Reversing Type 1 Diabetes After it is Established

The primary purpose of this study is to determine if giving the combination therapy consisting of Thymoglobulin® (ATG) and Neulasta® (GCSF) to patients with established Type 1 Diabetes (T1D) is safe and secondarily, if the ATG and GCSF will preserve insulin production.

This is a randomized, placebo controlled, phase I/II trial. Potential subjects will be screened via a 4 hour mixed meal tolerance test to assess residual beta cell (C-peptide) function. If the C-peptide level at any time is ≥ 0.1 pmol/ml, and the subject meets the additional inclusion and exclusion criteria, they will be eligible for randomization and enrollment. The study will be randomized 2:1 such that 17 subjects will receive active therapy and 8 will receive placebo. Subjects must receive Thymoglobulin®/ Neulasta® or placebo within 8 weeks of randomization. Thymoglobulin® (2.5mg/kg)/placebo will be given as 0.5 mg/kg IV on day 1 and 2 mg/kg on day 2. Six doses of Neulasta® (6mg/dose)/placebo will be given SC every 2 weeks, with the first dose given prior to discharge after the Thymoglobulin® infusion. Complete metabolic panel (CMP) and CBC will be done at the screening visit, just prior to study drug initiation, daily during the Thymoglobulin® infusion admission, and at follow up visits. Following discharge, daily phone calls will be made to the subjects during the first 5 days of therapy and weekly thereafter. In addition, weekly phone calls for the month following completion of therapy will be used to document adverse reactions. Thereafter calls will be made every two weeks.

• Drug: Anti-Thymocyte Globin plus pegylated GCSF
  Anti-Thymocyte Globin (ATG)will be given as 0.5/mg/kg on day 1 and 2mg/kg on day 2, plus 6 doses of pegylated GCSF (6mg/dose)given subcutaneously every 2 weeks beginning after the ATG infusion
  Other Names:

  • Anti-Thymocyte Globin (Thymoglobulin)
  • Pegylated GCSF (Neulasta)
• Drug: Placebo
  Saline infusions will be given on Day 1 and Day 2 followed by placebo injections given in identical volumes in identical syringes

• Experimental: ATG + GCSF
  Subjects will receive an infusion of ATG followed by 6 doses of GCSF every 2 weeks for 10 weeks.
  Intervention: Drug: Anti-Thymocyte Globin plus pegylated GCSF
• Placebo Comparator: Placebo
  Saline infusion will be given on both Day 1 and Day 2 followed by placebo injection given in identical volumes in identical syringes in the identical subcutaneous manner
  Intervention: Drug: Placebo

Inclusion Criteria:

• Must be > 12 years < 45
• Must have a diagnosis of T1D of greater than 4 months duration, with an upper limit of 2 years, Now only recruiting for those diagnosed greater than 1 year but less than 2 years.
• Must have at least one diabetes-related autoantibody present (e.g., ICA, GAD, ZnT8, or IA2 autoantibodies)
• Must have stimulated C-peptide levels ≥ 0.1 pmol/ml (0.3ng/mL) when measured during a mixed meal tolerance test (MMTT), conducted at least 4 months from diagnosis of diabetes, and within 8 weeks of randomization
• Must be EBV PCR negative within two weeks of randomization if EBV seronegative at screening
• Be at least 6 weeks from last live immunization
• Be willing to forgo live vaccines for 3 months following last dose of study drug
• Be willing to comply with intensive diabetes management
• Normal screening values for CBC, renal function and electrolytes (CMP).

Exclusion Criteria:

• Be immunodeficient or have clinically significant chronic lymphopenia: (Leukopenia (< 3,000 leukocytes /μL), neutropenia (<1,500 neutrophils/μL), lymphopenia (<800 lymphocytes/μL), or thrombocytopenia (<125,000 platelets/μL).
• Have a chronic infection at time of randomization
• Have a positive PPD
• Be currently pregnant or lactating, or anticipate getting pregnant within the next two years
• Require use of other immunosuppressive agents
• Have serologic evidence of current or past HIV, Tuberculosis, Hepatitis B or Hepatitis C infection
• Have any complicating medical issues or abnormal clinical laboratory results that interfere with study conduct, or cause increased risk to include pre-existing cardiac disease, COPD, sickle cell disease, neurological, or blood count abnormalities (e.g., lymphopenia, leukopenia, or thrombocytopenia)
• Have a history of malignancies
• Evidence of liver dysfunction with AST or ALT greater than 3 times the upper limits of normal
• Evidence of renal dysfunction with creatinine greater than 1.5 times the upper limit of normal
• Vaccination with a live virus within the last 6 weeks
• Current use of non-insulin pharmaceuticals that affect glycemic control
• Active participation in another T1D treatment study in the previous 30 days
• Known allergy to G-CSF or ATG
• Prior treatment with ATG or known allergy to rabbit derived products
• Any condition that in the investigator's opinion, may adversely affect study participation or may compromise the study results

• The Helmsley Charitable Trust
• Genzyme