Clinical trial NCT01773707: CTLA4-Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At -Risk for Type 1
Official title: CTLA4-Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At -Risk for Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Abnormal Glucose Tolerance
Type 1 Diabetes
Keywords: prevention of type 1 diabetes
prevention of abnormal glucose tolerance
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: Juvenile Diabetes Research Foundation
First posted: 2013-01-23
Enrollment: 212
Sex: ALL
Minimum age (years): 6
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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 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).

Primary outcomes:
measure: Time From Randomization to Confirmed Abnormal Glucose Tolerance Test
timeFrame: 96 months
Secondary outcomes:
measure: Change in C-peptide Concentration to Oral Glucose Tolerance Test (OGTT)
timeFrame: 0 time to 30 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California - San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Denver
country: United States
facility: Barbara Davis Center for Childhood Diabetes, University of Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale Medical School
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami School of Medicine
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University-Riley Hospital for Children
state: Indiana
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Columbia University
state: New York
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Benaroya Research Institute at Virginia Mason
state: Washington
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Type 1 Diabetes TrialNet
name: Carla J Greenbaum, MD
role: STUDY_CHAIR
References:
citation: Orban T, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Marks JB, Monzavi R, Moran A, Raskin P, Rodriguez H, Russell WE, Schatz D, Wherrett D, Wilson DM, Krischer JP, Skyler JS; Type 1 Diabetes TrialNet Abatacept Study Group. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 2011 Jul 30;378(9789):412-9. doi: 10.1016/S0140-6736(11)60886-6. Epub 2011 Jun 28.
citation: Leung SS, Borg DJ, McCarthy DA, Boursalian TE, Cracraft J, Zhuang A, Fotheringham AK, Flemming N, Watkins T, Miles JJ, Groop PH, Scheijen JL, Schalkwijk CG, Steptoe RJ, Radford KJ, Knip M, Forbes JM. Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T Cells. Diabetes. 2022 Sep 1;71(9):1994-2008. doi: 10.2337/db22-0177.