Clinical trial NCT02293837
Conditions: Type 1 Diabetes Mellitus New-onset Type 1 Diabetes Mellitus T1DM T1D
Keywords: interleukin-6 (IL-6) receptor inhibitor
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2015-03-12; Completion date: 2020-08-31
Enrollment: 136 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Type 1 diabetes mellitus (T1DM) is an autoimmune disease. Based on previous research, study doctors think that giving medicines to affect the immune system soon after diabetes is diagnosed may stop, delay or decrease the destruction of beta cells, resulting in better glucose control.

Researchers believe that tocilizumab could have some effect on the cells in the immune system that are thought to be involved in the development of type 1 diabetes. This study will test whether tocilizumab can help preserve or delay destruction of remaining beta cells in people recently diagnosed type 1 diabetes.

Detailed description:
Staggered enrollment is planned for this trial.

Prior to initiating the study in the pediatric age group (6-17 years old), 30-99 eligible adults (ages 18-45 years) will be randomized 2:1 to tocilizumab or placebo, respectively. Once the first thirty adult participants have completed 12 weeks of treatment, the FDA and Data and Safety Monitoring Board (DSMB) will review available data (e.g., interim analysis) to weigh potential risks and benefits before opening the trial to pediatric participants.

As of ≥ May 15, 2017: Study enrollment limited to participants ages 6 to 17 years inclusive.

Arms: arm 1: Subjects will receive intravenous (IV) infusions of either 8.0 mg/kg (body weight ≥30 kg) or 10.0 mg/kg (body weight \<30kg) tocilizumab every 4 weeks for 24 weeks. Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines \[Standard of Care, SOC\]) arm 2: Subjects will receive IV infusions of either 8.0 mg/kg (body weight ≥ 30kg) or 10.0 mg/kg (body weight \<30kg) placebo every 4 weeks for 24 weeks. Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines \[Standard of Care, SOC\])
Interventions: intervention 1: Tocilizumab (TCZ) intervention 2: Placebo intervention 3: Standard of Care
Intervention descriptions: intervention 1: Subjects assigned to this group will receive tocilizumab intravenous (IV) infusions of either 8.0 mg/kg (body weight ≥ 30kg) or 10.0 mg/kg (body weight \<30kg) every 4 weeks for 24 weeks. intervention 2: Subjects assigned to this group will receive placebo intravenous (IV) infusions of either 8.0 mg/kg (body weight ≥ 30kg) or 10.0 mg/kg (body weight \<30kg) every 4 weeks for 24 weeks. intervention 3: Participants will also receive standard intensive diabetes management (in accordance with the American Diabetes Association guidelines \[Standard of Care, SOC\])

Protocol documents:
Prot_000.pdf: 
 
 
       
 
Immune  
Tolerance 
Network  
   
Preserving Beta-Cell Function with Tocilizumab in New-onset 
Type 1 Diabetes 
 Protocol ITN058AI 
 
Version V6.0 (June 13, 2018)   
 
 
Protocol Co-Chair 
 
 
 
 
    
   
Protocol Co-Chair 
 
 
 
 
 
  
ITN Clinical Trial Physician 
 
 
 
 
 
 
 
  
NIAID Medical Monitor 
 
  
  
 
  
 
 
 
  
 
 
ITN Clinical Operations Manager 
 
 
 
 
 
 
 
  
 
 
 
 
 
NIAID Project Manager 
 
 
  
  
 
 
 
  
  
 


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ITN Lead Biologist  
  
 
 
  
 
  
  
  
 
 
 
NIAID Regulatory Officer 
 
 
 
  
 
 
 
 
  
Rho Scientist 
 
 
 
 
 
 
  
 
 
This clinical study is supported and conducted by the Immune Tolerance Network, which is 
sponsored by the National Institute of Allergy and Infectious Diseases and Type 1 Diabetes TrialNet, 
which is sponsored by the National Institute of Diabetes and Digestive Diseases. 
This document is confidential.  It is provided for review only to investigators, potential 
investigators, consultants, study staff, and applicable ethics committees or institutional review 
boards.  It is understood that the contents of this document will not be disclosed to others without 
written authorization from ITN and NIAID unless it is necessary to obtain informed consent from 
potential study participants. 


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Protocol Approval 
 
Protocol:  ITN058AI 
Protocol Version:  V6.0 
Dated:  June 13, 2018 
US IND # 117725 
Protocol Co-Chairs:  
 
 
Title:     Preserving Beta-Cell Function with Tocilizumab in New-onset Type 1 Diabetes 
I confirm that I have read the above protocol in the latest version.  I understand it, and I will 
work according to the principles of good clinical practice (GCP) as described in the US Code of 
Federal Regulations (CFR)—45 CFR part 46 and 21 CFR parts 50, 56, and 312, and in the 
International Conference on Harmonization (ICH) document Guidance for Industry: E6 Good 
Clinical Practice: Consolidated Guidance dated April 1996.  Further, I will conduct the study in 
keeping with local legal and regulatory requirements. 
 
As the principal investigator, I agree to carry out the study by the criteria written in the protocol 
and understand that no changes can be made to this protocol without written permission of the 
NIAID. 
 
 
 
__________________________________________                                        
Principal Investigator                        (Print)                     
 
 
__________________________________________         _________________ 
Principal Investigator                        (Sign)                      Date 
 


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Table of Contents 
1. 
BACKGROUND AND RATIONALE ................................................................................ 14 
1.1 
BACKGROUND AND SCIENTIFIC RATIONALE .......................................................... 14 
1.1.1 
Type 1 diabetes (T1D) ............................................................................................................... 14 
1.1.2 
Tocilizumab ............................................................................................................................... 16 
1.2 
PRECLINICAL AND CLINICAL EXPERIENCE.............................................................. 18 
1.2.1 
Preclinical Studies ..................................................................................................................... 18 
1.2.2 
Clinical Studies .......................................................................................................................... 18 
1.3 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS FOR HUMAN 
PARTICIPANTS ............................................................................................................ 23 
1.3.1 
Overview ................................................................................................................................... 23 
1.3.2 
Risks .......................................................................................................................................... 24 
1.3.3 
Potential Risks and Benefits of Trial Participation for Children ............................................... 27 
1.3.4 
Benefits of Trial Participation ................................................................................................... 27 
2. 
OBJECTIVES .................................................................................................................... 28 
2.1 
PRIMARY OBJECTIVE .................................................................................................. 28 
2.2 
SECONDARY OBJECTIVES .......................................................................................... 28 
2.3 
EXPLORATORY OBJECTIVES ...................................................................................... 28 
3. 
STUDY DESIGN................................................................................................................ 29 
3.1 
DESCRIPTION ............................................................................................................... 29 
3.2 
STUDY DURATION ....................................................................................................... 30 
3.3 
STUDY ENDPOINTS ...................................................................................................... 31 
3.3.1 
Primary Endpoint ...................................................................................................................... 31 
3.3.2 
Secondary Endpoints ................................................................................................................. 31 
3.3.3 
Exploratory Endpoints ............................................................................................................... 31 
3.4 
RATIONALE FOR SELECTION OF DRUG, ROUTE, DOSE, AND REGIMEN ................ 31 
3.5 
PREMATURE TERMINATION OR SUSPENSION OF THE TRIAL ................................. 32 
3.5.1 
Ongoing Review ........................................................................................................................ 32 
3.5.2 
Stopping Rules .......................................................................................................................... 33 
4. 
ELIGIBILITY ................................................................................................................... 33 
4.1 
INCLUSION CRITERIA .................................................................................................. 33 
4.2 
EXCLUSION CRITERIA ................................................................................................. 34 
4.3 
PREMATURE TERMINATION OF A PARTICIPANT FROM THE STUDY ..................... 35 


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5. 
STUDY MEDICATIONS ................................................................................................... 35 
5.1 
INVESTIGATIONAL MEDICATION .............................................................................. 35 
5.1.1 
Formulation and Packaging ....................................................................................................... 36 
5.1.2 
Reconstitution ............................................................................................................................ 36 
5.1.3 
Dosage, Preparation, and Administration .................................................................................. 36 
5.2 
DOSE MODIFICATION AND MANAGEMENT OF ADVERSE EVENTS ........................ 37 
5.2.1 
Overview ................................................................................................................................... 37 
5.2.2 
Hematologic Abnormalities and Bleeding Events ..................................................................... 37 
5.2.3 
Blood Chemistry Abnormalities ................................................................................................ 37 
5.2.4 
Infections ................................................................................................................................... 38 
5.2.5 
Elevated Lipids .......................................................................................................................... 39 
5.2.6 
Hypersensitivity or Anaphylaxis ............................................................................................... 39 
5.3 
DISCONTINUATION OF STUDY MEDICATION IN AN INDIVIDUAL PARTICIPANT . 39 
5.4 
CONCOMITANT MEDICATIONS .................................................................................. 40 
5.4.1 
Prohibited Medications .............................................................................................................. 40 
5.5 
DRUG ACCOUNTABILITY............................................................................................ 40 
5.6 
ASSESSMENT OF COMPLIANCE WITH STUDY MEDICATION .................................. 41 
6. 
STUDY PROCEDURES .................................................................................................... 41 
6.1 
INTENSIVE DIABETES MANAGEMENT ...................................................................... 41 
6.2 
VISIT WINDOWS ........................................................................................................... 41 
6.2.1 
Scheduled Visits ........................................................................................................................ 41 
6.3 
RANDOMIZATION, MASKING, AND UNMASKING .................................................... 41 
6.3.1 
Randomization ........................................................................................................................... 41 
6.3.2 
Masking to treatment assignment .............................................................................................. 42 
6.3.3 
Unmasking................................................................................................................................. 42 
6.4 
GENERAL ASSESSMENTS ............................................................................................ 42 
6.5 
CLINICAL LABORATORY ASSESSMENTS .................................................................. 43 
6.6 
PHARMACOKINETIC ASSESSMENTS .......................................................................... 44 
6.7 
METABOLIC ASSESSMENTS ....................................................................................... 45 
6.8 
MECHANISTIC ASSESSMENTS .................................................................................... 45 
7. 
TOLERANCE ASSAYS ..................................................................................................... 45 
7.1 
MECHANISTIC HYPOTHESIS ....................................................................................... 45 
7.2 
RETENTION OF SAMPLES ............................................................................................ 46 
7.2.1 
Sample Types ............................................................................................................................ 46 


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7.3 
MECHANISTIC ASSAYS ............................................................................................... 46 
8. 
ADVERSE EVENTS .......................................................................................................... 47 
8.1 
OVERVIEW ................................................................................................................... 47 
8.2 
DEFINITIONS ................................................................................................................ 47 
8.2.1 
Disease-specific Adverse Event ................................................................................................ 47 
8.2.2 
Adverse Event ........................................................................................................................... 48 
8.2.3 
Suspected Adverse Reaction and Adverse Reaction ................................................................. 48 
8.2.4 
Serious Adverse Event .............................................................................................................. 48 
8.2.5 
Adverse Events of Special Interest (AESIs) .............................................................................. 49 
8.2.6 
Unexpected Adverse Reaction................................................................................................... 50 
8.3 
COLLECTING AND RECORDING ADVERSE EVENTS ................................................. 50 
8.3.1 
Methods of Collection ............................................................................................................... 50 
8.3.2 
Specific Instructions for Recording Adverse Events ................................................................. 50 
8.3.3 
Recording AEs .......................................................................................................................... 51 
8.3.4 
Recording SAEs ........................................................................................................................ 51 
8.4 
GRADING AND ATTRIBUTION OF ADVERSE EVENTS .............................................. 51 
8.4.1 
Grading of Major Hypoglycemic and Hyperglycemic Events................................................... 51 
8.4.2 
Grading for All Other Adverse Events ...................................................................................... 52 
8.4.3 
Attribution ................................................................................................................................. 52 
8.5 
REPORTING SERIOUS ADVERSE EVENTS .................................................................. 53 
8.5.1 
Reporting SAEs to the Global Study Sponsor (DAIT, NIAID, NIH)........................................ 53 
8.5.2 
Reporting SAEs to Health Authorities ...................................................................................... 54 
8.5.3 
Reporting SAEs to the DSMB ................................................................................................... 55 
8.5.4 
Reporting of Adverse Events to IRBs/ECs ................................................................................ 55 
8.5.5 
Reporting AEs to Genentech, Inc. ............................................................................................. 55 
8.5.6 
Reporting Pregnancy ................................................................................................................. 56 
9. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .................................... 57 
9.1 
ANALYSIS SAMPLES .................................................................................................... 57 
9.2 
ANALYSIS OF ENDPOINTS .......................................................................................... 57 
9.2.1 
Primary Endpoint ...................................................................................................................... 57 
9.2.2 
Secondary Endpoints ................................................................................................................. 58 
9.2.3 
Safety Analysis .......................................................................................................................... 59 
9.2.4 
Medical History ......................................................................................................................... 60 
9.2.5 
Use of Medications .................................................................................................................... 60 


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9.3 
INTERIM ANALYSES AND DATA REVIEW ................................................................. 60 
9.4 
SAMPLE SIZE ................................................................................................................ 61 
9.5 
PHARMACOKINETIC ANALYSES ................................................................................ 62 
9.6 
REPORTING DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN .................... 62 
10 
STUDY ADMINISTRATION ............................................................................................ 62 
10.1 
SPONSOR ...................................................................................................................... 62 
10.2 
RELATIONSHIP WITH INDUSTRY ............................................................................... 63 
11 
ACCESS TO SOURCE DATA/DOCUMENTS .................................................................. 63 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ..................................................... 63 
13 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE ................................................................................................................... 64 
13.1 
STATEMENT OF COMPLIANCE ................................................................................... 64 
13.2 
INFORMED CONSENT .................................................................................................. 64 
13.3 
PRIVACY AND CONFIDENTIALITY............................................................................. 65 
14 
PUBLICATION POLICY .................................................................................................. 65 
15 
REFERENCES .................................................................................................................. 65 
APPENDIX 1. SCHEDULE OF EVENTS .................................................................................. 69 
 
LIST OF TABLES 
Table 1. Pediatric Experience with Tocilizumab (N=330) ...................................................................... 23 
Table 2. Neutropenia Risk Mitigation ..................................................................................................... 37 
Table 3. Thrombocytopenia Risk Mitigation ........................................................................................... 37 
Table 4. Liver Function Tests Risk Mitigation ........................................................................................ 38 
Table 5. Elevated Total Bilirubin Risk Mitigation................................................................................... 38 
Table 6: Pharmacokinetic Samples .......................................................................................................... 44 
Table 7. Attribution of Adverse Events ................................................................................................... 53 
Table 8. Summary of Power/Sample Size Results for Pediatric Participants .......................................... 62 
 
LIST OF FIGURES 
Figure 1:  C-Peptide Positive Subjects According to T1D Duration and Age at Diagnosis (%) ............. 15 
Figure 2: Study Design for Tocilizumab in New-Onset T1DM ............................................................... 30 


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Synopsis 
Title 
Preserving Beta-Cell Function with Tocilizumab in New-onset Type 1 
Diabetes 
 
Short Title 
 
US IND 
TCZ in New-onset T1D 
 
117725 
 
Sponsor 
US and Global Study Sponsor: Division of Allergy, Immunology, and 
Transplantation (DAIT), National Institute of Allergy and Infectious Diseases 
(NIAID), National Institutes of Health (NIH), USA  
Local Sponsor in Australia: Pharmaceutical Product Development, Inc. (PPD) 
for NIAID, NIH  
 
Conducted by 
 
Immune Tolerance Network, an NIH grantee 
 
Protocol Co- 
Chairs  
 
 
 
Accrual Objective 
 
78 eligible pediatric subjects (6-17 years old) and 30-99 eligible adult subjects 
(18-45 years old) will be enrolled.  Only pediatric participants are eligible for 
randomization after May 15, 2017. 
 
Study Treatment 
 
Tocilizumab or placebo 
 
Study Design 
 
This trial will be conducted in the US and Australia as a multi-center, 
prospective, double-blind, placebo-controlled, 2:1 randomized, phase 2 
clinical trial for individuals with recent-onset T1DM aged 6−45 years, 
inclusive.  All groups will receive standard intensive diabetes management.  
The subjects will receive IV infusions of either 8.0 mg/kg (body weight 
≥30kg) or 10.0 mg/kg (body weight <30kg) tocilizumab or placebo every 4 
weeks for 24 weeks.  
 
A staggered enrollment plan is being used for this trial.  Prior to initiating the 
study in the pediatric age group (6-17 years old), adults (18-45 years old) were 
randomized 2:1 to tocilizumab or placebo, respectively.  After 30 adult 
participants completed 12 weeks of treatment, the DSMB and FDA reviewed 
the available data to weigh potential risks and benefits as well as prospect of 
benefit before opening the trial to pediatric participants.  The result of those 
reviews was to allow enrollment of children and adolescents 6-17 years old. 
 
Study Duration 
 
Total study duration will be approximately 4-5 years.   
 
The enrollment phase is expected to last up to 42 months.   
 
The study participation phase will be 104 weeks (2 years), which 
includes a treatment phase of 24 weeks and a follow-up phase of 80 
weeks. 
 


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Primary Objective 
Determine whether tocilizumab will slow the progression of the autoimmune 
destruction of ß cells and lead to the preservation of C-peptide secretion in 
T1DM. 
Primary Endpoint 
MMTT-stimulated mean 2-hour C-peptide AUC at week 52.  
Secondary 
Endpoints 
Efficacy: 
1. MMTT-stimulated mean 2-hour C-peptide AUC at weeks 12, 24, and 
104. 
2. MMTT-stimulated mean 2-hour C-peptide AUC assessed 
longitudinally at weeks 12, 24, 39, 52, 78, and 104. 
3. MMTT-stimulated peak and 4-hour C-peptide AUC at weeks 52 and 
104 for subjects ≥12 years old. 
4. Insulin use (U/kg/day) at weeks 12, 24, 39, 52, 78 and 104; HbA1c 
levels at weeks 12, 24, 39, 52, 78 and 104. 
5. Glycemic control. 
Safety: 
1. Rate of AEs related to infusion reactions and hypersensitivity. 
2. Frequency and severity of all AEs. 
Mechanistic: 
1. Determine the effect of TCZ on the ratio of Treg and Teff.  
 
Exploratory  
Endpoints 
 
Mechanistic: 
1. Determine effect of TCZ on measures of immune cell number and 
function such as: 
a. 
Changes in proportions and phenotype of Treg and Teff.  
b. Changes in sensitivity of Teff to suppression by Treg. 
c. 
Changes in circulating B cell compartment and activation 
state of innate immune cells including antigen presenting 
cells and NK cells. 
Metabolic: 
1. Explore the relationship between immune responses, metabolic 
outcomes and clinical variables. 
2. Explore the effect of TCZ on insulin sensitivity. 
 
Inclusion Criteria 
1. Male or female aged 6-45 years inclusive who meet the American 
Diabetes Association T1DM criteria. 
2. Diagnosis of T1DM within 100 days of enrollment (V0). 
3. Positive for at least one diabetes-related autoantibody, including but 
not limited to: 
a. 
Glutamate decarboxylase-65 (GAD-65); 
b. Insulin, if obtained within 10 days of the onset of exogenous 
insulin therapy; 
c. 
Insulinoma antigen-2 (IA-2); or 
d. Zinc transporter-8 (ZnT8). 
4. Peak stimulated C-peptide level ≥ 0.2 pmol/mL following a MMTT 
conducted at least 21 days from diagnosis and within 37 days of 
randomization (V0). 
5. Signed informed consent (and informed assent of minor, if 
applicable). 
 


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Exclusion Criteria 
1. Severe reaction or anaphylaxis to human, humanized or murine 
monoclonal antibodies. 
2. History of malignancy or serious uncontrolled cardiovascular, 
nervous system, pulmonary, renal, or gastrointestinal disease, or 
significant dyslipidemia. 
3. Any history of recent serious bacterial, viral, fungal, or other 
opportunistic infections. 
4. Have serologic evidence of current or past HIV, Hepatitis B, or 
Hepatitis C. 
5. Positive tuberculin skin test (PPD) or QuantiFERON TB test, history 
of tuberculosis, or active TB infection. 
6. Active infection with EBV as defined by EBV viral load ≥ 10,000 
copies per 106 PBMCs or ≥ 2,000 copies per mL of whole blood. 
7. Active infection with CMV as defined by CMV viral load ≥ 10,000 
IU or copies per mL of whole blood or plasma. 
8. Diagnosis of liver disease or elevated hepatic enzymes, as defined by 
ALT, AST, or both > 1.5 x the upper limit of age-determined normal 
(ULN) or total bilirubin > ULN. 
9. Current or prior treatment that is known to cause a significant, 
ongoing change in the course of T1D or immunologic status. 
10. Current or prior (within last 14 days of screening MMTT visit) use of 
drugs other than insulin to treat hyperglycemia (e.g. metformin, 
sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, 
DPP-IV inhibitors, or amylin). 
11. Current use of any medication known to significantly influence 
glucose tolerance (e.g., atypical antipsychotics, diphenylhydantoin, 
niacin). 
12. Any of the following hematologic abnormalities, confirmed by repeat 
tests: 
a. 
White blood count <3,000/μL or >14,000/μL;  
b. Lymphocyte count <500/μL; 
c. 
Platelet count <150,000 /μL; 
d. Hemoglobin <8.5 g/dL; or 
e. 
Neutrophil count <2,000 cells/μL. 
13. Females who are pregnant, lactating, or planning on pregnancy 
during the 2-year study period. 
14. History or diagnoses of other autoimmune diseases, with the 
exception of stable thyroid or celiac disease. 
15. History of alcohol, drug or chemical abuse within 1 year prior to 
screening (V-1). 
16. Any medical or psychological condition that in the opinion of the 
principal investigator would interfere with safe completion of the 
trial. 
17. Prior participation in a clinical trial that could increase risks 
associated with this clinical trial. 
18. Receipt of live vaccine (e.g. varicella, measles, mumps, rubella, cold-
attenuated intranasal influenza vaccine, bacillus Calmette-Guérin, 
and small pox) in the 6 weeks before randomization (V0). 
19. High lipid levels (fasting LDL cholesterol ≥160 mg/dL or 
≥4.1mmol/L). 
20. History of significant allergy (e.g. anaphylaxis) to milk or soy 
proteins. 


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Abbreviations  
ACR 
American College of Rheumatology 
ADA 
American Diabetes Association 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BRI 
Benaroya Research Institute 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CGM 
Continuous Glucose Monitoring 
CMV 
Cytomegalovirus 
CRF 
Case report form 
CRP 
C-reactive protein 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events (version 4.0, May 28, 2009) 
CVD 
Cardiovascular disease 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DKA 
Diabetic keto acidosis 
DMARD 
Disease-modifying antirheumatic drug 
DSMB 
Data and Safety Monitoring Board 
EBV 
Epstein-Barr virus 
EC  
Ethics Committee  
FDA 
US Food and Drug Administration  
FSIVGTT 
Frequently-sampled intravenous glucose tolerance test 


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GAD-65 
Glutamate decarboxylase-65 
GCP 
Good clinical practice 
HBsAg 
Hepatitis B surface antigen 
HbA1c 
Glycosylated hemoglobin 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
IA-2 
Insulinoma antigen-2 
IB 
Investigator’s Brochure 
ICA 
Islet cell antibody 
ICH 
International Conference on Harmonization 
IgA 
Immunoglobulin A 
IL-6 
Interleukin-6 
IND 
Investigational new drug 
IRB 
Institutional review board 
ITN 
Immune Tolerance Network 
LDL 
Low-density lipoprotein 
LFT 
Liver Function Test 
LTE 
Long term exposure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMTT 
Mixed-meal tolerance test 
MTX 
Methotrexate 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NFκB 
Nuclear factor kappa-light-chain-enhancer of activated B cells 
NIAID 
National Institute of Allergy and Infectious Diseases 


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NIH 
National Institutes of Health 
NOD 
Nonobese diabetic 
OGTT 
Oral glucose tolerance test 
PBMC 
Peripheral blood mononuclear cell 
PD 
Pharmacodynamics 
pJIA 
Polyarticular juvenile idiopathic arthritis 
PK 
Pharmacokinetics 
PPD 
Purified protein derivative 
RA 
Rheumatoid arthritis  
RMSE 
Root Mean Square Error 
SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious adverse event 
sJIA 
Systemic juvenile idiopathic arthritis 
T1D 
Type 1 diabetes 
T1DM 
Type 1 diabetes mellitus 
Teff 
T effector cells 
TNFα 
Tumor necrosis factor alpha 
Treg 
Regulatory T cells 
TB 
Tuberculosis 
TCZ 
Tocilizumab 
TGA 
Therapeutic Goods Administration  
ULN 
Upper limit of normal range 
VZV 
Varicella zoster 
WHO 
World Health Organization 
ZnT8 
Zinc transporter-8 


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1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND AND SCIENTIFIC RATIONALE 
1.1.1 Type 1 diabetes (T1D) 
Type 1 diabetes (T1D) affects about 1 million people in North America, with an 
incidence of approximately 30,000 new cases per year (~15,000 children and ~15,000 
adults—80 people per day—are diagnosed with T1D in the U.S).1  Standard of care 
comprises multiple daily shots of exogenous insulin or pump therapy, with multiple 
daily pricks for glucose checks.  Even with optimal therapy, patients can experience 
life-threatening episodes of hypoglycemia or diabetic ketoacidosis, and are at high 
risk for long-term complications, including nephropathy, retinopathy, neuropathy, and 
CVD. The financial impact to US families with children with T1D is tremendous with 
an average annual medical cost of ~$9,000 per year, compared to about ~$1,500 for 
those who don’t have diabetes.2  Although new tools to measure glucose and deliver 
insulin are available and intensive insulin therapy has been the standard of care for 
those with T1D for several decades, insulin therapy is woefully inadequate to treat this 
disease.  Thus, while the overall rate of complications is decreasing,3 T1D remains a 
substantial burden to those living with the disease and their families, and T1D still 
results in decreased quality of life (QOL), and increased morbidity and mortality.  The 
picture of T1D in the US has been recently described in a series of studies conducted 
by the T1D Exchange which includes data on more than 25,000 adults and children 
from almost 70 clinical centers in the US.  The vast majority of youth with T1D do 
not meet the American Diabetes Association (ADA) HbA1c targets.  This is 
particularly true among adolescents, where only 21% of T1D adolescents (ages 13-20) 
had HbA1c levels <7.5%, as recommended.  Less than half of those 6-12 years of age 
met the target HbA1c level of <8%, and only 64% of those younger than age 6 met the 
target of 8.5%, which corresponds to significant hyperglycemia.4  The T1D Exchange 
also documented that 7% of those with T1D experienced severe hypoglycemia 
(resulting in seizure or coma) and 8% had diabetic ketoacidosis (DKA) during the 
previous 12 months.5  Strikingly, 18.6% of those with T1D >40 years duration 
experienced severe hypoglycemia during the previous year.  Moreover, the poor 
glycemic control which increases the risk of DKA did not protect against severe 
hypoglycemia.6  The intractable problem of hypoglycemia is also highlighted by data 
illustrating that excellent self-management is associated with reduced DKA as 
compared to those with poorer control, but the rate of severe hypoglycemia was 
independent of these behaviors.7  The T1D Exchange data also found that ~5-10% of 
more than 6,000 individuals with T1D were classified as having probable major 
depression; this was associated with more complications, higher HbA1c, more DKA, 
and more severe hypoglycemia.8  Thus, there is a clear, unmet need to provide new 
therapeutic options for those with T1D.   
Despite progress toward understanding the genetic, environmental, and immunologic 
basis for T1D, the prevention and cure of this condition remains elusive.  While the 


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developing brain with neuroanatomical alterations and diminished cognitive ability.20  
Therefore, safe and effective interventions that can modify the course of T1D in 
pediatric populations are urgently needed.  
1.1.2 Tocilizumab 
IL-6 is a systemic cytokine, participating in proinflammatory pathways associated 
with immunity and autoimmunity.  In addition, IL-6 plays an important role in the 
communication between the innate and adaptive immune systems, mediated through 
the development and function of regulatory T (Treg) and pathogenic T effector (Teff) 
cells such as Th17 cells.  Data from murine models suggest that IL-6 receptor (IL-6R) 
blockade may promote both anti-inflammatory and pro-regulatory mechanisms 
simultaneously.  Therefore, IL-6 is considered a “master switch” that regulates Teff 
vs. Treg responses, and blockade of IL-6 signaling can restore immune tolerance in 
the setting of autoimmunity.  This mechanism is likely responsible for the clinical 
efficacy of IL-6 receptor blockade in autoimmunity as tocilizumab therapy decreases 
the frequency of Th17 cells and increases the frequency of Treg cells in patients with 
rheumatoid arthritis (RA).21   
Recent studies in murine autoimmunity suggest that Treg function is incapacitated by 
the local microenvironment, which is full of proinflammatory cytokines, particularly 
IL-6, which drives Teff lineages and/or inhibits FOXP3 a Treg transcriptional 
regulator.  CD4 T cells co-treated with TGFβ and IL-6 initially express FOXP3, but 
then Th17 differentiation occurs and FOXP3 expression and Treg function are lost.  In 
multiple mouse models, including autoimmune diabetes, a pivotal role of IL-6 in 
disease progression, operating through Treg inhibition, has now been validated.22  In 
an in vivo study with the non-obese diabetes (NOD) type 1 diabetes mouse model, it 
has been shown that IL-6 production was increased in isolated islet cells. Mice treated 
with anti-IL-6 antibodies had a significantly reduced rate of developing diabetes.23  Ex 
vivo studies with human T cells have shown that Teff from T1D subjects are resistant 
to suppression by Treg from healthy controls.24  This resistance of Teff cells to 
suppression by Tregs has been linked to IL-6.  Importantly, in humans, the IL6R 
358Ala allele, which impairs IL-6 signaling, confers a reduced risk of T1D.  The 
358Ala allele inhibits IL-6 signaling by reducing the surface expression of membrane-
bound IL-6 receptor, thereby providing a compelling rationale for evaluating an anti-
IL-6 receptor antibody, such as tocilizumab, in the treatment of new-onset T1D.25  
Other work has demonstrated an increase in Th17 cells in T1D subjects, including 
islet-antigen specific Th17 cells.26,27  Mechanistically IL-17 enhances IL-1, IFN-
andF--induced apoptosis in human islets.26  Mounting correlative evidence 
suggest IL-17 producing cells may be pathogenic in the early stages of T1D onset.28  
As noted above, tocilizumab treatment reduced the number of Th17 cells in 
rheumatoid arthritis subjects.21  Thus, immune dysregulation is a key component of 
T1D and restoration of Teff sensitivity to suppression by augmentation of Treg 


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activity and/or inhibition of Teff is likely to alter the course of disease.  IL-6R 
blockade with tocilizumab has the potential for achieving that goal. 
The IV formulation of TCZ is approved in the EU, US, and Japan for RA, sJIA, and 
pJIA. IV TCZ is also approved in more than 75 other countries for the treatment of 
RA, in more than 50 additional countries for the treatment of sJIA, and over 30 other 
countries for the treatment of pJIA. In India and Japan, IV TCZ has additional 
indications for treatment in Castleman’s disease. The SC formulation of TCZ is 
approved in more than 30 countries (including EU, US, New Zealand, Switzerland, 
Canada, Japan, South Korea and Taiwan) for the treatment of RA. 
Tocilizumab (TCZ) is an anti-IL-6 receptor antibody that is approved in the US and 
Australia for the treatment of adult rheumatoid arthritis, systemic juvenile idiopathic 
arthritis (sJIA) in patients 2 years of age and older, and polyarticular juvenile 
idiopathic arthritis (pJIA) in patients 2 years of age and older.  In the US, tocilizumab 
is additionally approved for giant cell arteritis, and in Japan, tocilizumab is also 
approved for Castleman’s disease.  In addition, preliminary efficacy has been shown 
in a variety of other autoimmune diseases.  In light of the murine data described above 
and a strong theoretical rationale, a trial of tocilizumab in new-onset T1D is 
particularly attractive because there is substantial experience in pediatric populations 
with approval for both sJIA and pJIA.  It is well known that T1D is a particular 
burden in children in whom the disease is more aggressive with a more rapid loss of 
residual β-cell function.17  Pediatric T1D therefore represents a major unmet medical 
need and this is the key population in which the efficacy of novel interventions needs 
to be demonstrated. 
This study will test whether ACTEMRA® (tocilizumab) can preserve remaining beta 
cells in individuals with recently diagnosed type 1 diabetes.  The study is a 2-arm, 
randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical trial.  All 
groups will receive standard intensive diabetes treatment with insulin and dietary 
management.  Subjects will be randomly assigned (2:1 drug-placebo) to receive either 
monthly IV infusions of tocilizumab or placebo for 6 months (total of 7 infusions).  
The effects of the treatment on general and diabetes-specific immune responses and 
the deterioration of β-cell function that occurs in T1D will be studied to determine the 
study drug’s mechanism of action.  Furthermore, how the drug alters T1D-associated 
immune responses and whether the drug has prolonged clinical efficacy will also be 
studied. 
As of the date of this current protocol version, review of data from the adult cohort 
has been completed by DSMB and FDA.  Enrollment of pediatric participants age 6-
17 years old, inclusive, is ongoing. 


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1.2 
PRECLINICAL AND CLINICAL EXPERIENCE 
1.2.1   Preclinical Studies 
1.2.1.1 Preclinical Safety Data 
1.2.1.1.1 
Overview 
 
 
 
 
 
 
1.2.1.1.2 
Toxicity Studies 
 
 
 
 
1.2.1.2 Preclinical Efficacy Data in Other Autoimmune Disease 
 
   
 
  
  
 
   
1.2.2 Clinical Studies  
1.2.2.1 Efficacy and Safety Data for Tocilizumab 
1.2.2.1.1 
Overview 
Tocilizumab
 
 
    
 
 
  
  
 
 
 


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Efficacy 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   


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 (GI) 
perforations) increased with increasing duration of treatment.   
1.2.2.1.2 
Giant Cell Arteritis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2.2.1.3 
Systemic Juvenile Idiopathic Arthritis 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
Safety 


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1.2.2.1.4 
Polyarticular Juvenile Idiopathic Arthritis 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
   
Safety 
 
 
 
  


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1.2.2.1.5 
Castleman’s Disease 
 
 
 
 
 
 
 
 
  
1.2.2.1.6 
Other Autoimmune and Inflammatory Diseases 
 
 
 
 
  
1.2.2.1.7 
Clinical Use in Diabetes 
IL-6 has been linked to defects in insulin action characteristic of metabolic syndrome 
and type 2 diabetes, but studies on the metabolic effects of IL-6R blockade are sparse.  
In a small open-label study of non-diabetic RA patients, tocilizumab therapy resulted 
in a significant decrease in the HOMA index for insulin resistance and a significant 
increase in serum adiponectin levels.43  There have been no clinical studies in diabetes 
with tocilizumab.  However, more than 200 subjects treated with tocilizumab as part 
of RA trials had concomitant diabetes at baseline.  No untoward effect on diabetes 
control was seen in this group, although no direct measurements of insulin action or 
secretion were performed.  Also of note are the results of a recent Mendelian 
randomization analysis for a SNP in the IL6R gene (Asp358Ala) that phenotypically 
recapitulates the effects of tocilizumab, which showed reduced risks for coronary 
heart disease and type 2 diabetes.44  Thus, IL-6R-mediated inflammatory pathways 
may have a causal role in atherosclerosis and, possibly, insulin resistance. 


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1.2.2.1.8 
Pediatric Experience with Tocilizumab 
As noted previously, tocilizumab is approved for use in children 2 years of age and 
older with sJIA and pJIA.  Tocilizumab has been studied in two phase 3 clinical trials 
(WA18221 and WA19977) and a supportive phase 3 study (MRA316JP) performed in 
Japan with pediatric populations.41,45-51  The clinical trials included a total of 367 
pediatric subjects, 330 of whom received tocilizumab [142 subjects with sJIA and 188 
subjects with pJIA].  See Table 1 for pediatric subject age breakdown data below.  
Table 1. Pediatric Experience with Tocilizumab (N=330) 
 
Indication 
 
sJIA 
Systemic Juvenile 
Idiopathic Arthritis 
sJIA 
Systemic Juvenile 
Idiopathic 
Arthritis 
pJIA 
Polyarticular 
Juvenile Idiopathic 
Arthritis 
Trial 
WA18221 (TENDER) 
[Ongoing] 
MRA316JP 
[Completed] 
WA19977 
(CHERISH) 
[Ongoing] 
Phase 
III (Pivotal) 
III (Supportive) 
III (Pivotal) 
Sponsor 
Roche/GEN 
Chugai 
Roche/GEN 
ClinicalTrials.Gov 
Identifier 
NCT00642460 
 
NCT00144599 (open-
label lead-in, double-
blind phases) 
NCT00144612 (open-
label extension phase) 
NCT00988221 
Number of 
Subjects Who 
Received TCZ 
75 
67 total = 56 [Phase 
III]  + 11 [Phase II]; 
Median exposure to 
TCZ = 3.4 yrs (177 
weeks); 
Part 1=188 total 
(open-label) every 4 
wks X4 = 16 wks; 
Part 2=82 [DB, rand. 
1:1 TCZ (n=82) or 
placebo (n=81)] for 24 
wks (starting at wk 
16); 
Age Range that 
Received TCZ 
10 ± 4.6 yrs 
 
2 to 19 yrs 
2 to 17 yrs 
TCZ Dose 
TCZ treated subjects with 
body wt < 30 kg received 
12 mg/kg those with body 
wt ≥ 30 kg received 8 
mg/kg.  TCZ was 
administered, every 2 
weeks. 
TCZ treated subjects 
received 8 mg/kg 
every 2 weeks. 
TCZ treated subjects 
with body wt < 30 kg 
were randomized (1:1) 
to receive either 8 
mg/kg or 10 mg/kg of 
TCZ and pts with 
body wt ≥ 30 kg 
received 8 mg/kg of 
TCZ, every 4 weeks. 
1.3 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS 
FOR HUMAN PARTICIPANTS  
1.3.1   Overview 
Like any immunomodulating therapy, the primary risks of tocilizumab relate to 
infections; however, these are generally well tolerated and the use of this drug is 
increasing rapidly in the approved autoimmune indications (rheumatoid arthritis, 
systemic juvenile idiopathic arthritis, and polyarticular juvenile idiopathic arthritis).  


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The information provided here is summarized from the current F. Hoffman La-Roche 
LTD Investigator’s Brochure for tocilizumab and country-specific Package Insert and 
is compiled from the clinical studies conducted in patients 2 years of age and older 
with systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, 
and rheumatoid arthritis. 
1.3.2   Risks  
1.3.2.1  Opportunistic Infections and Serious Infections  
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive 
fungal, viral, protozoal, or other opportunistic pathogens have been reported in 
patients receiving immunosuppressive agents including tocilizumab for rheumatoid 
arthritis.  
1.3.2.2 Gastrointestinal Perforations   
A total of 30 cases of medically confirmed serious GI perforation (primarily as 
complications of diverticulitis in RA patients, but also including those related to 
malignancy) were reported in clinical trials, corresponding to a rate of 0.2 per 100 
patient-years.  No GI perforations were seen in the two phase 3 studies in juvenile 
idiopathic arthritis with a pediatric population. 
1.3.2.3 Laboratory Abnormalities  
Neutrophils  
Treatment with tocilizumab in RA was associated with a higher incidence of 
neutropenia.  An observed decrease in neutrophils occurs in about half the subjects in 
trials, occurred largely within the normal range, and was reversible upon 
interruption/discontinuation of TCZ.  Out of more than 4000 patients, 5% had 
neutrophil counts < 1000−500/mm3 and 33 (< 1%) had counts < 500/mm3.  There was 
no clear relationship between decreases in neutrophils below 1000/mm3 and the 
occurrence of serious infections. 
Platelets  
Treatment with tocilizumab in RA was associated with a reduction in platelet counts. 
Transient decreases in platelet counts below 100,000/mm3  occurred in 1.3% and 1.7% 
of patients on 4 mg/kg and 8 mg/kg TCZ + DMARD, respectively, compared with 
0.5% of patients in the placebo + DMARD group.  In the long-term exposure all-
exposure population, 52/4002 patients (1.3%) had < 75,000−50,000/mm3; 18 patients 
(0.4%) had < 50,000−25,000/mm3; and 14 patients (0.3%) had platelet counts < 
25,000/mm3. There was no clear relationship between thrombocytopenia and clinical 
symptoms. 
Liver Function Tests  


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Treatment with tocilizumab in RA was associated with a higher incidence of 
transaminase elevations.  ALT and AST elevations were observed and most were 
transient and returned towards normal with treatment interruption or treatment 
discontinuation.  Transient elevations in ALT above three times the upper limit of 
normal (ULN) were observed in 6.5% of patients receiving 8 mg/kg TCZ + DMARD 
groups, respectively, compared with 1.5% of patients in the placebo + DMARD 
group. There is no evidence to date of a correlation between liver enzyme changes 
with TCZ and serious hepatic events; the majority of elevated transaminase reports 
have shown no clinical sequelae.  A total of 99 patients (2.4%) in the long term 
exposure population were prematurely withdrawn due to transaminase elevations. The 
percentage of patients with an increase in indirect bilirubin > ULN was higher in 
patients receiving TCZ than patients in the control group.  Based on the long term 
TCZ exposure data, 0.6% of patients had an indirect bilirubin level > 2 × ULN.  
However, the change in bilirubin levels when receiving TCZ treatment did not result 
in negative clinical outcomes. 
Lipids  
Treatment with tocilizumab in RA was associated with increases in lipid parameters 
such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol.  
LDL levels increased in the 8 mg/kg treatment groups and responded appropriately to 
statin therapy.  Long-term data from the TCZ phase 3 program over a mean duration 
of 3.7 years show no evidence that the observed changes in lipid levels in the TCZ-
treated patients result in an increase in the rate of reported cardiovascular events. 
Rates of myocardial infarction and stroke were similar across the TCZ and control 
treatment groups.   
A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count 
and lipid elevations is noted with tocilizumab treatment in the sJIA population.  
1.3.2.4 Immunosuppression 
The impact of treatment with tocilizumab on the development of malignancies is not 
known.  Tocilizumab is an immunosuppressant, and treatment with this class of drugs 
may result in an increased risk of malignancies.  In the 6-month double-blind studies 
in RA, the rate of malignant neoplasms was 1.33 and 1.27 events per 100 patient-years 
in the TCZ and control groups, respectively.  
1.3.2.5 Hypersensitivity Reactions, Including Anaphylaxis 
Hypersensitivity reactions, including anaphylaxis and death, have been reported in 
association with infusion of tocilizumab.  Anaphylaxis and other hypersensitivity 
reactions that required treatment discontinuation were reported in 0.1% (3 out of 
2644) of RA patients in the 6-month controlled trials, and in 0.2% (8 out of 4009) of 
patients in the all-exposure rheumatoid arthritis population.  Anaphylaxis and other 
hypersensitivity reactions that required treatment discontinuation were reported in 


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0.9% (1 out of 112 patients) of patients in the sJIA controlled trial.  No reports of 
anaphylaxis or serious hypersensitivity reactions were reported in the pJIA controlled 
trial (N=188).  In the postmarketing setting, a patient with a previous infusion reaction 
and premedicated with steroids and antihistamines experienced fatal anaphylaxis 
during subsequent treatment with tocilizumab. 
1.3.2.6 Other Potential Risks 
Demyelinating Disorders 
The impact of treatment with tocilizumab on demyelinating disorders is not known, 
but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were 
reported rarely in RA clinical studies.  
Vaccinations 
Live vaccines should not be given concurrently with tocilizumab as clinical safety has 
not been established.  No data are available on the secondary transmission of infection 
from persons receiving live vaccines to patients receiving tocilizumab.  Limited data 
are available on the safety and effectiveness of vaccination in patients receiving 
tocilizumab, but to date no impairment in seroprotection has been noted.  
Viral Reactivation 
Though rarely reported within the TCZ program due to exclusion criteria at study 
entry, reactivation of viral and other serious infections (e.g. EBV, herpes zoster and 
TB) have been observed with biologic therapies for RA, including TCZ. 
 Anti-TCZ Antibodies 
In the phase 3 RA trials, serum samples of 44/3945 patients (1.1%) tested positive 
post baseline in the confirmation assay for anti-TCZ antibodies. Five of the 44 anti-
TCZ antibody positive patients experience an anaphylactic reaction.  The remaining 
39 patients did not. 
Of 112 pediatric patients treated with tocilizumab in the sJIA trials, 2 (1.8%) 
developed positive anti-tocilizumab antibodies, of whom one experienced SAEs 
(urticaria and angioedema) consistent with an anaphylactic reaction which led to 
withdrawal. Of 19 pediatric patients treated with tocilizumab in the Japanese pJIA 
trial, one was positive for anti-TCZ antibodies. 
Drug Interaction 
The formation of CYP450 enzymes may be suppressed by increased levels of 
cytokines (e.g. IL-6) during chronic inflammation. Therefore, it is expected that for 
molecules that antagonize cytokine activity, such as TCZ, the formation of CYP450 
enzymes could be normalized. The clinical implications of this are unknown. 


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1.3.3   Potential Risks and Benefits of Trial Participation for Children 
As noted in section 1.3.2.1.8, tocilizumab has been used in pediatric populations and 
is approved for treatment of both sJIA and pJIA for children age 2 and older in many 
countries.  For children receiving placebo, the study procedures including blood 
draws, mixed meal tolerance testing, and IV placebo administration are either minimal 
risk or slightly greater than minimal risk; these subjects have the possibility of benefit 
in the close monitoring of their newly diagnosed T1D.  For those receiving 
tocilizumab, the study procedures are greater than minimal risk; however, overall 
tocilizumab has been well tolerated in both pediatric and adult populations.  The 
rationale for a prospect of benefit in children is motivated by the current approvals for 
pediatric populations and the specific mode of action affecting autoimmune diseases 
for which there is ample clinical evidence of efficacy in both adult and pediatric 
populations.  There are currently no approved interventions for new-onset T1DM.   
It is important to recognize that the natural history of disease in T1DM is considerably 
different in children as compared with adults, with adults having a much more 
indolent disease course.  The average reduction in MMTT-stimulated C-peptide AUC 
mean in adults is ~ 7.5% at 6 months and ~ 15% at 12 months, which is half of the 
change seen in children.  While the mechanisms underlying this difference is 
unknown, these difference in disease course are likely to be reflected in responses to 
therapy as well.  Like RA and sJIA or pJIA, T1D is a different disease in different 
aged populations.  Thus, either efficacy or lack of efficacy in an adult population is 
not likely to be informative as to efficacy or lack thereof in a pediatric population.   
Nonetheless, this study will be initiated in adults to assure no unexpected harms and 
both safety and efficacy data will be reviewed by the DSMB and FDA before 
enrollment of children.  
Assent of children along with consent of the parents will be obtained prior to any 
study procedures.  This research proposal in children is therefore consistent with 
United States Department of Health and Human Services, Protection of Human 
Subjects, subpart D, section 46.405 (research involving greater than minimal risk but 
presenting the prospect of direct benefit to individual subjects) and with FDA 21 CFR 
50.52 [Subpart  D].  (Clinical investigations involving greater than minimal risk but 
presenting the prospect of direct benefit to individual subjects). 
1.3.4 Benefits of Trial Participation 
In this study, all participants will receive intensive diabetes management aimed at 
achieving near-normal metabolic control per the standard ADA guidelines.45  
Although intensive diabetes management is recommended for all patients with T1DM, 
it is not always available to all subjects in the community.  The Diabetes Control and 
Complications Trial (DCCT) research group documented that improved metabolic 
control slows the onset of some long-term complications.13  The means to achieve this 
improved control in the DCCT has become the idealized standard of care, with 


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clinical management and education provided by a diabetes specialty team.  It should 
be noted that such care may not necessarily be available to those outside the study, 
and those who are not seen by a diabetes specialty team may have worse outcomes 
over time.52  
Improved metabolic control early in the course of T1DM will have a long-standing 
effect on lowering the risk for long-term complications for many years to follow; i.e., 
there appears to be a “metabolic memory” that influences later risk.  This effect has 
been documented in the Epidemiology of Diabetes Interventions and Complications 
(EDIC) study, the long-term follow-up of the DCCT cohort.13,14,53-55  Although the 
conventional group (with less stringent metabolic control) and the intensive group 
(with near-normal metabolic control) have had comparable HbA1c levels since the end 
of the formal DCCT study, the intensive group continues to have significantly lower 
risk for complications 10 years later.  An additional benefit that may be realized by all 
participants is that maintaining near-normal glycemic control through intensive 
diabetes management may, in and of itself, lead to the preservation of ß-cell 
function.56-59  The benefits of endogenous insulin secretion, even if one needs to 
continue exogenous insulin therapy, have been demonstrated in a number of studies, 
including the DCCT, where those subjects with residual C-peptide had improved 
metabolic control, with lower risk for severe hypoglycemia and less likelihood of 
microvascular complications.  
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
Determine whether tocilizumab will slow the progression of the autoimmune 
destruction of ß cells and lead to the preservation of C-peptide secretion in T1DM. 
2.2 
SECONDARY OBJECTIVES 
1. Longitudinal analysis of HbA1c, insulin dose (units/kg) and blood glucose by 
treatment group. 
2. Determine the efficacy and safety of tocilizumab in participants with T1DM. 
3. Determine how the ratio of Treg/Teff is altered with tocilizumab treatment    
2.3 
EXPLORATORY OBJECTIVES 
Mechanistic studies:  
1. Investigate the mechanism of action for tocilizumab in the maintenance of ß-cell 
function and determine whether the loss of tolerance associated with this disease 
is reversed. 
 
 
 


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Metabolic: 
1. Determine whether treatment with tocilizumab improves blood glucose and 
HbA1c and reduces individual insulin requirements. 
2. Explore whether tocilizumab affects insulin sensitivity. 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION 
This trial will be conducted in the US and Australia as a multi-center, prospective, 
double-blind, placebo-controlled, 2:1 randomized, phase 2 clinical trial for individuals 
with recent-onset T1DM aged 6−45 years old.  78 eligible pediatric subjects (6-17 
years old) and at least 30 eligible adult subjects (18-45 years old) will be enrolled (see 
Figure 2).  All groups will receive standard intensive diabetes management.  The 
subjects will receive IV infusions of either 8.0 mg/kg (body weight ≥30kg) or 10.0 
mg/kg (body weight <30kg) tocilizumab or placebo every 4 weeks for 24 weeks.  
 
A staggered enrollment plan is being used for this trial.  Prior to initiating the study in 
the pediatric age group (6-17 years old), adults (18-45 years old) were randomized 2:1 
to tocilizumab or placebo, respectively.  After 30 adult participants completed 12 
weeks of treatment, the DSMB and FDA reviewed the available data to weigh 
potential risks and benefits as well as prospect of benefit and allowed opening the trial 
to pediatric participants (children and adolescents 6-17 years old).   
 
The protocol continued to enroll adult participants during and after evaluation of the 
initial cohort with 55 eligible adult participants enrolled in this clinical trial.  Only 
pediatric participants are eligible for randomization after May 15, 2017. 


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3.3 
STUDY ENDPOINTS 
3.3.1 Primary Endpoint 
The primary endpoint is a MMTT-stimulated mean 2-hour C-peptide AUC at week 
52.  The mean 2-hour C-peptide AUC, measured in pmol/ml, is computed by dividing 
the total AUC by 120 minutes. 
3.3.2 Secondary Endpoints 
Efficacy: 
1. MMTT-stimulated mean 2-hour C-peptide AUC at weeks 12, 24, and 104. 
2. MMTT-stimulated mean 2-hour C-peptide AUC assessed longitudinally at weeks 
12, 24, 39, 52, 78, and 104. 
3. MMTT-stimulated peak and 4-hour C-peptide AUC at weeks 52 and 104 for 
subjects ≥12 years old. 
4. Insulin use (U/kg/day) at weeks 12, 24, 39, 52, 78 and 104; HbA1c levels at weeks 
12, 24, 39, 52, 78 and 104. 
5. Glycemic control.  
Safety: 
1. Rate of AEs related to infusion reactions and hypersensitivity. 
2. Frequency and severity of all AEs.  
Mechanistic 
1. Determine the effect of TCZ on the ratio of Treg and Teff. 
3.3.3 Exploratory Endpoints 
 
Mechanistic: 
1. Determine effect of TCZ on measures of immune cell number and function such 
as: 
a. Changes in proportions and phenotype of Treg and Teff.  
b. Changes in sensitivity of Teff to suppression by Treg. 
c. Changes in circulating B cell compartment and activation state of innate 
immune cells including antigen presenting cells and NK cells. 
Metabolic: 
1. Explore the relationship between immune responses, metabolic outcomes and 
clinical variables. 
2. Explore the effect of TCZ on insulin sensitivity. 
3.4 
RATIONALE FOR SELECTION OF DRUG, ROUTE, DOSE, AND 
REGIMEN 
The dose of 8 mg/kg every 4 weeks via the IV route is the FDA and Australian, 
Therapeutic Goods Administration (TGA)-approved dose for adults in rheumatoid 


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arthritis and will be used for adults and children ≥ 30kg in this study.  For children 
<30 kg, TCZ will be dosed at 10 mg/kg.  For systemic juvenile idiopathic arthritis 
(sJIA), the FDA-approved dose is 8 mg/kg every 2 weeks for patients with body 
weight ≥ 30kg and 12 mg/kg every 2 weeks for patients with body weight < 30 kg.  
However, in recent clinical trials of polyarticular juvenile idiopathic arthritis (pJIA), 
other dosing regimens were tested in patients age 2-17.  Participants with body mass < 
30 kg received 8 mg/kg or 10 mg/kg every 4 weeks.  Both pharmacokinetic 
measurements and clinical outcome in the 8 mg/kg ≥ 30 kg group were more similar 
to the 10 mg/kg < 30 kg group than the 8 mg/kg <30 kg group.  The dosing regimen 
selected for this trial is consistent with the pJIA dosing regimen because patients with 
T1DM, similar to those with pJIA likely do not have the systemic inflammation seen 
in sJIA.  The dosing frequency may be altered if an adverse event is encountered as 
outlined in section 5.2. 
In order to preserve blinding of the study, participants receiving placebo will be given 
an IV infusion of equal volume and appearance to treatment on the same schedule, 
formulated and prepared by each study site.  Placebo will be saline. 
3.5 
PREMATURE TERMINATION OR SUSPENSION OF THE TRIAL 
3.5.1 Ongoing Review 
As described in Section 10.1 of the protocol, this clinical trial is conducted through 
the NIAID NIH-funded Cooperative Agreement awarded to the Benaroya Research 
Institute at Virginia Mason (Seattle, WA) (BRI) to support the Immune Tolerance 
Network (ITN), a collaborative network for clinical research.  The ITN provides 
financial support for the conduct of the clinical trial to the clinical sites through 
subcontracts between the BRI and the clinical sites.  The NIAID NIH serves as the US 
Sponsor of the Investigational New Drug application (IND) for the Protocol and the 
Global Sponsor in Australia (represented by Pharmaceutical Product Development, 
Inc. (PPD) as Local Sponsor in Australia) and is responsible for all regulatory filings 
and safety reporting.  In addition, DAIT, NIAID NIH has appointed a medical monitor 
and convenes a Data and Safety Monitoring Board (DSMB) as described below.   
The joint National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
and NIAID ACE/ITN/TrialNet DSMB will formally review the safety data at least 
yearly.  The number of participants who discontinue study treatment will also be 
included in the reports prepared for the DSMB. 
In addition, safety data will be reviewed by the DSMB when an event occurs that is of 
sufficient concern to the DAIT, NIAID medical monitor, ITN physician, or the 
protocol chair to warrant review, or when an event occurs that contributes to a 
stopping rule listed in section 3.5.2. 


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3.5.2 Stopping Rules  
3.5.2.1 Study-related Adverse Events  
If any of the following events occur, enrollment will be suspended and the DSMB 
chair will be notified such that a review of safety data will determine if enrollment in 
the study will be stopped and/or administration of investigational study medication 
should be halted: 
 
Any death except those assessed as not related to study treatment on review by the 
ITN clinical trial physician, and the DAIT, NIAID medical monitor. 
 
Any demyelinating-related event. 
 
Any gastrointestinal perforation. 
 
Evidence of serious opportunistic infection, including tuberculosis, or EBV-
associated lymphoproliferative disorder. 
 
Any grade 4 or higher infusion-related event. 
 
Any unexpected, treatment-related SAE resulting in permanent treatment 
discontinuation and not related to glycemic events. 
 
Three of the first 10 participants or 30% thereafter, in either age cohort, require 
discontinuation of study medication for the same or similar serious adverse event 
based on MedDRA preferred term or at the discretion of the DAIT, NIAID 
medical monitor. 
 
Five of the first 10 participants, or 50% thereafter, in either age cohort, require 
discontinuation of study medication for individual stopping rules, as defined in 
Section 5.3 (excluding pregnancy). 
4. 
ELIGIBILITY 
4.1 
INCLUSION CRITERIA 
Patients must meet all of the following criteria to be eligible for this study: 
1. Male or female aged 6-45 years inclusive who meet the American Diabetes 
Association T1DM criteria. 
2. Diagnosis of T1DM within 100 days of enrollment (V0). 
3. Positive for at least one diabetes-related autoantibody, including but not limited 
to: 
a) Glutamate decarboxylase (GAD-65); 
b) Insulin, if obtained within 10 days of the onset of exogenous insulin therapy; 
c) IA-2; or 
d) ZnT8. 


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4. Peak stimulated C-peptide level ≥ 0.2 pmol/mL following a MMTT conducted at 
least 21 days from diagnosis and within 37 days of randomization (V0). 
5. Signed informed consent (and informed assent of minor, if applicable). 
4.2 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will not be eligible for this study: 
1. Severe reaction or anaphylaxis to human, humanized or murine monoclonal 
antibodies. 
2. History of malignancy or serious uncontrolled cardiovascular, nervous system, 
pulmonary, renal, or gastrointestinal disease, or significant dyslipidemia. 
3. Any history of recent serious bacterial, viral, fungal, or other opportunistic 
infections. 
4. Have serologic evidence of current or past HIV, Hepatitis B, or Hepatitis C. 
5. Positive tuberculin skin test (PPD) or QuantiFERON TB test, history of 
tuberculosis, or active TB infection. 
6. Active infection with EBV as defined by EBV viral load ≥ 10,000 copies per 106 
PBMCs or ≥ 2,000 copies per mL of whole blood. 
7. Active infection with CMV as defined by CMV viral load ≥ 10,000 IU or copies 
per mL of whole blood or plasma. 
8. Diagnosis of liver disease or elevated hepatic enzymes, as defined by ALT, AST, 
or both > 1.5 x the upper limit of age-determined normal (ULN) or total bilirubin 
> ULN. 
9. Current or prior treatment that is known to cause a significant, ongoing change in 
the course of T1D or immunologic status. 
10. Current or prior (within last 14 days of screening MMTT visit) use of drugs other 
than insulin to treat hyperglycemia (e.g. metformin, sulfonylureas, glinides, 
thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors, or amylin). 
11. Current use of any medication known to significantly influence glucose tolerance 
(e.g., atypical antipsychotics, diphenylhydantoin, niacin). 
12. Any of the following hematologic abnormalities, confirmed by repeat tests: 
a. White blood count <3,000/μL or >14,000/μL;  
b. Lymphocyte count <500/μL; 
c. Platelet count <150,000 /μL; 
Hemoglobin <8.5 g/dL; or 
d. Neutrophil count <2,000 cells/μL. 
13. Females who are pregnant, lactating, or planning on pregnancy during the 2-year 
study period. 


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14. History or diagnoses of other autoimmune diseases with the exception of stable 
thyroid or celiace disease. 
15. History of alcohol, drug or chemical abuse within 1 year prior to screening (V-1). 
16. Any medical or psychological condition that in the opinion of the principal 
investigator would interfere with safe completion of the trial. 
17. Prior participation in a clinical trial that could increase risks associated with this 
clinical trial. 
18. Receipt of live vaccine (e.g. varicella, measles, mumps, rubella, cold-attenuated 
intranasal influenza vaccine, bacillus Calmette-Guérin, and small pox) in the 6 
weeks before randomization (V0). 
19. High lipid levels (fasting LDL cholesterol ≥160 mg/dL or ≥4.1mmol/L). 
20. History of significant allergy (e.g. anaphylaxis) to milk or soy proteins. 
4.3 
PREMATURE TERMINATION OF A PARTICIPANT FROM THE 
STUDY 
Withdrawal of consent.  Participants who withdraw consent for further treatment. 
These participants will be asked if they would be willing to complete safety and 
outcome assessments and visits. 
Failure to return.  Participants who do not return for visits and who do not respond 
to repeated attempts by the site staff to have them return will be considered lost to 
follow-up.   
Investigator judgment. A severe or serious AE occurs, which, based on the medical 
judgment of the investigator, prevents completion of participation for study treatment. 
If study treatment is discontinued, the DAIT, NIAID medical monitor should be 
notified.  If feasible and medically appropriate, subjects will be asked to continue in 
safety and outcome assessments and visits.  
5. 
STUDY MEDICATIONS 
5.1 
INVESTIGATIONAL MEDICATION 
ACTEMRA® (tocilizumab) is the investigational agent and will be provided to the 
clinical research sites by the Sponsor.  For sites in the US, commercially-labeled 
licensed product will be obtained by the Sponsor from either the manufacturer 
(Genentech, Inc. a member of the Roche group, located in South San Francisco, CA) 
or acquired from commercial sources.  For sites in Australia, commercially labeled 
licensed ACTEMRA® (tocilizumab) will be obtained through each site pharmacy 
from commercial sources.  
Saline from clinical site pharmacies will be used as placebo in this Protocol. 


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5.1.1 Formulation and Packaging  
 
 
 
 
 
 
 
5.1.2 Reconstitution  
5.1.3 Dosage, Preparation, and Administration 
For those with weight ≥ 30 kg, tocilizumab will be administered at a dose of 8 mg/kg 
every four weeks as an IV infusion not to exceed 800 mg.  For those with weight < 30 
kg, tocilizumab will be administered at a dose of 10 mg/kg.  Dosing will be according 
to the individual’s weight and the value will be rounded up by excess to the next half 
kilogram; i.e. 45.6 kg weight will be rounded up to 46 kg.  Weight from the previous 
visit or current visit may be used.  If the previous visit was more than three months 
ago or if there is more than 10% change in body weight from previous dose, then, 
dosing of study drug will be calculated according to the individual’s weight on the day 
of the visit.  
For subjects <30 kg at the start of the trial and if their weight increases above 30 kg 
and is also greater than 10% from the start of the trial, their current weight will be 
used to calculate tocilizumab dose based on 8 mg/kg, otherwise the 10 mg/kg will 
continue to be used.   
Tocilizumab should be administered intravenously over approximately 60 minutes.  
Subjects will be observed in the clinic for 15 minutes after the end of the infusion.  
Vital signs (blood pressure and pulse) will be recorded within 10 minutes before, 15 
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5.2 
DOSE MODIFICATION AND MANAGEMENT OF ADVERSE EVENTS 
5.2.1 Overview 
Clinical evaluation including history and directed physical exam, review of adverse 
events and laboratory values from previous visit will be done prior to each infusion. 
5.2.2 Hematologic Abnormalities and Bleeding Events 
Decreases in neutrophil and platelet counts have been observed following treatment 
with TCZ in combination with MTX.   
The risk mitigation strategies for neutropenia and thrombocytopenia are summarized 
in Table 2 and Table 3, respectively. 
Table 2. Neutropenia Risk Mitigation  
ANC (cells/µL) 
Action 
> 1,000 
Maintain dose. 
500 – 1,000 
Interrupt tocilizumab dosing and recheck ANC as clinically 
relevant.  
When ANC increases to > 1,000, resume tocilizumab at the 
next expected 4 week interval.  The overall course of study 
treatment will not be extended and missed doses will not be 
administered. If the adverse event does not resolve in 8 
weeks, discontinue study treatment permanently. 
One suspension due to neutropenia is allowed during the 
treatment period. 
< 500 
Discontinue tocilizumab.  
ANC = absolute neutrophil count 
Table 3. Thrombocytopenia Risk Mitigation 
Platelet count (cells/µL) 
Action 
> 100,000 
Maintain dose. 
50,000 – 100,000 
Interrupt tocilizumab dosing and recheck platelet count as 
clinically relevant.  
When platelet count increases to > 100,000, resume 
tocilizumab at the next expected 4 week interval.  The 
overall course of study treatment will not be extended and 
missed doses will not be administered.  If the adverse event 
does not resolve in 8 weeks, discontinue study treatment 
permanently.  One suspension due to thrombocytopenia is 
allowed during the treatment period. 
< 50,000 
Discontinue tocilizumab.  
5.2.3 Blood Chemistry Abnormalities 
Elevations in ALT and AST have been observed during treatment with the study 
medications.  The recommended dose modification strategies for elevations in ALT 
and AST are summarized in Table 4. 


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Table 4. Liver Function Tests Risk Mitigation 
ALT/AST 
Action 
< 3xULN 
Maintain dose. 
>3xULN to <5xULN 
Interrupt tocilizumab dosing and recheck ALT/AST as 
clinically relevant.  
When ALT/AST decreases to <3xULN, resume tocilizumab 
at the next expected 4 week interval.  The overall course of 
study treatment will not be extended and missed doses will 
not be administered.  If the adverse event does not resolve in 
8 weeks, discontinue study treatment permanently.  One 
suspension due to elevated ALT/AST is allowed during the 
treatment period. 
> 5xULN 
Discontinue tocilizumab.  
 
The recommended dose modification strategies for elevations in bilirubin are 
summarized in Table 5. 
Table 5. Elevated Total Bilirubin Risk Mitigation 
Total Bilirubin Lab Values 
Action 
> 3 mg/dL 
For increases in this range, tocilizumab dosing will be stopped 
permanently.  Recheck total bilirubin as clinically relevant.  
5.2.4 Infections 
Tocilizumab should not be administered in patients with active infection including 
localized infections, or who report febrile illness within prior 48 hours.  These 
subjects will be rescheduled for another day within the study dosing window.  If the 
patient remains ill during the study window, the dose will be skipped and the subject 
will wait until the next scheduled dose.  Any subject who develops infection or 
reactivation of EBV or CMV, as defined by clinical signs of infection; or if the EBV 
viral load is ≥ 10,000 copies per 106 PBMCs or ≥ 2,000 copies per mL of whole blood 
or the CMV viral load is ≥ 10,000 IU or copies per mL whole blood or plasma, will 
not receive additional study drug until resolution of active infection.   
The overall course of study treatment will not be extended and missed doses will not 
be administered.  One suspension due to infection is allowed.  If a second suspension 
due to infection occurs during the treatment period, then discontinue study treatment 
permanently. 
Tocilizumab should be stopped permanently if a patient develops a serious infection, 
an opportunistic infection, or sepsis.  A patient who develops a new infection during 
treatment with tocilizumab should undergo a prompt and complete diagnostic workup 
appropriate for an immunocompromised patient, appropriate antimicrobial therapy 
should be initiated, and the patient should be closely monitored.  Patients should be 
closely monitored for signs and symptoms of tuberculosis. 


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5.2.5 Elevated Lipids 
Tocilizumab will not be administered in subjects with fasting LDL cholesterol ≥160 
mg/dL or ≥4.1 mmol/L.  Subjects with LDL values between 100 and 160 may be 
considered for treatment with lipid lowering agents.   
5.2.6 Hypersensitivity or Anaphylaxis  
An infusion/dose reaction is defined as an adverse event occurring during and within 
24 hours after the infusion or subcutaneous injection of tocilizumab.  This may 
include hypersensitivity reactions or anaphylactic reactions.  
Signs of a possible hypersensitivity reaction include but are not limited to:  
 
Fever, chills, pruritus, urticaria, angioedema, and skin rash. 
 
Cardiopulmonary reactions, including chest pain, dyspnea, hypotension or 
hypertension. 
If a patient has symptoms of anaphylaxis or hypersensitivity, or requires an 
interruption of the study drug because of symptoms of anaphylaxis or 
hypersensitivity, administration of TCZ must be discontinued permanently.  The 
patient should be treated according to the standard of care for management of the 
hypersensitivity reaction.  
5.3 
DISCONTINUATION OF STUDY MEDICATION IN AN INDIVIDUAL 
PARTICIPANT 
The dosing and administration of investigational medication according to study 
specification will be discontinued for an individual participant if any of the following 
criteria is met: 
 
Anaphylaxis or hypersensitivity reaction. 
 
A confirmed demyelinating event. 
 
Gastrointestinal perforation. 
 
Malignancy. 
 
Adverse events requiring study drug discontinuation as defined in section 5.2. 
 
The investigator determines that it is in the participant’s best interest to 
discontinue treatment. 
 
The participant, or participant’s legal representative, requests that treatment be 
halted. 
 
The participant becomes pregnant. 
Further care will be provided according to the judgment and practice of the 
investigator. 


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The participant will be asked to remain in the study and participate in follow-up.  If 
study treatment is discontinued, the DAIT, NIAID medical monitor should be 
notified. 
5.4 
CONCOMITANT MEDICATIONS 
5.4.1 Prohibited Medications 
Participants will be instructed not to use the following medications: 
 
Agents that are known to significantly influence insulin sensitivity or secretion. 
 
Medications known to affect the laboratory measurement of C-peptide (i.e. 
Strensiq® (asfotase alfa)). 
 
Non-insulin pharmaceuticals for glycemic control. 
 
Live vaccine (varicella, measles, mumps, rubella, cold-attenuated intranasal 
influenza vaccine, bacillus Calmette-Guérin, and smallpox) 6 weeks before 
enrollment, during study drug administration, and within 3 months after 
completing study drug.  
 
Agents that may result in immunosuppression or immunomodulation, including 
chronic and persistent use of inhaled, extensive topical or systemic 
glucocorticoids. 
If a participant receives, or if the investigator believes that a participant must receive, 
a prohibited medication, the case must be immediately discussed with the protocol 
chair, the DAIT, NIAID medical monitor, and the ITN clinical trial physician.  
The use of prohibited medications must be documented on the source document and 
CRF.  
5.5 
DRUG ACCOUNTABILITY 
Under US code of federal regulations (21CFR 312.62), Australian TGA regulations 
and ICH E6 Good Clinical Practice guidelines, an investigator is required to maintain 
adequate records of the disposition of the investigational product, including the date 
and quantity of drug that was received, the participants to whom drug was dispensed 
(participant by participant accounting), and an account of any drug accidentally or 
deliberately destroyed.  The investigator will ensure that the investigational product 
supplies are stored as specified in the protocol and pharmacy manual in a secured 
area, with access limited to authorized study personnel as described in the clinical 
study agreement. 
Records for receipt, storage, use, and disposition of the study drug will be maintained 
by the study sites.  A drug-dispensing log will be kept current for each participant and 
will contain the identification of each participant and the date and quantity of drug 
dispensed.  All remaining unused investigational product will be returned to the 


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Global Study sponsor (DAIT, NIAID, NIH) or sponsor’s representative after study 
termination, or destroyed with the permission of the sponsor in accordance with 
applicable law and study site procedures.  If investigational product is to be destroyed 
locally, the investigator will provide documentation in accordance with sponsor’s 
specifications. 
All records regarding disposition of the investigational product will be available for 
inspection by the clinical trial monitor. 
5.6 
ASSESSMENT OF COMPLIANCE WITH STUDY MEDICATION 
Tocilizumab will be administered intravenously by trained medical staff; compliance, 
therefore, will be monitored by the medical staff and documented on the CRF. 
6. 
STUDY PROCEDURES 
6.1 
INTENSIVE DIABETES MANAGEMENT 
During the study period, all participants will receive “intensive” management of their 
diabetes, and HbA1C will be assessed at every visit to evaluate metabolic control.  The 
goal of treatment will be to maintain the HbA1C levels within the currently 
recommended ADA age-specific target ranges in the absence of significant or severe 
hypoglycemia.  The primary responsibility for diabetes management will be the 
treating or referring diabetes care provider, but the research study team will provide 
close additional support through regular interaction.  Glucose levels should be 
checked frequently and records communicated regularly to the study team.   
6.2 
VISIT WINDOWS 
6.2.1 Scheduled Visits 
The initial treatment should begin within 100 days from the day of diagnosis and 
within 37 days of the screening MMTT.  Subsequent treatment visits are every 4 
weeks.  The treatment visits (V0-V6) must occur within 7 days on either side of the 
target date.  However, consecutive doses must be 21 days apart.  Treatment doses will 
not be administered outside of the window, will not be made up, and target dates will 
not be reset.  In this way, no one will receive more than 7 doses over the 6 month 
period.  The window for all subsequent visits is +/- 2 weeks.  Appendix 1 presents the 
schedule of events for this trial.   
6.3 
RANDOMIZATION, MASKING, AND UNMASKING  
6.3.1 Randomization 
Participants who sign the informed consent and meet the eligibility criteria will be 
randomly assigned in a 2:1 ratio to either the experimental or control group.  A central 
automated randomization system will be used for treatment assignment and to create a 
unique identifier for each new study participant.  Adults and children will be 


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randomized separately.  For subjects in the adult cohort, random assignment will be 
stratified by site.  For subjects in the child cohort, random assignment will be 
stratified by site and baseline mean 2-hour C-peptide AUC (<0.53, 0.53-0.79, >0.79 
pmol/ml).   
Note that the cutpoints for the baseline mean 2-hour AUC levels are the tertiles 
observed in a sample that included 104 placebo subjects aged 6 to 17 pooled across 5 
TrialNet studies.10,11,60-62 
6.3.2 Masking to treatment assignment 
Masking will be maintained throughout the study for all study participants and study 
personnel, except the pharmacists.   
6.3.3 Unmasking 
Unmasking before the study is completed will occur if a participant’s well-being is 
threatened and the investigator believes unmasking is necessary to protect the 
participant.  Unmasking may also occur in the case of pregnancy (participant or 
partner pregnancy) at the request of the pregnant woman. 
Before treatment assignment for an individual participant is unmasked, the 
investigator should attempt to confer with the DAIT medical monitor.  In the event 
that the DAIT medical monitor was not previously notified of the emergency 
unmasking, the site investigator will notify the DAIT medical monitor and ITN 
physician of an unmasking event as soon as possible after the fact.  
The emergency unmasking will be recorded and reported to the DSMB.  A full 
account of the event will be recorded, including the date and time of the emergency, 
the reason for the decision to unmask, and the names of the medical monitor and 
others who were notified of the emergency.  During site visits, the site monitor must 
verify that the DAIT medical monitor was notified and that a written account was 
completed.  The reasons for unmasking of a participant’s treatment will be included in 
the final study report. 
Unmasking will also occur for Safety Reports (SUSARs) that will be reported to the 
US and Australian Health Authorities, DSMB and IRBs/ECs as specified in the 
current FDA IND Safety Reporting guidance. 
ITN and DAIT, NIAID approval is required for unmasking the treatment of an 
individual participant or subgroups of participants for unplanned interim analyses to 
support DSMB reviews and final analysis.  
6.4 
GENERAL ASSESSMENTS 
 
Informed consent: Written informed consent will be obtained from the participant 
before any study assessments or procedures are performed. 


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 
Eligibility criteria: Eligibility for study participation will be assessed during the 
screening period.  
 
Medical history: This includes T1DM time of diagnosis and clinically significant 
diseases or medical procedures.   
 
Adverse events: Participants will be assessed for AEs. 
 
Concomitant medications: All concomitant medications and their indications will 
be recorded. 
 
Physical examination: This may be a comprehensive or directed exam as noted in 
the SOE (Appendix 1). 
 
Vital signs: Weight, temperature, blood pressure, respiration, and pulse will be 
obtained at all visits.  Height will be obtained at initial visits for all subjects and 
every 6 months for children. 
6.5 
CLINICAL LABORATORY ASSESSMENTS 
Clinical laboratory blood draws are to be performed after vital signs are assessed and 
prior to study drug infusion during the treatment period.  Participants will periodically 
undergo blood draws for both clinical and immunologic tests.  Blood volumes drawn 
will be based on participant body weight and may be modified to limit the total blood 
volume drawn at any one visit.  
Central laboratory assessments: 
 Serum chemistries: Electrolytes (sodium, potassium, chloride, phosphate, total 
CO2), blood urea nitrogen (BUN), creatinine, CRP and liver panel (AST, ALT, 
alkaline phosphate, direct and total bilirubin). 
 Hematology: Includes RBC, hematocrit, hemoglobin, platelet count, WBC and 
differential. 
 Lipid panel: Total cholesterol, HDL, LDL, triglycerides. 
 Urinalysis: Includes blood (RBCs), glucose, ketones, pH, protein and specific 
gravity. 
 Infectious disease serology: Serology will be performed at screening for HBV, 
HCV, HIV, EBV, CMV.  CMV or EBV serology will be repeated if participants 
show clinical signs of infection; or if the EBV viral load is ≥ 10,000 copies per 106 
PBMCs or ≥ 2,000 copies per mL of whole blood or the CMV viral load is ≥ 
10,000 IU or copies per mL whole blood or plasma. 
 Viral load testing: Viral load testing by PCR will be performed for CMV and EBV. 
 TB test: Exposure to tuberculosis will be assessed via QuantiFERON TB test (A 
PPD skin test may be performed locally if the QuantiFERON TB test is not 
performed at the central lab). 


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 Serum βHCG: Serum testing will be performed at screening to rule out pregnancy.  
Serum βHCG will be repeated after screening for participants with a positive urine 
HCG result at any study visit. 
Disease-Specific Assessments: 
 C-peptide (as part of MMTT). 
 Plasma glucose (as part of MMTT and FSIVGTT). 
 Insulin (as part of FSIVGTT). 
 HbA1c 
 Diabetes-related autoantibodies 
Drug-Related Assessments: 
 Pharmacokinetics (PK) 
 IL-6 and IL-6sR 
 Anti-TCZ antibodies 
Laboratory assessments evaluated at the site: 
 
Urine HCG: Urine HCG will be measured before study drug administration 
during the treatment period for female participants with reproductive capacity to 
monitor for pregnancy 
6.6 
PHARMACOKINETIC ASSESSMENTS 
All participants will have PK samples taken at the time points listed in Table 6. 
Table 6: Pharmacokinetic Samples 
 
Visit # 
Time Points 
Day of Infusion 
7 Days (Post infusion) 
V0 
(Week 0) 
 
before infusion 
 
within 10 minutes after infusion 
 
7 (±3) days after infusion 
V1 
(Week 4) 
 
before infusion 
 
V5 
(Week 20) 
 
before infusion 
 
within 10 minutes after infusion 
 
7 (±3) days after infusion 
V6 
(Week 24) 
 
before infusion 
 
 


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6.7 
METABOLIC ASSESSMENTS 
 
MMTT:  A 2-hour MMTT is to be performed at weeks 12, 24, 39, and 78.  A 4-
hour MMTT is to be performed at weeks -1 (screening), 52, and 104 for subjects 
≥12 years old (for subjects <12 years old, a 2-hour MMTT will be performed 
instead.  
 
HbA1c 
 
Glucose (glucometer readings) 
 
Continuous glucose monitoring (CGM) to obtain data to evaluate glycemic 
control; particularly frequency of hypoglycemia.  Randomized participants will be 
invited to use a commercially available FDA or appropriate Health Authorities 
approved CGM system and its components (Dexcom, Inc., San Diego, CA) for a 
14 day period at weeks 0, 12, 24, 52, 78, and 104.  Data may also be obtained for 
the study from the participant’s CGM system if used as part of their usual clinical 
care. 
 
Insulin use (U/kg body weight/day) 
 
Major hypoglycemic events 
 
FSIVGTT (Frequently sampled glucose tolerance test).  To obtain additional 
information about the possible effects of therapy on insulin sensitivity, a 
FSIVGTT will be offered to subjects age ≥15 at baseline, week 24 and week 52.  
Due to the additional visits required to conduct these tests, subjects may decline to 
participate in this aspect of the protocol, while remaining in the main study.  
Those who do participate will receive compensation for their time and effort.  
6.8 
MECHANISTIC ASSESSMENTS 
Mechanistic samples drawn during the study drug treatment period are collected prior 
to study drug infusion.  See section 7 for detailed discussion of additional mechanistic 
assays. 
7. 
TOLERANCE ASSAYS 
7.1 
MECHANISTIC HYPOTHESIS 
The primary mechanistic hypotheses are that anti-IL6R therapy in T1D will promote 
T regulatory cell activity, suppress innate immune responses, and alter B cell activity.  
Studies will address multiple questions but will be prioritized based on the amount of 
blood available.  Questions to be addressed in current rank order are:  
 
Anti-IL6R results in increased numbers of the peripheral regulatory T cell 
population and diminishes numbers of pro-inflammatory T cells, including Th17 
cells. 


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 
Anti-IL6R results in altered functional status of both regulatory T cells and pro-
inflammatory T cells.    
 
Anti-IL6R enhances the sensitivity of effector T cells to suppression by Tregs. 
 
Anti-IL6R alters the proportions of circulating B cell compartment. 
 
Anti-IL6R alters innate immune responses, including changes in the composition 
and activation of monocytes, dendritic cells, and NK cells. 
7.2 
RETENTION OF SAMPLES 
Specimens collected in this trial may be used to reevaluate biologic responses as new 
research tools become available.  Samples collected from this study in the United 
States, will be stored centrally at the ITN sample repository for future analysis.  
Samples collected in Australia will be stored centrally at the University of Queensland 
Diamantina Institute, Queensland, and some of these samples may be transferred to 
the ITN sample repository in the US for archive and future analysis as needed.  
Residual specimens may be used by investigators for development of new 
immunologic assays or for cross-trial comparisons.  While specimens are described in 
this protocol in the context of assays to be performed, it should be noted that not 
necessarily all assays will be performed for all participants at each time point.  
Decisions to perform assays will be made according to statistical and scientific 
planning, questions being asked, and current technologies to be utilized.  Finally, 
clinical outcomes will be taken into account to determine the potential value of the 
assays.  For example, if a significant clinical effect fails to occur, the assays 
performed by the ITN may be minimal.  Specimens and data may be used for future 
research related to diabetes and autoimmune diseases. 
7.2.1 Sample Types 
Samples will be collected under the auspices of the clinical sites as outlined in the 
schedule of events (Appendix 1). 
7.3 
MECHANISTIC ASSAYS 
The following assay methodologies may be used to address the mechanistic 
hypotheses: 
 
Multi-chromatic flow cytometry on banked PBMCs to monitor the changes in 
number and phenotype of various immune cell subsets including T cells, B cell 
subsets and innate cells.  Flow cytometry may also be used to assess the 
functional status of cells in response to ex vivo stimuli for example, 
phosphorylated status of STAT proteins (STAT-3 or STAT5) and intracellular 
cytokine secretion.  
 
Multiplex immunoassays may be used to measure changes in circulating markers 
using serum or plasma collected at multiple time points during therapy. 


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 
Cell-based proliferation assays may be used to examine the changes in resistance 
to Treg-mediated suppression of Teff cells using viably frozen PBMCs. 
 
Epigenetic analysis may be performed on DNA extracted from frozen whole 
blood to assess changes in native Treg, Th17, Th1 and Tfh cell numbers.   
 
One or more gene expression analysis platforms may be used to evaluate changes 
in expression of various genes using blood frozen in presence of RNA stabilizing 
agents. 
 
Genetic variation and SNP analysis of genes of interest may be performed on 
DNA isolated from frozen whole blood.               
 
Other assays as approved by the ITN study management team.  
8. 
ADVERSE EVENTS 
8.1 
OVERVIEW 
The investigator is responsible for the detection and documentation of events meeting 
the criteria and definition of an AE (adverse event) or SAE (serious adverse event) as 
described in Section 8.2 in this protocol. All AEs and SAEs will be recorded in the 
source documents and on the appropriate electronic CRF(s).  All data will be reviewed 
periodically by the DSMB, which may provide recommendations to NIAID about 
withdrawing any participant and/or terminating the study because of safety concerns. 
Adverse events that are classified as serious according to the definition of Health 
Authorities must be reported promptly and appropriately to the Global Study Sponsor 
(DAIT, NIAID, NIH), ITN, principal investigators in the trial, IRBs/ECs, and 
appropriate Health Authorities.  This section defines the types of AEs and outlines the 
procedures for appropriately collecting, grading, recording, and reporting them.  
Information in this section complies with 21CFR 312; ICH Guideline E2A: Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting; and 
ICH Guideline E-6: Guidelines for Good Clinical Practice; and applies the standards 
set forth in the National Cancer Institute’s Common Terminology Criteria for Adverse 
Events Version 4.03 (published June 14, 2010) with the exception of reporting of 
hyperglycemia and hypoglycemia as noted below.  This document referred to herein 
as the “NCI-CTCAE manual.”  
8.2 
DEFINITIONS 
8.2.1 Disease-specific Adverse Event 
For the purposes of this study, major hypoglycemic events will be recorded in the 
eCRF.  Major hypoglycemic events are defined as: 
 
Blood glucose concentration < 40 mg/dL; (Grades 3–5, NCI-CTCAE version 
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 
Hypoglycemic events involving seizure or loss of consciousness (coma), or 
requiring assistance from another individual in order to recover.  
All episodes of hypoglycemia that require hospitalization and/or emergency care will 
be reported to the DSMB in an expedited manner as described in Section 8.5.3.   
8.2.2 Adverse Event 
An adverse event (AE) is any occurrence or worsening of an undesirable or 
unintended sign, symptom, laboratory finding, or disease that occurs during 
participation in the trial.  An AE will be followed until it resolves or until 30 days 
after a participant terminates from the study, whichever comes first.  All AEs will be 
reported as specified in Section 8.3.1 whether they are or are not related to disease 
progression or study participation. 
8.2.3 Suspected Adverse Reaction and Adverse Reaction  
Suspected adverse reaction (SAR) means any adverse event for which there is a 
reasonable possibility that the study drug caused the adverse event.  For the purposes 
of safety reporting, ‘reasonable possibility’ means there is evidence to suggest a 
causal relationship between the drug and the adverse reaction.  A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug (21 CFR 312.32(a))/(ICH E2A). 
An adverse reaction (AR) means any adverse event caused by a study drug.  Adverse 
reactions are a subset of all suspected adverse reaction for which there is reason to 
conclude that the drug caused the event. 
8.2.4 Serious Adverse Event  
An AE or SAR is considered “serious” if, in the view of either the investigator or 
DAIT, NIAID it results in any of the following outcomes (21 CFR 312.32(a))/(ICH 
E2A): 
 Death: A death that occurs during the study or that comes to the attention of the 
investigator during the protocol-defined follow-up period must be reported 
whether it is considered treatment related or not. 
 A life-threatening event: An AE or SAR is considered “life-threatening” if, in the 
view of either the investigator or DAIT, NIAID, its occurrence places the subject 
at immediate risk of death.  It does not include an AE or SAR that, had it occurred 
in a more severe form, might have caused death.  
 Inpatient hospitalization or prolongation of existing hospitalization. 
 Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 


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 An event that requires intervention to prevent permanent impairment or damage. 
An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based on appropriate 
medical judgment, it may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
 Congenital anomaly or birth defect. 
8.2.5 Adverse Events of Special Interest (AESIs) 
Adverse Events of Special Interest (AESIs) are identified for ACTEMRA® 
(tocilizumab) and will be collected and reported as study-specific AEs or SAEs in 
this trial.  Investigators should use their clinical judgement to identify events falling in 
any of the following categories: 
 
Opportunistic and serious infections (including all opportunistic infections and all 
non-serious infections as defined by those treated with IV anti-infectives).  
 
Myocardial infarction/acute coronary syndrome. 
 
Gastrointestinal perforations and related events, including complications of 
diverticulitis, appendicitis, generalized purulent peritonitis, lower GI perforation, 
fistula, and/or abscess. 
 
Anaphylaxis (and/or related hypersensitivity reactions that require treatment 
discontinuation).  
 
Malignancies. 
 
Hepatic Events, including elevated hepatic transaminase levels (ALT/AST levels 
> 3 ULN) or total bilirubin > 3 mg/dL. 
 
Bleeding Events, including any clinical sign of hemorrhage that requires 
diagnostic studies, hospitalization, and/or treatment.  
 
Stroke, including ischemic or hemorrhagic stroke, or transient ischemic attack.  
 
Demyelinating disorders (with signs or symptoms of a demyelinating disorder 
such as multiple sclerosis or chronic inflammatory demyelinating 
polyneuropathy). 
If an adverse event meets any of the above study-specific categories, regardless of the 
relationship of the event to study drug or severity, the event must be reported to the 
Global Study Sponsor (DAIT, NIAID, NIH) as described in Section 8.5.1.  For all 
Adverse Events of Special Interest received by the Global Study Sponsor (serious and 
non-serious), a guided questionnaire will be used to obtain follow-up information. 


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8.2.6 Unexpected Adverse Reaction 
A SAR is considered “unexpected” when its nature (specificity), or severity, or rate of 
occurrence is not consistent with applicable product information as described in the 
safety information provided in the developmental core safety information section of 
the current F. Hoffman La-Roche LTD Investigator’s Brochure and country-specific 
package inserts for tocilizumab. 
8.3 
COLLECTING AND RECORDING ADVERSE EVENTS 
8.3.1 Methods of Collection 
All adverse events (AEs) will be collected and recorded from visit -1 until the time the 
participant completes the study, or prematurely withdraws from the study.  All serious 
adverse events (SAEs) will be collected from visit -1 until 30 days after the participant 
completes the study, or 90 days after the participant prematurely withdraws from the 
study.  
Adverse events and serious adverse events may be collected as follows: 
 Observing the participant. 
 Questioning the participant in an objective manner. 
 Receiving an unsolicited complaint from the participant. 
An AE that is an asymptomatic abnormal value or result from a clinical or laboratory 
evaluation (e.g., a radiograph, an ultrasound, or an electrocardiogram) will be 
documented and maintained in the source records.  Asymptomatic adverse events 
must be recorded on the AE form when they meet the criteria for a Grade 3 or greater 
AE per CTCAE criteria, with the exception of AESIs (Section 8.2.5) and 
hyperglycemia and hypoglycemia as defined in Section 8.4.1.  The evaluation that 
produced the value or result should be repeated until that value or result returns to 
normal or can be explained and the participant’s safety is not at risk. 
8.3.2 Specific Instructions for Recording Adverse Events 
Correct medical terminology/concepts should be used when reporting AEs and SAEs. 
Avoid colloquialisms and abbreviations. 
 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather 
than jaundice, asterixis, and elevated transaminases).  However, if a constellation 
of signs and/or symptoms cannot be medically characterized as a single diagnosis 
or syndrome at the time of reporting, it is ok to report the information that is 
currently available.  If a diagnosis is subsequently established, it should be 
reported as follow-up information. 


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 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 5.1.2), regardless of attribution, will be reported to the appropriate parties.  
When recording a death, the event or condition that caused or contributed to the 
fatal outcome should be reported as the single medical concept.  If the cause of 
death is unknown and cannot be ascertained at the time of reporting, report 
“Unexplained Death.” 
 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. 
Such conditions should be reported as medical and surgical history.  A preexisting 
medical condition should be re-assessed throughout the trial and reported as an 
AE or SAE only if the frequency, severity, or character of the condition worsens 
during the study.  When reporting such events, it is important to convey the 
concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE.  If a subject is hospitalized to undergo a 
medical or surgical procedure as a result of an AE, the event responsible for the 
procedure, not the procedure itself, should be reported as the SAE.  For example, 
if a subject is hospitalized to undergo coronary bypass surgery, record the heart 
condition that necessitated the bypass as the SAE. 
8.3.3 Recording AEs 
Throughout the study, the investigator will record all symptomatic AEs on the 
appropriate eCRF regardless of their severity or relation to study participation and 
asymptomatic AEs of grade 3 or above.  The investigator will treat participants 
experiencing AEs appropriately and observe them at suitable intervals until their 
symptoms resolve or their status stabilizes. 
8.3.4 Recording SAEs 
Serious AEs will be recorded on the SAE eCRF and Health Authorities will be 
notified as outlined in Section 8.5. 
8.4 
GRADING AND ATTRIBUTION OF ADVERSE EVENTS 
8.4.1 Grading of Major Hypoglycemic and Hyperglycemic Events 
For this study of participants with type 1 diabetes, the NCI-CTCAE will not be used 
to grade hypoglycemia and hyperglycemia.  Please refer to the grading criteria for 
major hypoglycemic and hyperglycemic events below.  In this study, non-major 
hypoglycemic and hyperglycemic events will not be reported as AEs. 


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Major hypoglycemic events will be graded as follows: 
 
Grade 3 = blood glucose concentration < 40 mg/dL or <2.2 mmol/L; (Grades 3–5, 
NCI-CTCAE version 4.03), or events resulting in seizures, loss of consciousness, 
or requiring the assistance of others for the purpose of altered consciousness.  
 
Grade 4 = events resulting in coma or life-threatening event requiring 
hospitalization. 
 
Grade 5 = death. 
Major hyperglycemic events will be graded as follows: 
 
Grade 4 = coma or life-threatening event or event resulting in hospitalization. 
 
Grade 5 = death. 
For this study significant diabetic ketoacidosis (DKA) will be reported together with 
grade 4 hyperglycemia (as a single adverse event) resulting in hospitalization and life 
threatening consequences.    
8.4.2 Grading for All Other Adverse Events 
The study site will grade the severity of AEs experienced by study participants 
according to the criteria set forth in the National Cancer Institute‘s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE, v 4.03) manual and provides 
a common language to describe levels of severity, to analyze and interpret data, and to 
articulate the clinical significance of all AEs, with the exception of hypoglycemia and 
hyperglycemia.   
Adverse events will be graded on a scale from 1 to 5 according to the following 
standards in the NCI-CTCAE manual: 
 Grade 1 = mild adverse event. 
 Grade 2 = moderate adverse event. 
 Grade 3 = severe and undesirable adverse event.  
 Grade 4 = life-threatening or disabling adverse event. 
 Grade 5 = death. 
For additional information and a printable version of the NCI-CTCAE manual, go to 
http://ctep.cancer.gov/reporting/ctc.html.  
8.4.3 Attribution  
Adverse events will be categorized for their relation to tocilizumab.  The principal 
investigator will make the initial determination of the relation, or attribution, of an AE 
to study drug and will record the initial determination on the appropriate eCRF and/or 
SAE reporting form.  Infusion reactions occurring within 24 hours of starting study 


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drug infusion will be considered related to the study drug as defined in Section 5.2.6.  
The relation of an AE to study drug will be determined using definitions in Table 7.  
Final determination of attribution for safety reporting will be decided by DAIT, 
NIAID. 
Table 7. Attribution of Adverse Events 
8.5 
REPORTING SERIOUS ADVERSE EVENTS 
8.5.1 Reporting SAEs to the Global Study Sponsor (DAIT, NIAID, NIH)  
The following process for reporting a SAE ensures compliance with 21CFR 312 and 
ICH guidelines. After learning that a participant has experienced a SAE, the 
investigator or designee will report the SAE via the electronic SAE report form (SAE 
eCRF) within 24 hours of becoming aware of the event. Initial SAE eCRF should 
include as much information as possible, but at a minimum must include the 
following: 
 AE term. 
 Study drug treatment. 
 Relationship to study medications. 
 Reason why the event is serious. 
 Supplementary CRF pages that are current at the time of SAE reporting: medical 
history, concomitant medications, demographics, study drug administration, death.  
As additional details become available, the SAE eCRF should be updated and 
submitted.  Every time the SAE eCRF is submitted, it should be electronically signed 
by the investigator or subinvestigator.  
Code 
Descriptor 
Definition 
Unrelated Category  
1 
Unrelated 
The adverse event is clearly not related. 
2 
Unlikely 
The adverse event is unlikely related. 
Related Categories* 
3 
Possible 
The adverse event has a reasonable possibility to be related; there is 
evidence to suggest a causal relationship. 
4 
Probable 
The adverse event is likely related. 
5 
Definite 
The adverse event is clearly related. 
*Infusion reactions defined as fever, chills, pruritus, urticarial, angioedema, skin rash, anaphylaxis, 
and  cardiopulmonary reactions, not limited to chest pain, dyspnea, hypotension or hypertension, 
occurring within 24 hours of starting study drug infusion will be considered related to the study drug 
per section 5.2.6 


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For additional information regarding SAE reporting, contact Rho Product Safety: 
Rho Product Safety  
 
 
 
 
 
  
8.5.2 Reporting SAEs to Health Authorities 
After the SAE has been reported by the principal investigator and assessed by the 
Global Study Sponsor (DAIT, NIAID, NIH).  In the US, the IND sponsor (DAIT, 
NIAID, NIH) must report an event to the FDA using one of these two options: 
 Standard reporting (report in the IND annual report).  This option applies if 
the AE is classified as one of the following:  
o Serious, expected, suspected adverse reactions described in Sections 8.2.4 and 
8.2.5. 
o Serious and not a suspected adverse reaction described in Section 8.2.3. 
 Expedited reporting is required. This option applies if the AE is classified as one 
of the following: 
o Serious and unexpected suspected adverse reactions described in Section 
8.2.3, and unexpected per Section 8.2.5.    
o The sponsor must report any suspected adverse reaction that is both serious 
and unexpected.  The sponsor must report an adverse event as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship 
between the study drug and the adverse event, such as: 
 
A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure (e.g., angioedema, hepatic 
injury, or Stevens-Johnson Syndrome). 
 
One or more occurrences of an event that is not commonly associated 
with drug exposure, but is otherwise uncommon in the population 
exposed to the drug (e.g., tendon rupture).  
o Aggregate analysis of specific serious adverse events observed in a clinical 
trial (such as known consequences of the underlying disease or condition 
under investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events occur 
more frequently in the drug treatment group than in a concurrent or historical 
control group. 


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o Any findings from clinical or epidemiological studies, analysis of data pooled 
across multiple studies, published or unpublished scientific papers, or from 
animal or in vitro testing that would result in a safety-related change in the 
protocol, informed consent, Investigator’s Brochure, or other aspects of the 
overall conduct of the trial will be reported. 
Safety reports must be reported by DAIT, NIAID to the FDA within 15 calendar days; 
fatal or immediately life-threatening, serious, unexpected, suspected adverse reactions 
must be reported within 7 calendar days.  
Australian Suspected Unexpected Serious Adverse Reactions (SUSARs) should be 
reported to the TGA by the Study Sponsor following the timelines outlined below: 
 Fatal or life-threatening SUSARs: as soon as possible but no later than 7 calendar 
days after first knowledge, followed by as complete a report as possible within 8 
additional calendar days. 
 All other serious SUSARs: as soon as possible but no later than 15 calendar days 
after first knowledge. 
All principal investigators must report SAEs to their respective IRBs/ECs as mandated 
by them. 
8.5.3 Reporting SAEs to the DSMB 
The Study Global Sponsor (DAIT, NIAID, NIH) will provide the DSMB with data of 
all SAEs on a regular basis, including quarterly reports of all SAEs.  Major 
hypoglycemic events that require emergency care will also be reported to the DSMB 
in an expedited fashion regardless of whether they met the criteria for an SAE or not. 
8.5.4 Reporting of Adverse Events to IRBs/ECs 
All investigators must report adverse events, including expedited reports, in a timely 
fashion to their respective IRBs/ECs in accordance with applicable regulations and 
guidelines.  All Safety Reports to the FDA or the appropriate Health Authorities shall 
be distributed by DAIT NIAID or designee to the participating institution for site 
IRB/EC submission according to local regulation and guidelines. 
8.5.5 Reporting AEs to Genentech, Inc. 
The DAIT, NIAID will provide Genentech, Inc. with data for AEs of Special Interest 
(AESIs) and SAEs on an ongoing basis as specified in the protocol-specific safety 
management plan part B.   
 
Distribution as follows: 
1. DAIT SACCC (Rho Federal) will forward a notification including a copy of the 
eCRF of all SAEs including significant follow-ups, AESIs, and pregnancies to 
DAIT, NIAID and Genentech Drug Safety (GDS) within 24hrs of becoming 
aware of the event. 


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2. DAIT SACCC (Rho Federal) will forward the final version of all SAEs, AESIs 
and pregnancies to Genentech, Inc. within 15 days of sponsor notification. 
3. All IND Safety Reports with an Analysis of Similar Events will be sent to GDS at 
the time of transmission to the FDA. 
4. Any study report submitted to the FDA by the Sponsor should be copied to 
Genentech, Inc.  This includes all IND annual reports and the Clinical Study 
Report (final study report).   
5. Final Reports format: 
a. For expedited reports: MedWatch 
b. For non-expedited related reports: Medical Summary Report 
c. AESIs: Event-Specific Guided Questionnaire 
d. All other non-serious AEs: Line listings 
6. DAIT SACCC (Rho Federal) statistician will post cumulative line listings of 
serious and non-serious AEs and pregnancy reports monthly to Rho Portal. 
Genentech, Inc. will receive an email notification when the reports are posted or 
updated and will be able to access the study website to retrieve the listings as 
needed. 
8.5.6 Reporting Pregnancy  
The investigator should be informed immediately of any pregnancy in the participant 
or a partner pregnancy of a male participant occurring from randomization through the 
end of the follow-up period (two-year study period).  All available pregnancy 
information should be entered into the electronic data capture (EDC) system within 24 
hours of becoming aware of the event.  The investigator should be available to counsel 
the participant or refer the participant (or partner) for counseling to discuss the risks of 
continuing with the pregnancy and the possible effects on the fetus.  The pregnant 
woman will have the option to be informed of treatment assignment should she wish 
to know.  She will be asked to sign a specific informed consent giving her approval 
for the site to monitor and report the conclusion of the pregnancy.  Follow-up 
information detailing the outcome of the pregnancy should be entered into the EDC 
system as it becomes available.  Any premature termination of the pregnancy would 
also be reported.  
Pregnancy will be recorded as an AE for tracking purposes.  Any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
recorded as an AE or SAE as described in Sections 8.3.2 and 8.3.3.  


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9. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
9.1  
ANALYSIS SAMPLES  
Modified Intent to Treat (mITT) sample will include all randomized participants 
who received any dose of study treatment.  The efficacy analyses will be based on the 
mITT sample according to the group to which the participants are assigned. 
Per protocol samples will be assessed for week 52 (PP1) and week 104 (PP2), and 
will include all participants in the mITT sample with no major protocol deviations that 
impact efficacy assessments, who have completed at least 5 of the 7 monthly infusions 
of study drug and who received at least 80% of the expected dose in each infusion, 
and who have the week 52 and week 104 MMTT assessment for C-peptide, 
respectively.  The reported major deviations will be reviewed during a masked data 
review after the last subject’s primary endpoint visit and the end of the study to 
determine which participants should be excluded from the per-protocol populations. 
Safety sample (SS) will be defined as all participants who received any degree of 
study treatment.  Safety analyses will be based on actual treatment the participants 
receive. 
9.2  
ANALYSIS OF ENDPOINTS 
Because the natural history of disease in T1DM is considerably different in children as 
compared with adults, with adults having a much more indolent disease course, the 
primary analysis of the primary endpoint will be evaluated using the pediatric 
participants in the mITT sample.  Primary analysis of treatment effect will be 
conducted under the mITT principle of eligible patients, whereby outcome data from 
all pediatric patients in the mITT sample will be included regardless of treatment 
compliance or duration of study participation. 
All analyses for the primary and secondary endpoints will be completed in the 
pediatric mITT sample (ages 6 to 17 years) and will also be repeated on the pooled 
mITT sample (i.e. both adult and pediatric subjects) as secondary analyses.   
9.2.1 Primary Endpoint 
The primary analysis of the primary endpoint, change in MMTT-stimulated mean 2-
hour C-peptide AUC at week 52, will test the null hypothesis of “no treatment group 
difference” versus the two-sided alternative using pediatric participants from the 
mITT sample.  The hypothesis test and baseline-adjusted treatment group estimates 
will be derived from an ANCOVA model fit to the change in mean 2-hour C-peptide 
AUC response at week 52 with fixed effects for treatment group, baseline mean 2-
hour C-peptide AUC, and age.  Transformations of data will be considered if evidence 
of significant departures from model assumptions are apparent. 


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For a participant who misses the entire week 52 MMTT assessment, the missing AUC 
values will be imputed using the following approach for the primary analysis of the 
primary endpoint: 
 
If the subject’s last observed AUC value is 0, the missing week 52 AUC will be 
imputed to zero. 
 
If the subject’s last observed AUC value was at time t and was >0, then the 
missing AUC at week 52 will be imputed using data from subjects in the same 
arm and age group who had available AUC values at both time t and week 52.  
Specifically, a linear regression line will be fit where week 52 AUC values are 
regressed on AUC values at time t (e.g. week 24). In each arm and age group, a 
missing week 52 AUC value will be imputed as the value predicted from the 
linear regression line. 
At a minimum, the following sensitivity analyses for the primary endpoint will be 
performed: 
 
An analysis analogous to the primary endpoint analysis using only mITT subjects 
with observed data at week 52 (i.e., without imputing any missing week 52 AUC 
values). 
 
An analysis analogous to the primary endpoint analysis using the PP1 subjects. 
 
An analysis analogous to the primary endpoint analysis in the mITT sample using 
imputed values for missing week 52 AUC values as described above but using a 
conservative approach.  In the active therapy arm, a missing week 52 AUC value 
will be imputed as the value predicted from the estimated lower limit of a 90% 
confidence band about the linear regression line.  In the Control group, a missing 
week 52 AUC value will be imputed as the value predicted from the estimated 
upper limit of a 90% confidence band about the regression line. 
Note that, if research suggesting better methods for handling missing C-peptide AUC 
data becomes available, changes to the above plan will be pre-specified in the 
Statistical Analysis Plan prior to data lock and unmasking of treatment assignments 
for planned end-of-study analyses.  
9.2.2 Secondary Endpoints 
The null hypothesis proposes that there is no difference in the secondary endpoint 
(measured either as means or proportions) between study groups.  The alternative 
hypothesis proposes the opposite; that there is a difference in the secondary endpoints 
between the treatment and control groups.  All secondary inferential analyses are 
considered supportive; p-values will be presented without adjustment for multiple 
comparisons.  


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Treatment group differences in change in mean 2-hour C-peptide AUC from baseline 
at weeks 12, 24, 39, 78, and 104 will be compared using ANCOVA analyses 
controlling for baseline.  Effect modification by baseline mean 2-hour C-peptide AUC 
and age will be evaluated.  In addition, treatment groups will also be compared at 
weeks 12, 24, 39, and 52 using a random regression approach.  A random regression 
model will be fit to the mean 2-hour C-peptide AUC responses at baseline and weeks 
12, 24, 39, and 52 with fixed effects for treatment, time, age, and interactions for 
treatment*time and age*time.  Random within-subject effects for intercept and slopes 
over time will be included assuming an unstructured covariance matrix.  All subjects 
with at least 1 post-baseline assessment will be included in the random regression 
model.  A separate random regression model will include C-peptide assessments 
through week 104.  For these models, piece-wise slopes will be considered to allow 
for the potential rise and fall in mean 2-hour C-peptide. Transformations of data will 
be considered if evidence of significant departures from model assumptions are 
apparent.  Alternative covariance structures will be considered if models fail to 
converge. 
Treatment group differences in the change in mean 4-hour C-peptide AUC from 
baseline at weeks 52 and 104 will be compared using ANCOVA analyses controlling 
for baseline.  ANCOVA models adjusting for baseline will also be used to analyze the 
change in peak 4-hour C-peptide at weeks 52 and 104. 
In addition, analogous analyses will be used to analyze glucose values, insulin use and 
HbA1c.   
The mechanistic hypothesis for secondary endpoint determination (Section 3.3.2) is 
that the treatment will promote Treg and/or reduce Teff cell frequency in the 
periphery.  Multi-chromatic flow cytometry will be used to monitor the frequency of 
Treg and Teff cell populations during the course of study and the ratio of Treg/Teff 
will be determined to investigate the effect of TCZ on these cell types.  A linear mixed 
model analysis will be used to evaluate Treg/Teff longitudinal differences between 
control and treatment groups at weeks 12, 24, 39, 52, 78 and 104. 
9.2.3 Safety Analysis 
Reports summarizing safety data will be prepared at the end of the study and 
periodically throughout the study for regulatory filings, the DSMB, and for the 
medical monitor and study management team. Safety reports will be prepared to meet 
the needs of those groups and individuals responsible for monitoring safety and may  
include (but are not limited to) masked summaries and listings of SAEs, AEs, changes 
in vital signs, events requiring drug discontinuations for individual subjects (See 
Section 5.3), and events listed as study stopping rules (Section 3.5.2.1).  AEs and 
SAEs in the summary displays and listings will be coded using the MedDRA system 
organ classes and/or preferred terms.  Severity will be reported using NCI-CTCAE 


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grading criteria, with the exception of hypoglycemia and hyperglycemia.  
Relationship to study drug will be reported as per Section 8.4.2. 
The joint NIDDK and NIAID ACE/ITN/TrialNet DSMB will perform ongoing review 
of C-peptide data to monitor for unexpected declines, as follows:   
 
For adult subjects, mean 2-hour C-peptide AUC levels within 12 weeks of 
randomization will be reviewed on an ongoing basis in a masked fashion for 
all subjects.  Once > 30% of randomized subjects are shown to have a mean 
2-hour C-peptide AUC at 12 weeks that is ≥ 50% of their baseline mean 2-
hour C-peptide AUC, monitoring may be discontinued.  However, if 70% or 
more of the subjects show a > 50% drop in mean 2-hour C-peptide AUC by 
week 12, then the data will be unmasked by study statisticians, the percent of 
events in each arm will be computed, and the DSMB will be notified. 
 
For pediatric subjects, mean 2-hour C-peptide AUC levels within 12 weeks of 
randomization will be reviewed on an ongoing basis.  Once there are at least 
10 subjects with week 12 C-peptide data available in the active treatment 
group, the C-peptide data will be monitored using the following guideline.  If 
70% or more of the subjects in the active treatment group show a > 50% drop 
in mean 2-hour C-peptide AUC by week 12, then the DSMB will be notified 
of the overall C-peptide data from the study by age cohort and treatment 
assignment. 
For the end of study analyses, the proportions of subjects in each treatment arm 
experiencing safety endpoints of particular interest (see Section 3.3.2) will be 
compared using the Fisher’s Exact statistics.  
9.2.4 Medical History 
Medical history within the past 12 months—including the existence of current signs 
and symptoms—will be collected for each body system. 
9.2.5 Use of Medications 
All medications taken by or administered to study participants beginning 30 days 
before enrollment and continuing throughout the study will be collected.  All 
medications used will be coded according to the World Health Organization (WHO) 
drug dictionary.  The number and percentage of participants receiving prior and 
concomitant medications/therapies will be presented overall and by medication class. 
9.3  
INTERIM ANALYSES AND DATA REVIEW 
Per the protocol, an interim report of safety and metabolic data from adult participants 
was reviewed by the DSMB and FDA.  At least 30 adult subjects had week 12 C-
peptide data available for the report.  


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Prior to initiating the study in the pediatric age group (6-17 years old), adults (18-45 
years old) were randomized 2:1 to tocilizumab or placebo, respectively.  After 30 
adult participants completed 12 weeks of treatment, the DSMB and FDA reviewed the 
available data to weigh potential risks and benefits as well as prospect of benefit 
before opening the trial to pediatric participants.  The result of those reviews was to 
allow enrollment of children and adolescents 6-17 years old. 
Progress of the study will be monitored at least yearly throughout the trial by the 
DSMB.  The DSMB will review interim data on subject accrual, subject disposition, 
early C-peptide levels (baseline through week 12), safety (see Section 9.2.3), site 
performance, and data quality.  In addition, data will be reviewed by the DSMB when 
an event occurs that is of sufficient concern to the DAIT, NIAID medical monitor, 
ITN physician or protocol chairs to warrant review. 
 
Study-related AEs associated with stopping rules (Section 3.5.2) will be brought 
immediately to the attention of the DSMB.  
 
SAEs will be reported to the DSMB per Section 8.5 of the protocol. 
9.4  
SAMPLE SIZE  
The primary analysis of the primary endpoint will be conducted using data from the 
78 pediatric participants.  This target number was selected with the goal of detecting a 
clinically meaningful improvement of 39% for tocilizumab over placebo.  Power 
estimates associated with these targets are discussed below (see Table 8).  Prior to 
enrolling pediatric subjects, 55 adult participants were enrolled to support safety, 
mechanistic, and exploratory analyses. 
Control subject estimates used in these calculations are based on data from 104 
control pediatric subjects (aged 6 to 17 years) pooled from 5 new-onset T1DM 
studies.10,11,60-62  At baseline, the mean (SD) for the mean 2-hour C-peptide equaled 
0.70 (0.312) pmol/ml. Control group estimates for average change in the mean 2-hour 
C-peptide AUC from baseline to Month 12 and the associated root mean square error 
(RMSE) were derived from analysis of covariance models (ANCOVA) using baseline 
AUC as a covariate.  The average change in the mean 2-hour C-peptide AUC (RMSE) 
equaled -0.31 (0.221) pmol/ml (i.e. a 44% drop).  
Under the assumption that these computed values represent the parameters expected 
for the control group and using a 2:1 random assignment of tocilizumab versus 
placebo with a significance level of 5%, a study of 78 eligible pediatric subjects will 
have at least 80% power to detect a 39% improvement of tocilizumab over controls.  
That is, assuming a control group drop in mean 2-hour C-peptide AUC of 44% at 
Month 12 (i.e. 0.70 at baseline, 0.39 at Month 12) and a drop of 22% in the 
tocilizumab (i.e. 0.70 at baseline, 0.542 at Month 12), then power equals 80%.  The 
design has 89% power to detect a 44% improvement (i.e. groups differ by 0.17 
pmol/ml).  If the RMSE equals 0.25, which is the upper 90% confidence limit for 


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RMSE estimated from the control data, then power to detect a 44% improvement 
drops to 80%. 
Table 8. Summary of Power/Sample Size Results for Pediatric Participants 
Total 
N 
mean 
AUC at 
baseline 
Average 
change in 
mean AUC  
at Month 12: 
placebo 
Average 
change in 
mean AUC  
at Month 12: 
tocilizumab 
RMSE 
Difference 
between groups at 
Month 12 (% 
improvement of 
tocilizumab over 
placebo) 
% Power 
78 
0.70 
-0.310 
 (44% drop) 
-0.158 
(a 22% drop) 
0.22 
0.15 (39%) 
80% 
78 
0.70 
-0.310 
-0.138 
(a 20% drop) 
0.22 
0.17 (44%) 
89% 
78 
0.70 
-0.310 
-0.138 
0.25 
0.17 (44%) 
80% 
Note:  % improvement of tocilizumab over placebo is computed as: (AUC12_tocilizumab – 
AUC12_placebo) divided by AUC12_placebo. 
9.5 
PHARMACOKINETIC ANALYSES 
All PK analyses will use the actual sampling times.  PK parameters Cmax (µg/mL), tmax 
(h), Cmin (µg/mL), AUC 0–28 d (µgh/mL) (following the first and last infusions), and 
AUC 0-t or AUC 0-∞, will be estimated, as data permit.  In addition, terminal phase 
half-life (t1/2,z) and clearance (CL) may also be estimated from the data.  
PK data may be used to explore the exposure-response relationship in T1DM patients. 
9.6 
REPORTING DEVIATIONS FROM THE ORIGINAL STATISTICAL 
PLAN 
The principal features of both the study design and the plan for statistical data analysis 
are outlined in this protocol and in the statistical analysis plan (SAP).  Any change in 
these features requires either a protocol or an SAP amendment, which is subject to 
review by the DSMB, the study sponsor(s), and the appropriate Health Authorities.  
These changes will be described in the final study report as appropriate. 
10   
STUDY ADMINISTRATION 
10.1 
SPONSOR 
This clinical trial is conducted through the NIAID NIH-funded Cooperative 
Agreement awarded to the Benaroya Research Institute at Virginia Mason (Seattle, 
WA) (BRI) to support the Immune Tolerance Network (ITN), a collaborative network 
for clinical research.  The ITN provides financial support for the conduct of the 


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clinical trial to the clinical sites through subcontracts between the BRI and the clinical 
sites.  The NIAID NIH serves as the US Sponsor of the Investigational New Drug 
application (IND) for the Protocol and the Global Study Sponsor in Australia 
(represented by Pharmaceutical Product Development, Inc. (PPD) as Local Sponsor in 
Australia) and is responsible for all regulatory filings and safety reporting.  
10.2 
RELATIONSHIP WITH INDUSTRY 
Tocilizumab provided by the drug manufacturer (Genentech, Inc. a member of the 
Roche group, South San Francisco, CA) free of charge will be used in the United 
States for treatment of adult and pediatric participants, and Genentech, Inc. will also 
be providing additional financial support for the conduct of the study.  They will 
receive de-identified samples to conduct mechanistic studies solely as directed by ITN 
or the Global Study Sponsor (DAIT, NIAID, NIH).   
11   
ACCESS TO SOURCE DATA/DOCUMENTS 
The investigational sites participating in this study will maintain the highest degree of 
confidentiality permitted for the clinical and research information obtained from 
participants in this clinical trial.  Medical and research records should be maintained 
at each site in the strictest confidence.  However, as a part of the quality assurance and 
legal responsibilities of an investigation, the investigational sites must permit 
authorized representatives of the Global Study Sponsor (DAIT, NIAID, NIH); Local 
Sponsor – (PPD Australia), ITN, Genentech, Inc. (the study drug manufacturer), and 
the Health Authorities (US FDA, Australian TGA) to examine (and to copy when 
required by applicable law) clinical records for the purposes of quality assurance 
reviews, audits, and evaluation of the study safety and progress.  Unless required by 
the laws permitting copying of records, only the coded identity associated with 
documents or other participant data may be copied (and any personally identifying 
information must be obscured).  Authorized representatives as noted above are bound 
to maintain the strict confidentiality of medical and research information that may be 
linked to identified individuals.  The investigational sites will normally be notified in 
advance of auditing visits. 
12   
QUALITY CONTROL AND QUALITY ASSURANCE 
The investigator is required to keep accurate records to ensure that the conduct of the 
study is fully documented.  The investigator is required to ensure that all CRFs are 
completed for every participant entered in the trial. 
The Global Study Sponsor (DAIT, NIAID, NIH) is responsible for regular inspection 
of the conduct of the trial, for verifying adherence to the protocol, and for confirming 
the completeness, consistency, and accuracy of all documented data. 
The CRFs will be completed online via a web-based electronic data capture (EDC) 
system that has been validated and is compliant with Part 11 Title 21 of the U.S. Code 


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of Federal Regulations.  Study staff at the site will enter information into the 
electronic CRFs, and the data will be stored remotely at a central database.  Data 
quality will be ensured through the EDC system’s continuous monitoring of data and 
real-time detection and correction of errors.  All elements of data entry (i.e., time, 
date, verbatim text, and the name of the person performing the data entry) will be 
recorded in an electronic audit trail to allow all changes in the database to be 
monitored and maintained in accordance with federal regulations.  
13 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE 
13.1 
STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, current Good Clinical 
Practice (GCP) guidelines—adopting the principles of the Declaration of Helsinki—
and all applicable regulatory requirements. 
Prior to study initiation, the protocol and the informed consent documents will be 
reviewed and approved by the sponsor and an institutional review board or 
appropriate ethics review committee (IRB/EC).  Any amendments to the protocol or 
consent materials must also be approved by the Global Study Sponsor (DAIT, NIAID, 
NIH) and the sponsor representative (PPD Australia), the IRB/EC and submitted to 
the appropriate Health Authorities before they are implemented. 
13.2 
INFORMED CONSENT 
The informed consent form is a means of providing information about the trial to a 
prospective participant and allows for an informed decision about participation in the 
study.  All participants (or their legally acceptable representative) must read, sign, and 
date a consent form before participating in the study, taking the study drug, and/or 
undergoing any study-specific procedures.   
The informed consent form must be updated or revised whenever important new 
safety information is available, whenever the protocol is amended, and/or whenever 
any new information becomes available that may affect participation in the trial. 
A copy of the informed consent will be given to a prospective participant for review.  
The attending health care provider will review the consent and answer questions.  The 
participant will be informed that participation is voluntary and that he/she may 
withdraw from the study at any time, for any reason.  Assent will also be obtained 
from children with due consideration for age appropriate private conversations 
between study health care provider and participant. 


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13.3 
PRIVACY AND CONFIDENTIALITY 
A participant’s privacy and confidentiality will be respected throughout the study.  
Each participant will be assigned a sequential identification number.  This number, 
rather than the participant’s name, will be used to collect, store, and report participant 
information. 
14   
PUBLICATION POLICY 
The ITN policy on publication of study results will apply to this study.  Authorized 
participants may find details regarding the policy statement on the ITN internet 
website 
  As a jointly sponsored study with Type I 
Diabetes TrialNet, publications will also comply with TrialNet publications policy and 
procedures
 
15   
REFERENCES 
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Shrestha SS, Zhang P, Albright A, Imperatore G. Medical expenditures associated with 
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Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 
1990-2010. The New England Journal of Medicine. 2014;370(16):1514-1523. 
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Wood JR, Miller KM, Maahs DM, et al. Most youth with type 1 diabetes in the T1D Exchange 
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Beck RW, Tamborlane WV, Bergenstal RM, Miller KM, DuBose SN, Hall CA. The T1D 
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Weinstock RS, Xing D, Maahs DM, et al. Severe hypoglycemia and diabetic ketoacidosis in 
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Simmons JH, Chen V, Miller KM, et al. Differences in the management of type 1 diabetes 
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Trief PM, Xing D, Foster NC, et al. Depression in Adults in the T1D Exchange Clinic 
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Herold KC, Gitelman SE, Masharani U, et al. A single course of anti-CD3 monoclonal 
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and preservation of beta-cell function. N Engl J Med. 2009;361(22):2143-2152. 
11. 
Orban T, Bundy B, Becker DJ, et al. Co-stimulation modulation with abatacept in patients with 
recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 
2011;378(9789):412-419. 
12. 
Gallagher MP, Goland RS, Greenbaum CJ. Making progress: preserving beta cells in type 1 
diabetes. Ann N Y Acad Sci. 2011;1243:119-134. 
13. 
The effect of intensive treatment of diabetes on the development and progression of long-term 
complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications 
Trial Research Group. N Engl J Med. 1993;329(14):977-986. 
14. 
Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular 
disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-2653. 


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TCZ in New-onset T1D 
 
15. 
Patterson CC, Dahlquist GG, Gyurus E, Green A, Soltesz G. Incidence trends for childhood 
type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre 
prospective registration study. Lancet. 2009;373(9680):2027-2033. 
16. 
Davis A, et al. Residual C-Peptide in Patients 3-81 Years from Diagnosis of T1D: A T1D 
Exchange Study. General Poster Session presented at American Diabetes Association, 
Chicago, IL. 2013. 
17. 
Greenbaum CJ, Beam CA, Boulware D, et al. Fall in C-peptide during first 2 years from 
diagnosis: evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet 
data. Diabetes. 2012;61(8):2066-2073. 
18. 
Karjalainen J, Salmela P, Ilonen J, Surcel HM, Knip M. A comparison of childhood and adult 
type I diabetes mellitus. N Engl J Med. 1989;320(14):881-886. 
19. 
Bonfanti R, Bazzigaluppi E, Calori G, et al. Parameters associated with residual insulin 
secretion during the first year of disease in children and adolescents with Type 1 diabetes 
mellitus. Diabetic Medicine : A Journal of the British Diabetic Association. 1998;15(10):844-
850. 
20. 
Marzelli MJ, Mazaika PK, Barnea-Goraly N, et al. Neuroanatomical correlates of dysglycemia 
in young children with type 1 diabetes. Diabetes. 2014;63(1):343-353. 
21. 
Samson M, Audia S, Janikashvili N, et al. Brief report: inhibition of interleukin-6 function 
corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis and 
rheumatism. 2012;64(8):2499-2503. 
22. 
Liu SM, Lee DH, Sullivan JM, et al. Differential IL-21 signaling in APCs leads to disparate 
Th17 differentiation in diabetes-susceptible NOD and diabetes-resistant NOD.Idd3 mice. The 
Journal of clinical investigation. 2011;121(11):4303-4310. 
23. 
Campbell IL, Kay TW, Oxbrow L, Harrison LC. Essential role for interferon-gamma and 
interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice. The Journal of 
clinical investigation. 1991;87(2):739-742. 
24. 
Schneider A, Rieck M, Sanda S, Pihoker C, Greenbaum C, Buckner JH. The effector T cells of 
diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells. Journal of 
Immunology. 2008;181(10):7350-7355. 
25. 
Ferreira RC, Freitag DF, Cutler AJ, et al. Functional IL6R 358Ala allele impairs classical IL-6 
receptor signaling and influences risk of diverse inflammatory diseases. PLoS genetics. 
2013;9(4):e1003444. 
26. 
Arif S, Moore F, Marks K, et al. Peripheral and islet interleukin-17 pathway activation 
characterizes human autoimmune diabetes and promotes cytokine-mediated beta-cell death. 
Diabetes. 2011;60(8):2112-2119. 
27. 
Ferraro A, Socci C, Stabilini A, et al. Expansion of Th17 cells and functional defects in T 
regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes. 
Diabetes. 2011;60(11):2903-2913. 
28. 
Marwaha AK, Leung NJ, McMurchy AN, Levings MK. TH17 Cells in Autoimmunity and 
Immunodeficiency: Protective or Pathogenic? Front Immunol. 2012;3:129. 
29. 
Boe A, Baiocchi M, Carbonatto M, Papoian R, Serlupi-Crescenzi O. Interleukin 6 knock-out 
mice are resistant to antigen-induced experimental arthritis. Cytokine. 1999;11(12):1057-1064. 
30. 
Alonzi T, Fattori E, Lazzaro D, et al. Interleukin 6 is required for the development of collagen-
induced arthritis. J Exp Med. 1998;187(4):461-468. 
31. 
Sasai M, Saeki Y, Ohshima S, et al. Delayed onset and reduced severity of collagen-induced 
arthritis in interleukin-6-deficient mice. Arthritis Rheum. 1999;42(8):1635-1643. 
32. 
Takagi N, Mihara M, Moriya Y, et al. Blockage of interleukin-6 receptor ameliorates joint 
disease in murine collagen-induced arthritis. Arthritis Rheum. 1998;41(12):2117-2121. 
33. 
Atreya R, Mudter J, Finotto S, et al. Blockade of interleukin 6 trans signaling suppresses T-cell 
resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and 
experimental colitis in vivo. Nature medicine. 2000;6(5):583-588. 


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June 13, 2018 
TCZ in New-onset T1D 
 
34. 
Yamamoto M, Yoshizaki K, Kishimoto T, Ito H. IL-6 is required for the development of Th1 
cell-mediated murine colitis. J Immunol. 2000;164(9):4878-4882. 
35. 
Mudter J, Neurath MF. Il-6 signaling in inflammatory bowel disease: pathophysiological role 
and clinical relevance. Inflammatory Bowel Diseases. 2007;13(8):1016-1023. 
36. 
Firestein GS, Alvaro-Gracia JM, Maki R. Quantitative analysis of cytokine gene expression in 
rheumatoid arthritis. Journal of Immunology. 1990;144(9):3347-3353. 
37. 
Steiner G, Tohidast-Akrad M, Witzmann G, et al. Cytokine production by synovial T cells in 
rheumatoid arthritis. Rheumatology(Oxford). 1999;38(3):202-213. 
38. 
Hyams JS, Fitzgerald JE, Treem WR, Wyzga N, Kreutzer DL. Relationship of functional and 
antigenic interleukin 6 to disease activity in inflammatory bowel disease. Gastroenterology. 
1993;104(5):1285-1292. 
39. 
Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with 
tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-
controlled, randomised trial. Lancet. 2008;371(9617):987-997. 
40. 
Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves 
treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis 
factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann 
Rheum Dis. 2008;67(11):1516-1523. 
41. 
Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with 
systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, 
withdrawal phase III trial. Lancet. 2008;371(9617):998-1006. 
42. 
Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the interleukin-6 receptor. Annu 
Rev Pharmacol Toxicol. 2012;52:199-219. 
43. 
Schultz O, Oberhauser F, Saech J, et al. Effects of inhibition of interleukin-6 signalling on 
insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PloS 
one. 2010;5(12):e14328. 
44. 
Hingorani AD, Casas JP. The interleukin-6 receptor as a target for prevention of coronary heart 
disease: a mendelian randomisation analysis. Lancet. 2012;379(9822):1214-1224. 
45. 
Brunner H, Ruperto N, Zuber Z, et al. Efficacy and Safety of Tocilizumab in Patients with 
Polyarticular Juvenile Idiopathic Arthritis: Data From a Phase 3 Trial. Paper presented at: 
American College of Rheumatology2012; Washington, DC. 
46. 
De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic 
juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2385-2395. 
47. 
De Benedetti F, Brunner H, Ruperto N, et al. Catch-up growth during tocilizumab therapy for 
systemic juvenile idiopathic arthritis: results from a phase III trial. Arthritis Rheumatol. 
2015;67(3):840-848. 
48. 
Yokota S, Imagawa T, Mori M, et al. Longterm safety and effectiveness of the anti-interleukin 
6 receptor monoclonal antibody tocilizumab in patients with systemic juvenile idiopathic 
arthritis in Japan. J Rheumatol. 2014;41(4):759-767. 
49. 
Aoki C, Inaba Y, Choe H, et al. Discrepancy between clinical and radiological responses to 
tocilizumab treatment in patients with systemic-onset juvenile idiopathic arthritis. J 
Rheumatol. 2014;41(6):1171-1177. 
50. 
Brunner HI, Ruperto N, Zuber Z, et al. Efficacy and safety of tocilizumab in patients with 
polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-
blind withdrawal trial. Ann Rheum Dis. 2015;74(6):1110-1117. 
51. 
Roche Group Press Release, August 3, 2011.  
http://www.roche.com/media/store/releases/med-cor-2011-08-03.htm.  
52. 
Zgibor JC, Songer TJ, Kelsey SF, Drash AL, Orchard TJ. Influence of health care providers on 
the development of diabetes complications: long-term follow-up from the Pittsburgh 
Epidemiology of Diabetes Complications Study. Diabetes care. 2002;25(9):1584–1590. 
53. 
Nathan DM, Lachin J, Cleary P, et al. Intensive diabetes therapy and carotid intima-media 
thickness in type 1 diabetes mellitus. N Engl J Med. 2003;348(23):2294-2303. 


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Version 6.0 
June 13, 2018 
TCZ in New-onset T1D 
 
54. 
Nathan DM, Zinman B, Cleary PA, et al. Modern-day clinical course of type 1 diabetes 
mellitus after 30 years' duration: the diabetes control and complications trial/epidemiology of 
diabetes interventions and complications and Pittsburgh epidemiology of diabetes 
complications experience (1983-2005). Arch Intern Med. 2009;169(14):1307-1316. 
55. 
White NH, Sun W, Cleary PA, et al. Prolonged effect of intensive therapy on the risk of 
retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes 
Control and Complications Trial. Arch Ophthalmol. 2008;126(12):1707-1715. 
56. 
Effects of age, duration and treatment of insulin-dependent diabetes mellitus on residual beta-
cell function: observations during eligibility testing for the Diabetes Control and 
Complications Trial (DCCT). The DCCT Research Group. The Journal of clinical 
endocrinology and metabolism. 1987;65(1):30-36. 
57. 
Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the 
diabetes control and complications trial. A randomized, controlled trial. The Diabetes Control 
and Complications Trial Research Group. Ann Intern Med. 1998;128(7):517-523. 
58. 
Montanya E, Fernandez-Castaner M, Soler J. Improved metabolic control preserved beta-cell 
function two years after diagnosis of insulin-dependent diabetes mellitus. Diabetes 
Metabolism. 1997;23(4):314-319. 
59. 
Steffes MW, Sibley S, Jackson M, Thomas W. Beta-cell function and the development of 
diabetes-related complications in the diabetes control and complications trial. Diabetes care. 
2003;26(3):832-836. 
60. 
Wherrett DK, Bundy B, Becker DJ, et al. Antigen-based therapy with glutamic acid 
decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised 
double-blind trial. Lancet. 2011;378(9788):319-327. 
61. 
Gottlieb PA, Quinlan S, Krause-Steinrauf H, et al. Failure to preserve beta-cell function with 
mycophenolate mofetil and daclizumab combined therapy in patients with new- onset type 1 
diabetes. Diabetes care. 2010;33(4):826-832. 
62. 
Moran A, Bundy B, Becker DJ, et al. Interleukin-1 antagonism in type 1 diabetes of recent 
onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 
2013;381(9881):1905-1915. 
 
 


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APPENDIX 1. SCHEDULE OF EVENTS 1 
Phase of Trial 
Dosing 
Follow Up 
Unsch. 
Week 
-1 
0 
4 
8 
12 
16 
20 
24 
39 
52 
78 
104 
U 
Visit  
V-1 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V102 
U3 
GENERAL ASSESSMENTS 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
 
Eligibility criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
 
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
 
Medical history 
X 
  
  
  
  
  
  
  
  
  
  
  
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive 
physical 
examination  
X 
  
  
  
  
  
  
X4 
  
X 
  
X 
 
Directed physical 
examination 
  
X4 
X4 
X4 
X4 
X4 
X4 
  
X 
  
X 
  
X 
Additional vital 
signs (during 
infusion) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
CENTRAL LABORATORY ASSESSMENTS 
Serum Chemistries 
(includes liver 
panel and CRP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipid Panel 
X 
  
X 
  
  
  
  
X 
  
X 
X 
X 
X 
Viral load (PCR)5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infectious disease 
serology5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum ßHCG6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
QuantiFERON TB 
test7 
X 
  
  
  
 
  
  
 
  
 
 
 
 
LOCAL LABORATORY ASSESSMENTS 
Urine HCG6 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TB test7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
                                                          
 
1 With approval of study sponsor (DAIT, NIAID) and after informed consent, study procedures and/or sample collections may be 
performed at a location convenient for the participant as described in the Manual of Operations (MOP). 
2 Participants who terminate early from the study should complete all procedures listed for this visit (see sections 4.3 and 5.3). 
3 Assessments for unscheduled visits will be at the discretion of the principal investigator.  
4 Physical exam should be conducted prior to study drug administration. 
5 Serology will be repeated after screening for CMV and EBV if participants show clinical signs of infection; or if viral load 
testing shows that the EBV viral load is ≥ 10,000 copies per 106 PBMCs or ≥ 2,000 copies per mL of whole blood or the CMV 
viral load is ≥ 10,000 IU or copies per mL whole blood or plasma.   
6 Female participants with reproductive capacity will be monitored for pregnancy. 
7 Sites may perform a PPD skin test in place of a QuantiFERON TB test. 


Immune Tolerance Network 
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TCZ in New-onset T1D 
 
Phase of Trial 
Dosing 
Follow Up 
Unsch. 
Week 
-1 
0 
4 
8 
12 
16 
20 
24 
39 
52 
78 
104 
U 
Visit  
V-1 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V102 
U3 
DISEASE-SPECIFIC ASSESMENTS 
2-Hour MMTT8 
 
  
  
  
 X 
  
  
X 
X  
 
X 
 
 
4-Hour MMTT9 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
FSIVGTT10 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Diabetes-related 
autoantibodies  
X 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Glucometer 
Readings 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGM Readings11 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
Insulin use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hypoglycemic 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
STUDY DRUG ADMINISTRATION AND DRUG-RELATED ASSESSMENTS 
Study drug 
infusion 
  
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
 
Pharmacokinetics 
(PK)  
 
X12 
X13 
 
 
 
X12 
X13 
 
 
 
 
 
IL-6 and IL-6sR 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
Anti-TCZ 
antibodies14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MECHANISTIC ASSESSMENTS15 
Serum  
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X  
X 
 
Cellular Assays 
  
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
 
Gene Expression  
  
X 
  
  
X 
  
  
X 
  
X 
  
X 
 
DNA  
  
X 
  
  
X 
  
  
X 
  
X 
  
X 
 
 
                                                          
 
8 A 2-hour MMTT is to be performed at weeks 12, 24, 39, and 78.  MMTT should be performed prior to study drug infusion for 
weeks 12 and 24. 
9 A 4-hour MMTT is to be performed at weeks -1 (screening), 52, and 104 for subjects ≥12 years old (for subjects <12 years old, 
a 2-hour MMTT will be performed instead).   
10 FSIVGTT will be offered to subjects age  ≥15.  Week 0 visit may be done on the same day before the first infusion or within 2 
weeks prior to week 0.  Week 24 and week 52 visits will be done on a separate day than the MMTT visits; the window for these 
two visits are +/- 2 weeks of target date.   
11 Randomized participants will be invited to use a commercially available FDA approved CGM system and its components for a 
14 day period at weeks 0, 12, 24, 52, 78, and 104; the window for the CGM will be ± 3 weeks.  Participants may repeat the 14 
day period once during these widows if less than 10 days of data is evaluable from initial wearing.   
12 Pharmacokinetics (PK) samples for week 0 and week 20 will be collected before, 10 minutes after, and 7 (±3) days after the 
infusions (see section 6.6). 
13 Pharmacokinetics (PK) samples for week 4 and week 24 will be collected before the infusions (see section 6.6). 
14 Baseline anti-TCZ antibodies samples will be collected for all participants and will only be analyzed in event of specified 
adverse event (defined as anaphylaxis, serious hypersensitivity, or study treatment discontinuation due to hypersensitivity, 
whether serious or non-serious).  Additional anti-TCZ antibodies samples will be collected at the time of an adverse event and 
then again at least 6 or 8 weeks after the last TCZ dose. 
15 The schedule for these assessments may vary as appropriate.  At no time will the blood draw volume exceed what is allowable 
according to the subject’s age and body weight per country specific requirements.  

SAP_001.pdf: 
 
 
 
DAIT/Rho STATISTICAL ANALYSIS PLAN 
 Version 2.0  
 
 
ITN058AI EXTEND: Preserving Beta-Cell Function with Tocilizumab in 
New-onset Type 1 Diabetes 
VERSION: 
2.0 
DATE: 
02Oct2020 
SPONSOR: 
Division of Allergy, Immunology, and Transplantation 
National Institute of Allergy and Infectious Diseases – NIH 
 
 
 
 
 
 
PREPARED BY: 
Rho 
 
 
 
 
 
 
 


Immune Tolerance Network 
Statistical Analysis Plan 
Protocol No. ITN058AI 
02 October 2020 
 
 
Version: 2.0 
Page  2 of 30 
 
DAIT/Rho STATISTICAL ANALYSIS PLAN 
ACKNOWLEDGMENT AND SIGNATURE SHEET 
 
ITN058AI EXTEND: Preserving Beta-Cell Function with Tocilizumab in 
New-onset Type 1 Diabetes 
Approved: 
__________________________________ Date: 
_______________ 
 
 
 
 
 
Protocol Chair 
 
 
 
Approved: 
__________________________________ Date: 
_______________ 
 
 
 
 
 
NIAID Medical Monitor 
 
 
 
Approved: 
__________________________________ Date: 
_______________ 
 
 
 
 
 
ITN Clinical Trial Physician 
 
 
 
Approved: 
__________________________________ Date: 
_______________ 
 
 
 
 
 
Rho Scientist 
 
 
 
Approved: 
__________________________________ Date: 
_______________ 
 
 
 
 
 
Rho Statistician 
 
 
 
Approved: 
__________________________________ Date: 
_______________ 
 
 
 
 
 
Rho Statistician 
 
 
 
 
 


Immune Tolerance Network 
Statistical Analysis Plan 
Protocol No. ITN058AI 
02 October 2020 
 
 
Version: 2.0 
Page  3 of 30 
 
Table of Contents 
 
1. 
PROTOCOL SYNOPSIS ............................................................................................. 7 
2. 
INTRODUCTION ....................................................................................................... 10 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..................................... 10 
4. 
ANALYSIS SAMPLES .............................................................................................. 11 
5. 
STUDY SUBJECTS .................................................................................................. 12 
5.1. 
Disposition of Subjects ................................................................................... 12 
5.2. 
Demographic and Other Baseline Characteristics .......................................... 12 
6. 
STUDY OPERATIONS .............................................................................................. 13 
6.1. 
Major Protocol Deviations .............................................................................. 13 
6.2. 
Treatment Adherence ..................................................................................... 13 
7. 
ENDPOINT EVALUATION ........................................................................................ 13 
7.1. 
Overview of Efficacy Analysis Methods .......................................................... 13 
7.1.1. Timing of planned analyses ....................................................................... 13 
7.1.2. Multicenter Studies .................................................................................... 14 
7.1.3. Efficacy Endpoints ..................................................................................... 14 
7.2. 
Primary Endpoint ............................................................................................ 16 
7.2.1. Computation of the Primary Endpoint ........................................................ 16 
7.2.2. Primary Analysis of the Primary Endpoint .................................................. 17 
7.2.3. Sensitivity Analyses of the Primary Endpoint ............................................. 17 
7.3. 
Secondary Endpoints ..................................................................................... 17 
7.3.1. Secondary Analyses: C-peptide ................................................................. 17 
7.3.2. Secondary Analyses: Insulin ...................................................................... 18 
7.3.3. Secondary Analyses: HbA1c ..................................................................... 19 
7.3.4. Secondary Analyses: Major Hypoglycemic Events .................................... 20 
7.4. 
Exploratory Analyses ...................................................................................... 20 
7.4.1. Continuous Glucose Monitor (CGM) .......................................................... 20 
7.4.2. Frequently-sampled Intravenous Glucose Tolerance Test (FSIVGTT) ....... 21 
8. 
SAFETY EVALUATION ............................................................................................ 21 
8.1. 
Overview of Safety Analysis Methods ............................................................ 21 
8.2. 
Adverse Events .............................................................................................. 21 
8.3. 
Deaths and Serious Adverse Events and AEs of Special Interest................... 22 
8.4. 
Clinical Laboratory Evaluation ........................................................................ 23 
8.5. 
Vital Signs, Physical Findings, and Other Observations Related to Safety ..... 23 
8.5.1. Vital Signs ................................................................................................. 23 
8.5.2. Physical Examinations ............................................................................... 23 
8.5.3. Other Safety Measures .............................................................................. 24 
8.5.4. Pregnancy ................................................................................................. 24 
9. 
OTHER ANALYSES .................................................................................................. 25 
9.1. 
Use of Medications ......................................................................................... 25 
9.2. 
COVID-19 Listing ........................................................................................... 25 


Immune Tolerance Network 
Statistical Analysis Plan 
Protocol No. ITN058AI 
02 October 2020 
 
 
Version: 2.0 
Page  4 of 30 
 
10. 
INTERIM ANALYSES AND DATA MONITORING .................................................... 25 
11. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................... 26 
12. 
REFERENCES .......................................................................................................... 26 
13. 
APPENDICES ........................................................................................................... 27 
13.1. 
Study Flow Chart ............................................................................................ 27 
13.2. 
Schedule of Events ........................................................................................ 28 
14. 
ATTACHMENTS ....................................................................................................... 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Immune Tolerance Network 
Statistical Analysis Plan 
Protocol No. ITN058AI 
02 October 2020 
 
 
Version: 2.0 
Page  5 of 30 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
CDC 
Centers for Disease Control 
CGM 
Continuous Glucose Monitoring 
CMV 
Cytomegalovirus 
CRF 
Case report form 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events (version 4.0, May 28, 
2009) 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DKA 
Diabetic ketoacidosis 
DSMB 
Data and Safety Monitoring Board 
EBV 
Epstein-Barr virus 
FDA 
US Food and Drug Administration  
FSIVGTT 
Frequently-sampled intravenous glucose tolerance test 
HbA1c 
Glycosylated hemoglobin 
HDL 
High-density lipoprotein 
Hgb 
Hemoglobin 


Immune Tolerance Network 
Statistical Analysis Plan 
Protocol No. ITN058AI 
02 October 2020 
 
 
Version: 2.0 
Page  6 of 30 
 
IND 
Investigational new drug 
IRB 
Institutional review board 
ITN 
Immune Tolerance Network 
LDL 
Low-density lipoprotein 
LFT 
Liver Function Test 
mAUC 
Mean area under the curve 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMTT 
Mixed-meal tolerance test 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
RMSE 
Root Mean Square Error 
SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious adverse event 
T1D 
Type 1 diabetes 
T1DM 
Type 1 diabetes mellitus 
TCZ 
Tocilizumab 
ULN 
Upper limit of normal range 
WHO 
World Health Organization 
 
 


Immune Tolerance Network 
Statistical Analysis Plan 
Protocol No. ITN058AI 
02 October 2020 
 
 
Version: 2.0 
Page  7 of 30 
 
1. 
PROTOCOL SYNOPSIS 
Title 
Preserving Beta-Cell Function with Tocilizumab in New-onset Type 1 
Diabetes 
 
Short Title 
 
US IND 
TCZ in New-onset T1D 
 
117725 
 
Sponsor 
US and Global Study Sponsor: Division of Allergy, Immunology, and 
Transplantation (DAIT), National Institute of Allergy and Infectious Diseases 
(NIAID), National Institutes of Health (NIH), USA  
Local Sponsor in Australia: Pharmaceutical Product Development, Inc. (PPD) 
for NIAID, NIH  
 
Conducted by 
 
Immune Tolerance Network, an NIH grantee 
 
Protocol Co- 
Chairs  
 
 
 
Accrual Objective 
 
78 eligible pediatric subjects (6-17 years old) and 30-99 eligible adult subjects 
(18-45 years old) will be enrolled.  Only pediatric participants are eligible for 
randomization after May 15, 2017. 
 
Study Treatment 
 
Tocilizumab or placebo 
 
Study Design 
 
This trial will be conducted in the US and Australia as a multi-center, 
prospective, double-blind, placebo-controlled, 2:1 randomized, phase 2 
clinical trial for individuals with recent-onset T1DM aged 6−45 years, 
inclusive.  All groups will receive standard intensive diabetes management.  
The subjects will receive IV infusions of either 8.0 mg/kg (body weight 
≥30kg) or 10.0 mg/kg (body weight <30kg) tocilizumab or placebo every 4 
weeks for 24 weeks.  
 
A staggered enrollment plan is being used for this trial.  Prior to initiating the 
study in the pediatric age group (6-17 years old), adults (18-45 years old) were 
randomized 2:1 to tocilizumab or placebo, respectively.  After 30 adult 
participants completed 12 weeks of treatment, the DSMB and FDA reviewed 
the available data to weigh potential risks and benefits as well as prospect of 
benefit before opening the trial to pediatric participants.  The result of those 
reviews was to allow enrollment of children and adolescents 6-17 years old. 
 
Study Duration 
 
Total study duration will be approximately 4-5 years.   
 
The enrollment phase is expected to last up to 42 months.   
 
The study participation phase will be 104 weeks (2 years), which 
includes a treatment phase of 24 weeks and a follow-up phase of 80 
weeks. 
 
Primary Objective 
Determine whether tocilizumab will slow the progression of the autoimmune 
destruction of ß cells and lead to the preservation of C-peptide secretion in 
T1DM. 
Primary Endpoint 
MMTT-stimulated mean 2-hour C-peptide AUC at week 52.  
Secondary 
Endpoints 
Efficacy: 
1. MMTT-stimulated mean 2-hour C-peptide AUC at weeks 12, 24, and 
104. 


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2. MMTT-stimulated mean 2-hour C-peptide AUC assessed 
longitudinally at weeks 12, 24, 39, 52, 78, and 104. 
3. MMTT-stimulated peak and 4-hour C-peptide AUC at weeks 52 and 
104 for subjects ≥12 years old. 
4. Insulin use (U/kg/day) at weeks 12, 24, 39, 52, 78 and 104; HbA1c 
levels at weeks 12, 24, 39, 52, 78 and 104. 
5. Glycemic control. 
Safety: 
1. Rate of AEs related to infusion reactions and hypersensitivity. 
2. Frequency and severity of all AEs. 
Mechanistic: 
1. Determine the effect of TCZ on the ratio of Treg and Teff.  
 
Exploratory  
Endpoints 
 
Mechanistic: 
1. Determine effect of TCZ on measures of immune cell number and 
function such as: 
a. 
Changes in proportions and phenotype of Treg and Teff.  
b. Changes in sensitivity of Teff to suppression by Treg. 
c. 
Changes in circulating B cell compartment and activation 
state of innate immune cells including antigen presenting 
cells and NK cells. 
Metabolic: 
1. Explore the relationship between immune responses, metabolic 
outcomes and clinical variables. 
2. Explore the effect of TCZ on insulin sensitivity. 
 
Inclusion Criteria 
1. Male or female aged 6-45 years inclusive who meet the American 
Diabetes Association T1DM criteria. 
2. Diagnosis of T1DM within 100 days of enrollment (V0). 
3. Positive for at least one diabetes-related autoantibody, including but 
not limited to: 
a. 
Glutamate decarboxylase-65 (GAD-65); 
b. Insulin, if obtained within 10 days of the onset of exogenous 
insulin therapy; 
c. 
Insulinoma antigen-2 (IA-2); or 
d. Zinc transporter-8 (ZnT8). 
4. Peak stimulated C-peptide level ≥ 0.2 pmol/mL following a MMTT 
conducted at least 21 days from diagnosis and within 37 days of 
randomization (V0). 
5. Signed informed consent (and informed assent of minor, if 
applicable). 
 
Exclusion Criteria 
1. Severe reaction or anaphylaxis to human, humanized or murine 
monoclonal antibodies. 
2. History of malignancy or serious uncontrolled cardiovascular, 
nervous system, pulmonary, renal, or gastrointestinal disease, or 
significant dyslipidemia. 
3. Any history of recent serious bacterial, viral, fungal, or other 
opportunistic infections. 
4. Have serologic evidence of current or past HIV, Hepatitis B, or 
Hepatitis C. 
5. Positive tuberculin skin test (PPD) or QuantiFERON TB test, history 
of tuberculosis, or active TB infection. 
6. Active infection with EBV as defined by EBV viral load ≥ 10,000 
copies per 106 PBMCs or ≥ 2,000 copies per mL of whole blood. 
7. Active infection with CMV as defined by CMV viral load ≥ 10,000 
IU or copies per mL of whole blood or plasma. 


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8. Diagnosis of liver disease or elevated hepatic enzymes, as defined by 
ALT, AST, or both > 1.5 x the upper limit of age-determined normal 
(ULN) or total bilirubin > ULN. 
9. Current or prior treatment that is known to cause a significant, 
ongoing change in the course of T1D or immunologic status. 
10. Current or prior (within last 14 days of screening MMTT visit) use of 
drugs other than insulin to treat hyperglycemia (e.g. metformin, 
sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, 
DPP-IV inhibitors, or amylin). 
11. Current use of any medication known to significantly influence 
glucose tolerance (e.g., atypical antipsychotics, diphenylhydantoin, 
niacin). 
12. Any of the following hematologic abnormalities, confirmed by repeat 
tests: 
a. 
White blood count <3,000/μL or >14,000/μL;  
b. Lymphocyte count <500/μL; 
c. 
Platelet count <150,000 /μL; 
d. Hemoglobin <8.5 g/dL; or 
e. 
Neutrophil count <2,000 cells/μL. 
13. Females who are pregnant, lactating, or planning on pregnancy 
during the 2-year study period. 
14. History or diagnoses of other autoimmune diseases, with the 
exception of stable thyroid or celiac disease. 
15. History of alcohol, drug or chemical abuse within 1 year prior to 
screening (V-1). 
16. Any medical or psychological condition that in the opinion of the 
principal investigator would interfere with safe completion of the 
trial. 
17. Prior participation in a clinical trial that could increase risks 
associated with this clinical trial. 
18. Receipt of live vaccine (e.g. varicella, measles, mumps, rubella, cold-
attenuated intranasal influenza vaccine, bacillus Calmette-Guérin, 
and small pox) in the 6 weeks before randomization (V0). 
19. High lipid levels (fasting LDL cholesterol ≥160 mg/dL or 
≥4.1mmol/L). 
20. History of significant allergy (e.g. anaphylaxis) to milk or soy 
proteins. 
 
 
 


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2. 
INTRODUCTION 
This statistical analysis plan (SAP) only includes analyses related to the clinical endpoints 
outlined in the protocol.  Mechanistic analyses will be performed at the Immune Tolerance 
Network (ITN) and a separate analysis plan will be created to detail the planned analyses.  
Relevant clinical data from the study will be submitted to the ITN Biomarker and Discovery 
Research (BDR) and ITN Bioinformatics Groups (BiG) to augment the mechanistic analyses. 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following analysis and reporting conventions will be used: 
 
Categorical variables will be summarized using counts (n) and percentages (%) and will 
be presented in the form “n (%)”.   
 
Numeric variables will be summarized using n, mean, standard deviation (SD), median, 
minimum (min), maximum (max).  The min/max will be reported at the same level of 
significance as original data. The mean and median will be reported at one more 
significant digit than the precision of the data, and SD will be reported at two more 
significant digits than the precision of the data. 
 
The median will be reported as the average of the two middle numbers if the dataset 
contains an even number of observations. 
 
Test statistics including t and z test statistics will be reported to two decimal places.  
 
P-values will be reported to three decimal places if greater than or equal to 0.001.  If less 
than 0.001, the value will be reported as “<0.001.”  A p-value can be reported as “1.000” 
only if it is exactly 1.000 without rounding.  A p-value can be reported as “0.000” only if it 
is exactly 0.000 without rounding. 
If departures from these general conventions are present in the specific evaluations section of 
this SAP, then those conventions will take precedence over these general conventions.  


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4. 
ANALYSIS SAMPLES 
Modified Intent to Treat (mITT) sample will include all randomized participants who received 
any dose of study treatment.  The efficacy analyses will be based on the mITT sample 
according to the group to which the participants are assigned. 
 
Per protocol samples will be assessed for week 52 (PP1) and week 104 (PP2), and will 
include all participants in the mITT sample with no major protocol deviations that impact 
efficacy assessments, who have completed at least 5 of the 7 monthly infusions of study drug 
and who received at least 80% of the expected dose in each infusion, and who have the week 
52 and week 104 MMTT assessment for C-peptide, respectively. The reported major deviations 
will be reviewed during a masked data review after the last subject’s primary endpoint visit and 
the end of the study to determine which participants should be excluded from the per-protocol 
populations. 
 
Safety sample (SS) will be defined as all participants who received any degree of study 
treatment. Safety analyses will be based on actual treatment the participants receive. 
 
 
 


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5. 
STUDY SUBJECTS 
5.1. 
Disposition of Subjects  
The disposition of all randomized subjects will be summarized in tables by treatment group and 
age cohort (pediatric and adult) and listed. 
The numbers and percentages of subjects randomized, in each analysis sample, and 
completing the Week 52 and 104 visits will be presented. Additionally, reasons for early 
termination from the study and reasons for early discontinuation of study treatment will be 
presented.  
5.2. 
Demographic and Other Baseline Characteristics  
Summary descriptive statistics for baseline and demographic characteristics will be reported for 
the mITT sample. Data will be summarized by treatment group and age cohort. Demographic 
and baseline data will include age, race, ethnicity, gender, height, weight, 2-hour C-peptide 
mAUC, HbA1c, insulin use, and time from diagnosis of T1DM to randomization. BMI will also 
be presented; for adults BMI will be summarized and for pediatric subjects BMI z-scores based 
on CDC data will be summarized.1 Baseline (Visit 0) results will be presented; if a 
measurement is missing for a subject at baseline, the screening value (Visit -1) will be used. 
Some demographic and baseline characteristics will also be presented in data listings by 
treatment group and age cohort. Auto-antibody status at screening will be listed. 
 


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6. 
STUDY OPERATIONS 
6.1. 
Major Protocol Deviations 
Major protocol deviations will be listed by site and subject with information such as category of 
deviation, date of occurrence, details of the deviation, steps taken to address the deviation, 
whether the deviation resulted in an AE, whether the deviation met IRB reporting requirements, 
and whether the deviation led to the subject being excluded from the PP1 or PP2 samples. 
Additionally, protocol deviations will be summarized in a table and information summarized will 
include total number of deviations, number of site and subject level deviations, number of 
subjects with at least one protocol deviation, number of deviations in each category, number of 
deviations resulting in an AE, and number of deviations leading to exclusion from the PP1 or 
PP2 samples. 
6.2. 
Treatment Adherence 
The subjects will receive IV infusions of either 8.0 mg/kg (body weight ≥30kg) or 10.0 mg/kg 
(body weight <30kg) tocilizumab or placebo every 4 weeks for 24 weeks, for a total of up to 7 
infusions. Study drug is administered intravenously in the clinic over approximately 60 minutes. 
Since study drug is administered at the study visits, compliance is monitored by the medical 
staff and documented on the eCRF. 
Study drug infusion data will be listed for each subject with information such as number and % 
of infusions received, date of infusion, whether the infusion was withheld, reason the infusion 
was withheld, the prescribed dose, and the actual dose. A table and bar chart will be created to 
summarize the number of infusions received.  
7. 
ENDPOINT EVALUATION 
7.1. 
Overview of Efficacy Analysis Methods 
7.1.1. Timing of planned analyses 
Analysis of the primary endpoint (mean 2-hour C-peptide AUC in response to an MMTT at week 
52) as well as secondary analyses on secondary efficacy endpoints at week 52 will be 
performed after all randomized subjects have either completed the week 52 assessment or 
terminated from the study prematurely, and the primary and key secondary efficacy data in EDC 
for visits through week 52 are cleaned and locked. Note that some data are subject to change 
after week 52 and will not be locked at this time; these include data on adverse events, 
concomitant medications, protocol deviations, and study status. Analysis results and summary 
tables by treatment group will be created; subject level treatment assignments will not be 
released. 
Additional analyses on week 104 endpoints will be completed after all randomized subjects 
have either completed the week 104 assessment or terminated from the study. Data for visits 
through week 104 will be cleaned and locked prior to completing these additional analyses. In 
order to maintain the mask and ensure the validity of the assessments through week 104, 
randomized treatment assignments at the subject level will not be available until the last 
subject’s week 104 visit is completed and data have been locked.    


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7.1.2. Multicenter Studies 
Study subjects will be recruited from 19 study sites total (17 in the U.S. and 2 in Australia). Due 
to the large number of sites, study data will be analyzed as a whole, and no formal 
accommodation for site-to-site variation will be made.  
 
7.1.3. Efficacy Endpoints 
Table 7-2 
Table of Efficacy Endpoints and Analysis Methods 
Efficacy Endpoint 
Method  
Primary 
 
2-hour C-peptide mAUC at week 52 
(Sample: mITT) 
Primary Analysis: 
ANCOVA 
Covariates: treatment, screening C-peptide 
mAUC, age 
Sensitivity Analyses for the 
Primary Endpoint 
 
Primary endpoint without imputation 
Same as Primary 
Primary endpoint (Sample: PP1) 
Same as Primary 
Primary endpoint with multiple 
imputation 
Same as Primary 
MANCOVA results at week 52, 
using C-peptide data through week 
52 
Analysis: MANCOVA 
Covariates: treatment, categorical time, 
treatment*time, screening C-peptide 
mAUC, age 
 
 
Secondary¹ 
 
2-hour C-peptide mAUC at weeks 
24, 52, and 104 
Analysis: ANCOVA 
Covariates: treatment, screening C-peptide 
mAUC, age 
2-hour C-peptide mAUC at weeks 
12, 24, 39, 78, 104 
Analysis: MANCOVA 
Covariates: treatment, categorical time, 
treatment*time, screening C-peptide mAUC, 
age 
Longitudinal 2-hour C-peptide 
mAUC from screening to week 52 
Analysis: Mixed effects model 
Covariates: treatment, time, age, 
treatment*time, age*time 
Longitudinal 2-hour C-peptide 
mAUC from screening to week 104 
Analysis: Mixed effects model 
Covariates: treatment, time, age, 
treatment*time, age*time 
4-hour C-peptide mAUC at weeks 
24, 52, and 104 
Analysis: ANCOVA 
Covariates: treatment, screening C-peptide 
mAUC, age 
Peak 4-hour C-peptide at weeks 52 
and 104 
Analysis: ANCOVA 
Covariates: treatment, peak screening C- 
peptide, age 


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Efficacy Endpoint 
Method  
Average insulin use per kg at weeks 
24, 52, and 104. 
Analysis: ANCOVA 
Covariates: treatment, baseline insulin use, 
age 
Average insulin use per kg at weeks 
12, 24, 39, 52, 78 and 104 
Analysis: MANCOVA 
Covariates: treatment, categorical time, 
treatment*time, baseline insulin use, age 
Longitudinal average insulin use per 
kg from baseline to week 52  
Analysis: Mixed effects model 
Covariates: treatment, time, age, 
treatment*time, age*time 
Longitudinal average insulin use per 
kg from baseline to week 104 
Analysis: Mixed effects model 
Covariates: treatment, time, age, 
treatment*time, age*time 
HbA1c at weeks 24, 52, and 104 
Analysis: ANCOVA 
Covariates: treatment, baseline HbA1c, age 
HbA1c at weeks 12, 24, 39, 52, 78 
and 104 
Analysis: MANCOVA 
Covariates: treatment, categorical time, 
treatment*time, baseline HbA1c, age 
Longitudinal HbA1c from baseline to 
week 52  
Analysis: Mixed effects model 
Covariates: treatment, time, age, 
treatment*time, age*time 
Longitudinal HbA1c from baseline to 
week 104 
Analysis: Mixed effects model 
Covariates: treatment, time, age, 
treatment*time, age*time 
Proportion of subjects with a major 
hypoglycemic event at intervals 
baseline – week 52, week 52 – 
week 104, baseline – week 104 
Analysis: Fisher’s exact test 
 
¹ ANCOVA models for C-peptide, HbA1c, and insulin use at week 104 will be repeated with an additional 
covariate of “days week 104 visit out of window” for the pediatric and pooled cohorts. This sensitivity 
analysis will be done because some week 104 pediatric subject visits were delayed due to the COVID-19 
pandemic. 
 
The sample used for the primary analysis of the primary endpoint will be the mITT sample with 
pediatric subjects. Both the mITT sample and the appropriate PP sample (depending on if the 
analysis is at week 52 or 104) will be used for the ANCOVA analyses of 2-hour C-peptide 
mAUC at weeks 52 and 104. All other endpoints will be analyzed using the mITT sample only. 
Additionally, all primary and secondary endpoints will be analyzed using the pediatric cohort 
only, the adult cohort only, and the pooled data consisting of both adults and pediatric subjects.  
 


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7.2. 
Primary Endpoint 
The primary endpoint is the mean 2-hour C-peptide AUC in response to a mixed-meal 
tolerance test (MMTT) at Week 52 in pediatric subjects. 
 
7.2.1. Computation of the Primary Endpoint 
The MMTT will be done at screening and weeks 12, 24, 39, 52, 78, and 104. During the MMTT, 
C-peptide levels are measured at –10, 0, 15, 30, 60, 90, and 120 minutes for a 2 hour MMTT, 
and additionally at minutes 150, 180, 210, and 240 for a 4 hour MMTT. 
The 2-hour C-peptide mean AUC (mAUC) will be calculated using the trapezoidal rule over the 
2-hour period as shown in Formula 1. 
 
Formula 1: Calculating AUC: 
   
AUC = ∑
(tk+1 −tk) 
 (0.331 × f(tk+1)   +   0.331 × f(tk))
2
 
N
k=1
 , 
where t represents the time point (e.g. 𝑡0 = 0, 𝑡1 = 15, etc.), and f(t) is the C-peptide result at 
time t in conventional units of ng/mL.  For this computation, the “time 0” C-peptide value will be 
taken as the average of C-peptide values measured at time points -10 and 0 minutes. The AUC 
calculation will be based on the time points available from the MMTT. The actual time points 
(e.g. 14 minutes) will be used for calculating the AUC. If the actual time is not provided, the 
prescribed time point (e.g. 15 minutes) will be used. Results reported as less than the lower 
limit of detection will be imputed as ½ the lower limit of detection. Since C-peptide results are 
typically reported in the International System of Units (SI) unit, pmol/mL, f(t) in Formula 1 is 
multiplied by the conversion factor 0.331, which is based on the molecular weight of C-peptide 
(3020.29 g/mole). By stoichiometry, the derivation is as follows: 
1 𝑛𝑔𝑚𝐿
⁄
× 1 𝑛𝑚𝑜𝑙3020.29 𝑛𝑔× 1000 𝑝𝑚𝑜𝑙1 𝑛𝑚𝑜𝑙= 0.331 𝑝𝑚𝑜𝑙𝑚𝐿
⁄
⁄
⁄
 
Since the quantity (tk+1 −tk) is in minutes, the final unit for AUC is (pmol*min/mL).  The mean 
2-hour C-peptide AUC (mAUC) = AUC/120 minutes; the unit for mAUC is pmol/mL.  
 
Four-hour C-peptide mAUC will be calculated analogously. 
 
For the primary analysis only, for a participant who misses the entire week 52 MMTT 
assessment, the missing mAUC values will be imputed using the following approach for the 
primary analysis of the primary endpoint: 
 
If the subject’s last observed C-peptide measurements are less than the lower limit of 
detection (LLD) at all timepoints, the missing week 52 mAUC will be imputed to the 
previously calculated mAUC value, where ½ LLD was used at all timepoints to 
calculate the mAUC. 
 
If the subject’s last observed mAUC value was at week x and at least one C-peptide 
timepoint was greater than the LLD, then the missing mAUC at week 52 will be 
imputed using data from subjects in the same arm who had available mAUC values 
at both week x and week 52. Specifically, a linear regression line will be fit where 
week 52 mAUC values are regressed on mAUC values at week x (e.g. week 24) and 
age. In each arm a missing week 52 mAUC value will be imputed as the value 
predicted from the linear regression line. 


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7.2.2. Primary Analysis of the Primary Endpoint 
The primary analysis of the primary endpoint, change in MMTT-stimulated mean 2-hour C-
peptide AUC at week 52, will test the null hypothesis of “no treatment group difference” versus 
the two-sided alternative using only pediatric participants from the mITT sample. The 
hypothesis test and screening-adjusted treatment group estimates will be derived from an 
ANCOVA model with response of change in mean 2-hour C-peptide AUC at week 52 and fixed 
effects for treatment group, screening mean 2-hour C-peptide AUC, and age. If departures 
from model assumptions are apparent alternative approaches (such as using a generalized 
linear model or transformation) will be considered as secondary analyses. 
 
7.2.3. Sensitivity Analyses of the Primary Endpoint 
At a minimum, the following sensitivity analyses for the primary endpoint will be performed: 
 
An analysis analogous to the primary endpoint analysis using only mITT subjects 
with observed data at week 52 (i.e., without imputing any missing week 52 mAUC 
values). 
 
An analysis analogous to the primary endpoint analysis using the PP1 subjects. 
 
An analysis analogous to the primary endpoint analysis in the mITT sample using 
multiple imputation to fill in missing C-peptide mAUC values. 
 
Week 52 results from a MANCOVA model that uses data from screening through 
week 52 will be presented. More details on the MANCOVA model are in section 
7.3.1. 
P-values will be considered descriptive and no corrections for multiple tests are planned. 
7.3. 
Secondary Endpoints 
The null hypothesis proposes that there is no difference in the secondary endpoint (measured 
either as means or proportions) between study groups. The alternative hypothesis proposes 
the opposite; that there is a difference in the secondary endpoints between the treatment and 
control groups. All secondary inferential analyses are considered supportive; p-values will be 
presented without adjustment for multiple comparisons. All analyses will be performed on the 
mITT sample with available data. Additionally, the ANCOVA analyses of 2-hour C-peptide 
mAUC at weeks 52 and 104 will be performed on the corresponding PP samples. Analyses will 
be performed on pediatric subjects separately, adult subjects separately, and on all subjects 
pooled unless otherwise specified. 
The original laboratory that processed the C-peptide and HbA1c samples closed before all 
week 104 pediatric data were analyzed; adult data and pediatric data through the week 52 
primary endpoint were not affected. The data will be used as-is with no adjustment for lab. If 
indicated by the results, exploratory graphs and models will compare results from the 2 labs. 
 
7.3.1. Secondary Analyses: C-peptide 
 
Summary statistics for 2-hour and 4-hour C-peptide mAUC will be presented in tables 
and box plots by visit, treatment, and age cohort for the mITT population with available 
data. 


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 
2-hour and 4-hour C-peptide mAUC will also be listed by subject, treatment group, and 
cohort for all visits. 
 
Analyses similar to those described in Section 7.2.2 Primary analysis of the primary 
endpoint, will be performed for the following endpoints. All non-missing data will be used. 
o 2-hour C-peptide mAUC at weeks 24, 52, and 104 using the mITT sample. The 
week 52 analysis will additionally use the PP1 sample and the week 104 analysis 
will additionally use the PP2 sample. 
o 4-hour C-peptide mAUC at weeks 24, 52, and 104 using the mITT population 
with available data. 
o Peak 4-hour C-peptide at weeks 52 and 104 using the mITT population with 
available data. 
o For all the ANCOVA models at week 104, a sensitivity analysis will be done 
where an additional covariate will be added to the models for the pediatric and 
pooled cohorts only. The additional covariate added to these models will be a 
variable indicating the number of days the week 104 visit was out of window 
since some pediatric subjects had their week 104 visit delayed due to the 
COVID-19 pandemic. 
 
A MANCOVA-type mixed model will be created using 2-hour C-peptide mAUC as the 
response. This will coincide with the primary analysis at week 52 and will include 
assessments at screening and weeks 12, 24, 39, and 52. All subjects with at least 1 C-
peptide assessment will be included in the model. The model will include fixed effects for 
time point (categorical), treatment, and their interaction as well as screening C-peptide 
mAUC and age, as covariates. For fitting the model, an unstructured covariance matrix 
for repeated measures within subject is preferred, but alternative simplified matrices will 
be considered, if necessary. Mean estimates and confidence intervals at each week will 
be presented. 
 
Two mixed models will be created using 2-hour C-peptide mAUC as the response. The 
first will use C-peptide assessments at screening and weeks 12, 24, 39, and 52, and the 
second will additionally include C-peptide assessments at weeks 78 and 104. All 
subjects with at least 1 post-screening assessment will be included in these models. The 
model will include fixed effects for treatment, time, age, and interactions for 
treatment*time and age*time. The time variable will be continuous variable study week, 
which will be defined as the MMTT assessment date - treatment start date divided by 7. 
Piece-wise slopes will be considered for study week by graphing the means across time 
and checking for rises and falls in the 2-hour C-peptide mAUC. Random within-subject 
effects for intercept and slopes over time will be included assuming an unstructured 
covariance matrix. Transformations of data and alternative link functions will be 
considered if evidence of significant departures from model assumptions are apparent. 
Alternative covariance structures will be considered if models fail to converge. 
 
7.3.2. 
Secondary Analyses: Insulin 
The amount (basal, bolus, and total units) of insulin used per day will be reported for the five 
days prior to each study visit along with the primary route of administration (injection vs. pump). 
The subject’s weight will also be collected at every study visit. At each scheduled visit, average 
insulin use per kg will be computed as the average number of units per day (over the five-day 
period) divided by weight in kilograms. If a subject’s weight is not collected or is missing at the 
study visit where insulin use was collected, the subject’s weight for that visit will be derived as 
the average of the subject’s weight at the visits before and after the visit in question. 


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Analyses of total insulin use will use the mITT population with available data. 
 
Average insulin use per kg will be summarized by visit, treatment, and age cohort in a 
table and boxplot for each scheduled visit. Change from baseline summary statistics will 
also be included in the table. 
 
Insulin use and administration information will be listed by subject, treatment group, and 
age cohort. 
 
ANCOVA models adjusting for baseline insulin use and age will be used to analyze 
average insulin use per kg at weeks 24, 52, and 104. 
o For the ANCOVA models at week 104, a sensitivity analysis will be done where 
an additional covariate will be added to the models for the pediatric and pooled 
cohorts only. The additional covariate will be a variable indicating the number of 
days the week 104 visit was out of window since some pediatric subjects had 
their week 104 visit delayed due to the COVID-19 pandemic. 
 
A MANCOVA model will be created and an analysis analogous to that described in 
section 7.3.1 will be performed. The response will be average insulin use per kg and the 
covariates will be treatment, categorical time, age, baseline average insulin use per kg, 
and an interaction for treatment*time.  
 
Two mixed models will be created and an analysis analogous to that described in 
section 7.3.1 will be performed. The response will be average insulin use per kg and the 
covariates will be treatment, continuous time, age, and interactions for treatment*time 
and age*time. 
Basal insulin use will be analyzed separately. All analyses listed above will also be performed 
using basal insulin, using the pediatric cohort only. 
7.3.3. 
Secondary Analyses: HbA1c 
HbA1c will be collected at each study visit. Analyses of HbA1c will use the mITT population with 
available data. 
 
HbA1c will be summarized by visit, treatment, and age cohort in a table and boxplot for 
each scheduled visit. Change from baseline summary statistics will also be included in 
the table. 
 
HbA1c will be listed by subject, treatment group, and age cohort. 
 
ANCOVA models adjusting for baseline HbA1c and age will be used to analyze HbA1c 
at weeks 24, 52, and 104.  
o For the ANCOVA models at week 104, a sensitivity analysis will be done where 
an additional covariate will be added to the models for the pediatric and pooled 
cohorts only. The additional covariate will be a variable indicating the number of 
days the week 104 visit was out of window since some pediatric subjects had 
their week 104 visit delayed due to the COVID-19 pandemic. 
 
A MANCOVA model will be created and an analysis analogous to that described in 
section 7.3.1 will be performed. The response will be HbA1c and the covariates will be 
treatment, categorical time, age, baseline HbA1c, and an interaction for treatment*time. 


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 
Two mixed models will be created and an analysis analogous to that described in 
section 7.3.1 will be performed. The response will be HbA1c and the covariates will be 
treatment, continuous time, age, and interactions for treatment*time and age*time. 
 
7.3.4. 
Secondary Analyses: Major Hypoglycemic Events 
Information on major hypoglycemic events will be collected at each study visit and reported on 
the Adverse Events eCRF. Data from the glucometers will be reviewed for blood glucose 
values < 40 md/dL. For each subject, the number of major hypoglycemic events will be 
tabulated from baseline to week 52 and from week 52 to week 104 (or last study visit).  
 
For each time period (i.e. baseline-week 52, week 52-week 104/last study visit, and 
baseline-week 104/last study visit), the number and percent of subjects experiencing 
hypoglycemic events and the total number of events will be summarized by treatment 
and age cohort. The proportion of subjects experiencing a major hypoglycemic event 
during each time period (i.e. baseline-week 52, week 52-week 104, and baseline-week 
104) in each treatment group will be analyzed using Fisher’s exact test by age cohort. 
Additionally, Fisher’s exact test will be used on the combined cohorts. 
 
Major hypoglycemic event information will be listed. 
 
7.4. 
Exploratory Analyses 
7.4.1. 
Continuous Glucose Monitor (CGM) 
Subjects are given the option to use a continuous glucose monitor (CGM) for clinical care. 
CGMs were provided by the study, but a subject could also provide data from a personal CGM 
if they were not using the study CGM. CGM use was added to the protocol in v4.0 (May2016), 
which is after over half of adult subjects had been randomized. Therefore, many adult subjects 
will not have CGM data at baseline available. Furthermore, this is an optional device for all 
subjects. 
Sites were instructed to download CGM data from the 14 days prior to weeks 0, 12, 24, 52, 78, 
and 104; these contain readings of a subject’s glucose values in frequent intervals, typically 
every 5 minutes. In all summaries, CGM data collected the 14 days prior to the visit will be 
used. There must be data for at least 70% of the expected times over the 14 days or else the 
data will not be used in the tabular summaries. The following analyses will be performed using 
glucose data from the CGMs for the mITT population with available data: 
 
The mean, SD, coefficient of variation (CV), and proportion of time in key ranges (<54, 
54-<70, < 70 mg/dL, 70-180 mg/dL, >180 mg/dL) will be computed for each subject and 
visit. Each of these metrics will be summarized in a table by visit, treatment group, and 
age cohort. Additionally, time in key ranges will be summarized in box plots. 
 
Hypoglycemic events from CGM data will be defined using the following definition2: 
15 consecutive minutes with a sensor glucose value below 70 mg/dL. At least two 
sensor values <70 mg/dL that are 15 or more minutes apart plus no intervening values 
≥ 70 mg/dL are required to define an event. The end of the event will be defined as at 


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least two sensor values ≥ 70 mg/dL that are 15 or more minutes apart with no 
intervening values < 70 mg/dL. 
o Additionally, these hypoglycemic events will be separated into level 1 and level 
2 events3. Level 1 hypoglycemic events are those in a range of 54-<70 mg/dL 
and level 2 hypoglycemic events are those <54 mg/dL. 
 
 
All CGM data received will be used for the following analysis. A longitudinal poisson 
regression model will be created with number of CGM hypoglycemic events as the 
response and covariates of treatment and study visit. Additionally, a treatment by study 
visit interaction will be considered if these are indicated after reviewing graphs of the 
data and they improve the fit of the model. The amount of time of CGM data provided 
by each subject prior to each visit will be used as an offset. The offset will subtract out 
any time that is part of a hypoglycemic event. Separate models using data through 
week 52 and data through week 104 will be created and separate models will be 
created for each age cohort. 
 
7.4.2. 
Frequently-sampled Intravenous Glucose Tolerance Test (FSIVGTT) 
A frequently-sampled intravenous glucose tolerance test (FSIVGTT) will be offered to subjects 
age >= 15 at baseline, week 24, and week 52. Subjects may decline to participate in this aspect 
of the protocol. 
Minimal model analysis will be used to calculate insulin sensitivity from the FSIVGTT results. 
Summary descriptive statistics for insulin sensitivity will be reported. Of particular interest is the 
change in insulin sensitivity from baseline to Week 24 and from Week 24 to Week 52 in each 
treatment group. Additionally, the relationship between insulin sensitivity and C-peptide mAUC 
will be investigated and correlations will be provided if appropriate. 
8. 
SAFETY EVALUATION 
8.1. 
Overview of Safety Analysis Methods 
All safety analyses will be carried out using the safety sample defined in Section 4 unless 
otherwise noted.  Missing safety information will not be imputed.   
Safety will be analyzed in each treatment group through the reporting of adverse events (AEs), 
vital signs, physical examination findings, and changes in routine laboratory values. 
Listings will be prepared for all safety measurements. All listings will be sorted in order of age 
cohort, treatment, subject identifier (ID), and date/time of assessment. 
8.2. 
Adverse Events 
All AEs will be classified by system organ class (SOC) and preferred term, according to a 
standardized thesaurus (Medical Dictionary for Regulatory Activities [MedDRA] version 17.1).  
The severity of AEs will be classified using the National Cancer Institute’s (NCI’s) Common 
Toxicity Criteria for Adverse Events (CTCAE) version 4. Each AE is entered on the electronic 
case report form (eCRF) once at the highest severity. As such, no additional data manipulation 
is needed to identify events. 
AEs will be collected from screening (Visit -1) until the participant completes the study, or 
prematurely withdraws from the study. Treatment-emergent AEs will be identified as those with 
an onset date on or after the first dose of study medication. If the start of the AE in relation to 


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the start of study medication cannot be established (e.g., the start date for the AE is missing), 
then the AE will be considered treatment-emergent.  All data tabulations will be of only 
treatment-emergent events while non-treatment-emergent AEs will be listed separately.  
COVID-19 adverse events will be collected in the following manner: any cases of COVID-19 that 
have been confirmed by a positive PCR test or serology will be called “COVID-19 confirmed”. 
For other adverse events that are not confirmed cases of COVID-19, typical reporting 
procedures will be used to describe a diagnosis if available, or a list of symptoms if no diagnosis 
is available. A listing of confirmed COVID-19 cases will be created if any occur. 
An overall summary table by treatment group and age cohort will be developed to report the 
number of events and the number and percentage of subjects having at least one event in the 
following categories:  
 
All AEs 
 
AEs indicated as serious 
 
AEs of special interest 
 
AEs that were reported as being related (possibly, probably, or definitely related) to study drug 
 
AEs reported by severity 
 
Infections 
 
Infusion reactions  
 
AEs that lead to study drug discontinuation 
 
AEs with an outcome of death 
 
In addition, AEs classified by MedDRA SOC and preferred term will be summarized for each 
treatment group and overall for each of the following: 
 
All AEs 
 
AEs by maximum severity  
 
AEs by relationship to study drug 
Summary tables will present the total number of events as well as the number and percentage 
of subjects experiencing the events. If a subject experiences the same AE on multiple 
occasions, the event will be counted once for each occurrence when reporting the number of 
AEs. When reporting the number of subjects experiencing the events, a subject will only be 
counted once if they experience an event within the particular SOC or preferred term.  
Percentages will be based on the number of subjects in the safety population. 
In addition, the following specific AEs will be summarized by treatment group and overall. 
Fisher’s exact test will be used to compare proportions of subjects experiencing the events: 
 
Infusion reactions  
 
Hypersensitivity 
Additionally, an analysis analogous to section 7.3.4 (Major Hypoglycemic Events) will be done 
using the safety sample, if this sample differs from the mITT sample. 
 
8.3. 
Deaths and Serious Adverse Events and AEs of Special Interest 
Serious adverse events (SAEs) will be summarized in the overall AE summary table and also 
in a separate table by SOC and preferred term. A listing showing all SAEs and AEs of special 


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interest (AESIs) will be created. Separate displays listing and summarizing death, including 
time to death and cause of death, will be created if a death occurs. 
8.4. 
Clinical Laboratory Evaluation 
Clinical laboratory measurements include serum chemistry, hematology, lipid panel, EBV and 
CMV viral load, and urinalysis. Lab results are reported as AEs if they are symptomatic, or if 
they meet grade 3 or higher criteria if they are asymptomatic. Lab results are provided by a 
central lab, and sites are also able to enter local lab results when necessary. For results from 
local labs, results will be converted to standardized units where possible. Summary data by 
visit will only include central lab results, but listings will include all lab (central and local) results.  
For numeric laboratory results, descriptive statistics of laboratory values and the change from 
baseline of laboratory values will be presented for each treatment group and age cohort. For 
categorical laboratory results, the number and percentage of subjects reporting each result will 
be presented for each treatment group and age cohort. A listing will also be created that shows 
all lab results that met a dose modification criteria or Grade 3+ criteria.   
Laboratory data will be plotted to show patterns over time. Summary statistics including 25th 
percentile, median, and 75th percentile will be plotted for each visit by treatment group and age 
cohort. Lines connecting individual subject results from subjects with grade 3 or higher values 
will be overlaid on each figure. For lab results that are not gradable, results from subjects with 
values outside of 2*upper limit of normal or 0.5*lower limit of normal will be overlaid. Tests with 
qualitative results (such as “present” or “positive”) will not be plotted. 
 
8.5. 
Vital Signs, Physical Findings, and Other Observations Related to Safety 
8.5.1. Vital Signs 
Vital signs of height, weight, BMI, temperature, heart rate, respiratory rate, and blood pressure 
will be obtained at all visits. These vital signs and their grade per the NCI-CTCAE will be 
displayed in a listing. Also, vital signs will be summarized in a table by treatment group and age 
cohort for each scheduled visit. Regarding BMI, BMI z-scores based on CDC data will be 
presented for pediatric subjects only. 
Vital signs of BMI, temperature, heart rate, respiratory rate, and blood pressure will be plotted to 
show patterns over time. Summary statistics including 25th percentile, median, and 75th 
percentile will be plotted for each visit by treatment group and age cohort. Lines connecting 
individual subject results from subjects with grade 3 or higher values will be overlaid on each 
figure. 
Infusion vital signs will be displayed in a separate listing. 
 
8.5.2. Physical Examinations 
Either a comprehensive or directed physical examination will be performed at each scheduled 
study visit. A data listing will be provided for physical examination results and sorted by age 
cohort, treatment group, subject, and body system. A separate listing of only abnormal physical 
exam results will also be provided. 
 


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8.5.3. Other Safety Measures 
8.5.4. 
Pregnancy 
A listing of any pregnancies that occur in a study participant or their partner will be created. 
Information provided will include: whether the pregnancy was in the participant or their partner, 
outcome of the pregnancy, and description of any abnormalities. 
 


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9. 
OTHER ANALYSES 
9.1. 
Use of Medications 
Medications will be coded according to the World Health Organization (WHO) Drug Dictionary 
(version 2015.01). Medications reported on the CRF will be categorized for analysis as prior, 
concomitant, or after study treatment by comparing the medication start and stop dates with the 
first and last dose of study medication dates.  Prior medications will have both the medication 
start and stop dates prior to the first dose of study medication date.  After medications will have 
both the medication start and stop dates after the last dose of study medication date. All other 
medications will be classified as concomitant, indicating that use of the medication overlapped 
with use of the study medication by at least one day. 
The number and percentage of subjects receiving prior, concomitant, and after medications will 
be presented overall and by standardized medication name. When reporting the number of 
subjects receiving the medication, a subject will only be counted once if they ever received the 
medication within the medication class. Percentages will be based on the number of subjects in 
the safety population. Separate data listings will be provided for prior, concomitant, and after 
medications. 
9.2. 
COVID-19 Listing 
All visits affected by the COVID-19 pandemic and a description of how they were affected (e.g. 
out of window, visit done remotely) will be listed.   
10. 
INTERIM ANALYSES AND DATA MONITORING 
The progress of the study will be monitored by the Data and Safety Monitoring Board (DSMB).  
The joint NIAID/NIDDK TrialNet DSMB will be chartered to review safety data and to make 
recommendations regarding continuation, termination, or modification of the study. The DSMB 
will formally review the safety data at least yearly. 
In addition, safety data will be reviewed by the DSMB when an event occurs that is of sufficient 
concern to the National Institute of Allergy and Infectious Diseases (NIAID) medical monitor or 
protocol chair to warrant review, or when an event occurs that could contribute to a predefined 
stopping rule specified in the protocol.  
Findings will be reported to Institutional Review Boards (IRBs) and health authorities. 
The FDA put the IND on a partial clinical hold prior to initiating enrollment in the INT058AI 
EXTEND trial, and stated that a “prospect of benefit” needed to be shown in adult subjects 
before enrolling pediatric subjects. After at least 30 adults completed 12 weeks of treatment, 
the unblinded safety and efficacy data were reviewed in an interim report by the FDA and 
DSMB to evaluate prospect of benefit. The interim analysis was submitted to the DSMB in 
December 2017. The FDA removed the partial clinical hold and opened the trial to pediatric 
participants (children and adolescents 6-17 years old). The interim analysis plan is attached. 
The primary efficacy analysis in the pediatric cohort of 2-hour C-peptide mAUC in response to 
an MMTT at Week 52 will be performed upon completion of data collection and verification for 
all week 52 assessments (prior to end of study) (see section 7.1.1 for more details). 


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11. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
 
Regarding missing data for the primary analysis of C-peptide mAUC (section 7.2.1):  
o The protocol stated that if a subject’s mAUC was zero at the last observed visit, 
future mAUC values will be imputed to zero. However, when calculating mAUC, if 
C-peptide is less than the lower limit of detection (LLD), ½ the LLD is used to 
calculate mAUC. Therefore, the mAUC will never be exactly 0. Language in the 
SAP was updated to state that if at the last observed visit all of the subject’s C-
peptide measurements are less than the LLD, then the week 52 mAUC will be 
imputed to have this same value. 
o The method of imputing missing values if at least one C-peptide time point was 
greater than the LLD was updated. For the linear regression model to impute 
missing values, age was added as a covariate. Additionally, the SAP has clarified 
that this imputation method is only planned to be used for the primary analysis of 
the primary endpoint (i.e. ANCOVA analysis at week 52 for pediatric subjects). 
 
 
Under secondary endpoints for C-peptide, HbA1c, and insulin use: a MANCOVA model 
will be created instead of creating separate ANCOVA models at all specified study 
weeks. ANCOVA models will still be created for weeks 24, 52, and 104. 
 
 
Updates to secondary endpoints for C-peptide, HbA1c, and insulin use due to the 
COVID-19 pandemic: 
o Sensitivity analyses for the ANCOVA models through week 104 were added. 
These analyses will include an additional covariate of “days week 104 visit out of 
window” for the pediatric and pooled cohorts. 
o The MANCOVA-type models will no longer be created for visits through week 
104. Only a longitudinal model using continuous study week will be created for 
data through week 104. 
12. 
REFERENCES
1 A SAS Program for the 2000 CDC Growth Charts (ages 0 to <20 years); 
https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm 
2 Russell SJ, Beck RW. Designs Considerations for Artificial Pancreas Pivotal Studies. Diabetes Care. 
2016;39:1161-1167. 
3 Danne T, Nimri R, Battelino T. International Consensus on Use of Continuous Glucose Monitoring. 
Diabetes Care. 2017;40(12):1631-1640. 
                                               


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C-Peptide / 
Safety Review of 
Week 12 data*
≥10
Follow-up at 
weeks 39 & 52
Follow-up at 
weeks 78 & 104
At least 30 adult 
participants age 18-45 
(Randomly assign 2:1)
≥20
Tocilizumab 8 mg/kg (weight ≥ 30kg) 
IV every 4 weeks for 24 weeks
Placebo IV every 4 weeks for 24 weeks
26
Follow-up at 
weeks 39 & 52
Follow-up at 
weeks 39 & 52
Follow-up at 
weeks 78 & 104
Follow-up at 
weeks 78 & 104
Enroll 78 pediatric 
participants age 6-17 
(Randomly assign 2:1)
52
Tocilizumab 8 mg/kg (weight ≥ 30kg) 
or 10 mg/kg (weight < 30 kg) 
IV every 4 weeks for 24 weeks
Placebo IV every 4 weeks for 24 weeks
Follow-up at 
weeks 39 & 52
Follow-up at 
weeks 78 & 104
Assess Primary Endpoint at week 52:  C-peptide AUC in response to 2-hr MMTT
Assess Secondary Endpoints at week 104

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13.2. Schedule of Events 
SCHEDULE OF EVENTS1 
Phase of Trial 
Dosing 
Follow Up 
Unsch. 
Week 
-1 
0 
4 
8 
12 
16 
20 
24 
39 
52 
78 
104 
U 
Visit  
V-1 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V102 
U3 
GENERAL ASSESSMENTS 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
 
Eligibility criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
 
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
 
Medical history 
X 
  
  
  
  
  
  
  
  
  
  
  
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive 
physical 
examination  
X 
  
  
  
  
  
  
X4 
  
X 
  
X 
 
Directed physical 
examination 
  
X4 
X4 
X4 
X4 
X4 
X4 
  
X 
  
X 
  
X 
Additional vital 
signs (during 
infusion) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
CENTRAL LABORATORY ASSESSMENTS 
Serum Chemistries 
(includes liver 
panel and CRP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipid Panel 
X 
  
X 
  
  
  
  
X 
  
X 
X 
X 
X 
Viral load (PCR)5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infectious disease 
serology5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum ßHCG6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
QuantiFERON TB 
test7 
X 
  
  
  
 
  
  
 
  
 
 
 
 
LOCAL LABORATORY ASSESSMENTS 
Urine HCG6 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TB test7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
DISEASE-SPECIFIC ASSESMENTS 
2-Hour MMTT8 
 
  
  
  
 X 
  
  
X 
X  
 
X 
 
 
                                               
1 With approval of study sponsor (DAIT, NIAID) and after informed consent, study procedures and/or sample collections may be performed at a 
location convenient for the participant as described in the Manual of Operations (MOP). 
2 Participants who terminate early from the study should complete all procedures listed for this visit (see sections 4.3 and 5.3). 
3 Assessments for unscheduled visits will be at the discretion of the principal investigator.  
4 Physical exam should be conducted prior to study drug administration. 
5 Serology will be repeated after screening for CMV and EBV if participants show clinical signs of infection; or if viral load testing shows that 
the EBV viral load is ≥ 10,000 copies per 106 PBMCs or ≥ 2,000 copies per mL of whole blood or the CMV viral load is ≥ 10,000 IU or copies 
per mL whole blood or plasma.   
6 Female participants with reproductive capacity will be monitored for pregnancy. 
7 Sites may perform a PPD skin test in place of a QuantiFERON TB test. 
8 A 2-hour MMTT is to be performed at weeks 12, 24, 39, and 78.  MMTT should be performed prior to study drug infusion for weeks 12 and 24. 


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Phase of Trial 
Dosing 
Follow Up 
Unsch. 
Week 
-1 
0 
4 
8 
12 
16 
20 
24 
39 
52 
78 
104 
U 
Visit  
V-1 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V102 
U3 
4-Hour MMTT9 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
FSIVGTT10 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Diabetes-related 
autoantibodies  
X 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Glucometer 
Readings 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGM Readings11 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
Insulin use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hypoglycemic 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
STUDY DRUG ADMINISTRATION AND DRUG-RELATED ASSESSMENTS 
Study drug 
infusion 
  
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
 
Pharmacokinetics 
(PK)  
 
X12 
X13 
 
 
 
X12 
X13 
 
 
 
 
 
IL-6 and IL-6sR 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
Anti-TCZ 
antibodies14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MECHANISTIC ASSESSMENTS15 
Serum  
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X  
X 
 
Cellular Assays 
  
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
 
Gene Expression  
  
X 
  
  
X 
  
  
X 
  
X 
  
X 
 
DNA  
  
X 
  
  
X 
  
  
X 
  
X 
  
X 
 
 
 
 
 
 
                                               
9 A 4-hour MMTT is to be performed at weeks -1 (screening), 52, and 104 for subjects ≥12 years old (for subjects <12 years old, a 2-hour MMTT 
will be performed instead).   
10 FSIVGTT will be offered to subjects age  ≥15.  Week 0 visit may be done on the same day before the first infusion or within 2 weeks prior to 
week 0.  Week 24 and week 52 visits will be done on a separate day than the MMTT visits; the window for these two visits are +/- 2 weeks of 
target date.   
11 Randomized participants will be invited to use a commercially available FDA approved CGM system and its components for a 14 day period at 
weeks 0, 12, 24, 52, 78, and 104; the window for the CGM will be ± 3 weeks.  Participants may repeat the 14 day period once during these 
widows if less than 10 days of data is evaluable from initial wearing.   
12 Pharmacokinetics (PK) samples for week 0 and week 20 will be collected before, 10 minutes after, and 7 (±3) days after the infusions (see 
section Error! Reference source not found.). 
13 Pharmacokinetics (PK) samples for week 4 and week 24 will be collected before the infusions (see section Error! Reference source not f
ound.). 
14 Baseline anti-TCZ antibodies samples will be collected for all participants and will only be analyzed in event of specified adverse event 
(defined as anaphylaxis, serious hypersensitivity, or study treatment discontinuation due to hypersensitivity, whether serious or non-serious).  
Additional anti-TCZ antibodies samples will be collected at the time of an adverse event and then again at least 6 or 8 weeks after the last TCZ 
dose. 
15 The schedule for these assessments may vary as appropriate.  At no time will the blood draw volume exceed what is allowable according to the 
subject’s age and body weight per country specific requirements.  


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14. 
ATTACHMENTS 
 
Attachment 1: Interim Analysis Plan