Preservation of Pancreatic Production of Insulin Through Immunosuppression (TN02)

General Description

Type 1 diabetes (T1D) is a chronic, slowly progressive autoimmune disease characterized by the destruction of β-cells in the pancreas. Results from previous studies of T1D have suggested that an intervention that prolongs β-cell function would be expected to improve metabolic control and reduce complications in patients. The Preservation of Pancreatic Production of Insulin Through Immunosuppression (TN02 MMF/DZB) trial was established by TrialNet, a network of 18 clinical centers that conducts research on T1D, to investigate the effects of immunosuppressive agents on the progression of β-cell destruction in patients with recent-onset T1D. The study was a randomized, multicenter, placebo-controlled clinical trial that sought to determine the efficacy of mycophenolate mofetil (MMF) alone or in combination with daclizumab (DZB) in preserving β-cell function.

Eligible patients aged 8-45 years with evidence of β-cell function who were affected with autoimmune T1D for less than 3 months were enrolled. Participants were randomized to receive MMF alone (with DZB placebo), MMF and DZB in combination, or control (MMF placebo and DZB placebo). Study visits were conducted to evaluate safety, including assessment of diabetes care, adverse events, and laboratory measurements to assess medication side effects. Participants were followed for 2 years. The primary outcome measure was the geometric mean difference between active- and placebo-treated subjects of the area under the stimulated C-peptide curve over the first 2 hours of a 4-hour mixed meal glucose tolerance test conducted at the 2-year visit. Secondary outcome measures included differences in A1C hemoglobin levels, insulin dose, hypoglycemic episodes, rates of infection, and adverse events over time.

Results showed comparable rates of diminishing C-peptide levels between the MMF and MMF and DZB treatment groups and the control group. The study found no treatment benefit from either MMF alone or from the combination of MMF and DZB on the preservation of β-cell function in patients with recent-onset T1D.

Objectives

The trial investigated whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing β-cells in patients with recent-onset type 1 diabetes.

Outcome Measure

The primary outcome measure was the geometric mean difference between active- and placebo-treated subjects of the area under the stimulated C-peptide curve over the first 2 hours of a 4 hour mixed meal glucose tolerance test conducted at the 2-year visit. Secondary outcome measures included differences in A1C hemoglobin levels, insulin dose, hypoglycemic episodes, rates of infection, and adverse events over time.

Criteria

Individuals between the ages of 8-45 years who met the following criteria were eligible for the trial:
- Autoimmune type 1 diabetes for less than 3 months (defined by the presence of any of four islet autoantibodies within 14 days of diagnosis [GAD, insulinoma-associated protein 2, or islet cell autoantibodies])
- Evidence of β-cell function, confirmed by stimulated C-peptide > 0.2 pmol on a 2 hour mixed meal tolerance test
- No major systemic illness
- No allergic or autoimmune conditions requiring treatment with immunosuppressive agents or steroids

Exclusion criteria are documented in the study protocol.

Outcome

Results showed comparable rates of diminishing C-peptide levels between the MMF and MMF and DZB treatment groups and the control group. There was an increase in adverse events when MMR was used in combination with DZB, as compared to MMF alone or placebo. While higher doses may have greater therapeutic effect, potential benefits of higher doses need to be measured against the increased risk of side effects. The study found no treatment benefit from either MMF alone or from the combination of MMF and DZB on the preservation of β-cell function in patients with recent-onset T1D.