Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial.

"code availability all the code used for the descriptive tables and the analysis of the primary and safety endpoints is publicly available at https://github com/ericaponzi/dividint-r-code ."

"Competing interests H.H. is a shareholder and member of the board of Vactech Ltd, which develops vaccines against picornaviruses. N.L. and J.W. are employees of Apodemus/Curovir AB, which own the rights to the commercialization of the results of this trial. Curovir AB is developing antiviral drugs for enterovirus-induced diseases. The other authors declare no competing interests."

"We thank the participants and their families for their tremendous efforts during the COVID-19 pandemic lockdowns. We thank our colleagues at the local pediatric departments in Norway for their help recruiting the participants for the trial. We thank the study nurses T. Roald and C. Steinhovden, Oslo University Hospital, and A. Hillersborg, Herlev University Hospital. We thank L. Sandvik who performed the statistical power calculations. This trial is associated with the INNODIA Consortium: we thank C. Matthieu and the late D. Dunger for their support; P. Jaroslaw Chmura and S. Brunak, University of Copenhagen for managing the INNODIA database and electronic case record forms (CRFs) used in the trial; S. Bruggraber, University of Cambridge for practical support and advice regarding the shipment of samples and biobanking; M. Knip, University of Helsinki for performing the autoantibody analysis; C. Brede and Ø. Skaberg, Stavanger University Hospital, for performing the analysis of the glycated albumin; J. P. Berg, University of Oslo for mentoring I.M.M.; the Data Safety Monitoring Committee (T. J. Berg (leader), University of Oslo, R. Hanås, Uddevalla Hospital, Sweden, M. LeBlanc, Statistician, Oslo University Hospital and M. Lagging, University of Gothenburg); J. R. Larsen, Oslo University Hospital for support with study planning; the Clinical Trial Support Unit, Oslo University Hospital (M. Colban for assisting with the applications to the Norwegian Medicines Agency, B. L. Adamsen for the GCP monitoring of the trial, and I. Christoffer Olsen and M. Valberg for supervising the statistical analysis); B. Sonne Rasmussen for GCP monitoring in Copenhagen; and A. Mander, University of Cardiff for advice regarding the SAP. This study was funded by the Health Region South East, Norway (grant no. 2016119); the Juvenile Diabetes Research Foundation (grant no. 2-SRA-2019-810-M-B); and European Union supported by IMI2-JU under grant agreement no. 115797 (INNODIA) and no. 948268 (INNODIA HARVEST). This joint undertaking received support from the Union’s Horizon 2020 research and innovation program and through the EFPIA, JDRF and The Leona M. and Harry B. Helmsley Charitable Trust. All grants were provided to the principal investigator K.D.-J. The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the manuscript."

"Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6–15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin (n = 47) or placebo (n = 49) for 6 months, with the aim of preserving β cell function. The primary endpoint was the mean stimulated C-peptide area under the curve (AUC) 12 months after the initiation of treatment (less than 3 weeks after diagnosis) using a mixed linear model. The model used longitudinal log-transformed serum C-peptide AUCs at baseline, at 3 months, 6 months and 1 year. The primary endpoint was met with the serum C-peptide AUC being higher in the pleconaril and ribavirin treatment group compared to the placebo group at 12 months (average marginal effect = 0.057 in the linear mixed model; 95% confidence interval = 0.004–0.11, P = 0.037). The treatment was well tolerated. The results show that antiviral treatment may preserve residual insulin production in children and adolescent with new-onset T1D. This provides a rationale for further evaluating antiviral strategies in the prevention and treatment of T1D. European Union Drug Regulating Authorities Clinical Trials identifier: 2015-003350-41."