Protocol for the target trial investigating the impact of insulin use on cystic fibrosis-related diabetes (CFRD) outcomes and the corresponding emulated trial using UK Cystic Fibrosis Registry data
| Protocol component | Target trial | Emulated trial |
| Eligibility criteria | Include: Individuals diagnosed with CFRD in the UK aged 12 years and older at time of diagnosis Exclude: Individuals who have had an organ transplant or are taking oral corticosteroids or CFTR modulators, prior to CFRD diagnosis | Include: Individuals observed in the UK CF Registry and labelled with CFRD between 2008 and 2016, meeting criteria in the target trial and who had data for at least one visit within 2 years prior to CFRD diagnosis and at least 1 year of follow-up after diagnosis Exclude: As in the target trial. We also exclude people with missing data on baseline confounders, including outcome at baseline, or missing data on infection or pancreatic insufficiency during the follow-up period |
| Treatment strategies | 1) Initiate insulin at CFRD diagnosis and continue to take it throughout follow-up 2) Do not initiate insulin at CFRD diagnosis and continue not to take insulin throughout follow-up. Individuals in the no insulin group may use other non-insulin treatments for CFRD | As in the target trial |
| Assignment procedures | Participants will be randomly assigned to a treatment strategy when they are diagnosed with CFRD and will be aware of the strategy to which they have been assigned | In the emulated trial individuals are not randomly assigned to the treatment strategy, which is addressed in the analysis |
| Follow-up period | 1, 2, 3, 4 and 5 years from diagnosis | As in the target trial |
| Outcome | We consider two outcomes: 1) FEV1 % (obtained using GLI equations) 2) Body mass index (BMI) z-score | As in the target trial |
| Causal contrasts of interest | Per-protocol | As in the target trial |
| Analysis plan | Mean difference in outcome between treatment groups at follow-up, adjusted for baseline level. Estimated using a linear regression model for the outcome, with treatment group and baseline measure of the outcome as explanatory variables | Confounding by measured baseline and time-varying covariates is addressed using IPTW of MSMs or G-formula (see section “Statistical analysis”) |
CFRD: cystic fibrosis-related diabetes; CF: cystic fibrosis; CFTR: cystic fibrosis transmembrane conductance regulator; FEV1 %: % predicted forced expiratory volume in 1 s; GLI: Global Lung Function Initiative; BMI: body mass index; IPTW: inverse-probability-of-treatment weighting; MSMs: marginal structural models.