Diabetes Islet Preservation Immune Treatment

There is a critical need to test therapies that afford long-lasting immunomodulation through
the combined use of short courses of depleting agents, more chronic use of drugs that promote
immunoregulation and critically control the rebounding effector populations, together with
interventions that quell inflammation and support beta cell function and glucose metabolism.
Such combined regimens would rely on lower doses of many of these agents, for increased
safety and tolerability. Here, we propose a combinatorial regimen based on the administration
of drugs that are already FDA approved and marketed, all of which have been used in clinical
trials in patients with T1D, alone or in some combination. This trial will test if the
regimen proposed, for the first time combining all of these agents, will be successful in
preserving insulin secretion in recent onset type 1 diabetes.

Inclusion Criteria:

- Patients must meet all of the following criteria to be eligible to participate in this
study:

1. Subject must be able to understand and provide informed consent.

2. Males and females, 18-35 years of age.

3. New onset T1D for no longer than 120 days at the time of randomization.

4. Affected by T1D, according to ADA standard criteria, and confirmed by positivity
of at least one T1D-associated autoantibody, to GAD65, IA-2, ZnT8, or insulin
autoantibodies (if patient has been treated with insulin for less than 2 weeks).

5. Being on insulin therapy.

6. Stimulated C-peptide peak level >0.2 nmol/L at the baseline 1 visit MMTT.

7. Female subjects of childbearing potential must have a negative pregnancy test
upon study entry.

8. Female (and male) subjects with reproductive potential must agree to use two FDA
approved methods of birth control for the entire duration of the study.

9. Adequate venous access to support study required blood draws.

Exclusion Criteria:

- Potential participants must not meet any of the following exclusion criteria:

1. Inability or unwillingness of a participant to give written informed consent or
comply with study protocol.

2. BMI>30 Kg/m2.

3. Contra-indications to ATG, GCSF, exenatide, etanercept and IL-2 (as per package
insert, e.g., knowledge of hypersensitivity to drugs or its excipients).

4. Uncompensated heart failure, fluid overload, myocardial infarction or liver
disease or severe impairment of a vital organ within the last 6 weeks before
enrollment.

5. Any of the following laboratory findings: hemoglobin <10.0 g/dL; leukocytes
<3,000/μL; neutrophils <1,500/μL; lymphocytes <800/μL; platelets <100,000/μL.

6. Any sign or diagnosis of significant chronic active infection (e.g., hepatitis,
tuberculosis, EBV, or CMV), or screening laboratory evidence consistent with a
significant chronic active infection (such as positive for HIV, IGRA test for TB,
or hepatitis B-C).

7. Ongoing acute infections, e.g., acute respiratory tract urinary tract, or
gastrointestinal tract infections.

8. Ongoing or anticipated use of diabetes medications other than insulin.

9. Current or ongoing use of non-insulin pharmaceuticals that affect glycemic
control within prior 7 days of screening.

10. Current or prior use of immunomodulators or systemic steroids in the last 2
months that could potentially affect diabetes or immunologic status.

11. Recent recipient of any licensed or investigational live attenuated vaccine(s)
within 6 weeks of randomization.

12. Use of investigational drugs within 3 months of participation.

13. Concomitant therapy with immunosuppressive drugs, immunomodulators, or cytotoxic
agents, or previous therapy less than 3 months from randomization.

14. History or diagnosis of malignancy. Any history of gastroparesis or other severe
gastrointestinal disease, pancreatitis, thyroid nodules or malignancy with the
exception of a history of localized basal cell carcinoma.

15. Presence of an allograft.

16. AST, ALT or Alkaline Phosphatase >2 times upper limit of normal or total
bilirubin >1.5 times upper limit of normal.

17. Current, diagnosed, mental illness or current, diagnosed or self-reported drug or
alcohol abuse; or any situation that, in the opinion of the investigator, would
interfere with the participant's ability to comply with study requirements.

18. Pregnancy or ongoing breastfeeding for women; unwillingness or inability of both
females and males of childbearing age to use a reliable and effective form of
contraception, for the entire duration of the study.

19. Past or current medical problems, or findings from physical examination, or
laboratory testing, that are not listed above which, in the opinion of the
investigator, may pose additional risks from participation in the study, may
interfere with the participant's ability to comply with study requirements or
that may impact the quality or interpretation of the data obtained.