Existencialismo-misantropía

Adverse events

The CASPER plus study was not a Clinical Trial of an Investigational Medicinal Product and was, therefore, not subject to any additional restrictions. Decisions regarding prescription of medications were made by the participant in conjunction with their GP: participation in the study had no bearing on this process. Any participants who asked a member of the CASPER plus study team for an opinion on medication issues were strongly encouraged to seek advice from their GP.

The study recorded details of all serious adverse events (SAEs). Any judged to have been related to the study were required to be reported to the REC under the terms of the standard operating procedures for RECs.51_{In the context of the older adult population of the CASPER plus study, many of the SAEs were}

expected: unscheduled hospitalisations, life-threatening conditions, incapacitating illnesses and deaths. These were not perceived as unexpected events; therefore, they would be reported as SAEs only if they appeared to be related to an aspect of taking part in the study (e.g. participation in treatment, completion of follow-up questionnaires, participation in qualitative substudies or telephone contact).

When a SAE was identified, the trial manager was informed by e-mail using a participant’s trial identification number, and not by any identifiable data. He or she then informed the chief investigator and two members of the Trial Management Group, who jointly decided if the event should be reported to the REC as a SAE. A SAE form was completed and a copy was filed securely at the core study centre. Any unexpected SAEs that were also judged to have been related should have been reported to the main REC within 15 days of the chief investigator becoming aware of the event. In the CASPER plus study, none of the SAEs were judged to have been related to the trial.

The occurrence of adverse events during the trial was monitored by an independent Data Monitoring Ethics Committee and the Trial Steering Committee. The Data Monitoring Ethics Committee/Trial Steering Committee would have seen immediately all SAEs thought to be treatment related.

Data collection schedule

An overview of the time points at which trial data were collected is presented inTable 2.

Statistical assumptions

Participants, care deliverers and the study team were not blinded to treatment allocation. However, allocations were concealed (group A and group B) for interim study reports, for example for the purpose of independent

data monitoring reporting. The trial statistician who was responsible for the final statistical analysis was kept blind to group allocation until the primary analysis had been completed.

All analyses were conducted on intention-to-treat basis, using a two-sided statistical significance level of 0.05 unless otherwise stated. A full specification of the statistical analyses is documented in the CASPER plus statistical analysis plan (version 1.0). Any additional data assumptions for data, once received from the York Trials Unit data management team and the CASPER plus trial management team, for the purpose of this report, are documented separately.

Statistical analysis

Baseline characteristics

All participant baseline data (demographics from the background information form, outcome data from the baseline questionnaire, PHQ-9 and MINI responses from the diagnostic interview) were summarised descriptively by trial arm for all randomised participants and all participants included in the primary analysis.

The analysis population included all patients in their randomised groups with available outcome data (for the primary analysis: PHQ-9 score at 4, 12 or 18 months’follow-up) as well as complete baseline covariates specified for the analysis.

Primary analysis

Unadjusted descriptives of depression severity (PHQ-9) at all follow-up time points were presented. A covariance pattern linear mixed-effects model was used to compare collaborative care with usual care on PHQ-9 scores at 4 months. Effects of interest and baseline covariates were specified as fixed effects, and the correlation of observations within patients over time was modelled by a covariance structure to describe the random effects. The mixed model provided increased statistical power by utilising all patients with outcomes for at least one follow-up time point.

TABLE 2 Data collection schedule

Data collected Time point Invitation Baseline Diagnostic interview/ randomisation 4 months_’ follow-up 12 months_’ follow-up 18 months_’ follow-up Consent/decline ✓ Demographics _✓ Whooley questions ✓ ✓

Physical health problems _✓

MINI major depressive module ✓

PHQ-9 _{✓ ✓ ✓ ✓ ✓} SF-12 ✓ ✓ ✓ ✓ EQ-5D-3L _{✓ ✓ ✓ ✓} GAD-7 ✓ ✓ ✓ ✓ PHQ-15 _{✓ ✓ ✓ ✓} CD-RISC2 ✓ ✓ ✓ ✓

Mental health medication _{✓ ✓ ✓ ✓}

Mortality ✓ ✓ ✓

The outcome modelled was PHQ-9 at 4, 12 and 18 months. The model included time, trial arm and time-by-treatment interaction as fixed effects, adjusting for PHQ-9 score at randomisation and physical/ functional limitations (as measured by the baseline SF-12 PCS score). Different covariance structures for the repeated measurements available in the analysis software were explored, and the most appropriate pattern was used for the final model based on the model Akaike information criterion. The primary end point was the estimate of the effect of the intervention at 4 months, which is presented with 95% confidence intervals (CIs) and associatedp-values.

Secondary analyses

The primary analysis model was repeated (1) including case managers as a random effect to account for clustering within case managers, (2) including additional covariates predictive of PHQ-9 scores at 4 months as identified by univariate regressions, (3) including additional covariates predictive of non-response at 4 months as identified by univariate regressions and (4) using multiply imputed data. Results from the secondary analyses were compared with those from the primary analysis in order to ascertain the robustness of any observed treatment differences.

Secondary outcomes

Patient Health Questionnaire 9-items depression severity estimates at 12 and 18 months were extracted from the primary analysis model and presented with 95% CIs and associatedp-value. A logistic

mixed-effects model was used to compare PHQ-9 depression caseness (scores of≥10), using the same covariates as the primary analysis. Odds ratios and 95% CIs are presented for the effect of the intervention at 4, 12 and 18 months. Analyses of other secondary outcomes were conducted using linear or logistic mixed models, depending on the outcome measure, adjusting for PHQ-9 score at randomisation and baseline SF-12 PCS score as well as the outcome measure at baseline. Treatment effects at each time point were reported. EQ-5D-3L responses were reported descriptively as part of the statistical analysis and analysed fully as part of the economic analysis. Frequencies of adverse events were reported descriptively by treatment arm, including breakdown by type and estimated relatedness to the intervention. The number of deaths occurring in the 18-month trial period was summarised by trial arm and overall. A chi-squared test was used to compare proportions between trial arms if more than five participants died in each arm.