Clinical trial NCT01106157: Reversing Type 1 Diabetes After it is Established
Official title: Reversing Type 1 Diabetes After it is Established: A Pilot Safety and Feasibility Study of Anti-Thymocyte Globulin (Thymoglobulin®)and Pegylated GCSF (Neulasta®) in Established Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Diabetes Mellitus, Type 1
Keywords: Autoimmune, Diabetes Mellitus, Glucose Metabolism
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: The Leona M. and Harry B. Helmsley Charitable Trust
name: Genzyme, a Sanofi Company
First posted: 2010-04-19
Enrollment: 25
Sex: ALL
Minimum age (years): 12
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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 as standard of care every 2 weeks, with the first dose given prior to discharge after the Thymoglobulin® infusion. Complete metabolic panel (CMP) and complete blood count (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.

Eligibility criteria: 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., islet cell autoantigen (ICA), GAD, ZnT8, or islet antigen 2 (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 complete blood count (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, chronic obstructive pulmonary 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 angiotensin sensitivity test (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

Primary outcomes:
measure: Change in Metabolic Function Baseline to 12 Months.
timeFrame: Baseline and 12 months
Secondary outcomes:
measure: Percent Change in Regulatory T Cells (Treg) Baseline to 12 Months
timeFrame: Change in Baseline to 12 months
measure: A1c
timeFrame: Change in baseline to 12 months
measure: Change in Insulin Requirements, Baseline to 12 Months
timeFrame: Change from baseline to 12 months
measure: Change in Glutamic Acid Decarboxylase Antibodies (GADA) From Baseline to 12 Months
timeFrame: Change from baseline to 12 months
measure: Change in Insulin Autoantibodies (IAA) From Baseline to 12 Months
timeFrame: Change from baseline to 12 months
measure: Change in Insulinoma Associated 2 Autoantibodies (IA-2A) From Baseline to 12 Months
timeFrame: Change from baseline to 12 months
measure: Change in Zinc Transporter 8 Autoantibodies (ZnT8A) From Baseline to 12 Months
timeFrame: Change from baseline to 12 months
measure: Percentage of Neutrophils
timeFrame: Change from baseline to 12 months
measure: Change in White Blood Count (WBC) From Baseline to 12 Months
timeFrame: Change from baseline to 12 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Aurora
country: United States
facility: Barbara Davis Center for Childhood Diabetes
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
Study officials:
affiliation: University of Florida Pediatric Endocrinology
name: Michael J. Haller, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Parker MJ, Xue S, Alexander JJ, Wasserfall CH, Campbell-Thompson ML, Battaglia M, Gregori S, Mathews CE, Song S, Troutt M, Eisenbeis S, Williams J, Schatz DA, Haller MJ, Atkinson MA. Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice. Diabetes. 2009 Oct;58(10):2277-84. doi: 10.2337/db09-0557. Epub 2009 Jul 23.
citation: Haller MJ, Gitelman SE, Gottlieb PA, Michels AW, Rosenthal SM, Shuster JJ, Zou B, Brusko TM, Hulme MA, Wasserfall CH, Mathews CE, Atkinson MA, Schatz DA. Anti-thymocyte globulin/G-CSF treatment preserves beta cell function in patients with established type 1 diabetes. J Clin Invest. 2015 Jan;125(1):448-55. doi: 10.1172/JCI78492. Epub 2014 Dec 15.