CTLA4-Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At -Risk for Type 1

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor:
Collaborators:
American Diabetes Association
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:
NCT01773707
First received: January 10, 2013
Last updated: February 6, 2014
Last verified: February 2014
  Purpose

The study is a 2-arm, multicenter, 1:1 randomized, placebo controlled clinical trial.

All subjects will receive close monitoring for development of AGT or T1DM. Subjects will receive Abatacept or placebo and close monitoring for development of AGT or T1DM. To assess the safety, efficacy, and mode of action of Abatacept to prevent AGT and T1DM.

The primary objective is to determine whether intervention with Abatacept will prevent or delay the development of AGT in at-risk autoantibody positive non-diabetic relatives of patients with T1DM.

Secondary outcomes include: the effect of Abatacept on the incidence of T1DM; analyses of C-peptide and other measures from the OGTT; safety and tolerability; and mechanistic outcomes.


Condition Intervention Phase
Abnormal Glucose Tolerance
Type 1 Diabetes
Drug: CTLA4-Ig (Abatacept)
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
Official Title: CTLA4-Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At -Risk for Type 1 Diabetes

Resource links provided by NLM:


Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Primary Outcome Measures:
  • Change from Normal Glucose Tolerance to Abnormal Glucose Tolerance [ Time Frame: every six months for 5-6 years ] [ Designated as safety issue: Yes ]

    Measured by Oral Glucose Tolerance Test (OGTT):

    Abnormal Glucose Tolerance is primary endpoint and defined as:

    1. Fasting plasma glucose ≥ 110 mg/dL (6.1 mmol/L) and < 126 mg/dL (7 mmol/L), or
    2. 2 hour plasma glucose ≥ 140 mg/dL (7.8 mmol/L) and < 200 (11.1 mmol/L), or
    3. 30, 60, 90 minute plasma glucose during OGTT ≥ 200 mg/dL (11.1 mmol/L)


Secondary Outcome Measures:
  • Change in C-peptide response to Oral Glucose Tolerance Test (OGTT) [ Time Frame: Every six months for 5-6 years ] [ Designated as safety issue: Yes ]
    To Determine whether treatment with Abatacept is superior to placebo with respect to C-peptide response to oral glucose tolerance


Estimated Enrollment: 206
Study Start Date: March 2013
Estimated Study Completion Date: February 2018
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: abatacept IV infusion
CTLA4-Ig (Abatacept) will be administered as 14 (30 minute) infusions over one year (3 infusions every other week the first month; monthly for the following 11 months)
Drug: CTLA4-Ig (Abatacept)
Given as 30 minute IV infusion
Other Name: Abatacept
Placebo Comparator: Placebo
The placebo arm will receive 14 (30 minute) IV infusions (containing saline) given 3 times (every other week) the first month and monthly for the following 11 months.
Drug: Placebo
Saline given as 30 minute IV infusion

  Hide Detailed Description

Detailed Description:

Study Purpose and Rationale:

In this study, relatives who are confirmed to have two or more antibodies, not including mIAA, and normal glucose tolerance will be eligible for randomization to experimental treatment or placebo groups with the aim to determine whether experimental treatment will prevent or delay the occurrence of abnormal glucose tolerance and type 1 diabetes mellitus. Individuals with normal glucose tolerance are earlier in the disease process; that is, have less beta cell destruction than those with abnormal glucose tolerance or frank diabetes, yet will inevitably progress to clinical disease and essentially complete beta cell loss. Treatment at this early stage in a population who will inevitably progress to type 1 diabetes provides the greatest opportunity for a clinically important impact on disease prevention. With abnormal glucose tolerance rather than diabetes as the primary endpoint, study participants, regulators, funders, and investigators will be able to determine whether the therapy can alter disease progression.

Therefore, the rationale for this study is that individuals with immunologic markers of T1DM and normal glucose tolerance will inevitably develop clinical T1DM. Prior to development of clinical T1DM they will progress from normal glucose tolerance to abnormal glucose tolerance; and abnormal glucose tolerance results in clinical T1DM within 5 years in almost 80% of subjects. They have a condition that differs from overt diabetes only in the duration of the autoimmune process that results in beta cell destruction. Intervention early in the course of disease may be more effective than intervention in those with abnormal glucose tolerance or clinical T1DM.

Description of Treatment Groups

Subjects will be randomized to receive either Abatacept or placebo infusions along with close monitoring for abnormal glucose tolerance or diabetes. The infusions will be conducted at approved TrialNet clinical sites with appropriate facilities. All blood and serum samples for the primary and secondary outcome determinations will be sent to the Core Laboratories for analysis. Clinical laboratory studies may be done at the local sites.

Participants will be randomly assigned in a 1:1 ratio (within the two strata defined by age at enrollment: <18 and 18 or older) to the following 2 groups:

  • to receive Abatacept (intravenous infusion at 0, 2, and 4 weeks following randomization, and then every 28+/-7 days) thereafter for a total of 14 doses. Close monitoring for diabetes development through the duration of study.
  • to receive placebo intravenous infusion at 0, 2, and 4 weeks following randomization and then every 28+/- 7 days thereafter for a total of 14 doses. Close monitoring for diabetes development through the duration of study.

Treatment Assignment

After participants sign the consent form, complete the screening visit(s), and meet all of the inclusion criteria and none of the exclusion criteria, participants will be randomized to receive either Abatacept and close monitoring or placebo with close monitoring.

Participants will be randomized in equal allocations to each group. The randomization method will be stratified by TrialNet study site and whether the participant is less than 18 years of age or 18 years and older. This approach ensures that study site will not be a potential confounder. The TNCC will generate the randomization numbers and tables.

Study Assessments

During the course of the study, participants will frequently undergo assessments of their glucose tolerance status, insulin production, immunologic status, and overall health and well-being.

Samples will be drawn for storage in the National Institute for Diabetes and Digestive and Kidney Disease (NIDDK) Repository and at TrialNet Laboratory Sites for future analysis related to T1DM.

Study Duration

The study has been designed to provide 80% power to detect a 40% risk reduction in the occurrence of abnormal glucose tolerance using a two-sided test at the 0.05 level after six years of study duration. A total of approximately 206 patients will be allocated in a 1:1 ratio to the two groups.

  Eligibility

Ages Eligible for Study:   6 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participant in TrialNet Natural History/Pathway to Prevention Study and thus, a relative of a proband with T1DM.
  • Between the ages of 1-45 years at the time of enrollment in TN01 and age ≥ 6 at time of randomization in this trial.
  • Willing to provide Informed Consent or have a parent or legal guardian provide informed consent if the subject is <18 years of age.
  • Normal glucose tolerance by OGTT confirmed within 7 weeks (no more than 52 days) of baseline (visit 0). If previous abnormal glucose tolerance, has had two consecutive OGTTs with normal glucose tolerance.

    1. Fasting plasma glucose < 110 mg/dL (6.1 mmol/L), and
    2. 2 hour plasma glucose <140 mg/dL (7.8 mmol/L), and
    3. 30, 60, or 90 minute value on OGTT< 200mg/dL (11.1 mmol/L)
  • At least two diabetes-related autoantibodies confirmed to be present on two occasions, not including mIAA. Confirmation of 2 positive autoantibodies must occur within the six months prior to randomization, but the confirmation does not have to involve the same 2 autoantibodies.
  • Weight ≥ 20 kg at Baseline Visit.
  • If a female participant with reproductive potential, willing to avoid pregnancy and undergo pregnancy testing prior to each infusion.
  • At least three months from date of last live immunization.
  • Willing to forgo live vaccines while receiving treatment on study and for three months following last study drug administration.

Exclusion Criteria:

  • Abnormal Glucose Tolerance or Diabetes

    1. Fasting plasma glucose ≥ 110 mg/dL (6.1 mmol/L), or
    2. 2 hour plasma glucose ≥ 140 mg/dL (7.8 mmol/L), or
    3. 30, 60, 90 minute plasma glucose during OGTT ≥ 200 mg/dL (11.1 mmol/L)
  • Insulin autoantibodies (mIAA).
  • Are immunodeficient or have clinically significant chronic lymphopenia.
  • Have an active infection at time of randomization.
  • Have a positive PPD test result or history of previously treated TB, or positive interferon-gamma release assay (IGRA) test.
  • Be currently pregnant or lactating, or anticipate getting pregnant within 3 months of the last study drug administration.
  • Use of medications known to influence glucose tolerance.
  • Require use of other immunosuppressive agents.
  • Have serologic evidence of current or past HIV, Hepatitis B (positive for Hepatitis B core antibody or surface antigen), or Hepatitis C infection.
  • Have serological evidence of current CMV infection.
  • Have evidence of active EBV infection.
  • Have any complicating medical issues or abnormal clinical laboratory results that interfere with study conduct or cause increased risk. These include pre-existing cardiac disease, COPD, neurological, or blood count abnormalities (such as lymphopenia, leukopenia, or thrombocytopenia).
  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: NCT01773707

Contacts
Contact: Jay Skyler S Skyler, MD 305-243-6146 jskyler@miami.edu
Contact: Lisa E Rafkin, MS 305-243-6146 lrafkin@miami.edu

Locations
United States, California
University of California - San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: David Ng    415-514-3730    NgDavid@peds.ucsf.edu   
Contact: Kathy Breen, RN, CDE    (415) 502-8640    breenk@peds.ucsf.edu   
Principal Investigator: Stephen Gitelman, MD         
Stanford University Medical Center Recruiting
Stanford, California, United States, 94305-5208
Contact: Trudy Esrey, RD    650-498-4450    tesrey@stanford.edu   
Principal Investigator: Darrell Wilson, MD         
United States, Colorado
Barbara Davis Center for Childhood Diabetes, University of Colorado Not yet recruiting
Denver, Colorado, United States, 80262
Contact: Laurie Weiner, RN    303-315-0266    Laurie.Weiner@uchsc.edu   
Principal Investigator: Peter Gottlieb, MD         
United States, Connecticut
Yale Medical School Not yet recruiting
New Haven, Connecticut, United States
Contact: Laurie Feldman, RN    203-737-2760    laurie.feldman@yale.edu   
Principal Investigator: Kevan Herold, MD         
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32610-
Contact: Roberta Cook, RN    352-294-5759    cookrb@peds.ufl.edu   
Principal Investigator: Desmond A. Schatz, MD         
University of Miami School of Medicine Recruiting
Miami, Florida, United States, 33136
Contact: Della Matheson, RN    305-243-3781    dmatheso@miami.edu   
Principal Investigator: Jennifer Marks, MD         
United States, Indiana
Indiana University-Riley Hospital for Children Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Maria Nicholson       malnicho@iupui.edu   
Principal Investigator: Linda DiMeglio, MD         
United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 57931
Contact: Jennifer Smith, RN    612-624-6682    smit5759@umn.edu   
Principal Investigator: Antoinette Moran, MD         
United States, New York
Columbia University Recruiting
New York, New York, United States
Contact: Ellen Greenberg, MPH    212-851-5425    emg25@columbia.edu   
Principal Investigator: Robin Golan, MD         
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Karen Riley, RN    412-692-5210    karen.riley@chp.edu   
Principal Investigator: Dorothy Becker, MD         
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Karen Riley, RN    412-692-5210    karen.rileyy@chp.edu   
Principal Investigator: Dorothy Becker, MD         
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States
Contact: Margo Black, RN, CDE         
Principal Investigator: William Russell, MD         
United States, Texas
University of Texas Medical Center at Dallas Recruiting
Dallas, Texas, United States, 75390-8858
Contact: Philip Raskin, M.D.    214-648-4844    philip.raskin@utsouthwestern.edu   
Contact: Marilyn Alford, RN    (214) 648-4844    Marilyn.Alford@utsouthwestern.edu   
Principal Investigator: Philip Raskin, M.D.         
United States, Washington
Benaroya Research Institute at Virginia Mason Recruiting
Seattle, Washington, United States, 98101
Contact: Marli McCulloch-Olson    800-888-4187    marli@vmresearch.org   
Principal Investigator: Carla Greenbaum, MD         
Canada, Ontario
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, MSG-1X8
Contact: Lesley Eisel, RN    416-813-8159    lesley.eisel@sickkids.ca   
Principal Investigator: Diane Wherrett, MD         
University of Toronto Recruiting
Toronto, Ontario, Canada, M5G-1X8
Contact: Diane Wherrett, M.D.    866-699-1899    diane.wherrett@sickkids.ca   
Contact: Natasha Razack, RN    866-699-1899    natasha.razack@sickkids.ca   
Principal Investigator: Diane Wherrett, M.D.         
Sponsors and Collaborators
American Diabetes Association
Juvenile Diabetes Research Foundation
Investigators
Study Chair: Jay S Skyler, MD University of Miami
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT01773707     History of Changes
Other Study ID Numbers: Abatacept (IND)
Study First Received: January 10, 2013
Last Updated: February 6, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
prevention of type 1 diabetes
prevention of abnormal glucose tolerance

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Intolerance
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Hyperglycemia
Abatacept
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 27, 2014