Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial

Abstract

Objective: To evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid decarboxylase (GAD-alum) therapy combined with vitamin D supplementation in preserving endogenous insulin secretion in all patients with type 1 diabetes (T1D) or in a genetically prespecified subgroup.

Research design and methods: In a multicenter, randomized, placebo-controlled, double-blind trial, 109 patients aged 12-24 years (mean ± SD 16.4 ± 4.1) with a diabetes duration of 7-193 days (88.8 ± 51.4), elevated serum GAD65 autoantibodies, and a fasting serum C-peptide >0.12 nmol/L were recruited. Participants were randomized to receive either three intralymphatic injections (1 month apart) with 4 μg GAD-alum and oral vitamin D (2,000 IE daily for 120 days) or placebo. The primary outcome was the change in stimulated serum C-peptide (mean area under the curve [AUC] after a mixed-meal tolerance test) between baseline and 15 months.

Results: Primary end point was not met in the full analysis set (treatment effect ratio 1.091 [CI 0.845-1.408]; P = 0.5009). However, GAD-alum-treated patients carrying HLA DR3-DQ2 (n = 29; defined as DRB1*03, DQB1*02:01) showed greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126-2.153]; P = 0.0078) after 15 months compared with individuals receiving placebo with the same genotype (n = 17). Several secondary end points showed supporting trends, and a positive effect was seen in partial remission (insulin dose-adjusted HbA1c ≤9; P = 0.0310). Minor transient injection site reactions were reported.

Conclusion: Intralymphatic administration of GAD-alum is a simple, well-tolerated treatment that together with vitamin D supplementation seems to preserve C-peptide in patients with recent-onset T1D carrying HLA DR3-DQ2. This constitutes a disease-modifying treatment for T1D with a precision medicine approach.

Trial registration: ClinicalTrials.gov NCT03345004.

© 2021 by the American Diabetes Association.

Figures

Figure 1

Trial profile. Between December 2017 and April 2019, a total of 140 patients were screened for a fasting C-peptide ≥0.12 nmol/L and positivity for GAD65 antibodies (1Information on HLA genotype was missing for one patient in the placebo group.

Figure 2

Primary and key secondary study outcomes. Relative change from baseline (back transformed from log scale model) in C-peptide AUCmean 0–120 min during an MMTT for the two treatment groups (GAD-alum and placebo) in the FAS (A) and the prespecified subgroup HLA DR3-DQ2 (B). Error bars indicate SD. C: Forest plot depicting estimated treatment difference between GAD-alum and placebo groups for key secondary end points (IDAA1c and HbA1c in nmol/mol and daily exogenous insulin dose in units/kg/24 h) observed in the FAS and in the the prespecified subgroup HLA DR3-DQ2. Error bars indicate 95% CI. P values are indicated. Primary and key secondary efficacy end point variables were analyzed using a restricted maximum likelihood–based repeated measures approach (mixed-model repeated measures), as described in Research Design and Methods.

Figure 3

Pharmacological outcomes. Median changes from baseline of GADA and proliferation (Pr) of PMBC (stimulation index [SI]) (A) and GAD-stimulated secretion by PBMC of IL-10 and IL-13 levels (B) for GAD-alum–treated patients with and without the DR3-DQ2 haplotype as well as placebo-treated patients. P values by Wilcoxon test are indicated.