Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE - SUGAR STUDY)
Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE - SUGAR STUDY)
The primary aim of the study is to compare the effects of the two blood glucose targets on 90
 day all-cause mortality in Intensive Care patients who are predicted on admission to stay in
 the ICU for at least one full calendar day. The hypothesis is that there is little difference
 in the relative risk of death between patients assigned a glucose range of 4.5 - 6.0 mmol/L,
 and those assigned a glucose range of less than 10.0 mmol/L with insulin being infused if
 blood glucose exceeds 10.0 mmol/L, and adjusted when needed to maintain blood glucose of 8.0
 - 10.0 mmol/L.
The NICE-SUGAR study is a multi-centre, open label, randomised controlled trial of blood
 glucose management with an intensive insulin regimen to maintain blood glucose between 4.5 -
 6.0 mmol/L versus an insulin regimen maintaining blood glucose less than 10.0 mmol/L with
 insulin being infused if blood glucose exceeds 10.0 mmol/L, and adjusted when needed to
 maintain blood glucose between 8.0 - 10.0 mmol/L.

 To ensure patient safety, the target blood glucose concentration must be closely monitored
 and the results known to the clinical staff treating the patients. As patient safety is
 paramount, it is not possible to blind the clinical staff to treatment allocation. In this
 open-label trial, bias will be minimised by ensuring concealment of treatment allocation
 prior to randomisation. The unblinded design risks introducing a systematic difference in
 some other treatment between the two groups, this is unlikely in the ICU setting where many
 other interventions will be administered simultaneously. The primary outcome measure is
 mortality and therefore not subject to ascertainment bias.

 Patient recruitment

 The treatment effect in Van den Berghe's study was limited to patients who stayed in
 Intensive Care for five days or longer, but all ventilated patients were admitted to the
 study at the time of ICU admission. Identifying patients who will stay in the ICU for five
 days or longer is problematic whereas it is relatively easy to identify patients,
 particularly patients admitted for routine post-operative monitoring, who will be discharged
 alive from the ICU after the day following admission. For that reason we propose to consider
 all patients but exclude those expected to be discharged alive or dead before the end of the
 day following admission.

 The attending Intensive Care physician will make this assessment. In addition it is essential
 that patients who will stay in the ICU for greater than the eligible criteria time frame but
 who have a very low risk of death are excluded. For this reason we will exclude patients who
 are able to eat (or who are tube fed due to pre-existing bulbar or laryngeal dysfunction) and
 patients who do not merit an arterial line as part of their normal management.

 Patients who are moribund and at imminent risk of death (brain death or cardiac standstill)
 will be excluded. This exclusion is on the basis that treatment allocation can not alter the
 patient's outcome.

 Sample size and power calculations

 The ANZICS adult patient database contains information on mortality of patients staying more
 than 48 hours in ICUs. In the financial years 2000, 2001 and 2002, of 43,760 patients treated
 in intensive care for greater than 48 hours for whom complete data were available, 9476 died
 prior to hospital discharge. The hospital mortality rate was 22%. As we will exclude less
 sick patients who stay greater than 48 hours and 90-day mortality is the primary outcome
 measure, the study has assumed a 90-day mortality rate of 26% in the control group.

 A total of 6100 patients will be recruited, approximately 5100 of these patients will be
 recruited from the ANZICS CTG centres and approximately 1000 patients will be recruited in
 Canada.

 The George Institute for International Health will take responsibility for the web-based
 randomisation. This will be available 24 hours a day. A minimisation program will stratify
 treatment allocation by type of critical illness (medical vs. surgical) and by country.
 Randomisation will be achieved via a password protected fully secure study website.

 Study treatments

 In the lower range group, a continuous infusion of insulin administered by syringe pump will
 be commenced if the blood glucose concentration exceeds 6.0 mmol/L and the infusion rate will
 be adjusted to maintain the blood glucose concentration between 4.5 - 6.0 mmol/L.

 In the higher range group, a continuous infusion of insulin administered by syringe pump will
 be started if the blood glucose concentration exceeds 10.0 mmol/L and the infusion rate
 adjusted to keep the blood glucose concentration to less than 10.0 mmol/L and titrated when
 needed to maintain the blood glucose concentration between 8 - 10 mmol/L.

 Adjustments to the insulin dose will be made based initially on the measurement of whole
 blood glucose in undiluted arterial blood performed initially at hourly intervals. Sampling
 of arterial blood will require the presence of an intra-arterial catheter in situ for routine
 clinical management at the time of enrolment. The frequency of blood glucose measurement may
 be reduced to two-hourly and then four hourly once the insulin regimen, blood glucose
 concentration and calorie intake are sufficiently stable.

 Clinical staff (both doctors and nurses) in the study ICUs will undergo formal training and
 familiarisation with the insulin regimens by local study coordinators assisted by staff from
 the appropriate national study coordinating centre. Subsequently the administration of
 insulin will be adjusted by the intensive care doctors and nurses using the study algorithm
 accessed via the secure, password protected, encrypted study website. The study algorithm
 recommends insulin infusion rates whilst allowing clinician discretion, ultimate
 responsibility for the safe and effective use of insulin infusions remains with the treating
 clinicians

 Patients being discharged from the ICU will receive conventional blood glucose management
 subsequent to discharge.

 Reducing the Incidence of Hypoglycaemia

 A major focus of the research coordinators and principal investigators will be to educate
 staff on the safe use of both insulin regimens in the study. All episodes of biochemical
 hypoglycaemia will be considered serious adverse events and be reported to the coordinating
 centre within 24 hours. These data will also be reported to the independent data and safety
 monitoring committee. If it apparent that there is an unacceptable incidence of
 hypoglycaemia, either in the study overall or in any particular centre or centres, then the
 study committees will take appropriate steps to reduce the incidence. Depending on the timing
 and cause of the episodes, this may include any or all of altering the blood glucose control
 algorithm, altering the nutrition guidelines, instituting routine IV glucose supplementation,
 increased education at one or more centres or suspending the study at one or more centres.

 Discontinuation of randomised treatment

 Study treatment will continue until the patient is eating and not requiring supplementary
 enteral or parenteral nutrition, or until the earlier of ICU discharge or death or 90 days
 after randomisation. If during the 90-day follow up period the study treatment is ceased and
 the patient subsequently deteriorates so that they again satisfy the study entry criteria,
 the study treatment will be recommenced.

 If at any time during the trial the treating ICU physician deems it in the patient's best
 interest (for example if the patient suffers significant or repeated episodes of
 hypoglycaemia) then, at the discretion of the treating physician, the study treatment can be
 withdrawn. Patients withdrawn from the randomised treatment will be followed up according to
 the study follow up schedule and analysed according to the intention to treat principle
 unless they or their legal surrogate specifically requests such follow up be ceased.

 Ancillary Treatments

 Other aspects of patient management are unaffected by study procedures and the treating
 clinicians will be free to provide whatever care is deemed appropriate and necessary.

 Outcomes

 The principal study outcome will be whether the patient is alive or dead at 90 days. This
 will be determined by the research coordinator at each participating centre. The study
 monitor will verify the source documentation at each monitoring visit. As death is such a
 robust outcome, unintended bias in outcome assessment is unlikely. Intentional bias would
 require collusion between the study monitor and research nurses and is considered most
 unlikely. Given the robustness of the outcome measure, it is unnecessary to establish a
 blinded outcome committee.

 Secondary outcomes, also determined over the same period include:

 -  Death in the ICU, by 28 days and by 90 days

 -  Length of ICU stay

 -  Length of hospital stay

 -  The need for organ support (inotropes, renal replacement therapy and positive pressure
 ventilation)

 -  Incidence of blood stream infections

 -  Incidence and severity of hypoglycaemia

 -  In the subgroup of patients admitted with diagnosis of traumatic brain injury, a follow
 up to determine long term functional status as determined by Extended Glasgow Outcome
 Scores (GOSE) will be collected at Day 90 and Six months.

 Analysis of results

 The George Institute will be conducting the statistical analyses. All analyses will be
 performed on an intention-to-treat basis. Baseline and outcome variables will be compared
 using Students t test, Chi squared and the Mann-Whitney U test as appropriate. Odds ratios
 will be estimated using multiple logistic regression analysis. Survival analysis will be
 performed using Kaplan Meier and Cox's proportional hazards regression analysis.

 An independent statistician will conduct two blinded interim analyses when we have primary
 outcome data for 2000 and 4000 patients and these will be submitted to the DSMC.

 Safety and Data Monitoring Committee

 An independent Safety and Data Monitoring Committee chaired by Professor Sir Richard Peto at
 Oxford University, comprising experts in clinical trials, biostatistics, and intensive care
 has been established. The committee will review unblinded data on patient characteristics,
 treatment compliance and study outcomes at two interim analyses (availability of primary
 outcome for 1500 and 3500 patients), at any other time point the committee may deem necessary
 to protect study participants, and at the final analysis. The committee will be charged with
 informing the study management committee if at any time there emerges:

 1. Evidence beyond reasonable doubt of a difference between randomised groups in all cause
 mortality

 2. Evidence likely to change the practice of many clinicians already familiar with the
 available evidence about the comparative effects of the two blood glucose regimens

 While the definition of beyond reasonable doubt will be left to the judgement of the Safety
 and Data Monitoring Committee, other committees have considered that a difference in total
 mortality between randomised groups of three standard deviations would normally constitute
 such evidence. While a major focus of the Committee's brief will be to monitor total
 mortality, they would also be provided data on serious adverse events and would not be
 precluded from making recommendations based on other outcomes such as cause-specific death or
 serious non-fatal adverse events.

 This study will provide reliable evidence about the comparative effects of different targets
 for blood glucose concentration in patients treated in the Australasian and Canadian
 intensive care setting. This evidence will have direct relevance to decisions about the care
 of critically ill patients admitted to ICUs in Australia and New Zealand, Canada and the rest
 of the world. If the study confirms the treatment effect reported in Van den Berghe's study,
 maintaining normoglycaemia would likely become a treatment standard worldwide.
Inclusion Criteria:

 -  Patients are eligible for INCLUSION in the study if ALL the following criteria are
 met:

 1. At time of the patient's admission to the ICU the treating ICU specialist expects
 the patient will require treatment in the ICU that extends beyond the calendar
 day following the day of admission.

 2. Patient has an arterial line in situ or placement of an arterial line is imminent
 (within the next hour) as part of routine ICU management.

 Exclusion Criteria:

 Patients will be EXCLUDED from the study if ONE or MORE of the following criteria are
 present:

 1. Age < 18 years.

 2. Imminent death (cardiac standstill or brain death anticipated in less than 24 hours)
 and the treating clinicians are not committed to full supportive care. This should be
 confirmed by a documented treatment-limitation order that exceeds a
 "not-for-resuscitation" order.

 3. Patients admitted to the ICU for treatment of diabetic ketoacidosis or hyperosmolar
 state.

 4. Patient is expected to be eating before the end of the day following admission

 5. Patients who have suffered hypoglycaemia without documented full neurological
 recovery.

 6. Patient thought to be at abnormally high risk of suffering hypoglycaemia ( e.g. known
 insulin secreting tumour or history of unexplained or recurrent hypoglycaemia or
 fulminant hepatic failure)

 7. If a patient has previously been enrolled in the NICE-SUGAR Study (patients cannot be
 enrolled in the NICE-SUGAR Study more than once).

 8. If the patient can not provide prior informed consent, there is documented evidence
 that the patient has no legal surrogate decision maker and it appears unlikely that
 the patient will regain consciousness or sufficient ability to provide delayed
 informed consent

 9. The patient has been in the study ICU or another ICU for longer than 24 hours for this
 admission.

 There is no upper age limit for inclusion into the study unless any of the specific
 exclusion criteria are present.

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