Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial
What this study found
Primary end point not met in the full analysis set: treatment effect ratio 1.091 (95% CI 0.845–1.408); P = 0.501. In prespecified HLA DR3-DQ2 subgroup (n=29 active, n=17 placebo), GAD-alum significantly preserved C-peptide AUC0–120 min at 15 months (ratio 1.557; 95% CI 1.126–2.153; P = 0.0078). Higher proportion reached partial remission (IDAA1c ≤9; 78.6% vs 40.0%; P = 0.0310) and maintained stimulated C-peptide >0.2 nmol/L and 90-min C-peptide >0.2 nmol/L at 15 months (P = 0.0310, 0.0284, 0.0086). Vitamin D supplementation had no significant effect on the primary outcome across all patients…
- Study & population
- Multicenter, randomized, double-blind, placebo-controlled phase IIb trial; 109 participants aged 12–24 years with recent-onset type 1 diabetes (diabetes duration 7–193 days), elevated GAD65 autoantibodies, and fasting C-peptide >0.12 nmol/L; conducted at 18 clinics across the Czech Republic, the Netherlands, Spain, and Sweden.
- Intervention
- Three intralymphatic injections of 4 mg GAD-alum into inguinal lymph nodes on days 30, 60, and 90; oral vitamin D 2,000 IU daily for 120 days (starting day 1) if screening vitamin D < 100 nmol/L; two participants had vitamin D ≥ 100 nmol/L and received no vitamin D.
- Key limitation
- Not powered for the prespecified DR3-DQ2 subgroup; small subgroup size; baseline differences between groups in HbA1c and IDAA1c within the subgroup; multiple endpoints analyzed without explicit adjustment.
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Open PDFOriginal 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.