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

Objectives: To evaluate the efficacy of intra-lymphatic GAD-alum therapy together with vitamin D supplementation on preserving endogenous insulin secretion in all patients with Type 1 diabetes (T1D) or in a genetically pre-specified subgroup.

Research Design and Methods: In a multicenter, randomized, placebo-controlled double-blind trial (NCT03345004), 109 patients aged 12-24 (16.4 ± 4.1) years with a diabetes duration of 7-193 (88.8 ± 51.4) days, elevated serum GAD65 autoantibodies (GADA) and a fasting serum C-peptide >0.12 nmol/L, were recruited. Subjects were randomized to receive either three intra-lymphatic injections (one month apart) with 4 µg GAD-alum and oral vitamin D (2000 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-month.

Results:

Primary endpoint 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 to placebo individuals with the same genotype (n=17). Several secondary end points showed supporting trends and a positive effect was seen in partial remission (IDAA1c≤9, p=0.0310). Minor transient injection site reactions were reported.

Conclusions: Intra-lymphatic 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.