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Study protocol and statistical analysis plan for the Liberal Glucose Control in Critically Ill Patients with Pre-existing Type 2 Diabetes (LUCID) trial
Alexis P Poole, Mark E Finnis, James Anstey, Rinaldo Bellomo, Shailesh Bihari, Vishwanath Biradar, Sarah Doherty, Glenn Eastwood, Simon Finfer, Craig J French, Angaj Ghosh, Simon Heller, Michael Horowitz, Palash Kar, Peter S Kruger, Matthew J Maiden, Johan Mårtensson, Colin J McArthur, Shay P McGuinness, Paul J Secombe, Antony E Tobin, Andrew A Udy, Paul J Young, Adam M Deane, On behalf of the LUCID Study Investigators and the ANZICS Clinical Trials Group
Crit Care Resusc 2020; 22 (2): 133-141
- Alexis P Poole 1, 2
- Mark E Finnis 1, 2
- James Anstey 3
- Rinaldo Bellomo 4
- Shailesh Bihari 5, 6
- Vishwanath Biradar 7
- Sarah Doherty 3
- Glenn Eastwood 4, 8
- Simon Finfer 9
- Craig J French 10
- Angaj Ghosh 11
- Simon Heller 12
- Michael Horowitz 13, 14
- Palash Kar 1, 2
- Peter S Kruger 15, 16
- Matthew J Maiden 1, 2, 17
- Johan Mårtensson 18
- Colin J McArthur 19
- Shay P McGuinness 20
- Paul J Secombe 21
- Antony E Tobin 22
- Andrew A Udy 23
- Paul J Young 24, 25
- Adam M Deane 3, 26
- On behalf of the LUCID Study Investigators and the ANZICS Clinical Trials Group 27
BACKGROUND: Contemporary glucose management of intensive care unit (ICU) patients with type 2 diabetes is based on trial data derived predominantly from patients without type 2 diabetes. This is despite the recognition that patients with type 2 diabetes may be relatively more tolerant of hyperglycaemia and more susceptible to hypoglycaemia. It is uncertain whether glucose targets should be more liberal in patients with type 2 diabetes.
OBJECTIVE: To detail the protocol, analysis and reporting plans for a randomised clinical trial — the Liberal Glucose Control in Critically Ill Patients with Pre-existing Type 2 Diabetes (LUCID) trial — which will evaluate the risks and benefits of targeting a higher blood glucose range in patients with type 2 diabetes.
DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: A multicentre, parallel group, open label phase 2B randomised controlled clinical trial of 450 critically ill patients with type 2 diabetes. Patients will be randomised 1:1 to liberal blood glucose (target 10.0–14.0 mmol/L) or usual care (target 6.0–10.0 mmol/L).
MAIN OUTCOME MEASURES: The primary endpoint is incident hypoglycaemia (< 4.0 mmol/L) during the study intervention. Secondary endpoints include biochemical and feasibility outcomes.
RESULTS AND CONCLUSION: The study protocol and statistical analysis plan described will delineate conduct and analysis of the trial, such that analytical and reporting bias are minimised.
TRIAL REGISTRATION: This trial has been registered on the Australian New Zealand Clinical Trials Registry (ACTRN No. 12616001135404) and has been endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group.
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The Normoglycemia in Intensive Care Evaluation — Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial 8
Type 2 diabetes is a common comorbidity in critically ill patients, 11, 12, 13, 14, 15
The outcomes of single centre sequential period studies, which have compared a so-called liberal approach to glycaemic control (insulin initiated when blood glucose > 14.0 mmol/L; target 10.0–14.0 mmol/L) with usual care (insulin initiated when blood glucose > 10.0 mmol/L; target 6.0–10.0 mmol/L), suggest that a more liberal strategy is beneficial. 22, 23, 24
Despite the recognition that critically ill patients with type 2 diabetes may benefit from a more liberal approach to management of hyperglycaemia with insulin compared with current recommended glycaemic control, 26, 27
DesignMulticentre, parallel group, open-label phase 2B randomised controlled clinical trial.
SettingLUCID will be conducted in 23 ICUs in Australia and New Zealand.
InterventionThe trial will compare two blood glucose thresholds with complementary target ranges for the initiation and management of insulin therapy in critically ill patients with type 2 diabetes.
Participants assigned to the intervention of a liberal approach will have insulin commenced at a blood glucose level greater than 14.0 mmol/L and titrated to a target blood glucose in the range 10.0–14.0 mmol/L. If the blood glucose is below 10.0 mmol/L, no attempt to lower or increase blood glucose will be made, with the exception of local protocols for management of hypoglycaemia.
Participants assigned to the usual care group will have the usual care for the institution, which will be aligned to the NICE-SUGAR results, with insulin initiated at a blood glucose level greater than 10.0 mmol/L and titrated to a target blood glucose level in the range of 6.0–10.0 mmol/L.
At each site, the approach to maintaining blood glucose within the relevant ranges will be informed by local practice and will employ local institutional blood glucose and insulin algorithms rather than a standardised protocol across all sites. This pragmatic approach will facilitate external validity and enable real-world comparisons.
ScreeningAll patients admitted to a participating ICU will be considered for enrolment. Patients will be eligible if they fulfil all the inclusion criteria and none of the exclusion criteria (Table 1). Inclusion and exclusion of patients (including reasons for exclusion) will be reported according to the Consolidated Standards for Reporting of Trials (CONSORT) guidelines (Figure 1). 28
Assignment of interventionRandomisation will be performed using a secure, web-based interface, with allocation concealment maintained using a permuted, variable size block randomisation stratified by site. Randomisation will not be performed until a participant fulfils all eligibility criteria and can be assigned to study treatment. Group assignment will be unblinded for all involved in the trial.
Baseline dataBaseline data will be recorded and presented (Online Appendix).
Outcome dataThe primary outcome is incident hypoglycaemia defined as blood glucose below 4.0 mmol/L. Other outcomes, broadly categorised as feasibility, physiological and clinical outcomes, and processes of care will be reported (Table 2). When using the term “blood glucose”, we are referring to “point of care blood glucose” or “laboratory plasma glucose”, given that the test used for each glucose concentration may vary, the measurement technique of each sample is being collected.
On Days 1–7, blood glucose will be recorded as the nearest sample to four time points (00:00 h, 06:00 h, 12:00 h and 18:00 h). If no sample is taken within 3 hours of the designated interval, data will be recorded as missing. If the daily minimum or maximum blood glucose concentration occurred outside of these periods, these will be recorded separately. On study days 8–14, the blood glucose closest to 08:00 hours will be recorded. Blood glucose will not be recorded after Day 14.
Hypoglycaemia will be defined as a blood glucose level below 4.0 mmol/L, obtained from arterial, capillary or venous blood and measured using point-of-care glucometer, arterial blood gas analyser or hospital laboratory testing. An incident event will be defined as hypoglycaemia in the absence of recorded hypoglycaemia in the preceding 4 hours. Because recurrent hypoglycaemia may cause greater harm than a single episode, 20, 29
Feasibility outcomes include recruitment and consent rates. The number of study participants assigned to usual care who subsequently receive insulin and the number of overall participants in whom blood glucose is 10.0 mmol/L or greater will be reported, given that insulin-induced hypoglycaemia and glycaemic variability are proposed as key mechanisms underlying harm of usual care. 29
Criteria for discontinuing or modifying allocated interventionStudy participants will continue to receive the intervention while in the ICU or censored at 28 days from randomisation. Glucose management outside the ICU will be at the discretion of the treating physician. The intervention will cease if consent is withdrawn before Day 28, the treating clinician determines that it is in the patient’s best interest to cease the trial intervention, or the treating clinician wishes to transition the participant to an alternative regimen, such as long-acting insulin or oral agents, before discharge from ICU.
Clinical outcomesClinical outcomes include 90-day all-cause mortality; length of ICU and hospital stay, with death as a competing risk; hospital discharge destination; and location at Day 90. Infectious complications will be recorded as the number of patients with established blood stream infections and sternal wound infections in cardio-thoracic surgical patients up to Day 28 (Online Appendix). 31
Protocol registration and endorsementThe concept for the trial was presented at the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS-CTG) 2016 Annual Meeting on Clinical Trials in Intensive Care. The protocol was subsequently drafted, registered with the Australian New Zealand Clinical Trials Registry (2 August 2016, Trial ID: ACTRN12616001135404), and endorsed as an ANZICS-CTG trial (10 November 2016).
Funding and supportThe trial has received funding from four separate project grants:
- the Royal Adelaide Hospital Research Committee Project Grant (2017);
- the Intensive Care Foundation Fisher and Paykel Research Project Grant (2017);
- the Diabetes Australia Research Trust Project Grant (2018); and
- the Melbourne Academic Centre for Health Rapid Applied Research Translation Grant (2019).
Participant safetyPatients will be withdrawn from the trial if the treating clinician determines that it is in the patient’s best interest to cease the trial intervention. Adverse and serious adverse events will be recorded along with relationship to therapy and action taken (Online Appendix).
Analysis and reporting of results
Data managementStudy data will recorded on paper case report forms and then entered into REDCap — a secure web-based data capture tool. 32
Presentation of outcome dataThe proposed table and figures are shown in Table 3. A complete set of mock tables and figures is provided in the Online Appendix.
Sample sizeThe sample size was based on pilot data from a single-centre exploratory study of liberal glucose control against usual care, with the relative risk of hypoglycaemia being 0.47, 23
Analysis of primary and secondary outcomesData will be presented as n/N (%), mean (SD) or median (interquartile range [IQR]), with between-group comparisons using X2, t test or rank-sum test as indicated. Because of the consent model, the main analyses will be conducted on a modified intention to treat basis (Figure 1). 33
The primary outcome will be reported as the incident rate with corresponding 95% confidence interval (CI) and as the raw number of events per group and the proportion of individuals experiencing one or more events. Secondary outcomes will be presented as point estimates with 95% CI. Group point estimates and confidence intervals will be adjusted for within-subject correlation using generalised estimating equations regression with robust standard errors. The incident rate will be standardised to a defined ICU exposure interval; for example, incident rate = X (95% CI) events per N ICU days.
Mortality at Day 90 will be analysed by X2 test and adjusted for pre-set covariates (age, sex, Acute Physiology and Chronic Health Evaluation [APACHE] II, invasive mechanical ventilation and post-operative admission) by logistic regression, with standard errors adjusted for ICU site.
Pre-defined subgroup analysesAn exploratory subgroup analysis will be conducted based on HbA1c53 mmol/mol or greater, taken to reflect chronic hyperglycaemia or suboptimal glycaemic control. Stratified randomisation based on this subgroup will not be employed, as this information will frequently be unavailable at randomisation. 34
Interim analysisAn interim safety analysis will be conducted after 200 patients are enrolled. An independent Data Safety Monitoring Board (DSMB), composed of an experienced clinical researcher and biostatistician without other connection to the LUCID trial, will operate under a charter based on the recommendations of the DAMOCLES Study Group 35
Missing dataNo imputation will be undertaken for missing data. Rates for missing data will be reported in the supplement when more than 10% values are missing.
Ethics approvalThe Royal Adelaide Hospital/Central Adelaide Local Heath Network Human Research Ethics Committee has approved the current protocol version 3 dated 26 May 2017 (HREC/16/RAH/220 and Online Appendix). Under the National Mutual Acceptance (NMA) Scheme, this covers all sites in South Australia, Victoria, New South Wales and Queensland, except for the Alfred Hospital in Victoria. The Alfred Hospital Human Research Ethics Committee has approved a modified protocol allowing only prior written informed consent (Project No. 411/17). The protocol has been approved by the Central Australian Human Research Ethics Committee (Alice Springs Hospital, HREC-16-446) and by the Northern A Health and Disability Ethics Committee in Auckland for sites in New Zealand (ethics reference No. 18/NTA/144).
Consent processAs 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 National Statement 36
In New Zealand, we will use an approach consistent with section 7.4 of the Health and Disability Code, 37
- to consider whether participation is in the best interest of each individual patient; and
- as soon as it is practical and reasonable to do so, to seek the advice of persons interested in the patient’s welfare to establish that study participation is consistent with the patient’s wishes.