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Protocol summary and statistical analysis plan for the Targeted Therapeutic Mild Hypercapnia after Resuscitated Cardiac Arrest (TAME) trial
Alistair Nichol, Rinaldo Bellomo, Bridget Ady, Niklas Nielsen, Carol Hodgson, Rachael Parke, Shay McGuinness, Markus Skrifvars, Dion Stub, Stephen Bernard, Fabio Taccone, John Archer, Ary Serpa Neto, Tony Trapani, Kate Ainscough, Anna Hunt, Jim Kutsogiannis, Glenn M Eastwood, for the TAME study and the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), the Irish Critical Care Clinical Trials Network (ICC-CTN), and the Australian Resuscitation Outcomes Consortium (Aus-ROC)
Crit Care Resusc 2021; 23 (4): 374-385
- Alistair Nichol 1, 2, 3
- Rinaldo Bellomo 2, 4
- Bridget Ady 2
- Niklas Nielsen 5
- Carol Hodgson 2
- Rachael Parke 6
- Shay McGuinness 6
- Markus Skrifvars 7
- Dion Stub 8, 9
- Stephen Bernard 8
- Fabio Taccone 10, 11
- John Archer 12
- Ary Serpa Neto 2
- Tony Trapani 2
- Kate Ainscough 1
- Anna Hunt 13
- Jim Kutsogiannis 14
- Glenn M Eastwood 2, 4
- for the TAME study and the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), the Irish Critical Care Clinical Trials Network (ICC-CTN), and the Australian Resuscitation Outcomes Consortium (Aus-ROC)
BACKGROUND: Targeted therapeutic mild hypercapnia may attenuate brain injury in comatose adults resuscitated from out-of-hospital cardiac arrest.
OBJECTIVE: To describe the study protocol and statistical analysis plan for the Targeted Therapeutic Mild Hypercapnia after Resuscitated Cardiac Arrest (TAME) trial.
DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: TAME is a phase 3, multicentre, parallel-group, participant- and outcome assessor-blinded randomised controlled trial that will be conducted in intensive care units in Australia, Canada, Ireland, Saudi Arabia, New Zealand, Scandinavia, Singapore, Central and Western Europe, and the United Kingdom. A total of 1700 comatose adults resuscitated from out-of-hospital cardiac arrest will be randomly assigned to 24 hours of targeted therapeutic mild hypercapnia (arterial carbon dioxide tension 50–55 mmHg) or targeted normocapnia (arterial carbon dioxide tension 35–45 mmHg) in a 1:1 ratio. TAME recruitment began in March 2018 and is expected to be complete in September 2021.
MAIN OUTCOME MEASURES: The primary outcome measure is the proportion of participants with a favourable functional outcome at 6 months. Functional outcomes will be assessed using the Glasgow Outcome Scale-Extended (GOSE); this scale ranges from 1 to 8, with a higher value indicating a better outcome. We will define participants with a GOSE of 5 to 8 as having a favourable functional outcome. Secondary outcomes include 6-month mortality, cognitive function and quality of life. All analyses will be conducted on an intention-to-treat basis.
RESULTS AND CONCLUSIONS: TAME will compare the effect of targeted therapeutic mild hypercapnia versus targeted normocapnia on functional outcomes in adults resuscitated from out-of-hospital cardiac arrest who are admitted to an intensive care unit.
TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12617000036314p) and ClinicalTrials.gov (NCT03114033).
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Setting and population
Randomisation and treatment masking (blinding)
Neurological prognostication and withdrawal of life-sustaining therapies
Data collection and management
Ethical issues and good clinical practice
Data safety monitoring committee and interim safety analysis
Sample size and power
Statistical analysis planAll data will initially be assessed for normality. We will analyse data on an intention-to-treat basis, defined as all randomly assigned participants except those for whom consent was withdrawn, without imputation of missing data unless specified. Baseline comparisons and comparisons of physiological descriptors and processes of care will be performed using χ2 tests to test for equal proportions, Student t tests to compare normally distributed data and Wilcoxon rank-sum tests to compare other types of data, with results reported as number (percentage), mean ± standard deviation, and median (interquartile range), respectively. Comparisons of longitudinal data will be performed using a mixed-effect linear model, fitting main effects for treatment, time and an interaction between the two, and with centres and participants entered as random effects to account for the clustering effect and for repeated measurements.
Paco2 data will be reported as time-weighted averages for each treatment group with linear interpolation. We will evaluate Paco2 separation, exposure and study protocol compliance over the intervention period by evaluating systematically obtained Paco2 recordings.
Binary outcomes, including the primary outcome, will be presented as proportions of participants in each group with the event. Unadjusted differences in proportions will be provided. Risk ratios and 95% confidence intervals will be assessed using a mixed-effect generalised linear model with a logit link, with centre as a random intercept and co-enrolment included as a fixed effect. Survival data, including time to death at ICU discharge, hospital discharge, 30 days and 180 days, will be presented in Kaplan–Meier curves and analysed using shared frailty Cox proportional hazard models, with centre included as frailty and co-enrolment included as a fixed effect. The proportional hazard assumption will be assessed through Schoenfeld residuals.
Continuous outcomes will be analysed using mixed-effect linear regression, with centre as a random intercept and co-enrolment included as a fixed effect. We expect that a large proportion of the participants will die before assessment of quality of life. So, when assessing health-related quality of life in the primary analysis, we will impute a 0 for all participants who died or could not participate in the quality-of-life assessment due to incapacitation. In a secondary analysis of quality of life, we will only include survivors at 6 months.
If more than 5% of missing data are primary or secondary outcomes data, a sensitivity analysis will be performed using multiple imputation conditional on prognostic baseline and post-baseline variables under the assumption that missing data are conditional on observed covariates and were assumed to be missing at random. As an additional sensitivity analysis for the primary outcome, GOSE data will be assessed in its original scale considering a mixed-effect cumulative logistic model (ordinal regression).
Analyses will be performed on five pre-defined subgroups irrespective of whether there is evidence of an overall treatment effect. Heterogeneity between subgroups will be determined by fitting an interaction between treatment and subgroup on the model described above. The following pre-defined subgroups will be assessed:
- age ≤ 65 years versus > 65 years on admission;
- female versus male;
- time from cardiac arrest to ROSC higher than median versus time from cardiac arrest to ROSC lower than median;
- shockable versus non-shockable initial cardiac rhythm; and
- shock versus no shock on admission.
Analyses will also be performed on the per-protocol population and the population of participants who are not co-enrolled in the TTM2 trial. 23