Study of Antithymocyte Globulin for Treatment of New-onset T1DM

Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which the immune system
mistakenly attacks the insulin-producing beta cells in the pancreas. Without these cells,
the body cannot maintain proper blood glucose levels in response to daily activities, such
as eating or exercise. Generally, at the time someone is diagnosed with T1DM, not all of a
person's beta cells have been destroyed - between 15-40% remain healthy and are still able
to produce insulin. Importantly, even small amounts of naturally produced insulin can
improve blood sugar control, make daily management of diabetes less complicated, and reduce
the risk of long term complications. Preserving the remaining precious beta cells is
therefore the goal of the START trial.

The medication being tested in the START trial is antithymocyte globulin (e.g.,
Thymoglobulin®), a mixture of specialized proteins called antibodies. ATG attaches itself to
white blood cells known as T cells, some of which are responsible for the immune system's
attack on beta cells that occurs in T1DM. ATG can change how T cells work, and can eliminate
a large proportion of the T cells from the bloodstream temporarily. Treatment of new onset
T1DM with ATG is therefore expected to alter the behavior of the T cells to halt their
attack, and also reduce T cell numbers, so that new T cells that grow in their place will
learn to accept the beta cells, rather than attacking them.

Following an initial screening appointment, eligible participants will be randomly assigned
to one of two groups: the Experimental Group will receive the study treatment while the
Control Group that will receive placebo. Each participant has a 2 in 3 chance of being
assigned to the treatment group, and a 1 in 3 chance of being assigned to the placebo. The
START trial is a blinded study, so neither participants nor study physicians will know to
which group an individual has been assigned. All participants will receive intensive
diabetes management. Participants in both groups will be admitted to the hospital for 5-8
days to receive infusions of either the study drug or placebo.

The duration of the study is 2 years. Participants will have 8 follow-up appointments in the
first year and 4 visits in the second year. Most of these visits will last 1- 2 hours. A
review of interval health, a physical exam, an assessment of diabetes control including
recent 5 day insulin use and blood sugar (e.g., glucose) testing, and blood collection for
laboratory testing will occur at each visit. Four of the visits will last about 5 hours,
during which participants will undergo mixed-meal tolerance testing (MMTT). This involves
drinking a special drink, similar to a milkshake, and having blood specimens taken over a
4-hour period.

Subjects will be reimbursed for travel and parking expenses, and will receive compensation
for their participation in the longer mixed meal tolerance test visits.

Inclusion Criteria:

- Diagnosis of type 1 diabetes (according to American Diabetes Association [ADA]
criteria) within100 days of enrollment

- Positive for one or more autoantibodies (anti-glutamic acid decarboxylase [GAD],
anti-insulin, or IA-2 autoantibodies)

- Peak stimulated C-peptide level >0.4 pmol/mL or >1.2ng/mL following an MMTT

- Serologic evidence of prior Epstein-Barr virus (EBV) infection (EBV seropositive)

- Willing to use acceptable forms of contraception

Exclusion Criteria:

- Any sign of active infection (e.g., hepatitis, tuberculosis, EBV, cytomegalovirus
(CMV), or toxoplasmosis) at screening

- Positive for human immunodeficiency virus (HIV), tuberculosis, or hepatitis B surface
antigen (HBsAg) at screening

- Prior history of any significant cardiac disease, such as congestive heart failure,
arrhythmia, or structural defects, or suspicion thereof

- Use of glucocorticoids in the 28 days prior to study entry; or topical use of
glucocorticoids

- Use of diabetes medications (other than insulin) that may affect glucose homeostasis,
such as metformin, sulfonylureas, thiazolidinediones, or amylin

- Evidence of liver dysfunction

- Evidence of kidney disease

- Pregnancy or plan to become pregnant

- Leukopenia (<3,000 leukocytes/µL), neutropenia (<1,500neutrophils/µL), lymphopenia
(<800 lymphocytes/µL), or thrombocytopenia (<125,000 platelets/µL).

- Prior treatment with rabbit ATG or known hypersensitivity or exposure to rabbit
sera-derived products

- Vaccination with a live virus within the last 6 weeks before enrollment

- Prior or current therapy that is known to cause a significant, ongoing change in the
course of T1DM or immunologic status

- Any condition that may compromise study participation or may confound the
interpretation of the study results