Table 2. Key components of the emulated target trials on dose adjustment strategy following interruptions using the observational data.
| Protocol components | Hypothetical target trial | Emulation of the trial from BC health administrative data |
|---|---|---|
| Eligibility criteria | Adults aged 18 years or older who initiated methadone or buprenorphine/naloxone between 1 January 2010 and 31 December 2022 will be included. Individuals who interrupted methadone for 1–3 days will be eligible for trial 1. Similarly, trials 2 and 3 will include methadone initiators interrupted for 4 days and 5–14 days, respectively. Trials 4 and 5 will include buprenorphine/naloxone initiators interrupted for 1–5 days and 6–14 days, respectively. Participants must not be pregnant, incarcerated on the reinitiation date after the interruption, or have a history of cancer or palliative care. | The same eligibility criteria as the hypothetical target trial will be applied. The emulation will include both incident user and prevalent new-user designs. |
| Treatment strategies | Initiation of trial-specific treatment strategies defined in figure 2 which is based on 2023 BC clinical guideline.18 | Same. |
| Assignment procedures | Eligible individuals of specific trial will be randomly assigned to one of the treatment strategies on the reinitiation date. The prescribers, healthcare teams and individuals are aware of the treatment status. | We will classify individuals into one of treatment strategies based on their dispensation records on the reinitiation date. The prescribers, healthcare teams and individuals are aware of the treatment status. |
| Time zero | The date when eligible individuals are randomised to treatment strategies. | The date when eligible individuals reinitiate treatment following the trial-specific interruption. |
| Outcomes | Time to overdose-related acute care visits and treatment discontinuation are the primary outcomes of interest. The first visit date due to overdose after the time zero will be considered to define the time to overdose-related acute care visits. Treatment discontinuation is defined if methadone or buprenorphine/naloxone dispensation is interrupted for >14 days. |
Same. Due to the lack of inpatient information in our linked database, we assume individuals starting treatment before hospitalisation will continue treatment during their hospital stay without discontinuation. |
| Follow-up | Follow-up begins on the date of randomisation and concludes on treatment discontinuation (only for the outcome of OAT discontinuation), death, overdose-related acute care visits, loss to follow-up, 1 year after time zero or the administrative end of follow-up on 31 December 2022 whichever occurs first. | Follow-up begins on the reinitiation date and ends at the earliest of the following events: treatment discontinuation (only for the outcome of OAT discontinuation), overdose-related acute care visits, death, loss to follow-up, 1 year after time zero or the administrative end of follow-up on 31 December 2022. |
| Causal contrasts | Intention-to-treat | Treatment initiator analysis |
| Analysis plan | Unadjusted Cox-PH regression to estimate the association between treatment strategies and treatment discontinuation. HRs, cumulative incidence (risk) differences and cumulative incidence curves will be estimated from fitted Cox-PH model for comparison purposes.63 64 81 Model-based SE will be used for inference. | IPTW, hdPS and IVs will be applied to control observed and unobserved confounders alongside weighted Cox-PH regression models. The weights will be calculated from the fitted exposure models through binary or multinomial logistic regression approach.* HRs, risk differences and cumulative incidence curves will be estimated for comparison. Sandwich variance will be used to construct 95% CIs for the HR, but bootstrap-based method will be applied to construct the confidence intervals for the risk difference and cumulative incidence curves under IPTW, hdPS and IV analysis.63 64 81 |
*
Least absolute shrinkage and selection operator models for hdPS analysis.
BC, British Columbia; Cox-PH, Cox-proportional hazard; hdPS, high dimensional propensity score estimation; hdPS, high-dimensional propensity score; IPTW, inverse probability of treatment weighting estimation; IV, instrumental variable.