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Reversing Type 1 Diabetes After it is Established

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
The Leona M. and Harry B. Helmsley Charitable Trust
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
University of Florida
ClinicalTrials.gov Identifier:
NCT01106157
First received: April 15, 2010
Last updated: August 10, 2016
Last verified: August 2016
  Purpose
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.

Condition Intervention Phase
Diabetes Mellitus, Type 1
Drug: Anti-Thymocyte Globin (ATG)
Drug: Placebo
Drug: Pegylated GCSF
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by University of Florida:

Primary Outcome Measures:
  • Change in Metabolic Function Baseline to 12 Months. [ Time Frame: Baseline and 12 months ] [ Designated as safety issue: No ]
    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


Secondary Outcome Measures:
  • Percent Change in Regulatory T Cells (Treg) Baseline to 12 Months [ Time Frame: Change in Baseline to 12 months ] [ Designated as safety issue: No ]
    Change in regulatory T cells (Treg) baseline to 12 months

  • A1c [ Time Frame: Change in baseline to 12 months ] [ Designated as safety issue: No ]
    Change in A1c baseline to 12 months

  • Change in Insulin Requirements, Baseline to 12 Months [ Time Frame: Change from baseline to 12 months ] [ Designated as safety issue: No ]
    Change in Insulin Requirements, baseline to 12 months

  • Change in Glutamic Acid Decarboxylase Antibodies (GADA) From Baseline to 12 Months [ Time Frame: Change from baseline to 12 months ] [ Designated as safety issue: No ]
    Change in Glutamic Acid Decarboxylase Antibodies (GADA) over 12 months

  • Change in Insulin Autoantibodies (IAA) From Baseline to 12 Months [ Time Frame: Change from baseline to 12 months ] [ Designated as safety issue: No ]
    Change in Insulin Autoantibodies (IAA) over 12 months

  • Change in Insulinoma Associated 2 Autoantibodies (IA-2A) From Baseline to 12 Months [ Time Frame: Change from baseline to 12 months ] [ Designated as safety issue: No ]
    Change in Insulinoma Associated 2 Autoantibodies (IA-2A)

  • Change in Zinc Transporter 8 Autoantibodies (ZnT8A) From Baseline to 12 Months [ Time Frame: Change from baseline to 12 months ] [ Designated as safety issue: No ]
    Change in Zinc Transporter 8 Autoantibodies (ZnT8A) over 12 months

  • Percentage of Neutrophils [ Time Frame: Change from baseline to 12 months ] [ Designated as safety issue: No ]
    Change in Neutrophil Count over 12 months

  • Change in White Blood Count (WBC) From Baseline to 12 Months [ Time Frame: Change from baseline to 12 months ] [ Designated as safety issue: No ]
    Change in WBC over 12 months


Enrollment: 25
Study Start Date: April 2010
Estimated Study Completion Date: January 2018
Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Thymoglobulin
Drug: Pegylated GCSF
6 doses of pegylated GCSF (6mg/dose) will be given subcutaneously every 2 weeks beginning after the ATG infusion.
Other Name: 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 Name: Saline infusion

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

Ages Eligible for Study:   12 Years to 45 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01106157

Locations
United States, California
University of California, San Francisco
San Francisco, California, United States, 94143-0748
United States, Colorado
Barbara Davis Center for Childhood Diabetes
Aurora, Colorado, United States, 80045-6511
United States, Florida
University of Florida
Gainesville, Florida, United States, 32610-0296
Sponsors and Collaborators
University of Florida
The Leona M. and Harry B. Helmsley Charitable Trust
Genzyme, a Sanofi Company
Investigators
Principal Investigator: Michael J. Haller, MD University of Florida Pediatric Endocrinology
  More Information

Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT01106157     History of Changes
Other Study ID Numbers: UF-ATG-GCSF001 
Study First Received: April 15, 2010
Results First Received: October 14, 2015
Last Updated: August 10, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Florida:
Autoimmune, Diabetes Mellitus, Glucose Metabolism

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases

ClinicalTrials.gov processed this record on September 30, 2016