INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes

Abstract

Background The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples 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. Methods 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 individuals 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. Discussion 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 sample size calculations and future baseline stratification using existing and novel biomarkers.

Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes

“…T1DUK has as its principal aim "to help get immune therapy into the market as part of the management for type 1 diabetes" and has provided its infrastructure and expertise to various industry-and academia-led trials. T1DUK has also partnered with INNODIA on its master protocol platform (82). This standardization with platform protocols can clarify the regulatory pathway for DMTs for T1D and reduce logistical uncertainties in clinical development (83).…”

A set of circulating microRNAs belonging to the 14q32 chromosomic locus identifies two clinically and phenotypically different subgroups of individuals with recent onset Stage 3 type 1 diabetes

“…Circulating microRNAs profiling from blood-derived plasma was performed in two independent cohorts (initial and validation cohort) of individuals enrolled within 6 weeks from clinical diagnosis of stage 3 T1DM in the European consortium INNODIA Natural history study (https://www.innodia.eu) 52 . The schematic of the study design is reported in Figure 1 .…”

“…In the current study we sought to characterise circulating miRNAs in a large cohort of T1DM individuals using a multiplatform sequencing approach coupled to the analysis of two cohorts of T1DM individuals belonging to the European INNODIA study consortium 52 . It is important to highlight that within the consortium, plasma samples were collected and processed uniformly and consistently, following a standardized operating procedure 51 adopted by multiple clinical centres and specifically designed to minimize pre-analytical biases that could potentially impact the stability and expression of circulating miRNAs 64 .…”

“…Additionally, to date, an unsupervised and unbiased analysis of circulating miRNAs in T1DM individuals, with the aim of stratifying them into multiple subgroups based solely on their circulating expression levels, has not yet been attempted. In light of the limited overlap among different reports and the lack of a miRNA-based unsupervised classification of T1DM individuals, we employed two different high-throughput sequencing platforms to comprehensively and unbiasedly investigate the circulating expression profile of miRNAs 51 within two large cohorts of recently diagnosed T1DM individuals (within 6 weeks from diagnosis) who were recruited and followed up as part of the INNODIA consortium project 52 . This approach has allowed us to detect and validate two distinct subgroups of T1DM individuals characterised by different expression levels of a set of miRNAs belonging to the 14q32 chromosomal locus and reporting differences in glycaemic control, HLA, and peripheral blood immune cells profiles.…”

Multi-omics analysis reveals drivers of loss of β-cell function after newly diagnosed autoimmune type 1 diabetes: An INNODIA‡multicenter study

“…Such a systems-based approach can address key questions with less bias and generate novel hypotheses on disease drivers. We used this strategy in the setting of a pan-European research consortium in which people with newly diagnosed type 1 diabetes as well as people at risk of developing type 1 diabetes (antibody positive) were enrolled into a master protocol 9 to conduct a prospective study in search of factors that correlate with the rate of decline in β-cell mass/function. This endeavor was supported by the Innovative Medicines Initiative-2 Joint Undertaking, where INNODIA was created, being a private-public partnership of 40 partners in 16 countries.…”