Clinical trial NCT02306746: The Augmented Versus Routine Approach to Giving Energy Trial
Official title: The Augmented Versus Routine Approach to Giving Energy Trial: A Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Critical Illness
Keywords: Enteral nutrition
randomised control trial
Critical care
Outcome
Lead sponsor: Australian and New Zealand Intensive Care Research Centre
Sponsor class: OTHER
First posted: 2014-12-03
Enrollment: 4000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: All cause mortality
timeFrame: Day 90
Secondary outcomes:
measure: Mortality
timeFrame: At hospital discharge an average of 28 days
measure: Mortality
timeFrame: Day 28
measure: Time from randomisation until death
timeFrame: Day 180
measure: Number of days alive and not in ICU
timeFrame: Day 28
measure: Number of days alive and not in hospital
timeFrame: Day 28
measure: Ventilator free days
timeFrame: Day 28
measure: Proportion of patients receiving vasopressor support
timeFrame: Day 28
measure: Vasopressor free days
timeFrame: Day 28
measure: Proportion of patients receiving any renal replacement therapy
timeFrame: Day 28
measure: Renal replacement therapy free days
timeFrame: Day 28
measure: Proportion of patients with positive blood cultures
timeFrame: Day 28
measure: Proportion of patients requiring intravenous antimicrobials
timeFrame: Day 28
measure: Mortality
timeFrame: Day 180
measure: Quality of life assessment
timeFrame: Day 180
measure: Functional outcomes for patients under 65 years in the work force
timeFrame: Day 180
measure: Functional outcomes for patients under 65 years and not in the work force and patients 65 years and over living dependently
timeFrame: Day 180
measure: Functional outcomes for patients 65 years and over living independently
timeFrame: Day 180
measure: Cause-specific mortality
timeFrame: Day 90
Other outcomes:
Locations:
city: Canberra
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Sydney
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Sydney
country: Australia
facility: Royal North Shore Hosptial
state: New South Wales
city: Sydney
country: Australia
facility: Sydney Adventist Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Concord Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Sydney
country: Australia
facility: St George Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Logan Hospital
state: Queensland
city: Toowoomba
country: Australia
facility: Toowoomba Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hosptial
state: South Australia
city: Adelaide
country: Australia
facility: Queen Elizabeth Hospital
state: South Australia
city: Adelaide
country: Australia
facility: Lyell McEwin
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Launceston
country: Australia
facility: Launceston General Hospital
state: Tasmania
city: Bendigo
country: Australia
facility: Bendigo Hospital
state: Victoria
city: Footscray
country: Australia
facility: Footscray Hospital
state: Victoria
city: Frankston
country: Australia
facility: Frankston Hosptial
state: Victoria
city: Geelong
country: Australia
facility: University Hosptial Geelong
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Sunshine Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Melbourne
country: Australia
facility: St Vincent's Hospital Melbourne
state: Victoria
city: Melbourne
country: Australia
facility: Monash Health Dandenong Hospital
state: Victoria
city: Bunbury
country: Australia
facility: Bunbury Hospital
state: Western Australia
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Perth
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Perth
country: Australia
facility: St John of God Hospital Murdoch
state: Western Australia
city: Auckland
country: New Zealand
facility: North Shore Hospital
city: Auckland
country: New Zealand
facility: Auckland City Hospital Cardiovascular Intensive Care Unit
city: Auckland
country: New Zealand
facility: Auckland City Hospital Department of Critical Care Medicine
city: Auckland
country: New Zealand
facility: Middlemore Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Hastings
country: New Zealand
facility: Hawkes Bay Fallen Soldiers Memorial Hospital
city: Lower Hutt
country: New Zealand
facility: Hutt Valley Hospital
city: Nelson
country: New Zealand
facility: Nelson Hospital
city: Rotorua
country: New Zealand
facility: Rotorua Hospital
city: Tauranga
country: New Zealand
facility: Tauranga Hospital
city: Wellington
country: New Zealand
facility: Wellington Regional Hospital
Study officials:
affiliation: University of Adelaide
name: Sandra Peake, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.