Reversing Type 1 Diabetes After it is Established

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: Anti-Thymocyte Globin (ATG); Drug: Pegylated GCSF; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143-0748
      • University of California, San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045-6511
      • Barbara Davis Center for Childhood Diabetes
  • Florida
    • Gainesville, Florida, United States, 32610-0296
      • University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 45 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Anti-Thymocyte Globin plus pegylated GCSF; Subjects will receive an infusion of Anti-Thymocyte Globin (ATG) followed by 6 doses of pegylated GCSF every 2 weeks for 10 weeks.	Drug: Anti-Thymocyte Globin (ATG); Anti-Thymocyte Globin (ATG) will be given as 0.5/mg/kg on day 1 and 2mg/kg on day 2.; Other Names: Thymoglobulin; Drug: Pegylated GCSF; 6 doses of pegylated GCSF (6mg/dose) will be given subcutaneously every 2 weeks beginning after the ATG infusion.; Other Names: Neulasta
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	Drug: Placebo; Saline infusions will be given on Day 1 and Day 2 followed by placebo injections given in identical volumes in identical syringes; Other Names: Saline infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Metabolic Function Baseline to 12 Months.	Area Under Curve (AUC) C-peptide production. Subjects underwent a 2 hour mixed meal tolerance test (MMTT) using a 6ml/kg load of boost to stimulate insulin production. Samples were collected at baseline, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes, and 120 minutes. AUC was then calculated. Subjects repeated the MMTT at baseline, 3, 6, 9, and 12 months following ATG/GCSF or placebo. The primary outcome for the study was the change over 12 months in AUC C-peptide (1 year - baseline) for those who received ATG/GCSF versus the change in AUC C-peptide (1 year - baseline) for those who received placebo	Baseline and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in Regulatory T Cells (Treg) Baseline to 12 Months	Change in regulatory T cells (Treg) baseline to 12 months	Change in Baseline to 12 months
A1c	Change in A1c baseline to 12 months	Change in baseline to 12 months
Change in Insulin Requirements, Baseline to 12 Months	Change in Insulin Requirements, baseline to 12 months	Change from baseline to 12 months
Change in Glutamic Acid Decarboxylase Antibodies (GADA) From Baseline to 12 Months	Change in Glutamic Acid Decarboxylase Antibodies (GADA) over 12 months	Change from baseline to 12 months
Change in Insulin Autoantibodies (IAA) From Baseline to 12 Months	Change in Insulin Autoantibodies (IAA) over 12 months	Change from baseline to 12 months
Change in Insulinoma Associated 2 Autoantibodies (IA-2A) From Baseline to 12 Months	Change in Insulinoma Associated 2 Autoantibodies (IA-2A)	Change from baseline to 12 months
Change in Zinc Transporter 8 Autoantibodies (ZnT8A) From Baseline to 12 Months	Change in Zinc Transporter 8 Autoantibodies (ZnT8A) over 12 months	Change from baseline to 12 months
Percentage of Neutrophils	Change in Neutrophil Count over 12 months	Change from baseline to 12 months
Change in White Blood Count (WBC) From Baseline to 12 Months	Change in WBC over 12 months	Change from baseline to 12 months

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: Genzyme, a Sanofi Company; The Leona M. and Harry B. Helmsley Charitable Trust
• Investigators: Principal Investigator: Michael J. Haller, MD, University of Florida Pediatric Endocrinology

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• University of Florida Diabetes Center of Excellence

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2010
• Primary Completion (ACTUAL): January 1, 2015
• Study Completion (ACTUAL): July 16, 2019

Study Registration Dates

• First Submitted: April 15, 2010
• First Submitted That Met QC Criteria: April 15, 2010
• First Posted (ESTIMATE): April 19, 2010

Study Record Updates

• Last Update Posted (ACTUAL): August 5, 2019
• Last Update Submitted That Met QC Criteria: July 16, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Autoimmune, Diabetes Mellitus, Glucose Metabolism
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Thymoglobulin
• Other Study ID Numbers: UF-ATG-GCSF001; IRB201702525 (OTHER: University of Florida); 041-2010 (Univeristy of Florida); OCR16038 (OTHER: University of Florida)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No