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The Plasma-Lyte 148 versus Saline (PLUS) statistical analysis plan: a multicentre, randomised controlled trial of the effect of intensive care fluid therapy on mortality
Laurent Billot, Rinaldo Bellomo, Martin Gallagher, David Gattas, Naomi E Hammond, Diane Mackle, Sharon Micallef, John Myburgh, Leanlove Navarra, Manoj Saxena, Colman Taylor, Paul J Young, Simon Finfer, On behalf of the PLUS Study investigators and the ANZICS Clinical Trials Group
Crit Care Resusc 2021; 23 (1): 24-31
- Laurent Billot 1, 2
- Rinaldo Bellomo 3, 4, 5, 6
- Martin Gallagher 2, 7, 8, 9
- David Gattas 10, 11
- Naomi E Hammond 2, 12, 13
- Diane Mackle 14, 15
- Sharon Micallef 12
- John Myburgh 2, 12, 16
- Leanlove Navarra 14, 15
- Manoj Saxena 12, 17
- Colman Taylor 2, 12
- Paul J Young 14, 15
- Simon Finfer 2, 12, 13, 18
- On behalf of the PLUS Study investigators and the ANZICS Clinical Trials Group 19
BACKGROUND AND OBJECTIVE:The Plasma-Lyte 148 versus Saline (PLUS) study is a prospective, multicentre, parallel-group, concealed, blinded, randomised controlled trial comparing the effect of Plasma-Lyte 148 versus 0.9% sodium chloride (saline) for fluid resuscitation and other fluid therapy on 90-day mortality among critically ill adults requiring fluid resuscitation. The original target for recruitment was 8800 participants, which was reduced to 5000 participants following the onset of the coronavirus disease 2019 (COVID-19) pandemic in 2020. This article describes the statistical analysis plan for the PLUS study.
METHODS: The statistical analysis plan was developed by the study statistician, chief investigator, and project manager, and was approved by the Management Committee before unblinding. The plan describes in detail the analysis of baseline characteristics, process measures, and outcomes, including covariate adjustments, subgroup analyses, missing data handling, and sensitivity analyses.
RESULTS AND CONCLUSIONS: A statistical analysis plan for the PLUS study was developed. This pre-specified plan accords with high quality standards of internal validity and should minimise future analysis bias.
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- Billot L, Finfer S; PLUS Management Committee. The PLUS study statistical analysis plan; version 1.0 (19 Aug 2020). https://osf.io/8gk3n (viewed Sept 2020).
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This study is endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Groups (ANZICS CTG). The approach of publication of a statistical analysis plan before the analysis of data has been used for previous randomised controlled trials conducted by the ANZICS CTG, 2
The statistical analysis plan for the PLUS study was developed by the study statistician (LB), the chief investigator (SF), and the project manager (SM), and approved by the PLUS study Management Committee, and released on a pre-print server 7
Design and setting
Randomisation and study treatment
A sensitivity analysis of the primary outcome will be conducted after sequentially (and cumulatively) excluding the following patients:
- patients who received 500 mL or more of the study fluid (Plasma-Lyte 148 or 0.9% saline) as an open label fluid before enrolment when they were assigned to the other fluid; and
- patients who received 500 mL or more of the study fluid (Plasma-Lyte 148 or 0.9% saline) as an open label fluid in the ICU (post-randomisation) when they were assigned to the other fluid.
In addition, we will create a chart showing, for each day between days 1–90, the proportion of patients in each arm who fall into one these five categories:
- alive and in the ICU;
- discharged from the ICU but still in hospital;
- discharged alive from hospital;
- dead; and
- unknown status.
Participant characteristics and baseline comparisons
Analysis of daily data
Analysis of the primary outcome
Adjusted analyses will be performed by adding the following covariates to the main logistic regression model: sex, Acute Physiology and Chronic Health Evaluation (APACHE) II score at randomisation (as a continuous variable), presence of sepsis, and source of admission (postoperative v other). The adjusted treatment effect will be reported as the adjusted OR and 95% CI.
Treatment of missing data
Other analyses of mortality
Analyses of other secondary outcomes
Durations and time to discharge. The hospital length of stay, ICU length of stay, duration of mechanical ventilation, and duration of treatment with vasoactive drugs will be analysed as the number of days alive and free of outcome (eg, days alive and free of mechanical ventilation or days alive and free/outside of ICU). Days alive and free of outcome will be calculated between randomisation and Day 90 and will therefore have values comprised between 0 and 90 days. They will be summarised using means (SDs), median (IQRs), minimum and maximum and compared between treatment groups using a linear regression with a fixed effect of the treatment group and a random effect of site. As a sensitivity analysis, we will allocate zero “free days” to patients who die by Day 90. Mechanical ventilation and treatment with vasoactive drugs are only expected to occur while in the ICU. Therefore, once discharged from the ICU, patients will be assumed to be free of respiratory support and vasopressors. While in the ICU, missing daily values (eg, unknown mechanical ventilation status) will be handled as follows:
- Step 1. For intermittent missing values (ie, missing values surrounded by non-missing values both before and after), we will replace the missing value with the closest (in time) non-missing value. In case the time intervals before and after are the same, the missing value will be replaced with the most pessimistic value of the two, meaning still in the ICU or hospital or still receiving the treatment of interest.
- Step 2. For missing values following the baseline assessment (ie, occurring on Day 1 onwards), the mechanical ventilation status at the time of randomisation and the most deranged cardiovascular score within 24 hours before randomisation will be used to guide imputation. In case of missing baseline values, the patient will be assumed to be free of the treatment of interest at baseline. After imputation of the baseline value, missing values will be imputed by following Step 1 above.
- Step 3. For missing values preceding ICU discharge, the patient will be assumed to be free of outcome on the day of discharge if discharged alive and not if they died within a day of ICU discharge. After imputation of the value on the day of discharge, missing values will be imputed by following Step 1 above.
New treatment with renal replacement therapy and vasoactive drugs. Comparison of proportions of patients newly treated with renal replacement therapy and of patients treated with vasoactive drugs will be summarised by treatment arm and compared using a logistics regression analysis analogous to that used for the primary outcome.
Quality of life. The information obtained from the Five-level EuroQol five dimensions (EQ-5D-5L) questionnaire will be used to conduct a cost–utility analysis at 6 months after randomisation and to report quality of life by treatment group and by subgroups. The cost utility analysis forms part of an extended program of health economic and outcomes research to be conducted after publication of the main trial findings.
Safety outcomes. Adverse drug reactions deemed possibly, probably or definitely related to study treatment as determined by the treating physician at site will be summarised as the number and proportion of patients experiencing at least one event. These will be summarised by category of event and overall numbers of events. In addition to the number of patients with at least one event, we will report the total number of events. Proportions of patients with adverse drug reactions will be compared between treatment arms using Fisher exact test, both overall and by category. This will be repeated for serious adverse drug reactions. A listing of all adverse drug reactions will be reported in an Online Appendix.