Tight Versus Liberal Blood Glucose Control in Adult Critically Ill Patients (TGC-fast)

Impact of Tight Blood Glucose Control Within Normal Fasting Ranges With Insulin Titration Prescribed by the Leuven Algorithm in Adult Critically Ill Patients

Critically ill patients usually develop hyperglycemia, which is associated with an increased risk of morbidity and mortality. Controversy exists on whether targeting normal blood glucose concentrations with insulin therapy, referred to as tight blood glucose control (TGC) improves outcome of these patients, as compared to tolerating hyperglycemia. It remains unknown whether TGC, when applied with optimal tools to avoid hypoglycemia, is beneficial in a context of withholding early parenteral nutrition. The TGC-fast study hypothesizes that TGC is beneficial in adult critically ill patients not receiving early parenteral nutrition, as compared to tolerating hyperglycemia.

Study Overview

• Status: Active, not recruiting
• Conditions: Hyperglycemia; Critical Illness
• Intervention / Treatment: Drug: Insulin

• Study Type: Interventional
• Enrollment (Actual): 9230
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • Department of Intensive Care Medicine, University Hospital Ghent
  • Hasselt, Belgium, 3500
    • Department of Intensive Care Medicine, Jessa Hospital Hasselt
  • Leuven, Belgium, 3000
    • Department of Intensive Care Medicine, University Hospitals Leuven
  • Leuven, Belgium, 3000
    • Medical Intensive Care Unit, University Hospitals Leuven

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

- Adult patient (18 years or older) admitted to a participating intensive care unit (ICU)

Exclusion Criteria:

• Patients with a do not resuscitate (DNR) 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 included in an IMP-RCT of which the PI indicates that co-inclusion is prohibited
• 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
• Informed consent refusal

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tight glucose control; Target normal fasting blood glucose concentrations (80-110 mg/dl) with insulin therapy, administered through continuous intravenous infusion.	Drug: Insulin; When blood glucose exceeds the preset target, insulin will be administered through continuous intravenous infusion. Insulin will be titrated according to frequent measurement of blood glucose and with use of the LOGIC-insulin algorithm in the experimental group. The intervention will be stopped upon ICU discharge, or until the patient is able to resume oral feeding, or until the patient no longer has a central venous catheter, whatever comes first.
Active Comparator: Liberal glucose control; Tolerate hyperglycemia up to 215 mg/dl. In patients requiring insulin therapy, insulin will be titrated to target blood glucose concentrations between 180 and 215 mg/dl.	Drug: Insulin; When blood glucose exceeds the preset target, insulin will be administered through continuous intravenous infusion. Insulin will be titrated according to frequent measurement of blood glucose and with use of the LOGIC-insulin algorithm in the experimental group. The intervention will be stopped upon ICU discharge, or until the patient is able to resume oral feeding, or until the patient no longer has a central venous catheter, whatever comes first.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of ICU dependency	crude number of days with need for vital organ support and time to live discharge from ICU	up to 1 year after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICU Mortality		up to 1 year after randomization (with and without censoring at 90 days post randomization)
Hospital Mortality		up to 1 year after randomization (with and without censoring at 90 days post randomization)
90-day mortality		up to 90 days post randomization
Blood glucose concentrations in ICU		up to 1 year post randomization, with and without censoring at 90 days post randomization
Duration of ICU dependency	crude number of days with need for vital organ support and time to live discharge from ICU	up to 90 days post randomization
Length of stay in hospital		up to 1 year post randomization, with and without censoring at 90 days post randomization
Time to (live) discharge from hospital		up to 1 year post randomization, with and without censoring at 90 days post randomization
Incidence of new infections in ICU		up to 1 year post randomization, with and without censoring at 90 days post randomization
Type of new infections in ICU		up to 1 year post randomization, with and without censoring at 90 days post randomization
Duration of antibiotic treatment in ICU		up to 1 year post randomization, with and without censoring at 90 days post randomization
Time course of daily C-reactive protein in ICU		up to 1 year post randomization, with and without censoring at 90 days post randomization
Time to final (live) weaning from mechanical respiratory support in ICU		up to 1 year post randomization, with and without censoring at 90 days post randomization
Number of participants with need for a tracheostomy during ICU stay		up to 1 year post randomization, with and without censoring at 90 days post randomization
Presence of clinical, electrophysiological and morphological signs of respiratory and peripheral muscle weakness in ICU		up to 1 year post randomization, with and without censoring at 90 days post randomization (in selected centers)
Incidence of acute kidney injury in ICU		up to 1 year post randomization, with and without censoring at 90 days post randomization
Duration of acute kidney injury		up to 1 year post randomization, with and without censoring at 90 days post randomization
Rate of recovery from acute kidney injury		up to 1 year post randomization, with and without censoring at 90 days post randomization
Number of participants with need for new renal replacement therapy in ICU		up to 1 year post randomization, with and without censoring at 90 days post randomization
Rate of recovery from new renal replacement therapy		up to 1 year post randomization, with and without censoring at 90 days post randomization
Number of participants with need for hemodynamic support in ICU	Hemodynamic support is defined as the need for either pharmacological (inotropes/vasopressors) and/or mechanical hemodynamic support.	up to 1 year post randomization, with and without censoring at 90 days post randomization
Duration of hemodynamic support in ICU		up to 1 year post randomization, with and without censoring at 90 days post randomization
Time to (live) weaning from hemodynamic support		up to 1 year post randomization, with and without censoring at 90 days post randomization
Time course of markers of liver dysfunction in ICU	including transaminases, gamma-glutamyltransferase, alkaline phosphatase and bilirubin	up to 1 year post randomization, with and without censoring at 90 days post randomization
Number of readmissions to the ICU within 48 hours after discharge		up to 1 year post randomization, with and without censoring at 90 days post randomization
Incidence of delirium in ICU (in selected centers)		up to 1 year post randomization, with and without censoring at 90 days post randomization
Rehabilitation/functional outcome	including the score obtained from the 36-item short form health survey (SF-36). The score ranges from 0 to 100, with 100 being the best possible outcome.	up to 2 years post randomization
Rehabilitation/functional outcome in patients with brain injury	including the score obtained on the modified Rankin scale. The score ranges from 0 to 6, with 0 being the best possible outcome.	up to 1 year post randomization
Rehabilitation/functional outcome in patients with brain injury	including the score obtained on the extended Glasgow outcome scale. The score ranges from 1 to 8, with 8 being the best possible outcome.	up to 1 year post randomization
Blood lipid concentrations in ICU		up to 4 years post randomization (in selected centers)
Muscle strength	including handgrip strength as % of the predicted value	up to 4 years post randomization (in selected centers)
Rehabilitation/Functional outcome	including the 6-minutes walking distance in meter	up to 4 years post randomization (in selected centers)
Rehabilitation/Functional outcome	including the score obtained from the SF-36 health survey. The score ranges from 0 to 100, with 100 being the best possible outcome.	up to 4 years post randomization (in selected centers)
Rate of recovery of organ function		up to 4 years post randomization (in selected centers)
Survival		up to 4 years post randomization (in selected centers)
Use of intensive care resources during index hospitalization		up to 1 year post randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biochemical markers on blood samples	including amino acid levels, blood lipid levels, cytokines, hypothalamic-pituitary hormones, glucagon, C-peptide, (epi)genetic markers	up to 4 years post randomization
Rate of patients with muscle degeneration during ICU stay	assessed by microscopy	up to 30 days post randomization (in selected centers)
Biochemical markers in muscle tissue during ICU stay	including tissular glucose and metabolites, lipid metabolites, myofibrillary proteins, mitochondrial complex activity, autophagy markers, proteasome activity, (epi)genetic markers	up to 30 days post randomization (in selected centers)
Rate of patients with pathological cellular alterations in fat tissue during ICU stay	assessed by microscopy	up to 30 days post randomization (in selected centers)
Biochemical markers in fat tissue during ICU stay	including tissular glucose and metabolites, lipid metabolites, mitochondrial complex activity, autophagy markers, (epi)genetic markers	up to 30 days post randomization (in selected centers)
Rate of patients with muscle degeneration	assessed by microscopy	up to 4 years post randomization (in selected centers)
Biochemical markers in muscle tissue	including tissular glucose and metabolites, lipid metabolites, myofibrillary proteins, mitochondrial complex activity, autophagy markers, proteasome activity, (epi)genetic markers	up to 4 years post randomization (in selected centers)
Rate of patients with pathological cellular alterations in fat tissue	assessed by microscopy	up to 4 years post randomization (in selected centers)
Biochemical markers in fat tissue	including tissular glucose and metabolites, lipid metabolites, mitochondrial complex activity, autophagy markers, (epi)genetic markers	up to 4 years post randomization (in selected centers)

Collaborators and Investigators

• Sponsor: KU Leuven
• Collaborators: Universitaire Ziekenhuizen KU Leuven; Research Foundation Flanders
• Investigators: Study Director: Greet Van den Berghe, MD, PhD, KU Leuven; Principal Investigator: Jan Gunst, MD, PhD, KU Leuven

Publications and helpful links

General Publications

• Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011 Aug 11;365(6):506-17. doi: 10.1056/NEJMoa1102662. Epub 2011 Jun 29.
• van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001 Nov 8;345(19):1359-67. doi: 10.1056/NEJMoa011300.
• Vlasselaers D, Milants I, Desmet L, Wouters PJ, Vanhorebeek I, van den Heuvel I, Mesotten D, Casaer MP, Meyfroidt G, Ingels C, Muller J, Van Cromphaut S, Schetz M, Van den Berghe G. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet. 2009 Feb 14;373(9663):547-56. doi: 10.1016/S0140-6736(09)60044-1. Epub 2009 Jan 26.
• Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006 Feb 2;354(5):449-61. doi: 10.1056/NEJMoa052521.
• NICE-SUGAR Study Investigators; Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hebert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283-97. doi: 10.1056/NEJMoa0810625. Epub 2009 Mar 24.
• Fivez T, Kerklaan D, Mesotten D, Verbruggen S, Wouters PJ, Vanhorebeek I, Debaveye Y, Vlasselaers D, Desmet L, Casaer MP, Garcia Guerra G, Hanot J, Joffe A, Tibboel D, Joosten K, Van den Berghe G. Early versus Late Parenteral Nutrition in Critically Ill Children. N Engl J Med. 2016 Mar 24;374(12):1111-22. doi: 10.1056/NEJMoa1514762. Epub 2016 Mar 15.
• Gunst J, Mebis L, Wouters PJ, Hermans G, Dubois J, Wilmer A, Hoste E, Benoit D, Van den Berghe G. Impact of tight blood glucose control within normal fasting ranges with insulin titration prescribed by the Leuven algorithm in adult critically ill patients: the TGC-fast randomized controlled trial. Trials. 2022 Sep 19;23(1):788. doi: 10.1186/s13063-022-06709-8.

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2018
• Primary Completion (Actual): November 30, 2022
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: August 29, 2018
• First Submitted That Met QC Criteria: September 7, 2018
• First Posted (Actual): September 11, 2018

Study Record Updates

• Last Update Posted (Actual): June 5, 2023
• Last Update Submitted That Met QC Criteria: June 2, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Disease Attributes; Hyperglycemia; Critical Illness; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin
• Other Study ID Numbers: S61145; 2018-000756-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data sharing will be considered only on a collaborative basis with PIs, after evaluation of the proposed study protocol and statistical analysis plan.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No