Statistical analysis
ADVERSE EVENTS, SECONDARY, RECRUITMENT, SENSITIVITY
The sample size calculation is based on the efficacy continuous variable ‘2-h AUC C-peptide’. Because this variable is strongly skewed to the right, a logarithmic transformation (log(Both efficacy and safety analyses included all participants who had received at least one dose of pleconaril and ribavirin or placebo.The primary null hypothesis was evaluated in the full analysis set (FAS), defined as all participants fulfilling the entry criteria who were randomly assigned to a treatment group. Sensitivity analysis was performed in the per protocol analysis set, which included all participants in the FAS who met the study eligibility criteria, with no major protocol deviations affecting treatment efficacy, and who complied with the prescribed treatment. Safety data were analyzed for all participants having taken the study medication. Individuals who withdrew from the study were included in the safety analysis. The primary endpoint was analyzed using a linear mixed model for repeated measures that was fitted on the log-transformed C-peptide AUC data. The model used the longitudinal log-transformed serum C-peptide AUCs at baseline, 3 months, 6 months and 1 year as the response variable and included categorical effects of site, treatment, time and treatment-by-time interaction, as well as a random effect for the patient ID to account for repeated measurements. The linear mixed model included all repeated measurements of C-peptide AUCs, which were available for 89 participants (42 in the pleconaril and ribavirin group and 47 in the placebo group, of which 87 had the 12-month measurement and the remaining 2 only had the previous measurements). The treatment effect was defined as the AME; the primary estimate of treatment effect was obtained as the AME at 12 monthsThe detailed statistical analysis plan (SAP) was produced before the final database lock, before extracting files from the INNODIA clinical database and before unblinding of treatment allocation. The SAP was signed by the authorized chief statistician of Oslo University Hospitals.We fitted a linear mixed model on the mean residual insulin secretion, using the values collected at baseline, 3 months, 6 months and 12 months as a longitudinal outcome variable, and including a random effect for patient ID to account for dependency among measurements taken for the same individual. We included categorical effects for the study site, treatment, time and an interaction term between treatment and time. Because baseline values were collected before randomization, the treatment effect was set to 0 at baseline. Including the baseline value as one of the repeated measurements and forcing the treatment effect to be null at baseline is not only equivalent to adjusting for baseline, but is also the preferred alternative to analyze longitudinal endpointsThe strength of the model we used lies in the fact that we also included the measurements taken at 3 and 6 months, which provides additional power for the analysis. Using exclusively the change from baseline to 12 months would have resulted in less power. The present study had 96 participants; only 87 had records at 12 months. Eighty-nine patients had records at 3 or 6 months; such information can be used to strengthen the conclusion of the analyses. The measurements at 3 and 6 months were listed in the protocol as secondary endpoints; we analyzed them simultaneously in the proposed model. To ensure that we did not incur issues of multiplicity, we defined the primary treatment effect as the treatment effect at 12 months, which is consistent with the protocol. Including the interaction between time and treatment in the model allows us to do so by defining the treatment effect at 12 months as the AME at 12 months.The use of multiple measurements reduces the uncertainty and increases the power of the findings, thus resulting in a statistically significant (To investigate the robustness of the results, we also ran a Wilcoxon The secondary endpoints of mean insulin dosage per body weight, HbA1c, glycated albumin and insulin dose-adjusted HbA1c, were analyzed using a linear mixed model for repeated measures with the same structure and covariates as for the primary endpoint.The dichotomous secondary endpoint corresponding to the proportion of patients with peak C-peptide above 0.2 pmol mlResults are reported as the mean (s.d.) for continuous outcomes and A safety and data monitoring committee was established before starting participant recruitment (committees members are listed in the ‘Acknowledgements’).The trial was monitored closely with regard to safety. The data monitoring committee assessed the safety data and adverse events through the course of the trial. Efficacy data (primary endpoint) were not analyzed before unblinding. Therefore, no interim analysis was performed on the primary endpoint and no adaptive design or error rate control was needed.