Conditions: Diabetes Mellitus, Type I Diabetes Mellitus, Insulin-Dependent, 1 Type 1 Diabetes Mellitus Insulin-Dependent Diabetes Mellitus 1 IDDM
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 67
Healthy volunteers: yes

Brief summary:
Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of insulin-producing ß cells. Although exogenous insulin is widely available, it is not possible for affected individuals to consistently achieve euglycemia with current technology, and thus they are at risk for devastating long-term complications. This phase II study is designed to evaluate the safety and efficacy of imatinib mesylate as a novel therapy for new-onset T1DM. Imatinib is a first-in-class tyrosine kinase inhibitor.

This study will explore the potential role of short-term therapy with imatinib to induce tolerance and possibly lead to a durable long-term remission of T1DM.

Detailed description:
Eligible participants will be randomized to receive either imatinib mesylate or placebo daily.

All participants randomized into this study will be seen at a study site for a follow-up evaluation, 2 weeks and 4 weeks after randomization, and every month month thereafter for the first year. Participants will come in for a visit ever 6 months for the second year.

At the study visits, participants will undergo assessments of their insulin production, immunologic status, and overall health. Subjects will be followed until the conclusion of the study. The trial is expected to last approximately 2-4 years or until the required amount of information is gathered.

Arms:
arm 1: 400 mg imatinib given once daily basis. arm 2: Placebo given once daily basis.

Interventions: intervention 1: Imatinib Mesylate intervention 2: Placebo (For imatinib mesylate)
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Safety and Efficacy of Imatinib for 
Preserving Beta-cell Function in New-
onset Type 1 Diabetes Mellitus 
 
Version:8.0 
 
August 23, 2016 
 
IND # 117,644 
 
 
 
 
 
 
 Sponsored by the Juvenile Diabetes Research Foundation International (JDRF). 


 
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SAFETY AND EFFICACY OF IMATINIB FOR PRESERVING BETA-CELL 
FUNCTION IN NEW-ONSET TYPE 1 DIABETES MELLITUS 
Version 7.0 ( January 29, 2016) 
IND # 117,644 
Protocol Co-Chair 
 
Jeffrey A. Bluestone, Ph.D. 
Professor of Medicine, Pathology, 
Microbiology & Immunology  
University of California, San Francisco 
Campus Box 0540 
513 Parnassus Avenue 
San Francisco, CA 94143 
Tel: 415-514-1683        Fax: 415-564-5813 
Email:  jbluest@diabetes.ucsf.edu 
Protocol Co-Chair 
 
Stephen E. Gitelman, MD 
Professor of Clinical Pediatrics 
Department of Pediatrics 
University of California, San Francisco 
Room S-679, Campus Box 0434 
513 Parnassus Avenue 
San Francisco, CA 94143 
Tel:  415-476-3748     Fax:  415-476-8214 
Email: sgitelma@peds.ucsf.edu 
 
This clinical study is supported by JDRF and conducted by the University of California, San 
Francisco. 
This document is confidential. It is provided for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent 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 the study sponsor unless it is necessary to obtain informed 
consent from potential study participants. 
 


 
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Protocol Approval 
 
 
Trial ID:   
Protocol Version:   8.0 
Dated:    August 23, 2016 
IND # 117,644 
Protocol Chairs: Jeffrey Bluestone, PhD and Stephen 
Gitelman, MD 
 
Title:     Safety and Efficacy of Imatinib for Preserving ß-cell Function in New-onset Type 1 
Diabetes Mellitus 
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 study 
sponsor. 
 
 
 
__________________________________________                                      
Principal Investigator                        (Print)                    
 
 
__________________________________________                        _________________ 
Principal Investigator                        (Sign)                                    Date 
 


 
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Synopsis 
Title 
Safety and Efficacy of Imatinib for Preserving Beta-cell Function in New-onset 
Type 1 Diabetes Mellitus 
IND Sponsor 
Stephen E. Gitelman, MD 
Conducted by 
University of California, San Francisco 
Protocol Chairs  
Jeffrey Bluestone, Ph.D. and Stephen E. Gitelman, MD 
Accrual Objective 
Total of 66 participants will be enrolled during ~78 to 104 weeks.  
Study Duration 
Each participant will be in the study for 104 weeks. 
Study Design 
 
 
 
 
 
 
The study will be a multicenter, two-arm, double-blind, placebo-controlled, 2:1 
randomly assigned, phase II clinical trial for individuals with recent-onset T1DM. 
The randomly assigned participants will receive either a 6-month course of 
imatinib or matching placebo tablets over a period of 26 weeks. Both treatment 
and placebo groups will undergo identical procedures and will be followed for 
104 weeks. The primary endpoint, 2-hour C-peptide AUC in response to a mixed-
meal tolerance test (MMTT), will be measured at 52 weeks. Safety, diabetes 
control, ß-cell function, and immune function will be assessed for 104 weeks. 
Both groups will receive intensive diabetes management. During the follow-up 
phase, participants will undergo serial clinical and immunologic assessments over 
the 104 week study period, and possible mechanisms of imatinib action will be 
assessed. 
Initial enrollment will be for subjects ages 18-45, with the goal to lower the age 
down to 12 upon acceptable safety review and prospect of benefit for this initial 
older cohort.  When the first 10 enrollees have completed their week 26 
assessment, the safety data will be reviewed by a subcommittee that includes the 
protocol chairs, the medical monitor, the clinical trial physician, and the DSMB. 
If the review concludes that significant safety concerns have been identified, then 
no further enrollment will occur pending further data review and evaluation by 
the DSMB.  If the DSMB decides that the study may proceed then the FDA will 
be notified of study progress and determine if further age restriction is necessary, 
or if enrollment may be opened for subjects down to age 12.  After the first 21 
subjects have completed 6 months, a further safety review will occur for the 
DSMB. Additionally, an interim efficacy assessment will occur for the DSMB 
and FDA.  The FDA will again be apprised of study progress, with further 
consideration for lowering the age of enrollees to 12, if this has not occurred 
earlier.  If and when the age is lowered, an identical review procedure will be 
followed when the first 10 pediatric participants (ages 12-17) have completed 
their week 26 assessment. If the review is satisfactory, then enrollment will 
continue for subjects ages 12-45 until the study is fully enrolled. Adult 
participants will receive a single 400 mg tablet of imatinib or the corresponding 
placebo tablet daily for the first 6 months. Pediatric patients will receive 260 
mg/m2/day or 400 mg/day (whichever is smaller) of active drug or placebo.  
Primary Endpoint 
MMTT--stimulated 2 hour C-peptide AUC at week 52. 
Secondary 
Endpoints 
Efficacy: 
 
MMTT-stimulated peak and 4 hour C-peptide AUC at weeks 52 and 104.  


 
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 
MMTT-stimulated 2 hour C-peptide AUC at week 104. 
 
MMTT-stimulated 2-hour C-peptide AUC assessed longitudinally at weeks 
-4, 13, 26, 52, 78, and 104. 
 
Insulin use in units per kilogram body weight per day at weeks 52 and 104.  
 
Major hypoglycemic events, as defined in section 8.2.1, occurring from 
randomization at weeks 0, 52 and 104. 
 
HbA1c levels at weeks 52 and 104 
 
Safety: 
 
The rate of the following AEs in participants receiving imatinib or placebo:  
1. Myelosuppression. 
2. Gastrointestinal disorders. 
3. Infections. 
4. Hepatotoxicity. 
5. Cardiac toxicity and edema. 
6. Cutaneous reactions. 
7. Muscle cramps, bone pain, arthralgias. 
8. Fluid retention or peripheral edema. 
9. Bone metabolism and growth abnormalities (not including bone 
turnover markers). 
10. Frequency and severity of all AEs in participants receiving imatinib or 
placebo.  
 
Mechanistic:   
Immunological assessments described in section 7 will be compared with clinical 
outcomes to determine whether there is evidence of immune tolerance to 
diabetes-associated autoantigens. 
 
Metabolic: 
 
Proportion of patients who are exogenous insulin-free (for at least 3 months) 
with an HbA1C ≤ 6.5% at weeks 52 and 104 in each treatment arm. 
 
Proportion of subjects who achieve a persistent reduction (for at least 3 
months) in insulin dose to < 0.5 units/kg at weeks 52 and 104 in each 
treatment arm. 
 
Effects on insulin resistance as derived from data on MMTT, and change in 
adiponectin, proinsulin levels (and proinsulin/c-peptide ratio), and glucagon 
levels.  
 
Inclusion Criteria 
 
Males and females age 12–45 years of age who meet the ADA standard 
T1DM criteria1. Positive for at least one islet cell autoantibody.  
 
Diagnosis of T1DM within 100 days of Visit 0.  
 
Peak stimulated C-peptide level >0.2 pmol/mL following an MMTT at 
screening. 
 
Participants of childbearing age who are sexually active must agree to 
effective contraception. For females, these contraceptive measures must be 
maintained throughout the study; for males these measures must be followed 
for a minimum of 3 months after discontinuation of imatinib therapy. 


 
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Exclusion Criteria 
 
Prior history of any significant cardiac disease such as congestive heart 
failure, myocardial infarction, arrhythmia, or structural defects or suspicion 
thereof. 
 
Leukopenia (<3,000 leukocytes/µL), neutropenia (<1,500 neutrophils/µL), 
or thrombocytopenia (<125,000 platelets/µL).  
 
Low Hemoglobin (baseline hemoglobin below lower limit of normal) 
 
Prior history of anaphylaxis, angioedema or serious cutaneous drug reactions 
 
Any sign of significant chronic active infection (e.g., hepatitis, tuberculosis, 
EBV, CMV, or toxoplasmosis), or screening laboratory evidence consistent 
with a significant chronic active infection (such as positive for HIV, 
PPD/IGRA, or HBSAg). Significant acute infections must be resolved before 
treatment may commence, e.g., acute respiratory tract, urinary tract, or 
gastrointestinal tract infections. 
 
Anticipated ongoing use of diabetes medications other than insulin that affect 
glucose homeostasis, such as metformin, sulfonylureas, thiazolidinediones, 
glucagon-like peptide 1 (GLP-1) mimetics, dipeptidyl peptidase IV (DPP-
IV) inhibitors, or amylin. 
 
Prior or current treatment that is known to cause a significant, ongoing 
change in the course of T1DM or immunologic status, including high-dose 
inhaled, extensive topical or systemic glucocorticoids.  
 
Evidence of liver dysfunction, with alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) >2.0 times the upper limit of normal 
persistent for 1 week or greater.  
 
Evidence of renal insufficiency as indicated by serum creatinine > 1.2 times 
the upper limit of normal and confirmed in a repeat test at least one week 
apart. Evidence of clinically significant metabolic bone disease (except 
adequately treated rickets). 
 
Females who are pregnant at the time of screening or unwilling to defer 
pregnancy during the 24-month study period.  
 
Prior treatment with imatinib or related tyrosine kinase inhibitor. 
 
Unable to avoid medications that affect CYP3A4: either inducers that may 
decrease imatinib levels, or inhibitors that may increase drug concentrations. 
(Refer to section 1.5.1.12 for a complete list of inducers and inhibitors.) 
 
Height standard deviation score ≥2 standard deviations below mean 
(participants of growing-age potential). 
 
Any sign of QT prolongation on Visit -1  noted on ECG (> 450 ms in males 
and > 470 ms in females). 
 
Known coagulation disorders or use of anticoagulants. 
 
Current and anticipated on-going treatment with drugs that may increase or 
decrease imatinib plasma concentrations (CYP3A4 family inhibitors or 
inducers) or drugs that may have their plasma concentration altered by 
imatinib (drugs metabolized by CYP3A4/5 and CYP2D6). 
 
Any condition that, in the investigator’s opinion, may compromise study 
participation or may confound the interpretation of the study results. 
 
 


 
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TABLE OF CONTENTS 
ABBREVIATIONS ................................................................................................................................ 10 
1. 
BACKGROUND AND RATIONALE......................................................................................... 13 
1.1 
OVERVIEW ............................................................................................................................... 13 
1.2 
BACKGROUND ........................................................................................................................ 13 
1.3 
SCIENTIFIC RATIONALE ....................................................................................................... 14 
1.4 
PRECLINICAL AND CLINICAL EXPERIENCE .................................................................... 16 
1.4.1 
Preclinical Studies ..................................................................................................................... 16 
1.4.2 
Clinical Studies in Patients with Diabetes ................................................................................. 19 
1.5 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS FOR HUMAN 
PARTICIPANTS ....................................................................................................................... 20 
1.5.1 
Risks .......................................................................................................................................... 20 
1.5.2 
Potential Risks and Benefits of Trial Participation for Children ............................................... 24 
1.5.3 
Potential Benefits ...................................................................................................................... 25 
2. 
OBJECTIVES ............................................................................................................................... 26 
2.1 
PRIMARY OBJECTIVE ............................................................................................................ 26 
2.2 
SECONDARY OBJECTIVES ................................................................................................... 26 
3. 
STUDY DESIGN ........................................................................................................................... 27 
3.1 
DESCRIPTION .......................................................................................................................... 27 
3.2 
STUDY DURATION AND PACE OF ENROLLMENT .......................................................... 29 
3.3 
STUDY ENDPOINTS ................................................................................................................ 29 
3.3.1 
Primary Endpoint ...................................................................................................................... 29 
3.3.2 
Secondary Endpoints ................................................................................................................. 29 
3.3.3 
Exploratory Endpoints ............................................................................................................... 30 
3.4 
RATIONALE FOR CLINICAL TRIAL DESIGN ..................................................................... 30 
3.5 
RATIONALE FOR SELECTION OF DRUG, ROUTE, DOSE, AND REGIMEN .................. 31 
3.6 
MEASURES TO MINIMIZE BIAS ........................................................................................... 32 
3.7 
STOPPING RULES ................................................................................................................... 32 
3.7.1 
Ongoing Review ........................................................................................................................ 32 
3.7.2 
Stopping Rule Guidance ............................................................................................................ 33 
4. 
ELIGIBILITY ............................................................................................................................... 34 
4.1 
INCLUSION CRITERIA ........................................................................................................... 34 
4.2 
EXCLUSION CRITERIA .......................................................................................................... 34 


 
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4.3 
PREMATURE TERMINATION OF A PARTICIPANT FROM THE STUDY ....................... 35 
5. 
STUDY MEDICATIONS ............................................................................................................. 36 
5.1 
INVESTIGATIONAL MEDICATION ...................................................................................... 36 
5.1.1 
Formulation and Packaging ....................................................................................................... 36 
5.1.2 
Dosage, Preparation, and Administration .................................................................................. 36 
5.1.3 
Recommended Storage Conditions ........................................................................................... 36 
5.2 
DOSE MODIFICATION AND MANAGEMENT OF ADVERSE EVENTS ........................... 36 
5.2.1 
Gastrointestinal Reactions ......................................................................................................... 37 
5.2.2 
Muscle Cramps, Bone Pain, Arthralgias.................................................................................... 38 
5.2.3 
Edema ........................................................................................................................................ 38 
5.2.4 
Cutaneous Reactions ................................................................................................................. 39 
5.2.5 
Hepatotoxicity ........................................................................................................................... 40 
5.2.6 
Myelosuppression ...................................................................................................................... 40 
5.2.7 
Infectious Disease Risk ............................................................................................................. 40 
5.2.8 
Pregnancy .................................................................................................................................. 41 
5.2.9 
Bone and Mineral Metabolism .................................................................................................. 42 
5.3 
DISCONTINUATION OF STUDY MEDICATION IN AN INDIVIDUAL PARTICIPANT .. 43 
5.4 
CONCOMITANT MEDICATIONS .......................................................................................... 43 
5.4.1 
Prohibited Medications .............................................................................................................. 43 
5.5 
DRUG ACCOUNTABILITY ..................................................................................................... 43 
5.6 
ASSESSMENT OF COMPLIANCE WITH STUDY MEDICATION ...................................... 44 
6. 
STUDY PROCEDURES .............................................................................................................. 44 
6.1 
INTENSIVE DIABETES MANAGEMENT ............................................................................. 44 
6.2 
RANDOM ASSIGNMENT, BLINDING, AND UNBLINDING .............................................. 45 
6.2.1 
Random Assignment ................................................................................................................. 45 
6.2.2 
Blinding ..................................................................................................................................... 45 
6.2.3 
Unblinding ................................................................................................................................. 45 
6.3 
VISIT WINDOWS ..................................................................................................................... 46 
6.3.1 
Scheduled Visits ........................................................................................................................ 46 
6.4 
GENERAL ASSESSMENTS ..................................................................................................... 46 
6.5 
LABORATORY ASSESSMENTS ............................................................................................ 46 
6.6 
DISEASE-SPECIFIC ASSESSMENTS ..................................................................................... 47 
6.7 
BONE AND MINERAL METABOLISM ASSESSMENTS ..................................................... 47 


 
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6.8 
GROWTH RATE ASSESSMENTS FOR GROWING-AGE PARTICIPANTS (AS DEFINED 
IN SECTION 5.2.9) ................................................................................................................... 47 
7. 
MECHANISTIC ASSAYS ........................................................................................................... 47 
7.1 
RATIONALE ............................................................................................................................. 47 
7.2 
RETENTION OF SAMPLES ..................................................................................................... 48 
7.3 
FROZEN PBMCS ...................................................................................................................... 49 
7.3.1 
Functional Cell-Based Assays ................................................................................................... 49 
7.3.2 
FLOW CYTOMETRY PANEL STAINING ............................................................................ 50 
7.3.3 
GENOMICS AND PROTEOMICS .......................................................................................... 50 
7.4 
SERUM ASSAYS ...................................................................................................................... 51 
7.4.1 
SERUM-AUTOANTIBODY ANALYSES .............................................................................. 51 
7.4.2 
SERUM ARCHIVE................................................................................................................... 51 
7.5 
WHOLE BLOOD-GENE-EXPRESSION PROFILING ............................................................ 52 
7.6 
WHOLE BLOOD DNA-HLA GENOTYPES ............................................................................ 52 
7.7 
CHANGE IN BETA CELL FUNCTION ................................................................................... 52 
8. 
ADVERSE EVENTS .................................................................................................................... 53 
8.1        ADVERSE EVENT DEFINITION ............................................................................................ 53 
8.1.1     Adverse Event ............................................................................................................................. 53 
8.1.2     Serious Adverse Event ................................................................................................................ 53 
8.1.3     Unexpected Adverse Event ......................................................................................................... 54 
8.1.4     Grading Event Severity ............................................................................................................... 54 
8.1.5   Attribution Definitions ......................................................................................................... 54 
8.2        ADVERSE EVENT REPORTING AND MONITORING ........................................................ 55 
8.2.1   Reporting Pregnancy ................................................................................................... 56 
9. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN .............................................. 56 
9.1 
PRIMARY OUTCOME AND ANALYSES .............................................................................. 56 
9.2 
SECONDARY OUTCOMES AND ANALYSES ...................................................................... 57 
9.4 
SAMPLE SIZE AND POWER CALCULATIONS ................................................................... 58 
9.5 
INTERIM MONITORING PLAN.............................................................................................. 59 
10. ACCESS TO SOURCE DATA/DOCUMENTS ......................................................................... 60 
11. QUALITY CONTROL AND QUALITY ASSURANCE .......................................................... 61 
12. ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE .............................................................................................................................. 61 


 
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12.1 
STATEMENT OF COMPLIANCE ........................................................................................... 61 
12.2 
INFORMED CONSENT ............................................................................................................ 61 
12.3 
PRIVACY AND CONFIDENTIALITY .................................................................................... 62 
13. PUBLICATION POLICY ............................................................................................................ 62 
14. REFERENCES .............................................................................................................................. 63 
 
LIST OF APPENDICES 
APPENDIX 1. SCHEDULE OF EVENTS.............................................................................................. 73 
APPENDIX 2. PROCEDURES FOR PERFORMING THE MIXED-MEAL TOLERANCE TEST ..... 76 
 
 
LIST OF FIGURES 
Figure 1. Induction of diabetes remission ................................................................................................ 17 
Figure 2. Long-lasting remission of diabetic NOD mice. ........................................................................ 18 
Figure 3. Study Schema 
……………………………………………………………………………...28 
 
 
 


 
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 ABBREVIATIONS  
ADA 
American Diabetes Association 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCA 
Anti-neutrophil cytoplasmic autoantibodies-associated vasculitis  
AST 
Aspartate aminotransferase 
ATG 
Antithymocyte globulin 
ATP 
Adenotriphosphate 
AUC 
Area under the curve 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CML 
Chronic myeloid leukemia 
CMV 
Cytomegalovirus  
CRF 
Case report form 
CRO 
Contract research organization 
CTL 
Cytotoxic T cell 
CY 
Cyclophosphamide 
DB/DB 
Diabetic dyslipidemia 
DC 
Dendritic cell 
DCCT 
Diabetes Control and Complications Trial  
DPT-1 
Diabetes Prevention Trial of Type I Diabetes 
DSMB 
Data and Safety Monitoring Board 
EBV 
Epstein-Barr virus 
EDIC 
Epidemiology of Diabetes Interventions and Complications Study 
FDA 
US Food and Drug Administration  
GAD 
Glutamate decarboxylase 


 
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GCP 
Good clinical practice 
GIST    
Gastrointestinal stromal tumors 
HbA1C 
Hemoglobin A1C 
HBSAg 
Hepatitis B surface antigen 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IFNγ 
Interferon gamma 
IGRA 
Interferon Gamma Release Assay 
IRB 
Institutional Review Board 
ITN 
Immune Tolerance Network 
LFTs 
Liver function tests 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major histocompatibility complex 
MMTT 
Mixed-meal tolerance test 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NFkB 
Nuclear factor kappa B 
NK 
Natural killer cell 
NKT 
Natural killer T cell 
NOD 
Nonobese diabetic 
PCR 
Polymerase chain reaction 
PDGFR 
Platelet-derived growth factor receptor  
PPD 
Purified protein derivative test 
PTH 
Parathyroid hormone 
IGRP 
Islet-specific glucose-6-phosphatase catalytic subunit related protein  
SAE 
Serious adverse event 


 
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SAP 
Statistical analysis plan 
 STZ 
Streptozotocin 
T1DM 
Type 1 diabetes mellitus 
TCR 
T cell receptor 
TK 
Tyrosine blocking 
TNFα 
Tumor necrosis factor alpha 
Tregs 
Regulatory T cells 
TUNEL + 
TdT-mediated dLJTP-biotin nick-end-labeling positive cells 
WHO 
World Health Organization 
 
 


 
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1. 
BACKGROUND AND RATIONALE 
1.1 
OVERVIEW 
Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of insulin-
producing ß cells. Although exogenous insulin is widely available, it is not possible for 
affected individuals to consistently achieve euglycemia with current technology, and 
thus they are at risk for devastating long-term complications. This phase II study is 
designed to evaluate the safety and efficacy of imatinib mesylate as a novel therapy for 
new-onset T1DM. Imatinib is a first–in-class tyrosine kinase inhibitor that has had 
remarkable success as a therapy for several cancers, including chronic myelogenous 
leukemia (CML). In preclinical studies, imatinib is one of only a handful of agents that 
has been shown in the nonobese diabetes (NOD) mouse to induce a durable remission 
of new-onset diabetes without continuous ongoing therapy. These findings have been 
extended to the clinical arena, where case reports and smaller studies have shown 
positive effects of imatinib in patients with autoimmune conditions and for type 2 
diabetes. Although the mechanism whereby this agent functions has not been fully 
elucidated, the possibility that short-term therapy with imatinib can induce tolerance 
and lead to a durable long-term remission makes it a very attractive potential therapy 
for new-onset T1DM. 
1.2 
BACKGROUND 
T1DM is a chronic autoimmune disease in which insulin-producing ß cells are 
completely destroyed, resulting in a lifelong dependence on exogenous insulin.2-5  
Current management of T1DM is not optimal. To avoid long-term complications, 
affected individuals must maintain near-normal glycemic control by frequent glucose 
monitoring, and by taking multiple daily doses of insulin (via injection or pump) 
adjusted for variations in diet and exercise.6  Such strict glycemic control is rarely 
achieved with current T1DM management, and can result in recurrent severe 
hypoglycemia. Thus, it is not possible to fully mimic ß-cell function with current 
therapies, and there are currently no established treatments that can prevent the 
autoimmune ß-cell destruction before diagnosis.  
After clinical presentation, affected individuals often enter a “honeymoon,” or 
remission, phase when they are still able to make substantial amounts of insulin.7-9 
Nevertheless, endogenous insulin secretion continues to slowly deteriorate over the first 
few years of disease, eventually becoming undetectable and necessitating increasing 
reliance on exogenous insulin. Past studies have demonstrated that preservation of even 
modest endogenous insulin secretion dramatically improves metabolic control of 
T1DM, which, in turn, is associated with reduced morbidity and mortality.10-13  The 
ultimate goal of this study is to identify a means of blocking further autoimmune 
destruction of the ß cells, retaining endogenous insulin secretion and thereby improving 
metabolic control. Eventually, such a therapy may also be used at an even earlier stage 
to prevent T1DM.  


 
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T1DM occurs in those who have an underlying genetic risk in synergy with one or more 
environmental exposures.2-5  Increasing evidence suggests that both adaptive and innate 
immunity may play a role.14,15  This process is mediated by the progression of a 
destructive T-cell infiltration of insulin-producing ß cells. Both CD4+ and CD8+ T cells 
cooperate in the initiation of insulitis and ß-cell destruction occurs via cytokines (e.g., 
IFNγ, TNFα) and direct cytolytic activity.2-4,16-19  Development and propagation of this 
autoimmune destruction is not solely dependent on T cells, with potential roles ascribed 
to B cells, NK cells, NKT cells, dendritic cells (DCs), and macrophages.3,20-24 For 
example, B-cell depletion  in the NOD mouse has been shown to prevent and reverse 
diabetes,25,26 and in a recent clinical trial subjects with new-onset T1DM treated with 
rituximab, an anti-CD20 monoclonal antibody (mAb) had slower decline in ß-cell loss 
than controls.27  Thus, agents affecting more than one cell type of the immune system, 
or with effects on inflammation, may have greater efficacy in modulating the 
autoimmune response.  
Several promising studies have shown that interventions shortly after the time of T1DM 
diagnosis can alter the natural course of the honeymoon phase. Cyclosporine prolongs 
endogenous insulin secretion, and some participants experienced complete 
remission.28,29 However, long-term treatment is limited by toxicity and by the transience 
of the effects.30-32  More targeted therapy with a short course of two different 
preparations of an anti-CD3 mAb have been promising, although not all respond, and 
the effects wane over time.33-36  Recent new onset trials with other agents have had 
mixed results, with some agents causing acute worsening in beta cell function (IL-2 
with rapamycin, Long et al, Diabetes, in press), some showing no effect37,38  and some 
showing initial preservation but without sustained effects.27,39  Despite these early 
successes, there is ongoing concern with the durability of the response, and the safety 
and tolerability of the agents offered. Thus, there is currently no established, acceptable 
immunotherapy for new-onset T1DM to preserve endogenous insulin secretion. The 
limitations may stem from the need for a multi-faceted approach to interdicting the 
autoimmune response, using either a combination of drugs40, or a drug that affects 
multiple different cell types or pathways. The drug proposed in this trial, imatinib, falls 
into this latter camp. 
1.3 
SCIENTIFIC RATIONALE 
Imatinib mesylate, also known as CGP57148B, STI-571, Gleevec®, or Glivec® 
(Novartis), is a specific inhibitor of the Abl protein tyrosine kinases (v-Abl, Bcr-Abl, 
and c-Abl).41-43  Imatinib’s activity against cells bearing the Bcr-Abl translocation, 
created by the Philadelphia chromosome abnormality, has resulted in a unique niche for 
the treatment of CML.44-48  However, imatinib’s activity is not limited to Abl, as it also 
inhibits other constitutively activated tyrosine kinases, such as platelet-derived growth 
factor receptor (PDGFR), c-kit (CD117), macrophage colony stimulating factor 
receptor (c-fms), Abl-related gene, and Lck, whereas other kinases are probably not 
affected.49-54  The inhibitory activity against c-kit and PDGFR has resulted in imatinib’s 


 
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expanded use as a therapy for gastrointestinal stromal tumors (GIST), 55 eosinophilic 
disorders, 56 and systemic mast cell disease.56,57 
In addition to its remarkable effect on malignant cells, imatinib has been shown to affect 
various arms of the immune system. Imatinib treatment may lead to impaired T-cell 
function and decreased DC number in CML patients,58-60 although other studies have 
not documented such effects.61-64  Similarly, while some reports suggest that imatinib 
enhances DC function both in human65,66 and mouse,67-69 other studies demonstrated 
that relatively high concentrations (1–5 µM) inhibited the development and the 
functional 
capacity 
of 
human 
or 
mouse 
DCs,70-72 
as 
well 
as 
human 
monocytes/macrophages.73-75  Several investigators have now shown that imatinib has 
significant anti-inflammatory properties in different mouse models. Wolf et al 
demonstrated in a mouse model of acute hepatic inflammation that imatinib inhibits 
tumor necrosis factor-alpha (TNFα) production in macrophages, conferring a strong 
anti-inflammatory effect.76  Dietz et al noted that delayed-type hypersensitivity was 
reduced in mice treated with imatinib.77  
Most recently, it has become clear that imatinib can function as an effective 
immunosuppressive drug. In preclinical studies, imatinib efficiently prevents disease 
and induces remission of mouse and rat models of autoimmune arthritis.78-80  Moreover, 
this drug inhibits collagen-induced arthritis effectively in mice and blocks PDGFR-
mediated signaling in synovial fibroblasts obtained from rheumatoid arthritis patients.81-
83  Efficacy in rheumatoid arthritis may also result from effects on mast cells: treatment 
of rheumatoid synovia in vitro with imatinib inhibits c-kit and induces apoptosis of mast 
cells.84  Furthermore, imatinib treatment ameliorates autoimmune nephritis in two 
mouse models of lupus.85,86  In studies of scleroderma, Soria et al reported that imatinib 
limits dermal fibroblast proliferation.87  Imatinib reduces production of extracellular 
matrix and suppresses experimental fibrosis,88 and prevents fibrosis in different models 
of systemic sclerosis.87  Imatinib inhibits PDGF-mediated responses related to the 
development of intimal hyperplasia in giant cell arteritis.89  Imatinib may also be 
effective in the treatment of anti-neutrophil cytoplasmic autoantibodies-associated 
vasculitis (ANCA), based on inhibition of T-cell activation in samples taken from 
affected patients.90  
These findings have been extended to the clinical arena, where a few case reports and a 
phase I study show positive effects of imatinib in patients with rheumatoid arthritis.79,91-
94  Early studies suggest that imatinib may have a role in the treatment of systemic 
sclerosis.95-98  Imatinib therapy improved cutaneous sclerosis and inflammatory 
manifestations of the disease in 3 treated subjects, 96,97 and a specific gene signature of 
imatinib response has been identified.96  Seven trials evaluating the efficacy of Imatinib 
in systemic sclerosis are now posted on the clinicaltrials.gov web site. Imatinib was also 
effective and well tolerated in a phase I study of 6 patients with active 
spondyloarthritis.99  There is a case report of a patient with bullous pemphigoid, the 
most frequent autoimmune blistering dermatosis, with eosinophilia and a deletion 


 
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consistent with hypereosinophilic syndrome, who responded to imatinib therapy.100  
There is one case report of imatinib therapy inducing a long-standing remission in a 
patient with Crohn’s disease, without significant side effects.101  Imatinib has also been 
reported to treat intractable psoriasis in a patient who was receiving this agent for 
GIST.102  
Although the aforementioned studies suggest efficacy, the mechanisms are unclear. In 
vitro studies suggest that imatinib may have direct effects on T-cell, B-cell, and antigen-
presenting cell signaling and function. Imatinib can inhibit human T-cell proliferation 
in vitro without inducing apoptosis,77,103,104 and analysis of the TCR-induced signaling 
cascade revealed a reduced phosphorylation of ZAP-70, LAT, Lck and ERK1/2, as well 
as reduced levels of activated NFκB.77,104,105  Interestingly, Lck has been suggested as a 
direct target of imatinib.52  Studies in the mouse demonstrated that imatinib could impair 
memory CD8+ T-cell development but did not affect the primary response and 
cytotoxic activity or induce apoptosis.106-108  However, lytic function of human CD8+ 
T cell has recently been shown to be inhibited by imatinib.109  
The proposed trial represents a unique approach to the treatment of T1DM and will 
provide critical validation of the hypothesis that a new class of kinase inhibitors, 
represented by the first-in-class compound imatinib, will demonstrate a novel therapy 
for T1DM. The possibility that short-term therapy with imatinib can induce tolerance 
and lead to a durable long-term remission makes it a very attractive potential therapy 
for patients with new-onset T1DM. If this therapy is safe and effective, then its use can 
be expanded to other autoimmune disorders, and possibly to T1DM prevention. 
1.4 
PRECLINICAL AND CLINICAL EXPERIENCE 
1.4.1 
Preclinical Studies  
1.4.1.1 Studies in the NOD Mouse 
The known mechanisms of imatinib action and observations in other autoimmune 
settings suggest that imatinib may have an important role in treating T1DM. Hagerkvist 
et al noted that imatinib prevents T1DM in the NOD mouse when administered from 9 
to 35 weeks of life; it did not affect the extent of islet inflammation when given from 3 
to 9 weeks of age or when treated out to 35 weeks, but the ß-cell area is significantly 
greater in treated animals.110  They also examined specific effects of imatinib on the ß 
cell. Three doses of imatinib partially protect against T1DM in streptozotocin (STZ)-
injected mice. It also protects cultured islets from various apoptosis-promoting agents, 
including pro-inflammatory cytokines, nitric oxide, and STZ.110,111  Thus, imatinib 
appears to act on multiple levels in diabetes, including reduction of insulin resistance 
and prevention of ß-cell apoptosis. The authors concluded that imatinib enhances ß-cell 
survival via a mechanism similar to ischemic preconditioning, as they found NFkB 
activation, increased nitric oxide and reactive oxygen species production, and 
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1.4.1.1.1 Prevention of T1DM  
Treatment of prediabetic NOD mice starting at 12 weeks of age (a stage when insulitis 
is firmly established)112 with imatinib orally once a day at 1.5 mg/mouse for 7 weeks 
led to complete protection from hyperglycemia during treatment, whereas half of the 
control mice developed diabetes. After cessation of treatment, only ~40% of the 
imatinib-treated animals became progressively diabetic. The majority of the mice 
remained nondiabetic at more than 50 weeks of age. Treatment of mice with 
cyclophosphamide (CY)-induced diabetes (a more robust model with rapid onset of 
disease) resulted in only ~30% of imatinib-treated animals developing diabetes within 
3 weeks after CY injection, in contrast to 85% of the control mice. These results 
confirmed that imatinib can prevent T1DM. 
1.4.1.1.2 Remission Induction  
Many agents prevent T1DM in the NOD mouse before the development of insulitis,20,113 
but only a handful of agents are successful in inducing remission in overtly diabetic 
NOD mice. Louvet et al112 found that only 1 week after initiation of treatment,  imatinib 
reversed diabetes in more than 40% of diabetic animals (Figures 1A and 1C) and after 
2 weeks the remission rate jumped to ~80% of the mice (n = 28). The effect of imatinib 
was most notable in mice with glucose levels that were modestly elevated at diagnosis 
(250–350 mg/dL) but was also effective in mice with glucose levels > 300–450 mg/dL, 
although less so. Mice treated with vehicle alone did not reverse diabetes (Figures 1B 
and 1C).  
 
Figure 1. Induction of diabetes remission. Imatinib or oil treatment was initiated at the time of disease onset (blood 
glucose >250 mg/dL) and continued for 3 weeks. Individual glucose readings for imatinib- (A) and oil-treated mice 
(B) are shown. (C) The percentage of diabetic mice is shown for each group : imatinib n=28, oil n=15. From 
Louvet et al.112 
1.4.1.1.3 Tolerance Induction  
With cessation of imatinib therapy at 3 weeks, all mice became hyperglycemic within 
10 weeks (Figure 2A). However, by increasing treatment duration from 3 weeks to 10 
weeks the majority of the mice remained euglycemic (Figure 2B).112 Thirty-five weeks 


 
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after initiation of therapy, ~50% of imatinib-treated animals had reversed from diabetes 
into a state of long-term tolerance without the need of continuous treatment.  
 
Figure 2. Long-lasting remission of diabetic NOD mice. Imatinib treatment (gray shaded area) was initiated at the 
time of disease onset and continued for (A) 3 weeks (n=8) or (B) 10 weeks (n=17). From Louvet et al.112 
1.4.1.1.4 Leukocyte Infiltration of the Pancreas  
Treatment of prediabetic NOD mice for variable periods of time with imatinib did not 
prevent insulitis.112 There were subtle differences in severe and mild insulitis in the 
drug-treated versus control islets, but these findings were not statistically significant, in 
accord with prior studies.110  Similarly, pancreatic islets from long-term normoglycemic 
mice after cessation of imatinib treatment still harbored significant insulitis. Thus, while 
preventing clinical disease, imatinib does not eliminate leukocyte infiltration of the 
pancreas. It should be noted that this observation is different from what has been 
observed for anti-T-cell agents such as Thymoglobulin and anti-CD3, which clear the 
islets of infiltration, suggesting a different mechanism of action.114,115  
1.4.1.1.5 Relevance of Tyrosine Kinase–blocking Activity 
As documented previously,116 imatinib can affect a series of tyrosine kinases in vitro 
including abl, c-kit, c-fms, and PDGFR. To pinpoint the relevant kinases in T1DM 
therapy, different TK-blocking agents that share targets with imatinib have been 
tested.112  These studies suggest that the dramatic effects of imatinib in the reversal of 
diabetes are not due to a single drug activity but due to the combination of the anti-


 
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inflammatory effects short term, due at least in part to its PDGFR antagonism, 
combined with longer term effects, perhaps due to its c-abl- and c-kit-specific activities. 
A clinical case report (see section 1.3.2) lends further support for this proposal.117  
1.4.1.2 Studies in Rat and Mouse Models of T2DM 
Hagerkvist et al reported that imatinib normalizes peripheral insulin resistance in rats 
fed a high-fat diet.118  Han et al extended these observations in the diabetic dyslipidemia 
(db/db) mouse, noting that imatinib reduces insulin resistance and induces diabetes 
remission.119  Liver steatosis and serum transaminitis are markedly reduced in treated 
animals. Imatinib also decreased TUNEL+ apoptotic ß cells and increased BrdU+ ß-
cell numbers. A unifying explanation for these effects is that imatinib ameliorates 
endoplasmic reticulum (ER) stress:  ER stress appears to play an important role in 
insulin resistance, and Abl kinase, an imatinib target, has been reported to play a role in 
this process.120  Indeed, a variety of ER stress markers in the liver and adipose tissue 
were reduced by imatinib treatment of these animals. Recent findings that kinase 
inhibition of IRE1α ameliorates ER stress and consequent apoptosis121 lends additional 
support to the potential role of imatinib in this process. 
1.4.2 
Clinical Studies in Patients with Diabetes 
Since approved for treatment of CML, several case reports and small case series have 
appeared describing patients with T2DM who have experienced significant 
improvement or resolution on imatinib.122-124  Reductions in cholesterol and 
triglycerides have also been described in treated patients.125 
 These changes have not been ascribed to significant effects with decreased appetite or 
weight loss. Fitter et al126 have further evaluated mechanisms whereby metabolic 
control improves for subjects with T2DM treated with imatinib. They have noted that 
adiponectin levels increase ~ 3-fold within 3 months of initiating imatinib, and remain 
elevated with on-going therapy out to 12 months. This adipokine increases glucose 
uptake and fatty acid oxidation in muscle, and decreases hepatic gluconeogenesis; low 
adiponectin levels are associated with increased insulin resistance and higher risk for 
T2DM.  
In a case report of another tyrosine kinase inhibitor, a 64-year-old man with metastatic 
renal cell carcinoma was started on sunitinib 8 months after the diagnosis of diabetes.117  
He was presumed to have T1DM, based on strongly positive GAD antibody titers. After 
~15 weeks on sunitinib, the insulin dose was decreased, until he discontinued insulin 
altogether at ~45 weeks on sunitinib. Sunitinib was discontinued at about that same 
time, but glycemic control has remained near normal over the ensuing 30 weeks, with 
persisting elevation of GAD antibody titers. His weight remained stable over the 
treatment period. 


 
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1.5 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS 
FOR HUMAN PARTICIPANTS  
1.5.1 
Risks  
1.5.1.1 Overview 
There is an extensive safety experience in patients treated with imatinib for CML and 
GIST (see larger clinical trials in Refs. 45,47,55,127-131 and the package insert at 
http://www.pharma.us.novartis.com/product/pi/pdf/gleevec_tabs.pdf) 
 
Overall, 
imatinib has been well tolerated in clinical trials. Adverse events (AE) are typically 
mild to moderate (grades 1 to 2) and manageable without dosage reduction or 
permanent discontinuation of therapy. The most common side effects include 
gastrointestinal reactions (nausea, vomiting, and diarrhea), edema, muscle cramps, and 
rash. Hematological toxicities (thrombocytopenia, neutropenia, and anemia) are dose-
dependent and reversible, and noted much more frequently in CML than in GIST, 
suggesting they relate in large part to the underlying disease. Specific issues are 
discussed in more detail below. These side effects tend to be more noticeable in older 
and sicker patients who are on higher doses of imatinib. Many of these adverse events 
may improve spontaneously while continuing therapy at the same dose. It is difficult to 
extrapolate fully from the past safety and tolerability experiences in cancer to a diabetes 
setting, in which our study participants will be younger, will be carefully selected so as 
not to have concurrent or chronic medical problems, and will be on lower doses of the 
drug and for a shorter duration. Our expectation, however, is that the therapy will be 
even better tolerated than in other settings in which it has been traditionally used (B. 
Druker, Oregon Health Sciences University, personal communication). The published 
and unpublished experience has been that imatinib is generally better tolerated in 
younger patients, including children.132-135  No AEs unique to children have been 
reported, with the possible exception of transient, reversible effects on growth rate (as 
detailed in section 1.5.1.11). 
1.5.1.2 Gastrointestinal Reactions 
Nausea constitutes the most common side effect of therapy. It has been noted in up to 
40%–60% of subjects with CML or GIST, and it is usually mild, grade 1, and dose 
related. Nausea occurs much more commonly when the drug is taken on an empty 
stomach, and can be avoided when taken with food. Ingestion with food has not been 
shown to affect pharmacokinetic parameters. Diarrhea is also experienced by some 
patients, possibly from imatinib blockade of c-kit, and is often dose related.  
1.5.1.3 Edema 
Edema is present in about half of patients on imatinib. It is usually superficial, mild to 
moderate in nature, and does not require specific therapy. It usually manifests as 
periorbital edema and is most noticeable first thing in the morning. Edema in the lower 
extremities is noted much less frequently. More marked issues with fluid retention, such 
as pulmonary edema or ascites, occur rarely, and have typically been limited to those 


 
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with more advanced stages of CML. This issue generally occurs at higher doses, and in 
elderly patients, and has been less common in children.   
1.5.1.4 Cutaneous Reactions 
Cutaneous reactions have been reported in ~30% of patients during imatinib treatment. 
The rashes are often pruritic, and most commonly erythematous, maculopapular lesions 
on the forearms and trunk, and sometimes also involve the face. The rashes are usually 
mild (grades 1–2) and self-limited. About 3% are higher grade, and again are usually 
associated with higher doses of therapy. Severe exfoliative rashes have been noted in 1 
in 500 treated subjects, and they usually occur early in the course of treatment. Imatinib 
treatment has been associated on rare occasions with induction of vitiligo-like lesions, 
which may be related to blockade of c-kit in melanocytes.136,137  This finding appears to 
increase with dose and duration of treatment, and is reversible with dose reduction or 
discontinuation. Paradoxically, a patient with vitiligo has been described who had 
repigmentation of his lesions while on imatinib treatment for GIST.138  
1.5.1.5 Muscle Cramps, Bone Pain, Arthralgias 
Arthralgias affect 25%–50% of treated patients. As with other issues, this is usually 
mild to moderate, and manageable without reduction of the drug dose. Cramps usually 
occur in the hands, feet, calves and thighs, and tend not to change over time in terms of 
location, frequency, and intensity. Ionized calcium and magnesium levels are normal. 
Bone pain and arthralgias are reported typically early in the course of therapy and 
usually subside after several months.  
1.5.1.6 Hepatotoxicity 
Liver toxicity, if an issue, usually emerges during the first few months of therapy, but 
can be a late finding. Frequent monitoring of liver function is suggested during therapy. 
Grade 1 elevations in transaminases occur in up to 10% of treated patients and often 
normalize while continuing on therapy. Grade 3 events have been reported in 2%–5% 
of subjects in GIST and CML trials, but these events may be confounded by a variety 
of other factors, including leukemic liver infiltration. For grade 3 events in oncology 
settings, therapy is temporarily interrupted. Imatinib is permanently discontinued for 
grade 3 events that recur with drug re-challenge. 
1.5.1.7 Myelosuppression 
The development of myelosuppression is much more common in CML than GIST, and 
may relate to the underlying effects of the cancer on the bone marrow. In the phase II 
study of imatinib for GIST, anemia (9% of subjects, 2% grades 3 or 4), neutropenia (7% 
of subjects, 5% grade 3 or 4), and leukopenia (5% of subjects, 1% grades 3 or 4) were 
the most commonly reported findings; grades 3 or 4 thrombocytopenia was noted in 
<1%. Complete blood counts with differential will be monitored at the same time points 
as liver function tests. For myelosuppression of grade 3 or higher severity in oncology 


 
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settings, therapy is temporarily interrupted, and permanently discontinued for grade 3 
events that recur with drug re-challenge.  
1.5.1.8 Cardiac Toxicity 
Prior concern was raised that imatinib may induce cardiac dysfunction, based on a 
report of 10 subjects with left ventricular dysfunction and congestive heart failure.139  
The ejection fraction for these subjects dropped significantly during the course of 
imatinib therapy, but the authors did not report the size of the underlying cohort from 
which these cases were derived, nor did they report baseline cardiac function, or other 
physiological risk factors that might be associated with cardiac dysfunction. A 
subsequent retrospective review of a large database of 942 GIST patients treated with 
400–800 mg of imatinib for a median of 24 months revealed only 2 patients (0.2%) who 
may have had a cardiotoxic effect from this drug.140  Atallah et al reported that 0.6% of 
1276 patients (median age 70) treated with imatinib developed congestive heart failure, 
and half of these continued therapy.141  The cases typically occurred in elderly patients 
with preexisting cardiac conditions. A recent study in knockout mice revealed that 
PDGFR-β signaling is required for the cardiac response to pressure overload-induced 
stress.142  This provides a mechanistic basis for the observation that cardiac toxicity 
induced by PDGFR inhibitors, such as imatinib, is generally observed only in patients 
with preexisting cardiac conditions. Druker (personal communication) has not noted 
any cardiac issues in treatment of over 1000 patients with imatinib, with the exception 
of 2 patients over age 65 who developed congestive heart failure; thus, aside from a 
careful past medical history he does not suggest routine cardiac studies for subjects on 
imatinib. The relatively short course of proposed treatment and younger, otherwise 
healthy population would suggest that this will not be an issue in this trial. Subjects 
enrolled in this trial will have careful baseline history and physical examination to 
ensure no preexisting cardiac problems. 
1.5.1.9 Infectious Disease  
Imatinib has been well tolerated, and patients receiving chronic therapy do not appear 
to be abnormally susceptible to viral infections or opportunistic infections. 
45,47,55,127,128,131  Further reassurance comes from evaluation in a mouse model in which 
imatinib selectively impaired expansion of memory cytotoxic T cells but the expansion 
of naïve cytotoxic T-cells (CTLs) in response to viral infection in vitro and in vivo was 
not impaired.107  
1.5.1.10 Reproductive Toxicity 
Despite the growing clinical experience with imatinib in CML and GIST, there is still 
only limited data on the effects of imatinib on fertility and/or pregnancy. Animal studies 
have shown that this drug is teratogenic in rats but not rabbits (Gleevec IB). 
Spermatogenesis is impaired in rats, dogs, and monkeys. Female rats receiving imatinib 
doses of 45 mg/kg, which approximates the usual clinical dose of 400 mg/day, 
experience significant post-implantation loss, including increased fetal resorption, 


 
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stillbirth, and early pup mortality. It does not appear to cause chromosome damage. 
Exposure to doses of 100 mg/kg (approximating a clinical dose of 800 mg/day) during 
organogenesis results in teratogenic effects, with exencephaly or encephalocele, and 
absent or reduced frontal and parietal bones. Based on these studies, it has been 
classified as a class D drug. However, there have been a series of case reports and small 
series reporting normal outcomes following pregnancies.143-151 The largest compilation 
of clinical experience is from a retrospective chart review of 180 women exposed to 
drug during pregnancy; outcome data were available for 125.150  Of these, 50% 
delivered normal children and 28% had elective terminations (3 following the 
identification of abnormalities). Twelve infants had abnormalities identified, 3 with a 
similar complex of malformations. There did not appear to be a higher rate of 
spontaneous abortion. Thus, although most fetuses exposed to imatinib appear to be 
unaffected, there is a risk for potential malformation. In light of these findings, 
investigators need to ensure that all participants avoid pregnancy.  
1.5.1.11 
Bone and Mineral Metabolism 
One small sub-study has noted hypophosphatemia with increased PTH, low normal 
serum calcium, and increased urinary phosphorous in patients treated with imatinib.152 
The authors postulate that this is an effect mediated by PDGFR inhibition. Further 
studies in vivo and in vitro suggest that short-term therapy with imatinib (on the order 
of 3-6 months) causes an uncoupling of bone turnover, with activation of bone 
formation via promotion of osteoblast differentiation, and inhibition of resorption by 
inhibition of osteoclastogenesis and promotion of osteoclast apoptosis.153  
 
A recent study in rats indicated that imatinib treatment (4–12 weeks duration) resulted 
in narrowing or premature closure of the growth plate in the proximal tibia, although 
the animals were not assessed for a follow-up period after drug was withdrawn.154  
Three recently published case studies report decelerated growth in juvenile CML 
patients undergoing imatinib therapy.155-157  Notably, one of the patients progressed 
through puberty and reached appropriate final adult height for family while being 
treated continuously with imatinib156; another patient experienced growth acceleration 
following discontinuation of imatinib155, but final height was not reported 155  
In the initial reports from the pediatric CML trials with imatinib, no growth or bone 
metabolism issues were reported.132-135,158  Following the case reports noted above, 
Japanese investigators performed a retrospective analysis of 48 children with CML 
treated with imatinib as a first line therapy for a median of 34 months159. They noted 
that growth rate decreased in pre-pubertal children (defined as girls < age 9 years, boys 
< 11 years), with a median decrease after 1 year of ~0.5 in height standard deviation 
score (Ht-SDS) for chronological age, and  further progressive decrement with on-going 
therapy. However, the growth rate improved during puberty, and children who initiated 
therapy at a pubertal age appeared to have little or no impact on growth rate. These 
growth issues may be confounded by a variety of issues associated with a chronic illness 


 
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such as CML, which in and of itself may impact growth rate, and one should note that 
decreased growth rate is associated with alternate therapies for CML, such as bone 
marrow transplantation160.  
1.5.1.12 
Drug Interactions 
Imatinib is metabolized by the CYP3A4/5 cytochrome P450 enzyme system. Drugs that 
induce or inhibit this P450 will affect imatinib levels, and should be used with caution, 
and if possible avoided, during the course of imatinib therapy. Major CYP3A4/5 
inducers may decrease imatinib levels; these include carbamazepine, dexamethasone, 
phenytoin, phenobarbital, progesterone, rifampin, and St. John’s wort. Major 
CYP3A4/5 inhibitors, which will serve to increase imatinib levels, include cimetidine, 
erythromycin, fluoxetine, ketoconazole, ritonavir, itraconazole, verapamil, and 
grapefruit juice. Participants who require chronic therapy with any of these agents will 
be excluded from participation.. 
1.5.1.13 
Malignancies  
On-going pharmaco-vigilance data is being collected to assess risk for malignancy 
following imatinib exposure (see data on file, Gleevec IND 55,666).  An integrated 
review of safety data from imatinib oncology clinical trials suggests that there may be 
an increased frequency of genito-urinary malignancies.  However, the effect is not 
statistically significant, and it is limited to those subjects treated for > 2 years.  Thus, 
we will exclude any subjects with prior malignancy, and will carefully monitor genito-
urinary risk throughout the study with serial urinalyses and prostate specific antigen 
(for male participants) 
When rats are treated with imatinib for 2 years, they had a shortened lifespan, and higher 
risk for developing cancers in the kidneys, bladder, urethra, clitoris, small intestine, 
parathyroid glands, adrenal glands, and stomach. The relevance of these findings to 
humans is not known. 
1.5.2 
Potential Risks and Benefits of Trial Participation for Children 
Imatinib has been used to treat Ph+ CML in children as young as age 3, and is FDA 
approved for this indication .132,134,135  Smaller trials have also been conducted in 
children with Ph positive acute lymphoblastic leukemia and some brain tumors133,161,162 
. Doses of 260-340 mg/m2 of imatinib in the pediatric population achieved a similar 
area under the curve (AUC) to the 400-mg dosing in adults; thus, we plan to employ 
such dosing in younger or smaller participants enrolled in this trial, offering whichever 
is the smaller of these two doses to pediatric participants. The safety profile was similar 
to that in adults, except that there were fewer reports of musculoskeletal pain and 
peripheral edema. As described in section 1.5.1.11, there is a potential concern about 
the effects of imatinib on growth, based on preclinical data several case reports, and a 
retrospective study of pre-pubertal Japanese children with CML (defined as girls < 9 
and boys < 11 years of age)159.  With these initial observations in mind, we will limit 


 
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enrollment to ages 12 and older for this trial. At age 12, girls have completed on average 
92% of their growth, and boys 83% of their final adult height163, thus limiting potential 
effects of drug on final height. Furthermore, as opposed to the studies referenced above 
in cancer, subjects in this trial will only have a brief 6-month exposure period on study 
drug, at a modest dose, and thus will not have the long term continuous exposure that 
has been associated with progressive slowing in growth rate for pre-pubertal children. 
As detailed in section 5.2.9, effects on growth rate will be carefully assessed in subjects 
with significant remaining growth potential at study entry, and all subjects will have 
frequent monitoring of bone metabolism and bone turnover markers. One of the study 
stopping rules relates to impact of imatinib on growth rate (Section 3.7).  
As one of the most common chronic childhood diseases, T1DM is a particular burden 
to children and their families. While T1DM can occur into adulthood, the worldwide 
incidence of T1DM is increasing rapidly in children younger than 15 years, as recently 
documented by the WHO Diamond Project.164  During the period 1995–1999, the global 
annual increase in childhood T1DM was 3.4% but was as high as 5.3% in North 
America.164  In Europe, the EURODIAB study group has found the greatest rate of 
increase in the 0-4 years age group and is predicting a doubling in the number of new 
cases in children younger than 5 years in the next decade.165 Overall, prevalence of 
T1DM in children under age 15 in Europe is predicted to rise from 94,000 in 2005 to 
160,000 in 2020.165 In contrast, the incidence of T1DM in young adults over age 15 is 
not increasing.165 For these reasons, there is considerable interest in identifying safe and 
effective interventions that can modify the course of T1DM in pediatric populations. 
Successful initial preservation of β-cell function in pediatric populations has recently 
been reported for several treatment modalities.27,33-36,39 
Evaluation of new interventions for T1DM in adults may not be informative about their 
success in children. It is known that the rate of β-cell decline is different in children 
versus adults (Greenbaum et al, Diabetes)178, and therefore lack of efficacy of a 
treatment in adults is not necessarily predictive of efficacy in children.27,36 There are 
currently no approved interventions for new-onset T1DM.  In contrast to many 
interventions currently being studied in the pediatric population, imatinib is approved 
for use in children and has an extensive clinical safety record. Imatinib is also unique 
among agents being studied for new-onset T1DM in that is an oral drug, which has 
special relevance in the pediatric age group.  
1.5.3 
Potential Benefits  
In this study, all participants will receive intensive diabetes management aimed at 
achieving near-normal metabolic control per the standard American Diabetes 
Association (ADA) guidelines.1  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 lowers the risk for long-term 
complications.6  The means to achieve this improved control in the DCCT has become 


 
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the idealized standard of care, with 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.166  
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. 6,12,167-170  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.10,11,13,171  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. Finally, the 
treatment group may have significant benefits from participation even if imatinib 
therapy has only modest effects on the preservation of endogenous insulin secretion, 
which is what was noted in the new-onset T1DM studies with anti-CD3 mAb 
therapy.34,172 
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
Determine whether imatinib 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 
Diabetes-related objectives: 
1. Assess whether the drug has prolonged clinical efficacy. 
2. Assess the effect of imatinib on selected secondary clinical outcomes. 
 
Safety: 
1. Determine the safety of imatinib in participants with T1DM, especially with respect 
to hepatic, bone marrow, cardiac, and cutaneous toxicity. 


 
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Mechanistic studies:  
1. Characterize how imatinib alters general and diabetes-specific immune responses. 
2. Gain a better understanding of the mechanism of action for imatinib in the 
maintenance of ß-cell function and determine whether the loss of tolerance 
associated with this disease is reversed. 
3. Assess effects of imatinib on insulin sensitivity. 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION 
The study will be a multicenter, two-arm, double-blind, placebo-controlled, 2:1 
randomly assigned, phase II clinical trial for individuals with recent-onset T1DM. The 
randomly assigned participants will receive either a 6-month course of imatinib or 
matching placebo tablets over a period of 26 weeks. Both treatment and placebo groups 
will undergo identical procedures and will be followed for 104 weeks. The primary 
endpoint, 2-hour C-peptide AUC measured at 52 weeks in response to a mixed-meal 
tolerance test (MMTT), will be measured at 52 weeks. Safety, diabetes control, ß-cell 
function, and immune function will be assessed for 104 weeks. Both groups will receive 
intensive diabetes management. During the follow-up phase, participants will undergo 
serial clinical and immunologic assessments over the 104 week study period, and 
possible mechanisms of imatinib action will be assessed. 
Initial enrollment will be for subjects ages 18-45, with the goal to lower the age down 
to 12 upon acceptable safety review and prospect of benefit for this initial older cohort.  
When the first 10 enrollees have completed their week 26 assessment, the safety data 
will be reviewed by a subcommittee that includes the protocol chairs, the medical 
monitor, the clinical trial physician, and the DSMB. If the review concludes that 
significant safety concerns have been identified, then no further enrollment will occur 
pending further data review and evaluation by the DSMB.  If the DSMB decides that 
the study may proceed then the FDA will be notified of study progress and determine 
if further age restriction is necessary, or if enrollment may be opened for subjects down 
to age 12.  After the first 21 subjects have completed 6 months, a further safety review 
will occur for the DSMB. Additionally, an interim efficacy assessment will be 
conducted for the DSMB and FDA.  The FDA will again be apprised of study progress, 
with further consideration for lowering the age of enrollees to 12, if this has not occurred 
earlier.  If and when the age is lowered, an identical review procedure will be followed 
when the first 10 pediatric participants (ages 12-17) have completed their week 26 
assessment. If the review is satisfactory, then enrollment will continue for subjects ages 
12-45 until the study is fully enrolled. 


 
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Enroll  subjects ages 12-45
(first 10 subjects 18-45)
Randomly assign 2:1
Assess Secondary Endpoints
Assess Primary Endpoint:
C-peptide AUC in response to 2-hr MMTT
Imatinib
400 mg/day PO x 26 weeks for adults
300 mg/m2/day or 400 mg/day (whichever 
is smaller) x 26 weeks for children
Assess Secondary Endpoints
Assess Primary Endpoint:
C-peptide AUC in response to 2-hr 
MMTT
Placebo
22
44
Q4 week follow-up to week 13,
Then every 13 weeks to week 52
Follow-up every 13 weeks to week 104
Q4 week follow-up to week 13,
Then every 13 weeks to week 52
Follow-up every 13 weeks to week 104
Imatinib in New-onset T1DM
Figure 3. Study Schema 


 
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3.2 
STUDY DURATION AND PACE OF ENROLLMENT 
Total study duration is expected to be approximately 4 years. Recruitment is anticipated 
to be completed in 18 to 24 months. Individual study participation is 24 months. 
3.3 
STUDY ENDPOINTS 
3.3.1 
Primary Endpoint 
The primary endpoint is an MMTT-stimulated 2 hour C-peptide AUC at week 52.  
3.3.2 
Secondary Endpoints 
Efficacy: 
1. MMTT-stimulated peak and 4 hour C-peptide AUC at weeks 52 and 104.  
2. MMTT-stimulated 2 hour C-peptide AUC at week 104. 
3. MMTT-stimulated 2-hour C-peptide AUC assessed longitudinally at weeks -2, 13, 
26, 52, 78, and 104. 
4. Insulin use in units per kilogram body weight per day at weeks 52 and 104.  
5. Major hypoglycemic events, as defined in section 8.2.1, occurring from 
randomization at weeks 0, 52 and 104. 
6. HbA1c levels at weeks 52 and 104. 
 
Safety: 
The rate of the following AEs in participants receiving imatinib or placebo:  
1. 
Myelosuppression. 
2. 
Gastrointestinal disorders. 
3. 
Infections. 
4. 
Hepatotoxicity. 
5. 
Cardiac toxicity and edema. 
6. 
Cutaneous reactions. 
7. 
Muscle cramps, bone pain, arthralgias. 
8. 
Fluid retention or peripheral edema. 
9. 
Bone metabolism and growth abnormalities  
10. Frequency and severity of all AEs in participants receiving imatinib or placebo.  
 
 
 
 


 
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3.3.3 
Exploratory Endpoints 
Mechanistic:   
Immunological assessments described in section 7 will be compared with clinical 
outcomes to determine whether there is evidence of immune tolerance to diabetes-
associated autoantigens. 
Metabolic (see section 6.1.1 for further discussion): 
1. Proportion of patients who are exogenous insulin-free (for at least 3 months) with 
an HbA1C ≤ 6.5% at weeks 52 and 104 in each treatment arm. 
2. Proportion of subjects who achieve a persistent reduction (for at least 3 months) 
in insulin dose to < 0.5 units/kg at weeks 52 and 104 in each treatment arm. 
3. Effects on insulin resistance will be evaluated using modeling from data obtained 
on MMTTs, and by assessing change in adiponectin, proinsulin levels (and 
proinsulin/c-peptide ratio), and glucagon. 
3.4 
RATIONALE FOR CLINICAL TRIAL DESIGN 
The proposed trial will evaluate imatinib, a tyrosine kinase inhibitor, as a novel 
tolerance-inducing intervention in new-onset T1DM. As with ITN and TrialNet new-
onset T1DM studies, endogenous insulin secretion will be assessed serially by 
measuring C-peptide AUC in response to a 4-hour MMTT. The proposed primary 
endpoint is a 2-hour C-peptide AUC in response to MMTT at week 52. This endpoint 
is in accord with an ADA workshop,173 and the TrialNet consensus guidelines for new-
onset T1DM studies. Other clinical outcome measures of efficacy include insulin use, 
HbA1C, and major hypoglycemic events. The safety of patients in this study will be 
closely monitored, and expected adverse events related to imatinib have been selected 
as the secondary endpoints for safety (see section 3.3.2).  
In accord with other ITN and TrialNet new-onset T1DM studies, we plan to randomly 
assign participants 2:1 (treatment vs. placebo). The greater chance of enrolling into a 
drug treatment arm has helped facilitate recruitment for such trials. Participants between 
ages 12 and 45 years will be recruited. T1DM can occur at any age, but it occurs with 
dramatically increased incidence in children. The average age of children at 
presentation of this disease is approximately 13 years, and most individuals present 
when they are under the age of 18 years. The incidence of T1DM is increasing at 
approximately 3% per year, mainly in the younger population.165 Beta cell function 
declines faster in those < 21 years of age, relative to those > age 21 (Greenbaum et al, 
Diabetes) 178. Many new-onset T1DM studies enroll up to age 45; the upper age limit is 
restricted in this study to45 so that the trial will enrich for a group of subjects who are 
more likely to have a faster rate of decline in beta cell function, and therefore enable a 
more pronounced difference between those in the treatment versus placebo group, 
assuming the therapy will have an effect. Imatinib is approved for the treatment of 
chronic myeloid leukemia in children down to age 3 years. The dosing is adjusted for 


 
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body surface area, and the safety spectrum appears to be comparable to that in adults. 
Additional justification for the inclusion of children is presented in section 1.5.2.  
We will treat participants within 100 days of their T1DM diagnosis. Past studies have 
suggested that subjects respond better with this earlier enrollment ,29,36 and currently all 
recent-onset T1DM immunotherapy trials conducted by TrialNet , ITN, and many 
pharmaceutical studies enroll patients within 100 days of diagnosis36,38. We have elected 
to have a 52-week primary endpoint for this trial, again in accord with ITN and TrialNet 
new-onset studies. It is important to consider whether the degree of C-peptide decline 
in the placebo group with optimal diabetes management is significant enough during 
the first year of diagnosis to detect a difference between the imatinib group and the 
placebo group. Steele et al. demonstrated that those with new-onset T1DM have steady, 
progressive loss in ß-cell function from the time of diagnosis, as assessed by C-peptide 
AUC in response to an MMTT, the measure to be employed in this study.9  This finding 
has been corroborated by others in a series of new onset T1DM trials.27,34,36-39,174,175  
The metabolic and immunological / tolerogenic effect of imatinib will continue to be 
assessed during the follow-up phase (months 12–24). Preservation of C-peptide levels 
at the end of the follow-up phase in the imatinib group will be an indication of whether 
imatinib induces tolerance. A host of immunologic assays performed throughout the 
study will also provide insight into the mechanism of imatinib action and its possible 
tolerogenic properties (Refer to section 7 for a complete discussion of immunologic 
assays.) 
3.5 
RATIONALE FOR SELECTION OF DRUG, ROUTE, DOSE, AND 
REGIMEN 
There have been a series of studies to define dose-response relationships with imatinib, 
beginning with the early phase 1 studies in CML.46,47,176  Doses between 200 to 300 
mg/day appear to be on the steep part of the dose response curve. A dose that achieves 
concentrations of 1 μmol/L, which inhibits Bcr-Abl kinase activity, appears to be 
optimal for inducing apoptosis, and these are the trough levels achieved in phase I 
studies of subjects on 260 mg/day. Thus, 260 mg has been considered a threshold dose 
for inducing optimal therapeutic responses. To ensure that the majority of treated 
subjects were above this threshold, 400 mg/day was adopted as the dose for phase II 
studies of patients with chronic disease, and with a half-life of 13–16 hours, once daily 
dosing was considered adequate. This dosing regimen has proven to be highly 
successful in treating CML and GIST.44-48  Doses higher than 400 mg/day may achieve 
better responses, particularly for those in accelerated and blast crisis studies. Doses of 
up to 1000 mg have been reached without convincing dose-limiting toxicity but, as 
noted above, the frequency and grade of adverse events increases, particularly above 
600 mg/day.  


 
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The responses in autoimmunity noted above were achieved in subjects receiving at least 
400 mg/day, and sometimes higher imatinib doses. Thus, 400 mg/day appears to be an 
effective dose in autoimmune diseases.  
It is difficult to extrapolate exactly from the mouse dose employed by Louvet et al112 to 
humans. They were successful with doses of 50 mg and 100 mg/kg and 1.5 to 3 
mg/mouse, and ultimately used 1.5 mg/mouse. Druker considers this dose roughly 
comparable to 400 mg/day used in clinical studies (personal communication). 
A common question with all studies is whether or not dose should be adjusted for a 
participant’s size. Peng et al conducted a study to determine whether obesity had an 
effect on plasma levels of imatinib, and concluded that there was no evidence that 
patient size needed to be taken into consideration.177  Deininger et al also reported that 
flat dosing was appropriate in a small number of obese subjects.129  Considerations for 
children were reviewed in section 1.5.2, and we will follow the standard dosing of 260 
mg/m2 or 400 mg, whichever is lower, stated in the Gleevec package insert.  
One additional consideration with regard to dosing is how long to continue drug 
therapy. Longer-term treatment (10 weeks versus 3 weeks) clearly resulted in a more 
robust and durable response in the NOD mouse. Based on this, we propose a 6-month 
treatment period—6 months strikes the appropriate balance between too short a period, 
with loss of long-term efficacy, and longer treatment (such as 12 months) with ongoing 
risk from the therapy. For its approved indications, Gleevec therapy is typically 
administered for years and even lifelong in some patients, but in this trial we will be 
assessing its role as a tolerizing agent after 6 months of therapy. 
3.6 
MEASURES TO MINIMIZE BIAS    
The proposed trial has a double-blind design. One salient issue is whether or not the 
side effect profile will be such that it will serve to unmask a significant number of 
participants and study personnel. We expect that the side effects will be milder and less 
frequent than seen in oncology settings, as we will be enrolling a younger and healthier 
patient population who will be treated at the lowest therapeutic imatinib dose (B. 
Druker, personal communication). Both the treatment and placebo groups will require 
close, regular monitoring, particularly during the treatment phase. Because endogenous 
insulin secretion is the primary outcome variable (i.e., C-peptide), and this in turn is 
affected by glycemic control, we will aim for comparable glycemic control in both 
groups, treating to established targets. The health care professionals managing T1DM 
will be blinded to treatment assignment. 
3.7 
STOPPING RULES 
3.7.1 
Ongoing Review 
The progress of the study will be monitored by a Data and Safety Monitoring Board 
(DSMB), which will review safety data and make recommendations regarding 


 
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continuation, termination, or modification of the study. Based on an 18- to 24-month 
recruitment period and an additional study period of 24 months, the DSMB will 
formally review the safety data at least yearly. The number of subjects 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 medical monitor, clinical trial physician, or protocol chairs to 
warrant review, or when an event occurs that contributes to a stopping rule listed in 
Section 5.3. 
3.7.2 
Stopping Rule Guidance 
3.7.2.1 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 be conducted to 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 
protocol chairs, the clinical trial physician, and the medical monitor. 
 
One or more participants experience treatment-emergent, clinically significant 
cardiac toxicity. 
 
Two or more of the first 10 treated participants or ≥20% of all treated participants 
experience a clinically significant, drug-related adverse event resulting in the 
permanent discontinuation of study treatment, as defined in section 5.3. 
 
If two or more of the first 10 treated growing-age participants, as defined in section 
5.2.9, or greater than 20% of all treated growing-age participants, exhibit a decrease 
in Height Standard Deviation Score (Ht-SDS) of  > 0.5 from baseline at 6 months, 
or > 0.8 from baseline at 12 months, then enrollment will pause for growing-age 
participants. Study enrollment will continue for participants who are not growing-
age. DSMB review will determine whether imatinib treatment can resume in 
growing-age participants based on available growth and bone-metabolism data, as 
well as bone-age radiographs.  
 
 


 
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4. 
ELIGIBILITY 
4.1 
INCLUSION CRITERIA 
Patents must meet all of the following criteria: 
1. Males and females age 12–45 years of age who meet the ADA standard T1DM 
criteria.  
2. Positive for at least one islet cell autoantibody (glutamate decarboxylase; insulin, if 
obtained within 10 days of the onset of insulin therapy; ICA 512-antibody; and/or 
ICA or ZnT8).  
3. Diagnosis of T1DM within 100 days of Visit 0.  
4. Peak stimulated C-peptide level >0.2 pmol/mL following an MMTT. 
5. Participants of childbearing age who are sexually active must agree to use an 
effective form of birth control (e.g., barrier method, oral contraception, or surgery). 
For females, these contraceptive measures must be maintained throughout the 
study; for males these measures must be followed for a minimum of 3 months after 
discontinuation of imatinib therapy.  
4.2 
EXCLUSION CRITERIA 
Patients must not meet any of the following criteria: 
1. Prior history of any significant cardiac disease such as congestive heart failure, 
myocardial infarction, arrhythmia, or structural defects or suspicion thereof. 
2. Leukopenia (<3,000 leukocytes/µL), neutropenia (<1,500 neutrophils/µL), or 
thrombocytopenia (<125,000 platelets/µL).  
3. Low Hemoglobin (baseline hemoglobin below the lower limit of normal) 
4. Prior history of anaphylaxis, angioedema or serious cutaneous drug reactions 
5. Any sign of significant chronic active infection (e.g., hepatitis, tuberculosis, EBV, 
CMV, or toxoplasmosis), or screening laboratory evidence consistent with a 
significant chronic active infection (such as positive for HIV, PPD/IGRA, or 
HBSAg). Significant acute infections must be resolved before treatment may 
commence, e.g., acute respiratory tract, urinary tract, or gastrointestinal tract 
infections. 
6. Anticipated ongoing use of diabetes medications other than insulin that affect 
glucose homeostasis, such as metformin, sulfonylureas, thiazolidinediones, 
glucagon-like peptide 1 (GLP-1) mimetics, dipeptidyl peptidase IV (DPP-IV) 
inhibitors, or amylin. 
7. Prior or current treatment that is known to cause a significant, ongoing change in 
the course of T1DM or immunologic status, including high-dose inhaled, extensive 
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8. Evidence of liver dysfunction, with alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >2.0 times the upper limit of normal persistent for 1 week 
or greater.  
9. Evidence of renal insufficiency as indicated by serum creatinine of >1.2 times the 
upper limit of normal confirmed in a repeat test at least 1 week apart. 
10. Evidence of clinically significant metabolic bone disease (except adequately treated 
rickets). 
11. Females who are pregnant at the time of screening, breastfeeding or unwilling to 
defer pregnancy during the 24-month study period. (Female participant must be at 
least 100 days postpartum before enrollment into study). 
12. Prior treatment with imatinib or related tyrosine kinase inhibitor. 
13. Unable to avoid medications that affect CYP3A4: either inducers that may decrease 
imatinib levels, or inhibitors that may increase drug concentrations. (Refer to 
section 1.5.1.12 for a complete list of inducers and inhibitors.) 
14. Height standard deviation score  ≥2 standard deviations below mean (participants 
of growing-age potential)  
15. Any sign of QT prolongation on Visit -1 ECG (> 450 ms in males and > 470 ms in 
females). 
16. Known coagulation disorders or use of anticoagulants 
17. Current and anticipated on-going treatment with drugs that may increase or 
decrease imatinib plasma concentrations (CYP3A4 family inhibitors or inducers) 
or drugs that may have their plasma concentration altered by imatinib (drugs 
metabolized by CYP3A4/5 and CYP2D6). 
18. Any condition that, in the investigator’s opinion, may compromise study 
participation or may confound the interpretation of the study results. 
4.3 
PREMATURE TERMINATION OF A PARTICIPANT FROM THE 
STUDY 
Prematurely terminated participants will be asked to remain in the study and participate 
in follow-up. If study treatment is discontinued, the medical monitor should be notified. 
Participants who prematurely terminate from the study will not be replaced.  
Withdrawal of consent. Participants who withdraw consent will be asked to participate 
in follow-up. If the participant does not consent to follow-up visits, they should 
complete an end-of-study visit, which will include all the assessments listed for Visit 
11 in Appendix 1.  
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.  


 
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Investigator judgment. A severe or serious AE occurs, which, based on the medical 
judgment of the investigator, prevents completion of participation in the study. 
5. 
STUDY MEDICATIONS 
5.1 
INVESTIGATIONAL MEDICATION 
5.1.1 
Formulation and Packaging  
Imatinib mesylate (Gleevec; Novartis, East Hanover, NJ) is produced as film-coated 
tablets, equivalent to 100 mg of imatinib free base. The placebo group will receive an 
identical pill that is manufactured and distributed by a designated drug distributor. If 
necessary to prevent unblinding, the distributor may need to overencapsulate the 
imatinib tablets.  
5.1.2 
Dosage, Preparation, and Administration 
Adult participants will receive four 100 mg tablets of imatinib or the corresponding 
placebo tablets daily for the first 6 months. Pediatric participants will receive 260 
mg/m2/day (rounded up or to the closest 100 mg) or 400 mg/day (whichever is smaller) 
of active drug or placebo.  
5.1.3 
Recommended Storage Conditions 
 
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). 
 
Protect from moisture. 
 
Dispense in a tight container, USP. 
5.2 
DOSE MODIFICATION AND MANAGEMENT OF ADVERSE EVENTS  
With the use of a relatively low dose of imatinib in an otherwise healthy population, we 
hope to minimize the nature and extent of AEs experienced. It is important to note here, 
as in section 1.4, that the AEs referenced below, if observed, will usually occur early in 
the course of treatment, are often self-limited, and do not usually require dose 
adjustment or discontinuation of imatinib. Nonetheless, the investigative team 
recognizes that cancer treatment is clearly different than the proposed elective clinical 
trial: side effects considered acceptable and tolerable in a cancer setting may not be 
considered in the same light for subjects in this study. Every effort will be made to 
carefully balance the intent to provide the maximum total prescribed dose of study drug 
to subjects, versus the discomfort and risk that may be accompanied with imatinib 
administration. The “art” of subject management in this study will be to minimize the 
number of subjects that drop out of the trial due to these side effects, working in close 
concert with the investigative team to either adjust study drug dose and/or provide 
symptomatic relief with concomitant medications. General guidelines are outlined 
below, but may need to be modified as deemed necessary, in consultation with the trial 
physicians and medical monitor. In general, when a dose reduction is required, the daily 
dose of imatinib or placebo will be halved: For adults, the dose will be reduced from 


 
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400 mg/day to 200 mg/day. Unless otherwise stated, the equivalent dose reduction in 
children will be from 260 mg/m2/day to 130 mg/m2/day. Investigators will be instructed 
to always round up to the nearest 50 mg increment for the half-dose dosage.  
5.2.1 
Gastrointestinal Reactions 
Nausea. To minimize issues with nausea, participants will be advised to take study 
medication with the largest meal of the day. If the problem persists, they may need to 
split the study medication into twice daily dosing.  
For recurrent, persistent vomiting, grades 1 and 2, lasting for 48 hours, investigators 
will consider the use of anti-emetics such as prochloropherazine or ondansetron. 
Subjects usually respond promptly, and dose reduction is seldom needed.  
For grade 2 vomiting that persists for 48 hours despite the use of antiemetic drugs, 
imatinib will be reduced to 50% of the initial daily dose. If vomiting resolves over the 
ensuing week, then the full dose will be restored. If vomiting recurs, then the subject 
will need to remain on the 50% tolerated lower dose, and re-evaluated weekly, with 
return to full dose reconsidered.  
For vomiting that is grade 3, or grade 2 that does not improve with anti-emetics and 
dose reduction for 48 hours,, imatinib will be suspended until the problem is resolved. 
Electrolytes should be obtained.  Imatinib will then be reintroduced at 50% of the initial 
daily dose. If vomiting does not recur over the ensuing week, the initial dose will be 
restored. If vomiting of grade 3 recurs, then the drug will be permanently discontinued.  
If nausea or vomiting resolve and then occur again at a later time, the same procedures 
may be followed as outlined above, depending on the grade. 
Diarrhea. If it occurs, diarrhea is often mild and requires no specific therapy. For 
persistent diarrhea (1 week or greater) of grades 1 and 2 the participant may be treated 
with antidiarrheal and antispasmotic drugs, such as Imodium®, Lomotil®, or paregoric, 
at the discretion of the investigator.  
For grade 2 diarrhea that persists for 1 week despite the use of antidiarrheal drugs, 
imatinib will be reduced to 50% of the initial dose. If diarrhea improves to less than or 
equal to grade 1 for at least 1 week, the initial dose will be restored. If diarrhea persists 
despite use of antidiarrheal drugs and dose reduction, permanent discontinuation of 
imatinib will be considered.  
For diarrhea of grade 3 or higher, imatinib will be suspended until the problem is 
resolved. Electrolytes should be obtained. Imatinib will then be reintroduced at 50% of 
the initial dose for 1 week. If diarrhea does not recur, the initial dose will be restored.  
If diarrhea greater than grade 2 recurs, imatinib will be permanently discontinued. If 
diarrhea resolves and then occurs again at a later time, the same procedure may be 
followed. 


 
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Chronic diarrhea, of 14 or more days in duration, should be evaluated to determine if 
there is an infectious cause. Evaluation will be conducted in consultation with local 
infectious disease consultants, and will include a thorough clinical and epidemiological 
evaluation, including travel history and any possible exposures. Stool culture and other 
evaluation may be required, and anti-microbial therapy offered as indicated. Other 
potential causes of diarrhea, such as lactase deficiency, should be considered.  
5.2.2 
Muscle Cramps, Bone Pain, Arthralgias 
Mild to moderate cramps may respond to calcium and magnesium supplementation, and 
some have responded to quinine. Mild to moderate bone pain and arthralgia can usually 
be relieved with nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and 
naproxen.  
For grade 2 muscle cramps, bone pain or arthralgia that persist for 1 week despite the 
use of symptom-relieving drugs, the dose of imatinib will be reduced to 50% of the 
initial daily dose. If symptoms improve to less than or equal to grade 1 for at least 1 
week, the initial dose will be restored. If symptoms persist despite symptomatic 
treatment and dose reduction, permanent discontinuation of imatinib will be considered.  
For grade 3 muscle cramps, bone pain or arthralgia, imatinib will be suspended until 
the problem is resolved. Imatinib will then be reintroduced at 50% of the initial dose 
for 1 week. If symptoms do not recur, the initial dose will be restored. If symptoms 
greater than grade 2 recur, imatinib will be permanently discontinued. 
5.2.3 
Edema 
Edema associated with imatinib is usually mild and self-limited, and often does not 
require therapy. Affected participants may consider a reduction in salt intake. Patients 
with periorbital edema may benefit from topical 0.25% phenylephrine or 1% 
hydrocortisone.  
Localized edema. Grade 2 localized edema, including periorbital edema and limb 
edema, that persists for longer than 1 week may be treated with diuretics. For grade 2 
edema that persists despite the measures described above, the dose of imatinib will be 
reduced to 50% of the initial daily dose. If edema improves to less than or equal to grade 
1 for at least 1 week, the initial dose will be restored. If edema persists despite 
reductions in salt intake, use of diuretics, and imatinib dose reduction, permanent 
discontinuation of imatinib will be considered. 
For edema of grade 3 or higher, imatinib will be suspended until the problem is 
resolved. Imatinib will then be reintroduced, with ongoing diuretic use, at 50% of the 
initial daily dose for 1 week. If edema does not recur, the initial dose will be restored. 
If edema greater than grade 2 recurs, imatinib will be permanently discontinued. If 
localized edema resolves and then occurs again at a later time, the same procedure may 
be followed. 


 
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Generalized fluid retention. Participants will be monitored for signs and symptoms of 
generalized fluid retention (including pulmonary and cardiac issues), and will be 
weighed regularly at each study visit to detect the early onset of fluid retention. If 
sudden increases in weight occur, participants should be examined for signs of 
pulmonary edema, pleural effusion, pericardial effusion, and ascites. If any signs of 
generalized fluid retention are found, imatinib should be suspended and diuretic therapy 
started. Electrolytes should also be obtained if greater than grade 2. If these measures 
lead to a prompt resolution of fluid retention, imatinib may be reintroduced at 50% of 
the initial daily dose. If fluid retention does not recur, the initial dose may be restored. 
If generalized fluid retention recurs, imatinib will be permanently discontinued. 
5.2.4 
Cutaneous Reactions 
Rash. Investigators should be prepared for rashes early in the course of therapy, when 
they are most likely to occur. These are usually grades 1 or 2 and are self-limited. 
Symptomatic treatment with antihistamines, salves, and coal tar preparations has been 
helpful.  
For grade 2 rash that persists for 1 week despite the measures described above, the dose 
of imatinib will be reduced to 50% of the initial daily dose. If the rash improves to less 
than or equal to grade 1 for at least 1 week, the initial dose will be restored. If the grade 
2 rash persists despite symptomatic treatment and imatinib dose reduction, permanent 
discontinuation of imatinib will be considered. If grade 2 rash resolves and then occurs 
again at a later time, the same procedure may be followed. 
For a rash of grade 3 or higher, imatinib will be suspended until the problem is resolved. 
Imatinib will then be reintroduced at 50% of the initial dose for 1 week. If the rash does 
not recur, the initial dose will be restored. If a rash greater than grade 2 recurs, imatinib 
will be permanently discontinued. 
Bullous dermatologic reactions. Rare cases of bullous dermatologic reactions, 
including erythema multiforme and Stevens-Johnson syndrome, have been reported 
with imatinib treatment.  
In cases of less than or equal to grade 1 erythema multiforme, imatinib will be 
suspended. If the condition resolves promptly, reintroduction of imatinib may be 
considered, starting at the lowest dose (100 mg/day) with gradual dose escalation, if 
tolerated. If the condition recurs at any grade, imatinib will be permanently 
discontinued. 
If a participant presents with Stevens-Johnson syndrome (any grade), toxic epidermal 
necrolysis (any grade), or > grade 1 erythema multiforme, imatinib will be permanently 
discontinued and supportive therapy, including systemic glucocorticoids, started 
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5.2.5 
Hepatotoxicity 
In general, guidelines established for imatinib use in CML and GIST will be followed, 
129,130 but a more conservative approach will be used, as follows. Liver function tests 
(LFTs) will be obtained every other week during the first month of therapy, and monthly 
thereafter.  
For grade-2 transaminase (ALT or AST > 3.0  ULN) or bilirubin (> 1.5  ULN) 
elevations, imatinib must be suspended, and the LFTs monitored weekly. When they 
have fallen to grade 1 or normalized, imatinib will be restarted at 50% of the initial daily 
dose. If the liver toxicity does not recur within 6–12 weeks, then the initial dose will be 
restored. If after resumption of treatment grade 2 transaminase or bilirubin elevations 
recur, study drug will be permanently discontinued. 
For grade-1 abnormalities (ALT or AST greater than or equal to 1.0–3.0  ULN; 
bilirubin greater than or equal to1.0-1.5  ULN), imatinib treatment can be continued 
but LFTs will be monitored weekly for 2 weeks and then, if no worsening is observed, 
every other week. Concomitant hepatotoxic agents, such as alcohol or acetaminophen, 
should be removed. Persisting grade 1 abnormalities should be managed by dose 
reduction, biweekly monitoring, and further evaluation in conjunction with 
gastroenterology consultation. 
5.2.6 
Myelosuppression  
In general, recommendations will be a conservative algorithm, derived from Deininger 
et al. for the chronic phase of CML will be followed.129  For grade 1 neutropenia 
(absolute neutrophil count [ANC] <LLN-1500/mm3) and thrombocytopenia (<LLN-
75,000/ mm3), the dose of imatinib will be reduced to 50% of the initial dose.  Counts 
will be monitored bi-weekly.  The initial dose will be restored when myelosuppression 
resolves. 
For grade 2 or greater events (ANC less than 1,500/mm3, or platelets less than 
50,000/mm3) imatinib should be suspended and the counts will be repeated weekly until 
they have recovered (ANC greater than 1,500/mm3, platelets greater than 75,000/mm3).  
For grade 1 neutrophil or platelet levels, imatinib will be restarted at 50% of the original 
dose, and the counts will be monitored biweekly; imatinib will be restored to the full 
dose when the counts normalize.    If myelosuppression resolves and then occurs again 
at a later time, the same procedure may be followed. 
5.2.7 
Infectious Disease Risk 
In general, higher risk for infections has not been a concern during the clinical use of 
imatinib. Nevertheless, all participants will undergo careful surveillance during the 
initial phase of the study. Baseline analyses will determine whether the participant has 
had a primary infection with EBV, CMV, or varicella. At each visit, participants will 
be assessed for signs and symptoms of new or reactivating infections. If there are 
concerns, including pyrexia of unknown origin, participants will be evaluated for 


 
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opportunistic infections, including PCR monitoring for EBV and CMV. If a diagnosis 
of a new or reactivating infection that is clinically significant is confirmed, imatinib 
treatment will be discontinued until successful treatment and resolution of the infection. 
In conjunction with an infectious disease consultation, reintroduction of imatinib will 
be considered. 
5.2.8 
Pregnancy 
Site staff will regularly review the concerns regarding avoidance of pregnancy with 
participants during the course of the study, especially during the initial 6 months on 
therapy. Urine pregnancy tests will be conducted at baseline and every following visit 
while on study drug. Male participants are to use birth control at least 3 months after 
study drug discontinuation. If, despite these measures, a participant becomes pregnant, 
imatinib will be permanently discontinued and the participant will be counseled on 
potential risks to the fetus. Pregnancies of partners of male participants will also be 
followed. 
Given the potential risk to the fetus, while on study drug/placebo, women of child-
bearing potential, defined as all women physiologically capable of becoming pregnant, 
must agree to use highly effective methods of contraception..  This contraception should 
start1 week or more prior to the start of study drug/placebo (noting that the terminal 
half-life of imatinib  is approximately 18 hours, and 5 times this duration is 90 hours or 
~4 days)) and continue during the subsequent 6 months of study drug/placebo dosing 
Highly effective contraception methods include: 
 
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment.  
In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment 
 
Male sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject 
 
Combination of any two of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone 
contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 


 
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c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/vaginal 
suppository 
In case of use of oral contraception women should have been stable on the 
same pill for a minimum of 3 months before taking study treatment. 
5.2.9 
Bone and Mineral Metabolism 
Small clinical studies in oncology have identified effects on bone metabolism. Further, 
in a pilot animal study there is a possible effect of imatinib on growth plate architecture, 
and in a few case reports and a retrospective analysis of children with CML there is a 
possible effect of therapy on growth rate (see section 1.5.1.11). Therefore, biochemical 
markers of bone metabolism will be measured in all subjects. At Visit 0, all subjects 
less than 18 years of age will have their bone age assessed using the Fels method (plain 
film) by a central reader who is an expert in skeletal maturation in order to determine 
their bone age and growth potential. Female subjects with a bone age of less than 14 
years and male subjects with a bone age less than 16 years will be considered to have 
significant remaining growth potential at study entry and referred to in this protocol as 
a “growing-age participant”. Growth assessments will be performed according to the 
Schedule of Events. 
Growing-age participants will have their Ht-SDS determined via standard reference 
charts published by CDC (2001). Additional factors that commonly affect growth will 
be evaluated at regular intervals, to distinguish the potential contribution from these 
issues versus those that may be attributed to study drug.  
Phosphorous and vitamin D supplementation may be needed if any deficiencies are 
noted, as suggested by Berman et al.152  Given the relatively short-term course of 
therapy, we do not expect any long-term problems with bone metabolism. 
5.2.10 QT Prolongation 
All participants will have electrocardiograms (ECGs) performed at Visit -1 (screening) 
and Visit 1. Participants will not be eligible for the study if QTc is > 450 ms in males 
or >470 ms in females at Visit -1, If QTc is >480 ms or there is > 60 ms change from 
the Visit -1 ECG, then study drug will be discontinued. Participants experiencing 
dizziness or syncope greater than a grade 2 should promptly seek medical attention and 
obtain an ECG and electrolytes. 
 
 


 
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5.3 
DISCONTINUATION OF STUDY MEDICATION IN AN INDIVIDUAL 
PARTICIPANT 
Study medication according to study specifications will be discontinued for an 
individual participant if any of the following occurs: 
 
A discontinuation criterion for imatinib, as noted in section 5.2, is met. 
 
Clinical evidence of cardiac toxicity, such as congestive heart failure or significant 
cardiac arrhythmias, is observed. 
 
Pregnancy occurs. 
 
A severe or serious AE occurs, which, based on the medical judgment of the 
investigator, prevents a participant from completing the study treatment (see section 
8 for classification of AEs).  
 
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. 
Further care will be provided according to the judgment and practice of the investigator. 
The participant will be asked to remain in the study and participate in follow-up. If 
study treatment is discontinued, the medical monitor should be notified. 
5.4 
CONCOMITANT MEDICATIONS 
Any participants who need to start a concomitant medication, for whatever reason, 
should contact the study team to review its potential effects on imatinib metabolism. 
Those who require an emergency therapy will be encouraged to pursue the necessary 
clinical care, but then contact the study team within 24 hours to review the potential 
effects on imatinib metabolism. Whenever possible, the recommendation will be to use 
concomitant medications that do not alter imatinib levels. 
5.4.1 
Prohibited Medications 
Use of cytochrome P450 inducers/inhibitors, unless considered essential by the 
investigator, are prohibited during the treatment phase. Imatinib is metabolized by the 
CYP3A4/5 cytochrome P450 enzyme system, and drugs that induce or inhibit this 
enzyme may alter imatinib levels (see section 1.5.1.12 for a list of inducers and 
inhibitors). 
5.5 
DRUG ACCOUNTABILITY 
Under federal regulations (21CFR 312.62) 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 


 
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(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 sponsor 
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 
Pill counts will be used to assess participant compliance with daily doses of the study 
medication. 
6. 
STUDY PROCEDURES 
6.1 
INTENSIVE DIABETES MANAGEMENT 
During the study, all participants will receive “intensive” management of their diabetes, 
and HbA1C will be assessed every 3 months to evaluate metabolic control. The goal of 
treatment will be to maintain the HbA1C level as close to normal as possible, without 
frequent occurrence of hypoglycemia. All individuals should strive for targets in 
accordance with current ADA recommendations,  with HbA1C levels of  less than 7% 
in adults and less than  7.5% in adolescents (age 12–17 years), and with preprandial 
glucose levels of 90–130 mg/dL (plasma), postprandial levels of less than 180 mg/dL, 
and bedtime levels of 110–150 mg/dL.178  All participants will be expected to take a 
sufficient number of daily insulin injections to meet the glycemic targets. In general, 
the expectation is that all participants will receive at least three injections of insulin 
daily, including short- and long-acting insulin preparations, or will utilize continuous 
subcutaneous insulin infusion (CSII insulin pump). Glucose levels should be checked 
at least four times daily. After reviewing these records, the diabetes management team 
will contact the treating physician about possible adjustments in the insulin regimen, 
referral to a registered dietitian, or other approaches that the diabetes management team 
believes would improve the glucose control if necessary. Records of glucose 
measurements and communication with the participant will be kept as source 
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between visits to assess their diabetes. In addition, insulin use and hypoglycemic events 
will be captured at each visit on the appropriate CRFs. Participants will be required to 
record the amount of insulin they have used during the 5-day period immediately 
preceding each study visit. Insulin use logs will be provided to participants at each study 
visit and collected at the next visit. These logs will serve as the source documents. 
6.2 
RANDOM ASSIGNMENT, BLINDING, AND UNBLINDING  
6.2.1 
Random Assignment 
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. Random assignment will be stratified 
according to site. 
6.2.2 
Blinding 
Blinding will be maintained throughout the study for all study participants and study 
personnel, except the pharmacists.  
6.2.3 
Unblinding 
Unblinding before the study is completed will occur only if a participant’s well-being 
is threatened and the investigator believes unblinding is necessary to protect the 
participant.  
Before treatment assignment for an individual participant is unblinded, the investigator 
must confer with the study sponsor and the medical monitor. The site investigator will 
notify the protocol chairs of the unblinding event, and the medical monitor will notify 
the study management team (SMT).  
The emergency unblinding 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 unblind, 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 
medical monitor was notified and that a written account was completed. The reasons 
for unblinding of a participant’s treatment will be included in the final study report. 
Sponsor approval is required for unblinding the treatment of an individual participant 
or subgroups of participants for unplanned interim analyses to support DSMB reviews 
and final analysis.  


 
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6.3 
VISIT WINDOWS 
6.3.1 
Scheduled Visits 
All scheduled study visits in Appendix 1 must occur within the time limits specified 
below. Visits that occur outside of the specified windows will be considered protocol 
deviations. 
 
Visit -1 
Up to 2-4 weeks before visit 0 
  
 
Visit 0 
No window 
 
 
 
Visit 1 
(± 3 days) 
 
 
 
Visits 2-7 
(± 7 days) 
 
Visits 8-11 
(± 14 days) 
 
6.4 
GENERAL ASSESSMENTS 
 
Medical history includes T1DM time of diagnosis and clinically significant diseases 
or medical procedures. Copies of growth velocity charts should be obtained if 
available 
 
Adverse events. Participants will be assessed for AEs 
 
Concomitant medications. All concomitant medications and their indications will 
be recorded 
 
Comprehensive physical examination and vital signs. Weight, temperature, blood 
pressure, respiration, and pulse  
6.5 
LABORATORY ASSESSMENTS 
 
Serum chemistries: Electrolytes (sodium, calcium, potassium, chloride, phosphate, 
total CO2), blood urea nitrogen (BUN), creatinine, and liver panel (AST, ALT, 
alkaline phosphate, direct and total bilirubin) 
 
Hematology: Complete blood cell count with differential, and platelets 
 
Infectious disease serology, hepatitis B (HBsAg and anti-HBcAb) and C, HIV, 
toxoplasmosis, VZV, EBV (IgG, IgM, EBNA), CMV (IgG, IgM)  
 
PPD skin test or IGRA 
 
Urine hCG 
 
Urinalysis 
 
C-peptide levels (measured as part of MMTT) 
 
Plasma Glucose (measured as part of MMTT) 
 
HbA1c levels 


 
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6.6 
DISEASE-SPECIFIC ASSESSMENTS 
 
MMTT  
 
Glucose (glucometer readings) 
 
Insulin use (U/kg body weight/day) 
 
Hypoglycemia events 
 
Serum Adiponectin levels 
 
Plasma Glucagon levels 
 
Plasma Proinsulin levels  
6.7 
BONE AND MINERAL METABOLISM ASSESSMENTS 
Serum calcium, serum phosphate, PTH, 25-OH Vitamin D and serum bone turnover 
markers (serum CTX, osteocalcin). Bone turnover markers are exploratory only and are 
not part of the secondary endpoint safety assessment, per section 3.3.2.  
6.8 
GROWTH RATE ASSESSMENTS FOR GROWING-AGE 
PARTICIPANTS (AS DEFINED IN SECTION 5.2.9) 
 
Plain radiograph of left hand to determine bone age using the FELS atlas (Assessing 
the skeletal maturity of the hand-wrist).179 
 
 Height measured by Stadiometer. 
 
Secondary sexual characteristics. 
 
Arm span. 
 
Biochemical assessments. IGF-1, IGF-BP3, LH, FSH, estradiol (females), 
testosterone (males), TSH, and tissue transglutaminase. 
7. 
MECHANISTIC ASSAYS 
The study team will partner with the ITN for mechanistic studies, taking full advantage 
of their systems for sample collection and archiving (see letter from Nepom). Following 
results of the study, various immunological assays will be considered through the 
available ITN cores, and beyond.  We recognize that this field is rapidly evolving, and 
thus novel assays that are particularly relevant to this study population, and to this drug, 
will be considered.  Our mechanistic assays plan is outlined below.   
7.1 
RATIONALE 
The rationale for treating T1DM patients with imatinib stems from results in animal 
studies where imatinib therapy led not only to reversal of T1DM but also to reversal of 
the loss of tolerance, a process ultimately responsible for the pathology of the disease. 


 
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Treatment with imatinib potentially leads to a change from a pro-inflammatory to an 
anti-inflammatory state. In the NOD mouse model it was shown that both adaptive 
immune and inflammatory mechanisms directly trigger insulitis, insulin resistance, 
faulty insulin signaling and islet cell destruction, all leading to the loss of tolerance to 
islets. 
It is anticipated that drug treatment is likely to affect T cells, B cells and mast cells 
directly, resulting in decreased numbers and function of islet antigen-specific T cells 
and perhaps changes in autoantibodies. In T1DM, there is a growing belief that 
generalized inflammation and adaptive immunity are major contributing factors to the 
induction and progression of this autoimmune process. Thus, a decrease in these cells 
or their function might help to eliminate activated autoreactive T cells resulting in 
tolerance to islet antigens in T1DM patients. In addition, we hypothesize that imatinib 
alters PDGF signaling that alters macrophage differentiation, affecting the balance of 
pathogenic versus alternatively activated macrophages and inflamed endothelial cells 
altering cell trafficking. 
The goal of the mechanistic studies will be to determine if the biological effects of 
imatinib correlate with therapeutic efficacy in T1DM patients. The proposed 
immunologic mechanistic studies are designed to determine how imatinib therapy may 
arrest ongoing autoimmune pancreatic β-cell destruction and preserve insulin secretion 
in patients with T1DM. These will be conducted in the existing Immune Tolerance 
Network core laboratories. We recognize that this field is rapidly evolving, and thus 
novel assays that are particularly relevant to this population and this agent may be 
incorporated into the trial at a later date. Whenever possible, samples will be frozen and 
archived for batch analysis at a later date. Finally, since this trial has a safety 
component, emphasis will be placed on the study of immune responses to pathogens 
and overall immune competence. 
7.2 
RETENTION OF SAMPLES 
Biological specimens collected in this trial may be used to re-evaluate biologic 
responses as new research tools become available. The specimens will be stored at the 
ITN sample repository until the end of the ITN contract. Residual specimens may be 
used by the investigators for development of new immunologic assays or for cross-trial 
comparisons. Specimens for mechanistic studies will be obtained throughout the study. 
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 clinical effect fails to occur, the assays performed by the 
ITN may be minimal. 


 
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7.3 
FROZEN PBMCS 
Peripheral blood will be collected at the sites, processed at an ITN core laboratory, and 
frozen cells stored in a central ITN repository. 
7.3.1 
Functional Cell-Based Assays 
The functional status of lymphocyte subsets, specifically T/ B cells, mast cells and 
monocytes, can be assessed in various cell-based assays. Inflammatory and TCR-driven 
autoantigen-specific stimulations need to be examined to fully evaluate the effect of 
imatinib on immunological responses. To address the participants’ overall 
inflammatory response potential during imatinib treatment, PBMCs or whole blood can 
be stimulated with anti-CD3 plus anti-CD28 and/or lipopolysaccharide (LPS) to 
determine the array of secreted cytokines and chemokines made by T and B cells, 
respectively. Since inflammatory cytokines direct the commitment of antigen-activated 
CD4 T cells to specific effector or FoxP3 regulatory cells, the overall pattern of secreted 
cytokines might indicate a preference towards specific CD4 T-cell commitment. T-cell 
assessments will include those measuring both the number and function of T cells. 
These measures may include the use of class I and class II tetramers to enumerate 
antigen-specific T cells. Additionally, in vitro cell culture techniques may be utilized to 
study T cell functionality. Readouts will include ELISPOT and intracellular staining 
technology for cytokine determination. Additional studies may be done to study 
regulatory T cells in these treated participants. Both carboxyfluorescein diacetate 
succinimidyl ester (CSFE) and 3[H]-thymidine assays could be employed depending on 
cell numbers. Harvested blood cells will be separated by flow-based sorting using CD4, 
CD25 and CD127 antibodies and assayed for their ability to suppress polyclonal T cell 
responses. Follow-up experiments can include examination of Treg cell function as well 
as Foxp3 methylation. Several assays can address responses to autoantigens implicated 
in T1DM. Secretion of various cytokines can be determined, thus enabling 
characterization of overall phenotype (Th1/Th17/Th2/Treg) of T-cell responses, which 
might indicate skewing towards a more regulatory phenotype during imatinib treatment.  
Imatinib can alter the differentiation of human and mouse DCs into mature APCs. The 
treated cells could not be induced to mature with IFNγ or CD40 agonists and were 
unable to stimulate T cells. In fact, the DCs look very much like the “tolerogenic” DCs 
defined in a number of settings. Other cell types may be analyzed that have been shown 
to play important roles in diabetes development and progression. These include B cells, 
NK cells, NKT cells and macrophages. We may perform functional analyses of these 
cells during and after therapy. 
PBMCs will be isolated from blood, frozen by established ITN protocols, and studied 
in batches for quality control and standardization. These assays will be used in an 
attempt to test the hypothesis that imatinib treatment in humans, as in the NOD model, 
will tip the balance of inflammation toward an anti-inflammatory state, thus triggering 


 
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beneficial changes in T cell-directed autoimmunity. 
7.3.2 
FLOW CYTOMETRY PANEL STAINING 
It is essential that we examine both in vivo and in vitro the effects of imatinib on DC 
maturation and function. The ITN core will perform multi-parameter flow cytometry 
on frozen cells. Changes in the following sub-sets of cells during treatment may be 
analyzed using various cell surface markers: B-cells (IgM, CD21, CD23, MHC class II, 
B7, etc); NK and NKT cells; macrophages, and mast cells. Myeloid DC and lymphoid 
DC-specific markers may also be examined to determine if DC number and subsets are 
altered. In addition, expression of activation markers MHC class II, CD40 and CD80, 
and CD86 molecules may be assessed to determine the state of DC maturation. Of 
special interest would be examination of various T cell subsets based on phosphoprotein 
and transcription factor expression, after activation. Flow cytometric evaluations of T 
cell and antigen-presenting cell subsets might complement the functional studies, 
enabling a better understanding of adaptive and innate immune compartments. Flow 
cytometric evaluations may also include the use of class I tetramers for detection of 
CD8 T cells implicated in the pathogenesis of T1DM. Specifically, HLA-A2 tetramers 
that enable detection of CD8 cells specific for the following antigenic peptides could 
be used: GAD 65 114-123, preproinsulin 2-10, IGRP 228-236, insulin B chain 10-18, 
and insulin A chain 1-10. As shown in preliminary studies, these cells can be visualized 
directly ex vivo without a need for in vitro auto-antigen induced expansion. When 
possible other validated class I tetramers may be included as they become available that 
utilize other autoantigen specificities and HLA restriction elements. Alternatively, other 
tools for visualization of autoantigen specific T cells might be used, such as engineered 
antibodies containing dimeric MHC/peptide complexes or other MHC/peptide 
multimers. Finally, we will work with Drs. Eisenbarth and Kappler in Denver to use 
newly developed class II MHC tetramers that take advantage of mutations that fix 
autoantigenic peptides in specific registers to maximize TCR binding. Identification of 
autoantigen-specific CD4 or CD8 T cells directly ex vivo would provide a unique 
opportunity to reveal the function of these cells without manipulation. In combination 
with ex vivo polyclonal activation with agents like 4-phorbol 12-myristate 13-acetate 
(PMA) and ionomycin, it would be possible to also address the cytokine production 
profile of these cells along with expression of co-stimulatory and activation molecules. 
7.3.3 
GENOMICS AND PROTEOMICS 
Imatinib has been shown to have several downstream targets. For instance, imatinib 
treatment of DCs resulted in decreased activation-induced upregulation of nuclear-
localized RelB, RelA, c-Rel, NFkB, p50 and reduced phosphorylation of AKT, 
suggesting that imatinib mediates its effects in part via the NFkB pathway (AKT is 
upstream of NFkB). A reduction of NFkB and phosphorylation of Lck and ERK1/2 
were observed in PHA-stimulated T cells treated with imatinib. These biochemical 
results suggest a series of pathways to be investigated in cells isolated from treated 


 
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individuals. We may analyze the biochemical effect of imatinib in T, B and dendritic 
cells, including the examination of the global effect of imatinib on tyrosine 
phosphorylation in T cells in vitro and in cells recovered from imatinib-treated patients. 
Studies will be designed to determine if imatinib affects phosphorylation of TCR, ZAP-
70 and LAT equally, differentially or not. More precise studies on important protein 
kinases in the TCR signaling pathway, notably ZAP-70, ERK1/2 and AKT, could be 
performed by immunoprecipitation followed by western blotting in order to track their 
phosphorylation state (intra-cellular phospho-flow cytometry may also be used). The 
active form of c-abl may also be assessed in these cells. Similar studies will be 
performed in B cells if data suggests that B cells are a major target for imatinib activity 
in T1DM. The ITN may also examine the effect of imatinib treatment on DCs. Purified 
splenic CD11c+ DCs could be cultured with LPS or CD40L and in the presence or 
absence of imatinib for 24 hours, then nuclear extracts prepared to assess translocation 
of NFkB.  
7.4 
SERUM ASSAYS 
7.4.1 
SERUM-AUTOANTIBODY ANALYSES 
Key markers for the presence of the autoimmune processes directed against pancreatic 
islets include assessing the presence and titers of anti-GAD65, anti-insulin, anti-
ICA512/IA-2, and anti-ICA autoantibodies. Detection of these autoantibody 
combinations has proven to be an accurate predictor of T1DM in several natural history 
studies. In the DPT-1 prevention study, over half of the individuals who were positive 
for two of these antibodies progressed to full disease. Shifts in the titers of Ig isotypes 
may indicate a change in the type of T-helper cell responses to autoantigen. For 
example, increases in titers of anti-GAD IgE, IgG2, or IgG4 antibodies could indicate 
a shift to a more regulatory-type cytokine profile following drug administration. In 
summary, this study will test the hypothesis that successful treatment will be associated 
with a reduction in the titer or isotype of diabetes-related autoantibodies. 
7.4.2 
SERUM ARCHIVE 
Patient serum will be archived for future studies. These studies might include 
measurements of cytokines and subsequent correlation with induction of clinical 
tolerance. The archived plasma samples could potentially be used for analysis of 
immune and inflammatory molecules at the proteosome and transcriptosome levels. In 
addition, expression of pro-inflammatory cytokines (PDGF, IL-1ß, IL-6, IL-12, TNFα), 
molecules that are induced by inflammation (SOCS1, 2, 3 and acute phase reactants, 
e.g., ceruloplasmin, SAA, CRP), and anti-inflammatory cytokines (TGF-ß, IL-10) 
could also be assessed to determine the effect of imatinib treatment. We anticipate that 
novel assays relating to beta cell death may also be run from archived samples using 
differentially methylated circulating DNA180. 


 
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7.5 
WHOLE BLOOD-GENE-EXPRESSION PROFILING 
To further elucidate possible changes in cytokine and cellular profiles, gene-expression 
profiling analysis may be performed on RNA isolated from peripheral blood using 
microarray or high-throughput real-time polymerase chain reaction (RT-PCR). RT-
PCR can be used to compare the expression of several genes reported to play a role in 
T1DM, which might include IFNγ, TGFβ,  IL-4, Tbet, RORγt, FOXP3, STAT 
molecules, IL-2, IL-5, IL-13, IL-15, IL-21, IL-23 and IL-25. The goal of these assays 
is to identify differences between a tolerant versus non-tolerant state and to find new 
genes that could serve as potential markers of disease. These types of analyses may also 
explain why some individuals respond better to this treatment or elucidate mechanisms 
resulting in adverse responses to treatment. This assay has proven informative in 
characterizing unique genes that determine the clinical course in systemic lupus 
erythematosus, and preliminary studies with this technology have enabled us to 
determine a distinct subset of genes that are either up- or down-regulated in those with 
new-onset T1DM as opposed to controls in other studies. 
7.6 
WHOLE BLOOD DNA-HLA GENOTYPES 
DNA collected from participants will be used to perform sequence-based HLA typing. 
A complete class I and class II haplotype will be performed, including fine typing of 
the DQB and DRB regions. Genotyping for single nucleotide polymorphisms (SNPs) 
in selected immune-response genes may also be performed. The results of genotype 
analyses might be used to correlate with disease progression and therapeutic responses 
(tolerance induction). In addition, collected DNA may be used for epigenetic analysis 
that includes histone modification and DNA methylation studies.  
7.7 
CHANGE IN BETA CELL FUNCTION 
Many of the measures that we will utilize in assessing changes in beta cell function are 
now standard assessments in new-onset T1DM trials (see Section 3.3). However, these 
studies have ignored changes in insulin sensitivity. Imatinib may have novel effects on 
beta cell function and insulin sensitivity, as noted by the pre-clinical studies and effects 
in subjects with type 2 diabetes. We recognize that euglycemic hyperinsulinemic 
clamps are the gold standard for assessment of insulin sensitivity, but pose significant 
additional subject and investigative team burden and expense. We will assess changes 
in adiponectin levels in study patients, as these have shown dramatic increases in 
patients with type 2 DM on imatinib126. We will also use data derived from MMTTs to 
model beta cell function and insulin sensitivity, as has been employed by 
others181,182(see letter of collaboration from Ferrannini).   In addition to glucose and c-
peptide levels, plasma glucagon, and proinsulin levels will be measured to further 
explore the effects of Imatinib on insulin sensitivity. 


 
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8. 
ADVERSE EVENTS 
8.1 ADVERSE EVENT DEFINITION 
8.1.1 Adverse Event 
In this clinical trial, an adverse event is any occurrence or worsening of an undesirable 
or unintended sign, symptom or disease whether or not associated with the treatment 
and study procedures.   
Throughout the study, the investigator must record all adverse events on source 
documents.  Events not related to hypo or hyperglycemia that are Grade 2 or greater per 
the NCI CTCAE 4.0 (see Section 8.1.4. Grading Event Severity below) must be 
reported to the Coordinating Center on the appropriate adverse event form.  The 
investigator should treat participants with adverse events appropriately and observe 
them at suitable intervals until the events resolve or stabilize. 
Adverse events may be discovered through: 
• observation of the participant; 
• questioning the participant; 
• unsolicited complaint by the participant 
In questioning the participant the questioning should be conducted in an objective 
manner. 
An abnormal value or result from a clinical or laboratory evaluation (e.g., a radiograph, 
an ultrasound, or an electrocardiogram) can also indicate an AE if it is determined by 
the investigator to be clinically significant.  If this is the case, it must be recorded in the 
source document and as an AE on the appropriate AE form(s). 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. 
8.1.2 Serious Adverse Event 
For this trial, an adverse event associated with the treatment or study procedure that 
suggests a significant hazard, contraindication, side effect or precaution (as described 
below) is to be reported as a serious adverse event (SAE).  A serious adverse event 
(experience) or reaction is any untoward medical occurrence that: 
• results in death, 
• is life-threatening, 
• requires inpatient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, or 
• is a congenital anomaly/birth defect. 


 
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Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious adverse events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
8.1.3 Unexpected Adverse Event 
An adverse event is considered unexpected when the nature (specificity) or severity of 
the event is not consistent with the risks described in the protocol or informed consent 
document for a particular protocol. 
8.1.4 Grading Event Severity 
This study has adopted usage of the National Cancer Institute (NCI) Common 
Technology Criteria for Adverse Events (CTCAE) version 4.0 and/or study-specific 
criteria for classification to describe the severity of adverse events with the exception 
of hyper and hypoglycemia.   For this study, a reportable hypoglycemic event is defined 
as those resulting in loss of consciousness, seizure, or requiring assistance of others due 
to altered state of consciousness and hyperglycemic event is one resulting in DKA. 
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   
8.1.5 
Attribution Definitions 
Adverse events will be categorized for their relation to imatinib.  The investigator will 
determine the relation, or attribution, of an AE to study participation and will record the 
determination on the appropriate CRF and/or SAE reporting form.  The relation of an 
AE to study participation will be determined using definitions in Table 1. 
 
 
 
 


 
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Table 1. Attribution of adverse events 
 
8.2 ADVERSE EVENT REPORTING AND MONITORING 
Study personnel will assess adverse events and the use of concomitant medications 
throughout the study. Adverse events will be reported to the Coordinating Center as 
described below. They will be graded as to severity according to common toxicity 
criteria or study-specific criteria and the investigator will make a determination as to the 
relation to therapy. Events will be assessed and reported in accordance with the ICH 
Guideline For Good Clinical Practice and per the guidance of the DHHS Office for 
Human Research Protections (OHRP). The adverse event case report form for the 
protocol must be completed for all adverse events (AE) of Grade 2 or greater severity 
regardless of relationship to therapy. For reporting serious adverse events (SAE), the 
MedWatch Form should also be completed and faxed to the Coordinating Center within 
24 hours of when the site was notified of the event. This will be reviewed by the study 
Safety Monitoring Committee, and the Data and Safety Monitoring Board (DSMB) as 
appropriate. Deaths must be reported immediately. Event outcome and other follow-up 
information regarding the treatment and resolution of the event will be obtained and 
reported when available, if not known at the time the event is reported. The follow-up 
information should contain sufficient detail to allow for a complete medical assessment 
of the case and an independent determination of possible causality. 
Adverse events will be assessed by the study designated Medical Monitor. The DSMB 
will conduct regular safety reviews approximately every three to six months (and, as 
needed) of adverse events by treatment group assignment. Serious adverse events as 
well as adverse events leading to treatment discontinuation will be reviewed by the 
DSMB. 
Code 
Descriptor 
Definition 
Unrelated Category  
1 
Unrelated 
The adverse event is clearly not related. 
Related Categories  
2 
Unlikely 
The adverse event is doubtfully related. 
3 
Possible 
The adverse event may be related. 
4 
Probable 
The adverse event is likely related. 
5 
Definite 
The adverse event is clearly related. 


 
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8.2.1 
Reporting Pregnancy  
The investigator should be informed immediately of any pregnancy. At each visit the 
investigator will determine the pregnancy status of female participants and that the 
sexual partners of male participants. Pregnancy information should be entered into the 
electronic data capture (EDC) system within 24 hours of becoming aware of the event.  
The investigator should counsel the participant and discuss the risks of continuing with 
the pregnancy and the possible effects on the fetus.  Monitoring of the participant should 
continue until 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 will be reported.  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
recorded as an AE or SAE as described in sections 8.2.1 and 8.2.2. 
9. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Analyses of study data will be conducted to address the primary and secondary 
objectives of the trial, other stated objectives, and other interrelationships among 
elements of study data of interest to the investigators and of relevance to the objectives 
of the study. Such analyses may also entail the use of data from other studies in 
combination with data from this study. Likewise, data from this study may be used in 
combination with data from another study to address objectives of that study.  Analyses 
by gender and race/ethnicity, as appropriate, are also planned. 
9.1 
PRIMARY OUTCOME AND ANALYSES 
The primary outcome of each participant is the area under the stimulated C-peptide 
curve (AUC) over the first 2 hours of a 4-hour mixed meal glucose tolerance test 
conducted at the one-year visit.  The AUC is computed using the trapezoidal rule that 
is a weighted sum of the C-peptide values over the 120 minutes.  By the mean value 
theorem of integral calculus, the weighted mean C-peptide in pmol/mL is simply 
AUC/120. 
The primary statistical hypothesis to be assessed in the study is whether: 
 
The mean C-peptide value for study subjects receiving imatinib is significantly 
higher than the mean value for placebo subjects. 
The primary analysis will employ the weighted mean derived from the 2 hour AUC for 
each participant transformed as log(mean C-peptide+1).  The comparison between the 
two treatment arms will be based on a t-test of treatment effect in an ANCOVA model 
adjusting for gender, baseline age and baseline log(C-peptide+1)190. 
 


 
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9.2 
SECONDARY OUTCOMES AND ANALYSES  
Additional analyses of the primary outcome will include:  
 
A log rank test of the difference in the hazard function between groups in the incidence 
of the loss of the 2 hour peak C-peptide < 0.2 pmol/ml on a semi-annual MMTT 191, and 
 
Longitudinal analyses using mixed effects models with a random intercept and slope of 
the C-peptide values over the post-treatment period, adjusted for the baseline level of 
C-peptide. The average intercept and slope will be compared between groups adjusting 
for age, gender and the baseline log(C-peptide+1). 
Additional secondary objectives are to examine how imatinib affects the following: 
 
Mean area under the stimulated C-peptide curve (AUC) curve at 12 months 
 
Mean area under the stimulated C-peptide curve (AUC) over 4 hours at 24 
months 
 
HbA1c levels over time 
 
Insulin dose (units/kg) over time 
 
Number of severe hypoglycemic events 
 
Number and severity of adverse events 
The mean levels of quantitative variables (e.g. HbA1c and insulin dose) over all follow-
up values will be compared between groups using a normal errors longitudinal analysis.  
The prevalence of a binary characteristic (e.g. yes/no or positive/negative) at a single 
visit (e.g. a history of hypoglycemia during follow-up) will be assessed using a logistic 
regression model. The prevalence of a binary characteristic over time will be assessed 
using generalized estimating equations.  
The rates of severe hypoglycemic events and severe adverse events will be computed 
(total number of events divided by total patient years of follow-up) and the rates 
compared using a Poisson regression model, allowing for over-dispersion using a quasi-
likelihood model as appropriate.  Tests of significance will employ a robust estimate of 
the variance. 
The above analyses will also be conducted to adjust for age, gender, baseline log(C-
peptide+1) and baseline HbA1c; and by race/ethnicity, as appropriate. Analyses will 
also be conducted to examine the effect of HLA or other genotype. 
Analyses will also be conducted to assess heterogeneity of the effect of treatment group 
(the group difference) as a function of age, gender, baseline log(C-peptide+1) and 
baseline HbA1c; and by race/ethnicity and HLA or other genotype. Heterogeneity will 


 
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be assessed using a test of treatment group by covariate interaction in an appropriate 
regression model. 
9.3 
ADDITIONAL OUTCOMES AND ANALYSES 
 
Additional outcomes of interest include 
 
Change in autoantibody levels and/or B cell function 
 
Antigen specific and non-specific T and B cell subset enumeration and function 
 
Responses to vaccination (tetanus and killed flu) 
 
The analyses of each outcome will be conducted using the methods for a quantitative 
outcome, binary outcome, or rate as described in Section 9.2 above. 
9.4 
SAMPLE SIZE AND POWER CALCULATIONS 
The primary analysis will compare the difference between the treated group versus the 
placebo group in the levels of the 2 hour AUC-mean using the log(mean C-peptide+1) 
in an ANCOVA model adjusting for gender, baseline age, and baseline log(C-
peptide+1).  Estimates of log(mean C-peptide+1) and root mean square error (RMSE) 
in the placebo group were obtained from prior studies.  Among subjects with baseline 
C-peptide > 0.2 pmol/ml and age <=21 years, the mean log(C-peptide + 1) values is 
0.306 with RMSE = 0.185.  
The planning parameters for the protocol were based upon the inclusion of adults and 
children. Unfortunately, the FDA has declined the request to lower the age and, 
therefore, the study will only enroll adults at this time.  
Hence, it is appropriate to revisit the design of the study in light of restricting the eligible 
population to be age 18 and over. In previous studies, it has shown the older a participant 
is, the lower the rate of C-peptide loss. This means that the current design of detecting 
a one-year C-peptide projected level 45% greater than expected on the control arm 
corresponds to an increase in C-peptide over the baseline value at enrollment, which is 
not practical. However, analyses completed after this study was initially designed 
indicate that the appropriate variance estimate to use for the sample size calculation 
should be smaller than what was used in the current design.  This has the net effect of 
increasing the sensitivity of the trial to detecting an effect size smaller than the 
advertised value in the current design. 
Using standard equations for the comparison of two means, a sample size of 40 Imatinib 
treated and 20 placebo treated subjects with complete data needed for the primary 
analysis, would provide power of 85% to detect a 0.35 increase in the mean log(C-
peptide + 1) (0.306 vs. 0.445, which corresponds to 75% of the RMSE) in the 
experimental treatment group using a two-sample T- test at the 0.05 level (one-sided). 
Assuming that 10% of the subjects will have missing data (one-year MMTT was not 
done or subject withdrew prior to the one-year assessment), the sample size goal for 


 
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this study is 66 subjects (46 + 22).  Should the number with missing data exceed 10%, 
the study will enroll additional replacement subjects as needed. 
9.5 
INTERIM MONITORING PLAN  
For purposes of the 6-month analysis, a trend for benefit would be an outcome that does 
not exclude a significant result being achieved at the end of Phase 2 with a twelve month 
outcome as specified by the protocol. Changes from baseline in stimulated C-peptide 
mean AUC in T1D patients on placebo have been reported as approximately 30% at 6 
months (Orban et al 201139, Raz et al 2007194). Sample size calculations were thus based 
on the assumption of a ~30% treatment effect at around 6 months of treatment  and a 
standard deviation for baseline- and placebo-adjusted stimulated C-peptide mean AUC 
of 0.39 nmol/liter/2h (Greenbaum et al 2012).  In this case, an interim analysis will 
calculate the conditional power after 21 participants have been evaluated. Based upon 
the table that follows, should the calculated interim  Z value be greater than or equal to 
0.8,  the conditional power would be estimated to be at least .26  and .74 if the true 
effect is as assumed under the alternative hypothesis at study conclusion.  Therefore, a 
threshold will be set on the conditional power as the level-of-proof that the difference 
in stimulated C-peptide mean AUC between gleevec  and placebo is of presumed 
benefit to allow the study to move forward to phase two.  
 
Table of Conditional Power Assuming an Alternate Effect Size (defined as (mu1-
mu0)/2(sd)   =   0.37, an interim analysis at 21 patients and a final analysis at 66 patients.  
Two-tailed alpha = 0.05 
 
Interim Z Value  
 
Conditional Power  
 
Conditional Power 
 
 
 
 
Under Observed Trend 
Under Protocol Assumed Effect 
 
0.0  
 
 
<.01 
 
 
 
.54 
0.4  
 
 
  .06 
 
 
 
.65 
0.8  
 
 
  .26 
 
 
 
.74 
1.2  
 
 
  .58 
 
 
 
.82 
1.6  
 
 
  .86 
 
 
 
.89 
 
Additional interim analyses will be conducted when 50% of the targeted number of 
study subjects have reached the planned end point (i.e., one year of follow up) and will 
be reviewed by the Data and Safety Monitoring Board (DSMB) for assessment of 
effectiveness and safety. If a group sequential stopping boundary is crossed, the DSMB 
may recommend termination of the trial early.   The Lan-DeMets195 spending function 
with an O’Brien-Fleming boundary will be used to protect the type I error probability 
for the primary outcome analyses, and to assess the significance of the interim results 


 
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periodically during the trial.  The spending function that approximates the O’Brien-
Fleming boundaries is: 
     
*
/2
1
*
( )
2
2
Z
t
t








 
 
where 
*t  is the information fraction (
*
0
1
t

), 
1
 is the 
-level

of the interim 
(one-sided) test and  is the over-all type I error. 
 
The DSMB will also consider early termination due to absence of a treatment effect (i.e. 
futility) based on the method suggested by Ellenberg et al196.  The stopping rule is: if 
the t-test (as described in the primary analysis and positive values reflect a higher values 
among the experimental group) is less than or equal to 0 at 
*
0.5
t 
, the study should 
be stopped based on the futility of rejecting the null hypothesis at the completion of the 
trial.  Simulation studies conducted confirmed that this rule combined with the Lan-
DeMets stopping rules have negligible effect on the type I and II error probabilities. 
Additional analysis will assess potential adverse outcomes of treatment and will assess 
the incidence of all severe adverse events.  
 
10. 
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 sponsor, and health authorities 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. 


 
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11. 
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 sponsor 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 Code 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.  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. 
Study staff will enter data from a study visit on the relevant eCRFs within 14 days 
following the visit or the time when data becomes available. 
12. 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE 
12.1 
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 appropriate ethics review committee or 
institutional review board (IRB). Any amendments to the protocol or consent materials 
must also be approved by the Sponsor, the IRB and submitted to FDA before they are 
implemented. 
12.2 
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. 


 
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A copy of the informed consent will be given to a prospective participant for review. 
The study investigator 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. 
12.3 
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. 
13. 
PUBLICATION POLICY 
The JDRF policy on publication of study results will apply to this study.  
 
 


 
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14. 
REFERENCES 
1. 
Association AD. Standards of medical care in diabetes--2012. Diabetes Care. Jan 2012;35 Suppl 
1:S11-63. 
2. 
Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes mellitus. N Engl 
J Med. Nov 24 1994;331(21):1428-1436. 
3. 
Bach JF. Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev. Aug 
1994;15(4):516-542. 
4. 
Castano L, Eisenbarth GS. Type-I diabetes: a chronic autoimmune disease of human, mouse, 
and rat. Annu Rev Immunol. 1990;8:647-679. 
5. 
Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 
1 diabetes. Nature. Apr 2010;464(7293):1293-1300. 
6. 
Group TDCaCTR. The effect of intensive treatment of diabetes on the development and 
progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 
Sep 30 1993;329(14):977-986. 
7. 
Madsbad S, Faber OK, Binder C, McNair P, Christiansen C, Transbol I. Prevalence of residual 
beta-cell function in insulin-dependent diabetics in relation to age at onset and duration of 
diabetes. Diabetes. 1978;27 Suppl 1:262-264. 
8. 
O'Meara NM, Sturis J, Herold KC, Ostrega DM, Polonsky KS. Alterations in the patterns of 
insulin secretion before and after diagnosis of IDDM. Diabetes Care. Apr 1995;18(4):568-571. 
9. 
Steele C, Hagopian WA, Gitelman S, et al. Insulin secretion in type 1 diabetes. Diabetes. Feb 
2004;53(2):426-433. 
10. 
Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the 
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Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist. 
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131. 
Hochhaus A, Druker B, Sawyers C, et al. Favorable long-term follow-up results over 6 years for 
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Champagne MA, Capdeville R, Krailo M, et al. Imatinib mesylate (STI571) for treatment of 
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133. 
Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in 
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134. 
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135. 
Millot F, Guilhot J, Nelken B, et al. Imatinib mesylate is effective in children with chronic 
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136. 
Cario-Andre M, Ardilouze L, Pain C, Gauthier Y, Mahon FX, Taieb A. Imatinib mesilate 
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Han H, Yu YY, Wang YH. Imatinib mesylate-induced repigmentation of vitiligo lesions in a 
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139. 
Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib 
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140. 
Verweij J, Casali PG, Kotasek D, et al. Imatinib does not induce cardiac left ventricular failure 
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141. 
Atallah E, Durand JB, Kantarjian H, Cortes J. Congestive heart failure is a rare event in patients 
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Chintalgattu V, Ai D, Langley RR, et al. Cardiomyocyte PDGFR-beta signaling is an essential 
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143. 
Ali R, Ozkalemkas F, Kimya Y, et al. Imatinib use during pregnancy and breast feeding: a case 
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Ali R, Ozkalemkas F, Ozcelik T, Ozkocaman V, Ozkan A. Imatinib and pregnancy. J Clin 
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Ault P, Kantarjian H, O'Brien S, et al. Pregnancy among patients with chronic myeloid leukemia 
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Buyukbayrak EE, Ergen B, Karsidag YK, Kars B, Turan C, Argon D. Pregnancy complicated 
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148. 
Dolai TK, Bhargava R, Mahapatra M, et al. Is imatinib safe during pregnancy? Leuk Res. Apr 
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149. 
Hensley ML, Ford JM. Imatinib treatment: specific issues related to safety, fertility, and 
pregnancy. Semin Hematol. Apr 2003;40(2 Suppl 2):21-25. 
150. 
Pye SM, Cortes J, Ault P, et al. The effects of imatinib on pregnancy outcome. Blood. Jun 15 
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151. 
Skoumalova I, Vondrakova J, Rohon P, et al. Successful childbirth in a patient with chronic 
myelogenous leukemia treated with imatinib mesylate during early pregnancy. Biomed Pap Med 
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152. 
Berman E, Nicolaides M, Maki RG, et al. Altered bone and mineral metabolism in patients 
receiving imatinib mesylate. N Engl J Med. May 11 2006;354(19):2006-2013. 
153. 
O'Sullivan S, Naot D, Callon K, et al. Imatinib promotes osteoblast differentiation by inhibiting 
PDGFR signaling and inhibits osteoclastogenesis by both direct and stromal cell-dependent 
mechanisms. J Bone Miner Res. Nov 2007;22(11):1679-1689. 
154. 
Vandyke K, Dewar AL, Fitter S, et al. Imatinib mesylate causes growth plate closure in vivo. 
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155. 
Kimoto T, Inoue M, Kawa K. Growth deceleration in a girl treated with imatinib. Int J Hematol. 
Mar 2009;89(2):251-252. 
156. 
Mariani S, Giona F, Basciani S, Brama M, Gnessi L. Low bone density and decreased inhibin-
B/FSH ratio in a boy treated with imatinib during puberty. Lancet. Jul 12 2008;372(9633):111-
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157. 
Schmid H, Jaeger BA, Lohse J, Suttorp M. Longitudinal growth retardation in a prepuberal girl 
with chronic myeloid leukemia on long-term treatment with imatinib. Haematologica. Aug 
2009;94(8):1177-1179. 
158. 
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Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group 
study. Journal of Clinical Oncology. 2009;27(31):5175-5181. 


 
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Shima Y, Nozu K, Nozu Y, et al. Recurrent EIARF and PRES with severe renal hypouricemia 
by compound heterozygous SLC2A9 mutation. Pediatrics. Jun 2011;127(6):e1621-1625. 
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Suttorp M, Yaniv I, Schultz KR. Controversies in the treatment of CML in children and 
adolescents: TKIs versus BMT? Biol Blood Marrow Transplant. Jan 2011;17(1 Suppl):S115-
122. 
161. 
Pollack IF, Jakacki R, Blaney s, et al. Phase I trial of imatinib in children withnewly diagnosed 
brainstem and recurrentmalignant gliomas: A Pediatric Brain TumorConsortium report1. Neuro-
Onc. 2007(April):145-160. 
162. 
Pollack IF, Jakacki R, Blaney S, et al. Phase I trial of imatinib in children with newly diagnosed 
brainstem and recurrent malignant gliomas: A Pediatric Brain Tumor Consortium report. Neuro-
Onc. 2007(April):145-160. 
163. 
Greulich W, Pyle S. Radiographic Atlas of Skeletal Development of the Hand and Wrist, 2nd 
edition. Stanford, CA: Stanford University Press; 1959. 
164. 
Incidence and trends of childhood Type 1 diabetes worldwide 1990-1999. DIAMOND Project 
Group. Diabet Med. Aug 2006;23(8):857-866. 
165. 
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. Jun 13 2009;373(9680):2027-2033. 
166. 
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. Sep 2002;25(9):1584-1590. 
167. 
Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. Jama. 
May 15 2002;287(19):2563-2569. 
168. 
Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular 
disease in patients with type 1 diabetes. N Engl J Med. Dec 22 2005;353(25):2643-2653. 
169. 
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. Jun 5 2003;348(23):2294-2303. 
170. 
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. Dec 2008;126(12):1707-1715. 
171. 
Montanya E, Fernandez-Castaner M, Soler J. Improved metabolic control preserved beta-cell 
function two years after diagnosis of insulin-dependent diabetes mellitus. Diabetes Metab. Sep 
1997;23(4):314-319. 
172. 
Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 
diabetes mellitus. N Engl J Med. May 30 2002;346(22):1692-1698. 
173. 
Palmer JP, Fleming GA, Greenbaum CJ, et al. C-peptide is the appropriate outcome measure for 
type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 
October 2001. Diabetes. Jan 2004;53(1):250-264. 
174. 
Ludvigsson J, Faresjo M, Hjorth M, et al. GAD treatment and insulin secretion in recent-onset 
type 1 diabetes. N Engl J Med. Oct 30 2008;359(18):1909-1920. 
175. 
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. Apr 2010;33(4):826-832. 
176. 
Braziel RM, Launder TM, Druker BJ, et al. Hematopathologic and cytogenetic findings in 
imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months' experience. 
Blood. Jul 15 2002;100(2):435-441. 
177. 
Peng B, Hayes M, Resta D, et al. Pharmacokinetics and pharmacodynamics of imatinib in a 
phase I trial with chronic myeloid leukemia patients. J Clin Oncol. Mar 1 2004;22(5):935-942. 
178. 
Greenbaum CJ, Beam CA, Coulware D, Gitelman SE, Gottlieb PA, Herold KC, Lachin JM, 
McGee P, Palmer JP, Pescovitz MD, Krause-Steinrauf H, Skyler JS, Sosenko JM, Type 1 
Diabetes TrialNet Study Group. Fall in C-peptide Over First Two Years from Diagnosis: 


 
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Evidence of At Least Two Distinct Phases from Composite TrialNet Data. Diabetes. 2012; 61: 
2066-2073. 
179. 
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180. 
Akirav EM, Lebastchi J, Galvan EM, et al. Detection of β cell death in diabetes using 
differentially methylated circulating DNA. Proc Natl Acad Sci U S A. Nov 2011;108(47):19018-
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Ferrannini E, Mari A, Nofrate V, Sosenko JM, Skyler JS, Group D-S. Progression to diabetes in 
relatives of type 1 diabetic patients: mechanisms and mode of onset. Diabetes. Mar 
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182. 
Cobelli C, Toffolo GM, Dalla Man C, et al. Assessment of beta-cell function in humans, 
simultaneously with insulin sensitivity and hepatic extraction, from intravenous and oral glucose 
tests. Am J Physiol Endocrinol Metab. Jul 2007;293(1):E1-E15. 
183. 
Lachin JM MM. Reassessment of Sample-size Requirements for TrialNet New-onset Studies. . 
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184. 
Lan K, DeMets D. Discrete sequential boundaries for clinical trials. Biometrika. 1983;70(3):659-
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Lachin JM. A Review of Methods for Futility Stopping Based on Conditional Power. Statistics 
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Diggle PJ, Liang KY and Zeger SL (1994). Analysis of Longitudinal Data. Clarendon Press, 
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187. 
Lachin JM (2000). Biostatistical Methods: The Assessment of Relative Risks. John Wiley and 
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Lachin JM. A review of methods for futility stopping based on conditional power. Statistics in 
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Diggle PJ, Liang KY and Zeger SL (1994). Analysis of Longitudinal Data. Clarendon Press, 
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Lachin JM. A review of methods for futility stopping based on conditional power. Statistics in 
Medicine, 24, 2747-2764, 2005. 
194. 
Raz I, Avron A, Tamir M et al. Treatment of new-onset type 1 diabetes with peptide DiaPep277 
is safe and associated with preserved beta-cell function: extension of a randomized, double-
blind, phase II trial. Diabetes Metab Res Rev. 2007: 23: 292–298. 
195. 
Lan KKG, DeMets DL (1983). Discrete sequential boundaries for clinical trials. Biometrika, 70: 
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Appendix 1. Schedule of Events 
Week 
-3 to  -4 
0 
2 
4 
9 
13 
17 
22 
26 
39 
52 
78 
104 
Visit 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
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 
Physical examination1 
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
Secondary sexual characteristics2 
 
X 
 
 
 
 
 
 
 
 
(X) 
 
(X) 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Monitoring (if applicable) 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
ECG 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
LABORATORY ASSESSMENTS 
Serum chemistries and liver panel3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Autoantibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology4  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infectious disease serology5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PPD skin test or IGRA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine hCG 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Prostate Specific Antigen (males only) 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
C-peptide levels (tested from MMTT)6 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
                                                          
1Excluding genitalia unless clinically indicated   
2 The Tanner stages will be assessed at the baseline visit for every participant under 18 years of age. 
After the baseline visit, Tanner stages will be assessed annually on all participants who are < stage 3. 
If the Tanner stage is ≥3  at the baseline visit or any subsequent visit, Tanner stages will not need to 
be assessed at any future visit. 
3 To include sodium, calcium, potassium, chloride, phosphate, total CO2, BUN, creatinine, AST, ALT, 
alkaline phosphate, direct and total bilirubin. 
4 Performed locally; to include CBC with differential and platelets. 
5 Hepatitis B and C, HIV, toxoplasmosis, VZV, EBV, and CMV serology. CMV/EBV PCR testing may 
be obtained (centrally) or locally, if necessary to confirm active infection. 
6 4-hour MMTT at Visits -1, 9, 11 and 2-hour MMTT at Visits 4, 7, and 10. 


 
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Week 
-3 to  -4 
0 
2 
4 
9 
13 
17 
22 
26 
39 
52 
78 
104 
Visit 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Plasma Glucose (tested from MMTT)5 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
HbA1C levels 
X 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
STUDY DRUG ADMINISTRATION 
Study drug administration 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Study drug compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
DISEASE SPECIFIC ASSESSMENTS 
Glucose (Glucometer Reading) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Insulin use 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypoglycemia assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum-Adiponectin7 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
Plasma-Glucagon6  
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Plasma-Proinsulin6 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
BONE AND MINERAL METABOLISM 
Serum Calcium8 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
Serum Phosphate7 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
PTH 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
25-OH Vitamin D 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Serum CTX9 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Osteocalcin8 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
GROWTH RATE ASSESSMENTS10 
Plain Radiograph of Left Hand 
 
X 
 
 
 
 
 
 
 
 
X11 
 
X10 
Height by Stadiometer12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Arm span 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
                                                          
7 Samples will be archived for potential future testing. 
8 Tested as part of serum chemistry panel. 
9 Samples will be archived and tested if clinically indicated. 
10 To be performed on growing-age participants per Section 5.2.9.   
11 Bone age will be assessed annually until epiphyses are near complete closure (98% of mature height 
at bone age of 15 yrs 9 months for boys, 14 yrs for girls). 
12 Subjects will need to be measured with a wall mounted stadiometer to insure accurate height 
measurements. 


 
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Week 
-3 to  -4 
0 
2 
4 
9 
13 
17 
22 
26 
39 
52 
78 
104 
Visit 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
IGF-1, IGF-BP3, LH, FSH, Estradiol 
(females), Testosterone (males)13 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
Total IgA 
 
X14 
 
 
 
 
 
 
 
 
 
 
 
TSH and T4 
 
X13 
 
 
 
 
 
 
 
 
X15 
 
X14 
Tissue transglutaminase (IgA)16 
 
X13 
 
 
 
 
 
 
 
 
X14 
 
X14 
MECHANISTIC ASSAYS 
Serum-Autoantibody Analysis 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
PBMC-Flow Cytometry Panel 
Staining 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
PBMC-Cell Based Assays 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
PBMC-Genomics, Proteomics 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
PBMC- FOXP3 Methylation Assay 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Whole Blood-Gene Expression 
Profiling 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Whole Blood DNA-HLA Genotypes 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Plasma-Archive 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Serum- Beta Cell Death Assay 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
X 
Serum-Cytokines 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
 
 
                                                          
13 Samples will be archived and tested if clinically indicated. 
14 Tested at Baseline only if not tested by referring physician within 3 months prior to Baseline. 
15 Samples will be collected at Visits 9 and 11 only if clinically indicated in growing age participants.  If 
required, testing will be performed real-time. 
16 Performed locally. 


 
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Appendix 2. Procedures for Performing the Mixed-Meal Tolerance Test 
The mixed-meal tolerance test (MMTT) is performed in the morning (between 7:00 
a.m. and 10:00 a.m.), which means that administration must begin within this time. It is 
recommended that the tests be scheduled early in the morning (7:00–7:30 am) because 
blood glucose will be more likely to be within the target range at that time. 
The mixed meal used in this protocol will be the Boost® High Protein Nutritional Drink 
(Nestlé Nutrition). If a participant has a known food allergy to one or more components 
of Boost, an equivalent substitution may be used. The MMTT should take 250 minutes 
to perform. 
Dietary Guidelines and Pretest Instructions 
Carbohydrates (CHO) should not be restricted from the diet before the test. A general 
guideline is that preadolescent participants should consume at least 25 kcal (6.25 g) 
CHO/kg/day and adolescent and adult participants should consume at least 15 kcal (3.75 
g) CHO/kg/day for 3 days before the test. These are minimum amounts of CHO; most 
diets will include greater amounts of CHO. There is no need to alter the participant’s 
diet unless he or she has been on a CHO-restricted diet. 
In preparation for the visit, each participant should: 
 
Fast for at least 10 hours (but not more than 16 hours) before the test. Fasting should 
start the night before the test, and should continue up until the start of the test. 
Participants should not eat or drink anything except water. This means no coffee, 
tea, soda, cigarettes, alcohol, or chewing gum during the fasting period. 
 
Refrain from vigorous exercise during the fasting period. 
 
Refrain from working the night before the morning of the test. 
 
Discontinue taking any prescription medications that must be taken daily. 
Glucose and Insulin Before the Test  
 
Short-acting insulin analogues (such as lispro or l-aspart) may be administered up 
to 2 hours before the test.  
 
Regular insulin may be administered up to 6 hours before the test.  
 
Intermediate-acting insulin (such as NPH) may be administered on the evening 
before the MMTT, but not on the morning of the test. Participants managed with 
intermediate-acting insulin (NPH or Lente) should administer their usual dose on 
the evening before the MMTT, but not on the morning of the test. 
 
Long-acting basal (such as glargine) insulin or continuous subcutaneous insulin 
infusion may be administered before, during and after the test as usual. Participants 
on glargine may take their usual injection at the appropriate time, and those on 


 
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continuous subcutaneous insulin infusion may continue with their usual basal 
settings. 
Target Glucose Level at the Start of Test 
The target glucose level at the start of the test is between 70 and 200 mg/dL. Regular 
insulin or short acting insulin analogues may be used up to 6 and 2 hours before the test, 
respectively, to achieve the desired glucose level. The investigator and the study 
participant should discuss the individual situation for insulin administration to attain the 
goal of meter capillary glucose values within the range of 70–200 mg/dL at the start of 
the test. For example, as a practical matter, participants may be instructed to check their 
blood glucose by meter at home 2 hours before the start of the test so that marked 
hyperglycemia can be treated with a short-acting insulin analogue. Alternatively, 
participants who arrive at the research unit with elevated blood glucose can receive 
additional short-acting insulin analogues at the time of their arrival, if the test itself does 
not start until at least 2 hours after insulin administration and occurs before 10 a.m.  
IV Placement During the Test 
 
The IV should be in place for the duration of the test and must be flushed after each 
draw with saline solution or heparin flush. 
 
The participant should remain sitting or resting in bed quietly throughout the test 
and until the test is completed. However, he or she may engage in quiet, non-
strenuous activities, such as reading, playing cards, or watching TV. The participant 
may walk to the bathroom between blood draws if necessary.  
Testing Instructions 
Time Point −10 minutes 
 
The first sample should be taken at least 10 minutes after establishing the line(s) 
and when the participant is calm and relaxed (if possible, depending on age) - this 
is the “−10 minute” sample. 
 
Draw one 1.2 mL sample into the lavender top K2 ETDA tube for C-peptide. After 
each sample is collected, the sample tube must be inverted gently at least 8 to 10 
times. Chill sample in a bucket of crushed ice or in a refrigerator set at 4˚C for 20 
to 30 minutes. At the laboratory, spin the tube in a refrigerated centrifuge (1000–
1300 g, ~3000RPM) for 10 minutes. Tubes must be spun within 60 minutes of blood 
draw. Freeze the sample at -80°C.  
 
Draw one 1.2 mL sample into the gray top K Oxalate / Na Fluoride tube for glucose. 
Invert tube gently 8 to 10 times. If it is not possible to centrifuge the sample 
immediately post collection, chill sample in a bucket of crushed ice or in a 
refrigerator set at 4˚C for 20 to 30 minutes. Refrigerate the sample no longer than 
one hour prior to centrifugation. 


 
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Protocol Final Version 8.0 
August 23, 2016  
 
 
Draw sample into the provided K2EDTA tube for glucagon/proinsulin. Invert tube 
gently 8 to 10 times. If it is not possible to centrifuge the sample immediately post 
collection, chill sample in a bucket of crushed ice or in a refrigerator set at 4˚C for 
20 to 30 minutes. Refrigerate the sample no longer than one hour prior to 
centrifugation. 
 
Time Point 0 minutes 
 
The second sample should be taken just before the participant drinks the Boost® 
High Protein; this is the “0- minute” sample. 
 
Then the MMTT dose should be given with 6 kcal/kg @ 1 kcal/mL of mixed meal, 
to a maximum of 360 mL. The participant should consume the MMTT dose in no 
more than 5 minutes. 
Time Points 15, 30, 60, 90, 120, 150, 180, 210, and 240 minutes 
 
Draw one 1.2 mL sample into the lavender-top K2 EDTA tube for C-peptide levels. 
Refrigerate the sample 
 
Draw one 1.2 mL sample into the gray-top K Oxalate / Na Fluoride tube for glucose 
at each of the time points specified.  
 
Draw one 1.2 mL samples into the lavender-top K2EDTA tube for 
glucagon/proinsulin at each of the time points specified. 
 
Invert all tubes gently 8 to 10 times after collection. If it is not possible to centrifuge 
the sample immediately post collection, chill sample in a bucket of crushed ice or 
in a refrigerator set at 4˚C for 20 to 30 minutes. Refrigerate the sample no longer 
than one hour prior to centrifugation.  
 
At the conclusion of the test, please check blood glucose by glucometer, and 
administer insulin as per participant’s standard insulin plan. 
Tube-Processing Instructions 
 
Spin the collection tubes. Then transfer the plasma into individual vials. Please 
make sure that each vial is properly identified with a label that indicates the time 
point. 
 
Freeze the samples for glucose, C-peptide levels, and glucagon/proinsulin. 
 
Ship the glucose and C-peptide specimens to the laboratory where the assays will 
be performed. 
 
Ship the glucagon/proinsulin specimens to the laboratory where the samples will be 
stored until testing is initiated at the end of the study. 
A clogged line, missed sample, or other deviation from the protocol must be noted on 
the Comments section of the MMTT specimen transmittal form. 


 
CONFIDENTIAL 
Page 79 
Imatinib in New-onset T1DM 
Protocol Final Version 8.0 
August 23, 2016  
 
 
 
Time 
(minutes) 
Glucose Sample 
Taken 
C-peptide / Sample 
Taken 
–10 
X 
X 
  0 
X 
X 
Participant drinks Boost® 
 
 
15 
X 
X 
30 
X 
X 
60 
X 
X 
90 
X 
X 
120 
X 
X 
150 
X 
X 
180 
X 
X 
210 
X 
X 
240 
X 
X