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December 2022

Original Article

Study protocol and statistical analysis plan for the 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-II (HAS FLAIR-II) trial

Geoffrey Wigmore*†, Rinaldo Bellomo*†, Adam M Deane, James Anstey, Michael Bailey, Shailesh Bihari, Glenn Eastwood, Rashmi Ghanpur, Matthew J Maiden, Jeffrey J Presneill, Jaishankar Raman, The HAS FLAIR-II trial investigators

Crit Care Resusc 2022; 24 (4): 309-18

Correspondence:geoffrey.wigmore@austin.org.au; rinaldo.bellomo@austin.org.au

https://doi.org/10.51893/2022.4.OA1

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  • Author Details

    * Equal first authors.
    † Corresponding author.

  • Competing Interests

    All authors declare that they do not have any potential conflict of interest in relation to this manuscript.

  • Abstract
    BACKGROUND: Fluid bolus therapy with 20% albumin may shorten the duration of vasopressor therapy in patients after cardiac surgery.
    OBJECTIVE: To describe the study protocol and statistical analysis plan for the 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-II (HAS FLAIR-II) trial.
    DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: HAS FLAIR-II is a phase 2b, multicentre, parallel group, open-label, randomised controlled trial that will be conducted at six Australian intensive care units. Patients requiring fluid bolus therapy after cardiac surgery will be randomly assigned in a 1:1 ratio to the intervention of fluid bolus therapy with 20% albumin or a comparator of fluid bolus therapy with a crystalloid solution.
    MAIN OUTCOME MEASURES: The primary outcome measure is the cumulative duration of vasopressor therapy. Secondary outcomes include vasopressor use, service utilisation, and mortality. All analyses will be conducted on an intention-to-treat basis.
    RESULTS AND CONCLUSION: The study protocol and statistical analysis plan will guide the conduct and analysis of the HAS FLAIR-II trial, such that analytical and reporting biases are minimised.
    TRIAL REGISTRATION: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN No. 12620000137998).
  • References
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Hypotension after cardiac surgery within the intensive care unit (ICU) is common and is a frequent trigger for the administration of a fluid bolus. 1 Such fluid bolus therapy contributes to about 50% of the total fluid volume patients receive in the first 24 hours after surgery. 2
 
Colloid solutions have been widely used for fluid bolus therapy in cardiac surgery. 3 This is due to the belief that their increased oncotic pressure leads to less total volume being administered to achieve equivalent haemodynamic effects than crystalloid therapy. 4 Such a reduction in volume may be beneficial. 5, 6, 7
 
Synthetic colloids cause worse outcomes than crystalloid fluids. 8, 9, 10, 11 However, a natural colloid, albumin solution, is safe for most patients, with possible benefits in certain subgroups. 12, 13, 14, 15, 16, 17 In Australia and New Zealand, albumin solution is available in two formulations: albumin 4% and albumin 20%. Of these, 4 % albumin is the most frequently used colloid, but the proportion of albumin in the fluid may affect patient outcomes. 2, 18 It is plausible that 20% albumin may be better than 4% albumin for fluid resuscitation because the same haemodynamic targets are achieved with much lesser volumes of fluid. 4, 19
 
We previously conducted a single centre, sequential period trial of 20% albumin compared with a predominantly crystalloid-based fluid bolus therapy strategy after cardiac surgery (HAS FLAIR-I). 20 We reported a reduction in fluid balance along with a reduction in the duration and total dose of noradrenaline administered. 20 However, our previous trial had substantial methodological limitations. Accordingly, there is uncertainty about the choice of optimal fluid bolus solution for patients in the ICU after cardiac surgery. 21, 22
 
For these reasons, we designed the 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-II (HAS FLAIR-II) trial. Our objective is to determine whether fluid bolus therapy after cardiac surgery with 20% albumin reduces the duration of vasopressor therapy compared with crystalloid therapy. In this article, we describe the protocol and statistical plan for the HAS FLAIR-II trial in order to reduce the risk of analysis bias arising from knowledge of the study findings as they emerge during the analysis of the study data. 23, 24, 25
 

Methods

Design

This is a phase 2b, multicentre, parallel group, open-label randomised controlled trial conducted at six metropolitan ICUs in Australia. HAS FLAIR-II has been designed with reference to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 23 checklist and the Consolidated Standards of Reporting of Trials (CONSORT) guidelines. 24
 

Study population

The study population of interest is patients admitted to the ICU after cardiac surgery who require a fluid bolus. The need for a fluid bolus will be determined by the patients’ treating doctor. Patients will be eligible to be enrolled if they fulfil all the inclusion criteria and none of the exclusion criteria (Table 1).
 

Intervention

The intervention is human albumin solution administered as 100 mL of 20% weight by volume of human albumin solution (CSL Behring, Melbourne, VIC, Australia). It is presented as a slightly viscous, almost colourless, liquid in a 100 mL clear glass bottle. 26 The intervention will be administered as a bolus (defined in the Online Appendix). Patients assigned to the intervention who are assessed by the treating doctor as requiring further fluid bolus therapy will receive this as 20% albumin up to a maximum of 400 mL (80 g albumin) per calendar day. If the daily maximum is reached, additional fluid bolus therapy on that calendar day will be administered as 4% albumin — presented as 4% weight by volume of human albumin solution (CSL Behring) as a slightly viscous almost colourless liquid in a 500 mL clear glass bottle. 27
 

Comparator

Participants assigned to the comparator will receive a crystalloid solution for at least the first 1000 mL of fluid bolus therapy, after which the treating clinician is permitted to use 4% albumin. The comparator group was chosen based on observational data. 2, 28 Suitable crystalloid solutions include, but are not limited to, 0.9% sodium chloride solution, compound sodium lactate or Plasma-Lyte148 (Baxter Healthcare). Administration of any albumin will be recorded and reported, with concentrations other than 4% being a protocol deviation.
 

Duration of the study treatment

The duration of study treatment is for a maximum of 7 days after randomisation, with study treatment and observations censored at ICU discharge. The intervention or comparator will continue for all fluid bolus therapy administered in the index ICU admission until vasopressors are discontinued for 4 consecutive hours in the presence of a mean arterial pressure (MAP) ≥ 65 mmHg, or an alternative target MAP set by the treating clinician. For patients not receiving vasopressor therapy, the intervention or comparator will continue for all fluid boluses until midnight on day 7.
 

Screening

All patients admitted to a participating ICU following cardiac surgery will be considered for enrolment. Screening will be conducted by a site investigator or a member of the research department. Screening commenced on 31 August 2020. Inclusion and exclusion of patients (including reasons for exclusion) will be reported according to the CONSORT guidelines (Figure 1). 24
 

Assignment of study treatment

Randomisation is performed using the randomisation module in REDCap (Research Electronic Data Capture) — a secure, web-based interface. 29, 30 Allocation concealment before randomisation is maintained using a permuted, variable size block schedule, stratified by site and the presence of a vasopressor at the time of randomisation. Randomisation is not performed until a participant fulfils all eligibility criteria and can be assigned to a study treatment.
 

Blinding of study treatment

It is not feasible to blind the study treatment and group assignment during trial conduct. However, during the analysis and drafting of the manuscript, the investigators, statisticians, and writing committee members will work with binary coded (A, B) data rather than the actual trial-group assignments. Further, the manuscript writing will be performed in duplicate, with the groups (A, B) interchanged. Importantly, group analyses of variables that may unblind the group allocation codes (eg, serum albumin, all fluid therapy volume and type) will be deferred until the two draft manuscripts have been completed.
 

Additional non-study treatment

All non-study treatments are left to the discretion of the treating clinicians. The use of maintenance fluids contributes to the daily fluid administration, the type and amount of maintenance fluid will be left to the discretion of the treating clinician. 31, 32 The use of 4% albumin for fluid bolus therapy in the comparator arm after 1000 mL of crystalloid fluid bolus therapy is at the discretion of the treating clinician. This crossover intervention will be specifically quantified and reported.
 

Strategies to improve adherence to interventions

The study protocol for HAS FLAIR-II was presented at each of the participating sites and has included discussions with both the intensive care physicians and cardiac surgeons. Should the scenario arise where there is not clinical equipoise regarding the study treatment for a patient, they will be excluded. Such consultations combined with visual aids of the protocol targeted at the clinical staff have been employed to improve consistency in protocol implementation.
 

Baseline and operative characteristics

Baseline data and operative characteristics will be recorded and presented (Online Appendix).

Outcome data

The primary outcome for this trial is the cumulative duration of vasopressor therapy until the first observed period of cessation of vasopressor therapy censored at midnight on study day 7 (randomisation occurs on calendar day 1). Vasopressor duration was chosen for this trial due to low baseline mortality following cardiac surgery, the biological plausibility that greater exposure to vasopressor therapy can lead to patient harm, the direct and indirect health care costs associated with vasopressor use, and the established use of vasopressor duration as the primary outcome in previous critical care trials. 33, 34, 35, 36, 37 The cumulative duration of vasopressor therapy will be recorded at midnight on study day 7, regardless of whether vasopressor therapy was being administered at randomisation or only commenced subsequently. “Cessation of vasopressors” is defined as no intravenous vasopressor drug administered for a period of ≥ 4 hours with a MAP ≥ 65 mmHg, or target MAP set by the treating clinician for the same 4-hour period. The trial event of cessation of vasopressors is defined to occur only once and cannot recur, even if a vasopressor is recommenced > 4 hours later.38 Patients who receive no vasopressor therapy within 7 days of randomisation will be assigned zero hours of vasopressor therapy. Drugs considered as vasopressors are listed in the Online Appendix.

Adrenaline and vasopressin doses will be converted to the equivalent noradrenaline dose using an established conversion scale. 38, 39 The total vasopressor dose will be calculated as the sum of the noradrenaline dose and the converted doses.
The trial secondary outcomes are listed in Table 2. The additional process of care measures concerning fluid administration will be presented (Online Appendix).

In addition, the following nested studies are planned:
  • haemodynamic profile of fluid bolus therapy using continuous haemodynamic monitoring;
  • health economic evaluation; and
  • biomarker assessment using baseline and 24-hour data relating to renal biomarkers.

Adverse events

Consistent with established international practice in ICU trials, events that are part of the natural history of the primary disease, or expected complications of critical illness, which are not reported as outcomes by the trial will not be reported as adverse events. 40 All adverse events considered to be potentially causally related to the study intervention or are otherwise of concern in the investigator’s judgment will be reported.
 

Analysis and reporting of results

Data collection and management

Trained research coordinators will collect data at each site which will be initially entered into a hard copy case report form and transcribed subsequently into a secure, electronic database (REDCap). Access to both hard copy and electronic data will be limited to study personnel. Study data will be de-identified, with a master linking log enabling re-identification stored separately and accessible only to site investigators. The data collected along with the time frames of data acquisition are detailed in Table 3.

Accuracy and consistency checks of collected data will be carried out by automatic validation, and by pre-specified and ad hoc checking by personnel at the coordinating centre. On-site or remote data monitoring will be performed to verify the data for the primary outcome of 30% of the patients enrolled into the study which will selected at random and stratified by group.
 

Statistical analysis plan

Sample size
The sample size was calculated using pilot data from our single centre exploratory study. 20 Based on a pooled standard deviation (SD) of 32 hours, a sample size of 200 patients per group provided 80% power (two-sided P = 0.05) to detect a difference in vasopressor duration of 9 hours. The difference of 9 hours was two-thirds of the effect observed in the previous HAS-FLAIR-I study, and we considered a 9-hour reduction in the duration of vasopressor therapy to be a meaningful difference. 20 To account for potential non-normality, we inflated the sample size by 15%. 41 To further account for potential consent withdrawal (5%), we decided upon a final sample size of 480 patients.

Baseline characteristics and primary outcomes
Firstly, all data will be assessed for approximate normality and presented by treatment allocation. Summary statistics for categorical variables will be presented as frequency (%) and compared using χ2 tests for equal proportion. Continuous variables will be summarised as mean (SD) or median (interquartile range [IQR]) and initially compared using a Student t tests for normally distributed variables or Wilcoxon rank sum tests otherwise.

The primary outcome will be reported as the difference (95% confidence interval [CI]) between the intervention and comparator in their median (quantile = 0.5) hours of vasopressor treatment as returned by a simple quantile linear regression model incorporating adjustment for the trial sites as a random effect.

Subsequent sensitivity analyses maybe performed using covariates showing baseline imbalance (P < 0.1) and may also include age, sex, estimated 30-day postoperative mortality as determined by the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II, and individual variables of the EuroSCORE-II risk model. Time to cessation of vasopressor therapy will be explored using Cox proportional hazards regression adjusting for trials sites as a random effect, with results reported as hazard ratio (95% CI) and also presented using Kaplan–Meier survival curves, with treatment comparison using log-rank tests.

In the present trial design, a patient death on or before day 7 may, by acting as a competing event, preclude observation of vasopressor cessation — the primary endpoint of interest. If such early deaths occur, exploratory analyses may assess according to treatment allocation:
  • cumulative duration of vasopressor therapy in survivors to end of day 7;
  • cumulative duration of vasopressor therapy-free time in survivors to end of day 7;
  • cumulative duration of vasopressor therapy in patients who die before the end of day 7; and
  • cumulative duration of vasopressor therapy-free time in patients who die before the end of day 7.
The time course of vasopressor therapy in those that receive a non-zero dose will be displayed graphically as log transformed doses and analysed using mixed linear modelling clustered at the individual patient level with main effects for treatment and time and their interaction.

All main statistical analyses will be conducted on an intention-to-treat basis. Pre-specified exploratory analyses will be performed within two subgroups irrespective of evidence for an overall treatment effect: i) presence or absence of any vasopressor therapy at randomisation, and ii) pre-operative plasma albumin concentration dichotomised at the median of the pooled group albumin (g/L). A two-tailed P < 0.05 will be used to indicate statistical significance of the primary outcome, and there will be no formal adjustment of this statistical threshold for non-primary outcomes, which are all exploratory in nature.

Missing data
No imputation will be undertaken for missing data. Rates for missing data will be reported in the Online Appendix.

Interim analysis
An independent Data Safety Monitoring Board (DSMB), composed of an experienced clinical researcher and biostatistician without other connection to the HAS FLAIR-II trial, will operate under a charter based on the recommendations of the DAMOCLES Study Group (Online Appendix). 42 One interim safety analysis will be conducted. This will apply the Haybittle–Peto criterion (|Z1| ≥  3) 43 for early stopping in a group sequential statistical assessment of the trial primary outcome at approximately 50% recruitment (n = 235 patients). Because of the negligible effect of this interim analysis on expenditure of error, the final analyses at full recruitment will be little affected and consequently all final analyses will be conducted with a type I error a = 0.05. This level of significance will not be adjusted for multiplicity, but the primary trial outcome is clearly defined.
 

Ethical considerations

Ethics approval

The Austin Health Human Research Ethics Committee has approved the current protocol version 4, dated 1 December 2020 (HREC/57780/Austin-2019). Under the National Mutual Acceptance (NMA) Scheme, this covers all sites in Victoria and South Australia.
 

Consent process

As many patients eligible for this trial will be too unwell to provide informed consent, the approach to obtaining consent in Australia will be based on that developed from the guidelines in Chapter 4.4 of the National Health and Medical Research Council (NHMRC) National statement on ethical conduct in human researchand is consistent with local laws. 44 The approach is a hierarchical consent model. For competent patients, informed consent will be obtained before enrolment. For patients who do not have capacity to consent, the approach to consent will be via the medical treatment decision maker. For patients who do not have capacity and for whom there is no immediately available medical treatment decision maker, patients can be enrolled and consent to continue participation obtained. Consent to continue participation will be obtained at the earliest opportunity. Patients who do not wish to continue participation have the option to allow data already collected to date to be included or all data to be deleted.
 

Funding

This investigator-initiated trial is supported by an unrestricted grant from CSL Behring ($350 000). CSL Behring has had no input into the study design or ongoing trial management. Furthermore, CSL Behring will have no input into the analysis and interpretation of the data and writing of the final manuscript. The final manuscript will be made available to CSL Bering 30 days before submission. The decision to submit the manuscript for publication remains the prerogative of the investigators.
 

Presentation of outcome data

The proposed table and figures for the primary manuscript are listed in Table 4. Detailed mock tables and figures for the primary manuscript are shown in the Online Appendix. The analyses of the three nested studies will be reported separately.
 

Approach to co-enrolment

The Australian and New Zealand Intensive Care Society Clinical Trials Group policy on co-enrolment will be followed. 45 Site investigators may co-enrol participants in HAS FLAIR-II and other trials as long as the intervention in other trials is unrelated to fluid bolus therapy or the administration of albumin-containing fluids. Trials with co-enrolment approval are listed in the Online Appendix.
 

Data sharing statement

De-identified individual participant data reported in this trial will be made available to researchers who provide a written, methodologically sound proposal between 3 and 7 years after publication. Proposals should be directed to the principal investigator. If approved, requestors will be required to enter into a data access and confidentiality agreement.
 

Summary

This study will provide important information to guide clinicians as to whether fluid bolus therapy with 20% albumin is superior to a crystalloid-based regimen in patients after cardiac surgery. This statistical analysis plan was prepared before the completion of recruitment and data collection.
 
Acknowledgements: All authors gave final approval of the version to be published and agreed to be accountable for all aspects of this work. The HAS FLAIR-II trial is supported by a grant from CSL Behring. Geoffrey Wigmore is supported by a National Health and Medical Research Council Postgraduate Scholarship. None of these funding organisations has contributed to the study design; collection, management, analysis and interpretation of data, writing of the report, or the decision to submit the report for publication.
 
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