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

Abstract

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 .

Fig. 1. CONSORT diagram.

CONSORT flow diagram for the DiViD interventional trial showing participant flow through each stage of the randomized controlled trial (enrollment, intervention allocation, follow-up and data analysis).

Fig. 2. Residual insulin production.

a, AUC for C-peptide levels. The box plots report the distribution of AUCs for the C-peptide levels. The numbers beneath the xaxis reflect the number of participants in each group with the respective endpoint at each time point. The line inside the box represents the median; the box boundaries represent the 25th and 75th percentiles (the box is the interquartile range (IQR)); the whiskers represent the highest or lowest values within 1.5× the IQR; the points outside 1.5× the IQR represent the potential outliers, including the maximum and minimum values. The C-peptide levels after 12 months were higher in the pleconaril and ribavirin group compared with the placebo group (AME = 0.057, P = 0.037 from the linear mixed model). b, Peak stimulated C-peptide. The proportion of participants with peak serum C-peptide greater than 0.2 pmol ml⁻¹ at different visits, divided according to antiviral treatment and placebo. *P = 0.04 in the logistic model; risk ratio = 1.29; two-sided 95% CI = 1.03–1.65.

Fig. 3. Metabolic control.

a,b, The box plots show HbA1c (a) and glycated albumin (b), respectively. HbA1c was significantly lower in the pleconaril and ribavirin group compared to the placebo group at 3 and 6 months, but not at 12 months. Glycated albumin was not significantly different between groups at any time point. The numbers beneath the x axis reflect the number of participants in each group with the respective endpoint at each time point. The line inside the box represents the median; the box boundaries represent the 25th and 75th percentiles (the box is the IQR); the whiskers represent the highest or lowest values within 1.5× the IQR; the points outside 1.5× the IQR represent the potential outliers, including the maximum and minimum values.

Extended Data Fig. 1. Individual trajectories of C-peptide AUC.

Longitudinal plots with trajectories of log transformed C-peptide AUC, all participants, divided into treatment and placebo group. N = 91 (47 in placebo and 44 in active group).