ORCID Profile
0000-0002-6952-9899
Current Organisations
Oslo University Hospital
,
University of Oslo
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Publisher: Springer Science and Business Media LLC
Date: 23-04-2019
Publisher: Springer Science and Business Media LLC
Date: 18-05-2022
DOI: 10.1186/S13063-022-06259-Z
Abstract: The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from in iduals with newly diagnosed type 1 diabetes combined with centralised collection of clinical s les to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. In this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in in iduals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust s le size calculations and future baseline stratification using existing and novel biomarkers.
Publisher: American Society for Clinical Investigation
Date: 20-09-2018
Publisher: Springer Science and Business Media LLC
Date: 23-01-2019
Publisher: Hindawi Limited
Date: 30-04-2013
DOI: 10.1111/PEDI.12036
Publisher: Springer Science and Business Media LLC
Date: 09-01-2008
DOI: 10.1007/S00125-007-0912-9
Abstract: The aim of this study was to evaluate the prognostic significance of autoantibodies to IA-2beta (IA2betaA) in a large, well-characterised population of islet cell antibody (ICA)-positive relatives followed for 5 years in the European Nicotinamide Diabetes Intervention Trial. Autoantibodies to insulin (IAA), glutamate decarboxylase (GADA) and IA-2 (IA2A) were measured in 549 participants at study entry, and IA2A-positive s les tested for IA2betaA. First-phase insulin response (FPIR) and oral glucose tolerance were determined at baseline. Of 212 ICA/IA2A-positive participants (median age 12.1 years 57% male), 113 developed diabetes (5 year cumulative risk 56%), and 148 were also GADA-positive and IAA-positive (4Ab-positive). IA2betaA were detected in 137 (65%) ICA/IA2A-positive participants and were associated with an increased 5 year diabetes risk (IA2betaA-positive 65 vs 39% in IA2betaA-negative, p=0.0002). The effect was most marked in 4Ab-positive relatives (72% vs 52%, p=0.003). Metabolic testing further refined risk assessment. Among 101 4Ab-positive relatives with IA2betaA, the 5 year risk was 94% in those with a low FPIR (vs 50% in those with a normal FPIR, p<0.0001), and 95% in those with impaired glucose tolerance (IGT) (vs 66% in those with normal glucose tolerance, p<0.0001). The median time to diagnosis of 4Ab/IA2betaA-positive participants with a low FPIR was 1.5 years. Multivariate analysis confirmed IA2betaA status, antibody number, young age, FPIR and IGT as independent determinants of risk. IA2betaA are associated with a very high risk of diabetes in ICA/IA2A-positive relatives. Testing for IA2A/IA2betaA compares favourably with the IVGTT in identifying a subgroup of autoantibody-positive relatives at increased risk. IA2betaA determination should be added to screening protocols of future intervention trials.
No related grants have been discovered for Knut Dahl-Jorgensen.