The Augmented Versus Routine Approach to Giving Energy Trial (TARGET)

The Augmented Versus Routine Approach to Giving Energy Trial: A Randomised Controlled Trial

Nutrition therapy is an essential standard of care for all critically ill patients who are mechanically ventilated and remain in the intensive care unit for more than a few days.

The investigators plan to conduct a 4,000 patient, double-blind, randomised controlled trial to determine if augmentation of calorie delivery using energy dense enteral nutrition in mechanically ventilated patients improves 90 day survival when compared to routine care.

Study Overview

• Status: Completed
• Conditions: Critical Illness
• Intervention / Treatment: Dietary supplement: TARGET protocol EN 1.5 kcal/mL; Dietary supplement: TARGET protocol EN 1.0 kcal/mL

Detailed Description

Each year around 130,000 Australians are admitted to ICU at a daily cost of approximately $4000 per patient. Their care consumes close to 3 billion dollars per year. These critically ill patients are the sickest in the hospital. They require substantial resources and multiple interventions. Some die and many of those who survive have delayed and compromised functional recovery which can persist for months or years.

Nutrition therapy is an essential standard of care for all ICU patients who are mechanically ventilated and remain in ICU for more than a few days. Enteral nutrition (via a nasogastric tube) is usually initiated within 24 hours of ICU admission with a formula containing 1 kcal/ml and prescribed at an approximate rate of 1 ml/kg/hour. However, standard enteral nutrition practice typically results in the delivery of only ~60% of the full-recommended calorie requirement.

Although prescribed calories can reliably be delivered using the intravenous route, the enteral route is preferred for a number of reasons and is recommended by all nutrition guidelines as first-line therapy. In particular, enteral nutrition is more physiological, less costly and associated with fewer infective complications. Delivery of nutrient into the gut also has beneficial effects on subsequent gut function and may reduce ongoing sepsis which can be fuelled by the movement of gut flora through a permeable mucosa that has not been exposed to nutrient. Intravenous nutrition is accordingly, generally used only when enteral feeding is impossible, or persistently limited. Although supplementing enteral with intravenous nutrition can increase calorie delivery, this has not been shown to have a therapeutic benefit and may worsen important clinical outcomes. This may be because adverse effects associated with intravenous nutrition counteract the benefits of increased calorie delivery.

Previous trials support the concept that optimising nutrition in the critically ill will improve outcome, however, the evidence is limited, inclusive and generally of low quality. It is extraordinary that there is not better (Level I) evidence to inform nutrition management in critically ill patients given the frequency of the intervention, the biologic rationale, the high mortality following ICU admission, the frequency of muscle wasting and the poor functional outcomes in survivors. This is especially true given the low cost of enteral nutrition (~$23/day).

The investigators recently completed pilot study clearly achieved all the key criteria which, for a pharmaceutical product, would lead to a phase III trial, namely: 1. feasibility; 2. safety; 3. separation; 4. excellent recruitment rate; 5. successful blinding; 6. a signal for benefit.

A definitive study must now be done to establish whether 90-day survival and functional outcomes following critical illness may be improved by increased calorie delivery.

• Study Type: Interventional
• Enrollment (Actual): 4000
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Canberra, Australian Capital Territory, Australia, 2605
      • Canberra Hospital
  • New South Wales
    • Gosford, New South Wales, Australia, 2250
      • Gosford Hospital
    • Sydney, New South Wales, Australia, 2145
      • Westmead Hospital
    • Sydney, New South Wales, Australia, 2170
      • Liverpool Hospital
    • Sydney, New South Wales, Australia, 2010
      • St Vincent's Hospital Sydney
    • Sydney, New South Wales, Australia, 2076
      • Sydney Adventist Hospital
    • Sydney, New South Wales, Australia, 2148
      • Blacktown Hospital
    • Sydney, New South Wales, Australia, 2217
      • St George Hospital
    • Sydney, New South Wales, Australia, 2139
      • Concord Hospital
    • Sydney, New South Wales, Australia
      • Royal Prince Alfred Hospital
    • Sydney, New South Wales, Australia, 2747
      • Nepean Hospital
    • Sydney, New South Wales, Australia, 2065
      • Royal North Shore Hosptial
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexandra Hospital
    • Brisbane, Queensland, Australia, 4029
      • Royal Brisbane and Women'S Hospital
    • Brisbane, Queensland, Australia, 4131
      • Logan Hospital
    • Toowoomba, Queensland, Australia, 4350
      • Toowoomba Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5011
      • Queen Elizabeth Hospital
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hosptial
    • Adelaide, South Australia, Australia, 5112
      • Lyell McEwin
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital
    • Launceston, Tasmania, Australia, 7250
      • Launceston General Hospital
  • Victoria
    • Bendigo, Victoria, Australia, 3550
      • Bendigo Hospital
    • Footscray, Victoria, Australia, 3011
      • Footscray Hospital
    • Frankston, Victoria, Australia, 3199
      • Frankston Hosptial
    • Geelong, Victoria, Australia, 3220
      • University Hosptial Geelong
    • Heidelberg, Victoria, Australia, 3084
      • Austin Hospital
    • Melbourne, Victoria, Australia, 3050
      • Royal Melbourne Hospital
    • Melbourne, Victoria, Australia, 3021
      • Sunshine Hospital
    • Melbourne, Victoria, Australia, 3065
      • St Vincent's Hospital Melbourne
    • Melbourne, Victoria, Australia, 3175
      • Monash Health Dandenong Hospital
  • Western Australia
    • Bunbury, Western Australia, Australia, 6230
      • Bunbury Hospital
    • Perth, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
    • Perth, Western Australia, Australia, 6150
      • Fiona Stanley Hospital
    • Perth, Western Australia, Australia, 6150
      • St John of God Hospital Murdoch
• New Zealand
  • Auckland, New Zealand, 2025
    • Middlemore Hospital
  • Auckland, New Zealand, 0622
    • North Shore Hospital
  • Auckland, New Zealand, 1023
    • Auckland City Hospital Cardiovascular Intensive Care Unit
  • Auckland, New Zealand, 1023
    • Auckland City Hospital Department of Critical Care Medicine
  • Christchurch, New Zealand, 4710
    • Christchurch Hospital
  • Hamilton, New Zealand, 3204
    • Waikato Hospital
  • Hastings, New Zealand, 4156
    • Hawkes Bay Fallen Soldiers Memorial Hospital
  • Lower Hutt, New Zealand, 5010
    • Hutt Valley Hospital
  • Nelson, New Zealand, 7010
    • Nelson Hospital
  • Rotorua, New Zealand, 3010
    • Rotorua Hospital
  • Tauranga, New Zealand, 3112
    • Tauranga Hospital
  • Wellington, New Zealand, 6021
    • Wellington Regional Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Intubated and receiving mechanical ventilation
• About to commence enteral nutrition or enteral nutrition commenced within the previous12 hours
• Expected to be receiving enteral nutrition in ICU until at least the day after tomorrow

Exclusion Criteria:

• Any Enteral Nutrition (EN) or Parenteral Nutrition (PN) received for >12 hours in this ICU admission
• Treating clinician considers the EN goal rate (i.e.1ml/kg of ideal body weight per hour) to be clinically contraindicated e.g. requirement for fluid restriction
• Requirement for specific nutritional therapy as determined by the treating doctor or dietitian i.e. TARGET protocol EN not considered to be in the best interest of the patient
• Death is deemed to be imminent or inevitable during this admission and either the attending physician, patient or substitute decision maker is not committed to active treatment
• The patient has an underlying disease that makes survival to 90 days unlikely
• ≥ 15% burns
• Previously enrolled in this study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TARGET protocol EN 1.5 kcal/mL; Enteral (EN) feed 1.5 kcal/mL. The goal rate for administration of TARGET protocol EN is 1ml/kg/hr. To calculate the goal rate, weight is based on ideal body weight.	Dietary supplement: TARGET protocol EN 1.5 kcal/mL; Enteral feed 1.5 kcal/mL
Active Comparator: TARGET protocol EN 1.0 kcal/mL; Enteral feed 1.0 kcal/mL The goal rate for administration of TARGET protocol EN is 1ml/kg/hr. To calculate the goal rate, weight is based on ideal body weight.	Dietary supplement: TARGET protocol EN 1.0 kcal/mL; Enteral feed 1.0 kcal/mL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All cause mortality	Mortality status	Day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality status	At hospital discharge an average of 28 days
Mortality	Mortality status	Day 28
Time from randomisation until death	Mortality status	Day 180
Number of days alive and not in ICU	Mortality status	Day 28
Number of days alive and not in hospital	Mortality status	Day 28
Ventilator free days	Organ support status	Day 28
Proportion of patients receiving vasopressor support	Organ support proportion	Day 28
Vasopressor free days	Organ support status	Day 28
Proportion of patients receiving any renal replacement therapy	Organ support proportion	Day 28
Renal replacement therapy free days	Organ support status	Day 28
Proportion of patients with positive blood cultures	Blood stream infection proportion	Day 28
Proportion of patients requiring intravenous antimicrobials	Patients requiring intravenous antimicrobials	Day 28
Mortality	Mortality status	Day 180
Quality of life assessment	European Quality of Life 5 Dimensions	Day 180
Functional outcomes for patients under 65 years in the work force	Questions from the Australian Labour Force Survey	Day 180
Functional outcomes for patients under 65 years and not in the work force and patients 65 years and over living dependently	World Health Organization Disability Assessment Schedule 2.0	Day 180
Functional outcomes for patients 65 years and over living independently	Adelaide Activities Profile	Day 180
Cause-specific mortality	Mortality status	Day 90

Collaborators and Investigators

• Sponsor: Australian and New Zealand Intensive Care Research Centre
• Investigators: Study Chair: Sandra Peake, MD, University of Adelaide

Publications and helpful links

General Publications

• Arunachala Murthy T, Chapple LS, Lange K, Marathe CS, Horowitz M, Peake SL, Chapman MJ. Gastrointestinal dysfunction during enteral nutrition delivery in intensive care unit (ICU) patients: Risk factors, natural history, and clinical implications. A post-hoc analysis of The Augmented versus Routine approach to Giving Energy Trial (TARGET). Am J Clin Nutr. 2022 Aug 4;116(2):589-598. doi: 10.1093/ajcn/nqac113.
• TARGET Investigators, for the ANZICS Clinical Trials Group; Chapman M, Peake SL, Bellomo R, Davies A, Deane A, Horowitz M, Hurford S, Lange K, Little L, Mackle D, O'Connor S, Presneill J, Ridley E, Williams P, Young P. Energy-Dense versus Routine Enteral Nutrition in the Critically Ill. N Engl J Med. 2018 Nov 8;379(19):1823-1834. doi: 10.1056/NEJMoa1811687. Epub 2018 Oct 22.

Helpful Links

• Statistical analysis plan publication, March 2018
• Protocol publication, March 2018

Study record dates

Study Major Dates

• Study Start (Actual): June 16, 2016
• Primary Completion (Actual): July 10, 2018
• Study Completion (Actual): August 1, 2018

Study Registration Dates

• First Submitted: November 11, 2014
• First Submitted That Met QC Criteria: December 1, 2014
• First Posted (Estimate): December 3, 2014

Study Record Updates

• Last Update Posted (Actual): September 13, 2018
• Last Update Submitted That Met QC Criteria: September 12, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Critical care; Outcome; Enteral nutrition; randomised control trial
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness
• Other Study ID Numbers: ANZIC-RC/MC001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED