A Phase 2 interventional study of CTLA4-Ig (Abatacept) and Placebo in Abnormal Glucose Tolerance and Type 1 Diabetes, sponsored by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Completed at 17 sites in 2 countries. Open to participants aged 6 Years to 45 Years. Per ClinicalTrials.gov, last updated 2024-06-06.
Sponsored by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) · Phase 2, Interventional, and Prevention
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.
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:
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.
10,925 studies on the registry are indexed under Diabetes Mellitus; 1,319 are open to participants now.
This study's enrollment of 212 is above the median of 80 across 8,367 interventional studies indexed under Diabetes Mellitus.
Browse Diabetes Mellitus studies →National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is the lead sponsor of 529 studies on the registry; 54 are open to participants now.
Of its 79 completed or terminated interventional studies of FDA-regulated products, 50 (63%) have results posted.
Counted across the registry records on this site, refreshed daily.
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.
Exclusion Criteria:
Abnormal Glucose Tolerance or Diabetes
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)
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
Given as 30 minute IV infusion
Also known as: Abatacept
Saline given as 30 minute IV infusion
Time From Randomization to Confirmed Abnormal Glucose Tolerance Test
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)
Time frame: 96 months
Change in C-peptide Concentration to Oral Glucose Tolerance Test (OGTT)
To Determine whether treatment with Abatacept is superior to placebo with respect to C-peptide response to oral glucose tolerance
Time frame: 0 time to 30 months
| Milestone | Abatacept IV Infusion | Placebo |
|---|---|---|
| Started | 101 | 111 |
| Completed | 99 | 108 |
| Not completed | 2 | 3 |
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)
| months | Abatacept IV Infusion | Placebo |
|---|---|---|
| Time From Randomization to Confirmed Abnormal Glucose Tolerance Test | 89.2 (41.1 to NA) | 71.6 (23.7 to NA) |
To Determine whether treatment with Abatacept is superior to placebo with respect to C-peptide response to oral glucose tolerance
| nmol/L | Abatacept IV Infusion | Placebo |
|---|---|---|
| Change in C-peptide Concentration to Oral Glucose Tolerance Test (OGTT) | 2.16 (1.61 to 2.50) | 2.07 (1.51 to 2.74) |
Collected over Baseline Visit through study endpoint, up to 6 years. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Abatacept IV Infusion | 0/101 (0%) | 2/101 (2%) | 63/101 (62.4%) |
| Placebo | 0/111 (0%) | 3/111 (2.7%) | 77/111 (69.4%) |
| Event | Abatacept IV Infusion | Placebo |
|---|---|---|
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specifyNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 2/101 | 0/111 |
| Surgical and medical procedures - Other, specifySurgical and medical procedures | 0/101 | 1/111 |
| StrokeNervous system disorders | 0/101 | 1/111 |
| AppendicitisInfections and infestations | 0/101 | 1/111 |
| Event | Abatacept IV Infusion | Placebo |
|---|---|---|
| Infections and infestationsInfections and infestations | 38/101 | 45/111 |
| Gastrointestinal DisordersGastrointestinal disorders | 22/101 | 29/111 |
| Musculoskeletal and Connective TissueMusculoskeletal and connective tissue disorders | 19/101 | 15/111 |
| General disorders and administration siteGeneral disorders | 14/101 | 20/111 |
| Skin and subcutaneous tissue disordersSkin and subcutaneous tissue disorders | 17/101 | 10/111 |
| Respiratory, thoracic and mediastinal disordersRespiratory, thoracic and mediastinal disorders | 16/101 | 15/111 |
| Injury, poisoning and proceduralInjury, poisoning and procedural complications | 15/101 | 8/111 |
| Nervous system disordersNervous system disorders | 13/101 | 8/111 |
| InvestigationsInvestigations | 3/101 | 10/111 |
| Surgical and medical proceduresSurgical and medical procedures | 9/101 | 9/111 |
| Age, Continuous(years) | Abatacept IV Infusion | Placebo | Total |
|---|---|---|---|
| Median | 16.3 (11.9 to 27.5) | 14.9 (11.4 to 22.0) | 15.6 (11.6 to 23.4) |
| Sex: Female, Male(Participants) | Abatacept IV Infusion | Placebo | Total |
|---|---|---|---|
| Female | 50 | 57 | 107 |
| Male | 51 | 54 | 105 |
| Ethnicity (NIH/OMB)(Participants) | Abatacept IV Infusion | Placebo | Total |
|---|---|---|---|
| Hispanic or Latino | 11 | 10 | 21 |
| Not Hispanic or Latino | 84 | 98 | 182 |
| Unknown or Not Reported | 6 | 3 | 9 |
| Race (NIH/OMB)(Participants) | Abatacept IV Infusion | Placebo | Total |
|---|---|---|---|
| American Indian or Alaska Native | 1 | 1 | 2 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 3 | 3 | 6 |
| White | 91 | 102 | 193 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 6 | 5 | 11 |
| Relationship to person with type 1 diabetes(Participants) | Abatacept IV Infusion | Placebo | Total |
|---|---|---|---|
| Sibling(s) | 53 | 56 | 109 |
| Identical twin | 1 | 2 | 3 |
| Offspring | 21 | 14 | 35 |
| Parent(s) | 14 | 23 | 37 |
| Sibling and another first degree relative | 6 | 9 | 15 |
| Second degree relative | 4 | 6 | 10 |
| Third degree relative | 2 | 1 | 3 |
| Autoantibodies positive(Participants) | Abatacept IV Infusion | Placebo | Total |
|---|---|---|---|
| Anti-GAD65 harmonized | 94 | 104 | 198 |
| Micro insulin | 4 | 2 | 6 |
| Anti-IA-2 harmonized | 49 | 61 | 110 |
| Autoantibodies (ICA) | 76 | 79 | 155 |
| Anti-ZnT8 | 47 | 65 | 112 |
| Autoantibodies titer(titers) | Abatacept IV Infusion | Placebo | Total |
|---|---|---|---|
| GADA | 317 (91 to 683) | 375 (100 to 707) | 335 (93.8 to 694) |
| Micro insulin | 0.002 (0.001 to 0.003) | 0.002 (0.001 to 0.004) | 0.002 (0.001 to 0.003) |
| Anti-IA-2 harmonized | 2 (0 to 225) | 23 (0 to 186) | 9 (0 to 202) |
| Autoantibodies (ICA) | 40 (10 to 160) | 40 (5 to 160) | 40 (5 to 160) |
| Anti-ZnT8 | 0.013 (0.001 to 0.168) | 0.041 (0.002 to 0.170) | 0.027 (0.001 to 0.169) |
| Glycated hemoglobin level(percentage of glycated hemoglobin) | Abatacept IV Infusion | Placebo | Total |
|---|---|---|---|
| Median | 5.1 (4.9 to 5.3) | 5.1 (4.9 to 5.25) | 5.1 (4.9 to 5.3) |
3 further baseline measures are reported on the registry.
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)