Stephen Gitelman | University of California San Francisco | San Francisco, CA

University of Minnesota | Minneapolis, MN

Children's Hospital of Los Angeles | Los Angeles, CA

Children's Mercy Hospital | Kansas City, MO

Children's Hospital of Oakland | Oakland, CA

University of California, San Francisco | San Francisco, CA

University of Colorado | Denver, CO

Children's Hospital of Philadelphia | Philadelphia, PA

University of California, San Diego | San Diego, CA

Emory University | Atlanta, GA

Yale University | New Haven, CT

University of Alabama, Birmingham | Birmingham, AL

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder that results from T cell mediated destruction of insulin producing beta cells. It is not currently possible to identify the majority of subjects who will develop T1DM in the general population in a pre-clinical phase of the disease. Yet, at the time of diagnosis, at least 10-20% of beta cell function remains, and endogenous insulin secretion at this stage often results in near normal metabolic control. However, over the ensuing 1-2 years, further destruction eliminates this residual beta cell mass, and metabolic control deteriorates, placing the affected individual at risk for long-term complications. Thus, interventions that affect T cells are logical targets to ameliorate further beta cell destruction in those with new onset DM.

Objectives: This is an early phase II study of the safety and efficacy of the rabbit polyclonal anti-thymocyte globulin Thymoglobulin (Thymo) in new onset Type 1 diabetes mellitus (T1DM) to determine if this treatment can induce tolerance and thereby prolong endogenous insulin secretion in affected individuals.

Basis/Rationale: Limited initial success in immunosuppression of T1DM has been gained from the use of monoclonal agents that attempt to disrupt T-cell activation via anti-CD3. We postulate that the broader specificity of the polyclonal drug Thymoglobulin will prove more efficacious, and may induce tolerance. ATG (antithymocyte globulin) has enjoyed widespread use for organ transplantation, and Thymoglobulin has emerged as the superior agent in this class. Recent studies suggest that it may function as at least a partial tolerizing agent in this setting. Thymo has also been used to treat various autoimmune conditions. Less is known about its potential role in T1DM. Preclinical studies have shown that anti-lymphocyte serum treatment of the NOD mouse and BB rat with recent onset DM can induce remission, supporting such an approach in humans. A mouse form of ATG has now been developed, and a few doses induces a lasting remission in NOD mice with recent onset diabetes. An early limited human study with equine ATG with new onset T1DM suggested efficacy in prolonging the honeymoon phase. A recent pilot trial with another form of ATG, ATG Fresenius, has shown positive effects on preserving beta cell function. Finally, a trial utilizing Thymo coupled with two other drugs (granulocyte colony stimulating factor and cyclophosphamide) has shown robust effects in preserving beta cell function, with some participants off of supplemental insulin for over 3 years.

Significance: This trial formally tests the hypothesis that Thymo will reset the immunologic rheostat, effecting dynamic immune regulation and perhaps tolerance induction in T1DM. Thymo has been chosen as it not only depletes lymphocytes, but acts at other levels, including modulation of T-cell activation, homing, and cytotoxic activities, induction of regualtory T cells, and may also affect antigen-presenting cells. Based on previous studies in T1DM, preservation of beta cell mass can lead to better metabolic control and reduced risk for long term complications. Moreover, success in this trial will encourage the use of this agent in younger subjects in a larger study, and in pre-diabetic, high-risk individuals.

Protocol Summary: We will enroll a total of 66 subjects from 11 participating clinical sites. Eligible subjects will have T1DM of < 3 months duration, aged 12-35 years. They will be randomized 2:1 to Thymo treatment and control groups (6.5mg/kg of Thymo will be given over 4 days). The primary outcome variable will be endogenous insulin secretion at 12 months, as assessed by mean area under the stimulated C-peptide concentration curve (AUC) in response to a mixed meal tolerance test, with secondary metabolic and mechanistic studies conducted over a 24 month interval. Anticipated outcome is that the treated group will have greater endogenous insulin secretion than controls, and utilize less exogenous insulin per day. Mechanistic studies may show deletion and modulation of autoreactive T cells, induction of Treg cell populations, shift in Th population towards Th2, change in autoantibody isotype and titer and alteration in APC function.