Safety and efficacy of autoantigen‐specific therapy with 2 doses of alum‐formulated glutamate decarboxylase in children with multiple islet autoantibodies and risk for type 1 diabetes: A randomized clinical trial

Objective Treatments have failed to delay or stop the autoimmune process, preceding onset of type 1 diabetes. We investigated if autoantigen‐specific treatment with alum‐formulated glutamate decarboxylase (GAD‐Alum) was safe and affected progression to type 1 diabetes in children with islet autoimmu...

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Published in:Pediatric diabetes Vol. 19; no. 3; pp. 410 - 419
Main Authors: Elding Larsson, Helena, Lundgren, Markus, Jonsdottir, Berglind, Cuthbertson, David, Krischer, Jeffrey
Format: Journal Article
Language:English
Published: Former Munksgaard John Wiley & Sons A/S 01.05.2018
John Wiley & Sons, Inc
Subjects:
Aluminum sulfate
Autoantibodies
Autoimmunity
Children
Clinical Medicine
Clinical trials
Diabetes
Diabetes mellitus
Diabetes mellitus (insulin dependent)
Endocrinology and Diabetes
Endokrinologi och diabetes
GAD‐Alum
Glucose
Glucose tolerance
Glutamate decarboxylase
Hematology
Immunological tolerance
Insulin
Insulinoma
Intravenous administration
Klinisk medicin
Medical and Health Sciences
Medicin och hälsovetenskap
Neuroendocrine tumors
Pediatrics
Pediatrik
prevention
Safety
Thyroid
type 1 diabetes
type 1 diabetes
autoimmunity
GAD-Alum
prevention
ISSN:1399-543X, 1399-5448, 1399-5448
Online Access:Get full text
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Summary:Objective Treatments have failed to delay or stop the autoimmune process, preceding onset of type 1 diabetes. We investigated if autoantigen‐specific treatment with alum‐formulated glutamate decarboxylase (GAD‐Alum) was safe and affected progression to type 1 diabetes in children with islet autoimmunity. Methods In an investigator‐initiated, double‐blind, placebo‐controlled clinical trial, non‐diabetic children aged 4 to 17.9 years with autoantibodies to glutamate decarboxylase (GADA) and at least one of insulinoma‐associated protein 2, insulin or zinc‐transporter 8, were randomized, stratified by 2 or ≥3 islet autoantibodies, to 2 injections of 20 μg GAD‐Alum or placebo, 30 days apart. Main outcome was safety, investigated by adverse events, hematology, chemistry, thyroid and celiac autoimmunity and titers of islet autoantibodies, and efficacy, investigated by cumulative incidence of diabetes onset over 5‐year follow‐up. Secondary variables: change in first‐phase insulin release (FPIR) after intravenous glucose tolerance tests, fasting, 120 minutes and Area under the curve (AUC) C‐peptide and p‐glucose after oral glucose tolerance tests and HbA1c. Results Fifty children (median age: 5.2) were assigned 1:1 to GAD‐Alum or placebo, all receiving full treatment and included in the analyses. GAD‐Alum did not affect any safety parameter, while GADA titers increased (P = .001). Time to clinical diagnosis was not affected by treatment (hazard ratio, HR = 0.77, P = .574) in the full population or in the separate stratum groups. Treatment did not affect any of the secondary variables. Conclusions GAD‐Alum as a subcutaneous prime and boost injection was safe in prediabetic young children but did not affect progression to type 1 diabetes. The safety of GAD‐Alum should prove useful in future prevention studies.
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ISSN:1399-543X
1399-5448
1399-5448
DOI:10.1111/pedi.12611