E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hyperglycemia in critically ill patients (stress hyperglycemia) |
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E.1.1.1 | Medical condition in easily understood language |
Elevated blood glucose levels during critical illness |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042216 |
E.1.2 | Term | Stress induced hyperglycemia |
E.1.2 | System Organ Class | 100000004861 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The purpose of the study is to investigate whether strictly targeting normal fasting ranges for blood glucose with use of a validated algorithm is clinically superior to tolerating hyperglycemia in adult critically ill patients in the context of withholding parenteral nutrition during the first week in the intensive care unit (ICU).
The primary objective is to study the short-term clinical impact of the studied intervention (short-term morbidity and mortality). |
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E.2.2 | Secondary objectives of the trial |
- To study the long-term impact of the intervention (morbidity and mortality) (partly depending on additional funding)
- To study the economic impact (healthcare resources)
- To study the pathophysiological mechanisms involved (depending on additional funding) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Adult (≥18 years of age) patient admitted to one of the participating intensive care units |
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E.4 | Principal exclusion criteria |
- Patients with a DNR (do not resuscitate) order at the time of ICU admission
- Patients expected to die within 12 hours after ICU admission (= moribund patients)
- Patients able to receive oral feeding (not critically ill)
- Patients without arterial and without central venous line and without imminent need to place it as part of ICU management (not critically ill)
- Patients previously included in the trial (when readmission is within 48 hours post ICU discharge, the trial intervention will be resumed)
- Patients already enrolled in another randomized controlled trial (RCT) powered for clinical endpoints
- Patients transferred from a non-participating ICU with a pre-admission ICU stay >7 days
- Patients planned to receive parenteral nutrition during the first week in ICU
- Patients suffering from diabetic ketoacidotic or hyperosmolar coma on ICU admission
- Patients with inborn metabolic diseases
- Patients with insulinoma
- Patients known to be pregnant or lactating
- No informed consent |
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E.5 End points |
E.5.1 | Primary end point(s) |
The incidence of new infections during ICU stay and the duration of ICU dependency (defined as the crude number of days with need for vital organ support and as the time to live discharge from ICU to account for death as competing risk), with and without censoring at 90 days |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- At the last day in ICU
- At 90 days |
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E.5.2 | Secondary end point(s) |
- Glucose metrics in ICU, with and without censoring at 90 days (mean/median morning blood glucose concentration, mean daily blood glucose concentration, incidence of moderate and severe hypoglycemia during ICU stay, peak blood glucose concentration after hypoglycemic event, duration of hypoglycemia, number of hypoglycemic events per patient, minimum and maximum blood glucose concentration per day, time within blood glucose target range, blood glucose variability, hyperglycemic index)
- Mortality in ICU and in hospital, with and without censoring at 90 days
- Mortality 90 days post randomization
- Hospital length of stay, with and without censoring at 90 days
- Time to (live) discharge from hospital, with and without censoring at 90 days
- Time to final (live) weaning from mechanical respiratory support, with and without censoring at 90 days
- The need for tracheostomy during ICU stay, with and without censoring at 90 days
- Presence of clinical, electrophysiological and morphological signs of respiratory and peripheral muscle weakness during ICU stay in patient subgroups in selected centers, with and without censoring at 90 days
- The presence or absence of new kidney injury during ICU stay, and duration and recovery herefrom, with and without censoring at 90 days
- The need for new initiation of renal replacement therapy in ICU (incidence, duration and recovery hereof), with and without censoring at 90 days
- The need for hemodynamic support during ICU stay, its duration and the time to (live) weaning from hemodynamic support, with and without censoring at 90 days
- The presence or absence of signs of liver dysfunction in ICU, with and without censoring at 90 days
- The duration of antibiotic treatment during ICU stay, with and without censoring at 90 days
- The incidence of bacteremia, and of airway, urinary tract, wound and other infections acquired during ICU stay, with and without censoring at 90 days
- Peak and time profile of C-reactive protein concentrations during ICU stay, with and without censoring at 90 days
- The number of readmissions to the ICU within 48 hours after discharge, with and without censoring at 90 days
- The presence or absence of delirium during ICU stay (in selected centers), with and without censoring at 90 days
- Biochemical, metabolic, immunological, inflammatory and (epi)genetic markers on blood and tissue samples up to 4 years post randomization (depending on additional funding and in selected centers)
- Muscle strength, rehabilitation, recovery of organ function and survival up to 4 years post randomization in selected centers and subgroups of patients (depending on additional funding)
- Long-term functional outcome:
o For all patients: a validated health questionnaire (Short Form 36, SF-36) 2 years after inclusion
o Subgroup of brain-injured patients: additional functional outcome after 6 and 12 months (extended Glasgow outcome scale and/or modified Rankin scale)
- Use of intensive care resources (costs for hospitalization, for honoraria for medical and allied healthcare services, for pharmacy, for blood products, for clinical chemistry, for radiology, for graft products and for other expenses) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Not every endpoint will be studied at each timepoint, as indicated in the list in E.5.2
Studied time points include:
- Last day in ICU and in hospital
- 90 days after randomization
- 6 months after randomization (subgroup of brain-injured patients)
- 12 months after randomization (subgroup of brain-injured patients)
- 2 years after randomization
- 4 years after randomization (depending on additional funding) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Intervention = target blood glucose 80-110 mg/dl; comparator = blood glucose <215 mg/dl |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |