Phase 3 Randomized Double-Blind Multinational Placebo-Controlled Study to Evaluate Efficacy and Safety of Teplizumab, a Humanized Fc Receptor (FcR) Non-Binding Anti-cluster of Differentiation 3 (CD3) Monoclonal Antibody, in Children and Adolescents With Newly Diagnosed Type 1 Diabetes
Phase: PHASE3
Conditions: Type 1 Diabetes Mellitus
Sponsor: Provention Bio, Inc.

Protocol PRV-031-001, version 4.0
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Approved, Date: 10 December 2020
Provention Bio, Inc.
Clinical Protocol
A Phase 3, Randomized, Double-Blind, Multinational, Placebo-Controlled Study to 
Evaluate Efficacy and Safety of Teplizumab (PRV-031), a Humanized, FcR Non-Binding, 
anti-CD3 Monoclonal Antibody, in Children and Adolescents with Newly Diagnosed Type 
1 Diabetes (T1D)
PROTECT: Pro
T1D Trial Evaluating C-Peptide with Teplizumab 
Protocol PRV-031-001; Phase 3
Teplizumab, PRV-031
EudraCT Number:
2018-004926-26
US IND Number:
100262
Version: 
4.0
Status:
Approved
Date:
10 December 2020
Prepared by:
Provention Bio, Inc.
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.

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TABLE OF CONTENT
TABLE OF CONTENT.................................................................................................................2
SUMMARY OF CHANGES.........................................................................................................7
SYNOPSIS....................................................................................................................................23
SCHEDULE OF EVENTS: SCREENING TO WEEK 20.......................................................31
SCHEDULE OF EVENTS: WEEK 26 TO WEEK 78.............................................................33
MODIFIED DOSING SCHEDULE (DUE TO COVID-19) OF EVENTS: 
SCREENING TO WEEK 26 ..............................................................................................35
MODIFIED DOSING SCHEDULE (DUE TO COVID-19) OF EVENTS: WEEK 34 
TO WEEK 78.......................................................................................................................37
ABBREVIATIONS......................................................................................................................41
1.
INTRODUCTION ...............................................................................................................44
1.1.
Background........................................................................................................................44
1.2.
Teplizumab Overview........................................................................................................46
1.3.
T1D and Teplizumab Experience in Children and Adults.................................................49
1.4.
Overall Rationale for the Study .........................................................................................50
1.5.
Risk and Benefit Assessment.............................................................................................51
2.
HYPOTHESIS, OBJECTIVES, ENDPOINTS ................................................................52
2.1.
Study Hypothesis ...............................................................................................................52
2.2.
Study Objectives................................................................................................................52
2.3.
Study Endpoints.................................................................................................................52
3.
STUDY DESIGN AND RATIONALE ..............................................................................55
3.1.
Overview of Study Design.................................................................................................55
3.1.1.
Screening and Participant Enrollment ............................................................................56
3.1.2.
Randomization and Stratification ...................................................................................56
3.1.3.
Study Treatment..............................................................................................................56
3.1.4.
Study Duration................................................................................................................60
3.1.5.
Data Monitoring Committee and Data Reviews.............................................................62
3.1.6.
Study Oversight ..............................................................................................................62
3.2.
Discussion of Study Design...............................................................................................63
4.
STUDY POPULATION......................................................................................................63
4.1.
Inclusion Criteria ...............................................................................................................63
4.2.
Exclusion Criteria ..............................................................................................................65
5.
TREATMENT ALLOCATION AND BLINDING ..........................................................68
5.1.
Treatment Allocation .........................................................................................................68
5.2.
Blinding..............................................................................................................................68
5.3.
Emergency Unblinding......................................................................................................69
6.
DOSAGE AND ADMINISTRATION...............................................................................69

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6.1.
Study Drug Preparation......................................................................................................70
6.2.
Vascular Access and Intermediate-Use Intravenous Catheters .........................................70
6.3.
Premedication and Study Drug Infusion............................................................................71
6.4.
Location of Infusion...........................................................................................................72
6.5.
Emergency Precautions......................................................................................................72
6.6.
Deviations from Study Drug Administration Schedule.....................................................73
7.
TREATMENT COMPLIANCE.........................................................................................73
8.
CONCOMITANT THERAPY ...........................................................................................74
8.1.
Documentation of Concomitant Therapy...........................................................................74
8.2.
Diabetes Management and Insulin Use..............................................................................74
8.3.
Permitted Medications .......................................................................................................75
8.4.
Prohibited Medications ......................................................................................................75
8.5.
Vaccines.............................................................................................................................76
8.6.
Contraception.....................................................................................................................76
9.
STUDY EVALUATIONS ...................................................................................................77
9.1.
Study Procedures ...............................................................................................................77
9.1.1.
Screening Procedures......................................................................................................77
9.1.2.
Randomization, Treatments and Monitoring..................................................................79
9.1.3.
Blood Draw Volume Required for Study Assessments..................................................83
9.2.
Efficacy Evaluations ..........................................................................................................83
9.2.1.
Mixed Meal Tolerance Tests ..........................................................................................83
9.2.2.
Hemoglobin A1c.............................................................................................................84
9.2.3.
Insulin Use ......................................................................................................................84
9.2.4.
Episodes of Hypoglycemia.............................................................................................84
9.2.5.
Glucose Monitoring........................................................................................................84
9.2.5.1.
Intermittent Glucose Monitoring (Fingerstick)............................................................84
9.2.5.2.
Continuous Glucose Monitoring..................................................................................85
9.2.6.
Additional Metabolic, Clinical, Immunologic, and Molecular Evaluations...................86
9.3.
Pharmacokinetics and Immunogenicity.............................................................................86
9.3.1.
Evaluations......................................................................................................................86
9.3.2.
Analytical Procedures.....................................................................................................86
9.3.3.
Pharmacokinetic Parameters...........................................................................................87
9.4.
Exploratory and Other Assessments..................................................................................87
9.4.1.
Immune and Serologic Assessments...............................................................................87
9.4.2.
.............................................................................................88
9.4.3.
Pharmacodynamic Substudy...........................................................................................88
9.5.
Pharmacogenomic (DNA) Evaluations..............................................................................88
9.6.
Quality of Life Assessment................................................................................................89
9.7.
Safety Evaluations .............................................................................................................89
9.7.1.
Responsibilities...............................................................................................................89
9.7.2.
Adverse Events ...............................................................................................................90
9.7.3.
Study Drug Infusion-Related Reactions .........................................................................91
9.7.4.
Assessment of Infections ................................................................................................94
9.7.5.
Clinical Laboratory Tests................................................................................................97
9.7.5.1.
Central Laboratory Tests..............................................................................................97
9.7.5.2.
Local Laboratory Tests ................................................................................................99

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9.7.6.
Data Collected by Participants or Caregivers.................................................................99
9.7.7.
Clinical Assessments ....................................................................................................100
9.7.7.1.
Vital Signs..................................................................................................................100
9.7.7.2.
Physical Examination.................................................................................................101
9.8.
Sample Collection and Handling .....................................................................................101
10.
PARTICIPANT COMPLETION, INTERRUPTION/DISCONTINUATION 
OF STUDY TREATMENT OR WITHDRAWAL FROM THE STUDY ...................102
10.1.
Participant Completion ....................................................................................................102
10.2.
Interruption or Discontinuation of Study Treatment .......................................................102
10.2.1.
Events That Lead to Discontinuation of Study Treatment During Course 1 or 
Course 2........................................................................................................................103
10.2.2.
Events Resulting in Interruption of Study Treatment in Course 1 or Course 2............104
10.2.3.
Criteria to Withhold Initiation of Course 2...................................................................105
10.3.
Withdrawal from the Study..............................................................................................106
10.3.1.
Participant Withdrawal .................................................................................................106
10.3.2.
Withdrawal from the Use of Research Samples ...........................................................107
11.
STATISTICAL METHODS.............................................................................................107
11.1.
General Considerations....................................................................................................107
11.2.
Analysis Data Sets ...........................................................................................................108
11.3.
Sample Size Determination..............................................................................................108
11.4.
Handling of Missing Data................................................................................................109
11.5.
Efficacy Analyses ............................................................................................................109
11.5.1.
Primary Endpoint Analysis...........................................................................................109
11.5.2.
Secondary and Exploratory Clinical Endpoints............................................................109
11.6.
Pharmacokinetic and Immunogenicity Analyses.............................................................110
11.7.
Concomitant Medications................................................................................................110
11.8.
Safety Analyses................................................................................................................111
11.9.
Exploratory Endpoint Analysis........................................................................................111
11.10. Interim Analysis...............................................................................................................112
11.11. Data Monitoring Committee............................................................................................112
12.
ADVERSE EVENT REPORTING..................................................................................114
12.1.
Definitions........................................................................................................................114
12.1.1.
Adverse Event...............................................................................................................114
12.1.2.
Serious Adverse Event..................................................................................................114
12.1.3.
Adverse Events of Special Interest ...............................................................................115
12.1.4.
Disease-Specific Adverse Events .................................................................................116
12.1.4.1.
Hypoglycemia............................................................................................................116
12.1.4.2.
Hyperglycemia and Diabetic Ketoacidosis................................................................117
12.1.4.3.
Anticipated Adverse Events.......................................................................................118
12.1.5.
Unlisted or Unexpected Serious or Nonserious Adverse Events..................................118
12.1.6.
Attribution Definitions..................................................................................................118
12.1.7.
Severity Criteria............................................................................................................119
12.2.
Special Reporting Situations............................................................................................119
12.2.1.
Safety Events of Interest...............................................................................................119
12.2.2.
Expedited Safety Report ...............................................................................................120
12.2.2.1.
Anticipated Adverse Event ........................................................................................120

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12.2.3.
Immediately Reportable Events....................................................................................120
12.3.
Procedures........................................................................................................................120
12.3.1.
All Adverse Events.......................................................................................................120
12.3.2.
Serious Adverse Events ................................................................................................121
12.3.3.
Procedure for Serious Adverse Event Reporting..........................................................122
12.3.4.
Pregnancy......................................................................................................................123
12.4.
Contacting Sponsor Regarding Safety.............................................................................123
13.
PRODUCT QUALITY COMPLAINT HANDLING.....................................................123
13.1.
Procedures........................................................................................................................123
13.2.
Contacting Sponsor Regarding Product Quality..............................................................124
14.
STUDY DRUG INFORMATION....................................................................................124
14.1.
Physical Description of Study Drugs...............................................................................124
14.2.
Packaging.........................................................................................................................124
14.3.
Labeling ...........................................................................................................................124
14.4.
Preparation, Handling, and Storage .................................................................................124
14.5.
Drug Accountability.........................................................................................................125
15.
STUDY-SPECIFIC MATERIALS ..................................................................................125
16.
ETHICAL ASPECTS........................................................................................................126
16.1.
Study-Specific Design Considerations ............................................................................126
16.1.1.
Investigator Responsibilities.........................................................................................126
16.1.2.
Independent Ethics Committee or Institutional Review Board ....................................126
16.1.3.
Informed Consent and Assent Form.............................................................................127
16.1.4.
Privacy of Personal Data...............................................................................................128
16.1.5.
Long-Term Retention of Samples for Additional Future Research..............................129
16.1.6.
Country Selection .........................................................................................................129
17.
ADMINISTRATIVE REQUIREMENTS .......................................................................129
17.1.
Protocol Amendments......................................................................................................129
17.2.
Regulatory Documentation..............................................................................................130
17.2.1.
Regulatory Approval/Notification................................................................................130
17.2.2.
Required Pre-study Documentation..............................................................................130
17.3.
Participant Identification, Enrollment, and Screening Logs............................................131
17.4.
Source Documentation.....................................................................................................131
17.5.
Case Report Form Completion ........................................................................................132
17.6.
Data Quality Assurance/Quality Control.........................................................................132
17.7.
Record Retention .............................................................................................................133
17.8.
Monitoring .......................................................................................................................133
17.9.
Study Completion/Termination .......................................................................................134
17.9.1.
Study Completion/End of Study...................................................................................134
17.9.2.
Study Termination ........................................................................................................134
17.10. On-Site Audits .................................................................................................................134
17.11. Use of Information and Publication.................................................................................135
REEFERENCES........................................................................................................................137
APPENDICES............................................................................................................................143

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INVESTIGATOR AGREEMENT ...........................................................................................155
LIST OF APPENDICES
Appendix 1: American Diabetes Association T1D Diagnostic Criteria ......................................143
Appendix 2: Mixed Meal Tolerance Test (MMTT) Procedures..................................................144
Appendix 3: Blood Draw Volumes..............................................................................................150
LIST OF IN-TEXT TABLES
None
LIST OF IN-TEXT FIGURES
Figure 1. Schematic Overview of the Study.................................................................................55
Figure 2. Modified Dosing Schedule for Participants Affected by COVID-19 Pandemic 
Restrictions....................................................................................................................57
Figure 3. PK Simulation of 12-Day and 14-Day Dosing Regimens ............................................59

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SYNOPSIS
A Phase 3, Randomized, Double-Blind, Multinational, Placebo-Controlled Study to Evaluate 
Efficacy and Safety of Teplizumab (PRV-031), a Humanized, FcR Non-Binding, anti-CD3 
Monoclonal Antibody, in Children and Adolescents with Newly Diagnosed Type 1 Diabetes 
(T1D)
Teplizumab (also known as PRV-
-Ala], and MGA031) is a humanized 150-kilodalton 
monoclonal antibody (mAb) that binds to the CD3-
Teplizumab was 
developed when preclinical studies demonstrated that targeting T cells (the cells that are instrumental in 
initiating and coordinating the autoimmune process responsible for type 1 diabetes [T1D] mellitus) via this 
mechanism altered diabetes immunopathogenesis and prevented and reversed disease in relevant animal 
models. A number of clinical studies have demonstrated the ability of teplizumab to slow or even halt the 
destruction of the insulin-
The 
goal of this study is to evaluate teplizumab in patients who may be most responsive to it as suggested in 
previous studies, namely children and adolescents very recently diagnosed with T1D. Teplizumab holds 
the promise to be the first disease modifying therapy available to improve both the medical management 
and overall outlook in those who suffer the most devastating short- and long-term consequences of this 
disease.
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
Hypothesis
The hypothesis of this study is that teplizumab is safe, well-
cells and maintaining a clinically relevant level of 
cell function in children and adolescents newly 
diagnosed with T1D while improving key aspects of T1D clinical management over an 18-month period.
Objectives
The primary objective is:
To determine 
cell
cell function 
over 18 months (78 weeks) in children and adolescents 8-17 years old who have been diagnosed 
with T1D in the previous 6 weeks.
The secondary objectives are:
To evaluate participant improvements in key clinical parameters of diabetes management, 
including insulin use, glycemic control (including hemoglobin A1c [HbA1c] and time in glycemic 
target range [TIR]), and clinically important hypoglycemic episodes
To determine the safety and tolerability of two courses of teplizumab, administered intravenously 
(IV)
To evaluate the pharmacokinetics (PK) and immunogenicity of two courses of IV teplizumab
The exploratory objectives are: 
cell function and T1D-focused clinical parameters  
To evaluate immunologic, endocrinologic, molecular, and genetic markers 

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Endpoints
1. The primary endpoint is:
The area under the time-concentration curve (AUC) of C-peptide after a 4-hour (4h) mixed meal 
tolerance test (MMTT),
cell function, at Week 
78.
2. The secondary endpoints are as follows:
A. Key Clinical Endpoints:
Exogenous insulin use: defined as a daily average in units per kilogram per day (U/kg/day), at 
Week 78
HbA1c levels: expressed in % and mmol/mol, at Week 78
TIR: expressed as a daily average of the percentage of time in a 24-hour day a participant s blood 
glucose (BG) is >70 but
180 mg/dL (>3.9 to 10.0 mmol/L), assessed using continuous glucose 
monitoring (CGM), at Week 78
Clinically important hypoglycemic episodes: defined as the total number of episodes of a BG
reading of <54 mg/dL (3.0 mmol/L) and/or episodes of severe cognitive impairment requiring 
external assistance for recovery, from randomization through Week 78
B. Safety Endpoints:
Incidence of treatment-emergent adverse events (TEAEs), adverse events of special interest 
(AESIs), and serious adverse events (SAEs) 
Incidence of treatment-emergent infections of special interest, including but not limited to 
tuberculosis, an infection requiring IV antimicrobial treatment or hospitalization, Epstein-Barr 
virus (EBV) and cytomegalovirus (CMV) infection, or significant viremia (ie, DNA-based 
polymerase chain reaction viral load >10,000 copies per mL or 106 cells), and herpes zoster
Incidence and severity of immediate or delayed study drug infusion-related reactions, such as 
hypersensitivity reactions, pain requiring interruption or discontinuation of infusions, cytokine 
release syndrome, and serum sickness
C. PK and Immunogenicity Endpoints:
Teplizumab serum concentrations 
Incidence and titers of anti-teplizumab antibodies after treatment courses
3. The exploratory endpoints are as follows:
A. 
cell function and health throughout the study:
4h MMTT C-peptide AUC
Participants with the recognized clinically significant stimulated peak C-peptide of
0.2 pmol/mL 
during 4h and 2-hour (2h) MMTTs 
Proinsulin-to-C-
cell endoplasmic reticulum stress and dysfunction
B. T1D-focused Clinical Endpoints during the study unless otherwise noted:
Exogenous insulin use (in U/kg/day)
HbA1c levels

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Participants with poor glycemic control, defined as HbA1c of 9%
The number of participants who do not require exogenous insulin because they are able to achieve
local, regional, or national age-based glycemic management goals for HbA1c and/or routine blood 
glucose levels
Evaluations of glycemic control based on BG values obtained from intermittent (ie, spot-check, 
fingerstick) glucometer readings
Evaluations of glycemic control based on BG values obtained from CGM readings, including but 
not limited to TIR; time in hyperglycemia and hypoglycemia ranges; daily, daytime, and nighttime 
average BG levels and estimated HbA1c; and glycemic variability
Clinically important hypoglycemic episodes from randomization through Week 39 and from Week 
39 through Week 78 
hypoglycemia, defined as BG levels 54 mg/dL (3.0 mmol/L) but <70mg/dL 
(3.9 mmol/L) and/or non-severe clinical episodes
Incidence of diabetic ketoacidosis (DKA) requiring medical attention, defined as a hyperglycemic 
episode with serum or urine ketones elevated beyond upper limit of normal (ULN) along with
serum bicarbonate <15 mmol/L or blood pH <7.3, or both, and resulting in outpatient, emergency 
room visit or hospitalization
Patient-reported outcomes measured by instruments, such as
Diabetes Module, the Hypoglycemia Fear Scale (HFS), and the Diabetes Treatment Satisfaction 
Questionnaire (DTSQ)
Impact on family life, measured by the parent-reported PedsQL Family Impact questionnaire  
C. Composite Clinical Endpoints:
Participants with both HbA1c in the American Diabetic Association (ADA) target range (ie, <7.5%) 
and exogenous insulin dose in specific ranges (<0.25, 0.25 to <0.50, 0.50 to <0.75, 0.75 to <1.0, 
1.0 to <1.25, and 1.25 U/k/d)   
Participants with both HbA1c of <6.5% and <7.0% and exogenous insulin dose of <0.5 U/kg/day 
or 0.25 U/kg/day
D. Immunologic and Endocrinologic Endpoints during the study:
Phenotypic and functional characterizations of white blood cell (WBC) populations, including T 
cells, B cells, and natural killer (NK) cells 
Serum proinflammatory and regulatory cytokine profiles and other immune mediators 
Number, type, and titer of T1D autoantibodies 
Antibody subclass levels 
Evidence of recent infection with coxsackie virus B (CVB)
Levels of circulating hormones (eg, glucagon, incretins, adiponectin) and other factors (eg, 
lipokines, cholesterol, triglycerides) associated with the course of T1D pathophysiology
E. Molecular and Genetic Endpoints during the study:
Circulating methylated- and unmethylated-
cell stress and 
damage 
Gene expression and transcriptome analyses 

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Association of human leukocyte antigen (HLA) type with clinical, metabolic and immune 
assessments 
OVERVIEW OF STUDY DESIGN
This is a Phase 3, randomized, double-blind, placebo-controlled, multinational, multicenter study. 
Approximately 300 participants will be enrolled and randomly assigned at a ratio of 2:1 to either the 
teplizumab group (N=200) or the placebo group (N=100).
To minimize bias in treatment assignment, potential confounders, and enhance the validity of statistical 
analysis, participants will be randomized at a 2:1 ratio using randomly permuted blocks and stratification 
based on the following criteria:
Peak C-peptide level at screening: within the range of 0.2 (inclusion criterion) to 0.7 pmol/mL
(inclusive) versus >0.7 pmol/mL 
Age at randomization: within the range of 8 to 12 years (inclusive) versus >12 to 17 years
Teplizumab or matching placebo will be administered via IV infusion in two courses, with the first course
starting on Day 1 (Week 1) and the second course approximately 6 months later at Day 182 (Week 26).
Each course of treatment will include daily infusions for 12 days.
Modified dosing schedule for participants affected by COVID-19 pandemic restrictions:
To address COVID-19-imposed force majeure, those participants who are unable to receive the second 
treatment course approximately 6 months after randomization (scheduled for the Day 182 [Week 26] visit) 
due to COVID-19-related restrictions will initiate the second course at the Day 364 (Week 52) visit instead, 
approximately 12 months after randomization.
References throughout the protocol (version 3.0 onward) to Day 364 (or Week 52) as the start of the second 
course of treatment is only applicable to this group of participants.
The total study duration for each participant will be up to 84 weeks. This includes a screening period of up 
to 6 weeks and a post-randomization period of 78 weeks. The treatment period includes two 12-day 
treatment courses separated by 6 or 12 months and a post-treatment observation period of approximately 
52 or 26 weeks, respectively.
An external, independent Data Monitoring Committee (DMC) will be commissioned for this study to 
provide oversight on safety and efficacy data and the conduct of the study. The DMC will make 
recommendations regarding the continuation, termination, or modification of the study.
STUDY POPULATION
This study will enroll male and female participants 8 to 17 years of age with new-onset T1D who are able 
to be randomized and initiate study treatment within 6 weeks of their diagnosis. To be eligible for 
randomization, participants must be positive for at least one T1D-associated autoantibody and have a peak 
stimulated C-peptide of 0.2 pmol/mL at screening. They must also meet all of the specific inclusion criteria 
and none of the exclusion criteria. 

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DOSAGE AND ADMINISTRATION
On the day of randomization (Day 1), each participant will receive the first dose of the study drug in the 
first 12-day treatment course, as shown in the table below. On approximately Day 182 or Day 364, each 
participant will receive the first dose of the second 12-day course. The study drugs (teplizumab or placebo) 
will be administered via IV infusion at the study site or other qualified facility by study-approved personnel.
The doses of study drug will be calculated based on
surface area (BSA) measured on 
the first day of each treatment course. No dose adjustment is permitted.
Treatment name
Teplizumab
Placebo
Description
Sterile solution for injection
Sterile solution for injection
Doses in each course
m2
m2
Days 3-
m2
Total per course: 9.0 mg/m2
Matching volumes to active drug
Frequency
Two courses starting at Week 1 and 
Week 26 or Week 52
Two courses starting at Week 1 and 
Week 26 or Week 52
Delivery method
IV infusion
IV infusion
KEY EVALUATIONS
MMTT: In order to
participants will undergo standardized 
provocative metabolic testing for C-peptide (a 1:1 by-product of insulin production). Participants 
will consume a fixed amount of a beverage with known amounts of carbohydrates, fats, and protein. 
Following consumption, BG, insulin, and C-peptide levels will be measured over time. A 2h
MMTT will be conducted at screening, and 4h MMTTs will be conducted at randomization and 
Weeks 26, 52, and 78 for key endpoint assessments.
HbA1c: This is the percent of red blood cells (measured as hemoglobin) that has become non-
enzymatic glycated proportional to blood glucose levels. This indicates, on average, approximately
a 3-month average of blood glucose values. It is a key clinical target in the management of T1D. 
In this study, it will be determined by a central laboratory.
Insulin use: As an average over 7 days of data collected before each specified visit to quantify
exogenously injected insulin.
Hypoglycemia: Clinically important and potentially life-threating hypoglycemia is the result of 
insulin therapy and more likely to occur in patients who are attempting to achieve glycemic control
goals. This study will ask participants to record information regarding BG levels of <70mg/dL (3.9 
mmol/L) and/or events that are consistent with hypoglycemia. A particular focus will be on 
clinically significant hypoglycemic events that are defined as a reliable glucose reading of 
<54 mg/dL (3.0 mmol/L) and/or severe cognitive impairment and/or physical status requiring 
external assistance for recovery.
Glucose Monitoring: Intermittent glucose monitoring (eg, spot-check or fingerstick) performed by 
participants or caregivers multiple times a day as a necessary part of glycemic management to 
gauge insulin dosing and assist in diet and activity. All participants are to bring in their glucometers
at all visits for review. In addition to data regarding glycemic control, at specified times during the 
study, participants will report their daily before-meal and before-bedtime BG readings and have
glucose levels assessed for 2-week intervals using CGM.
Quality of Life Questionnaires: Surveys will be used to assess the general health and wellbeing of 
participants and the effects of teplizumab, such as the PedsQL Diabetes Module, HFS, DTSQ, and 
parent-reported PedsQL Family Impact Module.

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PHARMACOKINETIC and IMMUNOGENICITY EVALUATIONS
Teplizumab concentrations will be analyzed in blood samples collected at specified time points throughout 
the study.
Anti-teplizumab antibodies will be determined, including those that are neutralizing antibodies (NAbs).
SAFETY EVALUATIONS
Adverse events, serious adverse events, and adverse events of special interest. The relatedness and 
severity will be evaluated by the investigator. Severity will be graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0.
Infusion-related reactions
Severe infections
Clinical laboratory tests
Vital signs and physical examination
STATISTICAL METHODS
General Considerations 
All statistical inferences will be based on 2-
-level of 0.05. All data will be summarized 
by study drug group. Categorical variables will be summarized by number and percent of individuals falling 
within each category. Continuous variables will be summarized by mean, median, standard deviation, 
minimum and maximum. Unless otherwise noted, baseline values will be defined as the most recent value 
collected prior to the first dose of study drug.
For efficacy endpoints, the analysis population will be all randomized participants who receive any amount 
of study drug, referred to as the intent-to-treat (ITT) population. For this population, participants will be 
analyzed in the treatment group corresponding to the treatment to which they are randomized, regardless 
of what treatment they actually receive.
For the safety endpoints, the analysis population will consist of all randomized study participants receiving 
at least one dose of study drug, referred to as the safety population. For this population, participants will be 
analyzed in the treatment group corresponding to the treatment they actually received, regardless of the 
treatment to which they were randomized.
For PK and immunogenicity, the analysis population will be all participants in the safety population who 
have provided at least one evaluable sample.
Sample Size Determination
The study sample size is calculated based on the desired clinically relevant effects and the results from 
placebo-treated participants in previous teplizumab studies. Since C-peptide AUC is skewed right, the data 
will be transformed using ln(AUC+1) for analysis. C-peptide data at 18 months from prior studies in 
children and adolescents who entered the studies with a stimulated C-peptide AUC of >0.2 pmol/mL are 
limited. Estimates range from approximately 0.22 nmol/L to 0.32 nmol/L with a standard deviation between 
0.18 and 0.22.  Using an estimate of 0.25 nmol/L, the transformation to geometric mean in the placebo 

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group is exp(0.25)-1) = 0.28. This study is designed to show a difference of at least a 40% in C-peptide 
response between teplizumab and placebo. In geometric means this translates to a value of (1.4*0.28) = 
0.392. Consequently, approximately 300 participants are planned for enrollment, assuming 2-
90% power, 2:1 randomization, and a 10% dropout rate.
Efficacy Analyses
The primary endpoint is the difference between treatment groups in C-peptide ln(AUC+1) at Week 78 using 
the ITT population. C-peptide will be measured in a 4h MMTT. Analysis of covariance (ANCOVA) will 
be used to assess the treatment difference in C-peptide at Week 78. Missing data from patients who drop 
out before the end of the study will be imputed based on those patients who similarly discontinue treatment 
in the same treatment arm but have measurement taken at scheduled visits. The model will include treatment 
(teplizumab or placebo), age, and peak C-peptide at baseline as covariates.
Sensitivity analysis will be performed using a tipping point approach. The same imputation and model will 
be used as in the primary analysis, but a tipping point that changes the C-peptide conclusion at 18 months 
will be sought. Repeated measures analysis may also be used to assess sensitivity.
The secondary clinical endpoints will be assessed using the Hochberg step-up method for addressing 
multiplicity if primary endpoint reaches p < 0.05. 
Like the primary endpoint, ANCOVA will be used to assess treatment differences in insulin use, HbA1c, 
and the 
at Week 78.
Average total exogenous insulin use (in U/kg/day) will be self-recorded in an eDiary for 7 days prior to 
study visits and at randomization. Data from at least 5 of these 7 days will be used for analysis. The model 
will include age, baseline insulin use, peak C-peptide at baseline and treatment group as covariates.
The model used to assess HbA1c will include age, baseline HbA1c, treatment group, and baseline peak C-
peptide as covariates.
Time in range for blood glucose will be defined as the average percentage of time in range for 10 to 14 days 
post each study visit. The model will include baseline time in range, treatment group, age and baseline peak 
C-peptide.
The rate (number of events/exposure time) of clinically important hypoglycemic episodes at Week 78 will 
be compared between groups. Data will be collected from intermittent glucose monitoring, continuous 
glucose monitors, participant eDiary and CRFs. A clinically important episode is defined as a reliable BG 
value of <54 mg/dL (3.0 mmol/L) and/or a hypoglycemia event requiring external assistance, (such as 
seizure, syncope, severe confusion with or without a confirmatory low BG reading). The event rate of 
clinically important hypoglycemic episodes per study participant will be assessed using a negative binomial 
model to allow for the potential for overdispersion in case episodes for hypoglycemia within participant 
groups are correlated. The model to assess clinically significant hypoglycemia will include age, treatment 
group, and baseline peak C-peptide as covariates.

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Other Analyses
Other analyses, including those for safety, PK, and immunogenicity, and exploratory endpoints will be 
conducted using established and accepted statistical approaches.
Additional safety and efficacy analyses will be performed on the subgroup of participants who receive the 
second treatment course starting at the Week 52 visit because of the COVID-19 pandemic restrictions.
Study Oversight 
The Sponsor recognizes that the study population, specifically children 8-17 years old recently diagnosed 
with T1D, is a vulnerable population at very high risk for disease- and therapy-related short- and long-term 
morbidity and mortality. There is no disease modifying therapy for T1D and the only therapeutic class of 
treatments approved for T1D was discovered almost a century ago. Therefore, the Sponsor has incorporated 
rigorous criteria and processes directed towards the best interest for the safety of study participants. This 
study will be regularly monitored, and data will be reviewed by the DMC, which will ensure the safe and 
appropriate conduct of this study and make decisions on the continuation, interruption, or termination of 
the study.

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ABBREVIATIONS
ADA
American Diabetes Association
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the time-concentration curve
-hCG
beta-human chorionic gonadotropin
BG
blood glucose
BP
blood pressure
BSA
body surface area
BUN
blood urea nitrogen
Celsius 
CBC
complete blood count
CD
cluster of differentiation 
CGM
continuous glucose monitoring
CL
clearance
Cmax
maximum concentration
CMV
cytomegalovirus
COVID-19
Coronavirus Disease 2019
CRF
case report form(s) (paper or electronic as appropriate for this study)
CTCAE
Common Terminology Criteria for Adverse Events
CVB
coxsackie virus b
DBili
direct bilirubin
DKA
diabetic ketoacidosis
DMC
Data Monitoring Committee
DNA
deoxynucleic acid
DPP-IV
dipeptidyl peptidase-4
DTSQ
Diabetes Treatment Satisfaction Questionnaire
EASD
European Association for the Study of Diabetes
EBV
Epstein-Barr virus
eCRF
electronic case report form
eDC
electronic data capture
EMA
European Medicines Agency
ET
early termination
Fahrenheit
Fc
fragment crystallizable region of an antibody/immunoglobulin molecule
FcR
receptor binding to the Fc component of antibody molecules
FDA
Food and Drug Administration
GAD
glutamic acid decarboxylase
GCP
Good Clinical Practice
HbA1c
hemoglobin A1c
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HLA
human leukocyte antigen

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HR
heart rate
HFS
Hypoglycemia Fear Scale
IA
islet antigen
IB
Investigator Brochure
ICA
islet cell cytoplasmic autoantibody
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
Ig
immunoglobulin
IGRA
interferon gamma release assay
IHSG
International Hypoglycaemia Study Group
IL
interleukin 
IM
intramuscular
IND
Investigational New Drug Application
INR
international normalized ratio
IRB
Institutional Review Board
IRE
immediately reportable event
ITT
intent to treat
IV
intravenous(ly)
IWRS
interactive web response system
KD
kilodalton
LDL
low density lipoprotein
LFT
liver function test
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MHC
major histocompatibility complex
MMTT
mixed meal tolerance test
MNAR
missing not at random
Nab
neutralizing antibody
NCI
National Cancer Institute
NK
natural killer
NONMEM
nonlinear mixed effects modeling
NSAID
nonsteroidal anti-inflammatory drug
PCR
polymerase chain reaction
PedsQL
Pediatric Quality of Life Inventory
PICC
peripherally inserted central catheter
PID
patient/participant identification number
PK
pharmacokinetic(s)
PMN
polymorphonuclear leukocyte
PQC
product quality complaint
PT
prothrombin time
PTT
partial thromboplastin time
RNA
ribonucleic acid
RR
respiratory rate
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD
standard deviation

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SOC
System Organ Class
SUSAR
suspected unexpected serious adverse reaction
T1D
type 1 diabetes
T1D AA
type 1 diabetes-associated autoantibody
TB
tuberculosis
TBili
total bilirubin
TCR
T cell receptor
TEAE
treatment-emergent adverse event
TIR
time in (glycemic target) range
Treg
U
T regulatory cell
unit
ULN
upper limit of normal range
VZV
varicella zoster virus
WBC
white blood cell 
ZnT8
zinc transporter 8

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1.
INTRODUCTION
Teplizumab (also known as PRV-
-Ala], and MGA031) is a humanized 150-
kilodalton (KD) monoclonal antibody (mAb) that binds to the CD3-
(TCR). Teplizumab was developed after preclinical studies demonstrated that targeting T cells (the 
cells that are instrumental in initiating and coordinating the autoimmune process responsible for 
type 1 diabetes [T1D] mellitus) via this mechanism altered diabetes immunopathogenesis and 
prevented and reversed disease in relevant animal models. A number of clinical studies have 
demonstrated the ability of teplizumab to slow or even halt the destruction of the insulin-secreting 
in populations of individuals with newly diagnosed T1D. The goal of this study is to 
evaluate teplizumab in patients who may be most responsive to it as suggested in previous studies,
namely children and adolescents very recently diagnosed with T1D. Teplizumab holds the promise 
to be the first disease modifying therapy available to improve both the medical management and 
overall outlook in those who suffer the most devastating short- and long-term consequences of this 
disease. 
For the most comprehensive nonclinical and clinical information regarding teplizumab, refer to 
the latest version of the Investigator Brochure (IB).
The term Sponsor
used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
T1D is a T cell-mediated autoimmune disease that targets and destroys the insulin secreting
located in the islets of Langerhans in the pancreas (Ziegler 2010, Atkinson 2014). The loss of these 
ty to sense glucose levels and produce insulin. In the absence of 
therapy, this leads to severe, unsustainable metabolic dysregulation, namely uncontrolled blood 
glucose elevation (hyperglycemia) and its short and long-term sequelae including rapid wasting 
and inevitable, near-term death. 
T1D is an immediate and lifelong, life-threatening disorder afflicting millions of people 
worldwide. It most often presents in children and adolescents and is one of the three most prevalent 
severe chronic diseases of childhood, along with asthma and cancer.  The annual incidence is 
highest in children and young adults with ~20 to 25 cases/100,000/year in those younger than 20 
years old in North America and many Westernized countries and is over 40-60 cases/100,000/year 
in some areas in Northern Europe and Sardinia (Atkinson 2014, Bluestone 2010, Streisand 2014,
Karvonen 2000). Due to its short- and long-term complications, T1D is both a daily and life-long
burden for individuals and their families and also has significant socio-economic and societal-
medical ramifications, which are intensifying as the worldwide incidence of T1D increases up to 
5% annually (Karvonen 2000).
Exogenous insulin is needed immediately for those diagnosed with T1D and is required for their 
lifetime. Prior to the discovery of insulin almost 100 years ago, T1D was a disease that was 
uniformly fatal, often within weeks to months. Significant advancements have been made in the 
types and delivery of insulin and glucose monitoring 

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inherent ability to maintain metabolic control. Glycemic management is a daily challenge and 
individuals must constantly balance current blood glucose readings, caloric intake and 
composition, type and amount of injected insulin, injection site locations, time of the day, health 
status and activity level to determine even a single dosing of insulin per day. Although needed for 
survival for those with T1D, exogenous insulin has significant side effects and dosing errors can 
result in hypoglycemia, seizures and death. Iatrogenic hypoglycemia is thought to contribute to the 
, which is a sudden unexplained death while sleeping in those with T1D
(Secrest 2011). The medical community realizes the significant risks of insulin administration. In
s
as it is a drug with a heightened risk of causing significant patient harm (Joint Commission 1999).
There are likely few, if any, other medical conditions for which individuals self-administer a 
potentially lethal therapy drug multiple times a day that they store in their homes. 
Even in the present day, with the availability of insulin and glucose monitoring and advanced 
understanding of T1D, failure of regular dosing can result in the prototypic T1D-associated 
conditions like hyperglycemia, dehydration, and diabetic ketoacidosis (DKA), which can result in 
cerebral edema and death. With even the most stringent control targeting current glycemic goals, 
those with T1D are at risk for longer-term complications including severe renal, cardiac, 
neurologic and micro- and macro-vascular disease (Atkinson 2014, Bluestone et al 2010, Steffes 
2003). These translate into blindness, myocardial infarctions, strokes/cerebral vascular accident, 
extremity amputation, erosive non-healing foot ulcers, chronic local and systemic infections, and 
renal failure requiring dialysis or transplantation. Those who develop T1D early in life are at 
increased risk for significant neurocognitive disorders including behavioral issues, lower 
intellectual performance and motor dysfunction, and associated structural changes in the brain (Lin 
2015).
The signs and symptoms of T1D, and thus the clinical diagnosis, occur when there is a significant
reduction in
(Matveyenko 2008, Campbell-Thompson 2016). The loss of function 
based on heightened metabolic stress and a direct effect of the local proinflammatory immunologic 
milieu (Akirav 2008, Greenbaum 2012, Keenen 2010, Matveyenko 2008).  However, recent 
many or most appear temporarily dysfunctional due to metabolic and inflammatory stress, and 
glucotoxicity (Akirav 2008, Matveyenko 2008). Many individuals, especially children, who are 
there is a substantial reduction in exogenous insulin needs (and in some cases, insulin 
independence) but inevitably full replacement doses of exogenous insulin are needed (Abdul-
Rasoul 2006, Mortensen 2009). This period
cells regain function. This phenomenon supports the premise that if these functional, and 
seemingly non-functional remaining 
, can be spared from autoimmune destruction, 
substantial clinical benefit could be achieved.
T1D is known to be the result of a multifaceted autoimmune attack on
. T1D appears to 
develop in genetically predisposed individuals who encounter an environmental stimulus that 
-specific self-reactive T cells (Ziegler 2010, Atkinson 2014).

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Putative triggers have included specific foods and infections, with mounting data supporting that 
coxsackie virus B (CVB) infection can precipitate T1D autoimmunity in some individuals (Ziegler 
2010, Laitinen 2014). A cascade of cellular and humoral immune mediators is activated over time 
(which may be many years) which destroys
until a critical mass is lost and an individual 
becomes symptomatic from hyperglycemia. Due to the autoimmune etiology of T1D, an 
immunomodulatory-based therapy is considered the most promising approach to
cells 
and endogenous insulin production, which could translate into
retention of at least partial 
endogenous glycemic control
which recent studies indicate can be critical in improving many 
short- and long-term outcomes of T1D. CD4+ and CD8+ T cells are instrumental in the initiation 
of the T1D autoimmune process, direct killing of 
cells and orchestrating the other immune
pr
cell destruction. Data from animal studies and several clinical trials 
support specifically that therapies targeting T cells, including abatacept (CTLA4Ig), alefacept 
(LFA3Ig) and antibodies targeting the CD3 complex, have the most potential, and have proven to 
be the most promising,
cells
in humans with T1D (Rigby 2013, Rigby 2016, Herold 2002, Herold 2005, Herold 2013 (Abate), 
Hagopian 2013, Masharani 2010, Orban 2011).
Preventing, halting or even significant slowing of 
cell destruction using a disease-modifying 
therapy, instead of just managing symptoms of hyperglycemia, is seen as the way to lessen the 
daily burden on those with T1D, and their families, and reduce the significant disease and 
therapies-associated morbidity and mortality (Mittermayer 2017). A clear example of this benefit 
was shown in the Diabetes Control and Complications Study (Diabetes Control and Complications 
Trial Research Group 1997) in which the rates of significant hypoglycemia were less in patients 
-peptide. Moreover, the risk 
of microvascular complications such as retinopathy and others were significantly reduced in those 
who maintained a C-peptide level of at least 0.2 pmol/mL (Lachin 2014, Palmer 2004, Palmer 
2009). In recent years, potential therapies to modify the course of the disease by targeting key 
components of the immune response have been identified and have started to be evaluated in 
clinical trials. Although to date there are no approved products to modify the course of T1D, 
teplizumab has substantial clinical data supporting further study and development to become the 
first disease-modifying therapy for T1D.
1.2.
Teplizumab Overview
Teplizumab was originally developed in the late 1980s, primarily as an investigational therapy for 
T1D following a number of preclinical studies showing efficacy in animal models of T1D. 
Teplizumab is a humanized monoclonal antibody (mAb) variation of OKT3 (Muromonab-CD3)
that binds to
(Masharani 2010, Herold 2002). It has 
a modified Fc portion aimed at disrupting Fc receptor and complement component C1q binding to 
minimize the cytokine-mediated toxicity of the parent mAb. The molecular weight of teplizumab 
is approximately 150 KD. 
Teplizumab has been evaluated in a number of clinical trials in new onset T1D, and in renal and 
islet allo-transplantation, and psoriatic arthritis. There are ongoing studies evaluating teplizumab 
in children and adults at high risk of developing T1D and a combination therapy of teplizumab 

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with a genetically modified strain of Lactobacillus designed to secrete human pro-insulin and 
human interleukin-10.
By far the most extensive clinical trial experience is in children and adults with newly diagnosed 
T1D, where over 1000 individuals were enrolled in 7 clinical studies, of whom 829 have been 
treated with teplizumab. Results from these studies suggest that it is one of the most promising 
candidates for disease modification of T1D. In pilot and proof-of-concept clinical studies 
conducted in young children, adolescents, and adults, short courses (approximately 2 weeks) of 
teplizumab treatment have been shown to be safe and well tolerated, resulting in relative sparing 
cell function in those who were recently diagnosed with T1D (Herold 2002, Herold 2005,
Herold 2013a, Herold 2013b).
As part of many of these clinical trials, there has been extensive mechanistic evaluation of 
teplizumab. These evaluations have shown a number of effects on specific subpopulations of T 
cells that are integral for the initiation and propagation of the 
cell destructive autoimmune 
process. Circulating T cells (and other lymphocytes) are transiently reduced following teplizumab 
treatment, in a process that may include margination and depletion (Long 2017, Sherry 2011). In 
addition to reduced effector function of T cells, teplizumab appears to both increase the number 
and function of regulatory T cells (Tregs) (Ablamunits 2010, Bisikirska 2005, Long 2017,
Waldron-Lynch 2012). More recent studies indicate that teplizumab induces immunologic 
+ T cells, perhaps making them more susceptible to 
regulation or deletion (Long 2016, Long 2017). Taken together, these mechanistic data suggest 
that teplizumab not only exerts
cell immune destructive processes but 
rather 
a rebalancing of effector and regulatory arms involved 
with T1D autoimmunity and supporting the notion that teplizumab may have the ability to 
contribute to the re-introduction of
cell self-tolerance (Lebastchi 2013).
A multi-
previously conducted by MacroGenics and Eli Lilly and Company. Over 500 children and adults 
8 to 35 years old with T1D were enrolled within 12 weeks of diagnosis and evaluated in 3 different 
teplizumab dosing regimens or placebo (Sherry 2011, Hagopian 2013). The study used a novel 
and untested composite primary endpoint integrating glycemic control, measured by hemoglobin 
A1c (HbA1c) level, and insulin use; specifically, participants were considered to meet the primary 
endpoint if they had HbA1c <6.5% and insulin use <0.5 units/kg/day at 1 year post randomization.
Although the study did not meet this primary endpoint, the study results in the randomized 
treatment group (14-day regimen, 9 mg/m2 dose per course) showed a statistically significant 
benefit in slowing the decline in C-peptide at 18 and 24 months, which supported the findings of 
previous studies that teplizumab does have the ability to preserve 
function in those newly 
diagnosed with T1D (Hagopian 2013). Furthermore, the effect of teplizumab treatment was even 
more notable in participants with the following characteristics at the time of study entry: enrolled 
in sites in the United States, 8 to 17 years of age, higher baseline C peptide levels, and randomized 
within 6 weeks of TID diagnosis (Hagopian 2013).
generally very well tolerated. In general, 
there are no major differences in overall adverse events (AEs) of clinical concern and serious 

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adverse events (SAEs) between teplizumab and placebo groups. The most common AEs associated 
with teplizumab are a decrease in white blood cell counts, nausea and/or vomiting, upper 
respiratory infections or nasopharyngitis and elevations in AST or ALT and anemia, all usually 
mild or moderate. The most frequent observation is a decrease in white blood cell count (WBC),
including, in order, transient lymphopenia, leukopenia, and neutropenia. Transient lymphopenia 
has occurred in ~2/3 of teplizumab recipients and is usually mild or moderate, which is consistent 
of action (Sherry 2011, Hagopian 2013). These events are usually 
self-limited and occur with teplizumab dosing and spontaneously reconstitute. For example, 
lymphocytes return to 80% of baseline levels within approximately 14 days of dosing.
Approximately half of those who receive teplizumab develop a mild rash, sometimes pruritic,
during dosing cycles, which spontaneously resolves within 7-14 days. Due to its mechanism of 
action, cytokine release syndrome is a potential concern with teplizumab dosing but occurs in
<10% of teplizumab-
mild-to-moderate and well tolerated. Prophylactic administration of non-steroidal anti-
inflammatory drugs (NSAIDs; eg, ibuprofen) and antihistamines (eg, diphenhydramine) appear to 
reduce the occurrence and the severity of its signs and symptoms significantly. 
, severe AEs were noted in approximately 63% and 30% of teplizumab and 
placebo participants, respectively (Sherry 2011, Hagopian 2013). The most common (though
occurring in less than 10% of teplizumab treated participants) was decreased white blood cell 
counts. Three deaths occurred and were categorized by the principal investigator (in accordance 
with International Conference on Harmonization (ICH)/Good Clinical Practice (GCP) guidelines) 
and included in the IB. The specific causes of deaths and relationship with teplizumab are listed 
;
infarction with ventricular tachycardia and cardio-
;
Despite the decrease in WBC, overall infections were not increased following teplizumab 
treatment. However, in the
study there were 10 cases of herpes zoster (the result of 
reactivation of varicella zoster virus [VZV], the causative agent of chicken pox and shingles) in 
teplizumab-treated patients; all cases resolved without consequence. In the study, other herpes 
virus infections (eg, cytomegalovirus and Epstein-Barr virus) were not increased with teplizumab 
treatment (Sherry 2011, Hagopian 2013).
A significant body of data exists indicating that in the appropriate individuals, teplizumab can have 
a significant beneficial effect in maintaining 
cell function and is well tolerated without side-
effects that would limit its consideration as a viable disease modifying therapy for children and 
adolescents newly diagnosed with T1D. 
In 2018, Provention Bio, Inc. acquired teplizumab (renamed as PRV-031) with a goal to further 
develop teplizumab as a first-in-class approved disease modifying therapy for T1D.

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1.3.
T1D and Teplizumab Experience in Children and Adults
Type 1 diabetes usually develops in childhood and adolescence; however, it can also present in 
adulthood as late as the 5th and 6th decades of life, although much less frequently (Atkinson 2014, 
Bluestone 2010, Streisand 2014). In addition to being more prone to some short- and long-term 
complications, there are differences in the clinical course and response to immune therapies 
between children/young adults and older adults. In the days or weeks before initial diagnosis,
children and adolescents often suffer from severe diabetes symptoms, including polydipsia, 
polyuria, and weight loss, which could result in a clinical presentation of DKA and shock which 
requires hospitalization (Atkinson 2014, Bluestone 2010, Streisand 2014, Mittermayer 2017).
Children and young adults with new-onset T1D usually have an immediate need for exogenous 
insulin. 
This sharply contrasts with the experience of adults who develop T1D who often have months or 
years of non-specific symptoms or present asymptomatically from routine glycemic screening.
These individuals can often be managed for prolonged periods of time (months or years) with diet 
or oral hypoglycemic agents before a demonstrable insulin need. More definitive studies have 
cells according to age (Greenbaum 2012; Ludvigsson 2013).
Following decades of study, the Diabetes TrialNet network has concluded
important factor impacting the rate of decline of C-
in that a significantly 
more rapid rate of decline occurs in children and adolescents compared to younger and older adults
with new-onset disease. This more rapid decline appears to be due to a much more virulent and 
aggressive autoimmune process in children compared to adults, ostensibly supporting that there 
are important differences in T1D immuno-pathoetiology in younger versus older individuals
(Greenbaum 2012, Campbell-Thompson 2016). Due to these fundamental differences, it is 
reasonable to expect that adults and children may respond differently to an immune-based disease 
modifying therapy. In other words, one treatment may be very effective in children but not 
effective at all in adults and vice versa (Rigby 2014).
These differences in disease pathophysiology between younger and older individuals with T1D 
are supported by the data from a number of recent new-onset T1D studies that have demonstrated 
differences in how younger and older individuals respond to immune interventions. Studies of 
abatacept, rituximab, alefacept, and teplizumab all appear to have a preferential effect on children 
and young adults; whereas thymoglobulin at doses at 6.5 mg/kg over four days appeared to 
cells in adults, but not children (Rigby 2014, Rigby 2015, Orban 2011, 
Hagopian 2013, Gitelman 2013).
In the case of teplizumab, both children (as young as age 7 years) and adults (up to age 35 years) 
have been studied concurrently in all previous clinical trials. In studies demonstrating metabolic 
and clinical benefit, the average age of participants was ~12-13 years old (Herold 2002, Herold 
2013b). Interestingly, although the Phase 3 study of teplizumab (the 
) also enrolled
children and adults (age 8 to 35 years old) the mean age was significantly higher than previous
positive studies, at ~18 years old. Although the primary endpoint
was not met in the 
overall study population, post-hoc analysis showed that children and adolescents 8-17 years old 

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did have a statistically significant retention of C-peptide at key time points, including 12, 18, and 
24 months post randomization (Hagopian 2013).
Children and adolescents are those at highest risk of developing disease and suffer most 
substantially from short- and long-term morbidity and mortality, and thus this group has the most 
to benefit from a disease modifying therapy (Wherrett 2015). This has recently been reinforced by 
a large study showing that those diagnosed with T1D in childhood and adolescence have a 4-6-
fold increase in lifetime mortality risk, including seven times the risk of mortality from 
cardiovascular disease, compared to counterparts without T1D. This mortality risk is in sharp 
contrast to individuals diagnosed with T1D in adulthood, who have a ~3-fold higher risk from all-
cause and cardiovascular disease-related mortality compared to their otherwise healthy peers
(Rawshani 2017, Rawshani 2018). Recent reports indicate that those with T1D have a life 
expectancy ~11-13 years less than otherwise healthy-age matched individuals (Lind 2014, Huo 
2016). While it is a goal in T1D research to reduce the morbidity and mortality for all with T1D, 
it is apparent that the most urgent need is for those who develop T1D in childhood and adolescence.
Because children and adolescents are those who appear to be most responsive to teplizumab and 
have the most to benefit from a disease modifying therapy, this study will enroll individuals who 
are 8-17 years old. Although adults (ie, those 18 years or older) with T1D may benefit with 
teplizumab, their response appears to be more variable than pediatric counterparts; therefore,
inclusion of adults into this study may diminish, or even preclude, the ability to identify a positive 
effect of teplizumab in children and adolescents and hamper the development of an important 
therapy for these individuals. While not currently approved for use in children or adults, 
teplizumab has been studied for almost 20 years in over 1000 individuals ~8-35 years old, 
including over 450 who have been less than 18 years old. Thus far, in doses and regimens similar 
to one that will be used in this study, teplizumab has been well tolerated in all age ranges with no
apparent differences in side effect profiles or safety signals in younger versus older individuals. 
Most importantly, as the urgent goal is to develop a therapy for those who will most likely benefit 
from it, this study will primarily focus on children and adolescents.
1.4.
Overall Rationale for the Study
The clinical trial detailed herein, the PROTECT study, builds on the evidence from a number of 
previous clinical trials of teplizumab and focuses on patients who are likely to be the most 
responsive to this therapy. This study will enroll children and adolescents 8 to 17 years old who 
have been recently diagnosed with T1D (within the previous 6 weeks) and demonstrate a critical 
level of residual, and recoverable
cell function. This population and approach to intervention 
can be considered a realistic paradigm to intervene in a disease with a significant unmet need in 
the population with this disease who have most to benefit from a disease modifying therapy.
cell function 
and improve clinical management of T1D compared with the natural course of disease and current 
standard of care including exogenous insulin therapy
cell function is 
anticipated to translate to clinical and/or metabolic benefits consistent with improved ability to 
maintain glycemic control and short- and/or long-term outcomes. This study will be conducted in 

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North America and Europe in children and adolescents with recently diagnosed T1D who have a
clinically relevant level of cell function at study entry. Participants will be treated with two full 
courses of teplizumab. The study will assess the internationally accepted primary endpoint, the
area under the time-concentration curve (AUC) of C-peptide following a mixed meal tolerance test 
(MMTT), at 78 weeks (18 months or 1.5 years), while also evaluating additional clinical endpoints 
(eg, insulin use, HbA1c, and clinically important hypoglycemic episodes), safety, and exploratory 
assessments over the course of the study. 
The goal of this study is to provide critical data, in accordance with the current guidelines by the 
European Medicines Agency (EMA) and Food and Drug Administration (FDA), to support the 
registration of teplizumab as a disease-modifying therapy for children and adolescents with T1D, 
those who have the most to benefit in both the short- and long-term from improved retention of 
cell function following the diagnosis of T1D.
1.5.
Risk and Benefit Assessment
Type 1 diabetes (T1D) is an autoimmune disease that results in a severe metabolic disease of 
glucose dysregulation. T1D is associated with significant short- and long-term complications and 
early death. Even with the best metabolic control using the most current insulins and glycemic 
monitoring devices, these risks are not eliminated. There is an urgent need to develop a disease 
modifying therapy for T1D. 
Clinical studies with teplizumab in T1D have shown that it is effective in preserving beta cell 
function (as measured by C-peptide) and hence endogenous insulin production (Herold 2019). In
the previous 
resulted in a statistically significant preservation of C-
peptide, compared to placebo, at 2 years. As described in natural history studies, preservation of 
residual beta cell function (as measured by C-peptide levels) is protective against short-
(hypoglycemic episodes) and long-term complications of T1D, including retinopathy, nephropathy 
and other cardiovascular events (Steffes 2003, Sorensen 2013, Lachin 2014, Kuhtreuber 2015).
Furthermore, the benefit of teplizumab in the preservation of beta cell function was more 
pronounced in younger participants (age 8-17 years), those who were treated early in the course of 
T1D (within 6 weeks of diagnosis), and those with higher baseline C-peptide levels. These latter 
characteristics were applied to the eligibility criteria in this study. In addition, a reduction in insulin 
use while maintaining glycemic control (as measured by HbA1c) was observed in participants who 
received teplizumab.  
n,
individuals with pre-symptomatic T1D (defined as the presence of at least two T1D-associated 
autoantibodies and dysglycemia), teplizumab was shown to delay the onset of clinical diabetes by 
at least 2 years (Herold 2019).
The main risks of teplizumab consist of transient lymphopenia and transient self-limited (mild to 
moderate) rash. Cytokine release syndrome is infrequent (~6%) and there is no overall increased 
risk of clinical infection or cancers. 
Given the potential for important benefit in short- and long-term T1D outcomes compared to the
transient, mild to moderate risks of teplizumab, the current study is investigating the previously 

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tested, two-course short-term dosing of teplizumab in younger patients who have the most to 
benefit from a disease-modifying therapy, specifically, children and adolescents with newly 
diagnosed T1D (within 6 weeks of diagnosis) and those with a critical threshold of endogenous 
production. Thus, the prospect of benefit outweighs the risk of participating in this study.
2.
HYPOTHESIS, OBJECTIVES, ENDPOINTS
2.1.
Study Hypothesis
The hypothesis of this study is that teplizumab is safe, well-tolerated, and effective in slowing the 
cell function in children and 
adolescents newly diagnosed with T1D while improving key aspects of T1D clinical management 
over an 18-month period.
2.2.
Study Objectives
The Primary Objective of this study is:
To determine whether two courses of teplizumab slow 
cell function over 18 months (78 weeks) in children and adolescents 8-17 years old who 
have been diagnosed with T1D in the previous 6 weeks.
The Secondary Objectives of this study are:
To evaluate participant improvements in key clinical parameters of diabetes management, 
including insulin use, glycemic control (as measured by HbA1c and time in glycemic target 
range [TIR]), and clinically important hypoglycemic episodes
To determine the safety and tolerability of two courses of teplizumab, administered 
intravenously (IV)  
To evaluate the pharmacokinetics (PK) and immunogenicity of two courses of IV 
teplizumab
The Exploratory Objectives of this study are: 
To assess cell function and T1D-focused clinical parameters 
To evaluate immunologic, endocrinologic, molecular, and genetic markers 
2.3.
Study Endpoints 
The Primary Endpoint of this study is:
The area under the time-concentration curve (AUC) of C-peptide after a 4-hour (4h) mixed 
function, at Week 78.
The Secondary Endpoints of this study are as follows:
A. Key Clinical Endpoints:

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Exogenous insulin use: defined as a daily average in units per kilogram per day (U/kg/day),
at Week 78
HbA1c levels: expressed in % and mmol/mol, at Week 78
TIR: expressed as a daily average of the percentage of time in a 24 hour-day a participant s
BG is >70 but
180 mg/dL (>3.9 to
10.0 mmol/L) assessed using continuous glucose 
monitoring (CGM), at Week 78
Clinically important hypoglycemic episodes: defined as the total number of episodes of a 
BG reading of <54 mg/dL (3.0 mmol/L) and/or episodes of severe cognitive impairment 
requiring external assistance for recovery, from randomization through Week 78
B. Safety Endpoints:
Incidence of treatment-emergent adverse events (TEAEs), adverse events of special 
interest (AESIs), and serious adverse events (SAEs)  
Incidence of treatment-emergent infections of special interest, including but not limited to 
tuberculosis, an infection requiring IV antimicrobial treatment or hospitalization, Epstein-
Barr virus (EBV) and cytomegalovirus (CMV) infection, or significant viremia (ie, DNA-
based polymerase chain reaction viral load >10,000 copies per mL or 106 cells), and herpes 
zoster
Incidence and severity of immediate or delayed study drug infusion-related reactions, such 
as hypersensitivity reactions, pain requiring interruption or discontinuation of infusions, 
cytokine release syndrome, and serum sickness
C. Pharmacokinetic and Immunogenicity Endpoints:
Teplizumab serum concentrations 
Incidence and titers of anti-teplizumab antibodies after treatment courses
The Exploratory Endpoints of this study are as follows: 
4h MMTT C-peptide AUC
Participants with the recognized clinically significant stimulated peak C-peptide of 
0.2 pmol/mL during 4h and 2-hour (2h) MMTTs 
Proinsulin-to-C-
dysfunction
B. T1D-focused Clinical Endpoints during the study unless otherwise noted: 
Exogenous insulin use (in U/kg/day)
HbA1c levels
Participants with poor glycemic control, defined as HbA1c of 9%

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The number of participants who do not require exogenous insulin because they are able to 
achieve local, regional, or national age-based glycemic management goals for HbA1c 
and/or routine blood glucose levels  
Evaluations of glycemic control based on BG values obtained from intermittent (ie, spot-
check, fingerstick) glucometer readings
Evaluations of glycemic control based on BG values obtained from CGM readings,
including but not limited to TIR; time in hyperglycemia and hypoglycemic ranges; daily, 
daytime, and nighttime average BG levels and estimated HbA1c; glycemic variability 
Clinically important hypoglycemic episodes from randomization through Week 39 and 
from Week 39 through Week 78. 
Incidence of typical hypoglycemia, defined as BG levels 54 mg/dL (3.0 mmol/L) but 
<70 mg/dL (3.9 mmol/L) and/or non-severe clinical episodes
Incidence of DKA requiring medical attention, defined as a hyperglycemic episode with
serum or urine ketones elevated beyond upper limit of normal (ULN) along with serum 
bicarbonate <15 mmol/L or blood pH <7.3, or both, and resulting in outpatient, emergency 
room visit or hospitalization
Patient-reported outcomes measured by instruments, such as
(PedsQL) Diabetes Module, the Hypoglycemia Fear Scale (HFS), and the Diabetes 
Treatment Satisfaction Questionnaire (DTSQ)
Impact on family life, measured by the parent-reported PedsQL Family Impact 
questionnaire  
C. Composite Clinical Endpoints:
Participants with both HbA1c in the American Diabetic Association (ADA) target range 
(ie, <7.5%) and exogenous insulin dose in specific ranges (<0.25, 0.25 to <0.50, 0.50 to 
<0.75, 0.75 to <1.0, 1.0 to <1.25, and 1.25 U/k/d)
Participants with both HbA1c of <6.5% and <7.0% and exogenous insulin dose of <0.5 
U/kg/day or 0.25 U/kg/day
D. Immunologic and Endocrinologic Endpoints during the study:
Phenotypic and functional characterizations of WBC populations, including T cells, B 
cells, and natural killer (NK) cells 
Serum proinflammatory and regulatory cytokine profiles and other immune mediators 
Number, type, and titer of T1D autoantibodies 
Antibody subclass levels 
Evidence of recent infection with CVB
Levels of circulating hormones (eg, glucagon, incretins, adiponectin) and other factors (eg, 
lipokines, cholesterol, triglycerides) associated with the course of T1D pathophysiology
E. Molecular and Genetic Endpoints during the study:

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populations, as long as there is a known and acceptable safety profile (Wherrett 2015, Greenbaum 
2012, Rigby 2014). There are no exclusions based on gender, sex, ethnicity or race.
In addition, the study will focus on individuals who have a significant amount of 
functional
capacity. It is recognized that 
s continue to be lost following T1D diagnosis. To maximize 
the effect of 
preservation in patients with a recoverable level endogenous insulin production,
this study will recruit participants within 6 weeks from T1D diagnosis and a peak C-peptide level 
of
0.2 pmol/mL during a mixed meal tolerance test (MMTT). The value of 0.2 pmol/mL was 
chosen as it is a key and accepted threshold of C-peptide correlated with clinically important lower 
rates of T1D-associated short- and long-term complications (Lachin 2014, Palmer 2001, Palmer 
2009). Analysis of previous clinical trials supports that individuals receiving teplizumab closer to 
the time of T1D diagnosis and those who have a higher, demonstrable levels of C-peptide have a 
more favorable response to teplizumab, in terms of maintenance of endogenous insulin production 
and clinically relevant benefits.
3.1.1. Screening and Participant Enrollment
The enrollment goal of this study is approximately 300 participants. Based on previous studies of 
teplizumab, the screen-failure rate is estimated to be ~33%, and it is anticipated that up to ~450
individuals may need to be screened for full enrollment.
3.1.2. Randomization and Stratification
Previous interventional studies in new-onset T1D (including earlier teplizumab clinical trials)
suggest clinical and metabolic response may be influenced, at least in part, by age and 
cell
function near the time of diagnosis. The peak C-peptide stratification level was chosen based on 
data showing that 0.7 pmol/mL is a threshold indicating differential responsiveness to teplizumab 
(Hagopian 2013). The age stratification of 12 years was chosen as this is the mid-point of the age 
range of 8-17 years and an accepted threshold separating childhood from adolescence. Twelve 
years old has been used as a cut-off in T1D natural history studies and in the post hoc analyses of 
, Greenbaum 2012).  
Therefore, to minimize bias in treatment assignment, potential confounders, and enhance the 
validity of statistical analysis, participants will be randomized at a 2:1 ratio using randomly 
permuted blocks and stratification based on the following criteria:
Peak C-peptide level at screening: within the range of 0.2 (inclusion criterion) to 
0.7 pmol/mL (inclusive) versus >0.7 pmol/mL
Age at randomization: within the range of 8 to 12 years (inclusive) versus >12 to 17 years
3.1.3.
Study Treatment 
Teplizumab or matching placebo will be administered via IV infusion in two courses, with the first 
course starting on Day 1 (Week 1) and the second course on approximately Day 182 (Week 26).
Each course of treatment will include daily infusions for 12 days. See Section 6 for details.
Modified dosing schedule for participants affected by COVID-19 pandemic restrictions:

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The most extensive and detailed
study, in which two multi-day courses of teplizumab were given 6 months apart to children and 
adults 8 to 35 years old who were diagnosed with T1D within 12 weeks of T1D diagnosis. In that 
study, three dosing regimens of teplizumab were evaluated: (1) a 14-day course with a cumulative 
dose of 9.0 mg/m2; (2) a 14-day course with a cumulative dose of 3.0 mg/m2; and (3) a 6-day 
course with a cumulative dose of 2.4 mg/m2. In the open-label Phase 2
participants received the 14-day regimen of 9.0 mg/m2/course at enrollment and 26 weeks later to 
assess safety and tolerability before the double-blind study was started. The Phase 3 segment 
studied the three teplizumab dosing regimens in comparison to placebo. The open label Phase 2 
-blind Phase 3 segment 
enrolled 207, 102, and 106 teplizumab-treated participants, respectively, and the placebo arm 98 
participants (Sherry 2011, Hagopian 2013).
immunogenicity evaluations. From this data, a detailed population PK model has been developed 
using a two-compartment (peripheral and central) model with saturable binding kinetics
incorporating body surface area (BSA), proportional dosing, and teplizumab AUC, Cmin, and Cmax.
These findings showed that PK was independent of age, gender, race, region, disease state or onset,
although it was influenced by antidrug-antibody response.
As described earlier, although the previously untested and unevaluated composite primary 
T1D was confirmed in
clinical studies. Specifically, participants from certain regions (eg, the United States) who were 8-
17 years old, who had teplizumab initiated within 6 weeks of T1D diagnosis and with higher C-
peptide levels at study entry showed significant retention of endogenous insulin production 
through 2 years compared to placebo treated participants.
Of note, the 14-
9.0 mg/m2
2, Day 2: 
2
2
2, and Days 5-
2/day. In
4-day ramp-up, approximately 8.6% of the total dose was given, with ~1.7% of the total dose in 
the first 2 days. In the last 10 days ~91% of the total dose was delivered in equally divided doses.  
A 14-day course of treatment necessitates participants and their parents or guardians (required by 
pediatric participants) to be available every day for 2 entire consecutive weeks. This requirement 
is seen to be particularly challenging to children and adolescents and their families due to work 
and school obligations and therefore may have a negative influence on recruitment and retention
as well as a significant bias in a pivotal study.
With the realization of the potential negative impact on many aspects of the clinical trial of a 14-
day treatment course combined with the significant experience with teplizumab, this study sought 
to develop a more participant and family-friendly treatment regimen that delivered clinically 
overlapping exposures that could support approval for teplizumab.

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In this study, participants will be randomized to placebo or teplizumab (9.0 mg/m2/course) for two 
courses. Each course will be administered in a more convenient manner over 12 days:  Day 1: 106 
2
2, and Days 3-
2/day. During the first 2 days of ramp-up, 
approximately 5.9% of the total dose is given. In the last 10 days, ~94% of the total dose is 
delivered in equally divided doses.
Compared to a 14-
-day teplizumab course has a modified 2-day 
ramp-up phase but also has a 10-day fixed-, maximal dosing period like the 14-day course. Based 
on calculations, the amount of teplizumab given in the 12- and 14-day approach only differs by 
0.005 mg/m2. But due to practical aspects of rounding and calculating the BSA and a given dose, 
these courses are considered clinically equivalent.
As shown in the PK simulations in Figure 3, the first 2 doses in the 14-day regimen are calculated 
to have very low, almost negligible, serum concentrations with serum concentrations of the last 11 
doses of both regimens that are superimposable. In both instances, >90% of the total dose per 
course is given in the final 10 days in similar equally divided doses (0.850 mg/m2 in the 12-day 
course versus 0.826 mg/m2 in the 14-day course). The first 2 days of the 14-day course delivers a 
nominal amount (ie,
ng/mL [14-
-day regimen]), as well as the 
elimination times are overlapping in both regimens. 
Figure 3.
PK Simulation of 12-Day and 14-Day Dosing Regimens
Taken together, this study will evaluate a more participant and family-friendly approach to deliver 
the same dose of 9.0 mg/m2 of teplizumab given 6 months apart, which has been shown to be well 

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of the regimens and exposures, data from this study can be combined with data from other studies 
to support the application and approval for teplizumab as a disease modifying therapy for the study 
population in those recently diagnosed with T1D. 
Rationale for Modified Dosing Schedule
As noted above, participants who are unable to receive the second course of study treatment as 
scheduled at Week 26 will receive the second treatment course at the Week 52 visit, approximately 
12 months after the first course. 
In a previous Phase 2, randomized, 2-arm open-label, multicenter study known as the AbATE 
study, a 12-month dosing interval for teplizumab was evaluated in 77 participants aged 8 to 30 
years with recent-onset (<8 weeks) T1D. They were randomly assigned at a 2:1 ratio to receive 
teplizumab plus standard diabetes management versus standard diabetes management alone. 
Subjects in the teplizumab group received a 14-day course of teplizumab, which was repeated 12 
2
2
2, 413
2
during the first 4 days, respectively, and 1
2. The primary 
efficacy endpoint of the AbATE study was the change from baseline in mean C-peptide area under 
the curve (AUC) in the 4h MMTT at Month 24. 
After accounting for baseline difference, comparisons of the mean change from baseline in 
C-peptide AUC in the 4h MMTT at Month 24 showed statistically significant difference in favor 
of teplizumab. The teplizumab group had a mean decline in C-peptide secretion of -0.28 (95% CI: 
-0.36, -0.20) nmol/L, which was smaller than that of the control group (-0.46 [95% CI: -0.57, -0.35]
nmol/L) (p=0.002). The most common AEs were rash, transient upper respiratory infections, 
headaches, and nausea. Study drug-related AEs were transient and resolved.
The results from the AbATE study indicate that increasing the interval between the 2 treatment 
courses from 6 months to 12 months does not increase the safety risk, while still conferring
potential effects of teplizumab, in participants who are unable to adhere to the planned treatment 
schedule.  
3.1.4.
Study Duration
The total study duration for each participant will be up to 84 weeks. This includes a screening 
period of up to 6 weeks and a post-randomization period of 78 weeks. The post-randomization 
period includes two 12-day treatment courses separated by 6 months and a post-treatment 
observation period of approximately 52 weeks. The final visit will take place at Week 78.
For participants under the modified dosing schedule, the treatment courses are separated by an 
interval of approximately 12 months, and the post-treatment observation period is approximately 
26 weeks. The final visit will also take place at Week 78.
The overall study length and timepoints for key assessments were chosen due to the natural course 
of remaining cell loss following the diagnosis of T1D and study goals to demonstrate durability 
of effect and to confirm post-treatment safety profiles of teplizumab.  At the time of diagnosis 

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there can be substantial 
cell reserves, often estimated at 10-20% but in some cases over 40% of 
normal 
cell mass (Matveyenko 2008, Campbell-Thompson 2016). At T1D diagnosis, the 
majority of this reserve appears to be functionally impaired due to metabolic or immunologic (ie,
cytokine induced) stress. With exogenous insulin treatment and correction of pH, electrolyte and 
fluid disturbances (ie, DKA) that are often present at diagnosis, some
cell function may return 
for days, weeks or many months. This observation is often referr
H
where insulin requirements can be substantially reduced and at times independence from 
exogenous insulin can be achieved. These effects are transient and over time, usually within a year 
from diagnosis, inevitably full insulin replacement is required due to autoimmune elimination of 
these remaining cells. Due to the known individual variability in the natural history of
cell loss,
the effect of disease modifying therapies intended to preserve 
cell function is difficult to 
distinguish from the Honeymoon period effects during the first 12 months of T1D diagnosis.
The 18-month time point for the primary and key secondary clinical endpoints will provide key 
data needed for the acceptance of teplizumab as a T1D disease modifying therapy into regular
medical practice and is consistent with existing guidelines for endpoints recommended by the 
EMA and FDA. Data from T1D natural history studies and interventional trials show that 
loss in those with T1D can be quite variable, especially within the weeks to months following 
diagnosis. As this study is enrolling participants in close proximity to T1D diagnosis (ie within 6 
weeks) who are younger, there may be the added complexity of the consideration of the 
Honeymoon phenomenon (or spontaneous, transient partial remission) - that may last up to ~1 year
in the study population (Abdul-Rasoul 2006). The 18-month timing of the primary and key 
secondary clinical endpoints allows for a substantial amount of the inherent, natural metabolic 
variability due to different trajectories of cell loss and/or transiently enhanced cell function due 
to the Honeymoon phenomenon to be minimized - so that the true effect on teplizumab on 
cell
function and clinical parameters can be differentiated from chance. 
Other key assessments will be done at randomization, Week 26 (6 months) and Week 52 (12 
months) to better understand the natural history of 
cell decline and the effect of teplizumab in 
this specific study population. 
In addition, the primary and key clinical endpoints will be assessed approximately 1 year after the
last dose of study drug administration (except participants who receive the modified dosing 
schedule). The length of effect is recognized as an important property of an intermittent disease 
modifying therapy for T1D. A 12-month off-therapy period whilst maintaining positive metabolic 
and clinical effects can, at this time, be considered a reasonable time frame to substantiate an
assertion of a metabolically and clinically relevant durable benefit.
Lastly, combined with the substantial body of data from previous clinical trials of teplizumab for 
T1D over the past 15-20 years, an 18-month trial provides additional critical data for and 
verification of the tolerability and safety of teplizumab. Throughout this study, participants will be 
assessed regularly via in-person and remote interviews, physical exams, self-reports, and 
laboratory examinations. Assessments occur daily during the two 12-day treatment courses and 
regularly between the courses and the post-treatment follow-up period. The on- and off-therapy 
observation times in this study are well within, if not significantly beyond, the periods traditionally 

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used to assess for safety and side effects for immune therapies approved for other autoimmune 
conditions, including those for pediatric indications. In doses and regimens similar to that being 
used in this study, teplizumab has overall been well tolerated with minimal side effects and no
signals of significant short- or long-term adverse effects. It is anticipated that with additional, 
confirmatory data from this study, the side-effect profile of teplizumab will continue to be 
considered acceptable for its integration into care plans for children and adolescents newly 
diagnosed with T1D.
3.1.5.
Data Monitoring Committee and Data Reviews
An external, independent Data Monitoring Committee (DMC) consisting of individuals with 
medical, scientific and biostatistical expertise will be commissioned for this study to provide 
oversight on safety and efficacy data and the conduct of the study. The DMC will make 
recommendations regarding the continuation, termination, or modification of the study. Refer to
Section 11.11 for details.
The DMC will monitor the progress of the study throughout its execution at scheduled intervals or
as requested. The DMC will review safety and efficacy data as well as study conduct, and make 
recommendations regarding continuation, termination, or modification of the study. The DMC will 
review tabulated safety summaries and efficacy data (ie, C-peptide, glycemic control and insulin 
use) in an unblinded fashion and may request additional blinded or unblinded data to assure safe 
and proper conduct of the study.
The DMC will be notified ad hoc of specific events, such as significant or unexpected events 
related to participant safety, when a study agent discontinuation criterion is met, unblinding has 
occurred, or any issue considered significant during a regular data review by
Monitor or designee. A formal review can be prompted by these notifications if deemed warranted 
by the DMC.
An organizational DMC meeting will take place prior to the start of study site initiation and 
scheduled data review meetings will occur approximately every 4 months following randomization 
of the first participant through the second course of teplizumab of the final study participant. At 
that point scheduled DMC meetings will take place approximately every 6 months until the last 
randomized participant completes their final study visit. Meeting schedules may be modified by 
the DMC as requested. Other intermittent scheduled meetings may take place at the request of the 
DMC, the Sponsor, and/or health authorities.  
The specific DMC responsibilities, authorities, and procedures will be documented in its charter.
3.1.6.
Study Oversight
One major objective of this study is to assess the safety and tolerability of teplizumab in children 
and adolescents with recent-onset T1D. The Sponsor recognizes that the study population, 
specifically children 8-17 years old recently diagnosed with T1D, is a vulnerable population at 
very high risk for disease- and therapy-related short- and long-term morbidity and mortality. There 
is no disease modifying therapy for T1D and the only therapeutic class of therapies approved for 
T1D was discovered almost a century ago. Therefore, the Sponsor has incorporated rigorous 

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criteria and processes directed towards the best interest for the safety of study participants. This 
study will be regularly monitored, and data will be reviewed by the DMC, which will ensure the 
safe and appropriate conduct of this study and make decisions on the continuation, interruption, or 
termination of the study.
This study has detailed criteria for interruption and/or discontinuation of study treatment and 
participant withdrawal, which will automatically trigger cessation of study drug dosing and in-
depth investigation in individual participants and the study in general (Section 10.2).
3.2.
Discussion of Study Design
Blinding, Control, Study Phase/Periods, Treatment Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical,
safety, metabolic and exploratory endpoints that may occur in the absence of active treatment.
Randomization with stratification will be used to minimize bias in the assignment of participants
to treatment groups, to increase the likelihood that known and unknown participant attributes 
(eg, demographic and baseline characteristics) are evenly balanced across treatment groups, and 
to enhance the validity of statistical comparisons across treatment groups. Blinded treatment will 
be used to reduce potential bias during data collection and evaluation of all study endpoints.
4.
STUDY POPULATION
The inclusion and exclusion criteria for enrolling participants in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
Investigator must consult with the appropriate Sponsor representative and resolve any issues 
before enrolling a participant in the study. Waivers are not allowed.
4.1.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study: 
1. Participant is male or female.
2. Participant is 8 to 17 years of age, inclusive, at the time of randomization/initiation of study
drug administration.
3. Participant has received a diagnosis of T1D according to ADA criteria (Appendix 1)
4. Participant is able to be randomized and initiate study drug within 6 weeks (42 days) of the 
formal T1D diagnosis according to the ADA criteria.
5. Participant has a peak stimulated C-
L from a 2-hour mixed meal 
tolerance test (2h MMTT) at screening. (Note: This screening 2h MMTT must occur only 
after 6 days following diagnosis to allow for reduction of metabolic instability.)

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6. Participant has a positive result on testing for at least one of the following T1D-related 
autoantibodies before randomization:
Glutamic acid decarboxylase 65 (GAD65) autoantibodies
Islet antigen 2 (IA-2) autoantibodies
Zinc transporter 8 (ZnT8) autoantibodies
Islet cell cytoplasmic autoantibodies (ICA) or 
Insulin autoantibodies (if testing obtained within the first 14 days of insulin treatment)
7. Female participants of childbearing potential must have a negative result on highly 
-HCG]) at screening. 
8. Participants who have reached puberty must agree to adhere to the following contraceptive 
requirements. (Note: In countries with legislation for the age of sexual activity, the 
participant must comply with the local age limit regarding the use of contraception.)
Females with childbearing potential (defined as premenopausal females who are 
capable of becoming pregnant, ie, having reached menarche or having reached Tanner 
stage 3 breast development even without menarche) or who gain childbearing potential 
during the study must practice abstinence or use 2 forms of contraception (including 
oral, transdermal, injectable, or implanted contraceptives, intrauterine device, female 
condom, diaphragm with spermicide, cervical cap, use of a condom by the sexual 
partner, or a sterile sexual partner) continuously from 30 days before the first dose of 
study drug through the end of the study. 
Males who have reached puberty (ie, spermatogenesis) with partners of childbearing 
potential must use barrier contraception in addition to having their partners use another 
method of contraception from 1 week before each study agent dose through 120 days 
(a complete spermatogenesis cycle) after receiving the last dose in each treatment 
course.
9. Prior to receiving study drug, participant must be up to date with and/or agree to receive 
routine age-appropriate immunizations and comply with the guidelines for 
immunosuppressed individuals and those with chronic disease (diabetes mellitus) 
according to current local, regional and/or country-specific guidelines.
10. Participant agrees not to receive other forms of experimental treatment during the study, 
particularly agents that may be immune modulatory in nature and/or stimulate pancreatic 
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11. Participant and/or appropriate legal guardian must sign an informed consent form (ICF)
and/or assent according to local, regional and/or country-specific guidance for study 
participation. 
4.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study: 
1. Participant has known allergies, severe reaction, intolerance, hypersensitivity, or 
anaphylaxis to human, humanized, or murine monoclonal antibodies, teplizumab or any of 
its components or its excipients. 
2. Participant has been an active participant in a therapeutic drug, invasive medical device, or 
vaccine clinical trial within 12 weeks before the first dose of study drug or has received an 
investigational treatment with the potential for T1D disease modification.
3. Participant has significant renal, cardiac, vascular, pulmonary, gastrointestinal, neurologic, 
hematologic, rheumatologic, oncologic, psychiatric disease, or immune deficiency. 
4. Participant has any autoimmune disease other than T1D (eg, rheumatoid arthritis, 
polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, 
multiple sclerosis, systemic lupus erythematous), with the exception of clinically stable 
thyroid or celiac disease. 
5. Participant has an active infection (including a positive SARS-CoV-2 test) and/or fever 
, is prone to infections, or 
has chronic, recurrent or opportunistic infectious disease, including but not limited to renal, 
respiratory or skin infections, Pneumocystis carinii, aspergillosis, latent or active 
granulomatous infection, histoplasmosis, or coccidioidomycosis.
6. Participant has a history of or serologic evidence at screening of current or past infection 
with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus 
(HCV).
7. Participant has any of the following in regards to tuberculosis (TB):
A history of latent or active TB
Signs and/or symptoms of TB
Recent close contact with a person with known or suspected active TB, unless 
appropriate isoniazid prophylaxis for tuberculosis was given 
A history of a chest X-ray consistent with active TB or old, inactive TB,

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A history of a positive purified protein derivative skin test result (>10 mm induration); 
or
At screening is positive or repeatedly indeterminate with an approved interferon-
gamma release assay (IGRA; eg, QuantiFERON-TB test)
If required by local, regional or national regulations, a recent (within 3 months) chest 
X-ray or one conducted at screening read by a qualified radiologist consistent with
current, active TB or old, inactive TB
8. At screening, participant has a clinically active infection with EBV, including but not 
limited to infectious mononucleosis, or an EBV viral load 10,000 copies per mL or per 
106 lymphocytes obtained at study screening (Rosenzweig 2010).
9. At screening, participant has a clinically active infection with CMV or a CMV viral load 
10,000 copies per mL or per 106 lymphocytes (Verkryse 2006).
10. Participant has a diagnosis of significant liver disease or at screening alanine
aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2X or total bilirubin 
(TBili) of >1.5X of the age- and sex-specific upper limit of normal (ULN) according to the 
central laboratory.
to enroll 
upon approval by the Medical Monitor.)
11. An individual has any of the following hematologic parameters, confirmed by repeat tests, 
within 10 days before randomization/first dose of study drug:
Hemoglobin: <10 g/dL
Note: specific hematologic, oncologic or other systemic conditions that might 
otherwise result in exclusion and/or is heretofore unrecognized should be considered 
in individuals who have one or more blood cell counts below or above the normal 
ranges 
12. Current or prior (within 30 days before screening) treatment that is known to cause a 
significant, ongoing change in the course of T1D or immunologic status, including high-
dose inhaled, extensive topical, or systemic glucocorticoids. (Note: Short courses, ie,
approximately 2 weeks or less, of corticosteroids for transient conditions are allowed.)

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13. Current or prior (within 30 days before screening) use of drugs other than insulin to treat 
hyperglycemia (eg, metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, 
liraglutide, dipeptidyl peptidase-4 [DPP-IV] inhibitors, or amylin).
14. Current or prior (within 30 days before screening) use of any medication known to 
significantly influence glucose tolerance (eg, atypical antipsychotics, diphenylhydantoin, 
niacin).
15. Current or planned highly restrictive dietary regimen(s) intended for T1D management, 
such as very-low or ultra-low carbohydrate diets.
16. Recent or planned vaccinations as follows:
Live vaccines (eg, varicella, measles, mumps, rubella, cold-attenuated intranasal 
influenza vaccine, and smallpox): Within the 8 weeks before randomization and
initiation of study drug or planned/required administration through Week 52 or Week 
78 (if Modified-Dosing Schedule is followed) of the study. 
Non-infectious (eg, 
-
: Within 
2 weeks before through 6 weeks after each dosing course.
17. A f
-HCG blood test at screening or a positive urine 
-HCG test prior to initiation of study drug, wishes to become pregnant, is planning on 
donating eggs (ova, oocytes), and/or is lactating with the intent to provide her own breast 
milk to a baby during the entire study.
18. A male who is planning to father a child or donate sperm from 1 week before each study 
agent dose through 120 days (a complete spermatogenesis cycle) after receiving the last 
dose in each treatment course.
19. An individual who has a history of alcohol, drug, or chemical abuse within 12 months prior 
to study screening.
20. An individual who has a medical, psychological or social condition that, in the opinion of 
the Principal Investigator, would interfere with safe and proper completion of the trial.
21. An individual who is an employee of the Investigator or study site, with direct involvement 
in the proposed study or other studies under the direction of that Investigator or study site, 
as well as family members of the employees or the Investigator. 
Although there is not a specific exclusion based on weight, due to country, regional and/or 
local difference in blood draw limits for participants in a research study there may be weight-
based criteria for participation depending on the location of the participant. Investigators are 
to confirm that potential participants meet any specific weight-based criteria due to any of 
these location-specific blood volume limitations. 

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NOTE: Investigators should ensure that all study enrollment criteria have been met at 
or receipt of additional medical records) after screening but before the first dose of study drug 
is given such that he or she no longer meets all eligibility criteria, then the participant should 
be excluded from participation in the study. 
5.
TREATMENT ALLOCATION AND BLINDING
5.1.
Treatment Allocation
Procedures for Randomization and Stratification
Participants will be randomly assigned to 1 of 2 treatment groups in a 2:1 ratio for participants in 
the teplizumab group and the placebo group, respectively. The randomization will be balanced by 
using randomly permuted blocks and will be stratified by peak C-peptide level at screening (0.2 to 
0.7 pmol/mL inclusive, versus >0.7 pmol/mL) and age at randomization (8 to 12 years inclusive, 
versus >12 to 17 years). The interactive web response system (IWRS) will assign a unique 
treatment code, which will dictate the treatment assignment and matching study drug kit for the 
participant. The requestor must use his or her own user identification and personal identification
number when contacting the IWRS and will then give the relevant details to uniquely identify the 
participant.
5.2.
Blinding
This is a double-blind study. Blinding will be maintained for all study participants throughout the 
study. In addition, all personnel at the sites, the Contract Research Organization, third-party 
laboratory vendors, and the Sponsor (Provention Bio, Inc.) will be blinded to the treatment 
assignment through the completion of the study. The S
Regulatory 
Affairs, Product Safety, Clinical Supplies, and Clinical Laboratory representatives or designee are 
excepted.
Teplizumab and placebo will be supplied to the sites in vials and kits that appear identical. Each 
kit will have a unique number printed on all labels, including the outer carton label and the label 
of each vial inside the kit. Detailed instructions for handling the blinded study drug kits will be 
provided in the Pharmacy Manual.
Teplizumab may cause transient reductions in WBC (including lymphocytes and neutrophils). 
Central laboratory results for WBC total and differential counts and platelet counts, as well as 
TBNK panel, will be reported to study sites in a blinded fashion (Section 10.2). If, at any time, the 
current or previous WBC or platelet count from the central laboratory, they will be provided with 
the unblinded laboratory results. 
During the study treatment courses (except the last day of dosing), WBC and differential and 
platelet counts are measured by local laboratories at the study site and reviewed by the Investigator 

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prior to dosing; these results are not blinded.  If a result meets a stopping rule, the Investigator 
should contact the Medical Monitor and conduct appropriate clinical and laboratory follow-up.
The treatment designation codes will be available to members of the DMC, the supporting 
independent statistician, the vendor for study product labeling, packaging and distribution, the 
Interactive Web Response System (IWRS) vendor, select individuals at Provention Bio, Inc. and 
other study associated personnel as indicated above.
5.3.
Emergency Unblinding 
Emergency unblinding is rarely required for medical reasons. If the Investigator believes that 
unblinding is necessary
, the Investigator may access the study assignment 
for the participant. Two methods are available for emergency unblinding. The Investigator may 
unblind via IWRS independently. If the Investigator is unable to access the IWRS for any reason 
to perform the unblinding, an emergency unblinding telephone number is also available.
6.
DOSAGE AND ADMINISTRATION
On the day of randomization (Day 1), each participant will receive the first dose of the study drug 
in the first 12-day treatment course, as shown in the table below. On approximately Day 182, each 
participant will receive the first dose of the second 12-day course. The study drugs (teplizumab or 
placebo) will be administered via IV infusion at the study site or other qualified facility by study-
approved personnel. The doses of study drug will be calc
BSA
measured on the first day of each treatment course. No dose adjustment is permitted.
Modified Dosing Schedule
Participants who are unable to receive the second 12-day course due to COVID-19 pandemic 
restrictions will be given the second course on approximately Day 364 (Week 52 visit). See Section
3.1.3.
The study drug infusion on each treatment day should be administered within 20 to 28 hours after 
the previous dose. For example, if the dose on Day 1 is given at noon, the dose on Day 2 should 
be given within the interval of 8 am and 4 pm.
Description of Interventions 
Treatment name
Teplizumab
Placebo
Description
Sterile solution for injection
Sterile solution for injection
Doses in each course
m2
m2
Days 3-
m2
Total per course: 9.0 mg/m2
Matching volumes to active 
drug
Frequency
Two courses at Week 1 and 
Week 26 or Week 52
Two courses at Week 1 and 
Week 26 or Week 52
Delivery method
IV infusion
IV infusion

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6.1.
Study Drug Preparation
At the beginning of each 12-
will be calculated using the Mosteller formula, BSA=square root [height (cm) x weight (kg) /
3600], using the height and weight obtained on that day. 
Teplizumab and placebo will be prepared according to the Pharmacy Manual provided to the site. 
The study drug will be prepared by qualified site personnel and administered by qualified site staff 
to the participant.
Two (2) mL of study drug should be drawn from the study drug vial and slowly diluted in 18 mL 
of 0.9% sodium chloride solution for injection by gentle mixing. The resulting 20 mL of 1:10 
dilution will be used as the initial study drug solution, which contains either placebo or teplizumab 
25 mL 0.9% 
sodium chloride solution. Finally, this resulting preparation should be gently mixed before 
administration to the participant.
6.2.
Vascular Access and Intermediate-Use Intravenous Catheters
This study requires two courses of intravenous infusions and blood draws over 12 days. It is 
recognized that intravenous access (for infusions and blood draws for laboratory sampling) in the 
pediatric population that is the focus of this study may pose a challenge. Children have smaller 
veins than adults, veins that may be more challenging to insert catheters and they may have a 
significant resistance to catheter placement and/or phlebotomy. 
this study will permit the use of temporary, intermediate term approaches for vascular access. 
) lines may be used for 
study drug infusions and blood draws (if appropriate according to the properties of the access line 
and local, regional or national guidance).
A midline is longer than a regular IV and usually put into a vein in the arm but can be inserted into 
a leg or other vein. Midlines can be used for vascular access for up to approximately one month. 
A PICC line is most often inserted into a larger vein in the upper extremity (but can be inserted 
into other areas) and most typically end in a larger vein 
often in or near the heart. A PICC line 
can often be used for vascular access for more than a month. 
Mid- or PICC-lines will require specific informed consent, which would document risks, benefits 
and language according to local, regional or national practice. Risks of these catheters often include 
pain or irritation, bleeding, and/or a specific risk of infection. These and other risks must be 
weighed against the potential need for multiple traditional IV catheter insertions and/or need for 
regular intermittent phlebotomy. 
Both types of vascular access require specific approaches for insertion (ie, sterile conditions) care 
and maintenance that may include, but not be limited to, specific approaches to regular cleaning, 

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dressing and flushing. As with most intravenous catheters (both peripheral and central) these 
catheters may experience access disruptions (eg, infusion administration and/or blood drawing) 
functionality. 
Not all sites are anticipated to have the ability to offer all approaches to vascular access. If a 
participant has a choice of vascular access and is a good candidate, all options should be presented 
by the Investigator. A site-specific informed consent will be completed as needed per local, 
regional or national requirements for the participant
choice of catheter. Any AEs related to any 
IV catheter (whether traditional IV, midline or PICC line) need to be appropriately identified, 
documented and reported by the study site Investigator.
6.3.
Premedication and Study Drug Infusion
Study participants will receive oral premedication consisting of an NSAID drug (tablet or liquid)
and a locally approved antihistamine (tablet or liquid), according to local availability and practice 
standard, for at least the first 5 days of each study drug course and can receive one or both of these 
for the rest of the study drug doses if the Investigator judges it to be appropriate for the tolerability 
of infusions. The premedication should be given at least 30 minutes prior to initiation of the study 
drug infusion.  If an NSAID is contraindicated, oral acetaminophen (tablet or liquid) may be given.
Study drug (teplizumab or placebo) will be prepared and supplied by designated personnel or 
pharmacist equivalent according to the Pharmacy Manual. 
Assure that the vascular access is patent (see Section 6.2). The Pharmacy Manual should be 
followed to ensure that the IV drug delivery devices used are made of materials compatible with 
the study drug.
Teplizumab for intravenous administration may only be prepared with 0.9% sodium chloride. No 
solutions other than 0.9% sodium chloride may be running through the same intravenous line when 
teplizumab is being administered. If the same intravenous line must be used for infusion of other 
drugs or solutions, the line should be flushed with 0.9% sodium chloride solution before and after 
infusion of teplizumab.
Study drug will be administered IV over a minimum of 30 minutes according to standard practices. 
When the infusion solution has been completely administered, infuse an additional volume of 
saline equal to the volume contained in the infusion tubing at the same constant rate to ensure that 
all study drug has been cleared from the infusion tubing. The starting and ending times for the 
infusion must be recorded. 
During the infusions and for an additional 60 minutes following the infusions, participants are to 
have vital signs (ie, BP, RR, and HR) assessed every 15 min and be monitored for signs or 
symptoms of infusion reactions. These include but are not limited to fever, chills, headache, 
nausea, vomiting, infusion-site pain, anaphylaxis, wheezing, dyspnea, urticaria, and hypotension.
If there are signs or symptoms of infusion reaction in a participant during the 60-minute post-

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infusion observation period, the participant should be observed for an additional 60 minutes or 
until the reaction resolves, whichever is longer.
6.4.
Location of Infusion
Infusions will be administered at a location consistent with adequate safety oversight and 
monitoring, to be determined by each site Investigator in accordance with any applicable local, 
regional, or country-specific regulations. The location could be in a hospital, ambulatory clinic, 
infusion center, or other similar facility. 
In addition to those facilities, if considered appropriate and consistent with local, regional and/or 
national regulations, study drug administration for the 5th through the 11th dose in each treatment 
course may occur at a site more convenient for the study participant. This shall only occur if (a) 
the site Investigator has documented that the dosing and procedures conducted on the first 4 
infusions in a course have been well tolerated and without consequence; (b) approved by the site 
Investigator and the participant and/or their parent/guardian and (c) that there is a documented 
level of monitoring, oversight and access to emergency precautions as there would be at the site. 
In the event where it is opted to conduct such study visits out of the research clinic, the participant 
can, at any time, return to the study clinic for upcoming visits. The visit for the final (12th) infusion 
in each treatment course must take place at the study site.
6.5.
Emergency Precautions
Before every infusion of study drug, appropriate emergency equipment and trained personnel 
should be present. At a minimum, the following will be available:
Epinephrine for IM or IV injection 
Dexamethasone (or equivalent glucocorticoid) for IV injection
Antihistamine for oral administration or IV injection
Resuscitation equipment and other supplies for the emergency management of an 
allergic/toxic reaction
Resuscitation doses of all drugs according to local, regional, or national recommendations
If AEs develop during infusion, the infusion may be slowed or interrupted, as determined by the 
Investigator. If interrupted, the infusion may be restarted, preferably at a slower rate, if deemed 
reasonable by the Investigator. Any changes in the infusion rate must be recorded with the reason 
for the change. In any cases of AEs determined or suspected to be related to the infusion of the 
study drug, the participant should be treated using appropriate medical practices and procedures. 
During or after the infusion of study drug, if a participant experiences any of the following signs, 
the participant will be observed, and the severity of the reaction will be evaluated: 
Rigors or myalgias
Pain, swelling, or edema near the infusion site

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Local or systemic rash
Mucosal congestion or edema
Significant (eg, 30%) drop in systolic or diastolic blood pressure or increase in resting heart 
rate 
Hyperventilation, wheezing or difficulty breathing
Change in mental status
Acetaminophen (or similar drug) and/or additional NSAID may be given if needed, and 
considerations made for glucocorticoid therapy. The participant should be treated using 
appropriate medical practices and procedures. The participant will be continuously monitored until 
their clinical status returns to baseline or is significantly improved.
If an infusion is discontinued, an estimate on the amount of the infusion given and a quantitative 
assessment of the remaining volume should be documented.
The Medical Monitor should be notified of all cases of actual or suspected infusion reactions and 
AEs thought to be related to the study drug infusion.
If cytokine release syndrome is suspected, see Section 9.7.3 for guidance. 
6.6.
Deviations from Study Drug Administration Schedule
The Medical Monitor must be notified immediately if any study drug infusion is delayed beyond 
the permitted interval or is missed for any reason. Administration of study drug should be 
permanently discontinued for a participant if any of the criteria in Section 10.2 are met. If more 
than 2 consecutive doses are missed, the Medical Monitor must be consulted if the remaining doses
of study drug administration should be administered (Section 10.2).
Study drug administration for a participant may also be discontinued or interrupted for mild or 
moderate acute illness or an abnormal laboratory result that, in the opinion of the participant and/or 
guardian or Investigator, raises safety concerns. If the illness does not resolve, the Medical Monitor 
must be notified. Study drug administration may be restarted as detailed in Section 10.2.
7.
TREATMENT COMPLIANCE
The study drug (teplizumab or placebo) will be administered as IV infusions by qualified study-
site personnel. The details of each administration will be recorded in the CRF (including date, start 
and stop times of the IV infusion, and whether full dose is administered).

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8.
CONCOMITANT THERAPY
8.1.
Documentation of Concomitant Therapy
Concomitant therapies must be recorded throughout the study, beginning at screening through
Week 78.
Concomitant therapies should also be recorded beyond Week 78 only in conjunction with ongoing
SAEs.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study drug must be recorded in the CRF. Recorded 
information will include a description of the name and type of the drug, the time of use, the amount 
of drug used, the route of administration, and the indication.
8.2.
Diabetes Management and Insulin Use
All enrolled participants, with assistance of their health-care providers, should receive intensive 
diabetes management of their T1D using approved therapies according to the recommendations of
American Diabetes Association (ADA) or local, regional, or national recommendations to achieve 
glucose levels that appear to decrease some of the short-term and long-term sequelae of T1D. 
Currently the glycemic targets by the ADA are focused at management strategies to achieve a
HbA1c level of <7.5% (58 mmol/mol) for individuals 17 years old and younger, and <7.0% (53
mmol/mol) 18 years and older while minimizing severe or frequent hypoglycemic events. If there 
are local, regional, or national recommendations to be followed that supersede ADA 
recommendations, these glycemic control targets (ie, HbA1cs or glucose levels) should not be 
more liberal (ie, higher) than the ADA recommendations. The Investigator will document in the 
CRF the glycemic goals.
The glycemic goal should be attempted through proper glycemic monitoring, administration of 
exogenous insulin, and monitoring of activity level and diet. Exogenous insulin may include rapid, 
intermediate, and/or long-acting insulins, administered intermittently or via the use of a personal 
insulin pump. Blood glucose levels should be measured at least 4 times a day, including before 
meals and before bedtime. Approaches to achieve these HbA1c goals will be the responsibility of 
the participant, their caregivers, and their healthcare providers. 
Insulin use, including the type of products, dosages, and dosing schedules, is expected to change 
during the course of the study. As part of routine T1D clinical care, if the caring physician judges 
it to b
discontinued. 
primary clinical care team about possible adjustments in the insulin regimen, referral to a registered 
dietitian, or other approaches that may improve the glucose control. 
Insulin Discontinuation

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If a participant has achieved a HbA1c level of 6.5% with insulin use of 0.25 U/kg/day, insulin 
therapy can be discontinued. The p
s blood glucose and HbA1c levels should continue 
to be monitored per protocol, and urine ketones should be monitored once a day. During routine 
blood glucose monitoring, if the participant
blood glucose level exceeds 200 mg/dL 
(11.1 mmol/L) and/or urine ketone is moderate or greater, the participant should consult with their 
primary physician and/or the clinical site staff for further evaluation. If the fasting blood glucose 
exceeds 126 mg/dL (7 mmol/L) or HbA1c exceeds 6.5%, as documented by repeat testing, the 
resumption of insulin therapy should be considered.
8.3.
Permitted Medications
There are no medications specifically contraindicated for use with teplizumab, so participants may 
continue to receive medications as needed for existing medical conditions, taking into account the 
exclusion criteria (Section 4.2), prohibited medicines during the study (Section 8.4) and guidance 
for vaccine administration (Section 8.5). Specific permitted medications that participants may 
need during the study include but are not limited to:
Low-dose estrogen oral contraception
Acetaminophen or similar analgesics
NSAIDs (eg, ibuprofen and naproxen) (acetaminophen if NSAID is contraindicated) 
Diphenhydramine or other antihistamines
Antibiotics as prescribed by a healthcare provider for a specific condition
8.4.
Prohibited Medications
The following drugs are not permitted concomitantly during the study from randomization through 
Week 78:
Agents other than subcutaneously administered insulin that may influence insulin 
sensitivity or secretion, which include but are not limited to inhaled insulin, oral 
hypoglycemic drug (eg, sulfonylureas), metformin, diphenylhydantoin, thiazide or other 
potassium-depleting diuretics, systemic -adrenergic blockers, or niacin
Drugs other than insulin to treat hyperglycemia for example metformin, sulfonylureas, 
glinides, thiazolidinediones, exenatide, liraglutide, dipeptidyl peptidase-4 (DPP-IV) 
inhibitors, or amylin
Agents that may result in immunosuppression or immunomodulation. This includes the 
initiation of long-term or chronic use of high-dose inhaled corticosteroids, extensive use of
topical corticosteroids, and systemic corticosteroids. This also includes biologic immune 
modulators. Note: A short course (ie, approximately 2 weeks or less) of systemic (including 
oral, inhaled or parenteral) corticosteroids may be used for treatment of a transient 
condition.
Vaccines (see Section 8.5 below)

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The Investigator may decide to administer a prohibited medication to a participant if necessary. 
The Investigator should subsequently discuss with the Medical Monitor whether the participant 
should remain in the study.
The Sponsor must be notified as soon as possible after any instances in which prohibited therapies 
are administered.
8.5.
Vaccines
Because vaccines are an important component of current general medical care, and because 
teplizumab is considered an immunomodulatory therapy for those with chronic diseases like T1D,
participants and Investigators are required to adhere by the following guidance for this study:
Prior to receiving study drug, participants must be up to date with and agree to receive 
routine age-appropriate immunizations according to current local, regional and/or country-
specific guidelines and to comply with relevant guidelines for immunosuppressed 
individuals and those with chronic disease (diabetes mellitus). Documentation of all 
vaccines given during screening and the treatment period in the study must be provided to 
the study site. 
Live vaccines (eg, varicella, measles, mumps, rubella, cold-attenuated intranasal influenza 
vaccine, and smallpox) cannot be given from 8 weeks before the initiation of study drug 
through Week 52 or Week 78, if Modified-Dosing Schedule is followed.
Non-infectious (eg, recombinant, inactivated,
-
generally 
should not be given from 2 weeks before the initiation of study drug through 6 weeks after 
the end of each course of study drug administration. If a vaccine is considered necessary 
within the time window, the Investigator should consult with the Medical Monitor as soon 
as possible. 
In some situations, a vaccine may be urgently required (eg, rabies or meningococcal
vaccine) to protect the safety of the participant and may be given. Influenza non-live 
vaccine can be given on an emergency basis, but all efforts should be made to follow the 
general guidance above.
8.6.
Contraception
Contraception (including abstinence) is required for all participants who have reached puberty (see 
Section 4).
Females with childbearing potential or who gain childbearing potential (having reached menarche 
or having reached Tanner stage 3 breast development without menarche) during the study must 
practice abstinence or use 2 forms of contraception (including oral, transdermal, injectable, or 
implanted contraceptives, intrauterine device, female condom, diaphragm with spermicide, 
cervical cap, use of a condom by the sexual partner, or a sterile sexual partner) continuously from 
30 days before the first dose of study drug through the end of the study. Males who have reached
puberty with partners of childbearing potential should use barrier contraception in addition to 
having their partners use another method of contraception from 1 week before the first dose of
study drug through 120 days (a complete spermatogenesis cycle) after the last dose in each 
treatment course.

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In countries with legislation for the age of sexual activity, the participant must comply with the 
local age limit regarding the use of contraception.
Participants should discuss all issues related to contraception methods with the study medical staff
and personal healthcare providers.
9.
STUDY EVALUATIONS
Participants who are not affected by the COVID-19 pandemic restrictions are required to undergo 
study procedures and assessments according to the Schedule of Events.
Those participants who are unable to receive the second course of treatment as scheduled because 
of COVID-19 pandemic restrictions will begin the second course of treatment at the Week 52 (Day 
364) visit. These participants will undergo all study procedures and assessments according to the 
Modified-Dosing Schedule of Events.
9.1.
Study Procedures
9.1.1.
Screening Procedures
For the purpose of this study, the date of T1D diagnosis for any subject is defined as the date on 
which a formal diagnosis of T1D is made according to the ADA diagnostic criteria for T1D. 
For participants randomized in this study, all screening procedures (with the possible exception of 
the T1D autoantibody assessments) are to take place at least 6 days after the T1D diagnosis. This 
interval allows for the reduction of metabolic instability that can be present at the time of T1D
diagnosis and may interfere with the screening MMTT and other assessments. Screening may take 
place over 1 day. Prior to screening, the I
procedures, and risks, and ask each potential participant/caregiver to consent/assent to participate. 
The start of the screening period of the study will be defined as the day written informed 
consent/assent is obtained. Participants will be assigned a unique participant number and 
evaluation for inclusion/exclusion criteria will be performed, which will include clinical and 
laboratory evaluations and the 2h MMTT (Appendix 2). A master log will be maintained by 
individual investigative sites of all screened participants, including the reason for screening failure.
The eDiary used to collect participant-reported data will be issued, and study-supplied glucometers 
and glucose monitoring strips will be provided to participants who request them. Training will be 
provided for use of these instruments to collect, for example, insulin use, blood glucose levels, 
hypoglycemic events (all), and AEs between study visits. Note: In situations where participants 
are not randomized in the study, they will be directed on how to return devices.
Laboratory and clinical assessments performed during the screening visit are identified in the
Schedule of Events. Documentation of vaccines must be provided. In anticipation of successful 
screening and continued interest in the study, study personnel should schedule a date for 

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randomization, recognizing that randomization must occur within 6 weeks (42 days) of the 
diagnosis of T1D and that the treatment course will be daily infusions over approximately 2 weeks. 
As part of the screening procedure, individuals must undergo testing for TB and their medical 
history assessment must include specific questions about a history of TB or known exposure to 
individuals with active or suspected TB, and clinical or radiographic evidence of TB, and past 
testing for TB, including responses to tuberculin skin or other TB testing. Screening includes a 
validated approved interferon-gamma release assay (IGRA; ie, QuantiFERON-TB test). 
Individuals with a positive IGRA must be excluded from the study and should be referred for 
they cannot be randomized, and the test should be repeated. In the event that the second IGRA test 
result is also indeterminate, the individual should be excluded from the study and should be 
referred for additional assessment by their primary healthcare provider.
Starting from protocol version 3.0 onward, participants will undergo local SARS-CoV-2 PCR 
testing before the first dose of each treatment course is given. The result must be negative before 
each treatment course can be initiated.
Type 1 Diabetes Autoantibody Pre-screening
Study sites will be given the option of evaluating individuals for the presence of T1D-associated
autoantibodies (T1D AAs) prior to engaging in the bulk of the screening evaluations. It is 
anticipated that Investigators and/or their designee may have the ability to introduce the 
opportunity to participate in this clinical trial when an individual first presents to a healthcare
facility which may include inpatient hospitalization for a number of days for medical stabilization, 
T1D education and initiating insulin therapy. One of the key study inclusion criteria is presence of 
at least 1 T1D AAs to confirm the diagnosis of T1D. 
Although often assessed at diagnosis, there are different clinical practice patterns of assessing the 
(complete) panel of T1D autoantibodies used in this study and such assessments (if not conducted 
by a study-approved laboratory) would not be valid to meet entry criteria.  At the time near 
diagnosis individuals and their families are likely to be busy learning how to manage their new 
condition. As such they may be hesitant to partake in the full screening procedure (which may take 
most of the day) which can only take place 6 days after diagnosis to allow for metabolic 
stabilization for the MMTT assessment.  
To assist in determining if the individual would meet the basic T1D AA entry criterion for this 
study, I
T1D AA analyses following completing the Informed Consent Form. If an individual participates 
-
do not have to repeat 
the T1D AA evaluations but must complete the rest of the screening procedures (eg, MMTT and 
other screening assessments) such that randomization and initiation of study drug administration
will occur within 6 weeks (42 days) of T1D diagnosis.
Retesting 

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If an individual undergoes screening but does not meet all study participation criteria, they may be 
eligible for retesting that may lead to randomization. Retesting of laboratory tests will be allowed 
once and will take place during an unscheduled visit in order to be eligible for randomization 
within 6 weeks (42 days) of T1D diagnosis.
Rescreening
Participants may be rescreened and be randomized as long as inclusion and exclusion criteria are 
met, and the participant is able to be randomized within 6 weeks (42 days) of T1D diagnosis. If 
rescreening is a possibility, the site should consult the Sponsor. Rescreening is allowed only once. 
Individuals who are rescreened will receive a new participant number, repeat the informed consent 
process, and then restart a new screening phase.
9.1.2.
Randomization, Treatments and Monitoring 
Study Visit Week 1 (Day 1): Randomization, 4h MMTT, and Study Drug Initiation 
Future target visit days are based on date of the first study day (Day 1) 
For all participants randomized in this study, randomization must occur within 6 weeks (42 days) 
of the diagnosis of T1D. 
On Study day 1, randomization, additional clinical and laboratory assessments and study drug
dosing initiation will occur. This visit, as well as other visits where study drug is administered, is 
in a location consistent with adequate safety oversight and monitoring, to be determined by each 
Principal Investigator and any applicable local or country-specific regulations. The location may
be a hospital, ambulatory clinic, infusion center, or a similar medical facility.
The Investigator or designee will confirm that the participant has signed the proper informed 
consent and/or assent forms. All assessments are to be conducted according to the Schedule of 
Events tables. For example, vital signs, weight and height determination, and a brief physical exam 
will be conducted. All inclusion and exclusion criteria, concomitant medications, interval medical 
history and laboratory evaluations should be reviewed documenting that the individual remains 
eligible for participation in the study. Documentation of vaccine records will be confirmed. All 
participant collected data (eg, insulin use, glucometer reading, hypoglycemic and AE records) will 
be collected and reviewed, noting that individuals are to have at least 5 days of daily insulin use 
recorded within the 7 days immediately preceding randomization. Individuals will be randomly 
assigned to receive teplizumab or placebo using central automated system as detailed in Section
5.1.
Additional laboratory (including but not limited to complete blood count [CBC], chemistries, 
HLA-typing, and blood samples for exploratory assessments) and quality of life questionnaires
will be completed as applicable, and the 4h MMTT will be conducted (Appendix 2).
The participant will then be able to receive study drug (teplizumab or placebo) with dosing based 
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(BSA=square root [height (cm) x weight (kg)/3600].) The site Investigator or designee should 
assure that all emergency precautions (Section 6.5) are in place before any study drug is 
administration is started. 
Participants will receive premedication of an NSAID (eg, ibuprofen) (acetaminophen if NSAID is 
contraindicated) and an antihistamine (eg, diphenhydramine) for at least the first 5 days of the 
treatment course, unless contraindicated by drug allergy or sensitivity. They can receive one, the 
other or both for the additional study drug administrations if the Investigator judges it to be 
appropriate to improve the tolerability of infusions. After at least 30 minutes following the 
premedication administration, the infusion of study drug can begin. Administration of study drug
should be performed according to the Pharmacy Manual. If there is a delay in administration of 
study drug such that it will not be administered on the day of preparation, the study monitor must 
be notified immediately. Study drug should be planned to be administered intravenously over 30 
minutes according to standard practices, but it may be slowed if there are signs or symptoms of 
intolerance. When the infusion solution has been completely administered, an additional volume 
of saline equal to the volume contained in the infusion tubing, at the same constant rate is to be 
infused to ensure that all study drug has been cleared from the infusion tubing. The starting and 
ending times for the infusion are to be recorded. 
On the days indicated in the Schedule of Events, blood samples will be drawn for trough 
teplizumab serum concentration within 30 minutes before the start of infusion, and the time of 
these blood draws are to be documented in the CRF.
During the infusions and for an additional 60 minutes following the end of infusions, participants 
are to be monitored for signs or symptoms of infusion reactions including but not limited to fever, 
chills, headache, nausea, vomiting, infusion-site pain, anaphylaxis, wheezing, dyspnea, urticaria, 
and hypotension. The participant is then able to leave the facility for return the following day for 
the next study drug infusion.
Day 2-12: Continued Treatment Course 1 Infusions
Participants will return to the clinical trial site and the Investigator or designee will review the 
status of the participant and complete assessments as indicated in the Schedule of Events tables.
If there are no clinical or laboratory concerns, the participant can proceed with the next infusion 
as described above at least 30 minutes following administration of prophylactic NSAID
(acetaminophen if NSAID is contraindicated) and antihistamine. Close monitoring is to occur 
during the infusions and for 60 minutes following the infusions for any signs or symptoms of 
intolerability or infusion reactions. 
Day 2-11*
On Days 2-11, the participant is then able to leave the facility and return the following day for the 
next study drug infusion.
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Where approved by appropriate local, regional and/or national authorities and where there is 
appropriate medical care and services, some or all evaluations, laboratory testing and study agent 
administration to be conducted from Day 5 through 11 may be performed outside of the research 
clinic at a site more convenient for the study participant (see Section 6). The visit on Day 12 must 
take place at the study site.
Days 12
The Day 12 visit must take place at the study site and all of the assessments and procedures will 
take place according to the Schedule of Events tables. Following the completion of the final 
infusion for this course and at least a 30-minute observation a continuous Glucose Monitoring 
(CGM) sensor will be applied and the participant is to be given instructions on CGM monitoring 
care and use.  
Study Visits Weeks 4, 8, 12*, and 20*
The vi
During these visits, participants will return to the site for their scheduled visit and have clinical 
and/or laboratory assessments conducted as indicated in the Schedule of Events tables. Of note at 
Week 12, a CGM sensor will be applied and the participant is to be given instructions on CGM 
monitoring care and use.  
At the Week 20 visit, give participant instructions for Week 26 4h MMTT including overnight fast 
and pre-MMTT insulin dosing.
*Study Visit Weeks 12 and 20
Where approved by appropriate local, regional and/or national authorities and where there is 
appropriate medical care and services, the evaluations and laboratory testing for Study Visits at 
Weeks 12 and 20 may be performed outside of the research clinic at a site more convenient for the 
study participant.  This shall only occur if the site Investigator and participant and/or their 
parent/guardian approve. In the event where it is opted to conduct such study visits out of the 
research clinic, the participant can, at any time, return to the study clinic for upcoming visits. 
Study Visit Week 26: 4h MMTT and Treatment Course 2 (or Week 52, if Modified-dosing 
schedule followed)
The visit window for these
7 days from the target visit day.
Days 182-193*
Participants are to return to the clinical trial site on Day 182 for the clinical and laboratory 
assessments (including a 4h MMTT) as detailed in the Schedule of Events tables and for initiation 
of the second course of study drug administration.

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Of specific note, height and weight are to be obtained at this visit and used for the BSA based 
dosing calculation for course 2. Following the guidance as with study drug course 1, the site 
Investigator or designee should assure that all emergency precautions (Section 6.5) are in place, 
the participant is to be premedicated with an oral NSAID (acetaminophen if NSAID is 
contraindicated) and anti-histamine at least 30 minutes before the first 5 study drug infusions is 
started (and on an as needed basis with subsequent infusions), administration of study drug should 
be performed according to the Pharmacy Manual, and an additional volume of saline equal to the 
volume contained in the infusion tubing is to be infused. During the infusions and for an additional 
60 minutes following the infusions participants are to be monitored for signs or symptoms of 
infusion reactions.
On the days indicated in the Schedule of Events, a blood sample will be obtained for teplizumab 
serum levels within 30 minutes before study agent infusion. In addition to time of study agent and 
flush start and stop, the time of the blood draw is to be documented in the CRF.
Days 183-192 (Day 2-11 of Course 2 dosing)
On Days 183-192, the participant may leave the facility and return the following day for the next 
study drug infusion.
*Days 186-192 (Day 5-11 of Course 2 dosing)
Where approved by appropriate local, regional and/or national authorities and where there is 
appropriate medical care and services, some or all evaluations, laboratory testing and study agent 
administration to be conducted from Day 186 through 192 may be performed outside of the 
research clinic at a site more convenient for the study (see Section 6).
Day 193 (Day 12 of Course 2 dosing)
The Day 193 visit must take place at the study site and all of the assessments and procedures will 
take place according to the Schedule of Events. Following the completion of the final infusion for 
this course and at least a 30-minute observation, a CGM sensor will be applied and the participant 
is to be given instructions on CGM monitoring care and use.  
Study Visits Week 30, 34, 39*, 52 and 65*
The visit window for Weeks 30, 34, 39, and 52 study visits is
The visit window for Week 65 visit is 7 days.
During these visits, participants will return to the site for their scheduled visit and have clinical 
and/or laboratory assessments conducted as indicated in the Schedule of Events tables.
Of specific note, at the Week 52 visit, a 4h MMTT will be conducted.
At the end of the Week 39, 52, and 65 visits, a CGM sensor is to be applied and additional training
and instruction updates on CGM care and use will be given as needed.  

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Study Visits Week 39 and Week 65
Give participant instructions for Week 52 and Week 78, respectively, 4h MMTT including 
overnight fast and pre-MMTT insulin dosing. At the Week 65 visit, dispense to participant CGM 
equipment for home application to start around Week 76.
*Study Visit Week 39 and 65
Where approved by appropriate local, regional and/or national authorities and where there is 
appropriate medical care and services, the evaluations and laboratory testing for Study Visit at
Week 39 may be performed outside of the research clinic at a site more convenient for the study 
participant.  This shall only occur if the site Investigator and participant and/or their 
parent/guardian approve. In the event where it is opted to conduct such study visits out of the 
research clinic, the participant can, at any time, return to the study clinic for upcoming visits. 
Study Visit Week 78 
The visit window for this study visit is
During this visit participants will return to the site for their scheduled visit and have clinical and/or 
laboratory assessments conducted as indicated in the Schedule of Events table. The 4h MMTT will 
be conducted.
The study staff will call to remind the participant or caregiver to apply a CGM sensor 2 weeks 
before the Week 78 visit. The CGM sensor will be returned to the study site at the Week 78 visit.
9.1.3.
Blood Draw Volume Required for Study Assessments
The volume of blood drawn required in this study is described in Appendix 3.
It is recognized that the amount of blood that may be drawn for research purposes in children and 
adults may not exceed certain limits, both at a single visit and over a set amount of time. In any 
participant whose clinical condition might be adversely affected by removal of the blood volumes 
stated, for example, a participant with significant anemia or compromised cardiac output, 
Investigators should consider further limiting the volume of blood withdrawn for research
purposes. In instances of medical need, it is the responsibility of the Investigator and/or 
protocol-stated 
volumes should occur. Because blood sampling in excess of those mandated by the protocol may 
be taken in the course of providing care during this study, sites must ensure that all instances of 
record.
9.2.
Efficacy Evaluations
9.2.1.
Mixed Meal Tolerance Tests 
The 2h and 4h MMTTs will be performed during this trial as indicated in the Schedule of Events.
A 2h MMTT will be performed at screening to determine study eligibility (based on peak 

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C-peptide level). A 4h MMTTs will be performed at randomization and at Weeks 26, 52, and 78 
to obtain 4h C-peptide AUCs and other data. A 4h MMTT is used at and post-randomization as it 
has been shown to be more precise and reliable in assessing the MMTT-induced C-peptide AUC 
than the 2h MMTT (Boyle 2015, Rigby 2013, Rigby 2016). Alternatively, the 2h-MMTT is used 
at screening as it is sufficient to capture the peak C-peptide level needed for study entry. Samples 
from these assessments will be assessed for C-peptide, serum glucose, and insulin. Samples will 
be stored for potential future evaluations including but not limited to proinsulin levels. The 
measurements of C-peptide and glucose in serum samples will be done in an approved laboratory. 
MMTTs are to take place in the morning between approximately 7:00 a.m. and 10:00 a.m. after an 
overnight fast with strict guidance on insulin use. The 2-hour MMTT takes approximately 130 
minutes to perform, and the 4-hour MMTT takes approximately 250 minutes.
The MMTT procedures are explained in Appendix 2.
9.2.2.
Hemoglobin A1c
HbA1c will be assessed as a blood test at select study visits as indicated in the Schedule of Events
tables.
9.2.3.
Insulin Use
n eDiary at select times 
for 7 days prior to randomization and at about Weeks 12, 26, 39, 52, 65 and 78 visits. The 
participant will record all short-, intermediate- and long-acting insulin administered as intermittent 
this time. Insulin use data are not recorded on the 
day before or the day of the study visit. If a participant forgets to record insulin use on one or more 
days before a visit, they should continue to record insulin use for up to 72 hours post-dose to obtain 
up to 7 days of data. Every effort should be made to collect a total of 7 days of insulin use data for
all the aforementioned visits except Week 78 (final visit), as participants will return the eDiary at 
the final visit.
The criteria for potential insulin discontinuation are outlined in Section 8.2.
9.2.4.
Episodes of Hypoglycemia 
Clinically important and other non-severe and non-serious hypoglycemic episodes are defined in 
Section 12.1.4. These episodes will be recorded throughout the study by participants and through 
evaluation of glucometer readings.
9.2.5.
Glucose Monitoring
9.2.5.1.
Intermittent Glucose Monitoring (Fingerstick)
Blood glucose levels outside of MMTT and CGM will be recorded and analyzed as an endpoint at 
various times. As part of routine care, BG levels are usually measured by a fingerstick glucometer 
at least 4 times a day, including before each meal and at bedtime. At screening, participants will 
be offered a study-supplied glucometer and glucometer strips, but participants are permitted to use 
their own glucometers if they choose. Each participant is instructed to bring their glucometer (or 

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glucometers if they use more than one, eg, at home and in school) to each visit for review. In 
addition, approximately 7 times throughout the study, participants will record their BG levels 
before breakfast, lunch, and dinner and at bedtime for 7 consecutive days in their study eDiary 
prior to the randomization visit and the Weeks 12, 26, 39, 52, 65, and 78 visits. Like the recording 
of the insulin use data (Section 9.2.3), BG data on the day before and the day of the study visit will 
not be recorded. If a participant forgets to record fingerstick glucose measurements before a visit, 
they should do so for 72 hours immediately after the visit. Every effort should be made to collect 
a total of 7 days of BG data for all the aforementioned visits except Week 78 (final visit), as 
participants will return the eDiary at the final visit.
If a participant is using an approved CGM device 
BG monitoring (which could include the study supplied CGM), values from the CGM can be 
s for these intermittent BG assessments. 
The device used to obtain the intermittent BG values will be documented.
9.2.5.2.
Continuous Glucose Monitoring
Continuous
nterstitial glucose levels (which closely approximate blood 
glucose values) at regular intervals, eg every 5-15 minutes depending on device. Increasingly 
clinical studies are supporting that such measurements and their assessments provides valuable 
and unique insights to glycemic control in diabetes. In this study, CGM assessments will be 
conducted to provide key secondary clinical and exploratory endpoint data to address if and how 
teplizumab affects glycemic control, such as glucose excursions, time in select glucose ranges, and 
average daily glucose values (Steck 2014, Helminen 2016, Danne 2017). A recent international 
consensus statement on CGM monitoring supported the use of percentages of time in ranges 
(target, hypoglycemia, and hyperglycemia) and measurement of glycemic variability as key 
diabetes control metrics in clinical trials (Danne 2017). 
CGM will be used to assess glycemic control approximately 7 times throughout the study: after
the completion of treatment courses at randomization and Week 26; after the visit at Weeks 12, 
39, 52, and 65; and before the visit at Week 78. CGM sensors will be placed by qualified study 
staff, and education and training on CGM use and care will be given. Sensors will remain in place
for up to 2 weeks. If during that 2-week period a sensor comes off, it can be replaced by the 
participant, a knowledgeable family member/guardian, or a qualified medical professional.
To reduce any confounding factors of glucose measurements during study drug infusions, CGM
sensors will be placed on participants after the study drug administration has completed for Course
1 and Course 2 and other clinical and laboratory assessments have been made on the days specified 
in the Schedule of Events tables. At the Weeks 12, 39, 52, and 65 visits, the sensor will be placed 
on participants after all clinical and laboratory assessments and the MMTT have completed. In 
addition, for Week 78 CGM data, study personnel will call the participants or caregivers and 
remind each participant to apply the CGM sensor from Week 76 to Week 78.
Study CGM readings are not intended for medical management of participant s diabetes but can 
. Of note, routine use of the personal 
CGM under guidance of 
regular healthcare provider is permitted. 

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Spot-check and CGM blood glucose assessments are anticipated to include but are not be limited 
to mean BG, glycemic variability (BG standard deviation [SD]), maximum and minimum BG 
values over time and incidence and/or percent time with BG >70 but 180 mg/dL (>3.9 but 
10.0 mmol/L, Level 1 (>180 but 
250 mg/dL (>10 but 
13.9 mmol/L)) and Level 2 
HYPERglycemia (>250 mg/dL (>13.9 mmol/L)) and Level 1 ( 70 but 54 mg/dL ( 3.9 but 
3.0 mmol/L)) and Level 2 (<54 mg/dL (<3.0 mmol/L)) HYPOglycemia (Seaquist 2013,
International Hypoglycaemia Study Group [IHSG] 2017, Agiostratidou 2017).
9.2.6.
Additional Metabolic, Clinical, Immunologic, and Molecular 
Evaluations 
Additional evaluations will be performed to assist in the understanding of how teplizumab may 
affect other metabolic parameters, general and T1D-specific immune and metabolic responses, and 
quality of life. These studies may help to explain inter-individual variability in clinical outcomes 
or may help to identify population subgroups in this study that respond preferentially to teplizumab 
and thus characteristics of those with T1D who might benefit the most from teplizumab therapy in 
the future.
9.3.
Pharmacokinetics and Immunogenicity
9.3.1.
Evaluations 
Venous blood samples will be collected for measurement of serum concentrations of teplizumab, 
anti-teplizumab antibodies and neutralizing antibody (NAb) according to the Schedule of Events
tables. Additionally, samples should also be collected at the Early Termination Visit for subjects 
who discontinue study treatment early and from subjects who experience an AE suspected to be 
related to immunogenicity (eg, infusion reactions, injection site reactions or hypersensitivity). 
Venous blood samples will be collected. Samples collected for analyses of teplizumab serum 
concentration and antibody to teplizumab may additionally be used to evaluate safety or efficacy 
aspects that address concerns arising during or after the study period for further characterization 
of immunogenicity or for the evaluation of relevant biomarkers. Genetic analyses will not be 
performed on these serum samples. Participant confidentiality will be maintained. Additional 
information about the collection, handling, and shipment of biological samples can be found in the 
Laboratory Manual.
The actual dates and times of blood sampling will be recorded in the CRF and/or laboratory 
requisition form. It is extremely important to accurately record the date and time of each serum 
sample collection as well as the start and stop time of each study drug infusion.  Instructions for 
the collection, handling, and shipment of these samples are found in the Laboratory Manual.
9.3.2.
Analytical Procedures
Serum samples will be analyzed using validated, specific, and sensitive immunoassay methods.

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9.3.3.
Pharmacokinetic Parameters 
Nonlinear mixed effects modeling (with NONMEM software) will be used to analyze the serum 
concentration-time data of teplizumab to obtain the primary PK parameters, clearance (CL) and 
volume of distribution. The PK profiles will be used, along with other available data, to develop a 
population PK model while including the effect of major covariates (eg, sex, ethnicity, race, 
antibody) on CL and volume of distribution. The starting model will be a previously developed 
model for teplizumab. All PK parameters will be presented by listings and descriptive summary 
statistics including, arithmetic mean, geometric mean (AUC, Cmax and their derived parameters), 
median, range, standard deviation and coefficient of variation. The data of this study may be pooled 
with data from other studies.
9.4.
Exploratory and Other Assessments
9.4.1.
Immune and Serologic Assessments
Immune assessments may include but are not limited to monitoring T cell profiles and B cell 
profiles by flow cytometry. In addition, serum levels of circulating pro- and anti-inflammatory 
cytokines and other soluble factors that can impact T1D progression may be assessed. 
To investigate if and how teplizumab induces changes in lymphocyte subpopulations and 
expression of markers indicative of functional state (ie, activation and exhaustion), flow cytometry 
is anticipated to be performed as part of an exploratory endpoint. As indicated in the Schedule of 
Events, quantitative subpopulation analysis that includes assessment of CD4+ T cells, CD8+ T 
cells, B cells and NK cells (ie, Quantitative Lymphocyte Subset Panel or TBNK panel) will be 
conducted by a licensed central laboratory on fresh samples. In addition, samples for PBMC 
evaluation
phenotypic analysis, antigen-specific analyses (ie, tetramer) and also functional responses to 
antigen-specific and non-specific stimuli. Some of these analyses may take place by traditional 
flow cytometry, mass cytometry (CyTOF) or other technology.  
To determine if and how teplizumab affects cytokine levels due to cytokine release or lymphocyte 
modulation, blood samples will be collected at select timepoints before and after study drug 
administration. Samples will be processed and stored. It is anticipated that analyses will be 
conducted only at select intervals that may include after a critical number of participants have 
completed the Week 52 visit or other key timepoints. Examples of cytokines that may be evaluated 
are interleukin (IL) 2 (IL-2), IL-4, IL-5, IL-6, IL-8, IL-10, interferon-gamma and tumor necrosis 
factor-alpha. In addition, other serum assessments, including those of hormones or other 
metabolically active substances (eg, glucagon, incretins, lipokines, adiponectin, or cholesterol) 
that may have an effect on metabolic control, may be performed. Approaches to evaluations may 
include antibody-based multiplex panels, modified-aptamer binding technology, or other 
platforms. 
Key markers for the presence of the autoimmune processes directed against pancreatic islets 
include assessing the presence and titers of anti-GAD65, anti-insulin, anti-IA-2, anti-ZnT8, and 
anti-ICA autoantibodies. Detection of these autoantibody combinations has proven to be an 

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accurate predictor of T1D in several natural history studies. Therapies that impact the progression 
of T1D may change the presence or shift titers of autoantibodies. In addition, teplizumab may have 
an effect on antibody subclasses in general. As such, it will be important to evaluate effects of 
teplizumab on T1D autoantibodies presence and titer in the context of assessment of total antibody 
subclasses. Qualitative and quantitative assessments of antibody subclasses, eg, IgG, IgA, and 
IgM, may indicate a change in the type of T-helper cell responses to T1D-associated autoantigens.  
Recent data suggest that infection with CVB may be a trigger that breaks self-tolerance in those 
predisposed to T1D and heralds destruction of 
cells and eventually T1D. Improved understand 
regarding the relationship of CVB infection in those newly diagnosed with T1D may assist in 
developing novels therapies to treat and/or prevent T1D. Blood samples obtained for exploratory 
analysis can be used for serologic, molecular and other assessments of CVB infection.
To allow for exploratory assessment as described above, blood samples will be collected as
indicated in the Schedule of Events and processed and analyzed or stored for future testing.  
9.4.2.
cell Stress
cell
specifically due to attempts at enhanced endogenous insulin produc
cells that may 
overwhelm intracellular processes and direct or bystander injurious inflammatory meditators. It 
cell produ
cell recovery due to immune interventions may result in a decrease of these markers. In this study, 
exploratory evaluation of two such markers, proinsulin-to-C-peptide ratios and serum levels of 
circulating methylated-insulin DNA, are to be evaluated. Samples that can be used for these 
analyses will be collected, processed and stored at times indicated in the Schedule of Events for 
future testing.
9.4.3.
Pharmacodynamic Substudy 
In order to evaluate the pharmacodynamic (PD) effects of teplizumab, namely its CD3 receptor 
occupancy and modulation, a substudy will be conducted in all North American sites. See 
Appendix 4 for a description of the PD substudy.
9.5.
Pharmacogenomic (DNA) Evaluations
The HLA system is a grouping of genes that encode the major histocompatibility complex (MHC) 
proteins in humans. 
MHC haplotype gives insight to interactions of distinct types 
of lymphocytes that may cause T1D and may help to identify those who are at risk of developing 
T1D (Roark 2014). The MHC haplotype of participants will be determined. The results of 
genotype analyses can be used to correlate with disease progression, therapeutic responses and 
identify subgroups that respond preferentially to teplizumab. 
Pharmacogenomic studies on DNA, RNA or other genetic matter may also provide insights into 
the mechanism of tepli
preferentially respond to teplizumab. One example is the methylated insulin-DNA assessment 
anticipated (see Section 9.4.2), but also may include studies on the transcript/transcriptome, 

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microarrays, or whole genome assessments. Samples that can be used for these analyses will be 
collected, processed and/or stored at times indicated in the Schedule of Events for future testing.  
9.6.
Quality of Life Assessment
Individuals with T1D may outwardly look healthy, but the management of their disease is a daily 
task for the rest of their life that requires multiple assessments and treatments per day along with 
close monitoring of diet, health status and exercise. As such there is a daily significant burden on 
those with T1D and their families (Monaghan 2015, Mittermayer 2017). In addition, those with 
even the most aggressively managed T1D are at risk for significant short and long-term morbidity 
and mortality. Therefore, it is realized that there are not just medical sequelae for those with T1D, 
but significant emotional, personal, familial and mental burdens as well (Monaghan 2015).
an 
increasingly recognized aspect of beneficial effects of therapies that may alter the disease course 
in T1D. This study will have participants complete questionnaires such as the PedsQL Diabetes 
Module, HFS, DTSQ, and PedsQL Family Impact Module at time points indicated in the Schedule 
of Events tables (Driscoll 2016, Trancone 2016, Bradley 2009, Gonder-Frederick 2011, Varni 
2018).
9.7.
Safety Evaluations
There will be thorough monitoring and evaluation of participants by the Sponsor and Investigators 
and their respective teams in this study focusing on study drug and disease-related safety issues.
Regulatory requirements followed by this study include FDA regulations, ICH Guideline for Good 
Clinical Practice (E6, R1), applicable EU Clinical Trials Directive and any other local regulatory 
requirements for safety monitoring and reporting responsibilities of Sponsors and Investigators to 
ensure the safety and protection of human participants participating in clinical trials.
9.7.1.
Responsibilities
The Sponsor (Provention Bio, Inc) is responsible for:
Conducting ongoing safety evaluation of investigational products
Notifying all Investigators and regulatory authorities of findings that could affect adversely 
the safety of participants or impact the conduct of the trial.
Reporting to the applicable regulatory authorities and Investigators certain SAEs (as 
expedited safety reports) and other relevant new safety information (safety updates and 
periodic reports) as required by applicable regulatory requirements
Investigators participating in this clinical trial are responsible for:
Protecting the safety and welfare of participants
Evaluating participant safety including physician assessment of AEs for seriousness, 
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Notifying the Sponsor of SAEs and other immediately reportable events (IREs) (see
Sections 12.3.2 and 12.3.3) within 24 hours, and providing necessary documentation 
requested by the Sponsor
Informing the IRB/IEC of AEs as required by applicable regulatory requirements.
Details regarding the independent DMC are provided in Section 11.11 and the DMC Charter. 
9.7.2.
Adverse Events
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the 
legally acceptable representative) starting after the informed consent form is 
signed and for the duration of the study. Adverse events will be followed by the Investigator as 
specified in Section 12, Adverse Event Reporting.
Specific Adverse Event Monitoring
Disease-related Hypoglycemia
As indicated elsewhere, participants, and when applicable their caregivers, must agree to follow 
the current recommendations of intensive glycemic control, for example blood glucose checks at 
least 4 times daily and insulin administration to achieve HbA1c of <7.5% (58 mmol/mol) if
younger than 18 years old or <7.0% (53 mmol/L) if 18 years old or older (ADA 2018). If there are
local, regional, or national recommendations to be followed that supersede ADA 
recommendations, these glycemic control targets (ie, HbA1cs or glucose levels) should not be 
more liberal (ie, higher) than the ADA recommendations. The Investigator will document in the 
CRF the glycemic goals. 
In order to achieve glycemic goals, this may require enhanced blood glucose monitoring and 
greater amounts and frequency of insulin administration and may have the unintended side effects 
of hypoglycemia.
Hypoglycemia may have severe sequelae including loss of consciousness, coma or death. 
Participants and their caregivers must work with local Investigators and their primary health care 
providers to determine an approach that is best, and most safely, allows participants to target their 
specific HbA1c goal.
Study Drug-related, Laboratory-based Events 
Safety evaluation will include regular monitoring of clinical laboratory tests, including blood cell 
counts and subsets, serum chemistry panels, and liver and renal function tests.
Infections of Special Interest and Malignancies
Teplizumab is a known immune modulator that suppresses certain aspects of the immune system. 
Some of the primary functions of the immune system are to fight viral, bacterial and fungal 
infections and also surveillance for and destruction of malignant cells. Although there are currently
no data indicating an increased risk of significant infections or cancer, there is a potential that 

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teplizumab may increase the risk for these events. Using both laboratory-based and clinical 
assessments, participants will be closely monitored for any signs or symptoms suggestive of either. 
For example, there will be active laboratory monitoring of early detection of significant CMV and 
EBV viremia to detect primary infection or reactivation of these viruses in those who have been 
infected previously. In addition, questioning about TB risks, exposures and signs and symptoms 
will be conducted at each study visit. Physical examinations, systems reviews and laboratory 
assessments (CBCs, chemistries and urinalysis) will employed to assess for malignant or pre-
malignant conditions. 
9.7.3.
Study Drug Infusion-Related Reactions
Infusion reactions which may include but are not limited to hypersensitivity and allergic reactions, 
anaphylaxis, and cytokine release syndrome have been observed with infusion of monoclonal 
antibodies targeting lymphocytes. Previous experience with teplizumab suggests that a small 
percentage (<10%) may experience such reactions, and they are usually characterized as mild to 
moderate.  Mild to serious local and systemic reactions (including anaphylaxis) may occur at any 
time during the administration of study drug.
Study drug must not be administered to individuals with known or suspected intolerance or 
hypersensitivity to any biologic medication or known allergies or clinically significant reactions 
to human proteins, to monoclonal antibodies or antibody fragments, or to any components of 
teplizumab or its excipients.
Two courses of study drug infusion daily for 12 days will be administered starting at the Week 1
(randomization) visit and the Week 26 visit (except participants who require the modified dosing 
schedule). These infusions will be given in an appropriate medical setting (eg, clinic, hospital, or 
infusion center) that has appropriate staff and cardiovascular and respiratory supplies to care for 
an individual undergoing a severe infusion reaction and have a plan for post resuscitation care. A 
physician must be immediately available during all infusions of study drug. Prior to each 
administration of study drug appropriate emergency equipment and trained personnel should be 
present. At a minimum, the following will be available: epinephrine for IM or IV administration, 
dexamethasone for IV administration, diphenhydramine (or equivalent antihistamine) and 
appropriate cardiovascular and respiratory resuscitation equipment and other supplies for the 
emergency management for a serious infusion reaction.
As indicated in Section 6.3, participants in this study will receive oral premedication NSAID drug 
(eg, ibuprofen) (acetaminophen if NSAID is contraindicated) and an antihistamine (eg, 
diphenhydramine) for at least the first 5 days of the treatment course, unless contraindicated by 
drug allergy or sensitivity.
During the infusions and for an additional 60 minutes following the infusions, participants are to 
be monitored for signs or symptoms of infusion reactions. If there are signs or symptoms of 
infusion reaction in a participant during the 60-minute post-infusion observation period, the 
participant should be observed for an additional 60 minutes or until the reaction resolves, 
whichever is longer.

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An infusion reaction may include but not be limited to any unfavorable or unintended sign or 
symptom that occurs at the time or in close temporal proximity to study drug administered 
intravenously. Signs and symptoms of an infusion reaction may include but not be limited to fever, 
chills, headache, change in mental status, nausea, vomiting, or pain, swelling, itching, induration, 
warmth, redness/erythema, local or systemic rash, bleeding, bruising at or distal to the infusion 
site, hypotension, tachycardia, hyperventilation, wheezing or other breathing difficulties.
Any signs or symptom consistent with an infusion reaction, allergy, anaphylaxis or cytokine 
release syndrome and the type of reaction should be recorded on the AE page of the CRF. 
As noted in Section 9.1.2, where approved by appropriate local, regional and/or national 
authorities and where there is appropriate medical care and services, study agent administration to 
be conducted from Day 5 through 11 of each course of study drug may be performed outside of 
the research clinic at a site more convenient for the study participant. In these instances, qualified 
medical personnel must be available to evaluate and manage these events.
Management of Cytokine Release Syndrome
In previous Phase 3 studies of teplizumab, ~6% of participants with T1D experienced cytokine 
release syndrome after receiving teplizumab. Symptoms of cytokine release syndrome included
but were not limited to rash, headache, nausea, vomiting, chills/rigor, and fever. Most of the 
symptoms occurred during the first few days of treatment and are mild or moderate in severity.
Cytokine release syndrome was time-limited and appeared to dissipate regardless of whether 
teplizumab dosing was interrupted.
The possibility exists that participants in this study may experience cytokine release syndrome 
despite premedications and may require supplemental therapy and/or modification of study drug 
administration. Recommendations for the management of these symptoms are as follows. 
Supplemental Therapy
Supplemental therapy is intended for symptom management. The same premedications can be 
used as follows: 
Locally approved NSAIDs should be given in compliance with appropriate age restrictions and 
practice standards, such as ibuprofen (tablet or liquid), diclofenac, naproxen, meloxicam, or 
tenoxicam
Acetaminophen may be added or used instead of a NSAID if the latter cannot be used.
Continuation of NSAID dosing should be considered if necessary. 
Antihistamines may be continued.
For more severe or prolonged symptoms, the following may be administered as consistent with
local practice standard:

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Antihistamines, eg, IV diphenhydramine 
Acetaminophen can be combined with antihistamines and can be repeated every 4 to 6
hours; hydroxyzine can be used during the day to avoid sedation
NSAIDs with higher potency, eg, ketorolac 
Acetaminophen with codeine or meperidine for myalgias, chills and rigors. 
Ondansetron for managing GI symptoms such as nausea and vomiting
Saline boluses to help with hemodynamic support 
Modification of Study Drug Administration
If the cytokine release syndrome is associated with anaphylaxis or angioedema with or 
without requiring hemodynamic support (ie, epinephrine and/or blood pressure 
medications) or mechanical ventilation, study drug should be permanently discontinued 
(Section 10.2.1)
Symptoms alone generally do not lead to study drug modification. However, if the cytokine 
release syndrome is associated with the following laboratory abnormalities, the drug should 
be withheld:
Study drug should be permanently discontinued: ALT and/or AST >5X ULN, Total 
Bilirubin >3X ULN. ALT and/or AST >3X ULN AND Total Bilirubin >2X ULN 
p
n
hemoglobin of <8.5 g/dL (laboratory test(s) should be confirmed on 2 consecutive 
dosing days (Section 10.2.1).
UL
platelet count >50,000 but 
h
on the same day)
the value is still in the above range or worsens, or if the test cannot be repeated on 
(Section 10.2.2).
If the above events resolve within 2 days, study drug dosing may be 
resumed according to the original schedule.
If the above events do not resolve after 2 consecutive days of interruption, 
the Medical Monitor must be consulted regarding continuation of study 
drug dosing.
Glucocorticoids (eg, prednisone 1-1.5 mg/kg/d given twice daily) should be reserved for 
intractable symptoms or Grade 3 or higher events that cannot be relieved with the above 

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medications. There is some evidence that glucocorticoids may interfere with the mechanism of
action of teplizumab and therefore should be given for as short a duration as possible. If the 
investigator feels that glucocorticoids are necessary to resolve intractable signs or symptoms, they
should follow applicable standard of care recommendations and treatment guidelines and inform 
the medical monitor without any delays. Blood glucose levels should be monitored carefully 
during glucocorticoid administration.
Delayed Drug Reactions
Reactions to intravenous administration of certain agents may occur up to approximately 21 days 
following infusion and presentation can be variable, and include, for example, myalgia, arthralgia, 
fever and/or rash. In some cases, these may be accompanied by other symptoms including pruritus, 
localized or systemic edema, dysphagia, urticaria, sore throat, and/or headache. Any such reactions 
and the type of reaction should be recorded on the AE page of the CRF.
9.7.4.
Assessment of Infections
Any Infection
As teplizumab is an immune modulator capable of suppressing certain aspects of protective 
immunity, there is an increased
, 52%
and 56.1% of teplizumab and placebo participants, respectively, were noted to have infections 
recorded as AEs. The most prevalent infections in all participants were upper respiratory tract 
infections, nasopharyngitis, pharyngitis, sinusitis, influenza, rhinitis, gastroenteritis, herpes zoster, 
of 
infections that were grade 3 or higher on the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) was 3.1% in recipients of any dosing regimen 
of teplizumab and 2.0% of the placebo participants and included viral gastroenteritis and herpes 
zoster (Sherry 2011, Hagopian 2013).
In the 
study, the incidence of Adverse Events of Special Interest (AESI) of infection was 
49% in all teplizumab groups and was 58% in the placebo group. For ~95% of participants with 
AESIs of infection, the maximum severity of the infection was grade 1 or 2; 3% to 6% of 
participants had a serious infection across the treatment groups.  The overall incidence of serious 
infections was 3.4% in participants receiving teplizumab and 3.1% in those receiving placebo. 
These included upper respiratory infection, influenza, sinusitis, and nasopharyngitis. Bacterial 
infections appeared lower in those that received teplizumab groups than in the placebo group, and 
there was no difference in the occurrence of fungal infection (Sherry 2011, Hagopian 2013).
Even though it is unclear to what extent teplizumab may increase the risk of infection, if at all, all 
participants will be closely monitored for any and all infections and classified and recorded.
Herpes Zoster
herpes zoster occurred in 10 of the 417 (2.4%) teplizumab-treatment 
participants and no participants in the placebo group.  Herpes zoster (also referred to as shingles) 

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is a disease characterized by a localized, painful, blistering skin rash that is the result of reactivation
of VZV, the causative agent for chicken pox. The age range was 12 to 34 years old.  No cases were 
reported as SAEs, and 2 participants had grade 3 events (Sherry 2011, Hagopian 2013).  Three
participants had herpes zoster within 28 days of starting course 1 all of whom discontinued receipt 
of study drug. There was one grade 3, one grade 2, and one grade 1 event. Five events of herpes 
zoster occurred after 270 days.  Although it is unclear how teplizumab impacts the occurrence of 
herpes zoster, all participants will be closely monitored for herpes zoster outbreaks. During 
screening all participants will undergo serologic evaluation (IgM and IgG) for VZV. Although 
study entry will not be based on these results, if there are participants who develop VZV-related 
infections or conditions, the serology data may assist in understanding risk. If it is believed that 
serologic status does influence VZV-related conditions (including herpes zoster) the study team in 
conjunction with the DMC will discuss modifying entry criteria. 
EBV and CMV 
Cytomegalovirus (CMV) is an infection that is usually acquired in childhood and is usually 
asymptomatic but may cause fever and fatigue and other more significant symptoms. Lifelong 
latent CMV infections persist and are usually of no consequence. However, individuals with 
impaired T-lymphocyte functions, recipients of solid organ or bone marrow transplants on 
significant immune suppression and individuals with cancer receiving chemo- or radiation-therapy 
are at risk for reactivation of CMV and sequela, some significant. Fever, malaise and fatigue can 
result. More severe effects include hematological abnormalities like leukopenia or 
thrombocytopenia, hepatitis/elevated LFTs, retinitis, and blindness, encephalitis, pneumonia, and 
gastrointestinal ulcers. In Pr
significant disease or reactivation did not appear higher 
in teplizumab-treated participants than in placebo-treated participants, although there were some 
participants with apparent transient re-activation.
Epstein Barr Virus (EBV) is also a viral infection that is usually first acquired in childhood and 
adolescence which can be asymptomatic or result in a syndrome know as infectious mononucleosis 
characterized by extreme fatigue, fever, sore throat, myalgias, swollen lymph nodes, liver and 
spleen. In situations of immune deficiency or immune suppression EBV can reactive and cause 
multisystem damage and an aggressive lymphoproliferative disorder and lymphoma. 
EBV reactivation was rare and acute mononucleosis syndrome was not increased.
To date, there has not been any association of teplizumab with significant AEs associated with 
CMV or EBV primary infection or reactivation. As this study will focus on younger individuals 
who may not been exposed to CMV or EBV previously, at screening participants will be 
serologically screened for previous exposure (ie, viral IgG positivity) and status documented. 
Recent studies in T1D and others suggest that quantitative polymerase chain reaction (PCR)-based 
assessment of viral DNA is a precise approach to document significant CMV and EBV infections 
and reactivations. Thus, this study will conduct CMV and EBV DNA viral load monitoring by 
quantitative PCR at screening and at other key times in the study and use the threshold of >10,000 
copies per ml blood or 106 cells as a definition of a clinically significant infection or reactivation
(Rosenzweig 2010, Verkruyse 2006). An EBV or CMV DNA viral load of >10,000 copies should 
trigger a confirmatory assessment and evaluation of the participant. If there is a confirmed viral 

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load of >10,000 copies and/or concerning signs or symptoms an immediate assessment should take 
place and if appropriate consultation with an infectious disease specialist.
Tuberculosis
Individuals who are receiving immunosuppressants may be at risk of acquiring a more severe 
course of primary infection with or reactivation of latent TB.
in India who received
the low dose 14-day regimen of teplizumab; and one in Ukraine who received placebo who were 
evaluated and treated for SAEs of TB (Sherry 2011, Hagopian 2013).
In this study, potential participants will undergo serologic screening via an interferon gamma 
release assay (IGRA; ie, Quantiferon Gold) test. A positive or repeat indeterminate result is an 
exclusion for participation. Questions regarding exposure and/or history will be asked and also can 
result in exclusion from study participation. In addition, to assist in the early detection of TB during 
the study, participants are to be evaluated for signs and symptoms of active TB, including questions 
regarding the following signs:
A new cough with a duration of more than 14 days
Change in a chronic cough
Persistent fever
Unintentional weight loss
Night sweats
Close contact with an individual with active TB
If the evaluation raises suspicion that a participant may have TB reactivation or new TB infection, 
an immediate and thorough investigation will be undertaken, including consultation with a 
physician specializing in TB if necessary.
Investigators should be aware that TB reactivation in immunocompromised participants may 
present as disseminated disease or with extrapulmonary features. Participants with evidence of 
active TB should be referred for appropriate treatment. 
Participants who experience close contact with an individual with active TB during the conduct of 
the study must have a chest radiograph, a repeat IGRA test, and referral to a physician specializing 
in TB if possible
sk of developing active TB and whether treatment 
for latent TB is warranted.
Study drug administration should be interrupted during a TB-related investigation. If the IGRA 
test result is indeterminate, the test should be repeated. Participants should be encouraged to return 
for all subsequent scheduled study visits according to the protocol.

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9.7.5.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected. The Investigator must 
review the laboratory results, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the CRF. The laboratory reports must be filed with 
the source documents. 
9.7.5.1.
Central Laboratory Tests
The following tests will be performed by a standard central laboratory: 
Hematology Panel (at specific visits per Schedule of Events)
WBC with differential
Hemoglobin
Hematocrit
Platelet count
Serum Chemistry Panel with Liver Function Tests (at specific visits per Schedule of Events)
Sodium
Potassium
Chloride
Bicarbonate
Blood urea nitrogen (BUN)
Creatinine
Glucose
Calcium
Phosphate
Albumin
Total protein 
Liver Function Tests
Total bilirubin (TBili)
Direct bilirubin (DBili)
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP)
Quantitative Lymphocyte Subset (TBNK) Panel
CD4+ T cells
CD8+ T cells

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B cells
NK cells 
Quantitative Immunoglobulin Panel
IgA
IgG
IgM
Lipid Panel (only done at select fasting visits)
Total cholesterol
High density lipoprotein (HDL)
Low density lipoprotein (LDL)
Triglycerides 
Coagulation Panel (only at screening)
Prothrombin time (PT)
Partial thromboplastin time (PTT)
International normalized ratio (INR)
Urinalysis (at specific visits per Schedule of Events)
pH
Specific gravity
Protein
Glucose
Ketones
Bilirubin
Nitrites
Leukocyte esterase
Blood cells/hemoglobin
Other Tests
Serum pregnancy testing (only at screening for females of childbearing potential) 
HIV antibody serology (only at screening)
HBV antibody serology /antigen panel (only at screening)
HCV antibody serology (only at screening)
VZV antibody serology
CMV serology

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EBV serology
CMV DNA PCR
EBV DNA PCR
MHC haplotype (only at Week 1, ie, randomization)
Interferon-gamma Release Assay (IGRA) Tuberculosis testing 
HbA1c
The following diabetes-related laboratory tests will be analyzed at an approved central 
laboratory:
Type 1 diabetes antibodies (anti-insulin, anti-GAD-65, ICA, anti-ZnT8, anti-IA2)
Connecting peptide (C-peptide)
Insulin
Proinsulin
9.7.5.2.
Local Laboratory Tests
The following tests will be performed at the local study site or local laboratory: 
Urine pregnancy testing (for females of childbearing potential)
Fingerstick BG levels as needed
Hematology, chemistry, LFTs, and urinalysis from the first to the 11th day in each 
treatment course
SARS-CoV-2 PCR test
During the study, all abnormal laboratory values will require further explanation from the 
Investigator. Clinically significant abnormal laboratory values should be repeated until they return 
to normal or are otherwise explained by the Investigator.
9.7.6.
Data Collected by Participants or Caregivers
Participants/caregivers will collect data related to insulin use, hypoglycemic events, intermittent 
(eg, spot-check or fingerstick) glucose measurements, AEs and internal medical and social history 
to be reviewed at clinical trial visits. The data will be collected in the eDiary. Training on data 
collection tools will be conducted by study-site staff at screening and at subsequent visits as 
needed. All data recorded by participants will be reviewed by study staff during study visits.
Exogenous insulin use: The participant will record all short-, intermediate- and long-acting 
in the eDiary during 
the 7 days before randomization, and Week 12, 26, 39, 52, 65 and 78. These measurements will 
be used to calculate a mean daily insulin use per kg of body weight. Recording of insulin use data 
is not to be collected the day before or the day of the study visit due to preparation for MMTTs. 
If a participant forgets to record insulin use in the eDiary before a study visit, they may do so at 
the visit or for 72 continuous hours immediately after the visit. All effort should be made to collect 
a total of 7 days of data prior to Week 78 visit.

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Hypoglycemia: Clinically important and non-serious and non-severe hypoglycemic episodes are 
defined in Section 12.1.4. All data regarding any B
70 (3.9 mmol/L) and/or 
symptoms consistent with hypoglycemia are to be collected throughout the 78-week duration of 
the study by study participants and through evaluation of glucometer readings. A specific focus 
should be made on recording data regarding BG levels of <54 mg/dL (3.0 mmol/L) or more severe 
events requiring assistance from another person. Data recorded in the eDiary should include 
information on specific blood glucose levels, clinical symptoms (including but not limited to 
change in mental status or loss of consciousness), length of the event, therapies used to treat the 
event, and if assistance or medical care (including clinic, emergency room or hospitalization) was 
required for the event (see Section 12.1 for AE definitions and reporting). In addition, data on 
glucose values meeting hypoglycemia criteria from both intermittent and continuous glucose 
monitors will be assessed.
Intermittent (fingerstick) blood glucose readings: As part of routine diabetes care, blood 
glucose levels should be checked at least 4 times a day including before each meal and at bedtime.
At screening, participants will be offered a study supplied glucometer and glucometer strips, but
participants are permitted to use their own glucometers if they choose. For the endpoint evaluations 
of finger-stick glucose values, participants are to bring their glucometer (or glucometers if they 
use more than one, such as at home and school) to each visit for data review and/or download. 
In addition, 7 times throughout the study, participants will record pre-breakfast, lunch, dinner, and 
bedtime blood glucose levels for 7 days in the eDiary prior to the randomization and Weeks 12, 
26, 39, 52, 65, and 78 visits. Like the collection of the insulin use data, recording BG data is not 
to be collected the day before or the day of the study visit due to preparation for MMTTs. If a 
participant forgets to record finger-stick glucose measurements before a visit, they may do so for 
72 hours immediately after the visit.
9.7.7.
Clinical Assessments
During screening and throughout the study a number of laboratory assessments will be obtained 
for safety assessment. These include, but are not limited to, CBC with differential account, 
chemistry panel, liver function tests, urinalysis, and CMV and EBV quantitative PCR analyses.
9.7.7.1.
Vital Signs
The following vital signs will be measured at time points indicated in the Schedule of Events
tables:
Temperature (using an approved device, eg oral, tympanic, or forehead)
Pulse/heart rate
Respiratory rate
Blood pressure
Blood pressure and pulse/heart rate measurements can be assessed with a completely automated 
device. Manual techniques will be used if an automated device is not available. Blood pressure 

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and pulse/heart rate measurements should be preceded by at least 5 minutes of rest in a quiet setting 
without distractions (eg, television, cell phones).
9.7.7.2.
Physical Examination
Physical examinations (complete or partial) sometimes including height and body weight will be 
conducted at times indicated in the Schedule of Events tables.
A complete physical exam includes: evaluation of general appearance, head, eyes, ears, nose, and 
throat evaluation, neck palpation for thyroid, lymphadenopathy and tenderness, auscultation of the 
heart, lungs and abdomen, palpation of abdomen, external evaluation of genitalia with Tanner 
Staging, evaluation of extremities and skin, and gross neurologic evaluation of strength, sensation 
and balance. 
A partial physical examination includes: general appearance, head, eyes, and throat evaluation, 
neck palpation for thyroid, lymphadenopathy and tenderness, auscultation of the heart, lungs and 
abdomen, palpation of abdomen, evaluation of extremities and skin. 
Any clinically relevant finding or change in physical exam occurring during the study must be 
recorded on the Adverse Event CRF. 
Weight and height will be measured using calibrated scales. At each measurement, participants 
will be instructed to remove shoes and outdoor apparel and gear. Details on how to conduct these 
measurements will be provided to sites.
9.8.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF and/or laboratory 
requisition form. 
Refer to the Schedule of Events for the timing and frequency of all sample collections. For visits 
with study drug administration, all blood samples for assessing teplizumab concentration and 
antibodies must be collected according to the laboratory manual. 
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.

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10.
PARTICIPANT COMPLETION, INTERRUPTION/DISCONTINUATION OF 
STUDY TREATMENT OR WITHDRAWAL FROM THE STUDY
10.1.
Participant Completion
A participant will be considered to have completed the study if he or she has completed 
assessments at Week 78 of the study. It should be specified on the CRF whether or not the 
participant completed the study follow-up procedures through Study Day 546.
Participants who prematurely terminate study participation for any reason before completion of 
the study will not be considered to have completed the study and can initiate the prohibited 
medications and activities (Section 8.4).
Participants will be considered lost to follow-up only if no contact has been established by the time 
status at Study Day 546. Investigators must document attempts to re-establish contact with missing 
participants throughout the study period. If contact with a missing participant is re-established, 
follow- up should resume according to the protocol.
10.2.
Interruption or Discontinuation of Study Treatment
A participant will not be automatically withdrawn from the study if they have to temporarily or 
permanently discontinue study drug before the end of the treatment regimen.
If a participant permanently discontinues study drug for any reason before the end of the treatment 
period (~Week 28, or ~Week 54 for the Modified Dosing Schedule), they should be encouraged 
to continue with all scheduled visits to and including the final study visit (Week 78) but without 
receiving study drug administration. If the participant is unwilling or unable to participate in all 
visits, they should be encouraged to participate in as many of the planned study visits as possible 
for continued assessment but without receiving study drug administration. If the participant is not 
able to attend the next 2 sequential study visits that include an MMTT, they should be encouraged 
to return for the Early Termination visit approximately 10 weeks after the last study drug 
administration, as applicable.
Similarly, if a participant withdraws following the treatment period (after ~Week 28), they should 
be encouraged to attend the Week 52 and Week 78 visits, as applicable. If a participant follows 
the Modified Dosing Schedule and is withdrawn after ~Week 54, the participant should be 
encouraged to attend Week 78 visit. If the participant is unwilling or unable to complete any of the 
remaining scheduled study visits, they should be encouraged to return for the Early Termination
visit approximately 10 weeks after their last dose administration, as applicable.
In the period between Week 1 and Week 78, consecutive MMTTs should not be repeated if the 
time interval between them is less than 10 weeks. The MMTT can be repeated in less than 10 
weeks only for repeat testing during the screening period or for rescreening. 
SAEs must be reported for participants who withdraw early from the study for a year after their 
last study drug dose (Section 12.3.2).

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Study drug may be temporarily or permanently discontinued due to events described below. 
10.2.1.
Events That Lead to Discontinuation of Study Treatment During 
Course 1 or Course 2
The participant withdraws consent.
The Investigator believes that for safety reasons or tolerability reasons it is in the best 
interest of the participant to discontinue study drug.
submitted for all pregnancies that occur in a study participant. Pregnancy should be 
followed for outcome and any premature terminations reported. The health status of the 
reported after delivery. 
A severe infection requiring inpatient hospitalization or repeated doses of parenteral 
antibiotics
A severe hypersensitivity reaction, such as anaphylaxis or angioedema with or without 
requiring hemodynamic support (ie, epinephrine and/or blood pressure medications) or 
mechanical ventilation, to the study drug or an infusion reaction (including cytokine release 
syndrome) with signs or symptoms categorized as an SAE. 
The participant has a clinically significant cardiovascular event.
The participant is diagnosed with a malignancy, lymphoma or a lymphoproliferative 
disorder.
The participant is deemed ineligible for receipt of study drug according to the following 
TB criteria: 
A diagnosis of active TB is made. 
Symptoms suggestive of active TB based on follow-up assessment questions and/or 
physical examination; or the participant has had recent close contact with a person 
with active TB and cannot or will not continue to undergo additional evaluation. 
A chest radiograph with evidence of current active TB 
A positive-IGRA test (ie, Quantiferon-TB test) result and/or an indeterminate IGRA 
test result on repeat testing (Section 9.7.4)
Clinical suspicion of significant CMV or EBV disease (ie, infectious mononucleosis) or a 
CMV or EBV viral DNA PCR titer of >10,000 copies per ml serum or 106 cells
If any of the following lab values is observed (normal range per local lab standard), the 
next study drug dose should be held until a repeat test is obtained and evaluated. If the out-
of-range result is confirmed on two consecutive dosing days, the Medical Monitor must be 
contacted before making a decision about further treatment. 
ALT and/or AST >5X ULN
Total Bilirubin >3X ULN
ALT and/or AST >3X ULN AND Total Bilirubin >2X ULN
Platelet count <

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Neutrophil count <500 cells
Hemoglobin of <8.5 g/dL 
other than:
Lymphopenia
Neutropenia
Low total WBC
Hypoglycemia or symptoms and signs of a hypoglycemic episode
Hyperglycemia or symptoms and signs related to hyperglycemia
Fatigue or malaise
Insomnia
Cheilitis
Dry skin
Nail changes
Hot flushes or flashes
Headache
Myalgia
Flu-like syndrome
Any medically important event, such as a concurrent illness, complications, or abnormal 
laboratory result, that, in the opinion of the Investigator, contraindicates continued dosing 
of the participant
Administration of prohibited medication or dose modification of concomitant medications
that necessitate discontinuation of study drug administration
A general lack of compliance with study visits and procedures per study team or missing 3
consecutive study drug administrations
A positive SARS-CoV-2 PCR test (protocol version 3.0 onward)
The Study Medical Monitor must be notified within 24 hours of any participant who is permanently 
discontinued from study drug dosing. Participants who have study drug dosing permanently 
discontinued will be encouraged to receive follow-up care and evaluation as scheduled, unless 
consent for follow-up is withdrawn.
10.2.2.
Events Resulting in Interruption of Study Treatment in Course 1 or 
Course 2
Study drug dosing may be interrupted temporarily, for an individual participant, if a medically 
important event occurs, such as concurrent illnesses, complications, or abnormal laboratory 
results:  
A significant infection, defined as: 

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Any severe infection meeting SAE criteria (Section 12.1.2), or
judgment might put the participant at risk, or  
An SAE, a study drug-related severe AE, or an AE that puts a participant at risk, defined 
as: 
Any SAE (as defined in Section 12.1.2) or
Any severe AE that is considered related (possibly, probably, or very likely related) to 
study drug (as defined in Section 12.1.2), including but not limited to an infusion 
reaction categorized as a severe or SAE by the Investigator.
Any AE (including mild or moderate) of any relatedness to study drug that leads the 
Investigator to believe that further dosing of study drug during that course puts the 
participant at undue risk.
If any of the following out-of-range lab results is observed (normal range per local lab 
reference ranges), the test may be repeated on the same day. If the repeated test result 
normalizes
. If the value is still in the indicated range or 
worsens, or if the test cannot be repeated on the same day,
withheld.
Hemoglobin
Note: When clinical and laboratory abnormalities are considered related to T1D disease activity 
(ie, hypoglycemia and hyperglycemia) and study drug is not considered a contributing factor, 
administration may not need to be modified. The site Investigator should consult with the Medical 
Monitor and Sponsor if this is encountered. 
If the above events resolve within 2 days, study drug dosing may be resumed according to the 
original schedule. The treatment course will not be extended beyond 12 days.
If the above events do not resolve after 2 consecutive days of interruption, the Medical Monitor 
must be consulted regarding continuation of study drug dosing.
10.2.3.
Criteria to Withhold Initiation of Course 2
Participants will have a scheduled study visit at Week 20, approximately 4 weeks before the 
scheduled study drug infusion in Course 2. If any of the following criteria are met and not resolved 
by Week 26, Course 2 of the study drug shall not be administered. However, these participants 
may receive Course 2 at Week 52, if all of these criteria are resolved.
ALT and/or AST >2X ULN 
Total bilirubin >1.5X ULN
and AST with approval of the Medical Monitor

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Hemoglobin <10 g/dL
Lymphocyte count <1000 cells
Platelet count <100,000 cells
Any condition consistent with a significant EBV or CMV infection or reactivation defined 
by clinical signs of infection; or if the EBV viral load is >10,000 copies per mL or 106 cells 
or the CMV viral load is >10,000 copies per mL or 106 cells
A positive SARS-CoV-2 PCR test
The development HIV, HBV of HCV infections. Noting that testing for these viruses is not 
required unless suspected by Investigator
In addition, if any of the following is present at the scheduled time of study drug administration, 
the second course of study drug will not be administered:
) common cold symptoms, 
sore throat, cough, vomiting or diarrhea
Antibiotics or any other active treatment for an infection.
In addition, at the Week 26 visit prior to receipt of the second course of the study drug, the 
Investigator should review all inclusion and exclusion criteria to determine if there are any 
conditions that should disqualify the participant from further study drug administration.
Modified Dosing Schedule
Participants under the modified dosing schedule will be evaluated according to the same criteria
at their Week 39 visit, before they begin the second course of treatment at the Week 52 visit. 
Note: The above criteria are recommendations and can be overridden
judgment in consultation with the Medical Monitor.
Participants who have study drug dosing permanently discontinued for any reason will be 
encouraged to receive follow-up care and evaluation as scheduled, unless consent for follow-up is 
withdrawn.
10.3.
Withdrawal from the Study
10.3.1.
Participant Withdrawal
A participant will be withdrawn from the study treatment for any of the following reasons: 
Lost to follow-up
Withdrawal of consent/assent
Death
Study Investigator or Sponsor, for any reason, decides the participant should be withdrawn 
from the study. 

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Pregnancy
If a participant is lost to follow-up, every reasonable effort must be made by the study-site 
personnel to contact the participant and determine the reason for discontinuation/withdrawal. The
measures taken to follow-up must be documented. 
When a participant withdraws before completing the study, the Sponsor and the DMC chair is to 
be notified and the reason for withdrawal is to be documented in the CRF and in the source 
document. The study drug assigned to the withdrawn participant may not be assigned to another 
participant. 
Participants who withdraw will not be replaced. If a participant withdraws from the study before 
the end of study, all attempts should be made to obtain Early Termination visit assessments.
10.3.2.
Withdrawal from the Use of Research Samples
A participant who withdraws from the study will have the following options regarding the optional 
research samples: 
The collected samples will be retained and used in accordance with the pa
separate informed consent/assent for optional research samples. 
The participant may withdraw consent/assent for optional research samples, in which case the 
samples will be destroyed, and no further testing will take place. To initiate the sample destruction 
process, the Investigator must notify the Sponsor study-site contact of withdrawal of 
consent/assent for the optional research samples and to request sample destruction. The Sponsor
study-site contact will, in turn, contact the facilities and representative storing the sample(s) to 
execute sample destruction. If requested, the Investigator will receive written confirmation from 
the Sponsor that the samples have been destroyed.
The participant may withdraw consent/assent for use of samples for future research. In such a case, 
samples will be destroyed after they are no longer needed for the clinical study. Details of the 
sample retention for research are presented in the main ICF/assent.
11.
STATISTICAL METHODS
11.1.
General Considerations
All statistical inferences will be based on 2-
-level of 0.05.
All data will be summarized by study drug group. Categorical variables will be summarized by 
number and percent of individuals falling within each category. Continuous variables will be 
summarized by mean, median, standard deviation, minimum and maximum. 
Unless otherwise noted, baseline values will be defined as the most recent value collected prior to 
the first dose of study drug.

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Data summaries and tabulations will be conducted using Statistical Analysis Software (SAS).
A detailed description of the statistical methods used in this protocol is in the Statistical Analysis 
Plan (SAP).
11.2.
Analysis Data Sets
Intent-to-Treat (ITT) Population
For efficacy endpoints, the analysis population will be all randomized participants who receive 
any amount of study drug.  This population will be referred to as the intent-to-treat population.  
For this population, participants will be analyzed in the treatment group corresponding to the 
treatment to which they are randomized, regardless of what treatment they actually receive.
Safety Population
For the safety endpoints, the analysis population will consist of all randomized study participants 
receiving any exposure to study drug.  For this population, participants will be analyzed in the 
treatment group corresponding to the treatment they actually receive, regardless of the treatment 
to which they are randomized.
PK/Immunogenicity Population
For PK and immunogenicity, the analysis population will be all participants in the safety 
population who have provided at least one evaluable sample.
Modified-Dosing Subset
Data from participants who receive the second course of treatment at Week 52 (instead of Week 
26) due to COVID-19 pandemic restrictions will be included in the ITT population and Safety 
population. Additional subgroup analyses for these participants will also be performed.
11.3.
Sample Size Determination
The study sample size is calculated based on the desired clinically relevant effects and the results 
from placebo-treated participants in previous teplizumab studies. Since C-peptide AUC is skewed
right, the data will be transformed using ln(AUC+1) for analysis and the assessment of sample 
size.  Analyses at 18 months from prior studies in children and adolescents who entered the studies
with a stimulated C-peptide AUC of >0.2 pmol/mL are limited. Estimates range from 
approximately 0.22 nmol/L to 0.32 nmol/L with a standard deviation between 0.18 and 0.22.  Using 
an estimate of 0.25 nmol/L, the transformation to geometric mean in the placebo group is 
exp(0.25) -1 = 0.28.  This study is designed to show a difference of at least a 40% in C-peptide
response between teplizumab and placebo. In geometric means this translates to a value of 
(1.4*0.28) = 0.392. Consequently, approximately 300 participants are planned for enrollment, 
assuming 2-
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11.4. Handling of Missing Data
The amount, pattern (arbitrary or monotone in nature), and reasons for missing data (such as 
administrative, adverse event, lack of efficacy) will be described. Multiple imputation (MI) with 
pattern-mixture model under the missing not at random (MNAR) assumption will be used to 
impute the missing values for the primary endpoint as well as the secondary endpoints of 
exogenous insulin use, HbA1c levels, and TIR.
This method will be carried out using the standard three-step procedure: 
Step 1. Generation of imputed datasets: The MI procedure of the SAS system will be used to 
generate m sets of data where missing data from participants who drop out before the end of the 
study are imputed based on participants who similarly discontinued study drug in the same 
treatment group but have measurements taken at scheduled visits.  The selection of m depends on 
the required computing time, but a reasonable range is 20 to 100 sets. Linear regression will be 
employed to model the missing values and will include treatment (teplizumab or placebo), age, 
and peak C-peptide at baseline as covariates. 
Step 2. Model-based analysis using each imputed dataset: Each of the m imputed data sets is 
analyzed using the same method as the corresponding endpoint analysis.
Step 3. Pooling the results from each model-based analysis: The results from the analysis of each 
imputed dataset will be combined by the MIANALYZE procedure of the SAS system. 
11.5.
Efficacy Analyses 
11.5.1.
Primary Endpoint Analysis
The primary endpoint is the difference between treatment groups in C-peptide ln(AUC+1) at Week 
78 using the ITT population. C-peptide will be measured in a 4h MMTT. Analysis of covariance 
(ANCOVA) will be used to assess the treatment difference on C-peptide at Week 78. Missing data 
from patients who drop out before the end of the study will be imputed based on those patients 
who similarly discontinue treatment in the same treatment arm but have measurement taken at 
scheduled visits. The model will include treatment (teplizumab or placebo), age, and peak C-
peptide at baseline as covariates.
Sensitivity analysis will be performed using a tipping point approach. The same imputation and 
model will be used as in the primary analysis, but a tipping point that changes the C-peptide 
conclusion at 18 months will be sought. Repeated measures analysis may also be used to assess 
sensitivity.
11.5.2.
Secondary and Exploratory Clinical Endpoints
The secondary clinical endpoints will be assessed using the Hochberg step-up method for 
addressing multiplicity if primary endpoint reaches p < 0.05. 

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Like the primary endpoint, ANCOVA at 78 weeks will be used to assess treatment differences in 
insulin use
Average total exogenous insulin use (in U/kg/day) will be self-recorded in the eDiary for 7 days 
prior to study visits and at randomization. Participants need to record at least 5 of the 7 days in 
order for this data to be used in the analysis. The model will include age, baseline insulin use, peak 
C-peptide at baseline and treatment group as covariates.
The model used to assess HbA1c will include age, baseline HbA1c, treatment group, and baseline 
peak C-peptide as covariates.
Time in range for blood glucose will be defined as the average percentage of time in range for 10 
to 14 days post each study visit.  The model will include baseline time in range, treatment group, 
age and baseline peak C-peptide.
The rate (number of events/exposure time) of clinically important hypoglycemic episodes at Week 
78 will be compared between groups. Data will be collected from intermittent glucose monitors,
continuous glucose monitors, the eDiary, and CRFs. A clinically important episode is defined as a 
reliable BG value of <54 mg/dL (3.0 mmol/L) and/or a hypoglycemia event requiring assistance 
of another, such as seizure, syncope, severe confusion with or without a confirmatory low BG 
reading). The event rate of clinically important hypoglycemic episodes per study participant will 
be assessed using a negative binomial model to allow for the potential for overdispersion in case 
episodes for hypoglycemia within participant groups are correlated. The model to assess clinically 
significant hypoglycemia will include age, treatment group, baseline peak C-peptide as covariates.
11.6.
Pharmacokinetic and Immunogenicity Analyses
PK analyses of teplizumab will be described in a separate PK analysis plan.
The incidence of positive anti-teplizumab antibodies will be summarized for all participants who 
receive at least 1 dose of teplizumab and have appropriate samples for antibody detection (ie, 
participants with at least 1 sample obtained after their first dose of teplizumab).
A listing of participants who are positive for antibodies to teplizumab will be provided. The 
maximum titers of antibodies to teplizumab will be summarized for participants who are positive 
for antibodies to teplizumab.
Other PK and immunogenicity analyses, including NAb, may be performed to further characterize 
the immune responses generated.
11.7.
Concomitant Medications
Concomitant medications throughout the study will be collected and coded using the World Health 
Organization dictionary.  The number and percent of study participants receiving each medication 
will be summarized.

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11.8.
Safety Analyses
Adverse Events
Safety and tolerability will be assessed primarily by summarizing AEs and SAEs including severe 
infection rates and drug infusion reactions through Week 78. AEs and SAEs will be summarized 
by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory 
Activities (MedDRA).  Events will be summarized by severity and relationship to study drug 
(assessed by Investigator). Participants will be counted only once for each preferred term, once for 
each system organ class and by the highest event severity, regardless of how many events a 
participant experienced.
These events will be recorded by the Investigators in the CRFs.  Verbatim terms will be coded to
the lower level terms in the MedDRA coding dictionary.
Only TEAEs will be summarized. An ongoing TEAE that increases in severity will be captured as 
a single event using the maximum severity experienced during the duration of the event.
Participants with AESIs (defined in Section 12.1.3) will be counted or listed.
Clinical Laboratory Tests
Summaries of laboratory values will display descriptive statistics for numerically quantified labs.  
Summaries will be grouped by lab panel (e.g. hematology, blood chemistry, and urinalysis) and 
will be displayed by visit for each lab parameter.
Laboratory values will be classified based on CTCAE toxicity criteria (NCI 2018). Shift tables 
will be used to display the percent of study participants who have a shift in their lab values from 
normal at baseline to each post-baseline visit by CTCAE severity grade.
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, and blood pressure (systolic 
and diastolic) values and changes from baseline will be summarized at each scheduled timepoint. 
The percentage of participants with values beyond clinically important limits will be summarized 
and a corresponding listing will be provided. 
Physical Examination
Proportion of participants with abnormal physical examination findings will be summarized at 
each scheduled timepoint. Participants with any post-treatment abnormalities will be listed.
11.9.
Exploratory Endpoint Analysis
Clinical, metabolic, immunologic, molecular and genetic exploratory endpoints will be 
summarized by treatment group.  No multiplicity adjustment will be used for these endpoints.  
Detailed descriptions of these summaries are included in the SAP.

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Additional safety and efficacy analyses will be performed on the subgroup of participants who 
receive the second treatment course starting at the Week 52 visit because of the COVID-19
pandemic restrictions.
PD Substudy
Data from the CD3 receptor occupancy and modulation assays and respective changes from 
baseline (see Appendix 4) will be listed and summarized by treatment and sample collection time
point.
values and changes from baseline will be plotted by treatment and 
time point. If notable trends over time in the teplizumab group are observed, further exploratory 
regression analyses on these repeated-measures data will be conducted to further elucidate any
relationship. Additional exploratory analyses may be performed, and methods and results will be 
documented in the CSR or under separate cover.
11.10. Interim Analysis 
No interim analysis is planned.
11.11. Data Monitoring Committee
An external, independent DMC consisting of at least 3 voting members who are medical and/or 
scientific field experts will be established to monitor data on an ongoing basis. The members are 
independent of the study with no scientific, financial, or other conflicts of interest related to the 
trial. A chairperson (voting member) will lead the committee and be its primary contact. An 
independent liaison statistician who is experienced in clinical trials conduct will be appointed as a
nonvoting member. Details of the composition, roles, and responsibilities of members will be 
described in a separate DMC charter.
The DMC will periodically review safety data and the conduct of the study and make 
recommendations regarding study continuance, pausing, termination, or modification. The DMC 
will have access to unblinded data and review tabulated safety summaries (if appropriate) and any 
additional data deemed warranted during the conduct of the study.
An organizational DMC meeting will take place prior to the start of study site initiation and 
scheduled data review meetings will occur approximately every 4 months following randomization 
of the first participant through the completion of the second course of study drug administration 
by the final study participant. At that point, scheduled DMC meetings will take place every 6 
months until the last randomized participant completes their final study visit. 
The DMC will be notified ad hoc of specific events occur, including events indicating significant 
or unexpected safety concerns, when study stopping rules are met, when unblinding has occurred,
or any other issue considered significant during a regular data review by
Monitor or designee. A formal review can be prompted by these notifications if deemed warranted 
by the DMC.
As an outcome of each meeting, the DMC will make recommendations to continue, modify or 
terminate the clinical trial. If additional information (blinded or unblinded) is required for the DMC 

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to make its recommendation the DMC can defer its recommendation until that data is obtained and 
reviewed. If warranted, additional recommendations to the trial conduct can be made by the DMC.
Cumulative safety data will be reviewed by the Medical Monitor and/or DMC, as expeditiously as 
is reasonable, if any of the following occurs:
Death of an enrolled participant
Occurrence of a CTCAE v5.0 Grade 4 allergic/hypersensitivity reaction (anaphylaxis, 
manifested by bronchospasm with or without urticaria or angioedema requiring 
hemodynamic support with pressor medications or mechanical ventilation)
Occurrence of a Grade 4 AE or SAE for:
Cytokine-release syndrome during dosing that is prolonged and not rapidly 
responsive to symptomatic medication and/or brief interruption of study drug 
administration AND is associated with other serious sequelae such as renal 
impairment or pulmonary infiltrates 
EBV or CMV reactivation at any time during the study that results in serious, life-
threatening disease manifestations such as splenic rupture or other serious sequelae 
such as hepatitis or liver function abnormalities or have viral PCR DNA titers of > 
10,000 copies per mL serum or 106 cells 
Any malignancy, lymphoma, or lymphoproliferative disorder appearing at any time 
during the study
Liver function abnormalities (TBili, AST or ALT) during dosing that do not return to 
ULN for TBili within 72 hours of 
discontinuing study drug administration
of drug-induced liver injury, defined 
as: The occurrence of ALT or AST >3x ULN and bilirubin >2x ULN and the absence 
of a cause other than the study drug, eg, acute viral hepatitis, alcoholic and 
autoimmune hepatitis, biliary tract disorders, or cardiovascular causes, such as right 
heart failure, or concomitant medications.
An overall pattern of symptomatic clinical or laboratory events that the Medical 
Monitor or DMC considers possibly, probably, or definitely related to the study drug,
which may appear minor individually but collectively may represent a serious 
potential concern for safety.
When events occur that appear to meet, in the opinion of the Medical Monitor or DMC, one or 
more of the criteria listed above, cumulative safety data will be reviewed as expeditiously as is 
reasonable for all participants. Upon completion of this review, the DMC will determine if study 
entry or study dosing should be interrupted or if study entry and study dosing may continue 
according to the protocol.
The DMC responsibilities, authorities, and procedures will be documented in its charter.

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12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of participants, Investigators, and the Sponsor, and are mandated by 
regulatory agencies worldwide. The Sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the Sponsor or its affiliates will be conducted in 
accordance with those procedures.
The determination of seriousness, severity and causality must be made by the physician 
Investigator who is qualified to review adverse event information, provide a medical evaluation of 
adverse events, and classify adverse events based upon medical judgment.
12.1.
Definitions
12.1.1.
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant from the time 
they formally agree to participate in the study (eg, by providing informed consent/assent) through 
their last study contact (eg, last visit or status update). An adverse event does not necessarily have 
a causal relationship with the study drug. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal finding), symptom, or disease temporally associated with 
the use of a study drug (investigational or non-investigational product), whether or not related to 
that study drug (investigational or non-investigational product).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
A treatment-emergent adverse event (TEAE) is defined as an AE that occurs after the first dose of 
study drug administration (Day 1) through the end of the study or early termination.
12.1.2.
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:
Results in death: A death that occurs during the study or that comes to the attention of the 
principal Investigator during the protocol-defined follow-up period must be reported 
regardless of whether it is considered treatment related or not.
Is life-threatening: The participant was at risk of death at the time of the event. It does not 
refer to an event that hypothetically might have caused death if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect

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Is Medically Important: Medical and scientific judgment should be exercised in deciding 
whether expedited reporting is also 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 participant or may require intervention to prevent 
one of the other outcomes listed in the definition above. These should usually be considered 
serious.
Serious adverse event reports will be provided to the DMC members on an ongoing basis. The 
DMC will have access to unblinded data and review tabulated safety summaries (if appropriate) 
and any additional data that the DMC may request during the conduct of the study. 
The Investigator must follow all SAEs (including serious AESIs) until resolution even if this 
extends beyond the study-reporting period. Resolution of a SAE is defined as the return to pre-
treatment status or stabilization of the condition with the expectation that it will remain chronic. 
At any time after completion of the study, if an Investigator becomes aware of a serious adverse 
event that s/he suspects is related to study drug, the Investigator should report the event to the 
Pharmacovigilance contact.
12.1.3.
Adverse Events of Special Interest
The following events are adverse events of special interest (AESIs):
infections (includes all opportunistic infections): viral, fungal, bacterial
Acute mononucleosis-like illness (eg, fever, pharyngitis, lymphadenopathy, clinical EBV 
and CMV infections and reactivations)
Malignancies including lymphomas
Severe hypoglycemic episodes that require assistance by another individual through the 
administration of oral or parenteral dextrose, glucagon or intervention
(AST, ALT, bilirubin), ie, an AST or ALT value 
>5.0 x ULN or a bilirubin value >3.0 x ULN
penia (
4 allergic/hypersensitivity reaction (anaphylaxis) 
Grade 3 Rash
4 cytokine-release syndrome 
3 neutropenia (<1000
different days)
Lymphocyte count <500/mm3 for 7 days or longer
Non-serious AESIs will be reported on the eCRF only. 
For all other AEs, record all information in source documents and the corresponding eCRF.
Additionally, any other event that the Investigator believes should be recorded is to be documented 
in the CRF.

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12.1.4.
Disease-Specific Adverse Events
12.1.4.1.
Hypoglycemia
Participants in this study are to follow current guidance for glycemic control using intensive insulin 
therapy. Specifically, a goal HbA1c of <7.5% in those 17 years old or younger and <7.0% in those 
18 years old and above (ADA 2018).  If there are local, regional, or national recommendations to 
be followed that supersede ADA recommendations, these glycemic control targets (ie, HbA1cs or 
glucose levels) should not be more liberal (ie, higher) than the ADA recommendations. The 
Investigator will document in the CRF the glycemic goals. 
Although glycemic control goals are suggested to reduce long-term complication of T1D, they 
have been shown to significantly increase the incidence of low blood glucose levels, vis- -vis 
hypoglycemia.  The ADA and EASD define hypoglycemia as a confirmed blood glucose reading 
of
70 mg/dL (3.9 mmol/L). In addition, there are other definitions of hypoglycemia based on 
and BG values of or slightly under 70 mg/dL (3.9 mmol/L) are not necessarily of clinical 
significance. Although all hypoglycemic events, including CTCAE Grade 1 events (BG 
<70 mg/dL or 3.9 mmol/L), should be recorded in the hypoglycemia eDiary, Grade 1 
hypoglycemic events may not need to be reported as AEs, at 
Recently the International Hypoglycemia Study Group from the ADA and EASD published a 
position statement on hypoglycemia suggesting that clinical trials report as clinically important 
hypoglycemia BG values of <54 mg/dL (3.0 mmol/L)
and also 
significant impairment consistent with hypoglycemia requiring assistance often referred to as 
(IHSG 2017). Level 3 events may include cognitive impartment, altered/loss of consciousness, 
confusion, seizure, syncope/fainting, or coma, and support may be general assistance, glucagon, 
or oral carbohydrate (ie, fruit juice or glucose tablets). These events may or may not require 
medical attention or hospitalization. A BG assessment demonstrating a low glucose level is not 
required to categorize severe hypoglycemia. 
Taking together this guidance above, this study will consider clinically important hypoglycemia 
Level 2 and/or Level 3 Hypoglycemia using the definitions above. These events will constitute 
one of key secondary endpoints. 
Recognizing that there may be episodes of hypoglycemia that might not meet these criteria, BG 
values of 54-70 mg/dL (3.0 3.9 mmol/L) and other milder symptoms should also be recorded and 
will be part of the exploratory analyses (Seaquist 2013, IHSG 2017). Participants are to collect and 
record such BG readings (if available), signs and symptoms, level of support, medical care and 
hospitalization (if needed), and other relevant information on health and wellbeing, recent insulin 
use, recent diet, exercise and concomitant medicines. 
It is anticipated these non-Level 2 and 3 hypoglycemia events will be categorized as follows, 
using existing definitions from the ADA (Seaquist 2013, IHSG 2017):

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Documented non-severe symptomatic hypoglycemic:
Non-severe hypoglycemia 
mmol/L)  
Asymptomatic hypoglycemia: A BG readi
55 mg/dL (3.0 
mmol/L) not accompanied by hypoglycemia symptoms 
Probable symptomatic hypoglycemia:
Non-severe hypoglycemia symptoms not 
accompanied by a BG measurement
Pseudo-hypoglycemia: Non-severe hypoglycemia symptoms but with a BG of >70 mg/dL 
(3.9 mmol/L)
In terms of adverse event reporting in this study, the severity of a hypoglycemia adverse event 
should be identified by the site Investigator and classified according to CTCAE v5.0 hypoglycemia 
as follows:
Grade 1 hypoglycemia: A BG reading of 55-70 mg/dL (3.0 3.9 mmol/L). This is 
considered mild and either asymptomatic or with mild symptoms. It requires observation 
(clinical or diagnostic) only. Specific interventions are not indicated.
Grade 2 hypoglycemia: A BG reading of 40 54 mg/dL (2.2 2.9 mmol/L). This is 
considered moderate with minimal, local or noninvasive intervention indicated. It limits
age-appropriate activities
Grade 3 hypoglycemia: A BG reading of 30 39 mg/dL (1.7 2.1 mmol/L). This is 
considered severe or medically significant but not immediately life-threatening. 
Hospitalization or prolongation of hospitalization is likely indicated. It is considered 
disabling and limits self-care.
Grade 4 hypoglycemia: A
29 mg/dL (1.6 mmol/L). This is considered life 
threatening (eg. seizures) with urgent intervention indicated.
Grade 5 hypoglycemia: This is defined as hypoglycemia resulting in death.
AEs of hypoglycemia will be classified by the site Investigator as mild, moderate, or severe or an
SAE along with relatedness to study drug as described in Sections 9.7.2 and 9.7.3.
Grade 1 hypoglycemia does not need to be reported as an AE. 
12.1.4.2.
Hyperglycemia and Diabetic Ketoacidosis
In this study hyperglycemia will be reported as a disease-specific AE if it meets Grade 4 severity 
and/or if associated with clinically significant DKA, defined as: 
Current (or very recent) hyperglycemia, for example, a BG level of >180 mg/dL (10 
mmol/L) 
Acidemia, for example a venous or arterial bicarbonate level <15 mmol/L and/or blood pH
<7.3, 
Ketonemia or ketonuria 
for example serum or urine ketones elevated beyond the upper 
limit of the normal, and

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Requiring medical attention such as unplanned outpatient care, emergency room care, or
hospitalization 
12.1.4.3.
Anticipated Adverse Events
An anticipated event is any adverse event (serious or non-serious) that commonly occurs as a 
consequence of the underlying disease or condition under investigation (disease-related) or 
background regimen.
For the purposes of this study the following events will be considered anticipated events:
1. Hypoglycemia. This is a condition of low BG that can occur in individuals with T1D on 
insulin therapy. The definition is provided above in Section 12.1.4.1).
2. DKA. This is a condition of ketosis and metabolic acidosis that can occur in individuals 
with T1D. The definition is provided above in Section 12.1.4.2.
Both hypoglycemia and DKA may present along a spectrum of severity. The principal Investigator 
will be responsible for the AE classification according to Section 12.1.7.
Reporting of Anticipated Events
These events will be captured on the CRF and reported to the Sponsor as described in Section 
12.2.2.1. Any event that meets serious adverse event criteria will be reported to the Sponsor within 
the appropriate timeline as described in Section 12.2.2. These anticipated events are exempt from 
expedited reporting as individual single cases to health authorities. However, if based on an 
aggregate review, it is determined that an anticipated event is possibly related to study drug, the 
Sponsor will report these events in an expedited manner.
12.1.5.
Unlisted or Unexpected Serious or Nonserious Adverse Events
An adverse event, the nature or severity of which is not consistent with the applicable product 
reference safety information (eg, IB for an unapproved investigational study drug product). For 
teplizumab, the expectedness of an adverse event will be determined by whether it is listed in the 
IB.
12.1.6.
Attribution Definitions
The Investigator is required to provide an assessment of causality or relationship of adverse events 
to the study drug based on 1) temporal relationship of the event to the administration of study drug; 
2) whether an alternative etiology has been identified; and 3) biological plausibility. The causality 
assessment categories that will be used for this study are described below.
Causality assessments considered not related to study drug:
Unrelated: The event is related to an etiology other than the study drug (the alternative 

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Unlikely: The event is unlikely to be related to the study drug and likely to be related to 
factors other than study drug.
Causality assessments considered related to study drug:
Possible: There is an association between the event and the administration of the study drug 
and there is a plausible mechanism for the event to be related to study drug; but there may 
underlying disease.
Probable: There is an association between the event and the administration of study drug, 
a plausible mechanism for the event to be related to the study drug and the event could not 
alternative etiology is not apparent.
Definite: There is an association between the event and the administration of study drug, a 
plausible mechanism for the event to be related to the study drug and causes other than the 
study drug have been ruled out and/or the event re-appeared on re-exposure to the study 
drug.
12.1.7.
Severity Criteria
An assessment of severity grade for each AE will be made by the site Investigator according to the 
a common 
language to describe levels of severity, to analyze and interpret data, and to articulate the clinical 
significance of all AEs. The Investigator should use clinical judgment in assessing the severity of 
events not directly experienced by the participant (eg, laboratory abnormalities).
Adverse events will be graded according to National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0:
Grade 1 = Mild adverse event.
Grade 2 = Moderate adverse event.
Grade 3 = Severe adverse event. 
Grade 4 = Life-threatening or disabling adverse event.
Grade 5 = Death
12.2.
Special Reporting Situations
12.2.1.
Safety Events of Interest 
Safety events that may require expedited reporting and/or safety evaluation include, but are not 
limited to:
Overdose of a Sponsor study drug
Suspected abuse/misuse of a Sponsor study drug
Accidental or occupational exposure to a Sponsor study drug

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Medication error involving a sponsor product (with or without participant exposure to the 
Sponsor study drug, eg, name confusion)
Special reporting situations should be recorded in the CRF. Any special reporting situation 
that meets the criteria of an SAE should be recorded on the SAE page of the CRF.
12.2.2.
Expedited Safety Report
An expedited safety report is a written narrative report summarizing a serious adverse event that 
meets expedited safety reporting criteria (7- or 15-day report), which is documented using the 
appropriate form and format, and submitted within the required reporting timeframe of applicable
regulatory authorities and/or IRBs/IECs of participating countries.
12.2.2.1.
Anticipated Adverse Event
An anticipated event is any adverse event (serious or non-serious) that commonly occurs as a 
consequence of the underlying disease or condition under investigation (disease-related) or 
background regimen. These anticipated events (Section 12.1.4.3) are exempt from expedited 
reporting as individual single cases to health authorities. However, if based on an aggregate review, 
it is determined that an anticipated event is possibly related to study drug, the Sponsor will report 
these events in an expedited manner.
12.2.3.
Immediately Reportable Events
Immediately reportable events (IREs) include events other than SAEs that must be reported 
immediately within 24 hours of being identified. An IRE includes but is not limited to:
AESIs of viral, fungal, or bacterial infection Grade 3 or higher
Events leading to discontinuation of study drug in an individual participant 
Protocol deviations/violations due to emergency or accident
Non-serious AEs including laboratory results identified during the DMC review to be 
reported immediately, eg, lymphocyte counts <500 cells/ L that persist for 1 week
A participant missing a full dose on any dosing day
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until completion of the participant's last study-
related procedure, which may include contact for follow-up of safety. 
Serious adverse events, including those spontaneously reported to the Investigator within 52 weeks 
after the last dose of study drug (which is the end of the study), must be reported using the Serious 
Adverse Event Form. In addition, SAEs will be requested to be submitted for participants who 
withdraw early from the study for a year after their last study drug dose. The Sponsor will evaluate 
any safety information that is spontaneously reported by an Investigator beyond the time frame 
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All events that meet the definition of an SAE will be reported as SAEs, regardless of whether they 
are protocol-specific assessments. Anticipated events will be recorded and reported as described 
in Section 12.1.4.3.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug or
device, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
"upper respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to Sponsor
instructions. 
Continuous glucose monitors are to be applied at specified Study Visits and worn for up to 2 weeks 
to record participant glucose levels at a high frequency. If there are any AEs associated with the 
CGMs (ie, device-related AEs) will be investigated and may include the return of the device to the 
Sponsor for inspection.
The Sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The Sponsor will also report to the Investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). Further, 
local regulation regarding reporting requirements for SUSARs will be applied. The Investigator 
(or Sponsor where required) must report SUSARs to the appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise 
required and documented by the IEC/IRB. A SUSAR will be reported to regulatory authorities 
unblinded. Participating Investigators and IEC/IRB will receive a blinded SUSAR summary, 
unless otherwise specified. 
For all studies with an outpatient period, the participant must be provided with a wallet (study) 
card
and instructed to carry this card with them for the duration of the study indicating the 
following: 
Study number 
Statement, in the local language(s), that the participant is participating in a clinical study 
Investigator's name and 24-hour contact telephone number 
Local Sponsor's name and 24-hour contact telephone number (for medical staff only) 
Site number 
Participant number 
Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate Sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event. 

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All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the participant's participation in the study, must be followed until any of the 
following occurs: 
The event resolves 
The event stabilizes 
The event returns to baseline, if a baseline value/status is available 
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
It becomes unlikely that any additional information can be obtained (participant or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts).
Suspected transmission of an infectious agent by a study drug should be reported as an SAE,
Important Medical Event, and/or according to any other applicable seriousness criteria.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a participant's participation in a study must be reported as an SAE, except 
hospitalizations for the following: 
Hospitalizations not intended to treat an acute illness, worsening of a preexisting condition,
or an event considered possibly, probably, or definitely related to the study or study agent 
(Section 12.1.6). For example, a hospitalization for social reasons such as pending 
placement in long-term care facility
Surgery or elective procedure not considered possibly, probably, or definitely related to the 
study or study agent (Section 12.1.6) or planned before entry into the study.
Disease progression should not be recorded as an adverse event or SAE term; instead, signs and 
symptoms of clinical sequelae resulting from disease progression/lack of efficacy will be reported 
if they fulfill the SAE definition (refer to Section 12.1.2).
12.3.3.
Procedure for Serious Adverse Event Reporting 
Within 24 hours of identifying an SAE (Section 12.1.2), regardless of the presumed relationship 
to the study drug, the Investigator must obtain an SAE report form, complete the form, and transmit 
it to the designated Pharmacovigilance contact.
Minimum information to be documented on the SAE report form: 
Protocol number; name and contact phone number of the Principal Investigator
Participant number and year of birth
Serious adverse event, date of event onset, date of last study drug administration, current 
status of participant, and Investigator causality assessment
Concomitant Medication information
Relevant laboratory/diagnostic test results and medical record progress notes

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Pharmacovigilance contact information for SAE report will be provided to the study sites.
12.3.4.
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be 
provided to the Sponsor by the study-site personnel within 24 hours of their knowledge of the event 
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and 
must be reported using the Serious Adverse Event Form. Any participant who becomes pregnant 
during the study must be promptly withdrawn from the study and discontinue further study drug 
administration.
Any pregnancy (in female participants or female partners of male participants) that occurs at any 
time during study participation should be reported. For participants who withdraw from all study 
visits, the study staff will make every effort to obtain any pregnancy information through the end of 
the study (Week 78 visit).
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
participants included in the study will be reported as noted above. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information page(s), 
which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of participants, Investigators, 
and the Sponsor, and are mandated by regulatory agencies worldwide. The Sponsor has established 
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting of 
PQC information; all studies conducted by the Sponsor or its affiliates will be conducted in 
accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the Sponsor by the study-site personnel within 24 hours after 
being made aware of the event.

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If the defect is combined with a serious adverse event, the study-site personnel must report the PQC 
to the Sponsor according to the serious adverse event reporting timelines (refer to Section 12.3.3
Serious Adverse Events). A sample of the suspected product should be maintained for further 
investigation if requested by the Sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be provided 
as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drugs
The Sponsor will provide adequate supplies of the study drugs: teplizumab and placebo sterile 
solution for injection. 
The formulation of teplizumab will consist of 10 mM sodium phosphate, 150 mM sodium chloride, 
and 0.05 mg/mL Tween 80 with pH 6.1. The final drug product will be provided at a concentration 
of 1 mg/mL for a total of 2 mg of recoverable drug product per vial. 
The placebo formulation will consist of the same formulation buffer without teplizumab.
14.2.
Packaging
Teplizumab and placebo will be supplied in 2 mL type 1 glass vials with rubber stoppers and flip-
off seals.
14.3.
Labeling
The study drugs (teplizumab and placebo) will be labeled with, at a minimum, the protocol number, 
vial number, kit number, pharmaceutical dosage form (including product name and quantity in 
kit), directions for use, storage conditions, expiry date (if applicable), batch number, the statements 
Limited by Federal (United States) 
Sponsor's name and address. Any additional labeling 
requirements for participating countries will also be included on the label.  
Please see the Pharmacy Manual for detailed information about the packaging of the study drug or 
placebo and additional labeling information.
14.4.
Preparation, Handling, and Storage 
Teplizumab should be stored, prepared, and handled according to the Pharmacy Manual. The 
Pharmacy Manual should be followed to ensure that intravenous drug delivery devices used are 
made of compatible materials. 
Compatibility testing of teplizumab with solutions other than 0.9% sodium chloride has not been 
conducted. Teplizumab for IV administration may only be prepared with 0.9% sodium chloride. 
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teplizumab is being administered. If the same intravenous line must be used for infusion of other 
drugs or solutions, the line should be flushed with 0.9% sodium chloride solution before and after 
infusion of teplizumab.
The vials should be stored at controlled temperatures from 
not be frozen. To ensure compliance, temperature logs will be maintained. The refrigerator should 
have a digital min/max thermometer.
Refer to the Pharmacy Manual for additional guidance on study drug preparation, handling, and 
storage.
14.5.
Drug Accountability
The Investigator or his designee is required to maintain accurate drug accountability records. A 
binder containing instructions and the required accountability documentation will be provided to 
the Investigator or his designee. When the study is completed, study drug accountability records 
must be sent to the Sponsor. The drug accountability records must be maintained with the rest of 
the documentation at the site in accordance with Section 17.7. All unused study drug must be 
returned to the Sponsor or disposed of upon authorization by the Sponsor or its designee. All 
records regarding the disposition of study drug must be available for inspection by the study 
monitors.
Study drug should be dispensed under the supervision of the Investigator or a qualified member of 
the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to 
participants participating in the study. The Investigator agrees neither to dispense the study drug 
from, nor store it at, any site other than the study sites agreed upon with the Sponsor.
15.
STUDY-SPECIFIC MATERIALS
The Investigator will be provided with study-specific manuals and materials, including the 
following:
Pharmacy manual
Laboratory manual
NCI CTCAE Version 5.0
IWRS manual
CRF Completion Guidelines
Sample ICF
eDiary

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16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 
they would otherwise be entitled. Only participants who are fully able to understand the risks, 
benefits, and potential adverse events of the study, and provide their consent voluntarily will be 
enrolled.
When referring to the signing of the ICF, the terms legal guardian and legally acceptable 
representative refer to the legally appointed guardian of the child with authority to authorize 
participation in research. For each participant, his or her parent(s) (preferably both parents, if 
available) or legally acceptable representative(s), as required by local regulations, must give 
written consent (permission) according to local requirements after the nature of the study has been 
fully explained and before the performance of any study-related assessments. Assent must be 
obtained from children (minors) capable of understanding the nature of the study, typically 
participants 7 years of age and older, depending on the institutional policies. For the purposes of 
this study, all references to participants who have provided consent (and assent as applicable) 
refers to the participants and his or her parent(s) or the participant's legal guardian(s) or legally 
acceptable representative(s) who have provided consent according to this process. Minors who 
assent to a study and later withdraw that assent should not be maintained in the study against their 
will, even if their parents still want them to participate.
The total blood volume to be collected is noted in Section 9.1.3. The local, regional and national
acceptable amount of blood to be collected over this time period from the population is detailed 
in Appendix 3.
16.1.1.
Investigator Responsibilities
The Investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.1.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the Investigator (or Sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):
Final protocol and, if applicable, amendments

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Sponsor-approved ICF (and any other written materials to be provided to the participants)
IB (or equivalent information) and amendments/addenda
Sponsor-approved recruiting materials
Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable
Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)
Information regarding funding, name of the Sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for participants
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the Sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
16.1.3.
Informed Consent and Assent Form
Each participant and a legally acceptable representative must give written consent according to 
local requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) and assent form that is/are used must 
be approved by both the Sponsor and by the reviewing IEC/IRB and be in a language that the 
participant can read and understand. The informed consent should be in accordance with principles 
that originated in the Declaration of Helsinki, current ICH and GCP guidelines, applicable 
regulatory requirements, and Sponsor policy.
Before enrollment in the study, the Investigator or an authorized member of the study-site 
personnel must explain to potential participants and their legally acceptable representatives the 
aims, methods, reasonably anticipated benefits, and potential hazards of the study, and any 
discomfort participation in the study may entail. Participants will be informed that their 
participation is voluntary and that they may withdraw consent to participate at any time. They will 
be informed that choosing not to participate will not affect the care the participant will receive for 
the treatment of his or her disease. Participants will be told that alternative treatments are available 
if they refuse to take part and that such refusal will not prejudice future treatment. Finally, they 
will be told that the Investigator will maintain a participant identification register for the purposes 
of long-term follow up if needed and that their records may be accessed by health authorities and 
authorized Sponsor personnel without violating the confidentiality of the participant, to the extent 
permitted by the applicable law(s) or regulations. By signing the ICF/assent, the participant and
legally acceptable representative are authorizing such access. It also denotes that the participant
agrees to allow his or her study physician to recontact the participant for the purpose of obtaining 
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The participant and legally acceptable representative will be given sufficient time to read the ICF 
and the opportunity to ask questions. After this explanation and before entry into the study, 
assent/consent should be appropriately recorded by means of the participant's and his or her legally 
acceptable representative's personally dated signature. After having obtained the assent/consent, a 
copy of the ICF must be given to the participant and his or her legally acceptable representative.
If the participant or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the assent/ICF after the oral consent 
of the participant or legally acceptable representative is obtained.
Children (minors) or participants who are unable to comprehend the information provided can be 
enrolled only after obtaining consent of a legally acceptable representative. Assent must be 
obtained from children (minors) capable of understanding the nature of the study, typically 
participants 7 years of age and older, depending on the institutional policies. Written assent should 
be obtained from participants who are able to write. A separate assent form written in language 
the participant can understand should be developed for adolescents. After having obtained the 
assent, a copy of the assent form must be given to the participant, and to the participant's parent or 
if applicable legally acceptable representative.
16.1.4.
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. The objectives of the 
study and the nature and detail of the personal data to be recorded by the Sponsor as a consequence 
of study participation will be explained to each study participant (or their legally acceptable 
representative) in the ICF and during the consent process.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. In Europe the Study 
a Protection 
Appropriate technical and organizational measures to protect the personal data 
against unauthorized disclosures or access, accidental or unlawful destruction, or accidental loss 
or alteration must be put in place. Sponsor personnel whose responsibilities require access to 
personal data shall be approved by the local IEC/IRB and shall agree to keep the 
participants
confidential.
The informed assent/consent obtained from the participant and his or her legally acceptable 
representative shall include explicit consent for the processing of personal data and for the 
Investigator/institution to allow direct access to his or her original medical records (source 
data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory authority 
inspection. This consent also addresses the transfer of the data to other entities and to other 
countries.
The participant has the right to request access to his or her personal data and the right to request 
rectification of any data that are not correct or complete. Details of which party to contact in respect 

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of such requests shall be included in the ICF and in the consent process. Reasonable steps will be 
taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
In addition to these rights, a participant may restrict the processing of incorrect data, request a 
copy of the data or ask for them to be transferred to a third party (portability). A participant can 
also withdraw consent on the data, in which case no further information about the participant will 
be collected from that moment onward.
Any limitation placed upon the par
their personal data from study 
records resulting from the need to conduct the study in compliance to locally applicable regulations 
and laws shall be explained in the ICF and in the consent process.
Exploratory research is not conducted under standards appropriate for the return of data to 
participants. In addition, the Sponsor cannot make decisions as to the significance of any findings 
resulting from exploratory research. Therefore, exploratory research data will not necessarily be 
returned to participants or Investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
16.1.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected from randomized participants in this study may be stored for up to 15 years or
more (or according to local regulations) for additional research. Samples can be used to understand 
the effects of teplizumab on Type 1 diabetes, differential drug responders, and to develop 
tests/assays related to teplizumab or other autoimmune conditions. The research may begin at any 
time during the study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3.1, Withdrawal From the Use of Samples in Future 
Research).
16.1.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16.1, Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the Investigator nor the Sponsor will modify this protocol without a formal amendment by 
the Sponsor. All protocol amendments must be issued by the Sponsor and signed and dated by the 

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Investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the participants, in which case the amendment must 
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the Investigator and IEC/IRB must be provided to the Sponsor. When the 
change(s) involves only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the Investigator or other physician in attendance will contact the appropriate Sponsor
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the Sponsor must be made as soon as possible 
to discuss the situation and agree on an appropriate course of action. Protocol deviations will be 
documented. 
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Pre-study Documentation
The following documents must be provided to the Sponsor before shipment of study drug to the 
study site:
Protocol and amendment(s), if any, signed and dated by the Principal Investigator
A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, participant compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee.
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an Investigator or 
a member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.
Regulatory authority approval or notification, if applicable
Signed and dated statement of Investigator (eg, Form FDA 1572), if applicable
Documentation of Investigator qualifications (eg, curriculum vitae)

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Completed Investigator financial disclosure form from the Principal Investigator, where 
required
Signed and dated clinical trial agreement, which includes the financial agreement
Any other documentation required by local regulations
The following documents must be provided to the Sponsor before enrollment of the first 
participant:
Completed Investigator financial disclosure forms from all sub-investigators
Documentation of sub-investigator qualifications (eg, curriculum vitae)
Name and address of any local laboratory conducting tests for the study, and a dated copy 
of current laboratory normal ranges for these tests, if applicable
Local laboratory documentation demonstrating competence and test reliability 
(eg, accreditation/license), if applicable
17.3.
Participant Identification, Enrollment, and Screening Logs
The Investigator agrees to complete a participant identification, screening, and enrollment log to 
permit easy identification of each participant during and after the study. This document will be 
reviewed by the Sponsor study-site contact for completeness.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
drug receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the Investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and Section 
4.2, Exclusion Criteria that specify a need for documented medical history are as follows:
Referral letter from treating physician or
Complete history of medical notes at the site

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Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents.
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as the 
clinical study-specific data fields as determined by the protocol. 
17.5.
Case Report Form Completion
Study-specific CRFs are prepared for each participant in electronic format. 
Electronic Data Capture (EDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto electronic CRFs (eCRF) via the secure EDC 
system in accordance with the study calendar, and within the timeframe agreed upon between the 
Sponsor and the study site.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the participant's source documents. Data must be entered into 
CRF in English. The CRF must be completed as soon as possible after a participant visit and the 
forms should be available for review at the next scheduled monitoring visit.
When necessary, queries will be generated in the EDC system. If corrections to a CRF are needed 
after the initial entry into the CRF, this can be done in either of the following ways:
Investigator and study personnel can make corrections in the EDC system at their own 
initiative or as a response to a query (from the EDC system).
Sponsor or Sponsor delegate can generate a query for resolution by the Investigator and 
study-site personnel.
All CRF entries, corrections, and alterations must be made by the Investigator or authorized study-
site personnel. The Investigator must verify that all data entries in the CRF are accurate and correct.
Investigator will review, sign, and date completed CRFs at regular intervals as determined by the 
Sponsor.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the Investigator and 
study-site personnel before the study, and periodic monitoring visits by the Sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the Sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. 

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Clinical monitors will review CRF for accuracy and completeness during on-site monitoring visits 
and after transmission to the Sponsor; any discrepancies will be resolved with the Investigator or 
designee, as appropriate. 
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the Investigator/institution will maintain all CRF and 
all source documents that support the data collected from each participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
Investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the Sponsor. It is 
the responsibility of the Sponsor to inform the investigator/institution as to when these documents 
no longer need to be retained.
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the Investigator relocate or dispose of any study documents 
before having obtained written approval from the Sponsor.
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the Investigator/institution must permit access to such reports.
17.8.
Monitoring
The Sponsor will use a combination of monitoring techniques (eg, central, remote, or on-site 
monitoring) to monitor this study.
The Sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the CRF
with the source documents
(eg,
. The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
CRF are known to the Sponsor and study-site personnel and are accessible for verification by the 
Sponsor study-site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying 
that the recorded data are consistent with the original source data. Findings from this review will 

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be discussed with the study-site personnel. The Sponsor expects that, during monitoring visits, the 
relevant study-site personnel will be available, the source documents will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor will 
meet with the Investigator on a regular basis during the study to provide feedback on the study 
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of the 
study at the site. 
Central monitoring will take place for data identified by the Sponsor as requiring central review.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study will be considered to have completed when the database is locked after the last 
The Investigator will notify the IRB/IEC when the study has been completed. 
17.9.2.
Study Termination
The Sponsor reserves the right to close a study site or terminate the study at any time for any reason 
at the sole discretion of the Sponsor. Study sites will be closed upon study completion. A study
site is considered closed when all required documents and study supplies have been collected and 
a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are not 
limited to:
Failure of the Investigator to comply with the protocol, the requirements of the IEC/IRB 
or local health authorities, the Sponsor's procedures, or GCP guidelines
Inadequate recruitment of participants by the Investigator
Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the Sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Participant privacy must, however, be 
respected. The Investigator and study-site personnel are responsible for being present and available 
for consultation during routinely scheduled study-site audit visits conducted by the Sponsor or its 
designees. 

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Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The Investigator should immediately notify the Sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding teplizumab or the Sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the Sponsor to the Investigator and not 
previously published, and any data, including exploratory biomarker research data, generated as a 
result of this study, are considered confidential and remain the sole property of the Sponsor. The 
Investigator agrees to maintain this information in confidence and use this information only to 
accomplish this study and will not use it for other purposes without the Sponsor's prior written 
consent.
The Investigator must agree to send to the Sponsor for review all manuscripts, abstracts and 
presentations using data from this study prior to their submission for publication. The Sponsor 
reserves the right to delete from such materials any part or parts deemed to be confidential or 
proprietary.
The Investigator understands that the information developed in the study will be used by the 
Sponsor in connection with the continued development of teplizumab, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the Investigator is obligated to provide the Sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the Sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating Investigator. Results of exploratory analyses 
performed after the Clinical Study Report has been issued will be reported in a separate report and 
will not require a revision of the Clinical Study Report. Study participant identifiers will not be 
used in publication of results. Any work created in connection with performance of the study and 
contained in the data that can benefit from copyright protection (except any publication by the 
Investigator as provided for below) shall be the property of the Sponsor as author and owner of 
copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the Sponsor shall have the right to publish such primary (multicenter) data and 
information without approval from the Investigator. The Investigator has the right to publish study 
site-specific data after the primary data are published. If an Investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the Sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the Sponsor in 
writing, the Investigator will withhold such publication for up to an additional 60 days to allow for 

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filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the Sponsor will review these issues with the Investigator. The Sponsor
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
Investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the Sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on authorship, 
such as those described in the Uniform Requirements for Manuscripts Submitted to Biomedical 
Journals, which state that the named authors must have made a significant contribution to the 
design of the study or analysis and interpretation of the data, provided critical review of the paper, 
and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The Sponsor will register and disclose the existence of and the results of clinical studies as required 
by law.

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APPENDICES
Appendix 1: American Diabetes Association T1D Diagnostic Criteria
As defined by the American Diabetes Association (ADA) for the diagnosis of diabetes, the 
individual must meet one of the following 4 criteria: 
defined as no 
caloric intake for at least 8 hours.
A 2-
tolerance test (OGTT). The test should be performed as described by the World Health 
Organization (WHO), using a glucose load containing the equivalent of 75 g anhydrous 
glucose dissolved in water.
laboratory using a method that is National Glycohemoglobin Standardization Program 
(NGSP) certified and standardized to the Diabetes Control and Complications Trial 
(DCCT) assay.
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random PG 
Note: In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results
from the same sample or in two separate test samples.
For the diagnosis of Type 1 diabetes (T1D), the ADA suggests that plasma blood glucose rather 
than HbA1C should be used to diagnose the acute onset of T1D in individuals with symptoms of 
hyperglycemia.
According to ADA, a patient with classic symptoms, measurement of plasma glucose is sufficient 
to diagnose diabetes (symptoms of hyperglycemia or hyperglycemic crisis plus a random plasma 
L]). In these cases, knowing the plasma glucose level is critical 
because, in addition to confirming that symptoms are due to diabetes, it will inform management 
decisions. Some providers may also want to know the HbA1C to determine how long a patient has 
had hyperglycemia. In addition, T1D,
-
-
10% of diabetes and is due to cellular-mediated autoimmune 
-cells. Autoimmune markers include islet cell autoantibodies and 
autoantibodies to GAD (GAD65), insulin, the tyrosine phosphatases IA-2 and IA-
T1D is defined by the presence of one or more of these autoimmune markers.

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Appendix 2: Mixed Meal Tolerance Test (MMTT) Procedures
The procedure below for the mixed-meal tolerance test (MMTT) is an overview of how participants 
and study personnel should prepare for and perform the test. Additional details will be provided 
in the Laboratory manual. Minor adjustments to this procedure may be made by the sponsor that 
will not necessitate a protocol amendment.
Overview
The preparation for both 2h and 4h MMTTs are the same; the difference primarily lies in the length 
of the assessment.
The MMTT is to be performed in the morning between approximately 7:00 a.m. and 10:00 a.m., 
meaning that the
-Johnson) is to be 
consumed within this time. It is recommended that the tests be scheduled early in the morning 
(7:00 7:30 am) because blood glucose is more likely to be within the target range. The 4h MMTT 
takes approximately 250 minutes to complete, and the 2-hour MMTT takes approximately 130 
minutes. 
There are several types of Boost nutritional drinks that contain different amounts of carbohydrates, 
fats and protein. This test should specifically use Boost High Protein Nutritional Energy Drink 
with the following content per bottle:
Total volume of drink per bottle: 8 ounces (237 mL)
Total calories: 240 
Total fat: 6 grams (saturated fat 1 gram and trans fat 0 grams)
Total carbohydrates: 28 grams (Sugars 15 grams)
Total protein: 20 grams 
If a participant has a known food allergy to one or more components of Boost, an equivalent 
substitution may be used contingent upon agreement with the study team and consultation with the 
Medical Monitor.
Dietary Guidelines and Pretest Instructions 
Carbohydrates should not be restricted from the diet before the test. A general guideline is that 
pre-adolescents should consume at least 25 kcal (6.25 g)/kg/day in carbohydrates and adolescents
and adults should consume at least 15 kcal (3.75 g)/kg/day in carbohydrates for 3 days before the 
test. These are minimum amounts of carbohydrates; most diets will include more carbohydrates.
carbohydrate-restricted 
diet.

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Participant Preparation 
Food and (non-insulin) medicines:
Fast for at least 10 hours but not more than 16 hours before the test. Fasting should start 
the night before the test and continue up until the start of the test. Participants should not 
eat or drink anything except water. Coffee, tea, soda, cigarettes, alcohol, or chewing gum
are prohibited. 
Refrain from vigorous exercise during the fasting period.
Refrain from working during the fasting period. 
If medically feasible, medications should be held from the start of the fast to the study visit. 
If a medicine must be taken during the fast, the participant is to consult with the 
investigator.
Insulin before the test:
At least routine monitoring of blood glucose should be conducted the evening and the night 
before and the morning of the test and be used to gauge insulin treatment.
Short-acting insulin analogues may be administered up to 2 hours before the test (eg, lispro 
or l-aspart).
Regular insulin may be administered up to 6 hours before the test. 
Intermediate-acting insulin may be administered on the evening before the MMTT, but 
NOT on the morning of the test. Participants managed with intermediate-acting insulin 
(NPH or Lente) should administer their usual dose on the evening before the MMTT but 
not on the morning of the test.
Long-acting basal insulin or continuous subcutaneous insulin infusions may be 
administered before, during, and after the test as usual. Participants on glargine may take 
their usual injection at the appropriate time. those on continuous subcutaneous insulin 
infusion may continue with their usual basal settings.
Glucose management and target blood glucose at the start of test:
The target glucose level at the start of the test is between 70 and 200 mg/dL (3.9-11.1 mmol/L).
The investigator and the study participant should discuss the individual situation for insulin 
administration to attain the goal of meter capillary glucose values within the range of 
70-200 mg/dL (3.9-11.1 mmol/L) at the start of the test. 
For example, participants may be instructed to check their blood glucose by glucometer at home 
2 hours before the start of the test, so that marked hyperglycemia can be treated with a short-acting 
insulin analogue. Alternatively, participants who arrive at the research unit with elevated blood 
glucose can receive additional short-acting insulin analogues at the time of their arrival, if the test 
is started at least 2 hours after insulin administration and occurs before 10 a.m. 

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If a 
blood glucose is below 70 mg/dL (3.9 mmol/L) prior to performing the MMTT, 
the participant should be treated according to local practice, and the MMTT should be rescheduled. 
Study site preparation for the MMTT
Calculating the dose of BOOST:
kg) should be obtained on the morning of the test.
The dose of BOOST is 6 kcal/kg. BOOST has a caloric concentration of 1 kcal/kg. 
The maximal volume of BOOST a participant should consume is 360 mL.
The study coordinator/investigator is to document the volume of BOOST to give the 
participant.
BOOST may be consumed at room temperature, refrigerated, or chilled on ice but should 
not be mixed with any other substances. It can be consumed directly from a cup or via a 
straw.
The participant is to be instructed that the BOOST is to be consumed in no more the 5 
minutes.
Preparation for sample collection:
As the MMTT may be fast paced and it is important to draw blood as close to the planned 
time points as possible; it is important to be prepared.
Blood drawing supplies, including syringes, needles, and flush solutions are obtained.
The sample collecting tubes are pre-labeled with times of the draw with spare tubes 
available.
An ice bucket is available to temporarily store the samples.
The centrifuge is readily 
.
A fingerstick/spot check glucometer and strips should be available. 
Participant preparation:
The intravenous (IV) catheter should be in place and confirmed to be able to draw blood.
There is no restriction on the size of the IV catheter to use, but smaller catheters (especially 
24 gauge) can be prone to clotting and malfunction and are not recommended. If possible,
a larger catheter (18 or 20 gauge) is preferred. 
If a participant receives the study drug infusion via a midline or PICC-line, blood can be 
drawn from those catheters for MMTT at visits when the study drug is administered.
The catheter is to be flushed after each draw with saline or heparin solution according to 
local practice. 
The participant should remain sitting or resting in bed quietly throughout the test and until 
the test is completed. Quiet, nonstrenuous activities, such as reading, playing cards, or 

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watching TV are allowed. The participant may walk to the bathroom between blood draws 
if necessary. 
Blood draw time points: 
The first blood sample should be taken at least 10 minutes after establishing the IV and 
when the participant is calm and relaxed as much as possible.
-
-peptide and insulin and blood glucose (using the 
glucometer). 
-
dose for consumption as described 
above.
BOOST right 
away (and consume in no more than 5 minutes) and process the sample.
For the 2-hour MMTT: Continue with blood sample collection (3 mL collection tube (C-
peptide and insulin) and glucometer (BG) evaluation) at: 15, 30, 60, 90, and 120 minutes 
for a TOTAL of 7 samples (including the -10 and 0 min samples).
For the 4-hour MMTT: Continue with blood sample collection (3 mL collection tube (C-
peptide and insulin) and glucometer (BG) evaluation) at 15, 30, 60, 90, 120, 150, 180, 210, 
and 240 minutes for a TOTAL of 11 samples (including the -10 and 0 min samples).
A
timepoints specified above. 
Sample processing procedures are provided in the Investigator Laboratory Manual.
meter, advance diet, and 
The study team should confirm all data, including details of the BOOST (type and volume 
consumed), BG levels at presentation and during the test, timing of tests, confirmation of blood 
draws and sample processing, type and placement of IV catheter, and any problems or deviations 
during the test, including a clogged IV catheter or missed samples in source and/or on the CRF.

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MMTT DATA SHEET EXAMPLE
Date:
Day:        _____
Month:    _____
Year:       _____
Participant is here for a: (circle one)      
2-hour MMTT
4-hour MMTT
IV Catheter:
                       Detail if needed:
Gauge: _____
Anatomic site of catheter: ______________
Participant Weight:
Kg: ______
Time of Day 
(24:00)
Study/Sample 
Time
BG value 
(circle 
mg/dL or 
mmol/L)
C-peptide sample 
collected/processed 
correctly
______:______
At
Presentation 
to Facility
N/A
______:______
-10 min
[ ] YES      Detail if needed:
[ ] NO
______:______
0 min
[ ] YES      Detail if needed:
[ ] NO
______:______
Consume 
BOOST
BOOST Type:  ___________________
Volume to be consumed:  ________ ml
( = 6 mls x ___kg  OR Max 360 ml)
All BOOST consumed: [ ] YES;  [ ] NO 
Consumed in 5 min or less: [ ] YES;  [ ] NO
______:______
15 min
[ ] YES      Detail if needed:
[ ] NO
______:______
30 min
[ ] YES      Detail if needed:
[ ] NO

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(Continued)
______:______
60 min
[ ] YES      Detail if needed:
[ ] NO
______:______
90 min
[ ] YES      Detail if needed:
[ ] NO
______:______
120 min
[ ] YES      Detail if needed:
[ ] NO
If a 2-hour MMTT is being performed
and Skip 
next section.
Continue with additional assessments ONLY with the 4-hour MMTT
______:______
150 min
[ ] YES      Detail if needed:
[ ] NO
______:______
180 min
[ ] YES      Detail if needed:
[ ] NO
______:______
210 min
[ ] YES      Detail if needed:
[ ] NO
______:______
240 min
[ ] YES      Detail if needed:
[ ] NO 
Pre-discharge 
assessments
______:______
Participant 
Discharge
Participant back to baseline 
T1D management:
[ ] YES; [ ] NO
CRF Complete: 
[ ] YES; [ ] NO

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Appendix 3: Blood Draw Volumes
The estimated blood volumes drawn during the study, corresponding to the Schedule of Events, 
are shown in the table below.
Study participants are otherwise healthy, except for their recently diagnosed T1D, with no 
significant respiratory or cardiovascular disease. Participants will be monitored for clinical 
consequences of blood draws. Throughout the study, the Principal Investigator has the discretion 
to modify the blood draw schedule for safety considerations.

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Appendix 4. Pharmacodynamic Substudy at North American Sites
In order to evaluate the effects of teplizumab on pharmacodynamic (PD) measures of CD3 receptor 
occupancy and modulation, a substudy will be conducted at all North American sites. 
In addition to all of the study procedures described in the protocol, participants in the PD substudy 
will provide additional blood samples for the assessment of CD3 receptor occupancy and 
modulation. 
PD samples will be drawn concurrently with the PK blood samples at the following time points: 
During Treatment Course 1: 
Pre-infusion: Day 1, Day 4, Day 9, Day 12
Day 28

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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. 
I will conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study drug, the conduct of the study, and the obligations of 
confidentiality.
Coordinating Investigator (where required):
Name (typed or 
printed):
Institution and 
Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or 
printed):
Institution and 
Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or 
printed):
Organization:
Provention Bio, Inc
Signature:
Note:If the address or telephone number of the Investigator changes during the course of the 
study, written notification will be provided by the Investigator to the Sponsor, and a protocol 
amendment will not be required.