AIMS: Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM). METHODS: DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 μg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values. RESULTS: We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR. CONCLUSIONS: Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.

Department of Endocrinology and Nutrition Hospital Universitario Ramón y Cajal 28034 Madrid Spain

Department of Endocrinology and Nutrition Vall d'Hebron Hospital 08035 Barcelona Ciberdem Spain

Department of Endocrinology in Linköping and Department of Health Medicine and Caring Sciences Linköping University 58183 Linköping Sweden

Department of Endocrinology Pediatric Service Vall d'Hebron Hospital 08035 Barcelona CibererSpain

Department of Endocrinology Virgen Macarena Hospital Department of Endocrinology and Nutrition Virgen Macarena University Hospital 41009 Sevilla Spain

Department of Internal Medicine School of Health and Medical Sciences Örebro University 70281 Örebro Sweden

Department of Molecular and Clinical Medicine University of Gothenburg 41345 Gothenburg Sweden Sahlgrenska University Hospital Gothenburg and NU Hospital Group S41553 Uddevalla Sweden

Department of Neurobiology Care Sciences and Society Karolinska Institutet 14183 Huddinge Sweden

Department of Pediatric Endocrinology Cruces University Hospital 48902 Bilbao Ciberdem Spain

Department of Pediatric Endocrinology Miguel Servet University Hospital 50009 Zaragoza Spain

Department of Pediatrics 2nd Faculty of Medicine Charles University and Motol University Hospital 15000 Prague Czech Republic

Department of Pediatrics NU Hospital Group 45153 Uddevalla Sweden

Diabeter National Treatment and Research Center for Children Adolescents and Young Adults with type 1 diabetes and Department of Pediatric Endocrinology Erasmus University Medical Center 3015 Rotterdam The Netherlands

Diabetes Centre of the Institute of Clinical and Experimental Medicine 14000 Prague Czech Republic

Diabetes Unit Department of Endocrinology and Nutrition Ibima Ciberdem General University Hospital 29010 Malaga Spain

Diamyd Medical AB 11135 Stockholm Sweden

Division of Pediatrics Department of Biomedical and Clinical Sciences Faculty of Medicine and Health Sciences and Crown Princess Victoria Children´s Hospital Linköping University 58183 Linköping Sweden

Division of Pediatrics Department of Biomedical and Clinical Sciences Faculty of Medicine and Health Sciences Linköping University 58183 Linköping Sweden

Institution of Clinical Science Department of Pediatrics Umeå University Norrland University Hospital 93451 Umeå Sweden

Pediatric Endocrinology Service Virgen del Rocío University Hospital 41013 Sevilla Spain

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ClinicalTrials.gov
NCT03345004