Clinical trial NCT01773707
Conditions: Abnormal Glucose Tolerance Type 1 Diabetes
Keywords: prevention of type 1 diabetes prevention of abnormal glucose tolerance
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Start date: 2013-03-01; Completion date: 2022-12-14
Enrollment: 212 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is a 2-arm, multicenter, 1:1 randomized, placebo controlled clinical trial.

All subjects will receive close monitoring for development of AGT or T1DM. Subjects will receive Abatacept or placebo and close monitoring for development of AGT or T1DM. To assess the safety, efficacy, and mode of action of Abatacept to prevent AGT and T1DM.

The primary objective is to determine whether intervention with Abatacept will prevent or delay the development of AGT in at-risk autoantibody positive non-diabetic relatives of patients with T1DM.

Secondary outcomes include: the effect of Abatacept on the incidence of T1DM; analyses of C-peptide and other measures from the OGTT; safety and tolerability; and mechanistic outcomes.

Detailed description:
Study Purpose and Rationale:

In this study, relatives who are confirmed to have two or more antibodies, not including mIAA, and normal glucose tolerance will be eligible for randomization to experimental treatment or placebo groups with the aim to determine whether experimental treatment will prevent or delay the occurrence of abnormal glucose tolerance and type 1 diabetes mellitus. Individuals with normal glucose tolerance are earlier in the disease process; that is, have less beta cell destruction than those with abnormal glucose tolerance or frank diabetes, yet will inevitably progress to clinical disease and essentially complete beta cell loss. Treatment at this early stage in a population who will inevitably progress to type 1 diabetes provides the greatest opportunity for a clinically important impact on disease prevention. With abnormal glucose tolerance rather than diabetes as the primary endpoint, study participants, regulators, funders, and investigators will be able to determine whether the therapy can alter disease progression.

Therefore, the rationale for this study is that individuals with immunologic markers of T1DM and normal glucose tolerance will inevitably develop clinical T1DM. Prior to development of clinical T1DM they will progress from normal glucose tolerance to abnormal glucose tolerance; and abnormal glucose tolerance results in clinical T1DM within 5 years in almost 80% of subjects. They have a condition that differs from overt diabetes only in the duration of the autoimmune process that results in beta cell destruction. Intervention early in the course of disease may be more effective than intervention in those with abnormal glucose tolerance or clinical T1DM.

Description of Treatment Groups

Subjects will be randomized to receive either Abatacept or placebo infusions along with close monitoring for abnormal glucose tolerance or diabetes. The infusions will be conducted at approved TrialNet clinical sites with appropriate facilities. All blood and serum samples for the primary and secondary outcome determinations will be sent to the Core Laboratories for analysis. Clinical laboratory studies may be done at the local sites.

Participants will be randomly assigned in a 1:1 ratio (within the two strata defined by age at enrollment: \<18 and 18 or older) to the following 2 groups:

* to receive Abatacept (intravenous infusion at 0, 2, and 4 weeks following randomization, and then every 28+/-7 days) thereafter for a total of 14 doses. Close monitoring for diabetes development through the duration of study.
* to receive placebo intravenous infusion at 0, 2, and 4 weeks following randomization and then every 28+/- 7 days thereafter for a total of 14 doses. Close monitoring for diabetes development through the duration of study.

Treatment Assignment

After participants sign the consent form, complete the screening visit(s), and meet all of the inclusion criteria and none of the exclusion criteria, participants will be randomized to receive either Abatacept and close monitoring or placebo with close monitoring.

Participants will be randomized in equal allocations to each group. The randomization method will be stratified by TrialNet study site and whether the participant is less than 18 years of age or 18 years and older. This approach ensures that study site will not be a potential confounder. The TNCC will generate the randomization numbers and tables.

Study Assessments

During the course of the study, participants will frequently undergo assessments of their glucose tolerance status, insulin production, immunologic status, and overall health and well-being.

Samples will be drawn for storage in the National Institute for Diabetes and Digestive and Kidney Disease (NIDDK) Repository and at TrialNet Laboratory Sites for future analysis related to T1DM.

Study Duration

The study has been designed to provide 80% power to detect a 40% risk reduction in the occurrence of abnormal glucose tolerance using a two-sided test at the 0.05 level after six years of study duration. A total of approximately 206 patients will be allocated in a 1:1 ratio to the two groups.

Arms: arm 1: CTLA4-Ig (Abatacept) will be administered as 14 (30 minute) infusions over one year (3 infusions every other week the first month; monthly for the following 11 months) arm 2: The placebo arm will receive 14 (30 minute) IV infusions (containing saline) given 3 times (every other week) the first month and monthly for the following 11 months.
Interventions: intervention 1: CTLA4-Ig (Abatacept) intervention 2: Placebo
Intervention descriptions: intervention 1: Given as 30 minute IV infusion intervention 2: Saline given as 30 minute IV infusion

Protocol documents:
Prot_000.pdf: 
Page 1 of 44
CTLA-4 Ig (Abatacept) FOR PREVENTION OF ABNORMAL 
GLUCOSE TOLERANCE AND DIABETES IN RELATIVES 
AT-RISK FOR TYPE 1 DIABETES MELLITUS 
(Protocol TN-18)
VERSION 8.0 
June 03, 2020
IND # 117,208
Supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
of the National Institutes of Health and the Juvenile Diabetes Research Foundation (JDRF)  
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PREFACE
The TrialNet Type 1 Diabetes Protocol TN-18, CTLA-4 Ig (abatacept) for Prevention of Abnormal 
Glucose Tolerance and Diabetes in Relatives At-Risk for Type 1 Diabetes Mellitus, describes the 
background, design, and organization of the study.  The protocol will be maintained by the TrialNet 
Coordinating Center (TNCC) over the course of the study through new releases of the entire protocol, 
or issuance of updates either in the form of revisions of complete chapters or pages thereof, or in the 
form of supplemental protocol memoranda.
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TABLE OF CONTENTS
1.
INTRODUCTION ...........................................................................................................................................5
1.1.
Study Overview ......................................................................................................................................5
1.2.
Statement of Purpose.............................................................................................................................6
2.
BACKGROUND AND SIGNIFICANCE..........................................................................................................7
2.1.
Type 1 Diabetes (T1DM) ........................................................................................................................7
2.1.1.
Definition and Metabolic Characteristics of Type 1 Diabetes Mellitus ............................................7
2.1.2.
Natural History of Type 1 Diabetes Mellitus (T1DM) ......................................................................7
2.2.
Rationale for use of CTLA-4 Ig .............................................................................................................11
2.2.1.
Presumed mechanism of action ...................................................................................................11
3.
CLINICAL AND PRE-CLINICAL DATA........................................................................................................12
3.1.
Pre-Clinical Data...................................................................................................................................12
3.2.
Clinical Trials ........................................................................................................................................13
3.2.1.
Type 1 Diabetes Mellitus (T1DM) .................................................................................................13
3.3.
Clinical Experience in Children: Type 1 Diabetes Mellitus (T1DM), Juvenile Idiopathic Arthritis (JIA), 
Rheumatoid Arthritis (RA), and Other Clinical Experience...............................................................................14
3.3.1        Type 1 Diabetes (T1DM) ………………………..……………………………………………………...14
3.3.2        Juvenile Idiopathic Arthritis (JIA)… …………………...……………………………………………….14
3.3.3        Rheumatoid Arthritis (RA)……………………………………………… ……………………………...15
3.3.4
Other Clinical Experience .............................................................................................................15
4.
STUDY DESIGN..........................................................................................................................................15
4.1.
Overview...............................................................................................................................................15
4.2.
Objectives.............................................................................................................................................16
4.2.1.
Primary Objective .........................................................................................................................16
4.2.2.
Secondary Objectives...................................................................................................................16
4.3.
Summary of Inclusion/Exclusion Criteria ..............................................................................................16
4.3.1.
Inclusion Criteria...........................................................................................................................16
4.3.2.
Exclusion Criteria..........................................................................................................................17
4.4.
Enrollment ............................................................................................................................................18
4.5.
Description of Treatment Groups .........................................................................................................18
4.6.
Treatment Assignment .........................................................................................................................18
4.7.
Study Assessments ..............................................................................................................................18
4.8.
Quality Assurance ................................................................................................................................19
4.9.
Study Timeline......................................................................................................................................19
4.9.1.
Study Duration..............................................................................................................................19
4.9.2.
Follow-up Studies .........................................................................................................................19
5.
PATIENT MANAGEMENT...........................................................................................................................20
5.1.
Screening Visit and Eligibility Assessment...........................................................................................20
5.2.
Abatacept Trial for At-risk Subjects Baseline Visit................................................................................20
5.3.
Randomization and Baseline visits.......................................................................................................20
5.4.
Close Monitoring...................................................................................................................................21
5.5.
Administration of CTLA-4 Ig .................................................................................................................21
5.5.1.
Dosing and Dose Withholding ......................................................................................................21
6.
STUDY VISIT ASSESSMENTS...................................................................................................................22
6.1.
General Assessments ..........................................................................................................................22
6.2.
Laboratory Assessments ......................................................................................................................22
6.3.
Mechanistic Outcome Assessments.....................................................................................................23
6.4.
Metabolic Outcome Assessments ........................................................................................................23
6.5.
Laboratory Measures Related to Abatacept Administration .................................................................23
6.6.
Visit Windows .......................................................................................................................................23
7.
ADVERSE EVENT REPORTING AND SAFETY MONITORING ................................................................23
7.1.
Adverse Event Definition ......................................................................................................................24
7.1.1.
Adverse Event ..............................................................................................................................24
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7.1.2.
Adverse Reaction .........................................................................................................................24
7.1.3.
Serious Adverse Event/Reaction..................................................................................................24
7.1.4.
Unexpected Adverse Event ..........................................................................................................25
7.1.5.
Grading Event Severity and Causality..........................................................................................25
7.2.
Adverse Event Reporting and Monitoring.............................................................................................25
8.
PARTICIPANT SAFETY ..............................................................................................................................26
8.1.
Risks, Benefits and Inclusion of Children .............................................................................................26
8.2.
Protecting Against or Minimizing Potential Treatment Risks................................................................26
8.2.1.
Prohibited Medications .................................................................................................................27
8.3.
Expected Side Effects and Adverse Events .........................................................................................27
8.3.1.
Infusion and Hypersensitivity Reactions.......................................................................................27
8.3.2.
Infectious Adverse Events ............................................................................................................27
8.3.3.
Immunizations...............................................................................................................................28
8.3.4.
Drug Interactions ..........................................................................................................................28
8.3.5.
Blood Glucose Testing..................................................................................................................28
8.3.6.
Other Reported Adverse Events...................................................................................................28
8.3.7.
Pregnancy.....................................................................................................................................29
9.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN .......................................................................29
9.1.
Primary Outcome..................................................................................................................................29
9.2.
Primary Analysis...................................................................................................................................30
9.3.
Secondary Outcomes and Analyses ....................................................................................................31
9.4.
Study Power and Accrual Target..........................................................................................................32
9.5.
Interim Monitoring Plan.........................................................................................................................32
9.6.
Withdrawal Criteria – Individual Subjects .............................................................................................33
10.
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE ........................33
10.1.
Statement of Compliance .................................................................................................................33
10.2.
Participating Centers ........................................................................................................................33
10.3.
Informed Consent .............................................................................................................................34
10.4.
Study Subject Confidentiality............................................................................................................34
10.5.
Risks and Benefits............................................................................................................................35
10.6.
Ethics................................................................................................................................................35
11.
STUDY ADMINISTRATION.........................................................................................................................35
11.1.
Organizational Structure...................................................................................................................35
11.2.
Role of Industry ................................................................................................................................36
11.3.
Groups and Committees...................................................................................................................36
11.3.1.
Abatacept Prevention Study Chair Committee .........................................................................36
11.3.2.
TrialNet Chairman’s Office and TNCC......................................................................................36
11.3.3.
Clinical Sites .............................................................................................................................36
11.3.4.
Endpoint Adjudication Committee.............................................................................................36
11.3.5.
Clinical Site Monitoring .............................................................................................................36
11.4.
Medical Monitor and Data Safety and Monitoring Board (DSMB) ....................................................37
11.5.
Sample and Data Storage ................................................................................................................37
11.6.
Preservation of the Integrity of the Study .........................................................................................37
11.7.
Participant Reimbursement and Compensation ...............................................................................38
APPENDIX 1 - Natural History/Pathway to Prevention to Abatacept in At-Risk Relatives Study Flow Chart...…39
APPENDIX 2 - Schedule of Assessments............................................................................................................41
12.
REFERENCES ............................................................................................................................................42
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1. INTRODUCTION
1.1.
Study Overview
Title
CTLA-4 Ig (abatacept) for prevention of abnormal glucose 
tolerance (AGT) and diabetes in relatives at-risk for Type 1 
diabetes mellitus (T1DM)
IND Sponsor
Type 1 Diabetes Trial Network (TrialNet)
Study Supported by
National Institute of Diabetes, Digestive and Kidney Diseases
Conducted By 
Type 1 Diabetes Trial Network (TrialNet)
Protocol Chair
Dr. William E. Russell, M.D.
Accrual Objective
206 
Study Design
The study is a 2-arm, double blinded, multicenter, 1:1 
randomized, placebo controlled clinical trial.  All subjects will 
receive close monitoring for development of AGT or T1DM
Treatment Description
Subjects will receive abatacept or placebo and close 
monitoring for development of AGT or T1DM.
Objective
To assess the safety, efficacy, and mode of action of 
abatacept to prevent AGT and T1DM. 
Primary Outcome
The primary objective is to determine whether intervention with 
abatacept will prevent or delay the development of AGT in at-
risk autoantibody positive non-diabetic relatives of patients 
with T1DM.  
Secondary Outcome
Secondary outcomes include: the effect of abatacept on the 
incidence of T1DM; analyses of C-peptide and other measures 
from the OGTT; safety and tolerability; and mechanistic 
outcomes.
Major Inclusion Criteria
Autoantibody positive relatives of T1DM proband with normal 
glucose tolerance who are currently ≥ age 6 and previously 
enrolled in TrialNet Natural History/Pathway to Prevention 
Study.
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1.2. Statement of Purpose
This protocol describes the background, design, and organization of study of the CTLA-4 Ig (abatacept) 
for prevention of abnormal glucose tolerance and diabetes in relatives at risk for type 1 diabetes.  The 
protocol was written by William E. Russell MD, Chair of the TrialNet Abatacept in Prevention Protocol 
Committee, the TrialNet Chairman’s Office at the University of Miami and the Benaroya Research 
Institute, and the TrialNet Coordinating Center (TNCC).  Significant changes that occur to this protocol 
during the course of the trial require the formal approval of the TrialNet Steering Committee.  The study 
protocol, along with the required informed consent forms, will be approved by each participating 
institution’s Institutional Review Board (IRB) or Ethics Committee/Research Ethics Board (EC/REB).
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2. BACKGROUND AND SIGNIFICANCE
2.1. Type 1 Diabetes (T1DM)
2.1.1. Definition and Metabolic Characteristics of Type 1 Diabetes Mellitus
Type 1 diabetes mellitus (T1DM) is an immune-mediated disease in which insulin-producing beta cells 
are completely or near completely destroyed, resulting in life-long dependence on exogenous insulin.  
It is a chronic and potentially disabling disease that represents a major public health and clinical 
concern.  The number of patients being diagnosed with type 1 diabetes is increasing each year and is 
approaching an epidemic level in some countries that track this information (1,2).
Compared to individuals with the more common form of diabetes, type 2 diabetes, (where individuals 
retain some endogenous insulin production which is inadequate to maintain normal glucose and lipid 
metabolism), the metabolic impairment in T1DM is much more severe and the loss of insulin production 
more complete. Continuous exogenous insulin therapy is needed to prevent ketoacidosis and other 
catabolic effects of insulin deficiency and to promote anabolism and to maintain life. Most likely as a 
consequence of the absolute deficiency of insulin, glucose counterregulation (the hormonal response 
to insulin-induced hypoglycemia) is impaired, and therefore, hypoglycemia is a frequent complication 
of the disease. The occurrence of hypoglycemia limits the ability to achieve near normal glucose control. 
The Diabetes Control and Complications study (DCCT) showed that the long term complications could 
be reduced with near normal control of glucose levels but at the cost of an increased frequency of 
severe hypoglycemia (3). While there have been significant improvements in insulin analogs and insulin 
delivery systems, such as continuous subcutaneous insulin infusions with insulin pumps, normal 
glucose control, particularly in children, is rarely achieved. Therefore, individuals with type 1 diabetes 
remain at risk for chronic secondary end-organ complications including visual impairment and 
blindness, renal failure, vascular disease and limb amputation, peripheral neuropathy, and stroke.  They 
are also at high risk for acute complications such as severe hypoglycemia, recurrent ketoacidosis, and 
others. Moreover, at the time of diagnosis, many individuals, and children in particular, suffer significant 
morbidity frequently requiring ICU admission.  As described below, virtually all the individuals identified 
for enrollment into this prevention trial will develop diabetes.  Clearly, prevention of the onset of the 
disease itself would represent a significant advancement.  
2.1.2. Natural History of Type 1 Diabetes Mellitus (T1DM)
Much is known about the natural history of the type 1 diabetes disease process (4). Although all 
people are susceptible, relatives of individuals with T1DM are at much greater risk for development of 
the disease.  In the general population, approximately 0.3 % of individuals will develop T1DM. In 
contrast, those with a relative with T1DM have a 5% incidence of disease – a 15 fold increase (5).  
Further risk stratification among family members depends upon genetic, immune and metabolic data 
(6).  
Beta cell destruction generally begins in genetically susceptible individuals years before clinical onset 
of disease(7). The autoimmune process that causes beta cell destruction is clinically silent and can 
only be identified by the detection of autoantibodies in the blood such as Islet Cell Antibodies (ICA), 
anti-glutamic acid decarboxylase (GAD)65ab, anti-ICA512ab/anti-IA2ab, anti-insulin autoantibodies 
(mIAA) (5), and the recently described antibodies to a zinc transporter (8). Continued immune mediated 
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Page 8 of 44
beta cell destruction involving both B- and T-cells occurs until physiologic insulin demand cannot be 
met by the remaining beta cells, resulting in hyperglycemia and clinical diagnosis of T1DM (9, 10).  
Based on data from the Diabetes Prevention Trial, Type 1 Diabetes (DPT-1), the TrialNet Natural 
History/Pathway to Prevention Study, and others, the risk for developing diabetes in relatives without 
the disease can be defined by the presence of autoantibodies and the degree of metabolic impairment 
(11-13).  The DPT-1 study was one of the first large-scale prevention trials of T1DM.  The aim of this 
trial, which tested >100,000 relatives of individuals with T1DM, was to study whether either low dose 
parenteral insulin or oral insulin administration would prevent the development of T1DM. The results of 
the DPT-1 showed that neither parenteral nor oral insulin prevented the development of T1DM, 
(although a secondary analysis of the data suggested some effect of oral insulin in delaying the onset 
of diabetes in a subgroup of subjects defined by high anti-insulin antibodies and normal glucose 
tolerance)(13).  Like the DPT-1, the ongoing TrialNet Natural History/Pathway to Prevention Study has 
tested more than 105,000 relatives for the presence of diabetes associated autoantibodies as of June 
1st, 2012.   
Approximately 5% of relatives tested are found to have at least one autoantibody.  Further testing 
enables risk assessment of this population.   Relatives with at least two autoantibodies and normal 
glucose tolerance have at least a 42% risk for development of T1DM over 6 years.  This was 
demonstrated in DPT-1 as well as ENDIT (European Nicotinamide Diabetes Intervention Trial), a large 
European trial enrolling antibody positive relatives (14).  This risk has been confirmed in the ongoing 
TrialNet Natural History/Pathway to Prevention Study (Figure 1).  Moreover, while the limited numbers 
of relatives followed for more than 10 years prevent precision around a 10 year risk estimate, it is 
noteworthy that available data from those in DPT-1 or TrialNet Natural History/Pathway to Prevention 
Study suggests no leveling off of this risk over time.  Thus our current understanding is that essentially 
all relatives confirmed to have two or more antibodies will eventually develop clinical T1DM.  
Figure 1: Cumulative incidence of type 1 diabetes in TN01 Natural History Pathway to Prevention Study 
participants with > 2 autoantibodies positive and normal glucose tolerance on first OGTT Test.
Prior to this clinical diagnosis, antibody positive relatives progress from normal glucose tolerance to 
impaired or indeterminate glucose tolerance (defined as any glucose level after ingestion of oral glucose 
of > 200 mg/dL and/or a glucose level 2 hours after ingestion of oral glucose of 140-199 mg/dL and/or 
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Page 9 of 44
fasting glucose between 110 – 125 mg/dL during a standard oral glucose tolerance test).  Subjects in 
the TN01 Natural History/Pathway to Prevention Study with multiple autoantibody positivity and normal 
glucose tolerance at baseline were found to have a 38% two-year risk of progression to confirmed 
abnormal glucose tolerance (Figure 2).  Once such abnormal glucose tolerance is present, there is a 
very high risk of clinical diagnosis; 68% over 4 years (Figure 3).  The risk is particularly high for 
individuals under the age of 18. The extremely high risk of this group has now been demonstrated in 
three independent studies: DPT-1, ENDIT and the ongoing TrialNet Natural History/Pathway to 
Prevention Study.  
Figure 2: Two year risk of confirmed abnormal glucose tolerance is 38% among individuals with 
multiple autoantibody positivity and normal glucose tolerance at baseline in the TN01 Natural 
History/Pathway to Prevention Study. 
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Page 10 of 44
  
Figure 3: Four year risk of diabetes onset is 68% among individuals with multiple autoantibody 
positivity and confirmed abnormal glucose tolerance in the TN01 Natural History/Pathway to Prevention 
Study. 
It is important to note that the diagnosis of diabetes is based on a glucose threshold that is associated 
with risk of secondary end-organ complications of disease rather than the pathologic process that leads 
to hyperglycemia. Detailed analyses of metabolic function in individuals who do and do not progress to 
diabetes in the DPT-1 have been published (10,15,16). These studies all describe a progressive 
predictable loss of beta cell function during the pre-diabetes period leading to abnormal glucose 
tolerance and clinical disease.  In addition, they also suggest that once metabolic impairment has 
occurred, the risk is extremely high. These combined immunologic and metabolic studies suggest to us 
that individuals with AGT differ from those in whom the diagnosis of T1DM has been made only in the 
duration of progression.  Intervention at the time of diagnosis of T1DM may be too late for new therapies 
to alter the course of disease.
The DPT-1 tested whether oral insulin could prevent progression to type 1 diabetes in antibody positive 
relatives with normal glucose tolerance.  That study took approximately ten years to complete and found 
no overall effect in progression to T1DM.  However, a sub-group analysis suggested that oral insulin 
administration delayed T1DM onset by at least four years in those with high levels of insulin 
autoantibodies.  This promising outcome is now being tested again in the TrialNet Oral Insulin 
Prevention study.  Enrollment in this ongoing trial is limited to individuals with two or more antibodies 
of which at least one must be insulin autoantibodies (mIAA) and normal glucose tolerance.
In this study, relatives who are confirmed to have two or more antibodies, not including mIAA, and 
normal glucose tolerance will be eligible for randomization to experimental treatment or placebo groups 
with the aim to determine whether experimental treatment will prevent or delay the occurrence of 
abnormal glucose tolerance and type 1 diabetes mellitus.  Individuals with normal glucose tolerance 
are earlier in the disease process; that is, have less beta cell destruction than those with abnormal 
glucose tolerance or frank diabetes, yet will inevitably progress to clinical disease and essentially 
complete beta cell loss.  Treatment at this early stage in a population who will inevitably progress to 
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Page 11 of 44
type 1 diabetes provides the greatest opportunity for a clinically important impact on disease prevention.  
With abnormal glucose tolerance rather than diabetes as the primary endpoint, study participants, 
regulators, funders, and investigators will be able to determine whether the therapy can alter disease 
progression.  
Therefore, the rationale for this study is that individuals with immunologic markers of T1DM and normal 
glucose tolerance will inevitably develop clinical T1DM.  Prior to development of clinical T1DM they will 
progress from normal glucose tolerance to abnormal glucose tolerance; and abnormal glucose 
tolerance results in clinical T1DM within 5 years in almost 80% of subjects. They have a condition that 
differs from overt diabetes only in the duration of the autoimmune process that results in beta cell 
destruction. Intervention early in the course of disease may be more effective than intervention in those 
with abnormal glucose tolerance or clinical T1DM.  
2.2.
Rationale for use of CTLA-4 Ig
2.2.1. Presumed mechanism of action
Antigen-specific T-cells are thought to play a central role in the pathogenesis of autoimmune diseases. 
Abatacept binds to CD80/CD86 receptors on antigen presenting cells, thereby inhibiting their binding 
to the co-stimulatory molecule CD28 on T-cells. By inhibiting full T-cell activation, abatacept also affects 
the downstream inflammatory cascade.
T lymphocytes are believed to play a major role in orchestrating the immune response that underlies 
T1DM.  T cell activation is thought to involve a “two-signal” model (17). According to this “two-signal” 
model, “signal 1” is the interaction of the T cell receptor (TCR) with the antigen-MHC complex, 
meanwhile “signal 2” is the engagement of the co-stimulatory receptors (18,19).  Both signals are 
required for optimal T cell activation; in the absence of signal 2, T cells fail to activate and became 
anergic.  Signal 2 can be stimulatory and inhibitory as well.  A large family of co-stimulatory molecules 
has been described and at the same time T-cell surface receptors providing inhibitory signals have also 
been reported (20,2).  There is an apparent delicate balance between positive and negative regulatory 
signals, which drives the direction of the specific immune response.  The B7-1/2 – CD28/CTLA-4 co-
stimulatory pathway has been studied in depth and plays a crucial role in T-cell activation/tolerance.  
This is, arguably, the most important co-stimulatory pathway for T cell antigen activation.
Both B cell molecules, B7-1 (CD80) and B7-2 (CD86) are ligands for CD28 and CTLA-4 and are 
expressed on the surface of the antigen presenting cells (APC)(21,22,23).  The binding affinity of B7 
molecules to CD28 and CTLA-4 on T cells differ substantially and this is important in T cell regulation 
(24).  B7-2 is constitutively expressed on most APCs at a low level and is quickly upregulated; 
meanwhile B7-1 is only inducibly expressed after activation.  CD28 is constitutively expressed on the 
T cell surface whereas CTLA-4 expression is upregulated 24- 48 hours after T cell activation (25).  
Engagement of CTLA-4 represents a crucial negative signal, inhibits TCR- and CD28 mediated signal 
transduction, also inhibits IL-2 production and terminates T cell response by inhibiting cell cycle 
progression (26,27).  CTLA-4 (CD152) is currently viewed as major negative regulator of T cell 
activation and an important regulator of peripheral tolerance induction.  
The effect of CTLA-4 Ig has been studied in various animal models as well as in human trials.  It has 
been used in a series of animal transplantation models, where it showed significant prolongation of 
transplanted organ survival (28,29,30) and in autoimmune models, where it slowed or prevented the 
autoimmune process (31,32).  It is also effective in animal pancreatic islet transplantation models as 
well as in prevention in autoimmune models of diabetes (33).  Lenschow and coworkers showed that 
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Page 12 of 44
co-stimulatory blockade with CTLA-4 Ig prevents diabetes in NOD mice model of T1DM, when 
administered after insulitis developed but before frank diabetes ensues (32,33).  Interestingly, in some 
transplantation models and in some animal models of autoimmunity CTLA-4 Ig effect persisted well 
beyond any detectable CTLA-4 Ig blood levels, leading to long-term graft survival or long-term 
suppression of the autoimmunity (29,32).
There is now considerable clinical experience with abatacept (Bristol-Myers Squibb CTLA-4 Ig).  As 
discussed below, abatacept has been extensively tested in subjects with rheumatoid arthritis and is 
now FDA approved and in clinical use in that patient population.  It is also approved for the treatment 
of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in pediatric patients 6 
years of age or older.   
CTLA-4 Ig (abatacept) is a novel immunosuppressive agent for type 1 diabetes mellitus.  It has shown 
strong beneficial effect in different animal models of transplantation and organ specific autoimmunity, 
including diabetes.  This agent inhibits/regulates T cell function, but does not deplete T cells in humans.  
The safety profile reported in human clinical trial appears to be better than any other 
immunosuppressive agent used to preserve beta cell function in T1DM (34,35,36,37,38).  As recently 
reported, the Type 1 Diabetes TrialNet clinical trial of CTLA-4 Ig (abatacept) in individuals with recently 
diagnosed T1DM, including children to age 6, demonstrated both an excellent safety profile and efficacy 
in preserving beta cell function. The combination of good safety profile and strong, therapeutically useful 
immuno-suppression/-modulation makes this drug particularly suitable for study in clinical trials to 
prevent T1DM.   
3. CLINICAL AND PRE-CLINICAL DATA
There is a large body of data available on the CTLA-4 Ig co-stimulatory blockade in different animal 
models of transplantation and autoimmunity; key studies in animal models relating to T1DM are 
described below.  Clinical data in patients with type 1 diabetes and other autoimmune diseases is also 
described.  Full information about studies is in the investigator brochure.  
3.1.
Pre-Clinical Data 
In BB rat model of diabetes, the recurrence of autoimmunity was completely prevented by 
adenovirus-mediated CTLA-4 Ig expression locally in the pancreas (39).  Lenschow and colleagues 
(33) administered human CTLA-4 Ig to female nonobese (NOD) mice and prevented the development 
of diabetes when treated at the time of the onset of insulitis (2-4 weeks of age) and prior to the onset 
of disease. In a later paper, however, Lenschow reported use of murine CTLA-4 Ig at the same NOD 
mouse age as it was used in the original study using the human CTLA-4 Ig (2-4 weeks) and found 
acceleration of the disease (40). It is difficult to reconcile the seemingly contradictory results of 
different species of CTLA- 4 Ig’s effect (human CTLA-4 Ig protective versus murine CTLA-4 Ig 
accelerating effect on NOD diabetes); the answer may lie in the opposite effect of B7-1 versus B7-2 
on diabetes in NOD mice (33) and may be due to differences in avidity of the murine versus human 
CTLA-4 Ig to B7-1 versus B7-2.  Importantly, CTLA-4 regulates peripheral tolerance induction and 
promotes Th2 development (41).  Moreover, marked prevention of diabetes in the NOD was 
demonstrated using human CTLA-4 Ig (abatacept) from Bristol-Myers Squibb (the drug we propose to 
use for this clinical trial) with diabetes occurring in 80% of control mice and 30% of the CTLA-Ig 
treated animals (Fiorina P et al., unpublished data).
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3.2.
Clinical Trials 
Clinical trials with abatacept have been conducted in individuals with recent onset type 1 diabetes as 
well as rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn’s disease, and polyarticular juvenile 
idiopathic arthritis (JIA) with more than 60,225 total person-years of exposure.  
3.2.1. Type 1 Diabetes Mellitus (T1DM)
Diabetes TrialNet study group conducted a double-masked, randomized clinical trial in 112 individuals 
with type 1 diabetes.  Subjects, ages 6-45 were enrolled within 3 months of clinical diagnosis of T1DM 
and received abatacept or placebo in a total of 27 infusions over a two year period.  As illustrated in 
Figure 4, those treated with abatacept had significantly more beta cell function at two years, the primary 
endpoint of the clinical trial.  The difference in the rate of fall of bell cell function over time between 
abatacept and placebo treated subjects was most pronounced within the first six months of treatment 
(42).  Continued treatment through two years and subsequent follow-up off treatment did not further 
alter the rate of decline.   Overall, there was a 9.6 month delay in the rate of fall (Figure 4).   The safety 
profile in this population was excellent, with no differences in adverse event rates between abatacept 
treated and placebo groups.  These data suggest that a 12 month course of treatment in individuals 
earlier in the disease process is likely to be safe in this population and significantly delay the 
progression of disease.  Subjects were followed for an additional year while off therapy.  Those treated 
with abatacept continued to demonstrate better beta cell function than placebo treated subjects three 
years after randomization (Skyler et al; unpublished observation TN).
Figure 4: Population mean of stimulated C-peptide 2-h AUC mean over time for each treatment group. 
The estimates are from the ANCOVA model adjusting for age, sex, baseline value of C-peptide, and treatment 
assignment. Y-axis is on a log(y+1) scale. Error bars show 95%CIs. AUC=area under the curve.
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Figure 5: Predicted population mean of stimulated C-peptide 2-h AUC mean over time for each 
treatment group. Estimates are from the analysis of mixed-effects model adjusting for age, sex, baseline value 
of C-peptide, and treatment assignment, and including a fixed effect for time as a linear line on the log(y+1) 
scale. AUC=area under the curve.
3.3.
Clinical Experience in Children: Type 1 Diabetes Mellitus (TIDM), Juvenile 
Idiopathic Arthritis (JIA), Rheumatoid Arthritis (RA), and Other Clinical Experience
3.3.1 Type 1 Diabetes Mellitus (T1DM)
Of the 77 individuals with recently diagnosed T1DM treated with abatacept in the Diabetes TrialNet 
study discussed above, 61 (79.2%) were children.  Thus the overall efficacy and safety data described 
above largely reflect clinical observations in children (42).  
3.3.2 Juvenile Idiopathic Arthritis (JIA)
In a Phase 3, multi-center, multi-national, randomized, withdrawal study to evaluate the safety and 
efficacy of abatacept in children and adolescents with active polyarticular JIA, 190 children and 
adolescents, ages 6-16 (mean 12.4 + 3 years), were treated with open-label abatacept at 10 mg/kg IV 
for 4 months in a lead-in phase (Period A).  One hundred twenty-two (122) subjects who responded 
according to the ACR 30 pediatric definition of improvement were randomized 1:1 into the double-blind 
withdrawal phase (Period B) either to continue abatacept (60 subjects), or to receive placebo (62 
subjects) for 6 months or until the appearance of flare.  Half (31/62) of those randomly assigned to 
continue abatacept completed Period B, while 82% (49/60) of those randomly assigned to placebo 
completed Period B.  Those who did not respond in Period A, those who completed Period B, and those 
who flared in Period B were offered the option to receive abatacept in Period C, the open-label 
extension phase of the study.  The difference in time to disease flare between the abatacept and 
placebo groups was statistically significant based on the log-rank test (p = 0.0002).  The risk of disease 
flare among children and adolescent subjects continuing on abatacept was less than one-third that for 
the placebo subjects withdrawn from the abatacept treatment (hazard ratio = 0.31, 95% CI [0.16, 0.59]).  
Treatment in children was well tolerated, although 13.2% reported headache, this did not result in 
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discontinuation of treatment.  Nausea, diarrhea, cough, fever, and abdominal pain were also reported.  
Infections were reported with similar frequencies in abatacept (45%) and placebo (43.5%) treated 
groups with a slight increase in influenza 8.3% versus 6.5% in abatacept treated subjects.  One subject 
had a varicella infection with normal clinical course.    There were no safety issues from the evaluation 
of the laboratory data (Abatacept: Investigator’s Brochure). 
3.3.3 Rheumatoid Arthritis (RA)
Results of a series of Phase I-III clinical trials involving 1955 subjects treated with abatacept and 989 
placebo treated subjects, have led to FDA approval of the IV formulation of abatacept for treatment of 
Rheumatoid Arthritis (RA).  Abatacept is indicated for reducing signs and symptoms, inducing major 
clinical response, slowing the progression of structural damage, and improving physical function in adult 
patients with moderately to severely active rheumatoid arthritis who have had an inadequate response 
to one or more Disease Modifying Anti-Rheumatoid Drugs (DMARDs), such as methotrexate or TNF 
antagonists.  Abatacept may be used as monotherapy or concomitantly with DMARDs other than TNF 
antagonists.
Adverse events possibly related to treatment were reported in 52.2% of abatacept treated and 46.1% 
of placebo treated adults, with the most frequent events in abatacept treated subjects being headache 
(≥10%) and nausea.  Treatment was discontinued due to these events in 3.4% of abatacept treated 
and 2.2% of placebo-treated subjects.  Other common (1-10%) adverse effects include upper and lower 
respiratory tract infection, hypertension and flushing, cough, rash and fatigue.
3.3.4 Other Clinical Experience
Clinical trials have been conducted in psoriasis, psoriatic arthritis, Crohn’s disease, SLE, and multiple 
sclerosis.
Both IV and subcutaneous formulations of abatacept have been studied in clinical trials involving 177 
subjects with psoriasis and 170 with psoriatic arthritis.  The dose-ranging study in subjects with 
relapsing-remitting multiple sclerosis (MS) was terminated by BMS when a Data and Safety Monitoring 
Board (DSMB) review detected an increase in enhancing T1 lesions and MS exacerbations in one of 
the randomized groups.  A descriptive analysis of the primary efficacy endpoint, cumulative new or 
recurrent T1-enhancing lesions, reported that the 2 mg/kg group (median number of lesions = 8.0) was 
greater than that in the placebo group (median number of lesions = 5.5), however the 10 mg/kg group 
(median number of lesions = 1.5) median was less than that in the placebo group.  The 10 mg/kg 
treatment group reported fewer protocol-defined exacerbations (20.6 versus 30.0%), fewer MS related 
AEs (52.9 versus 65.0%), and a lower mean annualized relapse rate (0.38 versus 0.73) compared with 
placebo.  A similar pattern was observed for other efficacy endpoints (unpublished data).  No clinical 
efficacy was demonstrated for abatacept in Crohn’s disease and the safety profile was consistent with 
studies in RA.  Although exploratory endpoints suggested possible biologic activity, a Phase 2 study of 
abatacept in SLE failed to meet its primary clinical endpoint. 
 
4. STUDY DESIGN
4.1.
Overview
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This is a double blinded, multicenter, randomized, placebo controlled trial to determine whether 
treatment of subjects at risk for diabetes with abatacept results in delay or prevention of abnormal 
glucose tolerance. 
4.2.
Objectives
4.2.1. Primary Objective
The primary objective of the study is to determine whether treatment of subjects at risk for diabetes 
with abatacept results in delay or prevention of abnormal glucose tolerance.
4.2.2. Secondary Objectives

To determine whether treatment with abatacept is superior to placebo with respect to the 
incidence of T1DM.

To determine whether treatment with abatacept is superior to placebo with respect to C-
peptide responses to oral glucose, as obtained from timed collections during longitudinal 
tests. 

To compare the safety and tolerability of abatacept to placebo. 

To assess the effects of treatment on mechanistic outcomes.
4.3.
Summary of Inclusion/Exclusion Criteria
Participants must meet all entry criteria for the protocol as outlined below.
4.3.1. Inclusion Criteria 
Study subjects must be or have:
1.
Participant in TrialNet Natural History/Pathway to Prevention Study (TN01) and thus, a relative 
of a proband with T1DM.
2.
Between the ages of 1-45 years at the time of enrollment in TN01 and age ≥ 6 at time of 
randomization in this trial.           
3.
Willing to provide Informed Consent or have a parent or legal guardian provide informed consent if the 
subject is <18 years of age.
4.
Normal glucose tolerance by OGTT within 7 weeks (no more than 52 days) of baseline (visit 0). If 
previous abnormal glucose tolerance, has had two consecutive OGTTs with normal glucose tolerance.  
a.
Fasting plasma glucose < 110 mg/dL (6.1 mmol/L), and
b.
2 hour plasma glucose <140 mg/dL (7.8 mmol/L), and
c.
30, 60, or 90 minute value on OGTT< 200mg/dL (11.1 mmol/L)
5.
At least two diabetes-related autoantibodies confirmed to be present on two occasions, not 
including mIAA.  Confirmation of 2 positive autoantibodies must occur within the six months 
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prior to randomization, but the confirmation does not have to involve the same 2 
autoantibodies. 
6.
Weight ≥ 16 kg at Baseline Visit. 
7.
If a female participant with reproductive potential, willing to avoid pregnancy during study drug 
treatment and up to 14 weeks after study drug administration and undergo pregnancy testing 
prior to each infusion.
8.
At least three months from date of last live immunization. 
9.
Willing to forgo live vaccines while receiving treatment on study and for three months following 
last study drug administration. 
4.3.2. Exclusion Criteria
Potential participants must not meet any of the following exclusion criteria:
1.
Abnormal Glucose Tolerance or Diabetes (43,44)
a. Fasting plasma glucose ≥ 110 mg/dL (6.1 mmol/L), or
b. 2 hour plasma glucose ≥ 140 mg/dL (7.8 mmol/L), or
c. 30, 60, 90 minute plasma glucose during OGTT ≥ 200 mg/dL (11.1 mmol/L)
2. Insulin autoantibodies (mIAA).
3. Immunodeficient or have clinically significant chronic lymphopenia.
4. Have an active infection at time of randomization. 
5. Have a positive PPD test result or history of previously treated TB, or positive interferon-gamma 
release assay (IGRA) test.
6. Be currently pregnant or lactating, or anticipate getting pregnant within 14 weeks of the last 
study drug administration.
7. Use of medications known to influence glucose tolerance. 
8. Require use of other immunosuppressive agents.
9. Have serologic evidence of current or past HIV, Hepatitis B (positive for Hepatitis B core 
antibody or surface antigen), or Hepatitis C infection. 
10. Have serological evidence of current CMV infection. 
11. Have evidence of active EBV infection.
12. Have any complicating medical issues or abnormal clinical laboratory results that interfere with 
study conduct or cause increased risk. These include pre-existing cardiac disease, COPD, 
neurological, or blood count abnormalities (such as lymphopenia, leukopenia, or 
thrombocytopenia).
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13. Have a history of malignancies.
14. Have Multiple Sclerosis.
4.4.
Enrollment
Potential study subjects will be identified through the ongoing TrialNet Natural History/Pathway to 
Prevention Study. In this study, first, second and third degree relatives of patients with T1DM are 
screened for diabetes related autoantibodies. Those individuals who test positive are then further 
staged with the performance of serial OGTTs. The results of these OGTTs will be used to determine 
eligibility for this protocol.
The TrialNet Natural History/Pathway to Prevention Study screens participants at multiple clinical sites.  
The infusion of study drug will occur at designated TrialNet infusion sites, whereas the initial visit and 
follow-up testing, as described in the Schedule of Assessments, may occur at other TrialNet sites. 
4.5.
Description of Treatment Groups
The intervention will be conducted only among those who consent to participate.  Subjects will be 
randomized to receive either abatacept or placebo infusions along with close monitoring for abnormal 
glucose tolerance or diabetes. The infusions will be conducted at approved TrialNet clinical sites with 
appropriate facilities. All blood and serum samples for the primary and secondary outcome 
determinations will be sent to the Core Laboratories for analysis. Clinical laboratory studies may be 
done at the local sites.
Participants will be randomly assigned in a 1:1 ratio (within the two strata defined by age at enrollment: 
<18 and 18 or older) to the following 2 groups:

to receive abatacept (intravenous infusion at 0, 2, and 4 weeks following 
randomization, and then every 28+/-7 days) thereafter for a total of 14 doses.  Close 
monitoring for diabetes development through the duration of study.

to receive placebo intravenous infusion at 0, 2, and 4 weeks following randomization 
and then every 28+/- 7 days thereafter for a total of 14 doses.  Close monitoring for 
diabetes development through the duration of study.
4.6.Treatment Assignment
After participants sign the consent form, complete the screening visit(s), and meet all of the inclusion 
criteria and none of the exclusion criteria, participants will be randomized to receive either abatacept 
and close monitoring or placebo with close monitoring.
Participants will be randomized in equal allocations to each group. The randomization method will be 
stratified by TrialNet study site and whether the participant is less than 18 years of age or 18 years and 
older. This approach ensures that study site will not be a potential confounder. The TNCC will generate 
the randomization numbers and tables.
4.7.Study Assessments
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During the course of the study, participants will frequently undergo assessments of their glucose 
tolerance status, insulin production, immunologic status, and overall health and well-being (see 
Schedule of Assessments).  
Samples will be drawn for storage in the National Institute for Diabetes and Digestive and Kidney 
Disease (NIDDK) Repository and at TrialNet Laboratory Sites for future analysis related to T1DM. 
4.8.Quality Assurance
During the study, duplicate collections of blood samples for assays will be obtained in a small sample 
of subjects for the purpose of external quality surveillance of the performance of the TrialNet central 
laboratories. 
4.9.Study Timeline
4.9.1. Study Duration
The study has been designed to provide 80% power to detect a 40% risk reduction in the occurrence 
of abnormal glucose tolerance using a two-sided test at the 0.05 level after six years of study duration.  
A total of approximately 206 patients will be allocated in a 1:1 ratio to the two groups.    
The assumptions underlying the sample size of are 1) 40% two year event rate in the placebo group, 
2) 25% two year event rate in the abatacept group, 3) less than a 10% two year dropout rate in both 
groups, and 4) survival curves which are consistent with an exponential survival distributions.  
Under the above assumptions, the target total number of events is equal to 95.  If the accrual rate is 
50 patients per year, with the above assumptions it is estimated that the enrollment period will last 
approximately 4 years and a study duration of approximately 6 years will provide a sufficient number 
of events to detect the assumed treatment difference. Note the accrual period and the study sample 
are only projections since the actual accrual rate and the loss to follow-up rate are unknown.
Participants who develop AGT will remain on study and be followed according to protocol to assess 
the secondary objective of time until T1DM development.
4.9.2. Follow-up Studies
Although subjects who develop confirmed abnormal glucose tolerance will have reached the primary 
study endpoint, while the Abatacept Prevention study is ongoing, these individuals will continue to be 
followed in the study for monitoring of diabetes development and safety assessments. At the end of the 
study, individuals without diabetes will be periodically contacted to ascertain whether they develop 
diabetes and/or continue monitoring in TN01 (Pathway to Prevention) study.  If subjects are diagnosed 
with diabetes they will be offered follow-up in the TrialNet Long Term Investigative Follow-Up in TrialNet 
(LIFT) Study. 
Individuals who develop T1DM may be eligible for interventional studies sponsored by TrialNet or other 
organizations under separate INDs. In the event that a subject wishes to participate in another 
investigational study the subject may request and be told of their treatment group assignment for the 
Abatacept prevention study.  Every attempt will be made to minimize potential bias that this may 
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introduce.  The TNCC will make treatment assignment information available to the site investigator of 
the new study after the subject is determined to be willing to participate and not otherwise excluded 
from the new study. Other study group members will not be informed of the treatment assignment 
information.  Mitigation of bias issues must be balanced against safety and interests of participants. 
5. PATIENT MANAGEMENT
5.1.
Screening Visit and Eligibility Assessment
This study will draw participants from the TrialNet Natural History/Pathway to Prevention Study.  
The initial testing for autoantibodies, HLA type, and Oral Glucose Tolerance Test (OGTT) will generally 
be done as part of Natural History/Pathway to Prevention Study.  Potential participants in the Abatacept 
trial will have at least two different diabetes related autoantibodies other than mIAA confirmed to be 
present on two occasions. The autoantibodies that may be confirmed are anti-GAD65, anti-ICA512/anti-
IA2, ZnT8, and/or ICA, but not anti-insulin (MIAA). The confirmation of 2 positive autoantibodies must 
occur within the six months prior to study drug administration but the confirmation does not have to 
involve the same 2 autoantibodies. 
Those individuals with two confirmed diabetes related autoantibodies (other than mIAA) will then be 
eligible for additional screening tests and possible enrollment into Abatacept Prevention Trial. A subject 
must have a normal OGTT either done as part of the Natural History/Pathway to Prevention Study or 
during Abatacept screening within 7 weeks (52 days) of randomization.  If a subject has a previous 
abnormal glucose tolerance, he/she must have two consecutive OGTTs with normal glucose tolerance 
in order to be eligible. 
Appendix 1 summarizes the flow of subjects from the Natural History/Pathway to Prevention Study into 
the Abatacept Prevention Trial.
5.2. Abatacept Trial for At-risk Subjects Baseline Visit
Prior to the initial visit, the Abatacept Prevention Trial will be described to the potential participant.  The 
participant/parent/guardian will be asked to sign an informed consent document describing the purpose, 
risks, and benefits of screening for the trial.  A participant’s signature indicates that he/she understands 
the potential risks and benefits of study participation.  During these visits, clinical tests will be done to 
determine eligibility. 
Any participant either not eligible or not willing to be randomized into the Abatacept Prevention Trial is 
eligible for continued follow-up as part of the TrialNet Natural History/Pathway to Prevention Study.  
5.3.
Randomization and Baseline visits
Prior to randomization, the intervention and follow-up parts of the study will be described to the 
participant.  The participant/parent/guardian will be asked to sign an informed consent document and 
minors will be asked to sign an age appropriate assent document indicating that he/she understands 
the study as well as the potential risks and benefits of study participation.  
Participants will be randomized to either the treatment arm or the placebo arm.  The randomization and 
the baseline visit may occur up to 24 hours apart and the infusion must occur within 7 weeks of a normal 
OGTT in order to ensure that participants have normal glucose tolerance at the time of randomization 
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and study drug administration.  Note, subjects who are febrile at the time of baseline visit, may have 
the visit postponed up to five days outside the 7 week window if needed because of intercurrent illness. 
5.4.
Close Monitoring
During the study period, all participants will receive close monitoring for development of abnormal 
glucose tolerance and diabetes.  OGTT tests will be performed at six month intervals thereafter.  In 
addition, at three month intervals starting with month 15 in which there is no OGTT scheduled, a random 
(post-prandial) glucose level will be measured. At each visit, subjects will be asked directed questions 
about the presence or absence of symptoms associated with diabetes such as blurry vision, unintended 
weight loss of more than 3 kg, polyuria, and polydypsia.  If subjects respond affirmatively to any of 
these questions or if any of the post-prandial glucose values are greater than 200 mg/dL, further 
evaluation, including fasting glucose or an OGTT, will be performed.  Individuals in both of the study 
arms will have laboratory and mechanistic studies performed as detailed in the Schedule of 
Assessments.
5.5.
Administration of CTLA-4 Ig (Abatacept)
The CTLA-4 Ig used in these human trials (abatacept) is a soluble fusion protein, which consists of the 
extracellular domain of the human CTLA-4 (CD152) and a fragment (hinge, CH2 and CH3 domains) of 
the Fc portion of human IgG1. 
A urine pregnancy test will be given to females with reproductive potential. An interim medical history 
and exam with directed questioning regarding infectious symptoms will be performed before each study 
infusion is administered.  
The study drug (abatacept/ placebo) is administered IV at 10 mg/kg for up to maximum of 1000 mg.    
The study drug is administered over 30 minutes and not mixed or diluted with other medications.  No 
routine pre-medication is needed; however medication such as acetaminophen and diphenhydramine 
may be administered according to investigator discretion as needed.
If mild hypersensitivity or an infusion related event develops, the study infusion should be temporarily 
interrupted.  Subjects may be dosed with acetaminophen and diphenhydramine as needed.  The study 
infusion can continue or be resumed upon improvement of patient symptoms. 
Subjects will be monitored for one hour after the end of the infusion.
5.5.1. Dosing and Dose Withholding  
The dose was chosen based on demonstrated safety and efficacy in children and adults with type 1 
diabetes as well as in other human autoimmune diseases.  Dosing will be according to the individual’s 
weight during the previous visit unless the previous visit was more than three months prior.  In that 
case, dosing will be according to the individual’s weight on the day of the visit. 
Subjects without previous exposure to EBV (EBV IgG and IgM negative during screening) will have 
EBV viral load determined at each study visit. Those that have evidence of active EBV infection before 
randomization will not be eligible for the study.  Those that have evidence of active EBV infection after 
randomization will not receive additional study drug until resolution (determined by laboratory 
assessments and absence of signs and symptoms associated with active disease). 
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The study drug infusions will also not be given if any subject has had a symptomatic illness with fever, 
sore throat, or lymphadenopathy during the previous 10 days.  The study drug infusions will also be 
withheld if there are any unresolved grade 3 laboratory abnormalities.  Administration of subsequent 
infusions can occur upon clinical and laboratory resolution. 
Subjects with grade 3 hypersensitivity or infusion reactions, those who have developed a serious 
infection (such as pneumonia, cellulitis or pyelonephritis) and/or those who require pressor support or 
epinephrine will not be restarted on therapy and will not receive subsequent doses but will continue to 
be monitored for safety and development of confirmed abnormal glucose tolerance or diabetes per 
the study schedule of assessments.
Participants who develop AGT will continue to receive a total of 14 doses as described above to address 
the T1DM study end point.
6. STUDY VISIT ASSESSMENTS
The schedule of evaluations and laboratory studies is presented in Appendix 2, Schedule of 
Assessments.  A summary of assessments for the Protocol is given below.
6.1.
General Assessments
General assessments for this Protocol will include:

Informed consent

Inclusion/exclusion criteria

Medical history including lifestyle and participant experience assessment 

Routine or directed Physical examination including height/weight

Concomitant medications

Adverse events
6.2.
Laboratory Assessments
The following clinical laboratory assessments will be performed during the study as described in the 
Schedule of Assessments:

Chemistry (sodium, potassium, chloride, CO2, glucose, BUN, creatinine)

Liver function tests (ALT, AST, LDH, alkaline phosphatase, total protein, albumin, total and 
direct bilirubin)

Hematology (complete blood count with differential and platelets)

Purified protein derivative (PPD) test or Interferon-Gamma Release Assay Test (IGRA)

Urine pregnancy test as appropriate

Antibodies to HIV, hepatitis B (anti-HBcAb, HBsAg), hepatitis C (HCV)

Cytomegalovirus antibodies (CMV IgG and IgM) 

Epstein-Barr virus antibodies (EBV IgG and IgM, EBNA) and viral load as indicated
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6.3.
Mechanistic Outcome Assessments
TrialNet will perform immune and genetic assays to further understand mechanisms that may be 
underlying the type 1 diabetes disease process and response to therapy.  For this purpose, samples 
for PBMC, DNA, RNA, plasma, and serum may be obtained.  Islet autoantibodies will be measured at 
six month intervals in the study. HLA testing may be done either under the auspices of TrialNet Natural 
History/Pathway to Prevention Study or this protocol.
At any time after the first month of study, subjects will receive their annual clinically indicated killed flu 
vaccine at the appropriate time of year during the treatment phase of the study.  Subjects may 
receive subsequent killed flu vaccinations later in the study.  Responses to these immunizations may 
be determined through analysis of pre- and 4 week post-dose samples. Samples for thyroid 
antibodies, virology and other immunization titers may also be collected.
6.4.
Metabolic Outcome Assessments
Metabolic assessments will consist of:
1.
OGTT                                                                                                                                                              

The OGTT will be performed every 6 months or more frequently if clinically indicated 
based on a random glucose level of ≥ 200 mg/dL. 

The C-peptide and insulin data from the OGTT will be used to measure insulin secretion.

The insulin, glucose and C-peptide data from the OGTT may be used to measure insulin 
sensitivity.                                                               
2.
HbA1c  

Measure of glycemic control.
6.5.
Laboratory Measures Related to Abatacept Administration
Determination of immunogenicity to abatacept, receptor occupancy, and drug levels may be done to 
assess pharmacokinetic profiles according to the schedule of assessments (Appendix 2).  
6.6.
Visit Windows
The baseline visit must occur within 7 weeks after a normal OGTT (with the exception that individuals 
who are febrile at the time of the scheduled baseline visit, may have up to an additional 5 days).  For 
the next two infusion visits (visit # 1 at 2 weeks, visit # 2 at 4 weeks), the window is +/- 3 days of the 
target date.  The subsequent infusion visits (visits # 3-14, every 28 days thereafter) should be +/- 7 
days on either side of the targeted date to be permissible.  Study doses outside of the window will not 
be made up (i.e. if treatment dose # 5, scheduled for day 84 cannot be accomplished between days 
77 and 91, this dose will not be given and the next dose will be on day 112 +/- 7 days).  Further, the 
clock will not be reset, i.e. if treatment dose # 5 is given on day 77 (day 84 -7 day window), the target 
date for treatment dose # 6 remains day 112.  In this way, no one will receive more than 14 study 
doses (infusions) over a one year period. Subsequent semi-annual follow-up visits should be within 
+/- 3 weeks of the targeted date.
7.  ADVERSE EVENT REPORTING AND SAFETY MONITORING
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7.1.Adverse Event Definition
7.1.1. 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 diabetes onset of hyperglycemia which are Grade 2 or greater per the NCI CTCAE (see 
Section 7.1.5. Grading Event Severity below) must be reported to TNCC.  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.
Questioning of the participant should be conducted in an objective manner.
7.1.2. Adverse Reaction
An adverse reaction means any adverse event caused by a drug.  Adverse reactions are a subset of 
all suspected adverse reactions for which there is reason to conclude that the drug caused the event.  
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  For the purposes of safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the adverse event. A 
suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction, which means any adverse event caused by a drug.  Examples of evidence that suggest a 
causal relationship (reasonable possibility) between the drug and the adverse event include:

A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure

One or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the populations exposed to the drug

An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of drug therapy) that indicates those 
events occur more frequently in the drug treatment group than in a concurrent or historical 
control group.
7.1.3. Serious Adverse Event/Reaction
A serious adverse event (SAE) or reaction is defined as “any adverse event occurring at any dose that 
suggests a significant hazard, contraindication, side effect, or precaution.”  An adverse event or 
suspected adverse reaction is considered “serious” if, in the view of either the investigator or sponsor, 
it results in any of the following outcomes:
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1.
Death.  A death that occurs during the study or that comes to the attention of the 
investigator during the protocol-defined follow-up after the completion of therapy must be 
reported whether it is considered to be treatment related or not.
2.
A life-threatening adverse event.  A life-threatening event is any adverse therapy 
experience that, in the view of the investigator, places the participant at immediate risk of 
death from the reaction as it occurred.
3.
Inpatient hospitalization or prolongation of existing hospitalization with the exception of 
hospitalization relating to initial diagnosis of type 1 diabetes.
4.
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions
5.
Congenital anomaly or birth defect.
6.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death.
Regardless of the relationship of the adverse event to study drug, the event must be reported as a 
serious adverse event if it meets any of the above definitions.
7.1.4. Unexpected Adverse Event
An adverse event/reaction is considered unexpected when the nature (specificity) or severity of the 
event is not consistent with the risks described in the Investigator’s Brochure or the informed consent 
document. Unexpected refers to an experience that has not been previously observed.  This includes 
events that occur more frequently than expected.
7.1.5. Grading Event Severity and Causality
TrialNet has adopted usage of the National Cancer Institute (NCI) Common Technology Criteria for 
Adverse Events (CTCAE) and/or study-specific criteria for classification to describe the severity of 
adverse events with the exception of hypoglycemia and hyperglycemia.  Hypoglycemia and 
hyperglycemia will be reported as adverse events only in the case of requiring the assistance of others 
due to loss of consciousness or DKA. TrialNet Investigators will also provide an assessment of 
relationship of AE to study drug as not, unlikely, possibly, probably, or definitely related. 
7.2.
Adverse Event Reporting and Monitoring
Adverse events will be reported to the TrialNet Coordinating Center.  The investigator will grade their 
severity according to common toxicity criteria or study-specific criteria and will make a determination of 
their relation to therapy.  Events will be assessed and reported consistent with the ICH Guideline for 
Good Clinical Practice, 21 CFR 312.32 for expedited safety reporting, and per the guidance of the 
DHHS Office for Human Research Protections (OHRP).  
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The adverse event case report form for the protocol must be completed for all adverse events (AE).  
For reporting serious adverse events (SAE), the MedWatch Form should also be completed and faxed 
to the TNCC within 24 hours of when the site was notified of the event.  This will be reviewed by the 
TrialNet Medical Monitor, the TrialNet Safety Monitoring Committee, and the 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 initially 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 TrialNet Medical Monitor.  The DSMB will conduct regular 
safety reviews approximately every three to six months (and otherwise as needed) of adverse events 
by treatment group assignment.  Serious adverse events as well as adverse events leading to study 
discontinuation will be reviewed by the DSMB. 
For SAEs that are unexpected and considered possibly or probably drug related, the Medical Monitor 
will provide information on frequency of similar events, and generate FDA form 3500A reports 
(MedWatch form) for distribution to FDA, NIDDK, DSMB and site investigators.  Expedited safety 
reports will be submitted to the IND by the TNCC on behalf of NIDDK.
8. PARTICIPANT SAFETY
8.1.Risks, Benefits and Inclusion of Children
The risks of this study are presented below and in the informed consent form and volunteer 
handbook.  This study will examine whether abatacept will delay or prevent the development of 
abnormal glucose tolerance and diabetes onset in antibody positive relatives, but there is no 
guarantee that this will occur.
There is the prospect of direct benefit to the individual subjects for their participation in the study.  These 
potential benefits include the recognized benefits of being in a clinical study, including close monitoring 
offered to all subjects regardless of group assignment.  Further, the intervention has the prospect of 
direct benefit to a given subject and is likely to yield general knowledge about T1DM which is of 
important for the understanding and amelioration of T1DM in children.
The study procedures, while greater than minimal risk, offer the possibility of benefit due to the close 
monitoring for all participants, including children.  Assent of children along with consent of the 
parent/legal guardian will be obtained prior to any study procedures.  This research proposal in children 
is therefore consistent with the United States Department of Health and Human Services, Protection of 
Human Subjects, subpart D, section 46.405 (research involving greater than minimal risk but presenting 
the prospect of direct benefit to individual subjects) and with Subpart D. 50. 52 (Clinical investigations 
involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects). 
8.2.
Protecting Against or Minimizing Potential Treatment Risks
As of the third quarter of 2010, there is an estimated 60,225 total person-years of exposure to abatacept 
have been documented in the abatacept clinical program with excellent safety profile and tolerability 
including in children.  
In addition, our previous Diabetes TrialNet study administered abatacept in 27 doses over two years in 
77 subjects with type 1 diabetes.  
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Subjects will not be enrolled who have other active serious medical problems. Frequent monitoring of 
patients with history, physical examination, and laboratory studies will allow for early identification of 
adverse events.  All participants will be required to have adequate hemoglobin to allow safe frequent 
venipuncture.  Every attempt will be made to minimize the number of venipunctures.
All infusions will take place in a facility that has resuscitation capabilities.
Participants will be counseled by study personnel and requested to avoid pregnancy for 3 months 
following drug administration for safety purposes.  
8.2.1. Prohibited Medications 
Participants will be instructed not to use Prednisone, other immunosuppressive agents, chronic inhaled 
or nasal corticosteroids, or retinoic acid during this trial in order to prevent possible impact on 
progression to diabetes. However, as an intention to treat study, no individual will be withdrawn from 
analysis if this occurs.
Participants who receive abatacept will be instructed not to receive live vaccinations during the dosing 
period and for 3 months after dosing.  
8.3.
Expected Side Effects and Adverse Events  
A full description of the adverse events experienced by subjects in trials using abatacept is in the 
Investigator’s Brochure.  The descriptions below highlight the most common drug related events and 
potential adverse events.
8.3.1. Infusion and Hypersensitivity Reactions
Between 5-9% of subjects in clinical trials of abatacept reported mild or moderate infusion reactions 
such as dizziness, hypertension, and headache.  No severe infusion reactions have been reported. 
In the Diabetes TrialNet study involving subjects with type 1 diabetes, infusion related adverse events 
occurred with low frequency (47 of 2514 infusions; 2%), none were considered to be clinically 
significant, and the frequency was not different between the abatacept and placebo treated subjects.
Hypersensitivity reactions are rare, with mild urticaria, hypotension and dyspnea occurring in <0.9% of 
subjects.  There have been two episodes of anaphylaxis reported (rate <1:1000).  Among 190 patients 
with juvenile idiopathic arthritis in clinical trials, one case of hypersensitivity reaction was seen.  No 
hypersensitivity reactions were seen among the individuals with type 1 diabetes. 
8.3.2. Infectious Adverse Events
As with all immunomodulating agents, there is a risk of infectious adverse events.  In placebo 
controlled clinical trials of adults with rheumatoid arthritis, infections were reported in 54% of 
abatacept and 48% of placebo treated subjects.  Infections occurred in 36% of patients with 
polyarticular juvenile idiopathic arthritis.  The most frequent infections reported were upper respiratory 
tract infection, and nasopharyngitis which occurred in ≥ 10% of subjects.  Other common infections 
include sinusitis, influenza, and bronchitis.  Other infections reported in <5% of subjects in a higher 
frequency in abatacept treated vs placebo subjects include rhinitis, herpes simplex and pneumonia.  
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In the Diabetes TrialNet study involving individuals with type 1 diabetes, there was no increase in 
infection including EBV or in neutropenia. 
Serious infections such as cellulitis, bronchitis, acute pyelonephritis, pneumonia and diverticulitis 
were reported in 3% of treated subjects versus 1.9% of placebo group participants.  
8.3.3. Immunizations
Although no data are available regarding the effects of live vaccination in patients receiving abatacept 
therapy, vaccination with live vaccines is not recommended.  The possibility exists for abatacept to 
affect host defenses against infections since the cellular immune response may be altered.  Therefore 
concurrent use of live vaccines within 3 months of abatacept therapy may result in reduced efficacy of 
vaccine.  Killed flu vaccine will be administered to subjects as part of the study (see Mechanistic 
Assessments).
8.3.4. Drug Interactions
Higher frequencies of adverse events including serious infections were reported in subjects with 
rheumatoid arthritis also treated with TNF blockers.
8.3.5. Blood Glucose Testing
The maltose present in abatacept can interfere with the readings of blood glucose monitors that use 
test strips with glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ).  GDH-PQQ based 
glucose monitoring systems may react with the maltose present in abatacept, resulting in falsely 
elevated blood glucose readings on the day of infusion.  Since individuals in this study do not have 
diabetes, the effect of abatacept on home glucose monitoring is unlikely to be relevant; however, clinical 
sites and subjects will be reminded of this effect of the study drug.  
8.3.6. Other Reported Adverse Events
More than 10% of subjects reported nausea and headache.  Among subjects with chronic obstructive 
pulmonary disease (COPD), more than 40% had acute exacerbations of COPD.   In children, 
diarrhea, cough and abdominal pain have been reported.
Antibodies directed against the abatacept molecule were assessed by enzyme-linked
immunosorbent assays, in rheumatoid arthritis subjects treated for up to two years with abatacept. 
Thirty-four of 1993 (1.7%) of subjects developed binding antibodies.  In subjects assessed for 
antibodies at least 56 days after discontinuation of abatacept, 9 of 154 (5.8%) subjects developed 
antibodies.  Samples with binding activity to the CTLA-4 region of the molecule were assessed for the 
presence of neutralizing antibodies.  Six of nine evaluable subjects were shown to possess neutralizing 
antibodies.   There was no correlation of antibody development to clinical response or adverse events. 
However, the number of subjects that developed antibodies was too limited to make a definitive 
assessment.  The clinical relevance of neutralizing antibody formation with Abatacept is not known. 
Similarly, antibodies directed against the abatacept molecule were assessed by enzyme-linked 
immunosorbent assays, in children and adolescents with JIA (age 6-16 years) treated with abatacept 
in a Phase 3, multi-center, multi-national, randomized, withdrawal study cited earlier. The presence of 
antibodies was transient and antibody titers were generally low. It did not correlate with any clinical 
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findings, including an increase in incidence of SAEs, acute infusional AEs, autoimmune disorders, 
diminution in clinical efficacy, or effect on serum concentrations of abatacept. Immunopositive subjects 
in the double-blind phase of the study were not at increased risk of experiencing SAEs, acute infusional 
AEs, or autoimmune disorders when re-initiating abatacept treatment in the open label follow up period.
Doses up to 50 mg/kg have been administered without apparent toxic effect.
There were no significant differences between abatacept and placebo subjects with respect to number 
of cancers, although more abatacept treated subjects developed lung cancer.  Other malignancies 
including lymphoma have been observed; however the relationship of abatacept to malignancies is 
unclear.
8.3.7. Pregnancy
Female subjects with reproductive potential will be instructed to avoid pregnancy and use birth control 
from randomization up to 14 weeks after study drug administration. They will undergo urine pregnancy 
testing at the start of every study visit.  All pregnancies that are identified during the study must be 
followed to conclusion and the outcome of each must be reported.  The investigator should be informed 
immediately of any pregnancy occurring in a female participant.  Monitoring of the participant should 
continue until the conclusion of the pregnancy. Subjects that are found to be pregnant while on this 
study shall have treatment withheld, but will still be followed for safety. Treatment may only be resumed 
when subjects are no longer pregnant or nursing.
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. Analyses by gender and race/ethnicity, as 
appropriate, are also planned.   
All analyses will be conducted under the intention-to-treat principle whereby all outcome data in all 
randomized subjects will be included in all analyses as appropriate. 
9.1.Primary Outcome 
The primary outcome is the elapsed time from random treatment assignment to the development of 
confirmed abnormal glucose tolerance or diabetes among those enrolled in the primary analysis 
cohort consisting of subjects with islet cell autoimmunity and absence of metabolic abnormalities 
(normal OGTT).  It is expected that abnormal glucose tolerance will be detected prior to diabetes 
onset by OGTT; however, the presence of diabetes is considered as an endpoint.
Although subjects who develop confirmed abnormal glucose tolerance will have reached the primary 
study endpoint, these individuals will continue to receive assigned treatment and will be followed in the 
study for continued monitoring for diabetes development and safety assessments. 
The study end point is realized with either confirmed OGTT criteria for abnormal glucose tolerance or 
diabetes or clinical criteria for diabetes.  
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OGTT criteria for abnormal glucose tolerance or diabetes: 
The presence of an OGTT consistent with abnormal glucose tolerance or diabetes on two 
sequential dates.  A subject with abnormal glucose tolerance or diabetes on an OGTT should 
undergo a repeat OGTT as soon as possible, but no less than one day apart.  Aim to repeat 
within one month.  The time of abnormal glucose tolerance or diabetes will then be taken as 
the date of the confirmatory abnormal OGTT.  
The definition of abnormal glucose tolerance is:
a.  Fasting plasma glucose ≥ 110 mg/dL (6.1 mmol/L) and < 126 mg/dL (7 mmol/L), or
b.
 2 hour plasma glucose ≥ 140 mg/dL (7.8 mmol/L) and < 200 (11.1 mmol/L), or
c.
 30, 60, 90 minute plasma glucose during OGTT ≥ 200 mg/dL (11.1 mmol/L)
Criteria for Diabetes Onset: 
Criteria for diabetes onset (T1DM) are, based on glucose testing, or the presence of 
unequivocal hyperglycemia with acute metabolic decompensation (diabetic ketoacidosis).  
One of the following criteria must be met on two occasions as soon as possible but no less 
than one day apart for diabetes to be defined: 
1.
Symptoms of diabetes plus casual plasma glucose concentration ≥ 200 mg/dL (11.1 
mmol/L). Casual is defined as any time of day without regard to time since last meal. 
The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight 
loss. 
2.
Fasting plasma glucose ≥ 126 mg/dL (7 mmol/L).  Fasting is defined as no caloric 
intake for at least 8 hours.
3.
2 hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L). The test should be performed 
using a glucose load containing the equivalent of 1.75g/kg body weight to a maximum 
of 75g anhydrous glucose dissolved in water. 
It is preferred that at least one of the two testing occasions involve an OGTT. Cases identified 
will be confirmed as having diabetes if the glucose values to make these determinations were 
obtained in a TrialNet laboratory as part of an OGTT.   Cases diagnosed with diabetes by 
symptoms and casual glucose ≥ 200mg/dL or by other criteria than the above will be 
adjudicated by the TrialNet Endpoint Adjudication Committee.
9.2.Primary Analysis 
The primary objective of the study is to assess the effect of abatacept therapy versus placebo on the 
risk of developing confirmed abnormal glucose tolerance (AGT) as measured from an OGTT.
The cumulative incidence of AGT over time since randomization within each treatment group will be 
estimated from a Kaplan-Meier estimate of the "AGT-free" survival function. The difference between 
groups in the cumulative incidence functions, and the associated hazard functions, will be tested at the 
0.05 level, two-sided, using the Cox regression including site and age group as covariates (45,46). The 
estimates of cumulative incidence and the test will adjust for periodic outcome assessment visits to 
assess diabetes status. The critical value for the test statistic, and confidence intervals in this primary 
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analysis will be determined by the group-sequential procedure. 
Data from the TrialNet Pathway to Prevention Study may be used to determine participant eligibility. 
Outcomes from other studies may be used in meta-analyses, but not in the evaluation of this study’s 
efficacy.
9.3.Secondary Outcomes and Analyses
A variety of secondary analyses are planned that include the following. 
Subgroup analyses will be conducted comparing the effects of abatacept versus placebo on the risk of 
AGT with a test of the group by subgroup factor interaction in a Cox proportional hazard (PH) Model. 
Subgroups of the population classified by age (children ≤ 12 years of age, adolescents 13-17 years 
and adults ≥ 18 years), gender, race/ethnicity, and specific antibody status at baseline. Differences in 
the treatment effect between subgroups will be tested using a covariate by treatment group effect in a 
Cox PH model (45).  The effects of age will also be assessed as quantitative covariates.  
Similar analyses will be conducted using the values of quantitative baseline factors including weight, 
BMI, and the immunologic and metabolic factors described in Section 6 that include the autoantibody 
titers, basal C-peptide, stimulated C-peptide (peak and AUC mean), and measures of insulin resistance 
modeled from the OGTT. The dependence of the treatment effect on the quantitative levels of a 
covariate will also be assessed by a covariate by treatment group interaction in a PH model. 
Additional factors may be defined before unmasking of the study data to the investigators. The analyses 
will distinguish between factors specified prior to unmasking, and those identified post-hoc during 
analysis. If the assumption of proportional hazard is not appropriate, the data will be examined to 
determine the cause of non-proportional hazard, such as the presence of a decaying, diverging, or 
crossing effect of hazard ratios over time.  Based on the cause of the non-proportional hazard, post-
hoc analyses such as frailty models, parametric models, or models with interactions and time-
dependent covariates may be employed.
Longitudinal analyses will assess the effects of abatacept versus placebo treatment on immunologic 
and metabolic markers over time up to the onset of AGT. Differences between groups in the mean 
levels of quantitative factors over time will be assessed using a normal errors linear model for repeated 
measures. Differences between groups in the prevalence of qualitative factors over time will be 
assessed using generalized estimating equations for categorical measures. Generalized estimating 
equations may also be employed for the analysis of quantitative factors if the assumption of multivariate 
normal random errors is violated.  
Immunologic and metabolic markers will be modeled to determine the effects of abatacept versus 
placebo treatment while adjusting for subject characteristics for each follow-up time point of interest.  
For continuous endpoints that lend themselves to normal error linear models, ANOVA and ANCOVA 
models will be employed.  Generalized linear modeling will be employed for dichotomous and 
categorical endpoints by using the most appropriate link functions.  Longitudinal analyses maybe 
employed in order to characterize the relationship among the repeated measures during the 
treatment period and possibly beyond.  Due to the exploratory nature of the longitudinal modeling, 
treatment effect hypothesis testing will not conducted.     
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The association of demographic, genetic, immunologic, metabolic, and lifestyle factors, the presence 
of illness and concomitant meds, among others, both at baseline and over time, with the risk of AGT 
onset will be assessed in Cox PH Models over time. The effects of changes in longitudinal factors on 
AGT risk will be assessed using time-dependent covariates for these factors. Analyses will be 
conducted separately within the abatacept and placebo groups, and differences between groups in 
covariate effects (group by covariate interactions) will be assessed. Models will then be assessed within 
the two groups combined, taking account of any group by covariate interactions. 
Additionally, as noted in section 4.9.2, subjects will be able to be followed for the occurrence of 
diabetes.  The treatment arms will be compared on the corresponding incidence rates of type 1 diabetes 
using the logrank statistic. Subgroup analyses analogous to those described for the AGT endpoint will 
be conducted on the endpoint of type 1 diabetes.  
9.4.Study Power and Accrual Target 
The study has been designed to provide 80% power to detect a 40% risk reduction in the rate of AGT 
using a two-sided test at the 0.05 level after six years of study duration.  
Study enrollment will stop on approximately July 31, 2019 and follow-up will continue for up to two 
additional years.  A model of observed events (confirmed abnormal glucose tolerance; AGT)  in the 
placebo group now provides a more realistic estimate of the number that will have developed AGT at 
the conclusion of the follow up period.  The model suggests that the total number of events will be 
between 64 and 70; resulting in detectable hazard ratios of 0.496 to 0.512. The hazard ratios and 
differences in cumulative incidence are based on 80% statistical power when testing at the 0.05 level 
(2-sided).  
The final test of significance up through the six year time point will employ group sequential critical 
values to protect against inflation in the type I error probability due to interim assessments of the 
emerging data for review by the DSMB. However, there is only a minimal loss in power with this 
approach so that the fixed sample size power based on the above information calculation is virtually 
identical to the group sequential power. Thus, there is no need to adjust for the group sequential critical 
values in these computations. 
Note the original accrual period and the study target sample are only projections since the actual 
accrual rate and the loss to follow-up rate are unknown. As the study progresses, more accurate 
projections of the study end date will be computed based on the observed rate of enrollment, the 
observed number of events,  and the observed rate of loss-to-follow-up. This data will be provided to 
the DSMB and the TrialNet governing body, and if need be, this document will be amended.
9.5.Interim Monitoring Plan 
The Lan-DeMets 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 
that emerge during the trial (49).  The DSMB may terminate the trial prematurely if a statistically 
significant effect is observed and it is considered that all major trial objectives have been met.  
The DSMB will also consider early termination due to absence of a treatment effect (i.e. futility) based 
on computations of conditional power conducted both under the initial study design and under the 
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current trend of the data (50).
9.6.Withdrawal Criteria – Individual Subjects
An intent–to-treat approach will be used. Subjects will not be replaced.  All data acquired prior to 
termination for the reasons outlined below will be included in the primary analysis unless a participant 
withdraws consent. Every effort will be made to conduct a final study visit with the participant and 
participants will be followed clinically until, if applicable, all adverse events resolve. 

Withdrawal of consent

Withdrawal by the participant

Withdrawal by the investigator 

Intercurrent illness or event that precludes further visits to the study site or ability to evaluate 
disease.
10.ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE
10.1. Statement of Compliance
This study will be conducted in compliance with the protocol and consistent with current Good Clinical 
Practices (GCP), adopting the principles of the Declaration of Helsinki, and all applicable regulatory 
requirements (ICH E6, 45CFR46, and FDA 21CFR sections 11, 50, 56, 312).
Prior to study initiation, the protocol and the informed consent documents will be reviewed and 
approved by an appropriate Independent Ethics Committee/Research Ethics Board (IEC/REB) or 
Institutional Review Board (IRB).  Any amendments to the protocol or consent materials must also be 
approved before they are implemented.
10.2. Participating Centers
Participating TrialNet clinical sites must have an appropriate assurance, such as a Federal-wide 
Assurance (FWA) or an Unaffiliated Investigators Agreement (UIA), with the Office for Human Research 
Protections (OHRP), since they are actively engaged in research and provide informed consent.  The 
protocol and consent forms will be approved by Institutional Review Boards or Ethics 
Committees/Research Ethics Boards at each of the participating clinical sites.  HIPAA and applicable 
local regulations will be followed by each participating institution in accordance with each institution’s 
requirements.  The participating international sites will obtain approval from their corresponding review 
boards in accordance with their local procedures and institutional requirements.
The investigator is required to keep accurate records to ensure the conduct of the study is fully 
documented.  The investigator is required to ensure that all case report forms are legibly completed for 
every participant entered in the trial.
The investigational sites participating in this study will maintain the highest degree of confidentiality 
permitted for the clinical and research information obtained from participants participating in this study.  
When a subject participates in this study at more than one TrialNet site, sharing of this information is 
required.  Sharing of information obtained during this study between TrialNet clinical centers and 
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affiliates will be done to assure subject understanding and consent, safety, and adherence to protocol.  
Medical and research records will 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 site must 
permit authorized representatives of the sponsor(s) and regulatory agencies to examine (and when 
required by applicable law, to copy) 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 (obscuring 
any personally identifying information).  Authorized representatives, as noted above, are bound to 
maintain the strict confidentiality of medical and research information that may be linked to identify 
individuals.  The investigational site will normally be notified in advance of auditing visits.
10.3. Informed Consent
The process of assuring that individuals (and parent/guardian if less than 18 years of age) are making 
an informed decision about participating in this study includes both verbal and written communication.  
Written materials include a Volunteer Handbook, Volunteer Understanding Assessment, and written 
consent forms.  There are several consent forms for this study.  One is a Screening consent form that 
describes the procedures, risks, and benefits, and determines eligibility for the study.  The second is 
the Intervention consent form, which describes the procedures, risks, and benefits for the remainder of 
the study.  A third consent form is for use at clinical sites that will be performing the post-treatment 
visits, but not the treatment visits.  The consent forms will be reviewed with participants (and their 
parent/guardian in the case of participants under 18 years of age) and the participant will be given time 
to review the written consent form and ask questions.  An assent form has also been developed for 
participants less than 18 years of age (unless local IRB/REB requirements differ in procedure). 
As part of the informed consent process, the participant and/or parent or guardian (if the participant is 
less than 18 years of age) will also be required to complete a short, written Volunteer Understanding 
Assessment that is designed to ensure that the subject understands the study, as well as what is being 
asked of him/her. The participant will be given a copy of their consent/assent forms.  
The consent process will be conducted by qualified study personnel (the Trial Investigator or Study 
Coordinator and/or other designee).  All participants (or their legally acceptable representative) must 
read, sign and date a consent form prior to participation in the study, and/or undergoing any study-
specific procedures.
When a participant turns 18 they are permitted to re-consent remotely should they be unable to return 
to the study site for an in-person visit. When providing remote consent (via phone or video conference) 
the POC will review the checklist and long-form informed consent document with the subject/parent or 
guardian. After the subject/parent or guardian is provided the printed long form informed consent 
document, the POC will address any questions the subject/parent or guardian may have before the 
informed consent form is signed and any procedures are performed. The informed consent document 
may be provided to the subject/parent or guardian using any method that the complete content can be 
available in print. Signed and completed documentation must be available to the subject/parent or 
guardian and the study team, by any method that assures that the complete content can be available 
in print. 
Re-assent when a participant reaches age 12 is waived until the participant returns for an in-person visit 
at the study site.
The informed consent form must be updated or revised whenever there is new, clinically significant  
information applicable to the safety of the participants,  when indicated for a protocol amendment, 
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and/or whenever any new information becomes available that may affect a subject’s participation in the 
study.  
Subjects will be re-consented if they reach the age of 18 years while enrolled in the study.
10.4. Study Subject Confidentiality
The investigational sites participating in this study will maintain the highest degree of confidentiality 
permitted for the clinical and research information obtained from subjects.  Participant identifying clinical 
and research information will be shared between TrialNet sites to support participants and assure 
protocol compliance as applicable. As a part of the quality assurance and legal responsibilities of an 
investigation, the investigational site must permit authorized representatives of the sponsor(s) and 
regulatory agencies to examine (and when required by applicable law, to copy) 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 (obscuring any personally identifying information). Authorized 
representatives, as noted above, are bound to maintain the strict confidentiality of medical and research 
information that may be linked to identify individuals. The investigational site will normally be notified in 
advance of auditing visits. Study records with the study subject’s information for internal use at the 
clinical sites will be secured at the study site during the study. At the end of the study, all records will 
continue to be kept in a secure location. There are no plans to destroy the records. 
Study subject data, which is for reporting purposes, will be stored at the TrialNet Coordinating Center.  
Case report forms sent to the Coordinating Center will identify participants by the unique TrialNet 
Identification Number.  The data entry system at the Coordinating Center is a secured, password 
protected computer system.  At the end of the study, all study databases will be archived at the 
Coordinating Center, and the data collection forms will be electronically scanned and saved in electronic 
format for long-term storage.  
Stored samples including genetic samples could be utilized to learn more about causes of type 1 
diabetes, its complications (such as eye, nerve, and kidney damage) and other conditions for which 
individuals with diabetes are at increased risk, and how to improve treatment.  The results of these 
future analyses, and any mechanistic studies will not be made known to the participant.
10.5. Risks and Benefits
The risks of this study are presented in this protocol, the Investigator’s Brochure and informed consent 
form.  There is no guaranteed benefit to subjects for their participation in the study.  This study will 
examine whether intervention with abatacept will delay or prevent the development of abnormal glucose 
tolerance and diabetes, but there is no guarantee that this will occur.  However, all subjects will benefit 
from close monitoring for the development of diabetes.  This close monitoring significantly reduces the 
morbidity typically associated with clinical onset of disease.
Special consideration regarding risks and benefits for children is described in section 8.1.
10.6. Ethics
The study protocol, along with the required informed consent forms, will be approved by each 
participating institution’s Institutional Review Board (IRB) or Ethics Committee/Research Ethics Board 
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Page 36 of 44
(EC/REB) at international sites prior to the initiation of any research procedures (at the site). In addition 
to details described in the sections above (informed consent, confidentiality, and risks and benefits), 
the investigators have reviewed and considered ethical ramifications in the design and development of 
this protocol. The investigators have made every effort to minimize and monitor risks and discomforts 
to participants throughout the course of the study. 
11.   STUDY ADMINISTRATION
11.1. Organizational Structure
This study is part of Type 1 Diabetes TrialNet, which is funded by the National Institutes of Health. 
Funding will cover the costs of administration and laboratory tests associated with this study. 
11.2. Role of Industry
Bristol-Myers Squibb will provide the abatacept for clinical trial conduct. Under TrialNet’s direction, 
Bristol-Myers Squibb may perform measurements such as PK and anti-Abatacept antibodies as 
indicated on coded samples.  Data and data analysis will be conducted by TrialNet investigators.
11.3. Groups and Committees
11.3.1. Abatacept Prevention Study Chair Committee
The Study Chair and TrialNet Executive Committee will receive periodic reports from the TNCC on the 
progress of the study.  These will include accrual rates and baseline demographic characteristics. 
Interim data summaries provided to others (except those that could lead to unmasking of study 
outcome) will first be supplied to the Study Chair for review. Criteria and results of ongoing monitoring 
of the TrialNet labs in terms of reproducibility will also be provided on a routine basis and reported on 
during TN18 Abatacept Prevention Study Chair Committee meetings, as scheduled. As appropriate, 
abstracts and manuscripts dealing with the progress of the trial shall be directed by the TN18 Abatacept 
Prevention Study Chair Committee. 
11.3.2. TrialNet Chairman’s Office and TNCC
The TrialNet Chairman’s Office and TNCC will work together in providing leadership to the TrialNet 
study group to include protocol and manual preparation, training for clinical sites, development of 
statistical design for each study, and analysis of study results.  The TNCC will also coordinate 
interactions among the participating TrialNet Clinical Centers, test laboratories including TrialNet Core 
Laboratories and other subcontract laboratories, NIDDK, and other sponsoring agencies.
11.3.3. Clinical Sites
Principal Investigators at each participating TrialNet clinical site will oversee all operations at that site.  
The clinical sites will forward all laboratory and data collection form information to the TNCC for 
analysis.  Direct communication and site visits, as needed, will facilitate evaluation of the trial 
management.  
11.3.4. Endpoint Adjudication Committee
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Page 37 of 44
A TrialNet Endpoint Adjudication Committee will review all relevant information for each subject who 
does not meet the criteria stated in section 9.1 but has been otherwise diagnosed as having developed 
diabetes or abnormal glucose tolerance. The Committee will determine whether the diagnosis of 
diabetes or abnormal glucose tolerance in each of these subjects is sufficiently sound so as to include 
that subject among the cases who have reached the primary outcome in the statistical analysis. The 
Committee will be masked to treatment assignment as it reviews each case.
11.3.5. Clinical Site Monitoring
In order to conduct this study with established research principles, site visits will be conducted during 
the study to evaluate study conduct and ensure subject safety.  All sites will be monitored by the TNCC 
and appropriate TrialNet committees for patient enrollment, compliance with protocol procedures, 
completeness and accuracy of data entry, the occurrence and reporting of adverse events (AEs) and 
serious adverse events (SAEs), site pharmacy accountability/operations and to confirm the presence 
of appropriate IRB/REB regulatory approvals/documents.  
11.4. Medical Monitor and Data Safety and Monitoring Board (DSMB)
All adverse events will be recorded on the adverse event forms, which will be sent to the local 
IRBs/REBs, per their reporting requirements, and to the Coordinating Center. 
An independent physician will be designated to serve as the medical monitor for this study who will 
maintain regular contact with the study and the Study Chair.  (S)he will review all adverse event reports, 
masked to treatment assignment, and will file event reports with regulatory authorities as appropriate.  
The DSMB will meet approximately every 3 months and as needed to review indicators of safety.  In 
addition, they will meet every 6 months to review the interim effectiveness and potential toxicity of the 
study treatments based on interim analyses of indicators of effectiveness and safety prepared by the 
TNCC separately by treatment group.  The DSMB will independently evaluate whether there are 
grounds to modify or discontinue the study.
11.5. Sample and Data Storage
Samples to be stored for research purposes will be located at the NIDDK Repository and at TrialNet 
Laboratory Sites.  While TrialNet is active, the use of the samples will be restricted to TrialNet 
researchers unless researchers from outside of TrialNet obtain approval from the TrialNet Steering 
Committee and the NIDDK to utilize the samples.  All samples will be coded with unique study numbers, 
but TrialNet researchers will be able to identify samples if it is necessary to contact participants for 
reasons of health or for notification to them about future studies. Approval from the TrialNet Steering 
Committee and the NIDDK would be required before such linkage could occur.  Researchers from 
outside of TrialNet will not be permitted to identify samples. 
Data collected for this study will be sent to the TNCC.  De-identified data will be stored at the NIDDK 
Repository, under the supervision of the NIDDK/NIH, for use by researchers including those outside of 
TrialNet.
With permission of the subject, when TrialNet is completed, samples will continue to be stored at the 
NIDDK Repository.  Since the stored data will be fully de-identified upon the completion of TrialNet, it 
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Page 38 of 44
will no longer be possible to identify samples.  Thus, whereas a sample can be destroyed upon a 
participant’s request during the existence of the TrialNet, it can no longer be destroyed once TrialNet 
is completed.  However, there will still be the potential to link data derived from the samples with data 
that had been derived from TrialNet studies.  Once TrialNet is completed, researchers will only obtain 
access to samples through grant proposals approved by the NIDDK.  The NIDDK will convene an 
external panel of experts to review requests for access to samples.
11.6. Preservation of the Integrity of the Study
The scientific integrity of the trial dictates that results be reported on a study-wide basis; thus, an 
individual Center will not report the data collected from its site alone.  All presentations and publications 
using TrialNet trial data must protect the main objectives of the study.  Data that could be perceived as 
threatening the study outcome will not be presented prior to release of the primary study outcomes.  
Approval as to the timing of presentations of data and the meetings at which they might be presented 
will be granted by the TrialNet Steering Committee.  Study results should be discussed with the news 
media only upon authorization of the Steering Committee, and never before the results are presented.  
Any written statements about this study that are shared with national media must be approved by 
TrialNet before release.
11.7. Participant Reimbursement and Compensation
Participants may be compensated for each visit attended in the study. In compliance with ICH Guidance 
E6, the amount and method of payments to subjects shall be designed to avoid coercion or undue 
influence on the study subjects. Payments to subjects will be prorated and not wholly contingent on 
completion of the trial by the subject.
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APPENDIX 1: Natural History/Pathway to Prevention to Abatacept in At-Risk Relatives:   
Study Flow Chart
Natural History/Pathway to Prevention Study Screening
Procedures
Relative of individual with type 1 diabetes
Age 1-45
Initial Autoantibody draw
Results to move on to
Autoantibodies
Natural History Monitoring
At least one autoantibody confirmed positive, or at least two 
autoantibodies present
Natural History/Pathway to Prevention Study Monitoring
Procedures
Confirmation of autoantibody status, OGTT, HLA
Results to move on to 
Autoantibodies1
Abatacept Prevention 
Screening
At least two diabetes related autoantibodies confirmed to be present on 
two occasions not including mIAA. Confirmation of 2 positive 
autoantibodies must occur within six months prior to randomization, but 
the confirmation does not have to involve the same 2 autoantibodies.
OGTT2
OGTT within 52 days of infusion:
Fasting Plasma Glucose <110 mg/dL (6.1 mmol/L) AND
2 hour Plasma Glucose <140 mg/dL (7.8 mmol/L) AND
30, 60 or 90 minute glucose < 200 mg/dL (11.1 mmol/L)
Abatacept Prevention Study Screening
Procedures
Screening consent is reviewed and signed. Laboratory assessments, PPD 
(or IGRA), History, PE, Volunteer Understanding Assessment, Study 
Education.
OGTT if not performed during Natural History Monitoring Visit
Results to move on to 
Meets all study inclusion criteria
Abatacept Randomization
Does not meet any exclusion criteria3
Abatacept Prevention Study Baseline and Randomization (infusion must occur within 24 hours of 
randomization)
Procedures
Intervention consent is reviewed and signed. Confirmation of eligibility, 
randomization, baseline laboratory assessments, administration of 
abatacept study drug/placebo.
1If autoantibodies are not confirmed positive on the second test a tiebreaker draw will be required.
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Page 40 of 44
2If previous abnormal glucose tolerance, has had two consecutive OGTTs with normal glucose tolerance.  
Note, individuals are permitted to undergo OGTT testing to determine eligibility for Abatacept during a screening 
visit if not yet eligible through OGTT testing in Natural History Monitoring Visit
3If subject is not eligible or unwilling to participate in this study, the subject may be followed in TN01 
Natural History/Pathway to Prevention Study.
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APPENDIX 2 - Schedule of Assessments
Week of Trial
 
 
2
4
8
12
16
 20
 24
 28
 32
 36
 40
 44
48
61
74
87 100 113
126
Month of Trial
 
 
 
1
2
3
4
5
6
7
8
9
10
11
12
15
18
21
24
27
301
Visit number
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
191
Study drug/placebo administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistries and liver function tests 
X
X
X
X
X
CBC with diff and platelet count
X
X
X
X
X
X
X
History/Physical exam2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oral Glucose Tolerance3
X3
X
X
X
X
X
EBV viral load4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EBV/CMV serology4
X
HIV, Hep B and C serology
X
PPD test or IGRA
X
Urine pregnancy test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
Islet Autoantibodies
X
X
 
X
X
X
X
Mechanistic assessments5
X
X
X
X
X
X
X
X
X
Interim Phone Contact and Glycemic 
status6
X
X
X
Flu Vaccine Administration7
1= Subjects will be followed every three months until development of diabetes or the end of the trial.
2= Interim medical history and directed/limited physical exam prior to study drug/placebo infusion and after 24 months. Routine exam at screening and months 12, 24. All include adverse event assessment and 
collection of concomitant medications.
3= If OGTT consistent with Abnormal glucose tolerance or DM, repeat as soon as possible, but no less than one day apart.  Aim to repeat within 1 month.  Glucose, insulin, and C-peptide are collected at each 
OGTT. In order to maintain the masking of the study outcome, a random subset of participants with a normal OGTT will also be brought back for an additional OGTT after undergoing a regularly scheduled 
OGTT.
Individuals may undergo OGTT testing for eligibility during the Abatacept Screening visit. 
4= Subjects will be screened for EBV infection with serology (VCA IgG, VCA IgM, and EBNA) with viral load measured in those except subjects who are IgG+, IgM-, EBNA+.  Those with positive viral load at 
screening are not eligible for at least 90 days after viral load becomes undetectable. During the study, EBV seronegative subjects will have viral loads determined at each visit through visit 12.  Those with 
positive viral loads will not receive additional study drug until laboratory and clinical evidence of resolution of EBV infection.  EBV assessments will be done after visit 12 as clinically indicated.
5= May include samples for RNA, plasma, serum, DNA, measures of B and T cell number and function to understand the effect of therapy on the immune system and infectious disease.  The schedule for these 
assessments may vary as appropriate.  At no time will the blood draw volume exceed what is allowable according to the subject’s age and body weight (For subjects <18 years, 5 mL/kg per visit, 9.5 mL/kg in 
an 8 week period.)
6= All subjects may have interim phone contact with study personnel for formal inquiry about adverse events, presence or absence of blurred vision, polyuria, polydypsia, unintended weight loss.  In addition, 
random glucose samples may be obtained at 3 month intervals beginning at month 15 in which there is no OGTT scheduled.   Those with symptoms or glucose ≥ 200 mg/dL will undergo fasting glucose or 
OGTT evaluation.
7= At any time after the first month of study, subjects will receive their annual clinically indicated killed flu vaccine at the appropriate time of year during the treatment phase of the study.  Subjects may receive 
subsequent killed flu vaccinations later in the study. Responses to these immunizations may be determined through analysis of pre- and 4 week post-dose samples.


Page 42 of 44
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SAP_001.pdf: 
1 
Version  09SEPT2021 
TN-18 Statistical Analysis Plan 
 
 
TRIAL FULL TITLE 
CTLA-4 Ig (Abatacept) FOR PREVENTION OF 
ABNORMAL GLUCOSE TOLERANCE IN RELATIVES 
AT-RISK FOR TYPE 1 DIABETES MELLITUS  
(Protocol TN-18) 
EUDRACT NUMBER 
 2013-002249-13 
Phase 
Phase IIb 
SAP VERSION 
 Version  
ISRCTN NUMBER 
SAP VERSION DATE 
Sepember 9, 2021  
TRIAL STATISTICIAN 
Brian Bundy 
TRIAL CHIEF 
INVESTIGATOR 
William Russell 
SAP AUTHOR 
Jeffrey Krischer 


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Contents 
Table of Contents ...................................................................................... Error! Bookmark not defined. 
1. 
Abbreviations and Definitions .......................................................................................................... 3 
2. 
Introduction ..................................................................................................................................... 3 
3. 
Primary Analysis ............................................................................................................................. 4 
4. 
Secondary Outcomes and Analyses ............................................................................................... 4 
5. 
Study Power and Sample Size ........................................................................................................ 6 
6. 
Interim Monitoring Plan ................................................................................................................... 7 
7. 
General Considerations .................................................................................................................. 7 
8. 
Safety Analyses ............................................................................................................................... 8 
9. 
Reporting Conventions .................................................................................................................... 9 
10. 
Per Protocol Analysis ...................................................................................................................... 9 
11. 
Technical Details ............................................................................................................................. 9 
12. 
References .................................................................................................................................... 10 
 


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1. 
Abbreviations and Definitions 
 
 
AE 
Adverse Event 
ADA 
American Diabetes Association 
AGT 
Abnormal Glucose Tolerance  
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
DSMB 
Data Safety Monitoring Committee 
ITT 
Intent to Treat 
OGTT 
Oral Glucose Tolerance Test 
PH 
Proportional hazards 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
T1DM 
Type 1 Diabetes Mellitus 
 
 
2. 
Introduction 
 
Preface 
 
The rationale for this study is that antigen-specific T-cells are thought to play a central role in the 
pathogenesis of autoimmune diseases. Abatacept binds to CD80/CD86 receptors on antigen 
presenting cells, thereby inhibiting their binding to the co-stimulatory molecule CD28 on T-cells. 
By inhibiting full T-cell activation, Abatacept also affects the downstream inflammatory cascade. 
 
  Purpose of the analyses 
 
Analyses of study data will be conducted to address all objectives and other interrelationships 
among elements of study data of interest to the investigators and of relevance to the objectives 
of the study. Analyses by sex, age, and race/ethnicity are also planned. 
 
All primary analyses will be conducted under the intention-to-treat principle whereby all outcome 
data in all randomized subjects will be included, regardless of treatment compliance. 
 
Primary Outcome 
 
The primary outcome is the elapsed time from random treatment assignment to the 
development of confirmed abnormal glucose tolerance or diabetes among those enrolled in the 
primary analysis cohort consisting of subjects with insulin autoimmunity and absence of 
metabolic abnormalities (normal OGTT).    
 
The study endpoint is realized with either OGTT criteria for abnormal glucose tolerance or 
diabetes or clinical criteria for diabetes.   
 
OGTT criteria for abnormal glucose tolerance or diabetes:  
 
The presence of an OGTT consistent with abnormal glucose tolerance or diabetes on two 
sequential dates.  A subject with abnormal glucose tolerance or diabetes on an OGTT should 
undergo a repeat OGTT as soon as possible, but no less than one day apart.  Aim to repeat 
within one month.  The time of abnormal glucose tolerance or diabetes will then be taken as 


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the date of the confirmatory abnormal OGTT. The definition of abnormal glucose tolerance or 
diabetes is: 
a. Fasting plasma glucose ≥ 110 mg/dL (6.1 mmol/L) and < 126 mg/dL (7 mmol/L) or 
b. 2 hour plasma glucose ≥ 140 mg/dL (7.8 mmol/L) and < 200 (11.1 mmol/L, or 
c. 30, 60, 90 minute plasma glucose during OGTT ≥ 200 mg/dL (11.1 mmol/L) 
 
Onset of Diabetes:  
Criteria for diabetes onset (T1DM) are based on glucose testing, or the presence of 
unequivocal hyperglycemia with acute metabolic decompensation (diabetic ketoacidosis). One 
of the following criteria must be met on two occasions as soon as possible but no less than 
one day apart for diabetes to be defined: 1. Symptoms of diabetes plus casual plasma glucose 
concentration ≥ 200 mg/dL (11.1 mmol/L). Casual is defined as any time of day without regard 
to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and 
unexplained weight loss. 2. Fasting plasma glucose ≥ 126 mg/dL (7 mmol/L). Fasting is 
defined as no caloric intake for at least 8 hours. 3. 2 hour plasma glucose ≥ 200 mg/dL (11.1 
mmol/L). The test should be performed using a glucose load containing the equivalent of 
1.75g/kg body weight to a maximum of 75g anhydrous glucose dissolved in water. It is 
preferred that at least one of the two testing occasions involve an OGTT. Cases identified will 
be confirmed as having diabetes if the glucose values to make these determinations were 
obtained in a TrialNet laboratory as part of an OGTT. Cases diagnosed with diabetes by 
symptoms and casual glucose ≥ 200mg/dL or by other criteria than the above will be 
adjudicated by the TrialNet Endpoint Adjudication Committee. 
 
The date of arriving at the study endpoint is the date of the second occasion that meets either of 
the above criteria or the date in which the participant presented in a state of DKA.  
 
3. 
Primary Analysis 
 
The study design is a randomized double-blind placebo-controlled trial. The primary objective 
of the study is to assess the effect of CTLA4-IG therapy versus placebo on the risk of 
developing abnormal glucose tolerance (AGT) as measured from an OGTT. 
 
The cumulative incidence of AGT over time since randomization within each treatment group 
will be estimated from a Kaplan-Meier estimate of the "AGT-free" survival function. The 
difference between groups in the cumulative incidence functions, and the associated hazard 
functions, will be tested at the 0.05 level, two-sided, using the Cox regression including age 
as a covariate (1, 5).  The critical value for the test statistic, and confidence intervals in this 
primary analysis will be determined by the group-sequential procedure.  
 
Data from the TrialNet Pathway to Prevention Study may be used to determine participant 
eligibility. Outcomes from other studies may be used in meta-analyses, but not in the evaluation 
of this study’s efficacy. 
 
 
4. 
Secondary Outcomes and Analyses 
 
4.1 Subgroup analyses.  
 
Subgroup analyses will be conducted comparing the effects of CTLA4-Ig versus placebo on 
the risk of AGT with a test of the group by subgroup factor interaction in a Cox proportional 
hazard (PH) Model. Subgroups of the population classified by age (children < 12 years of 


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age, adolescents 13-17 years and adults > 18 years), gender, race/ethnicity (white, 
nonwhite and Hispanic yes/no), and specific antibody status at baseline. Differences in the 
treatment effect between subgroups will be tested using Likelihood Ratio Test (LRT) in a 
Cox PH model (1).   
 
4.2 Covariate analyses.  
 
Similar analyses will be conducted using the values of quantitative baseline factors. They 
include age, weight, BMI, HbA1c, HLA (DR3/4 vs. others), autoantibody titers, basal C-
peptide, stimulated C-peptide ( peak and AUC), glucose (fasting, 2-hour, AUC and 
measures of insulin secretory rate (0-30 min) and sensitivity (ISI) (6,7) modeled from the 
OGTT) at study entry. The dependence of the treatment effect on the quantitative levels of 
a covariate will also be assessed by a covariate by treatment group interaction in a PH 
model. The ISI can also inform on the treatment effect independent of C-peptide. 
 
The association of demographic, genetic, immunologic, metabolic, and lifestyle factors, the 
presence of illness and concomitant meds, both at baseline and over time, with the risk of 
AGT onset will be assessed in Cox PH Models over time. The effects of changes in 
longitudinal factors on AGT risk will be assessed using time-dependent covariates for these 
factors.  
 
Using a step-up procedure additional covariates will be tested and included in the model 
only if they improve the log-likelihood at 0.10 level (2-sided). This will be accomplished 
with the treatment assignment variable included but the inclusion/exclusion of the 
candidate covariates will be completely independent of the treatment variable’s impact on 
the model.  The LRT associated with treatment variable in the full, adjusted model will be 
used for the test of treatment effect described in the previous paragraph. Thus, the 
adjustment of the significance level, as with multiple testing, is unnecessary. 
 
 
4.3 Longitudinal analyses. 
 
Longitudinal analyses will assess the effects of CTLA4-Ig versus placebo treatment on 
immunologic and metabolic markers over time up to the onset of AGT. Differences between 
groups in the mean levels of quantitative factors over time will be assessed using a normal 
errors linear model for repeated measures. Differences between groups in the prevalence 
of qualitative factors over time will be assessed using generalized estimating equations for 
categorical measures. Generalized estimating equations may also be employed for the 
analysis of quantitative factors if the assumption of multivariate normal random errors is 
violated.   
 
 
 
4.4 Diabetes.  
 
Additionally, as noted in section 4.9.2 of the protocol, subjects will be able to be followed for 
the occurrence of diabetes.  The treatment arms will be compared on the corresponding 
incidence rates of Type 1 diabetes using the logrank statistic. Subgroup analyses 
analogous to those described for the AGT endpoint will be conducted on the endpoint of 
Type 1 diabetes.   
 
Additional, pre-specified secondary analyses are identified as follows: 


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1. Although there is limited power, the AGT-free proportion at 1,2 and 3 years after 
randomization will be calculated and compared using the Kaplan-Meier estimates of the 
proportions and the Greenwood estimates of the variance. 
 
2. Evidence that the HR is not constant over the period of follow up will be assessed and 
the risk of diabetes will be assessed in a PH model. The primary test for treatment effect 
is based on the Cox model, which assumes a proportional hazard between treatment 
groups. If there is a true treatment effect but it is not proportional over the follow-up 
period the test will have substantially less statistical power than stated in the statistical 
section of the protocol. Therefore, to establish a reasonable guide to pursue the 
possibility of a non-proportional treatment effect we will use the guideline requiring a 
significance level of 0.10 or less of the LRT from the standard Cox model.  Graphical 
diagnostics using Schoenfeld residuals will be employed to explore evidence for a 
monotonically decreasing effect of treatment over the follow-up p e r i o d .  Also, plotting 
the Kaplan-Meier time-to-AGT rates by treatment group on the log-log scale will provide 
visual assessment of any diminishing effect of treatment (equal distance separation of 
curves indicates proportional hazard).  We will characterize any such decreasing effect 
of treatment by model parameterization with monotonically deceasing benefit over the 
follow-up time.  Initially, a treatment interaction with log-transformed time-on-study will be 
fit to the data and the log likelihood improvement in the fit noted. Other time transforms 
will be explored only to characterize mathematically the rate of the diminishing effect. Of 
particular interest will be characterizing the point in follow-up where the hazard ratio is 1. 
Any variations in proportional hazards other than a monotonically decreasing effect will 
not be of interest because of the possibility that it is simply random error. 
 
 
5. 
Study Power and Sample Size 
 
The study has been designed to provide 80% power to detect a 40% risk reduction in the rate of 
AGT using a two-sided test at the 0.05 level after six years of study duration. 
 
Study enrollment will stop on approximately July 31, 2019 and follow-up will continue for up to two 
additional years. A model of observed events (confirmed abnormal glucose tolerance; AGT) in the 
placebo group as of June 2019, provides a more realistic estimate of the number that will have 
developed AGT at the conclusion of the follow up period. The model suggests that the total 
number of events will be between 64 and 70; resulting in detectable hazard ratios of 0.496 to 
0.512. The hazard ratios and difference in cumulative incidence are based on 80% statistical 
power when testing at the 0.05 level (2-sided).   
 
The final test of significance up through the six-year time point will employ group sequential 
critical values to protect against inflation in the type I error probability due to interim assessments 
of the emerging data for review by the DSMB. However, there is only a minimal loss in power with 
this approach so that the fixed sample size power based on the above information calculation is 
virtually identical to the group sequential power. Thus, there is no need to adjust for the group 
sequential critical values in these computations.  
 
Note the original accrual period and the study target sample are only projections since the actual 
accrual rate and the loss to follow-up rate are unknown. As the study progresses, more accurate 
projections of the study end date will be computed based on the observed rate of enrollment, the 
observed number of events, and the observed rate of loss-to-follow-up. This data will be provided 


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to the DSMB and the TrialNet governing body, and if need be, this document will be amended. 
 
6. 
Interim Monitoring Plan 
 
The Lan-DeMets 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 that emerge during the trial.  
The spending function that approximates the O’Brien-Fleming boundaries is: 
 
 
 
Where t* is the information fraction ( 0 < t* ≤ 1) and α is the fixed-sample type I error (i.e.,0.025) 
The DSMB will also be informed if there is a serious lack of evidence of a treatment effect (i.e. 
futility analysis). The boundaries are based on the paper by Lachin (4). The study should be 
stopped based on the futility of rejecting the null hypothesis at the completion of the trial if: 
 
ZHR (t*) ≥ 0 when ≤ 0.5 if  t*  < 0.8 or  ZHR  (t* ) ≥ −0.8 when t*  ≥ 0.8 
 
Using Lachin’s formulas a onetime use of either boundary for the design parameters above  
( θ ≡ Z1−α  + Z1−β  = 2.8 ) raises the type II error to approximately 0.204 and 0.202, respectively. 
For larger values of t* the increase to the error probability is even less. Furthermore, by the laws of 
probability a single use of each rule will increase the type II error no more than the sum of the 
increase (i.e., 0.15+0.004+0.002 = 0.156). 
 
The DSMB may terminate the trial prematurely if a statistically significant effect is observed and it 
is considered that all major trial objectives have been met. The DSMB will also consider early 
termination due to absence of a treatment effect (i.e. futility) based on computations of conditional 
power conducted both under the initial study design and under the current trend of the data. 
 
An independent medical monitor will closely monitor the events in the trial as described in 
section 10.4 of the protocol. Additional analysis will assess potential adverse outcomes of 
treatment and will assess the incidence of all severe adverse events. 
 
7. General Considerations 
 
1. Analysis Populations 
 
The Intention to Treat Population (ITT) 
The intention to treat population comprises all randomized (as planned) subjects. 
 
Full Analysis Population 
The Full Analysis Set (FAS) will comprise all subjects who received any study drug and who 
participated in at least one post-baseline assessment. These will be analyzed as 
randomized. FAS will be the primary efficacy population. So, FAS is a subset of ITT. 
 


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Per Protocol Population 
The Per Protocol Set (PPS) will comprise all subjects who did not substantially deviate 
(defined as greater than or equal to 75% protocol compliance) from the protocol as to be 
determined on a per-subject basis before data base lock and unblinding.   
 
 
Safety Population 
All subjects who received any study treatment (including control) but excluding subjects who 
drop out prior to receiving any treatment. 
 
2. Timing of Analyses 
 
The final analysis will come after the total number of events (confirmed abnormal glucose 
tolerance) in the placebo group is between 64 and 70. This will result in detectable hazard 
ratios of 0.496 to 0.512 to  achieve the planned 80% statistical power when testing at the 0.05 
level (2-sided) for the primary analysis. 
 
3. Missing Data 
 
In general, missing values will be assumed to be missing completely at random (MCAR) 
unless empirical evidence to the contrary can be established internal to the study.  The 
methodology employed in analyzing time-to-T1D utilizes whatever follow-up has been 
recorded for each subject (i.e., maximum utilization of follow-up time).  Presuming no 
evidence against MCARno methods will be employed to impute additional follow-up of 
subjects that drop out (i.e., lost to follow-up).  All secondary endpoints will use the complete-
case analysis approach which limits the analytical cohort to those subjects that have the 
secondary endpoint of interest measured and recorded.  In modeling to adjust for risk factors 
associated with the endpoint (i.e. covariates), missing values will be assigned the mean from 
the known covariate cohort.  This simple rule will be employed only if the percent missing is 
less than 10% for the analytical cohort.  If the missing is 10% to 20% a separate indicator for 
missing will be included in the modeling.  If the missing in exceeds 20% the covariate will be 
removed from consideration. 
 
8. Safety Analyses 
Safety will be evaluated with summary of adverse events for the safety population. 
The following parameters will be assessed during the study: 
 
Adverse Events 
The summary statistics will be produced in accordance with Section 8. Treatment emergent 
adverse events (AEs) are those events that occur after the baseline assessment. Only Grade 
2 or greater adverse events were reported in this study. The incidence of the following AEs 
will be reported: 
 
A tabular summary of AE will present: Number of subjects with any AE; Number of SAEs 
with outcome death; Number subjects with SAE; Number subjects with AEs leading to 
discontinuation of study drug, even if by protocol; Number of subjects with AEs leading to 
discontinuation of study; Total number of AEs; Total number of SAEs [TABLE]. 
 
The Adverse Events summary tables will include number of adverse events, the number 
of subjects in each treatment group in whom the event occurred, and the incidence of 
occurrence and should be grouped by system organ class, preferred terms and/or other 


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interested variables (e.g., relatedness, intensity and seriousness). [TABLE] 
 
When calculating the incidence of adverse events, or any sub-classification thereof by 
treatment, time period, severity, etc., each subject will only be counted once and any repetitions 
of adverse events will be ignored; the denominator will be the total population size. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
 
All formal testing of adverse effects will be based on the subject as the experimental unit. Thus, 
for comparing incidence of AE within system organ by treatment group, a one-sided Fisher’s 
exact test will be conducted at 0.05 level (higher incidence in experimentally treated group is the 
alternative hypothesis). Also, highest AE grade will be determined for each subject and 
compared by treatment group using a 2 sample Wilcoxon test (one-sided at 0.05).  No 
correction for multiple testing will be employed in order that the statistical power is maintained. 
 
9. Reporting Conventions 
P-values ≥0.01 will be reported to 2 decimal places; p-values less than 0.01 and >0.001 will be 
reported to 3 decimal places; p-values less than 0.001 will be reported as “<0.001”. The mean, 
standard deviation, and any other statistics other than quantiles, will be reported to one decimal 
place greater than the original data. Quantiles, such as median, or minimum and maximum will 
use the same number of decimal places as the original data. Estimated parameters, not on the 
same scale as raw observations (e.g. regression coefficients) will be reported to 3 significant 
figures. 
 
10. Per Protocol Analysis 
 
Quantifying the evidence of any dose response relationship is part of a complete analysis of any 
well-run and completed clinical trial. This is especially true when the trial is negative when 
testing the primary outcome. To explore whether there is evidence that protocol treatment 
deviations may have played a role in the negative outcome, we plan to assess the treatment 
hazard ratio by the degree of compliance (percent missed infusions)  to the protocol scheduled 
dose in a quantitative manner. 
 
Using the Cox model we will assess the evidence for an effect of treatment compliance 
including the entire cohort. The number of infusions of treatment and the treatment dose (in a 
separate model) will be introduced into the model as a continuous variable (0=received no 
therapy; 1 = received the full prescribed dose) along with the interaction term with treatment 
group to determine its effect on risk.  The significance level of the interaction term (compliance 
value if abatacept subject; 0 otherwise) will be considered important if it is approximately 
0.05 or less one-sided and the coefficient is negative (indicating lower risk with greater 
compliance).  The procedure for including covariates, such as age, will follow the set up 
procedure as described above under Primary and Secondary analyses. 
 
11. Technical Details 
The analysis will be performed in R, S-Plus or SAS. The distributional assumptions as well as 
other assumptions underpinning the planned analyses will be checked.  
 
 
 
 
 


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12. References 
 
1. Cox DR: Regression model and Life Tables J R Stat Soc 34B:187-220, 1972 
2. Reboussin DM, DeMets DL, Kim KM, Lan KK: Computations for group sequential boundaries 
using the Lan-DeMets spending function method. Control Clin Trials 21:190-207, 2000 
3. DeMets DL, Lan G: The alpha spending function approach to interim data analyses. Cancer 
Treat Res 75:1-27, 1995 
4. JM Lachin.  Futility interim monitoring with control of type I and II error probabilities using 
the interim Z-value or confidence limit.  Clinical Trials 2009; 6 (6) 565-573 
5. Diggle PJ, Heagerty PJ, Liang K-Y, Zeger SL: Analysis of longitudinal data. Oxford, UK, 
Oxford Clarendon Press, 1994 
6. Ursini et al. (2015) Medicine 94 DOI: 10.1097/MD.0000000000000888 
7. Matsuda and DeFronzo Diabetes Care 22:1462–1470, 1999