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 componentTarget trialEmulated trial
Eligibility criteriaInclude: 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 strategies1) 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 proceduresParticipants 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 assignedIn the emulated trial individuals are not randomly assigned to the treatment strategy, which is addressed in the analysis
Follow-up period1, 2, 3, 4 and 5 years from diagnosisAs in the target trial
OutcomeWe consider two outcomes:
1) FEV1 % (obtained using GLI equations)
2) Body mass index (BMI) z-score
As in the target trial
Causal contrasts of interestPer-protocolAs in the target trial
Analysis planMean 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 variablesConfounding 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.