
Appendix 6: Hyperglycaemic Clamp Procedure 
1. The evening before the clamp procedure: 
 
AIM: Keep blood glucose (BG) between 80-120mg/dl 
• 8pm+: Sc long acting insulin (if basal-bolus therapy) or sc rapid insulin (if 
sc insulin pump) are replaced by intravenous Actrapid with pump. Blood 
Glucose measurements every 2h and adapt Actrapid IV treatment as 
described in the SOP of the hospital, with aim of BG ≈ 90mg/dL at 8am 
on day of clamp, and without episodes of hypoglycaemia during the night 
before.  
 
2. Day of clamp procedure: 
 
A. Euglycemic Phase: 
 
AIM: Keep blood glucose between 60-90mg/dl during 180 minutes. 
Start Euglycemic phase only when BG 60-90mg/dL 
 
Measure blood glucose every 15 minutes and adapt according to Table A 
Table A: 
Blood Glucose 
(BG) 
Actrapid HM  
Pump  
IV 
Infusion 
100ml/hr 
Start = t0 
80-90 mg/dL 
Daily dose/24/hr 
NaCl 0.9% 
50-80 mg/dL 
0.5IU/hr 
NaCl 0.9% 
<50mg/dL 
STOP TEST* 
Glucose 5% 
Adaptation of insulin pump during test: 
Adapt Actrapid IV if BG >60mg/dL 
Increase >10mg/dL 
+0.5IU/hr 
NaCl 0.9% 
Decrease >10mg/dL 
- 0.5 IU/h 
NaCl 0.9% 

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Blood Glucose 
(BG) 
Actrapid HM  
Pump  
IV 
Infusion 
100ml/hr 
Adapt Actrapid IV if BG 50 - 60mg/dL 
 
0.5IU/h 
NaCl 0.9% 
Never stop insulin Pump during the test unless BG <50mg/dL  
= STOP TEST* 
 
 
*: Stop test + REPEAT Clamp 1 day later 
 
Take blood samples for C-Peptide (Trasylol-EDTA on ice) and glycaemia 
(NaF) at: 
 
Time 
Sample Name 
Time 0 + 150 min 
L150 
Time 0 + 165 min 
L165 
Time 0 + 180 min** 
L180 
  
B. Let blood glucose increase till 180mg/dL 
 
AIM: increase BG till 180mg/dL in a period of 30 minutes. 
At Time 0 + 180 min**: STOP Actrapid IV and START glucose 10% at 50 
mL/hr during 15 minutes. 
Measure blood glucose every 15 minutes and adapt according to Table B. 
Blood glucose should increase to minimally 180 mg/dL with help of glucose 
infusion.  

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Table B: 
 
Blood Glucose 
(BG) 
Actrapid HM  
Pump 
IV 
Glucose Infusion 
Adaptation of glucose infusion till BG 180mg:dl: 
15’ 
<180 mg/dL 
STOP 
Increase Glucose 10% to 100ml/h 
15’ 
<180 mg/dL 
STOP 
Replace Glucose 10% by Glucose 
20% at 100ml/h (same rate)  
15' 
<180 mg/dL 
STOP 
Keep Glucose 20% infusion at   
100ml/h (same rate) 
180-240mg/dL: START Test =Time 0*** 
 
C. Hyperglycemic Phase start BG 180-240mg/dL 
 
AIM: keep hyperglycaemia (range 180-240mg/dL) during 140 minutes. 
When blood glucose >180 mg/dL = Time 0*** 
Take blood samples for C-Peptide (Trasylol-EDTA on ice) and glycemia (NaF) 
at: 
 
Time 
Sample Name 
Time 0***  
H0 
Time 0 + 60 min 
H60 
Time 0 + 90 min 
H90  
 
Time 0 + 120 min 
H120 
Time 0 + 140 min 
H140 
 
 
Measure BG at least every 15 min and adapt according to Table C. 

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Table C: 
 
Blood Glucose 
(BG) 
Actrapid HM 
Pump 
IV 
Infusion 
 
 
180-240mg/dL 
STOP 
Keep glucose infusion 
Adaptation of glucose infusion if BG >240mg/dl: 
15’ 
>240 mg/dL 
STOP 
Glucose 10% 100ml/h 
15’ 
>240 mg/dL 
STOP 
Glucose 10% 50ml/h 
15’ 
>240 mg/dL 
STOP 
NaCl 0.9% 50ml/h 
Adaptation of glucose infusion if BG <200mg/dl: 
15’ 
<200 mg/dL 
STOP 
Glucose 10% 50ml/h 
15’ 
<200 mg/dL 
STOP 
Glucose 10% 100ml/h 
15’ 
<200 mg/dL 
STOP 
Glucose 20% 100ml/h 
 

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12.7. 
Appendix 7: ADA Classification 
 
 
Alert Value for Hyperglycemia: >13.9 mmol/L; >250 mg/dL 

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12.8. 
Appendix 8: Protocol Amendment Changes 
2011N129686_00 
2013-SEP-05 
Original 
2011N129686_01 
2014-FEB-27 
Amendment No. 1 
2011N129686_02 
2014-APR-02 
Amendment No. 2 
2011N129686_03 
2014-JUN-18 
Amendment No. 3 
2011N129686_04 
2014-JUL-28 
Republishing-Amendment 
No. 3 
2011N129686_05 
2015-FEB-11 
Amendment No. 4 
2011N129686_06 
2015-AUG-18 
Amendment No. 5 
2011N129686_07 
2016-SEP-12 
Amendment No. 6 
2011N129686_08 
2017-SEP-11 
Amendment No. 7 
2011N129686_09 
2017-OCT-26 
Amendment No. 8 
 
Protocol Changes for Amendment 8 (26-OCT-2017) from Protocol 
Amendment 7 (11-Sep-2017) 
Where the Amendment Applies 
All sites 
SUMMARY OF AMENDMENT CHANGES WITH RATIONALE 
Data which emerged from an interim analysis carried out in this study showed a prompt 
regain of immune competence observed in treated subjects and consequent rapid 
resolution of EBV reactivation, both clinically and virologically. The long term EBV 
related PTLD risk, as observed in solid organ transplant on a chronic immune 
suppression therapy, is negligible. 
Therefore, all references to month 48 and 60 have been removed as no patient currently 
enrolled in the study has reached month 48 of follow up. For the patients who have yet to 
complete their 24 month visit, this visit will be treated as a final visit and for those who 
have gone past month 24, they will be followed up with a final communication or visit 
(final follow up) upon approval of this protocol amendment. 
Data from the literature identified a causal relationship between the degree of 
immunosuppression and an increased incidence of EBV related Post Transplant 
Lymphoprolerative Disorders (PTLD) and for this reason a long-term follow-up was 
implemented at the start of the study.  

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LIST OF SPECIFIC CHANGES 
Section 2. Objectives and Endpoints 
 PREVIOUS TEXT 
Follow up Objectives  
Follow up Endpoints (Data Collected at 
Month 36, 48 & 60 if Available) 
• 
To assess long term safety follow-up with 
otelixizumab treatment. 
• 
Significant adverse events.  
• 
Severe (as per ADA classification, 
Appendix 7) hypoglycemic events which 
occurred between Months 24 up to 60.   
• 
Severe hyperglycemic events which 
occurred between Months 24 up to 60. 
• 
Mean daily insulin use over 7 consecutive 
days preceding the call.  
• 
HbA1c results around time of the phone 
call. 
 
REVISED TEXT 
Follow up Objectives  
Follow up Endpoints  - Data Collected at 
Month 36, 48 & 60 if Available from month 
36 (if available) or final follow-up. This will 
only be applicable for patients past month 
24 
• 
To assess long term safety follow-up with 
otelixizumab treatment. 
• 
Significant adverse events.  
• 
Severe (as per ADA classification, 
Appendix 7) hypoglycemic events which 
occurred following Month 24 visit up to 60 
(if available) until final follow-up.   
• 
Severe hyperglycemic events which 
occurred following Months 24 visit up to 
60 (if available) until final follow-up. 
• 
Mean daily insulin use over 7 consecutive 
days preceding the call.  
• 
HbA1c results around time of the phone 
call. 
Section 3.2. Study Schematics 

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PREVIOUS TEXT 
Figure 4 
Study Visits Schematic 
For study assessments see the Time and Events tables in Section 6.2 
 
 
REVISED TEXT 
 
Section 3.3.1.2. Study Duration 
PREVIOUS TEXT 
The overall study duration for each subject is 60 months (up to 61 months including the 
screening period). Primary study completion for each subject will be at 24 months when 
all available data will be analysed. Patients will then complete a further 36 month period 
to enable long-term safety follow-up. The Investigator will contact patients by telephone 
to discuss their clinical status at Months 36, 48 and 60. Further details are provided in the 
Study Reference Manual (SRM). If further follow up is required the Investigator will 

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request that the patient visits the site. See Section 9.3 for a description of analysis 
considerations. 
REVISED TEXT 
Data from the literature at the origin of the study design identified a causal 
relationship between the degree of immunosuppression and an increased incidence 
of EBV related Post Transplant Lymphoprolerative Disorders (PTLD) and for this 
reason a long-term follow-up (60 months) was implemented at the start of the study. 
The interim analysis data which emerged from this study showed a prompt regain 
of immune competence observed in treated subjects and consequent rapid resolution 
of EBV reactivation, both clinically and virologically. The long term EBV related 
PTLD risk, as observed in solid organ transplant on a chronic immune suppression 
therapy, is negligible. As a result,Tthe overall study duration for each subject is 60 
months (up to 61 months including the screening period). Primary study completion for 
each subject will be at 24 months when all available data will be analysed. Patients will 
then complete a further 36 month period to enable long-term safety follow-up. The 
Investigator will contact patients by telephone to discuss their clinical status at Months 
36, 48 and 60. will be 24 months, except for those patients who have already reached 
the 24 or 36 month follow up in which case they will have a final follow up 
communication (telephone call or visit) as soon as possible following approval of this 
amendment 08 of the protocol. Further details are provided in the Study Reference 
Manual (SRM). If further follow up is required the Investigator will request that the 
patient visits the site. See Section 9.3 for a description of analysis considerations. 
Section 3.4 Risk Management 
PREVIOUS TEXT 

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Abnormal 
Liver 
Chemistry 
• 
In the Belgian Diabetes Registry study, 
administration of high cumulative doses 
of otelixizumab (48-64mg) have been 
temporally associated with abnormal 
liver chemistry thought to be due to 
increased cytokine release.  In 
subsequent dose-finding studies 
conducted at lower doses, no trends with 
respect to changes in liver chemistry 
were observed. 
Patients with 
history of liver 
diseases and/or 
persistent  AST or 
ALT >2.0 ULN will 
not be included 
Liver chemistry will be 
monitored daily for the 
duration of treatment to detect 
any unanticipated liver event. 
Liver chemistry individual 
withdrawal and study stopping 
criteria and follow-up are in 
place (Section 5.3). 
Progressive 
Disease 
 
 
Intensive monitoring and care 
will be provided according to 
current standards of care for 
patients with type 1 diabetes. 
Diabetes care will be at the 
discretion of the investigator 
and may include consultations 
with a nutritionist or dietician 
and/or a diabetes educator 
according to the local 
institution’s guidelines for 
NOT1DM. Study centres are 
expected to work with each 
subject to optimize glycaemic 
control as per standard of 
care, with a target HbA1c less 
than 7% (53 mmol/mol). 
HbA1c will not be 
communicated to the trial 
centre by BDR unless HbA1c  
is ≥ 7% .  Diabetes 
management will be directed 
towards helping each subject 
reach this target or come as 
close to it as possible.  
 
REVISED TEXT 

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Abnormal Liver 
Chemistry 
• 
In the Belgian Diabetes Registry 
study, administration of high 
cumulative doses of otelixizumab 
(48-64mg) have been temporally 
associated with abnormal liver 
chemistry thought to be due to 
increased cytokine release.  In 
subsequent dose-finding studies 
conducted at lower doses, no 
trends with respect to changes in 
liver chemistry were observed. 
Patients with history of 
liver diseases and/or 
persistent  AST or ALT 
>2.0 ULN will not be 
included 
Liver chemistry will be 
monitored daily for the 
duration of treatment to 
detect any unanticipated 
liver event. 
Liver chemistry individual 
withdrawal and study 
stopping criteria and 
follow-up are in place 
(Section 5.3). 
Progressive 
Disease 
 
 
Intensive monitoring and 
care will be provided 
according to current 
standards of care for 
patients with type 1 
diabetes. Diabetes care 
will be at the discretion of 
the investigator and may 
include consultations 
with a nutritionist or 
dietician and/or a 
diabetes educator 
according to the local 
institution’s guidelines for 
NOT1DM. Study centres 
are expected to work 
with each subject to 
optimize glycaemic 
control as per standard 
of care, with a target 
HbA1c less than 7% (53 
mmol/mol). HbA1c will 
not be communicated to 
the trial centre by BDR 
unless HbA1c  is ≥ 7% .  
Diabetes management 
will be directed towards 
helping each subject 
reach this target or come 
as close to it as possible.  
Preterm birth 
• 
Preclinically, GLP reproductive 
toxicity studies have not been 
completed, however; [Gomez-
Lopez N, 2016] reported that 
pregnant B6 mice dosed with an 
antimouse CD3 monoclonal 
antibody (mAb) on Gestation 
Day 16.5 (late gestation) led to 
an increased frequency of 
preterm birth and increased pup 
mortality thought to be due to T-
cell activation, however, no data 
to demonstrate pharmacology 
was provided. 
 
• 
Clinically, one subject in a GDSK 
Eligibility criteria 
includes 
contraception 
requirements for 
female subjects and 
male subjects with 
female partners of 
child-bearing 
potential.  
Pregnancy will be 
monitored 
with serum pregnancy 
tests at all 
assessments. 

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clinical trial (RAO112438) was 
exposed to the investigational 
product before conception and 
during the first trimester of 
pregnancy. One hundred ninety 
nine (199) days after the last 
dose of IP, the subject 
developed Grade 2 or moderate 
impending parturition 
prematurus and Grade 2 or 
moderate hematemesis. The 
investigator considered that 
there was no reasonable 
possibility that the uterine  
contractions during pregnancy 
and hematemesis may have 
been caused by investigational 
product. After 37 weeks and six 
days gestation, the subject gave 
birth to a female live infant. 
There were no birth defects. 
Opportunistic 
Infections 
Mild to severe infections that 
generally respond to customary 
treatment have occurred in 
otelixizumab-treated subjects. There 
have been no opportunistic 
infections reported with otelixizumab 
in subjects with T1DM. 
Patients who are 
immunocompromised 
(e.g. HIV positive 
patients) or those on 
immunosuppressive 
medications may be at 
higher risk of 
infections are 
excluded from the 
clinical study with 
otelixizumab in T1DM. 
 
All safety data will be 
reviewed by the Safety 
Review Team per 
current practices. 
JC Virus (JCV) 
JCV reactivation has not been 
observed with other anti-CD3 MAbs; 
however, this has been an area of 
interest with other types of 
monoclonal antibodies.  
Patients with previous 
history of 
immunosuppression 
and/or on active 
immunosuppressant 
therapy are excluded 
from the study. 
 
 
Section 4.2.1 Inclusion Criteria 2 
PREVIOUS TEXT 
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply: 
1. Male or female aged between 16 and 27 years of age inclusive, at the time of signing 
the informed consent.  
NOTE: Subjects aged 16 to 17 years must be Tanner Stage ≥2 (see SRM). All 
subjects must weigh at least 31 kg. 

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2. Diagnosis of diabetes mellitus according to ADA and WHO criteria and consistent 
with Type 1a (autoimmune) DM, with an interval of approximately 28 days (not 
more than 32 days) between the initial diagnosis and the first dose of study drug). 
Written documentation of the diagnosis of DM, including the date of diagnosis, must 
be obtained from the diagnosing physician. 
3. Currently requires insulin treatment for T1DM and has received insulin therapy for 
at least 7 days prior to screening. 
4. Positive for at least one autoantibody associated with T1DM: antibody to glutamic 
acid decarboxylase (anti GAD), antibody to protein tyrosine phosphatase-like protein 
(anti IA 2), antibody to islet-cell antigen (ICA) or ZnT8 Autoantibody. 
5. Evidence of residual functioning β cells as measured by mixed meal stimulated C- 
peptide peak level ≥ 0.2 nmol/L.  
6. A female subject is eligible to participate if she has a negative pregnancy test as 
determined by a urine hCG test at screening or prior to dosing AND 
• 
Agrees to use one of the contraception methods listed in Section 4.3.1. Female 
subjects must agree to use contraception for 2 weeks prior to dosing and for 60 
days after the last dose of study drug. 
• 
OR has only same-sex partners (refrains from heterosexual intercourse), when 
this is her preferred and usual lifestyle. 
7. Male subjects with female partners of child-bearing potential must agree to use one 
of the contraception methods listed in Section 4.3.1.  This criterion must be followed 
from 2 weeks prior to dosing and for 60 days after the last dose of study drug. 
8. Willing to follow the procedures outlined in the protocol. 
9. AST and ALT <2xULN; alkaline phosphatase and bilirubin ≤1.5xULN (isolated 
bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin 
<35%).  
10. Subjects eligible for enrolment in the study must meet all of the following criteria: 
• QTc <450msec or  
• QTc <480msec for patients with bundle branch block 
The QTc is the QT interval corrected for heart rate according to either Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), or another method, machine or manual overread.  
• For subject eligibility and withdrawal, QTcF will be used. 
• For purposes of data analysis, QTcF will be used as primary. 
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms (ECGs) obtained over a brief recording period. 
11. Screening total lymphocyte counts within the normal range in two separate samples 
taken at least three days apart (eg screening and Day -1). 

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12. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form. In the case of minors (under 
18 years) written informed consent must also be obtained from a parent or Legally 
Acceptable Representative (LAR). 
REVISED TEXT 
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply: 
1. Male or female aged between 16 and 27 years of age inclusive, at the time of signing 
the informed consent.  
NOTE: Subjects aged 16 to 17 years must be Tanner Stage ≥2 (see SRM). All 
subjects must weigh at least 31 kg. 
2. Diagnosis of diabetes mellitus according to ADA and WHO criteria and consistent 
with Type 1a (autoimmune) DM, with an interval of approximately 28 days (not 
more than 32 days) between the initial diagnosis and the first dose of study drug). 
Written documentation of the diagnosis of DM, including the date of diagnosis, must 
be obtained from the diagnosing physician. 
3. Currently requires insulin treatment for T1DM and has received insulin therapy for 
at least 7 days prior to screening. 
4. Positive for at least one autoantibody associated with T1DM: antibody to glutamic 
acid decarboxylase (anti GAD), antibody to protein tyrosine phosphatase-like protein 
(anti IA 2), antibody to islet-cell antigen (ICA) or ZnT8 Autoantibody. 
5. Evidence of residual functioning β cells as measured by mixed meal stimulated C- 
peptide peak level ≥ 0.2 nmol/L.  
6. A female subject is eligible to participate if she has a negative pregnancy test as 
determined by a urine serum hCG test at screening or prior to dosing AND 
• 
Agrees to use one of the contraception methods listed in Section 4.3.1. Female 
subjects must agree to use contraception for 2 weeks prior to dosing and for 60 
days after the last dose of study drug. 
• 
OR has only same-sex partners (refrains from heterosexual intercourse), when 
this is her preferred and usual lifestyle. 
7. Male subjects with female partners of child-bearing potential must agree to use one 
of the contraception methods listed in Section 4.3.1.  This criterion must be followed 
from 2 weeks prior to dosing and for 60 days after the last dose of study drug. 
8. Willing to follow the procedures outlined in the protocol. 
9. AST and ALT <2xULN; alkaline phosphatase and bilirubin ≤1.5xULN (isolated 
bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin 
<35%).  
10. Subjects eligible for enrolment in the study must meet all of the following criteria: 
• QTc <450msec or  

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• QTc <480msec for patients with bundle branch block 
The QTc is the QT interval corrected for heart rate according to either Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), or another method, machine or manual overread.  
• For subject eligibility and withdrawal, QTcF will be used. 
• For purposes of data analysis, QTcF will be used as primary. 
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms (ECGs) obtained over a brief recording period. 
11. Screening total lymphocyte counts within the normal range in two separate samples 
taken at least three days apart (eg screening and Day -1). 
12. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form. In the case of minors (under 
18 years) written informed consent must also be obtained from a parent or Legally 
Acceptable Representative (LAR). 
 
Section 4.6 Patient Completion 
PREVIOUS TEXT 
A completed patient is one who has completed Month 24. 
The end of the study is defined as the last patient’s last visit at Month 60. 
REVISED TEXT 
A completed patient is one who has completed Month 24. 
The end of the study is defined as the last patient’s last visit at Month 60 Month 24 or at 
final follow-up. 
Section 6.1 Visit Windows 
PREVIOUS TEXT 
The following visit windows will be allowed to provide flexibility. Visits completed 
within the windows will not constitute a protocol deviation:  
• A ± 1 day window is permitted for the Day 14 and Day 21 visits and Week 4 
telephone call. 
• Visits from Week 6 to Month 3 inclusive are permitted a ± 3 day window 
• Visits from Month 6 to Month 24 inclusive are permitted a ± 7 day window 

2011N129686_09 
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• Telephone calls in the follow-up period at Month 36, 48 and 60 are permitted a 
±14 day window 
REVISED TEXT 
The following visit windows will be allowed to provide flexibility. Visits completed 
within the windows will not constitute a protocol deviation:  
• A ± 1 day window is permitted for the Day 14 and Day 21 visits and Week 4 
telephone call. 
• Visits from Week 6 to Month 3 inclusive are permitted a ± 3 day window 
• Visits from Month 6 to Month 24 inclusive are permitted a ± 7 day window 
• Telephone calls/visits in the follow-up period at Month 36, 48 and 60 and final-
up are permitted a ±14 day window 
 
Section 6.2.2 Dosing and follow-up 
PREVIOUS TEXT 
  
  
  
Day 
Month 
  
-
2 
-
1 
1 
2 
3 4 5 6 
1
4 
2
1 
 
 
Wee
k 4 
Wee
6 2 3 6 
9 
1
2 
1
8 
2
4 
36, 
48 
& 
60# 
Patient admitted to unit1 
X 
  
  
  
  
  
 
  
  
    
    
  
  
In Patient 
  
X 
X 
X 
X 
X
2 
X
2 
X
2 
  
  
 
  
  
  
  
    
  
  
Prophylaxis (Section 5.10) 
then  IV Dosing of study 
treatment 
  
  
X 
X 
X X X X 
 
 
Patient Discharged2 
X 
 
 
Out Patient# 
  
  
  
  
  
X
  
 
X 
 
X X X 
 
X 
X X X 
X X X X 
Telephone call to collect AEs, 
hypoglycemic and 
hyperglycemic events and 
concomitant 
 medication use 
X 
 
X 
Brief Physical Examination  
  
X 
X3 
X
3 
X
3 
X
3 
X
3 
X
3 
X X 
 
X 
X X X 
X X X X 
12 lead ECG4,6 
  
X 
X 
X 
X X X 
 
X X 
 
X 
X 
Vital Signs5,6 
  
X 
X 
X 
X X X X X X 
 
X 
X X X 
X X X X 
Urine Pregnancy Test  
  
X 
  
  
  
  
  
  
  
  
 
X 
X X X 
X X X X 
Alcohol & drugs of abuse test    
X 
  
  
  
  
  
  
  
  
 
  
  
 
Haematology7  
  
X 
  
X 
X X X X X X 
 
X 
X X X 
X X X X 

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Day 
Month 
  
-
2 
-
1 
1 
2 
3 4 5 6 
1
4 
2
1 
 
 
Wee
k 4 
Wee
6 2 3 6 
9 
1
2 
1
8 
2
4 
36, 
48 
& 
60# 
Clinical Chemistry7  
  
X 
X 
X 
X X X 
X
8 
X   
 
X 
  
X X 
X X X X 
HSV-1 & HSV-2 IgG & IgM9 
X 
 
 
EBV Viral Load (PCR)7 
  
X 
  
  
  
  
  
X   
 
X 
 
X 
X X 
X
10 
    
  
 X 
EBV Serology  - IgG and IgM 7 
  
X 
  
  
  
  
X 
X 
 
X 
X X X 
X   
X 
CMV  Serology  - IgG and IgM7  
X 
X 
 
X 
X X X 
X 
X 
PK Blood Sample6 
X 
X 
X X X X 
X
11 
 
 
CD3 Saturation, free CD3 
bound otelixizumab 
/CD4+/CD8+ Blood Sample6 
X 
X 
X X X X 
X
11 
 
 
Record insulin usage for 7 
days before visit / call 
X 
X X X 
X 
X X X 
X X X X 
X 
AE Assessment 
  
  
<---------------------------------------------------------------------------------------------------
------------------------------------------------------> 
Concomitant Medication 
Review 
  
  
<---------------------------------------------------------------------------------------------------
------------------------------------------------------> 
Hypoglycaemic / 
Hyperglycaemic Events 
<---------------------------------------------------------------------------------------------------
-----------------------------------------------> 
Anti-GAD, anti-IA2, antibody 
to islet-cell antigen (ICA), 
anti-ZnT8 & Insulin-antibodies 
(IAA) 
X 
 
 
Anti-otelixizumab antibodies 
Blood Sample  
  
X 
  
  
  
  
  
  
  
  
 
  
  
X X 
  
 
Mixed Meal Stimulated C-
peptide (MMTT)12 
  
  
  
  
  
  
  
  
  
  
 
  
  
X 
X
14 
  X X 
X
14 
Beta Cell Function by 
Hyperglycaemic Clamp13 
  
X 
  
  
  
  
  
  
  
  
 
  
  
  
X
14 
    
  
X
14 
HbA1c 
X 
 
X 
X 
X 
X1
5 
Bodyweight 
X 
 
X 
X X X 
X X X X 
Various Blood samples for 
Exploratory Biomarkers 
  
X 
  
  
  
  
  
X
16   
  
 
X 
  
X X 
  X   
X
17 
Saliva sample for 
Pharmacogenetics (PGx)18 
<---------------------------------
-> 
 
 
#Patients will record insulin usage for 7 days prior to out-patient visits (up to Month 24) and before telephone 
calls in Month 36, 48 and 60.  Significant AEs including hypoglycaemic (≤3.9 mmol/L; ≤70 mg dL) and 
hyperglycaemic (>13.9 mmol/L; >250 mg/dL) events will be recorded in a diary whenever they occur, to 
include start and stop dates. 
1. Patient admitted evening of Day -2 
2. Discharged on Day 6 if health considered satisfactory by the investigator. Dosing Day 4-6 may be performed on 
out-patient basis (see Section 3.1) 
3. Physical exam performed to monitor for changes in clinical status 
4. ECG pre-dose (in triplicate), at the end of the infusion and 6 hours post start infusion (if infusion <6 hours) 
5. Vital signs include temperature, blood pressure and pulse rate (in triplicate), and respiration rate 
6. See Section 6.2.3 for timings  
7. Pre-dose on dosing days 
8. If LFTs have shown an upward trend continue to monitor daily after day 6 

2011N129686_09 
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9. HSV-1 & HSV-2 IgG & IgM will be measured at Day -1 and during the study if clinically indicated 
10.  If still positive at 6 months EBV viral load will be monitored every 3 months until month 24 
11. One sample during visit 
12. Blood samples for C-peptide and glucose levels collected at -10, 0, 15, 30, 60, 90 and 120 minutes 
13. Plasma C-peptide and glucose levels will be measured during the hyperglycaemic clamp procedure at the 
following time points: L150, L165 and L180 minutes [during the euglycaemic (L)ow phase], H0, H60, H90, H120 
and H140 minutes [during the hyperglycaemic (H)igh phase] 
14. Mixed Meal and Glucose Clamp must be separated by at least 4 days 
15. Patients will be asked to report verbally their HbA1c at Month 36, 48 & 60 followed eventually (if available) by a 
printed result via regular mail (or scan electronically). 
16. Limited biomarkers on Day 6 pre-dose  
17. Blood samples for exploratory biomarkers will only be analysed at  Month 24 if indicated based on Month 12 
results 
18. One PGx (DNA) saliva sample taken between Day 1 and 6 
 
REVISED TEXT 
 
  
  
  
Day 
Month 
  
-
2 
-
1 
1 
2 
3 4 5 6 
1
4 
2
1 
 
 
Wee
k 4
Wee
6 2 3 6 
9 
1
2 
1
8 
2
4 
36, 
48 & 
60#3
6 
mont
h (if 
appli
cabl
e) 
and/
or 
final 
follo
w up 
Patient admitted to unit1 
X 
  
  
  
  
  
 
  
  
    
    
  
  
In Patient 
  
X 
X 
X 
X 
X
2 
X
2 
X
2 
  
  
 
  
  
  
  
    
  
  
Prophylaxis (Section 5.10) 
then IV Dosing of study 
treatment 
  
  
X 
X 
X X X X 
 
 
Patient Discharged2 
X 
 
 
Out Patient# 
  
  
  
  
  
X
  
 
X 
 
X X X 
 
X 
X X X 
X X X X 
Telephone call or out-patient 
visit to collect AEs, 
hypoglycemic and 
hyperglycemic events and 
concomitant 
 medication use 
X 
 
X 
Brief Physical Examination  
  
X 
X3 
X
3 
X
3 
X
3 
X
3 
X
3 
X X 
 
X 
X X X 
X X X X 
12 lead ECG4,6 
  
X 
X 
X 
X X X 
 
X X 
 
X 
X 
Vital Signs5,6 
  
X 
X 
X 
X X X X X X 
 
X 
X X X 
X X X X 

2011N129686_09 
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Day 
Month 
  
-
2 
-
1 
1 
2 
3 4 5 6 
1
4 
2
1 
 
 
Wee
k 4
Wee
6 2 3 6 
9 
1
2 
1
8 
2
4 
36, 
48 & 
60#3
6 
mont
h (if 
appli
cabl
e) 
and/
or 
final 
follo
w up 
Serum Pregnancy Test  
  
X 
  
  
  
  
  
  
  
  
 
X 
X X X 
X X X X 
Alcohol & drugs of abuse test    
X 
  
  
  
  
  
  
  
  
 
  
  
 
Haematology7  
  
X 
  
X 
X X X X X X 
 
X 
X X X 
X X X X 
Clinical Chemistry7  
  
X 
X 
X 
X X X 
X
8 
X   
 
X 
  
X X 
X X X X 
HSV-1 & HSV-2 IgG & IgM9 
X 
 
 
EBV Viral Load (PCR)7 
  
X 
  
  
  
  
  
X   
 
X 
 
X 
X X 
X
10 
    
  
 X 
EBV Serology - IgG and IgM 7 
  
X 
  
  
  
  
X 
X 
 
X 
X X X 
X   
X 
CMV Serology  - IgG and IgM7  
X 
X 
 
X 
X X X 
X 
X 
PK Blood Sample6 
X 
X 
X X X X 
X
11 
 
 
CD3 Saturation, free CD3 
bound otelixizumab 
/CD4+/CD8+ Blood Sample6 
X 
X 
X X X X 
X
11 
 
 
Record insulin usage for 7 
days before visit / call 
X 
X X X 
X 
X X X 
X X X X 
X 
AE Assessment 
  
  
<-----------------------------------------------------------------------------------------------------
----------------------------------------------------> 
Concomitant Medication 
Review 
  
  
<-----------------------------------------------------------------------------------------------------
----------------------------------------------------> 
Hypoglycaemic / 
Hyperglycaemic Events 
<-----------------------------------------------------------------------------------------------------
---------------------------------------------> 
Anti-GAD, anti-IA2, antibody 
to islet-cell antigen (ICA), 
anti-ZnT8 & Insulin-
antibodies (IAA) 
X 
 
 
Anti-otelixizumab antibodies 
Blood Sample  
  
X 
  
  
  
  
  
  
  
  
 
  
  
X X 
  
 
Mixed Meal Stimulated C-
peptide (MMTT)12 
  
  
  
  
  
  
  
  
  
  
 
  
  
X 
X
14 
  X X 
X
14 
Beta Cell Function by 
Hyperglycaemic Clamp13 
  
X 
  
  
  
  
  
  
  
  
 
  
  
  
X
14 
    
  
X
14 
HbA1c 
X 
 
X 
X 
X 
X15 
Bodyweight 
X 
 
X 
X X X 
X X X X 
Various Blood samples for 
Exploratory Biomarkers 
  
X 
  
  
  
  
  
X
16   
  
 
X 
  
X X 
  X   
X
17 
Saliva sample for 
Pharmacogenetics (PGx)18 
<---------------------------------
-> 
 
 

2011N129686_09 
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#Patients will record insulin usage for 7 days prior to out-patient visits (up to Month 
24) and before telephone call/visit in Month 36 (if applicable) or final follow up.  
Significant AEs including hypoglycaemic (≤3.9 mmol/L; ≤70 mg dL) and 
hyperglycaemic (>13.9 mmol/L; >250 mg/dL) events will be recorded in a diary 
whenever they occur, to include start and stop dates 
1. Patient admitted evening of Day -2 
2. Discharged on Day 6 if health considered satisfactory by the investigator. Dosing Day 4-6 may be performed on 
out-patient basis (see Section 3.1) 
3. Physical exam performed to monitor for changes in clinical status 
4. ECG pre-dose (in triplicate), at the end of the infusion and 6 hours post start infusion (if infusion <6 hours) 
5. Vital signs include temperature, blood pressure and pulse rate (in triplicate), and respiration rate 
6. See Section 6.2.3 for timings  
7. Pre-dose on dosing days 
8. If LFTs have shown an upward trend continue to monitor daily after day 6 
9. HSV-1 & HSV-2 IgG & IgM will be measured at Day -1 and during the study if clinically indicated 
10.  If still positive at 6 months EBV viral load will be monitored every 3 months until month 24 
11. One sample during visit 
12. Blood samples for C-peptide and glucose levels collected at -10, 0, 15, 30, 60, 90 and 120 minutes 
13. Plasma C-peptide and glucose levels will be measured during the hyperglycaemic clamp procedure at the 
following time points: L150, L165 and L180 minutes [during the euglycaemic (L)ow phase], H0, H60, H90, H120 
and H140 minutes [during the hyperglycaemic (H)igh phase] 
14. Mixed Meal and Glucose Clamp must be separated by at least 4 days 
15. Patients will be asked to report verbally their HbA1c at Month 36 48 & 60 (if applicable) and/or final follow-up; 
followed eventually (if available) by a printed result via regular mail (or scan electronically). 
16. Limited biomarkers on Day 6 pre-dose  
17. Blood samples for exploratory biomarkers will only be analysed at Month 24 if indicated based on Month 12 
results 
18. One PGx (DNA) saliva sample taken between Day 1 and 6 
 
Section 6.4.4. 2 Clinical Chemistry 
PREVIOUS TEXT 
BUN 
Potassium 
AST (SGOT) 
Total and direct bilirubin* 
Creatinine 
Chloride 
ALT (SGPT) 
Uric Acid 
Glucose, fasting 
Total CO2 
GGT 
Albumin 
Sodium 
Calcium 
Alkaline phosphatase 
Total Protein 
To include CRP (Day -1 only) 
• 
It is not mandatory to measure fractionated bilirubin if total bilirubin is not above the 
normal range. 
NOTE: Details of Liver Chemistry Stopping Criteria and Follow-Up Procedures are 
given in Section 5.3.4 
Other 
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines). 
Pregnancy (Urine test) 
 

2011N129686_09 
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REVISED TEXT 
BUN 
Potassium 
AST (SGOT) 
Total and direct bilirubin* 
Creatinine 
Chloride 
ALT (SGPT) 
Uric Acid 
Glucose, fasting 
Total CO2 
GGT 
Albumin 
Sodium 
Calcium 
Alkaline phosphatase 
Total Protein 
To include CRP (Day -1 only) 
• 
It is not mandatory to measure fractionated bilirubin if total bilirubin is not above the 
normal range. 
NOTE: Details of Liver Chemistry Stopping Criteria and Follow-Up Procedures are 
given in Section 5.3.4 
Other 
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines). 
Pregnancy (Urine Serum test) 
 
Section 6.7.3 Daily Insulin Use 
PREVIOUS TEXT 
Patients will be asked to record their daily insulin usage thoroughly and accurately for 
7 consecutive days in a diary during the week before all outpatient visits or phone calls, 
ie, at Baseline, Day 14 and 21, Week 4 and 6 and Months 2, 3, 6, 9, 12, 18, and 24, and 
before each telephone call in the long term follow-up period (Month 36, 48 and 60). 
Information on insulin usage will be transcribed from diaries into the eCRF. 
REVISED TEXT 
Patients will be asked to record their daily insulin usage thoroughly and accurately for 
7 consecutive days in a diary during the week before all outpatient visits or phone calls, 
ie, at Baseline, Day 14 and 21, Week 4 and 6 and Months 2, 3, 6, 9, 12, 18, and 24, and 
before each telephone call in the long term follow-up period (Month 36, 48 and 60). 36 
(if applicable) and final follow up (if applicable). Information on insulin usage will be 
transcribed from diaries into the eCRF. 
Section 6.7.4 Glycosylated Haemoglobin, HbA1c 
PREVIOUS TEXT 
HbA1c will be recorded at visits as shown in the Time and Events Table. Patients will be 
asked to report verbally their HbA1c (if available) around the time of month 36, 48 and 
60 followed eventually by a printed result via regular mail (or scan electronically) if 
available. HbA1c values will be captured in the eCRF.  
REVISED TEXT 

2011N129686_09 
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HbA1c will be recorded at visits as shown in the Time and Events Table. Patients will be 
asked to report verbally their HbA1c (if available) around the time of month 36, 48 and 
60 (if applicable) and/or final follow-up; followed eventually by a printed result via 
regular mail (or scan electronically) if available. HbA1c values will be captured in the 
eCRF.  
Section 7.1.1 Time Period for Collecting AE and SAE Information 
PREVIOUS TEXT 
AEs will be collected from signing the Informed Consent Form until the follow-up 
contact, approximately 5 years post last dose.   
REVISED TEXT 
AEs will be collected from signing the Informed Consent Form until the follow-up 
contact, approximately 5 2 years post last dose.   
Section 9.3.2.1 Final Analyses (24 Months) 
PREVIOUS TEXT 
The final primary analysis will occur when the last planned cohort (i.e. based on the dose 
escalation criteria) have completed 24 months study duration.  
REVISED TEXT 
The final analysis will occur when the last planned cohort (i.e. based on the dose 
escalation criteria) have completed 24 months study duration or have had a final follow-
up for subjects who, at the time of the implementation of Amendment 08 of the 
protocol, will have already reached months 24.  
Section 9.3.2.2 Final Analyses (60 Months) 
PREVIOUS TEXT 
The final analysis will occur when the last planned cohort (i.e. based on the dose 
escalation criteria) has completed 60 months study duration and last subject last visit has 
been achieved. 
REVISED TEXT 
The final analysis will occur when the last planned cohort (i.e. based on the dose 
escalation criteria) has completed 60 months study duration and last subject last visit has 
been achieved. 
AMENDMENT 7 
11-SEP-2016 

2011N129686_09 
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Where the Amendment Applies 
All sites 
SUMMARY OF AMENDMENT CHANGES WITH RATIONALE 
All details of how the currently used Ensure powder (Abbott) is prepared has been 
removed from the Mixed Meal Tolerance Test (Appendix 5). This has been amended 
because the manufacturer (Abbott) has discontinued the currently used powder and the 
new product has a slightly different formulation. The details for each of the products will 
now be detailed in the Study Reference Manual.  
LIST OF SPECIFIC CHANGES 
Section 12.5 Appendix 5: Mixed Meal Tolerance Test (MMTT) 
PREVIOUS TEXT 
When both unstimulated and Mixed Meal stimulated C-peptide analysis should be done, 
each subject will consume a standardized amount of Ensure Powder (Abbott) drink 
supplied by the CRO/GSK. This drink will be prepared by dissolving 9 cups (± 81g) into 
210 ml cold water. This mixture results in a 300 ml drink containing 375 kcal. The 
volume of dissolved Ensure Powder will contain 6 kcal per kg body weight up to a 
maximum of 300 ml with 375 kcal.  
Weight 
Volume Ensure Powder Drink (375 kcal/300 ml) 
45 kg 
216 ml 
50 kg 
240 ml 
55 kg 
264 ml 
60 kg 
288 ml 
>60 kg 
300 ml 
Please see the SRM for further details regarding volumes 

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REVISED TEXT 
When both unstimulated and Mixed Meal stimulated C-peptide analysis should be done, 
each subject will consume a standardized amount of Ensure Powder (Abbott) drink 
supplied by the CRO/GSK. Further details on this product are provided in the study 
reference manual. This drink will be prepared by dissolving 9 cups (± 81g) into 210 ml 
cold water. This mixture results in a 300ml drink containing 375 kcal. The volume of 
dissolved Ensure Powder will contain 6 kcal per kg body weight up to a maximum of 
300ml with 375 kcal.  
Weight 
Volume Ensure Powder Drink (375 kcal/300 ml) 
45 kg 
216 ml 
50 kg 
240 ml 
55 kg 
264 ml 
60 kg 
288 ml 
>60 kg 
300 ml 
Please see the SRM for further details regarding volumes 
AMENDMENT 6 
Where the Amendment Applies 
All sites 
SUMMARY OF AMENDMENT CHANGES WITH RATIONALE 
The exploratory objectives and endpoints were amended to allow greater flexibility in 
biomarker assays to evaluate efficacy following treatment with otelixizumab and to probe 
novel aspects of the biology of T1D. Previously it was stated that Month 24 blood 
samples for exploratory biomarker analysis would only be collected if indicated based on 
results from Month 12 biomarker analysis, however, this is no longer correct as Month 24 
samples are being collected routinely. In addition, it was previously stated that 
exploratory biomarker samples would be collected and only analysed after review of 
efficacy endpoints, however, this is incorrect and has been clarified as after review of 
safety endpoints. The Time and Events table was updated to show requirement for 
telephone calls to patients at Month 36, 48 and 60. Minor changes were made to the 
12 Month Interim Analysis, mainly to clarify that a second interim analysis will occur 
when all patients have completed 12 months study duration. The section header “novel 
biomarker analyses” was changed to “Exploratory biomarker analyses” for consistency. 
The name Quest was amended to Q2 Solutions following a company name change, and 
Study Procedures Manual was changed to Study Reference Manual in line with recent 
renaming by GSK. 

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LIST OF SPECIFIC CHANGES 
Section 2 OBJECTIVES AND ENDPOINTS, Exploratory Objectives and 
Exploratory Endpoints 
PREVIOUS TEXT 
Exploratory Objectives* 
Exploratory Endpoints* 
• 
To assess the effect of a single course of 
otelixizumab treatment on circulating 
lymphocyte populations over 24 months in 
NOT1DM patients. 
• 
Change from baseline in absolute 
lymphocyte counts and subsets (CD3+ 
CD4+, CD3+ CD8+, and CD19+ cells) and 
phenotype (eg effector, memory, regulatory 
T cells, eg CD45RA, CCR7+) over Week 6 
to Month 24. 
• 
To assess the effect of a single course of 
otelixizumab treatment on circulating 
regulatory T cell numbers (as quantified by 
demethylated FoxP3 expression) over 
24 months in NOT1DM patients. 
• 
Change from baseline in demethylated 
FoxP3 expression in whole blood over 
Week 6 to Month 24. 

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Exploratory Objectives* 
Exploratory Endpoints* 
• 
To assess the effect of a single course of 
otelixizumab treatment on absolute 
numbers of circulating antigen 
specificCD8+ T cells over 24 months in 
HLA-A2+ NOT1DM patients. 
• 
Change from baseline in absolute numbers 
of HLA-A2-restricted CD8 T lymphocytes 
reactive to specific auto-antigens (by 
multimer) over Week 6 to Month 24. 
• 
To assess the effect of a single course of 
otelixizumab treatment on frequency of 
cytokine-producing antigen specific T cells 
over 24 months in NOT1DM patients. 
• 
Change from baseline in frequency of 
cytokine producing cells following in vitro 
stimulation with auto-antigens (by 
ELISPOT) over Week 6 to Month 24. 
• 
To assess the effect of a single course of 
otelixizumab treatment on serum auto-
antibodies titers and serum analytes 
associated with treatment or autoimmune 
pathology over 24 months in NOT1DM 
patients.  
• 
Change from baseline in auto-antibody 
titres (using a panel of common auto-
antibodies associated with T1DM antigens 
and possibly other auto-antigens) and 
serum analytes (such as cytokines/ 
chemokines) over Week 6 to Month 24.  
• 
To assess the effect of a single course of 
otelixizumab treatment on clonal repertoire 
of circulating T cell populations over 
24 months in NOT1DM patients. 
• 
Change from baseline in T cell clonal 
repertoire by TCR deep sequencing over 
Week 6 to Month 24.  
• 
To assess the effect of a single course of 
otelixizumab treatment on β-cell death 
over 24 months in NOT1DM patients.  
• 
Change from baseline in serum by 
measuring relative levels of unmethylated 
INS DNA and/or other biomarkers for β-
cell death in serum over Week 6 to Month 
24.  
• 
To assess the effect of a single course of 
otelixizumab treatment on suppression 
activity of circulating T lymphocytes over 
24 months in NOT1DM patients. 
• 
Change from baseline in relative levels of 
T lymphocyte suppression using micro 
suppression assay over Week 6 to Month 
24.  
 
REVISED TEXT 
Exploratory Objectives* 
Exploratory Endpoints* 
• 
To assess the effect of a single course of 
otelixizumab treatment on circulating 
lymphocyte populations over 24 months in 
NOT1DM patients. 
• 
Change from baseline in absolute 
lymphocyte counts and ratios in some or 
all, but not limited to and subsets (CD3+ 
CD4+, CD3+ CD8+, and CD19+ cells) and 
phenotype (eg effector, memory, regulatory 
T cells, eg CD45RA, CCR7+) over Week 6 
to Month 24. 

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Exploratory Objectives* 
Exploratory Endpoints* 
• 
To assess the effect of a single course of 
otelixizumab treatment on circulating 
lymphocytes such as regulatory T cell 
numbers (as quantified by CD3 and  
demethylated FoxP3 expression) and Th17 
cells over 24 months in NOT1DM patients. 
• 
Change from baseline in cell-type specific 
methylation marker demethylated FoxP3 
expression in some or all, but not limited 
to CD3, FoxP3 and Th17 in whole blood 
over Week 6 to Month 24. 
• 
To assess the effect of a single course of 
otelixizumab treatment on absolute 
numbers and ratios of circulating antigen 
specificCD8+ T cells over 24 months in 
HLA-A2+ NOT1DM patients. 
• 
Change from baseline in absolute numbers 
and ratios of HLA-A2-restricted CD8 T 
lymphocytes reactive to specific auto-
antigens (by multimer) over Week 6 to 
Month 24. 
• 
To assess the effect of a single course of 
otelixizumab treatment on frequency of 
cytokine-producing antigen specific T cells 
over 24 months in NOT1DM patients. 
• 
Change from baseline in frequency of 
cytokine producing cells following in vitro 
stimulation with auto-antigens and viral 
antigens (by ELISPOT) over Week 6 to 
Month 24. 
• 
To assess the effect of a single course of 
otelixizumab treatment on serum auto-
antibodies titers and serum analytes 
associated with treatment or autoimmune 
pathology over 24 months in NOT1DM 
patients.  
• 
Change from baseline in auto-antibody 
titres (using a panel of common auto-
antibodies associated with T1DM antigens 
and possibly other auto-antigens) and 
serum analytes (such as cytokines/ 
chemokines) during the first 14 days of 
treatment and over Week 6 to Month 24.  
• 
To assess the effect of a single course of 
otelixizumab treatment on clonal repertoire 
of circulating T cell populations and/or 
trancriptomic gene expression changes 
over 24 months in NOT1DM patients. 
• 
Change from baseline in T cell clonal 
repertoire by TCR deep sequencing over 
Week Day 6 to Month 24.  
• 
Change from baseline in 
transcriptomic gene expression 
profile(s) by micro-array and/or 
alternative equivalent technologies 
including RNA sequencing at 
selected timepoint(s) post dosing. 
• 
To assess the effect of a single course of 
otelixizumab treatment on β-cell death 
over 24 months in NOT1DM patients.  
• 
Change from baseline in serum by 
measuring relative levels of unmethylated 
INS DNA and/or other biomarkers for β-
cell death in serum over Week 6 to Month 
24.  
• 
To assess the effect of a single course of 
otelixizumab treatment on suppression 
activity of circulating T lymphocytes over 
24 months in NOT1DM patients. 
• 
Change from baseline in relative levels of 
T lymphocyte suppression using micro 
suppression assay over Week 6 to Month 
24. Suppression activity may be further 
evaluated by adapting assay conditions 
possibly through adding and/or blocking 
of stimuli. 

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Section 2 OBJECTIVES ANS ENDPOINTS, Change to last row in table 
(footnote) 
PREVIOUS TEXT 
*Samples will be collected and only analysed after review of efficacy endpoints 
 
REVISED TEXT 
*Samples will be collected and only analysed after review of efficacy safety endpoints 
 
Section 6.2 Time and Events Tables (6.2.2 Dosing and Follow-Up), row 6 
amended 
PREVIOUS TEXT 
Telephone call to collect AEs, 
hypoglycemic and 
hyperglycemic events and 
concomitant 
 medication use 
X 
 
 
REVISED TEXT 
Telephone call to collect AEs, 
hypoglycemic and 
hyperglycemic events and 
concomitant 
 medication use 
X 
 
X 
 
Section 6.2 Time and Events Tables (6.2.2 Dosing and Follow-Up), footnote 
17 amended 
PREVIOUS TEXT 
Blood samples for exploratory biomarkers will only be collected at Month 24 if indicated 
based on Month 12 results 
REVISED TEXT 
Blood samples for exploratory biomarkers will only be collected analysed at Month 24 if 
indicated based on Month 12 results 

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Section 6.6.4 Exploratory Biomarkers 
PREVIOUS TEXT 
Blood samples for exploratory biomarkers will be collected at the time points indicated in 
the Time and Event Table (Section 6.2). Blood will be collected and processed for the 
following biomarkers and sample types. Exploratory samples will be collected and only 
analysed after review of efficacy endpoints. Month 24 blood samples for exploratory 
biomarkers will only be collected if indicated based on results from Month 12 biomarker 
analysis. Full details on sample collection, processing and shipment will be provided in 
the SPM/Quest manual 
 
Biomarker Assay 
Sample Type D -1  D6 M1.5M3 M6 M12 M24* 
CD8+ Multimer analysis 
PBMC 
X 
 
X 
X 
X 
X 
X 
Whole Blood Absolute Lymphocyte Count + 
CD3+ CD4+, CD3+ CD8+, CD19+ 
BCT CytoChex 
X 
 
X 
X 
X 
X 
X 
Antigen-specific ex vivo ELISPOT responses PBMC 
X 
 
X 
X 
X 
X 
X 
Demethylated FoxP3/CD3 analysis 
BD Vacutainer 
Plus 2mL 
lavender/EDTA 
with Hemogard 
– part number 
368841 
X 
 
X 
X 
X 
X 
X 
Exploratory Lymphocyte Sub-set phenotyping  
of CD3+ T (eg effector, memory, regulatory T 
cells using cell surface markers such as 
CD45RA, CCR7) and CD19+ B cells 
PBMC 
X 
 
X 
X 
X 
X 
X 
Auto-antibody (serum analyte) analysis 
Serum 
X 
 
X 
X 
X 
X 
X 
TCR deep sequencing  
PAXgene 
Blood RNA 
Tube 
X 
X1 
X 
X 
X 
X 
X 
Beta cell death biomarker analysis 
Serum 
X 
 
X 
X 
X 
X 
X 
T lymphocyte suppression assay 
PBMC 
X 
 
X 
X 
X 
X 
X 
1Sample taken pre-dose * Blood samples for exploratory biomarkers will only be 
collected at Month 24 if indicated based on Month 12 results 
REVISED TEXT 
Blood samples for exploratory biomarkers will be collected at the time points indicated in 
the Time and Event Table (Section 6.2). Blood will be collected and processed for the 
following biomarkers and sample types. Exploratory samples will be collected and only 
be analysed after review of efficacy safety endpoints. Month 24 blood samples for 
exploratory biomarkers will only be collected analysed if indicated based on results from 
Month 12 biomarker analyses. Full details on sample collection, processing and shipment 
will be provided in the SRPM/Q2 Solutions Quest manual Below is a table with details 

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on the exploratory biomarker assays under consideration to address the exploratory 
objectives and endpoints as outlined in Section 2. As new data emerge, it may also 
be possible to probe novel aspects of the biology of T1D, as well as the biological and 
clinical responses to otelixizumab. If relevant, this approach will be extended to 
include the identification of biomarkers associated with adverse events. 
Biomarker Assay 
Sample Type D -1  D6 M1.5M3 M6 M12 M24* 
CD8+ Multimer analysis 
PBMC 
X 
 
X 
X 
X 
X 
X 
Whole Blood Absolute Lymphocyte Count + 
CD3+ CD4+, CD3+ CD8+, CD19+ 
BCT CytoChex 
X 
 
X 
X 
X 
X 
X 
Antigen-specific ex vivo ELISPOT responses PBMC 
X 
 
X 
X 
X 
X 
X 
Demethylated FoxP3/CD3/Th17 analysis 
BD Vacutainer 
Plus 2mL 
lavender/EDTA 
with Hemogard 
– part number 
368841 
X 
 
X 
X 
X 
X 
X 
Exploratory Lymphocyte Sub-set phenotyping  
of CD3+ T (eg effector, memory, regulatory T 
cells using cell surface markers such as 
CD45RA, CCR7) and CD19+ B cells 
PBMC 
X 
 
X 
X 
X 
X 
X 
Auto-antibody (±serum analytes) analysis 
Serum 
X 
 
X 
X 
X 
X 
X 
TCR deep sequencing2  
PAXgene 
Blood RNA 
Tube 
X 
X1 
X 
X 
X 
X 
X 
Beta cell death biomarker analysis 
Serum 
X 
 
X 
X 
X 
X 
X 
T lymphocyte suppression assay 
PBMC 
X 
 
X 
X 
X 
X 
X 
1Sample taken pre-dose 
2 Similar additional transcriptomics analysis may be performed using micro-array 
and/or alternative equivalent technologies including RNA sequencing  
* Blood samples for exploratory biomarkers will only be collected analysed at Month 24 
if indicated based on Month 12 results 
9.3.1.3. Interim Analysis (12 Months) 
PREVIOUS TEXT 
A formal unblinded interim analysis is also planned to occur:  
• When all patients have completed 12 months study duration for cohorts 1 and 2, but 
may also include available data from subsequent cohorts 3 and 4 as appropriate.   
• The purpose of this interim analysis is to provide the project team and GSK 
stakeholders with key data to inform internal decision making, in order to plan future 
studies within the clinical development for the asset. 
• There are no planned implications for the conduct of the study. 

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• Appropriate data summaries will be at the treatment group level for key endpoints of 
interest and the circulation of results will be restricted to selected members of the 
project team and key GSK stakeholders. Results or discussions will not be circulated 
to staff involved in the conduct of the study at the sites.  
• Full details of planned interim analysis will be included in the reporting and analysis 
plan (RAP). 
REVISED TEXT 
9.3.1.3. Interim Analysies (12 Months) 
A fFormal unblinded interim analysies isare also planned: to occur:  
• The first interim will occur Wwhen all patients in cohorts 1 and 2 have completed 
12 months study duration for cohorts 1 and 2, but may also include any available data 
from subsequent cohorts 3 and 4 as appropriate.   
• The second interim will occur when all patients from the last fully enrolled 
cohort (i.e. not stopped due to safety / tolerability) have completed 12 months 
study duration. 
 
• The purpose of this these interim analysis analyses is to provide the project team and 
GSK stakeholders with key data to inform internal decision making, in order to plan 
future studies within the clinical development for the asset. 
• There are no planned implications for the conduct of the study. 
• Appropriate data summaries will be at the treatment group level for key endpoints of 
interest and the circulation of results will be restricted to selected members of the 
project team and key GSK stakeholders. Results or discussions will not be circulated 
to staff involved in the conduct of the study at the sites.  
• Full details of planned interim analysis analyses will be included in the reporting and 
analysis plan (RAP). 
9.3.8. Novel Biomarker(s) Analyses 
PREVIOUS TEXT 
The results of these biomarker investigations may be reported separately from the main 
clinical study report. All endpoints of interest from all comparisons will be descriptively 
and/or graphically summarized as appropriate to the data. 
Additional exploratory analyses may be performed to further characterize the novel 
biomarker 

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REVISED TEXT 
9.3.8. Novel Exploratory Biomarker(s) Analyses 
The results of these exploratory biomarker investigations may be reported separately 
from the main clinical study report. All endpoints of interest from all comparisons will be 
descriptively and/or graphically summarized as appropriate to the data. 
Additional exploratory analyses may be performed to further characterize the novel 
exploratory biomarker. 
AMENDMENT 5 
Where the Amendment Applies 
All sites 
SUMMARY OF AMENDMENT CHANGES WITH RATIONALE 
Further clarification around the assay for assessing screening EBV IgG and IgM was 
included to ensure patients are not excluded unnecessarily. The risk management table 
was also updated to reflect the changes. Exclusion criterion number 18 was split into two 
exclusion criteria (18 and 19) to clarify that a patient will not be eligible if they have a 
positive EBV capsid Ab IgM in absence of a positive EBV EBNA Ab IgG (exclusion 
criterion 18), EBV viral load of >10,000 copies per 106 peripheral blood mononuclear 
cells (PBMCs) as determined by quantitative polymerase chain reaction (qPCR) (exlusion 
criterion 19). A footnote was added to Table 6 (Stopping Criteria for CRS-Adverse 
Events) to add further clarification on individual dosing stopping criteria, i.e., to clarify 
that objective or subjective endpoints must be of different types during one 24 hour 
dosing period for any of the scenarios involving more than one endpoint. The dose 
preparation section was updated to clarify that an additional maximum of 30 minutes is 
allowed for dose preparation tasks such as connection of line and filter, pump set up and 
priming and purging the lines and that if 6 hours is exceeded, then the syringe and 
infusion materials (IV line, stopcock and PES filter) must be discarded and a new syringe 
of dose and infusion materials used. This is to ensure that the stability period is not 
exceeded. EBV serology to assess IgG and IgM was included at Day -1 in Table 6.2.2 of 
the Time and Event Tables (Dosing and Follow-Up) to provide a baseline against which 
follow up results may be compared.    

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LIST OF SPECIFIC CHANGES 
Section 3.4 Risk Management.Table 2 Summary of Key Issues, their Impact 
and Strategy to Mitigate Risk. Potential Risk column on Epstein-Barr virus 
(EBV), 3rd column Impact-Eligibility Criteria 
PREVIOUS TEXT 
Patients within 3 months of evidence of acute/active EBV infection (e.g Symptomatic, 
positive EBV IgM or EBV viral load of >10,000 copies per 106 lymphocytes) will not be 
enrolled in the study. 
REVISED TEXT 
Patients within 3 months of evidence of acute/active EBV infection (e.g)  
• Symptomatic 
• Positive EBV capsid Ab IgM in absence of a positive EBV EBNA Ab IgG  
• EBV viral load of >10,000 copies per 106 lymphocytes  
will not be enrolled in the study 
Section 4.2.2 Exclusion Criterion number 18 amended and split into 
exclusion criteria 18 and 19 
PREVIOUS TEXT 
18. Positive EBV IgM or EBV viral load of >10,000 copies per 106 peripheral blood 
mononuclear cells (PBMCs) as determined by quantitative polymerase chain reaction 
(qPCR). 
 
REVISED TEXT 
18. Positive EBV capsid Ab IgM in absence of a positive EBV EBNA Ab IgG 
19. EBV viral load of >10,000 copies per 106 peripheral blood mononuclear cells 
(PBMCs) as determined by quantitative polymerase chain reaction (qPCR). 
 
Section 5.3.1 Cytokine Release Syndrome Stopping Criteria 
 Footnote added under Table 6 Stopping Criteria for CRS-Adverse Events. 
Note: in order to meet individual stopping criteria, the reported objective or 
subjective endpoints must be of different types during one 24 hour dosing period for 
any of the scenarios involving more than one endpoint. 

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Section 5.6.2 Study Medication Preparation, the following new bullets were 
added under bullet 2 
 Important Note: When drawn into the syringe for administration to the 
patient it must be administered within 6 hours If needed an additional 
maximum of 30 minutes is allowed for tasks such as connection of line 
and filter, pump set up and priming and purging the lines. However, every 
attempt should be made not to exceed a total time of 6 hours if 
possible.  
 Important Note: If the infusion period will exceed 6 hours, then the 
syringe and  infusion materials (IV line, stopcock and PES filter) must be 
discarded and a new syringe of dose and infusion materials used. 
Preparation of syringes(s) must be recorded on the Test Article 
Administration Form. 
• The dose will be drawn from a fresh bag of 0.1 mg/mL Otelixizumab 
solution.  
• The pharmacist should allow sufficient time to prepare the final solution 
and must ensure that infusion components are changed at the appropriate 
times.  
• The temperature must be controlled and should not exceed 25°C.  
• The temperature will be recorded at the pharmacy (when the IV bag is 
ready to be transferred to the dosing unit) and at the dosing unit (upon 
receipt). 
Section 5.6.3 Study Medication Administration, additional text added to first 
bullet 
PREVIOUS TEXT 
Withdraw the total required volume of Otelixizumab Solution for Infusion, 0.1 mg/mL or 
0.9% Sodium Chloride for the placebo, using the syringe(s) that will be used for 
administration with the infusion pump.  
REVISED TEXT 
Withdraw the total required volume of Otelixizumab Solution for Infusion, 0.1 mg/mL or 
0.9% Sodium Chloride for the placebo, using the syringe(s) that will be used for 
administration with the infusion pump (see Section 5.6.2 regarding stability time and 
time allowed for preparation). 
Section 6.2.2 Dosing and Follow-up, row 16 amended to include EBV IgG 
and IgM sample at Day -1 
PREVIOUS TEXT 
EBV Serology  - IgG and IgM 7 
  
  
  
  
  
X 
X 
 
X 
X 
X 
X 
X 
  
X 
 
 

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REVISED TEXT 
EBV Serology  - IgG and IgM 7 
  
X 
  
  
  
  
X 
X 
 
X 
X 
X 
X 
X 
  
X 
 
AMENDMENT 4 
Where the Amendment Applies 
All sites 
SUMMARY OF AMENDMENT CHANGES WITH RATIONALE 
To increase flexibility for patients, dosing on Day 4, 5 & 6 may be performed on an out-
patient basis if the Investigator is satisfied with the clinical status of the patient. 
Clarification that the requirement to replace a withdrawn patient will be based on the 
reason for withdrawal and that patient assessments following withdrawal will include 
safety monitoring and may include pharmacodynamic measures if appropriate. Inclusion 
criteria # 3 was amended to remove the need for intensive insulin therapy and 3 insulin 
injections daily as this is considered unnecessary. Screen failure data are to be collected 
so that CONSORT publication requirements can be met. Clarified that i.v. infusion kits 
are supplied to sites due to the need for kits to be constructed of specific types of 
materials. Assessment of EBV reactivation will now be conducted at 6 weeks after the 
first active dose (reduced from 12 weeks) as this is considered a sufficient period for 
adequate monitoring. The blinding status was amended to clarify that only the patient is 
blinded to treatment and not site, CRO or sponsor staff. A requirement for pharmacy staff 
to document investigational product shipping conditions were within a 2-8°C range to 
ensure product quality was added. The use of an anti-emetic was added as a permitted 
concomitant medication to be used in the case of nausea and vomiting. A window of ± 
1 day was added to the Day 14 and 21 visits and Week 4 telephone call to increase 
flexibility for both the site and patient. Section 6.2.2 was amended to include a telephone 
phone call at Week 4 to discuss with the patient AEs, hyperglycaemic and hypoglycaemic 
events and concomitant medications to check for CRS symptoms; and addition of 
assessments at Week 6 to facilitate the checking of EBV reactivation following the 
reduction of the monitoring period from 12 to 6 weeks after the last patient in a cohort 
receives active treatment. The endpoints were amended to reflect the changes to Week 4 
and Week 6.  Section 6.2.3 was amended to include ECG at 3 hours as a safety check 
prior to discharge and to clarify that assessments (ECGs and vital signs) may stop at 3 
hours post dose if the patient is discharged, but may continue if the Investigator has any 
concerns about the clinical status of the patient. Clarification that it is not mandatory to 
measure fractionated bilirubin if total bilirubin is not above the normal range as this is 
considered unnecessary. Clarification that insulin is to be recorded for a week prior to 
outpatient visits and phone calls. Clarification that the grading of cytokine release 
syndrome adverse events in Section 7.1.5 is shown in Table 5 and subjective and 
objective endpoints related to stopping criteria are shown in Table 6. Clarification on 
CRO responsibilities included in several areas in Section 10.5 and Section 10.6. 
Appendix 5 amended to clarify that CRO/GSK will supply Ensure powder to ensure 
consistency across sites. 

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LIST OF SPECIFIC CHANGES 
Section 2. OBJECTIVES AND ENDPOINTS, change of period of assessment 
times (only endpoints with changes are shown below) 
PREVIOUS TEXT 
Primary Endpoints (Safety) 
• 
Incidence of adverse events (AEs) 
particularly those related to Cytokine 
release syndrome (CRS).  
• 
Epstein-Barr virus (EBV) reactivation over 
Months 1-24.  
• 
Changes in laboratory values, 
electrocardiograms (ECGs) and vital signs 
over Months 1- 24. 
Secondary Endpoints (Efficacy) 
• 
Change from baseline in mean daily insulin 
use over 7 consecutive days during the 
week preceding the visit over Day 14 and 
21 and Months 1-24.  
Exploratory Endpoints* 
• 
Change from baseline in absolute 
lymphocyte counts and subsets (CD3+ 
CD4+, CD3+ CD8+, and CD19+ cells) and 
phenotype (eg effector, memory, regulatory 
T cells, eg CD45RA, CCR7+) over Months 
1-24. 
• 
Change from baseline in demethylated 
FoxP3 expression in whole blood over 
Months 1-24. 
• 
Change from baseline in absolute numbers 
of HLA-A2-restricted CD8 T lymphocytes 
reactive to specific auto-antigens (by 
multimer) over Months 1-24. 
• 
Change from baseline in frequency of 
cytokine producing cells following in vitro 
stimulation with auto-antigens (by 
ELISPOT) over Months 1-24. 

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• 
Change from baseline in auto-antibody 
titres (using a panel of common auto-
antibodies associated with T1DM antigens 
and possibly other auto-antigens) and 
serum analytes (such as cytokines/ 
chemokines) over Months 1-24.  
• 
Change from baseline in T cell clonal 
repertoire by TCR deep sequencing over 
Months 1-24.  
• 
Change from baseline in serum by 
measuring relative levels of unmethylated 
INS DNA and/or other biomarkers for β-
cell death in serum over Month 1-24.  
• 
Change from baseline in relative levels of 
T lymphocyte suppression using micro 
suppression assay over Month 1- 24.  
 
REVISED TEXT 
Primary Endpoints (Safety) 
• 
Incidence of adverse events (AEs) 
particularly those related to Cytokine 
release syndrome (CRS).  
• 
Epstein-Barr virus (EBV) reactivation over 
Day 21 to Month 24.  
• 
Changes in laboratory values, 
electrocardiograms (ECGs) and vital signs 
over Day 14 to Month 24. 
 
Secondary Endpoints (Efficacy) 
• 
Change from baseline in mean daily insulin 
use over 7 consecutive days during the 
week preceding all visits and phone calls. 
 

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Exploratory Endpoints* 
• 
Change from baseline in absolute 
lymphocyte counts and subsets (CD3+ 
CD4+, CD3+ CD8+, and CD19+ cells) and 
phenotype (eg effector, memory, regulatory 
T cells, eg CD45RA, CCR7+) over Week 
6 to Month 24. 
• 
Change from baseline in demethylated 
FoxP3 expression in whole blood over 
Week 6 to Month 24. 
• 
Change from baseline in absolute numbers 
of HLA-A2-restricted CD8 T lymphocytes 
reactive to specific auto-antigens (by 
multimer) over Week 6 to Month 24. 
• 
Change from baseline in frequency of 
cytokine producing cells following in vitro 
stimulation with auto-antigens (by 
ELISPOT) over Week 6 to Month 24. 
• 
Change from baseline in auto-antibody 
titres (using a panel of common auto-
antibodies associated with T1DM antigens 
and possibly other auto-antigens) and 
serum analytes (such as cytokines/ 
chemokines) over Week 6 to Month 24.  
• 
Change from baseline in T cell clonal 
repertoire by TCR deep sequencing over 
Week 6 to Month 24.  
• 
Change from baseline in serum by 
measuring relative levels of unmethylated 
INS DNA and/or other biomarkers for β-
cell death in serum over Week 6 to Month 
24.  
• 
Change from baseline in relative levels of 
T lymphocyte suppression using micro 
suppression assay over Week 6 to Month 
24.  
 

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Section 3.1. Study Design Detail, paragraph 3 and 4  
PREVIOUS TEXT 
Patients will be dosed within approximately 28 days of diagnosis (not more than 
32 days). Insulin usage will be documented for approximately 7 days prior to Day -1. 
There will be a 7 – 21 day period from screening to admission to the clinic on Day -2 for 
the first overnight stay of the in-patient period, this time period will ensure appropriate 
time to review laboratory results prior to randomisation.  During the screening period 
total lymphocytes will be quantified on two occasions at least 3 days apart (one of the 
assessments may be performed on Day -1); lymphocytes must be confirmed as being 
within normal limits before administration of the first dose. All screening procedures are 
outlined in the Time and Events Table in Section 6.2. 
On Day -1 safety assessments will be performed as outlined in the Time and Events 
Table in Section 6.2. If the investigator is satisfied that the patient still meets the entry 
criteria they will be randomized to treatment and the hyperglycemic clamp procedure 
performed.  Dosing will start on Day 1 and patients will remain in the unit as an in-
patient for 6 days for intravenous dosing of otelixizumab. If the investigator is satisfied 
with the clinical condition of the patient, they will be discharged on Day 6 after 
completion of dosing and all study procedures. If the investigator considers additional 
safety monitoring is necessary, the patient will be asked to stay in the unit after Day 6 
until they are in a satisfactory condition to be discharged. CRS experienced from dosing 
to the resolution of symptoms and EBV clinical reactivation will be monitored in all the 
patients dosed and specific decision criteria will be used for dose escalation based on 
these assessments. 
REVISED TEXT 
Screening Period: Patients will be dosed within approximately 28 days of diagnosis (not 
more than 32 days). Insulin usage will be documented for approximately 7 days prior to 
Day -1. There will be a 7 – 21 day period from screening to admission to the clinic on 
Day -2 for the first overnight stay of the in-patient period, this time period will ensure 
appropriate time to review laboratory results prior to randomisation.  During the 
screening period total lymphocytes will be quantified on two occasions at least 3 days 
apart (one of the assessments may be performed on Day -1); lymphocytes must be 
confirmed as being within normal limits before administration of the first dose. All 
screening procedures are outlined in the Time and Events Table in Section 6.2. 
Pre-Treatment Period: On Day -1 safety assessments will be performed as outlined in 
the Time and Events Table in Section 6.2. If the investigator is satisfied that the patient 
still meets the entry criteria they will be randomized to treatment and the hyperglycemic 
clamp procedure performed.   
Treatment Period: Dosing will start on Day 1 and patients will remain in the unit as an 
in-patient for Days 1, 2 and 3 for intravenous dosing of study treatment.   
 

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Patients will be given the following flexible options for dosing on Days 4, 5 and 6: 
• Option 1:  Receive study treatment on an out-patient basis on any of Days 4, 5 or 
6, if the Investigator is satisfied with the clinical condition of the patient. For 
these patients, safety monitoring will continue up to a minimum of 3 hours post-
dose.  
• Option 2: Patients will remain in the unit if there are any concerns about their 
clinical status, or if the patient prefers to remain in the unit for logistical 
reasons.  Patients will be fully discharged from the hospital unit on Day 6 after 
completion of dosing and all study procedures. If the Investigator considers 
additional safety monitoring is necessary, the patient will be asked to stay in the 
unit after Day 6 until they are in a satisfactory condition to be discharged.  
CRS experienced from dosing to the resolution of symptoms and EBV clinical 
reactivation will be monitored in all the patients dosed and specific decision criteria will 
be used for dose escalation based on these assessments. 
Section 3.2 Figure 4 Study Visits Schematic, note added under figure 
Note: Dosing on Days 4-6 inclusive may be performed on an out-patient basis, if 
judged acceptable on the basis of clinical condition of the patient by the 
Investigator. 
Section 3.3.2 Dose Rationale, text added under Table 1 
If there is any need to reduce the infusion rate or temporarily stop the infusion, the 
Investigator should first consult with the Medical Monitor who will consult with the 
Sponsor.  However, the Investigator has the flexibility to reduce or temporarily stop 
the infusion immediately (with no prior consultation with the Medical Monitor), if 
there are any immediate safety/tolerability concerns. In this case the Investigator 
must inform the Medical Monitor as soon as possible after reducing or stopping the 
dosing. 
Section 3.4 Risk Management, Table 2 Summary of Key Issues, their impact 
and Strategy to Mitigate Risk. Column 4 Strategy-Monitoring/Stopping 
Criteria related to Cytokine Release Syndrome, 2nd bullet point 
PREVIOUS TEXT 
• 
Inpatient clinical observation; Patients will be in-house for the entire duration of the 
infusion (six days) and will be discharged only after Investigator clinical approval. The 
facilities will be located within a hospital with provision for Intensive Care facilities and with 
immediate access to resuscitation and emergency care.  
 

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REVISED TEXT 
• 
Inpatient clinical observation; at a minimum patients will be in-house for the first 3 days 
of the infusion period. Days 4, 5 & 6 may be on an out-patient basis with safety 
monitoring for at least 3 hours post dose. Patients will be discharged only after 
Investigator clinical approval. The facilities will be located within a hospital with provision 
for Intensive Care facilities and with immediate access to resuscitation and emergency care 
Section 4.1 Number of Subjects, 2nd paragraph 
PREVIOUS TEXT 
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment at the discretion of the Sponsor 
in consultation with the investigator. Replacement subject numbers will be assigned to 
the additional subjects. 
REVISED TEXT 
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment at the discretion of the Sponsor 
in consultation with the Investigator.  
The decision whether to replace the patient will be based on the reason for 
premature discontinuation (see Section 4.5 for further information). 
Replacement subject numbers will be assigned to the additional subjects. 
Section 4.2.1 Inclusion criteria #3 
PREVIOUS TEXT 
Currently requires insulin treatment for T1DM and has received intensive insulin therapy 
(at least three injections per day) for at least 7 days prior to screening. 
 
REVISED TEXT 
Currently requires insulin treatment for T1DM and has received intensive insulin therapy 
(at least three injections per day) for at least 7 days prior to screening. 

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Section 4.4 Screen and Baseline Failures 
PREVIOUS TEXT 
Data for screen and baseline failures will be collected in source documentation at the site 
but will not be transmitted to GSK. 
REVISED TEXT 
Screen failures are defined as subjects who consent to participate in the clinical trial 
but are never subsequently randomized. In order to ensure transparent reporting of 
screen failure data to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements, and respond to queries from Regulatory 
authorities, a minimal set of screen failure information is required including: 
 
• Demography,  
• Reason for screen failure,  
• Eligibility criteria,  
• Serious adverse events. 
 

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Section 4.5 Withdrawal Criteria and Procedures 
PREVIOUS TEXT 
A patient may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. Subjects who withdraw will be replaced to ensure that data on 40 
subjects are obtained.  Subjects that have received treatment and who withdraw should 
continue to undergo all safety assessments as per protocol if possible. The date of 
withdrawal must be recorded in the eCRF. 
Refer to Section 5.3.1 for dose adjustment/stopping criteria.  
Liver chemistry threshold stopping criteria have been designed to assure patient safety 
and to evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance). See Section 5.3.4 for details. 
REVISED TEXT 
A patient may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. Subjects who withdraw may be replaced to ensure that data on 40 
subjects are obtained.   
The decision on whether to replace the patient will be based on the reason for 
premature discontinuation, as described in Table 3. 
Table 3 
Patient replacement 
Patients will be 
replaced if: 
• The reason for withdrawal was not treatment related (e.g. 
patient withdrew consent for personal reasons). 
• Adverse event judged unrelated to treatment. 
Patients will not be 
replaced if: 
• There is a lack of tolerability to treatment. 
• Individual or group stopping criteria are met. 
• Significant changes in any of the safety assessments (e.g. 
ECG, vital signs, laboratory tests, etc). 
Decisions regarding patient replacement will be made in consultation with the 
Medical Monitor who will discuss with GSK. 
Subjects that have received treatment and who withdraw should continue to undergo all 
safety assessments as per protocol including PK sampling, if possible. However, efficacy 
(hyperglycaemic clamp and MMTT) pharmacodynamic (PD) assessments may not 
always be performed. The need to perform PD assessments will be agreed on a case-
by-case basis. The date of withdrawal must be recorded in the eCRF. If the patient 
agrees they will follow the original scheduled visit plan after withdrawal. 
Refer to Section 5.3.1 for dose adjustment/stopping criteria.  

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Liver chemistry threshold stopping criteria have been designed to assure patient safety 
and to evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance). See Section 5.3.4 for details. 
Section 5.1 Investigational Product and Other Study Treatment, row 4 in 
table - Route/Administration/Duration: 
PREVIOUS TEXT 
Route/ 
Administration/ 
Duration: 
Intravenous infusion via syringe 
pump; administration duration 
varies  
 
Intravenous infusion via syringe 
pump; administration duration varies  
 
REVISED TEXT 
Route/ 
Administration/ 
Duration: 
Intravenous infusion via syringe 
pump; using only the infusion 
kits supplied by CRO/GSK, 
administration duration varies  
 
Intravenous infusion via syringe 
pump; using only the infusion kits 
supplied by CRO/GSK, 
administration duration varies  
 
Section 5.2 Treatment Assignment 
PREVIOUS TEXT 
A description of each regimen is provided in Table 3 
REVISED TEXT 
A description of each regimen is provided in Table 4 
 
5.3 Patient Specific and Dose Escalation Stopping Criteria 
PREVIOUS TEXT 
Table 4 CRS AE Grading System 
Table 5 Stopping Criteria for CRS-Adverse Events 
Table 6 Parameters used to Assess EBV Reactivation 
Table 7 Assessment of EBV Reactivation 

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REVISED TEXT 
Table 5 CRS AE Grading System 
Table 6 Stopping Criteria for CRS-Adverse Events 
Table 7 Parameters used to Assess EBV Reactivation 
Table 8 Assessment of EBV Reactivation 
PREVIOUS TEXT 
Table 7 shows the possible combinations of the three EBV parameters that will be used to 
assess whether the patient has clinical EBV reactivation for the purpose of the stopping 
criteria. The assessment will be conducted for each subject at approximately 12 weeks 
post dose. 
 
REVISED TEXT 
Table 8 shows the possible combinations of the three EBV parameters that will be used to 
assess whether the patient has clinical EBV reactivation for the purpose of the stopping 
criteria. The assessment will be conducted for each subject at approximately 6 weeks post 
first active dose. 
 
Figure 5 Dose Escalation Schematic, top section of figure 
PREVIOUS TEXT 
Collate Information at 
Week 12 
Cohort X 
Otelixizumab (n=8) 
 
REVISED TEXT 
Collate Information at 
Week 6 
Cohort X 
Otelixizumab (n=8) 
 

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5.4 Blinding 
PREVIOUS TEXT 
This will be a single blind study.  The patients will not be aware of the treatment they 
receive. In addition, some site staff will also be blinded, i.e. the study nurse or other 
member(s) of the clinical team who will administer the infusion and assess the patient for 
CRS and EBV symptoms and other AEs. The Diabetologist or Physician/Designee 
responsible for following up the management of the patient will also be blinded across 
the duration of the study. Unblinded personnel include the Pharmacist when preparing the 
dose for infusion; the Investigator to enable ongoing assessment and overview of patient 
safety; the Medical Monitor (CRO and GSK) and members of the GSK team who will 
review data at dose escalation meetings. See Table 8.  
Table 8 
Summary of blinding status of personnel 
Role 
Blinded 
GSK & CRO Medical Monitor 
N 
Therapeutic Area Representative 
N 
Study Operations Scientist 
N 
GCSP Representative 
N 
Pharmacokineticist 
N 
Data Manager 
N 
Statistician 
N 
Programmer(s) 
N 
Investigator 
N 
Site Pharmacist 
N 
Diabetologist and or physician assessing the patients during follow-up 
Y 
All Other Clinical Site Staff (e.g. infusion administration, AE assessment) 
Y 
CRO study Manager 
N 
Site Monitors 
Y 
Pharmacy Monitors 
N 
 
REVISED TEXT 
This will be a single blind study where the patients will not be aware of the treatment 
they receive. All staff including site personnel, CRO and sponsor team members will 
be unblinded. However, the randomisation code will be restricted to the pharmacist 
preparing the infusions In addition, some site staff will also be blinded, i.e. the study 
nurse or other member(s) of the clinical team who will administer the infusion and assess 
the patient for CRS and EBV symptoms and other AEs. The Diabetologist or 
Physician/Designee responsible for following up the management of the patient will also 
be blinded across the duration of the study. Unblinded personnel include the Pharmacist 
when preparing the dose for infusion; the Investigator to enable ongoing assessment and 
overview of patient safety; the Medical Monitor (CRO and GSK) and members of the 
GSK team who will review data at dose escalation meetings. See Table 8. 

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Table 8 
Summary of blinding status of personnel 
Role 
Blinded 
GSK & CRO Medical Monitor 
N 
Therapeutic Area Representative 
N 
Study Operations Scientist 
N 
GCSP Representative 
N 
Pharmacokineticist 
N 
Data Manager 
N 
Statistician 
N 
Programmer(s) 
N 
Investigator 
N 
Site Pharmacist 
N 
Diabetologist and or physician assessing the patients during follow-up 
Y 
All Other Clinical Site Staff (e.g. infusion administration, AE assessment) 
Y 
CRO study Manager 
N 
Site Monitors 
Y 
Pharmacy Monitors 
N 
 
Section 5.6 Preparation/Handling/Storage/Accountability, 3rd paragraph, 
3rd sentence 
PREVIOUS TEXT 
The responsible person(s) will document the amount of study medication received from 
GSK and destroyed at end of study and the amount administered to subjects.   
REVISED TEXT 
The responsible person(s) will document the amount of study medication received from 
GSK, document that it was shipped at 2-8°C by checking the temperature monitor, 
document the amount destroyed at end of study and the amount administered to 
subjects.   
Section 5.6.3 Study Medication Administration, text added at end of section 
If there is any need to reduce the infusion rate or temporarily stop the infusion, the 
Investigator should first consult with the Medical Monitor who will consult with the 
Sponsor.  However, the Investigator has the flexibility to reduce or temporarily stop 
the infusion immediately (with no prior consultation with the Medical Monitor), if 
there are any immediate safety/tolerability concerns. In this case the Investigator 
must inform the Medical Monitor as soon as possible after reducing or stopping the 
dosing. 

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Section 5.10.1.2 Treatment, 1st paragraph 
PREVIOUS TEXT 
If cytokine release symptoms persist despite the prophylactic treatment, additional 
treatment may be given at the discretion of the investigator, including more potent 
analgesics (e.g., opioids, such as acetaminophen with codeine, and/or triptans, for 
headache.  
REVISED TEXT 
If cytokine release symptoms persist despite the prophylactic treatment, additional 
treatment may be given at the discretion of the investigator, including more potent 
analgesics (e.g., opioids, such as acetaminophen with codeine, and/or triptans, for 
headache. An anti-emetic such as ondansetron may be given for nausea and/or 
vomiting). 
Section 6.1 Visit Windows, 1st and 2nd bullet points 
PREVIOUS TEXT 
• No windows are permitted up to and including the Day 21 visit 
• Visits from Month 1 to Month 3 inclusive are permitted a ± 3 day window 
REVISED TEXT 
• A ± 1 day window is permitted for the Day 14 and Day 21 visits and Week 4 
telephone call 
• Visits from Week 6 to Month 3 inclusive are permitted a ± 3 day window 
Section 6.2.2 Dosing and Follow-up, assessment time changed from Month 
1 to Week 4 and Week 6 
PREVIOUS TEXT 
  
  
  
Day 
Month 
  
-2 
-1 
1 
2 3 
4 
5 6 
14 
21 
1  
2 
3 6 9 
12 
18 
24 
36, 48 
& 60# 
 
REVISED TEXT 
 
  
  
Day 
Month 
 
-2 
-1 
1 
2 
3 
4 
5 6 
14 
21 
Week 4 Week 6 2 3 6 9 12 
18 
2
4 
36, 48 & 
60# 
 

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Section 6.2.2 Dosing and Follow-up, row 2 of table and footnote 2 
PREVIOUS TEXT 
In Patient 
  
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
  
 
2. Discharged on Day 6 if health considered satisfactory by the investigator.  
 
REVISED TEXT 
In Patient 
  
X 
X 
X 
X 
X2 
X2 
X2 
  
  
  
  
  
  
  
  
  
  
 
2. Discharged on Day 6 if health considered satisfactory by the investigator. Dosing Day 4-6 may be performed on out-patient basis (see Section 3.1) 
 
Following row added (6th row) 
  
  
  
Day 
Month 
  
-
2 
-
1 
1 2 3 4 5 6 
1
4 
2
1 
Wee
k 4  
We
ek 
6 
2 3 6 9 
1
2 
1
8 
2
4 
36, 48 & 
60# 
Telephone call to collect AEs, hypoglycaemic and hyperglycaemic events 
and concomitant medication use 
X 
 
 
 

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Section 6.2.2 Dosing and Follow-up, row 19 
PREVIOUS TEXT 
Record insulin usage for 7 days before visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
REVISED TEXT 
Record insulin usage for 7 days before visit / call 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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6.2.3 Detail for Vitals, ECG and Pharmacokinetic and Pharmacodynamic Monitoring over the Infusion Period 
(Cohorts 1-4), Day 4, 5 and 6 
PREVIOUS TEXT 
Day 
Cohort 
Assessment 
Pre Dose 
0 H 
30 M 
1 H 
2 H 
3 H 
4 H 
5 H 
6 H 
7 H 
8 H 
9 H 
10 H 
11 H 
12 H 
13 H 
14 H 
15 H 
16 H 
4 
C1-C4 
Dosing 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vitals1,2 
X 
X 
  
X 
X 
X 
X 
X 
  
  
X 
  
  
  
X 
  
  
  
X 
ECG 
X 
  
  
X 
  
  
  
  
 X 
  
  
  
  
  
  
  
  
  
  
PK/CD3 Saturation 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
5 
C1-C4 
Dosing 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vitals1,2 
X 
X 
  
X 
X 
X 
X 
X 
  
  
X 
  
  
  
X 
  
  
  
X 
ECG 
X 
  
  
X 
  
  
  
  
 X 
  
  
  
  
  
  
  
  
  
  
PK/CD3 Saturation 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6 
C1-C4 
Dosing 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vitals1,2 
X 
X 
  
X 
X 
X 
X 
  
  
  
  
  
  
  
  
ECG 
X 
  
  
X 
  
  
  
  
 X 
  
  
  
  
  
  
  
  
  
  
PK/CD3 Saturation 
X 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
1. Blood pressure to be taken in triplicate at Pre-dose 
2.  Vitals to be repeated at 30 min intervals should there be any safety concern 

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REVISED TEXT 
Day 
Cohort 
Assessment 
Pre Dose 
0 H 
30 M 
1 H 
2 H 
3 H 
4 H 
5 H 
6 H 
7 H 
8 H 
9 H 
10 H 
11 H 
12 H 
13 H 
14 H 
15 H 
16 H 
4 
C1-C4 
Dosing 
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vitals1,2 
X 
X 
  
X 
X 
X3 
ECG 
X 
  
  
X 
  
 X3 
PK/CD3 Saturation 
X 
  
  
  
5 
C1-C4 
Dosing 
  
  
 
  
 
  
Vitals1,2 
X 
X 
  
X 
X 
X3 
ECG 
X 
  
  
X 
  
 X3 
PK/CD3 Saturation 
X 
  
  
6 
C1-C4 
Dosing 
  
  
 
  
 
  
Vitals1,2 
X 
X 
  
X 
X 
X3 
ECG 
X 
  
  
X 
  
 X3 
PK/CD3 Saturation 
X 
  
  
X 
  
  
  
1. Blood pressure to be taken in triplicate at Pre-dose 
2.  Vitals to be repeated at 30 min intervals should there be any safety concern 
3. If patients are dosed on an out-patient basis on Day 4, 5 and 6, vital signs and ECGs will stop after the 3 hour post dose timepoint (if the Investigator is satisfied with 
the clinical status of the patient), if there are any concerns then vital signs and ECGs may be continued as judged necessary by the investigator until the investigator 
is satisfied 
 

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6.4.4.2 Clinical Chemistry, footnote added 
• It is not mandatory to measure fractionated bilirubin if total bilirubin is not 
above the normal range. 
6.7.3. Daily Insulin Use, 1st sentence 
PREVIOUS TEXT 
Patients will be asked to record their daily insulin usage thoroughly and accurately for 
7 consecutive days in a diary during the week before all outpatient visits, ie, at Baseline, 
Day 14 and 21, and Months 1, 2, 3, 6, 9, 12, 18, and 24, and before each telephone call in 
the long term follow-up period (Month 36, 48 and 60). Information on insulin usage will 
be transcribed from diaries into the eCRF. 
REVISED TEXT 
Patients will be asked to record their daily insulin usage thoroughly and accurately for 
7 consecutive days in a diary during the week before all outpatient visits or phone calls, 
ie, at Baseline, Day 14 and 21, Week 4 and 6 and Months 1, 2, 3, 6, 9, 12, 18, and 24, 
and before each telephone call in the long term follow-up period (Month 36, 48 and 60). 
Information on insulin usage will be transcribed from diaries into the eCRF. 
Section 7.1.5 Cytokine Release Syndrome Adverse Events 
PREVIOUS TEXT 
CRS is a well-known consequence of anti-CD3 therapy when administered via 
intravenous injection or infusion and therefore any CRS AEs experienced during the 
dosing period will be assessed against the grading system shown in Table 4 and Table 5. 
This grading system has been developed using NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v.4 (Table 5) by selecting AEs that are specifically thought to 
be associated with cytokine release syndrome. 
REVISED TEXT 
CRS is a well-known consequence of anti-CD3 therapy when administered via 
intravenous injection or infusion and therefore any CRS AEs experienced during the 
dosing period will be assessed against the grading system shown in Table 5. and Table 6. 
This grading system has been developed using NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v.4 (Table 5) by selecting AEs that are specifically thought to 
be associated with cytokine release syndrome. Pre-specified CRS individual patient 
and study dosing stopping criteria are shown in Table 6. The symptoms in Table 6 
have been classified as objective and subjective endpoints as follows: 
• Objective Endpoints: Fever, Diarrhoea, Vomiting, Hypotension 
• Subjective Endpoints: Headache, Chills, Nausea, Arthralgia, Myalgia 

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Section 9.3.1.2 Dose Escalation, 1st and 2nd bullet points 
PREVIOUS TEXT 
• Data will be reviewed after 10 patients have been dosed in cohort 1 (8 patients on 
otelixizumab 9 mg and 2 patients on placebo) and have completed approximately 12 
weeks of the study and required data is available.  
• If required, data reviews prior to 12 weeks may also be conducted to facilitate dose 
escalation to the next cohort. 
REVISED TEXT 
• Data will be reviewed after 10 patients have been dosed in cohort 1 (8 patients on 
otelixizumab 9 mg and 2 patients on placebo) and have completed approximately 6 
weeks of the study after the first active dose, and required data is available.  
• If required, data reviews prior to 6 weeks may also be conducted to facilitate dose 
escalation to the next cohort. 
Section 10.5 and Section 10.6 
CRO added as jointly responsible with Sponsor for activities 
 
Appendix 5: Mixed Meal Tolerance Test (MMTT), 5th paragraph, 1st sentence 
PREVIOUS TEXT 
When both unstimulated and Mixed Meal stimulated C-peptide analysis should be done, 
each subject will consume a standardized amount of Ensure Powder (Abbott) drink.  
REVISED TEXT 
When both unstimulated and Mixed Meal stimulated C-peptide analysis should be done, 
each subject will consume a standardized amount of Ensure Powder (Abbott) drink 
supplied by the CRO/GSK. 
Footnote added under table of Weight and volume 
Please see the SPM for further details regarding volumes 
 

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AMENDMENT 3 
Where the Amendment Applies 
All sites 
Summary of Amendment Changes with Rationale 
The third medical monitor had changed, the contact details were therefore updated.  
It was not clear that staggering the start of treatment by three days across each centre only 
applies to the first three patients in a cohort, as stated in the SPM. 
The eligibility inclusion criterion number 4 was changed from positive for at least two 
autoantibodies associated with T1DM to positive for at least one autoantibody. The 
rationale for this change is that two positive antibodies are only relevant when excluding 
LADA (also referred to as latent autoimmune diabetes in adults), typically manifesting 
around the age of 40. However, in this study the target population is between 16-27 years 
old and is insulin dependent at the time of recruitment, thus the need to show two positive 
autoantibodies is not scientifically relevant and was included in error. This proposed 
modification of the eligibility criteria does not have any impact on the safety of the 
patients. 
List of Specific Changes 
Sponsor/medical monitor Information Page 
Medical Monitor and Sponsor Contact Information (third row): 
PREVIOUS TEXT 
Third 
Medical 
Monitor 
(GSK) 
Experimental Medicine 
Unit, Immuno-
inflammation Therapy 
Unit 
GlaxoSmithKline 
Medicines  
Stevenage Hertfordshire  
SG1 2NY, UK 
PPD

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REVISED TEXT 
Third 
Medical 
Monitor 
(GSK) 
Experimental Medicine 
Unit, Immuno-
inflammation Therapy 
Unit 
GlaxoSmithKline 
Medicines  
Stevenage Hertfordshire  
SG1 2NY, UK 
 
Section 3.1. Study Design Detail, paragraph 5 
PREVIOUS TEXT 
Within each cohort administration of study treatment will be staggered by at least three 
days across each centre. 
REVISED TEXT 
Within each cohort administration of study treatment for the first three patients will be 
staggered by at least three days across each centre. 
 
Section 4.2.1. Inclusion Criteria 
PREVIOUS TEXT 
4. Positive for at least two of the following autoantibodies associated with T1DM: 
antibody to glutamic acid decarboxylase (anti GAD), antibody to protein 
tyrosine phosphatase-like protein (anti IA 2), antibody to islet-cell antigen 
(ICA) or ZnT8 Autoantibody. 
 
REVISED TEXT 
4. Positive for at least two of the following autoantibodies one autoantibody 
associated with T1DM: antibody to glutamic acid decarboxylase (anti GAD), 
antibody to protein tyrosine phosphatase-like protein (anti IA 2), antibody to 
islet-cell antigen (ICA) or ZnT8 Autoantibody. 
 
PPD

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AMENDMENT 2 
Where the Amendment Applies 
All sites 
Summary of Amendment Changes with Rationale 
Hyperglycaemic events included as a follow up endpoint and in the time and events table 
for consistency with the secondary efficacy endpoints for Month 1 – 24. 
Information for the screening syphilis test was updated because the laboratory performing 
the test has changed in order to provide faster analysis, therefore the wording Immuno-
Assay was removed as this is not the procedure followed by the site that will now 
perform the test.  
The volume of dose preparation required to prime/purge the IV infusion line was 
increased from 6mLs to approximately 8mLs. The increase in overage is required for the  
effective and complete delivery of the planned dose to the patient, as during the first 
infusion the pump was not able to administer the last 1mL of  the planned infusion.  
The time period for collecting AE and SAE information was clarified by removing 
reference to collecting medical history. 
List of Specific Changes 
Section 2 OBJECTIVES AND ENDPOINTS: Follow up Endpoints (Data 
collected at Month 36, 48 & 60 if Available) 
PREVIOUS TEXT 
Follow up Objectives  
Follow up Endpoints (Data Collected at 
Month 36, 48 & 60 if Available) 
• To assess long term safety follow-up 
with otelixizumab treatment. 
• 
Significant adverse events.  
• 
Severe (as per ADA classification, 
Appendix 7) hypoglycemic events which 
occurred between Months 24 up to 60.   
• 
Mean daily insulin use over 7 consecutive 
days preceding the call.  
• 
HbA1c results around time of the phone 
call. 
 

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REVISED TEXT 
Follow up Objectives 
Follow up Endpoints (Data Collected at 
Month 36, 48 & 60 if Available) 
• To assess long term safety follow-up 
with otelixizumab treatment. 
• 
Significant adverse events.  
• 
Severe (as per ADA classification, 
Appendix 7) hypoglycemic events which 
occurred between Months 24 up to 60.   
• 
Severe hyperglycemic events which 
occurred between Months 24 up to 60. 
• 
Mean daily insulin use over 7 consecutive 
days preceding the call.  
• 
HbA1c results around time of the phone 
call. 
 
Section 4.2.2 Exclusion Criteria, bullet point number 20 
PREVIOUS TEXT 
20. A positive result on an Immuno-Assay test for syphilis; and, if result of Immuno-
assay test is positive, then a confirmatory test will be performed. 
 
REVISED TEXT 
20. A positive result on an Immuno-Assay a test for syphilis; and if result of Immuno-
Assay the first test is positive, then a confirmatory test using another method 
will be performed. 
 
Section 5.6.2 Study Medication Preparation, 3rd bullet point 
PREVIOUS TEXT 
The required volume of Otelixizumab Solution for Infusion, 0.1 mg/mL (varies 
depending on target dose and includes an excess 6 mL volume to account for prime/ 
purge) must be withdrawn into an suitable size polypropylene syringe as close to the time 
of the start of the infusion as possible, to ensure product quality.  
REVISED TEXT 
The required volume of Otelixizumab Solution for Infusion, 0.1 mg/mL (varies 
depending on target dose) and includes an excess of approximately 8 mL volume to 

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account for prime/purge (6 mLs – see Section 5.6.3) plus an additional 2 mLs (or more 
if required) as an overage volume required for the syringe pump to deliver the exact 
volume to the patient as specified in Table 9 column 7. The additional overage must 
not be administered to the patient. The required volume must be withdrawn into a 
suitable size polypropylene syringe as close to the time of the start of the infusion as 
possible, to ensure product quality. 
Section 5.6.2 Study Medication Preparation, Table 9 Study Medication Dose 
Preparation, table header, column 8 
PREVIOUS TEXT 
Total Vol. Filled into Syringe, Includes 6 mL Fill Overage (Vol. not Infused) 
 
REVISED TEXT 
Total Vol. Filled into Syringe, Includes approximately 8 mL Fill Overage (Vol. not 
Infused) 
Section 5.6.2 Study Medication Preparation, Table 9 Study Medication Dose 
Preparation, change of total volume filled into syringe in column 8 and 
footnote added under table 
 
PREVIOUS TEXT 
Table 9 
Study Medication Dose Preparation 
Treat-
ment 
Regimen 
(cohort) 
Cumul-
ative 
Dose 
(mg) 
Dose 
per day 
(mg) 
Day of 
Dosing 
Period 
of 
Dosing 
(hours) 
# of 
Syringes 
Total Dosing 
Solution 
Volume to be 
Infused 
Total Vol. Filled into 
Syringe, Includes  
6 mL Fill Overage 
(Vol. not Infused) 
A (1) 
9 
1.5 
Day 1 
9 
2 
15 mL 
(7.5 mL x 2 
syringes)  
13.5 mL x 2 syringes 
Day 2 
6 
1 
15 mL 
21 mL 
Day 3 
3 
1 
15 mL 
21 mL 
Day 4-6 
1 
1 
15 mL 
21 mL 
B (2) 
18 
3 
Day 1 
12 
2 
30 mL (15 mL 
x 2 syringes) 
21 mL x 2 syringes 
Day 2 
6 
1 
30 mL 
36 mL 

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Treat-
ment 
Regimen 
(cohort) 
Cumul-
ative 
Dose 
(mg) 
Dose 
per day 
(mg) 
Day of 
Dosing 
Period 
of 
Dosing 
(hours) 
# of 
Syringes 
Total Dosing 
Solution 
Volume to be 
Infused 
Total Vol. Filled into 
Syringe, Includes  
6 mL Fill Overage 
(Vol. not Infused) 
Day 3 
3 
1 
30 mL 
36 mL 
Day 4-6 
1 
1 
30 mL 
36 mL 
C (3) 
27 
4.5 
Day 1 
12 
2 
45 mL 
(22.5 mL x 2 
syringes) 
28.5 mL x 2 syringes 
Day 2 
6 
1 
45 mL 
51 mL 
Day 3 
3 
1 
45 mL 
51 mL 
Day 4-6 
1 
1 
45 mL 
51 mL 
D (4) 
36 
6 
Day 1 
12 
2 
60 mL (30 mL 
x 2 syringes) 
36 mL x 2 syringes 
Day 2 
6 
2 
60 mL (30 mL 
x 2 syringes) 
36 mL x 2 syringes 
Day 3 
3 
2 
60 mL (30 mL 
x 2 syringes) 
36 mL x 2 syringes  
Day 4-6 
1 
2 
60 mL (30 mL 
x 2 syringes) 
36 mL x 2 syringes  
P 
0 
0 
0.9% w/v sodium chloride administered by intravenous infusion in the same 
manner as the active by study personnel following specified regimens 
 

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REVISED TEXT 
 
Table 9 
Study Medication Dose Preparation 
Treat-
ment 
Regimen 
(cohort) 
Cumul-
ative 
Dose 
(mg) 
Dose 
per day 
(mg) 
Day of 
Dosing 
Period 
of 
Dosing 
(hours) 
# of 
Syringes 
Total Dosing 
Solution 
Volume to be 
Infused 
Total Vol. Filled into 
Syringe, Includes  
Approximately 
*8 mL Fill Overage 
(Vol. not Infused) 
A (1) 
9 
1.5 
Day 1 
9 
2 
15 mL 
(7.5 mL x 2 
syringes)  
*15.5 mL x 2 syringes 
Day 2 
6 
1 
15 mL 
*23 mL 
Day 3 
3 
1 
15 mL 
*23 mL 
Day 4-6 
1 
1 
15 mL 
*23 mL 
B (2) 
18 
3 
Day 1 
12 
2 
30 mL (15 mL 
x 2 syringes) 
*23 mL x 2 syringes 
Day 2 
6 
1 
30 mL 
*38 mL 
Day 3 
3 
1 
30 mL 
*38 mL 
Day 4-6 
1 
1 
30 mL 
*38 mL 
C (3) 
27 
4.5 
Day 1 
12 
2 
45 mL 
(22.5 mL x 2 
syringes) 
*30.5 mL x 2 syringes 
Day 2 
6 
1 
45 mL 
*53 mL 
Day 3 
3 
1 
45 mL 
*53 mL 
Day 4-6 
1 
1 
45 mL 
*53 mL 
D (4) 
36 
6 
Day 1 
12 
2 
60 mL (30 mL 
x 2 syringes) 
*38 mL x 2 syringes 
Day 2 
6 
2 
60 mL (30 mL 
x 2 syringes) 
*38 mL x 2 syringes 
Day 3 
3 
2 
60 mL (30 mL 
x 2 syringes) 
*38 mL x 2 syringes  
Day 4-6 
1 
2 
60 mL (30 mL 
x 2 syringes) 
*38 mL x 2 syringes  
P 
0 
0 
0.9% w/v sodium chloride administered by intravenous infusion in the same 
manner as the active by study personnel following specified regimens 
*Overage volume may be adjusted to ensure optimal efficiency of syringe pump to 
deliver the exact dosing volume to be infused. Note the overage volume must NOT 
be delivered to the patient but remain in the syringe and discarded. 

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Section 5.6.3 Study Medication Administration, 3rd bullet point 
PREVIOUS TEXT 
The prime volume of the intravenous line and filter must not exceed a total of 3 mL.  The 
6 mL excess solution in the syringe(s) must be primed/purged (3 mL to waste, about 
3 mL fills the IV line); target a priming/purging rate of 1 mL/min or lower.  Purging 3 ml 
to waste is required to account for protein loss due to binding and to ensure that the full 
dose is administered. 
REVISED TEXT 
The prime volume of the intravenous line and filter must not exceed a total of 3 mL.  The 
approximate 8 mL excess solution in the syringe(s) must be primed/purged (3 mL to 
waste, about 3 mL fills the IV line); target a priming/purging rate of 1 mL/min or lower.  
Purging 3 ml to waste is required to account for protein loss due to binding and to ensure 
that the full dose is administered. The additional 2 mLs (or more if required) should 
remain as overage in the syringe and must not be administered to the patient. 
Table 6.2.2 Dosing and Follow-Up, 22nd row, addition of hyperglycaemic 
events  
 
PREVIOUS TEXT 
 
Hypoglycemic Events 
<----------------------------------------------------------------------------------> 
 
REVISED TEXT 
 
Hypoglycaemic / Hyperglycaemic Events 
<----------------------------------------------------------------------------------> 
 
Table 6.2.2 Dosing and Follow-Up, main footnote under table 
 
PREVIOUS TEXT 
 
#Patients will record insulin usage for 7 days prior to out-patient visits (up to Month 24) 
and before phone calls in Month 36, 48 and 60.  Significant AEs including 
hypoglycaemic events will be recorded in a diary whenever they occur, to include start 
and stop dates. 
REVISED TEXT 
 
#Patients will record insulin usage for 7 days prior to out-patient visits (up to Month 24) 
and before phone calls in Month 36, 48 and 60.  Significant AEs including 
hypoglycaemic (≤3.9 mmol/L; ≤70 mg dL) and hyperglycaemic (>13.9 mmol/L; >250 
mg/dL) events will be recorded in a diary whenever they occur, to include start and stop 
dates. 

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Section 7.1.1 Time Period for Collecting AE and SAE Information, 1st 
paragraph, 2nd sentence removed 
PREVIOUS TEXT 
AEs will be collected from signing the Informed Consent Form until the follow-up 
contact, approximately 5 years post last dose.  Medical occurrences that begin prior to the 
start of study treatment but after obtaining informed consent may be recorded on the 
Medical History/Current Medical Conditions eCRF. 
 
REVISED TEXT 
 
AEs will be collected from signing the Informed Consent Form until the follow-up 
contact, approximately 5 years post last dose.  Medical occurrences that begin prior to the 
start of study treatment but after obtaining informed consent may be recorded on the 
Medical History/Current Medical Conditions eCRF. 
Appendix 7 – Alert value for hyperglycaemia added as footnote under ADA 
classification table 
REVISED TEXT 
Alert Value for Hyperglycemia: >13.9 mmol/L; >250 mg/dL 

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AMENDMENT 1 
Where the Amendment Applies 
All sites 
Summary of Amendment Changes with Rationale 
An unblinded pharmacy monitor will check study drug records and this was clarified in 
Table 8. Reference to TCR complexes removed and CD3 requirements clarified 
throughout the protocol because terminology used was inaccurate; only CD3 saturation 
will be determined and not TCR. The time period for collecting information for the 
screening to start of dosing period was revised to improve logistics. The volume of dose 
preparation required to prime/purge the IV infusion line was changed from 5 mLs to 
6 mLs (3 mL to waste, about 3 mL fills the IV line - increased from 2 mLs) and the total 
volume filled into syringes was amended to reflect the change in prime/purge volume; 
and the word “micropore” was removed from the description of the IV line. The reason 
for these changes is because a different type of infusion line was sourced with a slightly 
longer line to fill. Insulin will be recorded for 7 days before each outpatient visit, this was 
not clear in the original protocol Objectives and Endpoints table, Time and Events Table 
(Section 6.2.2) or Section 6.7.3 Daily Insulin Use. Footnote 13 of the Time and Events 
Table (Section 6.2.2) was amended to clarify that glucose will be measured in addition to 
C-peptide during the hyperglycaemic clamp procedure because this is required to gain a 
full understanding. Secondary endpoints were updated in Section 2 to clarify that glucose 
will be measured along with C-peptide during the MMTT and clamp procedures. A typo 
was corrected on footnote 18 of the Time and Events Table (Section 6.2.2) as Day 6 was 
added. In Section 6.2.3 (details for vitals, ECG, PK and PD Monitoring over the infusion 
period (cohorts 1-4)) it was clarified that ECG will be measured 6 hours after the start of 
infusion to be consistent with footnote 4 of Section 6.2.2.  Section 6.4.3 was updated to 
clarify when triplicate and single ECGs will be collected as this was not clear in the 
original protocol. In Section 6.4.4 Exploratory Biomarkers, it was clarified that TCR deep 
sequencing will also be performed at Month 24, this was missed in error from the table 
listing biomarker analyses in the original protocol. Section 6.7.1 was amended to clarify 
that MMTT will be at least 7 days before the first dose of study medication for 
consistency with the table in Section 6.2.1. Appendix 5 was updated as it was 
subsequently decided when discussing logistics that c-peptide and glucose samples will 
be shipped frozen within 3 weeks of collection, and not 2 weeks. Appendix 6 was 
updated to clarify that the hyperglycaemic range of 180-240mg/dL is during 140 minutes 
(not 180 minutes) for consistency with blood sampling time points. 

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List of Specific Changes 
Section 2 OBJECTIVES AND ENDPOINTS, 1st, 2nd and 3rd row under 
Secondary Objectives and Endpoints (Efficacy) 
PREVIOUS TEXT 
Secondary Objectives (Efficacy) 
Secondary Endpoints (Efficacy) 
• 
To assess the effect of a single course of 
otelixizumab treatment on the rate of 
decline of pancreatic β-cell function over 
24 months in NOT1DM patients.  
• 
Change from baseline in C-peptide AUC 
(0-120) after a Mixed Meal Tolerance Test  
at Month 3, 6, 12, 18 and 24. 
 
• 
To assess the effect of a single course of 
otelixizumab treatment on the rate of 
decline of C-peptide response and insulin 
sensitivity of β-cell function determined 
after a hyperglycemic clamp over 24 
months in NOT1DM patients. 
• 
Change from baseline in C-Peptide AUC 
hyperglycemic phase [H60 to H140 
minutes] and insulin sensitivity (IS) index 
after a hyperglycemic clamp at Months 6 
and 24.  
 
• 
To assess the effect of a single course of 
otelixizumab treatment on exogenous 
insulin use for otelixizumab over 24 
months in NOT1DM patients.  
• 
Change from baseline in mean daily insulin 
use over 7 consecutive days during the 
week preceding the visit over Months 1-24.  
 
REVISED TEXT 
Secondary Objectives (Efficacy) 
Secondary Endpoints (Efficacy) 
• 
To assess the effect of a single course of 
otelixizumab treatment on the rate of 
decline of pancreatic β-cell function over 
24 months in NOT1DM patients.  
• 
Change from baseline in C-peptide and 
glucose AUC (0-120) after a Mixed Meal 
Tolerance Test at Month 3, 6, 12, 18 and 
24. 
 
• 
To assess the effect of a single course of 
otelixizumab treatment on the rate of 
decline of C-peptide response and insulin 
sensitivity of β-cell function determined 
after a hyperglycemic clamp over 24 
months in NOT1DM patients. 
• 
Change from baseline in C-Peptide and 
glucose AUC hyperglycemic phase [H60 
to H140 minutes] and insulin sensitivity 
(IS) index after a hyperglycemic clamp at 
Months 6 and 24.  
 
• 
To assess the effect of a single course of 
otelixizumab treatment on exogenous 
insulin use for otelixizumab over 24 
months in NOT1DM patients.  
• 
Change from baseline in mean daily insulin 
use over 7 consecutive days during the 
week preceding the visit over Day 14 and 
21 and Months 1-24.  
 

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Section 2 OBJECTIVES AND ENDPOINTS, 1st row under Secondary 
Objectives and Endpoints (Pharmacodynamics) 
PREVIOUS TEXT 
Secondary Objectives (Pharmacodynamics) 
Secondary Endpoints (Pharmacodynamics) 
• 
To assess the effect of a single course of 
otelixizumab treatment on the time course 
and magnitude of CD4 + and CD8+ cells 
and TCR/CD3 complex internalization and 
CD3 binding and saturation on all these 
cells during repeat dose administration of 
otelixizumab over 14 days in NOT1DM 
patients. 
• 
Relative change from baseline (%) in 
CD4+ and CD8+ cells, CD3/TCR 
complexes, free CD3, bound otelixizumab 
and CD4+ and CD8+ cells on Days 1 
through 14. 
 
REVISED TEXT 
Secondary Objectives (Pharmacodynamics) 
Secondary Endpoints (Pharmacodynamics) 
• 
To assess the effect of a single course of 
otelixizumab treatment on the time course 
and magnitude of CD4 + and CD8+ cells 
and TCR/CD3 complex internalization and 
CD3 binding and saturation on all these 
cells during repeat dose administration of 
otelixizumab over 14 days in NOT1DM 
patients. 
• 
Relative change from baseline (%) in 
CD4+ and CD8+ cells, CD3/TCR 
complexes, free CD3 and bound 
otelixizumab on and CD4+ and CD8+ cells 
on Days 1 through 14. 
 
Section 3.1. Study Design Detail, 3rd Paragraph, 2nd and 3rd sentences 
PREVIOUS TEXT 
Patients will be dosed within approximately 28 days of diagnosis (not more than 32 
days). Insulin usage will be documented for approximately 7 days prior to screening 
procedures. There will be an approximately 7 day period from screening to admission to 
the clinic on Day -2 for the first overnight stay of the in-patient period, this time period 
will ensure appropriate time to review laboratory results prior to randomisation 

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REVISED TEXT 
Patients will be dosed within approximately 28 days of diagnosis (not more than 32 
days). Insulin usage will be documented for approximately 7 days prior to screening 
procedures Day -1. There will be an approximately a 7-21 day period from screening to 
admission to the clinic on Day -2 for the first overnight stay of the in-patient period, this 
time period will ensure appropriate time to review laboratory results prior to 
randomisation 
Section 5.4 Blinding, addition of unblinded Pharmacy Monitors to Table 8 
PREVIOUS TEXT (only last row of Table 8 shown) 
Site Monitors 
Y 
 
REVISED TEXT 
Site Monitors 
Y 
Pharmacy Monitors 
N 
 
Section 5.6.2 Study Medication Preparation, 3rd bullet point 
PREVIOUS TEXT 
The required volume of Otelixizumab Solution for Infusion, 0.1 mg/mL (varies 
depending on target dose and includes an excess 5 mL volume to account for prime/ 
purge) must be withdrawn into an suitable size polypropylene syringe as close to the time 
of the start of the infusion as possible, to ensure product quality. 
REVISED TEXT 
The required volume of Otelixizumab Solution for Infusion, 0.1 mg/mL (varies 
depending on target dose and includes an excess 6 mL volume to account for prime/ 
purge) must be withdrawn into an suitable size polypropylene syringe as close to the time 
of the start of the infusion as possible, to ensure product quality. 
Section 5.6.2 Study Medication Preparation, Table 9 Study Medication Dose 
Preparation, table header, column 8 
PREVIOUS TEXT 
Total Vol. Filled into Syringe, Includes 5 mL Fill Overage (Vol. not Infused) 
 
REVISED TEXT 
 
Total Vol. Filled into Syringe, Includes 6 mL Fill Overage (Vol. not Infused) 

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Section 5.6.2 Study Medication Preparation, Table 9 Study Medication Dose 
Preparation, change of total volume filled into syringe in column 8 
PREVIOUS TEXT 
Table 12 
Study Medication Dose Preparation 
Treat-
ment 
Regimen 
(cohort) 
Cumul-
ative 
Dose 
(mg) 
Dose 
per day 
(mg) 
Day of 
Dosing 
Period 
of 
Dosing 
(hours) 
# of 
Syringes 
Total Dosing 
Solution 
Volume to be 
Infused 
Total Vol. Filled into 
Syringe, Includes  
5 mL Fill Overage 
(Vol. not Infused) 
A (1) 
9 
1.5 
Day 1 
9 
2 
15 mL 
(7.5 mL x 2 
syringes)  
12.5 mL x 2 syringes 
Day 2 
6 
1 
15 mL 
20 mL 
Day 3 
3 
1 
15 mL 
20 mL 
Day 4-6 
1 
1 
15 mL 
20 mL 
B (2) 
18 
3 
Day 1 
12 
2 
30 mL (15 mL 
x 2 syringes) 
20 mL x 2 syringes 
Day 2 
6 
1 
30 mL 
35 mL 
Day 3 
3 
1 
30 mL 
35 mL 
Day 4-6 
1 
1 
30 mL 
35 mL 
C (3) 
27 
4.5 
Day 1 
12 
2 
45 mL 
(22.5 mL x 2 
syringes) 
27.5 mL x 2 syringes 
Day 2 
6 
1 
45 mL 
50 mL 
Day 3 
3 
1 
45 mL 
50 mL 
Day 4-6 
1 
1 
45 mL 
50 mL 
D (4) 
36 
6 
Day 1 
12 
2 
60 mL (30 mL 
x 2 syringes) 
35 mL x 2 syringes 
Day 2 
6 
2 
60 mL (30 mL 
x 2 syringes) 
35 mL x 2 syringes 
Day 3 
3 
2 
60 mL (30 mL 
x 2 syringes) 
35 mL x 2 syringes  
Day 4-6 
1 
2 
60 mL (30 mL 
x 2 syringes) 
35 mL x 2 syringes  
P 
0 
0 
0.9% w/v sodium chloride administered by intravenous infusion in the same 
manner as the active by study personnel following specified regimens 

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REVISED TEXT 
Treat-
ment 
Regimen 
(cohort) 
Cumul-
ative 
Dose 
(mg) 
Dose 
per day 
(mg) 
Day of 
Dosing 
Period 
of 
Dosing 
(hours) 
# of 
Syringes 
Total Dosing 
Solution 
Volume to be 
Infused 
Total Vol. Filled into 
Syringe, Includes  
6 mL Fill Overage 
(Vol. not Infused) 
A (1) 
9 
1.5 
Day 1 
9 
2 
15 mL (7.5 
mL x 2 
syringes)  
13.5 mL x 2 syringes 
Day 2 
6 
1 
15 mL 
21 mL 
Day 3 
3 
1 
15 mL 
21 mL 
Day 4-6 
1 
1 
15 mL 
21 mL 
B (2) 
18 
3 
Day 1 
12 
2 
30 mL (15 mL 
x 2 syringes) 
21 mL x 2 syringes 
Day 2 
6 
1 
30 mL 
36 mL 
Day 3 
3 
1 
30 mL 
36 mL 
Day 4-6 
1 
1 
30 mL 
36 mL 
C (3) 
27 
4.5 
Day 1 
12 
2 
45 mL 
(22.5 mL x 2 
syringes) 
28.5 mL x 2 syringes 
Day 2 
6 
1 
45 mL 
51 mL 
Day 3 
3 
1 
45 mL 
51 mL 
Day 4-6 
1 
1 
45 mL 
51 mL 
D (4) 
36 
6 
Day 1 
12 
2 
60 mL (30 mL 
x 2 syringes) 
36 mL x 2 syringes 
Day 2 
6 
2 
60 mL (30 mL 
x 2 syringes) 
36 mL x 2 syringes 
Day 3 
3 
2 
60 mL (30 mL 
x 2 syringes) 
36 mL x 2 syringes  
Day 4-6 
1 
2 
60 mL (30 mL 
x 2 syringes) 
36 mL x 2 syringes  
P 
0 
0 
0.9% w/v sodium chloride administered by intravenous infusion in the same 
manner as the active by study personnel following specified regimens 
 

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Section 5.6.3 Study Medication Administration, 2nd bullet point 
 
PREVIOUS TEXT 
Connect a micropore polyethylene intravenous line with an in-line 0.2 µm 
polyethersulfone (PES) filter to the syringe.  If a second syringe is needed to provide the 
dose, a separate infusion line with 0.2 µm PES filter is required. 
REVISED TEXT 
Connect a micropore polyethylene intravenous line with an in-line 0.2 µm 
polyethersulfone (PES) filter to the syringe.  If a second syringe is needed to provide the 
dose, a separate infusion line with 0.2 µm PES filter is required. 
Section 5.6.3 Study Medication Administration, 3rd bullet point 
 
PREVIOUS TEXT 
The prime volume of the intravenous line and filter must not exceed a total of 2 mL.  The 
5 mL excess solution in the syringe(s) must be primed/purged (3 mL to waste, about 
2 mL fills the IV line); target a priming/purging rate of 1 mL/min or lower.  Purging 3 ml 
to waste is required to account for protein loss due to binding and to ensure that the full 
dose is administered. 
 
REVISED TEXT 
 
The prime volume of the intravenous line and filter must not exceed a total of 3 mL.  The 
6 mL excess solution in the syringe(s) must be primed/purged (3 mL to waste, about 
3 mL fills the IV line); target a priming/purging rate of 1 mL/min or lower.  Purging 3 ml 
to waste is required to account for protein loss due to binding and to ensure that the full 
dose is administered. 
 
Section 6.2.2 Dosing and Follow-Up, 18th row, removal of TCR complexes, 
addition of “Saturation” after CD3 
 
PREVIOUS TEXT 
 
CD3/TCR complexes, free CD3 bound 
otelixizumab /CD4+/CD8+ Blood 
Sample6 
X X X X X X 
X11 
 
 
REVISED TEXT 
 
CD3 Saturation/TCR complexes, free 
CD3 bound otelixizumab /CD4+/CD8+ 
Blood Sample6 
X X X X X X 
X11 
 
 

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Section 6.2.2 Dosing and Follow-Up, 19th row, addition of Day 14 and 21, 
and Month 1, 9, 36, 48 and 60 for collection of 7 days of insulin usage prior 
to the visit 
 
PREVIOUS TEXT 
 
  
  
  
Day 
Month 
  
-2 
-1 
1 2 3 4 5 6 
14 
21 
1 2 3 6 9 12 
18 
24 
36, 48 
& 60 
Record insulin usage 
for 7 days before visit 
X 
  
  
  
  
  
  
 
X 
 
X 
 
X   
 X 
 X 
 X 
 
REVISED TEXT 
 
  
  
  
Day 
Month 
  
-2 
-1 
1 2 3 4 5 6 
14 
21 
1 2 3 6 9 12 
18 
24 
36, 48 
& 60 
Record insulin usage 
for 7 days before visit 
X 
  
  
  
  
X 
 X 
 
X 
 
X 
 
X 
 
X 
 
X  X 
 X 
 X 
X 
 
Section 6.2.2 Dosing and Follow-Up, footnote 13, addition of glucose 
 
PREVIOUS TEXT 
 
13. Plasma C-peptide levels will be measured during the hyperglycaemic clamp procedure at the following time 
points: L150, L165 and L180 minutes [during the euglycaemic (L)ow phase], H0, H60, H90, H120 and H140 minutes 
[during the hyperglycaemic (H)igh phase] 
 
 
REVISED TEXT 
 
13. Plasma C-peptide and glucose levels will be measured during the hyperglycaemic clamp procedure at the 
following time points: L150, L165 and L180 minutes [during the euglycaemic (L)ow phase], H0, H60, H90, H120 and 
H140 minutes [during the hyperglycaemic (H)igh phase] 
 
Section 6.2.2 Dosing and Follow-Up, footnote 18, addition of Day 6 
 
PREVIOUS TEXT 
 
18. One PGx (DNA) saliva sample taken between Day 1 and 
 
REVISED TEXT 
 
18. One PGx (DNA) saliva sample taken between Day 1 and 6 
 

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Section 6.2.3 Details for Vitals, ECG and Pharmacokinetic and 
Pharmacodynamic Monitoring over the Infusion Period (Cohorts 1 – 4). 
 
Removal of TCR complexes, CD3/CD4/CD8 and addition of “Saturation” 
after CD3 on each day in the table, only column 3 of table shown below 
PREVIOUS TEXT 
 
Assessment 
Dosing 
VItals1,2 
ECG 
PK/CD3/TCR complexes 
free 
CD3 /CD4/CD8 
 
REVISED TEXT  
 
Assessment 
Dosing 
VItals1,2 
ECG 
PK/CD3 Saturation/TCR 
complexes free 
CD3 /CD4/CD8 
 
Update to Footnote 1 
PREVIOUS TEXT 
1. Blood pressure to be taken in triplicate 
REVISED TEXT 
1. Blood pressure to be taken in triplicate at pre-dose 
 

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Section 6.2.3  
Details for Vitals, ECG and Pharmacokinetic and Pharmacodynamic Monitoring over the Infusion 
Period (Cohorts 1 – 4), clarification that ECG will be measured 6 hours post start of infusion. Table shows ECG only 
on dosing Day 3-6 
 
PREVIOUS TEXT  
Day 
Cohort 
Assessment 
Pre 
Dose 
0 H 
30 M 
1 H 
2 H 
3 H 
4 H 
5 H 
6 H 
7 H 
8 H 
9 H 
10 H 
11 H 
12 H 
13 H 
14 H 
15 H 
16 H 
3 
C1-C4 
ECG 
X 
  
  
  
  
 X 
  
  
  
  
  
  
  
  
  
  
  
  
  
4 
C1-C4 
ECG 
X 
 
 
X 
 
 
 
 
  
  
  
  
  
 
  
 
 
 
 
5 
C1-C4 
ECG 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
C1-C4 
ECG 
X 
  
  
 X 
  
  
  
  
 
 
 
 
 
  
 
  
  
  
  
 
REVISED TEXT  
 
Day 
Cohort 
Assessment 
Pre 
Dose 
0 H 
30 M 
1 H 
2 H 
3 H 
4 H 
5 H 
6 H 
7 H 
8 H 
9 H 
10 H 
11 H 
12 H 
13 H 
14 H 
15 H 
16 H 
3 
C1-C4 
ECG 
X 
  
  
  
  
 X 
  
  
X 
  
  
  
  
  
  
  
  
  
  
4 
C1-C4 
ECG 
X 
 
 
X 
 
 
 
 
X 
  
  
  
  
 
  
 
 
 
 
5 
C1-C4 
ECG 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
6 
C1-C4 
ECG 
X 
  
  
 X 
  
  
  
  
X 
 
 
 
 
  
 
  
  
  
  
 

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Section 6.4.3 Electrocardiograms (ECG), second paragraph, clarification of  
triple or single recordings 
PREVIOUS TEXT 
At baseline (Day -1) ECG assessments will be performed in triplicate (5 minutes apart) to 
obtain an average, single ECGs will be performed at other timepoints. Refer to Section 
5.3.5 for QTc withdrawal criteria, which requires triplicate ECGs to assess QTc. 
REVISED TEXT 
At screening, baseline (Day -1) and predose on dosing days ECG assessments will be 
performed in triplicate (5 minutes apart) to obtain an average, single ECGs will be 
performed at other timepoints. Refer to Section 5.3.5 for QTc withdrawal criteria, which 
requires triplicate ECGs to assess QTc. 
Section 6.6.3. CD4+, CD8+ Levels and CD3/TCR Complexes. Free CD3 and 
bound otelixizumab on CD4 and CD8+ Cells 
PREVIOUS TEXT 
Whole blood samples will be drawn, as detailed on the Time and Events Table, for 
determining CD4+ and CD8+ levels, together with CD3/TCR complexes, free CD3 and 
bound otelixizumab on CD4 and CD8+ cells, respectively. The samples will be analysed 
by flow cytometry. 
REVISED TEXT 
Section 6.6.3.  CD4+, CD8+ Levels and CD3/TCR Complexes. Free CD3 and 
bound otelixizumab on CD4 and CD8+ Cells 
Whole blood samples will be drawn, as detailed on the Time and Events Table, for 
determining CD4+ and CD8+ levels, together with CD3/TCR complexes, free CD3 and 
bound otelixizumab on CD4 and CD8+ cells, respectively. The samples will be analysed 
by flow cytometry. 
Section 6.6.4.  Exploratory Biomarkers, Table showing Biomarker assay, 7th 
row, addition of TCR deep sequencing to Month 24 
 
PREVIOUS TEXT 
TCR deep sequencing  
PAXgene Blood 
RNA Tube 
X X1 X 
X 
X 
X 
 
 
REVISED TEXT 
TCR deep sequencing  
PAXgene Blood 
RNA Tube 
X X1 X 
X 
X 
X 
X 

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Section 6.7.1.  Mixed Meal Tolerance Test, (C-Peptide Unstimulated, Serum 
Stimulated C-Peptide Peak Levels and C-Peptide AUC), 2nd papagraph 
 
PREVIOUS TEXT 
An MMTT test will be performed in the screening period, at least 5 days before the first 
dose of study medication is given. 
REVISED TEXT 
An MMTT test will be performed in the screening period, at least 7 days before the first 
dose of study medication is given. 
Section 6.7.2.  Hyperglycaemic Clamp Serum Stimulated C-Peptide Levels 
and C-Peptide AUC, 1st paragraph, addition of glucose 
 
PREVIOUS TEXT 
Plasma C-peptide levels will be measured during the hyperglycaemic clamp procedure at 
the following time points: L150, L165 and L180 minutes [during the euglycaemic (L)ow 
phase], H0, H60, H90, H120 and H140 minutes [during the hyperglycaemic (H)igh 
phase]. 
REVISED TEXT 
Plasma C-peptide and glucose levels will be measured during the hyperglycaemic clamp 
procedure at the following time points: L150, L165 and L180 minutes [during the 
euglycaemic (L)ow phase], H0, H60, H90, H120 and H140 minutes [during the 
hyperglycaemic (H)igh phase]. 
Section 6.7.3 Daily Insulin Use, 1st Paragraph 
 
PREVIOUS TEXT 
Patients will be asked to record their daily insulin usage thoroughly and accurately for 
7 consecutive days in a diary during the week before the visits at Baseline and Months 1, 
2, 3, 6, 12, 18, and 24, and before each telephone call in the long term follow-up period 
(Month 36, 48 and 60). Information on insulin usage will be transcribed from diaries into 
concomitant medication pages of the eCRF. 
REVISED TEXT 
 
Patients will be asked to record their daily insulin usage thoroughly and accurately for 
7 consecutive days in a diary during the week before all outpatient visits, ie, at Baseline, 
Day 14 and 21 and Months 1, 2, 3, 6, 9, 12, 18, and 24, and before each telephone call in 
the long term follow-up period (Month 36, 48 and 60). Information on insulin usage will 
be transcribed from diaries into concomitant medication pages of the eCRF. 

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Section 9.3.7 Pharacokinetic/Pharmacodynamic Analyses 
 
PREVIOUS TEXT 
The relationship between dose, free serum otelixizumab concentration and 
pharmacodynamic endpoints including CD3/TCR complex, free CD3, CD4+ and CD8+ 
cells may be investigated  first by exploratory graphical analysis and then by non-linear 
mixed effects modelling. Further details of model terms and possible covariates will be 
included in the RAP. 
REVISED TEXT 
The relationship between dose, free serum otelixizumab concentration and 
pharmacodynamic endpoints including CD3/TCR complex, free CD3 or bound 
otelixizumab on CD4+ and CD8+ cells may be investigated  first by exploratory 
graphical analysis and then by non-linear mixed effects modelling. Further details of 
model terms and possible covariates will be included in the RAP. 
Appendix 5: Mixed Meal Tolerance Test, last paragraph 
 
PREVIOUS TEXT 
The tubes with the blood samples will be kept on ice during collection, until centrifuged 
for 15 min at 1530 x g and 4°C.  The plasma will be harvested into 2 green cap transfer 
vials 2.0 mL and stored at <-15°C until shipment (max 2 weeks).  The tubes will be sent 
at the end of each cohort for analysis.  The tubes must be shipped on dry ice and 
remained frozen until analysis.  Further details will be provided in the SPM. 
REVISED TEXT 
The tubes with the blood samples will be kept on ice during collection, until centrifuged 
for 15 min at 1530 x g and 4°C.  The plasma will be harvested into 2 green cap transfer 
vials 2.0 mL and stored at <-15°C until shipment (max 2 weeks within 3 weeks of 
collection).  The tubes will be sent at the end of each cohort for analysis.  The tubes must 
be shipped on dry ice and remained frozen until analysis.  Further details will be provided 
in the SPM. 
Appendix 6: Hyperglycaemic Clamp Procedure, C. Hyperglycemic Phase 
Start BG 180-240mg/dL, first sentence 
 
PREVIOUS TEXT 
AIM: Keep blood glucose between 180-240mg/dL during 180 minutes. 
REVISED TEXT 
AIM: Keep blood glucose between 180-240mg/dL during 140 minutes.