Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001008910
Ethics application status
Approved
Date submitted
11/06/2020
Date registered
6/10/2020
Date last updated
12/09/2022
Date data sharing statement initially provided
6/10/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Delivering a higher-protein diet for Trauma Patients (Ignite)
Scientific title
Feasibility of delivering a higher-protein diet to critically-injured patients (Ignite)
Secondary ID [1] 301495 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Ignite
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malnutrition 317826 0
Trauma 317827 0
Critical illness 318598 0
Condition category
Condition code
Diet and Nutrition 315885 315885 0 0
Other diet and nutrition disorders
Injuries and Accidents 316513 316513 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Currently, protein prescriptions for critically ill patients range from 0.5-3.8 g/kg/d. There is an insufficient evidentiary basis to establish which level of protein administration is right for which patient population. We will take usual practices (following the current ICU Nutrition guideline of Gold Coast Health) and create two groups randomising eligible patients to a lower prescription (equal to 1.2 g/kg/d) or to a higher prescribed protein intake (equal to 2.2 g/kg/d) for the duration of their ICU admission. Following randomisation, prescription according to group assignment will be undertaken by the ICU dietitian or ICU medical team with the intervention administered by ICU nurses as part of patient care practices. In both groups, targets will be set using pre-ICU dry actual weight. For patients with BMI greater than 30, ideal body weight based on a BMI of 25 will be used. For the higher protein group, we will use Nutrison Protein Intense (Nutricia; 10g protein/100ml) which provides a higher protein to energy ratio in line with current guidelines. The control group will receive Nutrison Protein Plus Multifibre (Nutricia; 6.3g/100ml). Enteral feeding solutions for both groups will be delivered as a continuous infusion. Once on the ward, protein supplementation will continue by providing high protein oral nutrition supplement (Resource 2.0; Nestlé Health Science) which will provide an additional 19.7g of protein in one 237ml supplement (an additional 40g of protein per day). In the event that flavour fatigue occurs, alternative protein supplementation will be prescribed using higher protein food supplements such as Up n Go Protein Energize (Sanitarium; 16.8g per serve), Quest Protein bars (Quest Nutrition; 21g protein), Chobani Fit high protein yoghurt (Chobani; 15 g). Intervention adherence in ICU is monitored as part of the clinical trial by reporting nutritional adequacy (proportion of prescribed nutrition received). When the patient is discharged to the ward, we will monitor (though chart audit and direct observation) the prescription, delivery and consumption of oral nutrition supplements in the intervention group to assess compliance with the study intervention. We will also collect consumption of ONS in the control group (both product and protein consumed) for the control group to assess the degree of treatment differentiation.
Although this trial is not about caloric dose, we want to encourage participating clinicians to be conservative in meeting energy targets and avoid overfeeding. Caloric goals should be the same in both groups. We will endorse the guidelines for energy targets set forth by American Society of Parenteral and Enteral Nutrition/ Society of Critical Care Medicine, especially as it pertains to the obese patient. For non-obese patients, we suggest that their caloric prescription be around 20-25 kcal/kg/day using a simple weight based formula. If the site chooses to use more sophisticated equations or indirect calorimetry, that is permissible. For obese patients, if indirect calorimetry is used, the goal of the nutritional prescription should be to provide energy not to exceed 65%–70% of measured requirements. If indirect calorimetry is unavailable or not used, consistent with the published guidelines, we suggest using the weight-based equation 11–14 kcal/kg actual body weight per day for patients with BMI in the range of 30–50 and 22–25 kcal/kg ideal body weight per day for patients with BMI >50.
In both groups, targets will be achieved through any combination of enteral nutrition (high protein content in high group if available), protein supplements, and parenteral nutrition or amino acids only (as clinically available). The only difference between the two groups is the protein targets that are set. Similar efforts should be used in both groups to achieve at least 80% of these targets. The remainder of care provided to eligible patients will be at the discretion of ICU providers.
Intervention code [1] 317802 0
Treatment: Other
Comparator / control treatment
Control patients receive 1.2 gram/kg/day of protein in the ICU and ONS on the ward as prescribed at the discretion of the treating team.
Additional protein supplements will not be given in the context of the study but may be prescribed at the discretion of the treating team. This information is included as part of our data collection strategy. The health service has a range of oral nutrition supplements which typically have approximately 19.7 g of protein per 237 mL.
Control group
Active

Outcomes
Primary outcome [1] 324090 0
Study feasibility is the primary (composite) outcome as defined by:
• >75% of patients enrolled in the study under delayed consent, for whom consent to continue is obtained once the patient is discharged from ICU will be determined from study data
• >75% of patients assigned to the intervention group will receive at least 2.2g/kg/day of protein as prescribed which will be determined using data from the study database will be determined from routinely collected hospital data
• >75% of outcome measures are able to be collected from patients who survive to hospital discharge will be determined from study data
• >75% of patients are able to complete outcome measures at 6-months via the phone-based follow up will be determined from study data.
Timepoint [1] 324090 0
Time points for feasiblity assessment are at 1) hospital discharge and 2) 6 month follow up.
Primary outcome [2] 324734 0
Acceptability of the study interventions and outcome measurements will be determined through qualitative interviews (guided by the Theoretical Domains Framework) with patients and/or family members, and health professionals. The interviews will be undertaken to identify factors influencing intervention implementation (including its acceptability to patients and/or family members and staff). Interviews, either group or individual, conducted face-to-face or by telephone, will be audio recorded and transcribed verbatim.
Timepoint [2] 324734 0
Prior to hospital discharge
Secondary outcome [1] 383734 0
60-day mortality, This will be assessed from medical records.
Timepoint [1] 383734 0
Assessed once 60 days post admission.
Secondary outcome [2] 385592 0
Time to discharge alive from hospital will be assessed from medical records.
Timepoint [2] 385592 0
Assessed once post hospital discharge.
Secondary outcome [3] 385593 0
Muscle quantity measured by quadriceps ultrasound.
Timepoint [3] 385593 0
We will collect baseline ultrasound (US) measures of muscle mass and cross-sectional area (within 24 hours of randomisation, 10 days post randomisation – if the patient is still in hospital, and just prior to hospital discharge). In the event that hospital discharge is prior to day 10, the day 10 measure will not be done.
Secondary outcome [4] 385594 0
Nutritional adequacy data will be calculated from data extracted from medical chart and calculated as the proportion of prescribed nutrition received by the patient.
Timepoint [4] 385594 0
Daily throughout ICU admission.
On ward: 3 day calorie count continues weekly until the patient is discharged from hospital or for a maximum of 4 weeks, whichever comes first.
Secondary outcome [5] 385595 0
Duration of mechanical ventilation data extracted from medical chart
Timepoint [5] 385595 0
Daily throughout ICU admission.
Secondary outcome [6] 385596 0
ICU length of stay data extracted from medical chart
Timepoint [6] 385596 0
Assessed once post hospital discharge..
Secondary outcome [7] 385597 0
Readmission to ICU data extracted from medical chart.
Timepoint [7] 385597 0
Assessed once post hospital discharge.
Secondary outcome [8] 385598 0
Readmission to hospital data extracted from medical chart
Timepoint [8] 385598 0
Assessed once 30 days post hospital discharge
Secondary outcome [9] 385599 0
Overall physical strength using Medical Research Council (MRC) sum-score evaluated via standardized “manual muscle testing” with each of 12 muscle groups assessed using a 6-point MRC scale and summed to a total score (range: 0-60). Upper muscle groups are assessed through shoulder abduction, elbow flexion and wrist extension; lower muscle groups are assessed through hip flexion, knee extension and ankle dorsiflexion.
Timepoint [9] 385599 0
Once prior to hospital discharge.
Secondary outcome [10] 385600 0
Quadriceps force, via hand-held dynamometry (HHD) of both lower extremities. Each will be scored by, averaging the results of three trials.
Timepoint [10] 385600 0
Once at ICU discharge and once at hospital discharge.
Secondary outcome [11] 385601 0
Distal strength measured via isometric hand grip strength via a hydraulic hand dynamometer performed bilaterally as per American Society of Hand Therapist guidelines and evaluated using age and gender normal values (adult males 35.1 -55.5kg; adult females 24.5-41.4kg).
Timepoint [11] 385601 0
Once at ICU discharge and once at hospital discharge.
Secondary outcome [12] 385602 0
Short Physical Performance Battery (SPPB) is a composite measure of physical function which measures balance, walking speed, and rising from a chair.
Timepoint [12] 385602 0
Once at ICU discharge and once at hospital discharge.
Secondary outcome [13] 385603 0
Functional Status Score for ICU (FSS-ICU), which is a 5-item (rolling, transfer from spine to sit, sitting at the edge of bed, transfer from sit to stand, and walking). Each task is evaluated using an 8-point ordinal scale ranging from 0 (not able to perform) to 7 (complete independence designed for ICU patients and was designed and is responsive to change during recovery for ICU patients. The total FSS-ICU score ranges from 0 to 35, with higher scores indicating better physical functioning.
Timepoint [13] 385603 0
Once at ICU discharge and once at hospital discharge.
Secondary outcome [14] 385604 0
Health related quality of life (QOL) will be measured using SF-36 version 2 (SF-36 v2) and EQ-5D-5L. The SF-36 is valid and reliable across a variety of patient groups, including ICU survivors. The EQ-5D-5L is included, in addition to SF-36 v2, because it is suitable for patients with inattention and fatigue recommended for use in ICU survivors
Timepoint [14] 385604 0
6 month phone based follow up post hospital discharge.
Secondary outcome [15] 385605 0
Physical functional status will be measured using Katz activities of daily living (ADL) scale.
Timepoint [15] 385605 0
6 month phone based follow up post hospital discharge.
Secondary outcome [16] 385606 0
Anxiety will be assessed using the Hospital Anxiety and Depression Scale as part the recommended Core Outcome Measurement Set for evaluating post-discharge outcomes in acute respiratory failure survivors.
Timepoint [16] 385606 0
6 month phone based follow up post hospital discharge.
Secondary outcome [17] 385607 0
Walking distance achieved during a 6-minute walk test (6MWT) . Implementation of the test will be based upon the 2014 ATS standards, with adaptation, as needed, for the in-patient setting and ICU survivor population. The 6MWT is a reliable, valid, responsive measure of physical function for survivors of acute respiratory failure.
Timepoint [17] 385607 0
Measured at hospital discharge.
Secondary outcome [18] 386789 0
Muscle quality
Timepoint [18] 386789 0
We will collect baseline ultrasound (US) measures of muscle quality (architecture and evidence of myonecrosis) (within 24 hours of randomisation, 10 days post randomisation – if the patient is still in hospital, and just prior to hospital discharge). In the event that hospital discharge is prior to day 10, the day 10 measure will not be done.
Secondary outcome [19] 386790 0
Physical functional status will be measured using Lawton’s Instrumental ADL (IADL) scale.
Timepoint [19] 386790 0
6 month phone based follow up post hospital discharge.
Secondary outcome [20] 386791 0
Post-traumatic stress disorder will be measured using the Impact of Events Scale-Revised as part the recommended Core Outcome Measurement Set for evaluating post-discharge outcomes in acute respiratory failure survivors.
Timepoint [20] 386791 0
6 month phone based follow up post hospital discharge.
Secondary outcome [21] 386792 0
Cognitive function will be measured using Montreal Cognitive Assessment-BLIND screening questionnaire (assessment of attention and concentration, memory, language, conceptual thinking, calculations, and orientation) as part the recommended Core Outcome Measurement Set for evaluating post-discharge outcomes in acute respiratory failure survivors.
Timepoint [21] 386792 0
6 month phone based follow up post hospital discharge.
Secondary outcome [22] 386793 0
Depression will be assessed using the Hospital Anxiety and Depression Scale as part the recommended Core Outcome Measurement Set for evaluating post-discharge outcomes in acute respiratory failure survivors.
Timepoint [22] 386793 0
6 month phone based follow up post hospital discharge.

Eligibility
Key inclusion criteria
Critically injured mechanically ventilated adult trauma patients (18 years of age or older) expected to remain mechanically ventilated for an additional 48 hours from screening and have one or more of the following risk factors that make them at high nutritional risk:
1. Low (at or below 25) or High BMI (at or above 35)
2. Moderate to severe malnutrition (as defined by local assessments). We will document the means by which sites are making this determination and capture the elements of the assessment (history of weight loss, history of reduced oral intake, etc.).
3. Frailty (Clinical Frailty Scale 5 or more from proxy)
4. Sarcopenia- (SARC-F score of 4 or more from proxy)
5. From point of screening, projected duration of mechanical ventilation more than 4 days
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Greater than 96 continuous hours of mechanical ventilation before screening
2. Expected death or withdrawal of life-sustaining treatments within 7 days from screening
3. Pregnant
4. The responsible clinician feels that the patient either needs low or high protein
5. Patient requires parenteral nutrition only and site does not have products to reach the high protein dose group.
6. Not ambulating independently prior to illness that lead to ICU admission (use of gait aid permitted)
7. Lower extremity injury or impairments that prevents them walking prior to hospital discharge (e.g. amputation, knee/hip injury)
8. Pre-existing cognitive impairment or language barrier that prohibits outcomes assessment
9. Pre-existing primary severe systemic neuromuscular disease resulting in severe weakness pre-ICU (e.g., Guillain Barre
10 Intracranial or spinal process affecting motor function
11. Patients in hospital more than 5 days prior to ICU admission
12. Not expected to stay 4 days after enrolment
13 Patients with acute kidney injury as defined by meeting any of the KDIGO criteria and not receiving renal replacement therapy: i) increase in serum creatinine of 0.3 mg/dl (26.52 umol/L) within 48 hours, or ii) increase in serum creatinine to which is 1.5 times baseline (this change was made after enrolment of 36 participants).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features

Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The feasibility outcomes (enrolment and consent rate, and compliance with outcome assessments) will be described by group as rates with 95% confidence intervals. As part of the screening procedures we will collect data on factors influencing recruitment and retention rates.

Intervention compliance (another feasibility outcome) will be determined by calculating the amount of protein consumed by the patient in ICU and again once the patient is on the ward. Prior to analysis, missing values will be described for all variables; all missing data and improbable values checked against source data. Nutritional adequacy at hospital discharge will be compared between the two groups using the rank-based Mann-Whitney U test, as we expect data to not be normally distributed. Secondary continuous outcomes will be analysed as described above. Categorical secondary outcomes will be analysed using Fisher’s exact tests. If >5% of outcome data are missing, multiple imputation will be used for the primary analysis and a ‘missing not at random’ sensitivity analysis will be performed using the tipping point approach of the pattern mixture model with multiple imputation.

Acceptability outcomes will be used to assess intervention acceptability, feasibility and to identify what factors helped or hindered adherence to intervention components. Qualitative data will be analysed using content analysis with an inductive approach.
We will provide secondary outcome data to the EFFORT trial where the data will be analysed following the procedures outlined for the cohort of patients in the EFFORT OUTCOMES substudy (Clinical trials.gov ID #NCT03160547).
Sample size and duration:
Given the main objective of the study related to feasibility, acceptability and intervention compliance we feel a sample size of 40 per group will allow us to assess these endpoints with reasonable precision and is consistent with the sample size of other Phase II studies. Based on the number of critically injured patients admitted to GCUH ICU each year (approx. 180 per year) we anticipate recruitment to take 3 years, with an anticipated consent rate of 50%.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/12/2020
Actual
9/03/2021
Date of last participant enrolment
Anticipated
31/10/2023
Actual
Date of last data collection
Anticipated
30/04/2024
Actual
Sample size
Target
80
Accrual to date
38
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 16873 0
Gold Coast University Hospital - Southport
Recruitment postcode(s) [1] 30523 0
4215 - Southport

Funding & Sponsors
Funding source category [1] 305934 0
Government body
Name [1] 305934 0
Gold Coast Health and Gold Coast Hospital Foundation Research Grant Scheme
Country [1] 305934 0
Australia
Primary sponsor type
Hospital
Name
Gold Coast University Hospital
Address
1 Hospital Blvd Southport Queensland, 4215
Country
Australia
Secondary sponsor category [1] 306389 0
None
Name [1] 306389 0
Address [1] 306389 0
Country [1] 306389 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306181 0
Gold Coast Hospital and Health District Human Research Ethics Committee
Ethics committee address [1] 306181 0
1 Hospital Blvd, Southport, QLD, 4215
Ethics committee country [1] 306181 0
Australia
Date submitted for ethics approval [1] 306181 0
16/10/2019
Approval date [1] 306181 0
18/12/2019
Ethics approval number [1] 306181 0
HREC/2019/QGC/50128

Summary
Brief summary
Aim: To evaluate the feasibility of a randomised controlled trial of critically injured patients with nutrition risk factors where intervention group patients receive a higher dose (equal to 2.2 grams/kg/day) of protein/amino acid administration in ICU and a high protein oral nutrition supplement (ONS) on the ward; control patients receive 1.2 gram/kg/day of protein in the ICU and ONS on the ward as prescribed at the discretion of the treating team.
Secondary aim: To contribute ICU data to the EFFORT trial which, is a large, multicenter, pragmatic, registry-based, patient randomised, clinical trial of 4000 nutritionally high-risk critically ill patients. In this study the administration of lower dose of protein/amino acids (equal to 1.2g/kg/day) will be compared with the administration of a higher dose of protein/amino acids (equal to 2.2g/kg/day) to nutritionally high-risk critically ill patients to determine if higher protein administration is associated with greater muscle mass, improved survival and a quicker rate of recovery.
Hypothesis: We hypothesise that the trial will be feasible as judged by enrolment rates, intervention fidelity and protocol compliance
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 102994 0
Prof Andrea Marshall
Address 102994 0
Gold Coast University Hospital, 1 Hospital Blvd Southport, QLD, 4215
Country 102994 0
Australia
Phone 102994 0
+61 756873235
Fax 102994 0
Email 102994 0
[email protected]
Contact person for public queries
Name 102995 0
Ms Julie Barker
Address 102995 0
Gold Coast University Hospital, 1 Hospital Blvd Southport, QLD, 4215
Country 102995 0
Australia
Phone 102995 0
+61 756873253
Fax 102995 0
Email 102995 0
[email protected]
Contact person for scientific queries
Name 102996 0
Prof Andrea Marshall
Address 102996 0
Gold Coast University Hospital, 1 Hospital Blvd Southport, QLD, 4215
Country 102996 0
Australia
Phone 102996 0
+61 756873235
Fax 102996 0
Email 102996 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data will be reported in a group manner to protect participant confidentiality, which is consistent with our conditions of ethical approval.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
8790Study protocol    379984-(Uploaded-13-08-2020-12-10-58)-Study-related document.docx
8791Informed consent form  [email protected] Multiple consent forms are available on request to... [More Details]
8792Ethical approval    379984-(Uploaded-13-08-2020-12-12-12)-Study-related document.pdf



Results publications and other study-related documents

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