Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000409279
Ethics application status
Approved
Date submitted
6/03/2018
Date registered
21/03/2018
Date last updated
28/04/2024
Date data sharing statement initially provided
22/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Is glycine absorbed in critical illness and can it prevent muscle loss?
Scientific title
The effect of enteral glycine on plasma glycine and muscle histopathology, structure and function in the critially ill
Secondary ID [1] 294023 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critical illness 306551 0
Muscle wasting and weakness 306552 0
Enteral glycine absorption 306553 0
Condition category
Condition code
Diet and Nutrition 305649 305649 0 0
Other diet and nutrition disorders
Musculoskeletal 306136 306136 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention 1: single test meal with supplemented glycine
- performed after a 2 hour period without continuous feeding
- group 1: 0.0667 g/kg glycine via enteral route (nasogastric tube) in 100ml standard enteral nutrition infused over 30 minutes
- group 2: 0.1333 g/kg glycine via enteral route (nasogastric tube) in 100ml standard enteral nutrition, infused over 30 minutes
- control: 100ml of standard enteral nutrition (without glycine supplementation), infused over 30 minutes
- blood will be taken at baseline and thirty minutely for four hours

Intervention 2: supplementation of standard enteral nutrition with glycine
- Arm 1: 0.2g/kg/day glycine via enteral route (nasogastric tube) in sterile water, infused in two doses per day, each over 1 hour (in addition to standard care)
- Arm 2: 0.4g/kg/day glycine via enteral route (nasogastric tube) in sterile water, infused in two doses per day, each over 1 hour (in addition to standard care)
- Control: standard care (same volume and type of enteral formula without glycine supplementation) and the same volume of sterile water, infused in two doses, each over 1 hour
-Duration: intervention will continue until the day of extubation or for a maximum of 7 days

Procedures performed:
1. Quadricep muscle ultrasound to assess quadriceps muscle layer thickness (QMLT)
- performed on days 0, 3 and 7 during intensive care unit (ICU) admission, at ICU discharge and 7 days after ICU discharge
- performed by a trained practitioner (Drs Ali Abdelhamid, Bellomo or Deane)

2. Percutaneous muscle biopsy (50-150mg of tissue) from the quadriceps (vastus lateralis muscle)
- performed under local anaesthetic and sterile technique
- performed by a trained practitioner (Drs Ali Abdelhamid, Bellomo or Deane)
- performed twice per patient [prior to the commencement of the intervention (day 0) and on the day of extubation (prior to extubation) or on day 7 of the intervention (whichever occurs earlier)]

Timing:
Intervention 1 will occur once informed consent is obtained and random allocation has occurred. Intervention 2 will begin on the same day, after intervention 1 has been completed. The decision maker may consent only to intervention 1, in which case the patient will be excluded from intervention 2.
Intervention code [1] 300296 0
Treatment: Drugs
Comparator / control treatment
Standard intensive care and standard enteral nutrition (Nutrison Protein Plus: 1.25 kcal/mL, carbohydrate 45%, fat 35%, protein 20%, providing 6.3g of protein)
Control group
Active

Outcomes
Primary outcome [1] 304762 0
Glycine absorption following administration of a test meal, measured as area under the plasma glycine concentration curve, where plasma glycine will be measured using high-performance liquid chromatography
Timepoint [1] 304762 0
Measured at baseline and thirty minutely for four hours post-test meal
Secondary outcome [1] 343024 0
Muscle glycine concentration
Timepoint [1] 343024 0
day 0 (prior to commencement of intervention) and on the day of extubation (prior to extubation) or on day 7 (whichever comes earlier)
Secondary outcome [2] 343025 0
Ultrasound-determined Quadriceps Muscle Layer Thickness (QMLT)
Timepoint [2] 343025 0
days 0, 3 and 7 (or day of extubation) of ICU admission, at ICU discharge and 7 days after ICU discharge
Secondary outcome [3] 343028 0
Functional independence, as assessed by the Functional Independence Measure (FIM) motor sub-score
Timepoint [3] 343028 0
At the conclusion of the intervention period, at ICU discharge and at 7 days after ICU discharge
Secondary outcome [4] 343029 0
Health related quality of life, as assessed with the EuroQol EQ-5D-5L
Timepoint [4] 343029 0
7 days after ICU discharge, 1 month after ICU discharge
Secondary outcome [5] 344341 0
ICU length of stay
Timepoint [5] 344341 0
At ICU discharge
Secondary outcome [6] 344342 0
Hospital mortality
Timepoint [6] 344342 0
1 month after ICU discharge
Secondary outcome [7] 344343 0
Ventilation hours
Timepoint [7] 344343 0
At ICU discharge
Secondary outcome [8] 344344 0
Hospital discharge destination
Timepoint [8] 344344 0
At hospital discharge
Secondary outcome [9] 344345 0
Vastus lateralis myofibre cross-sectional area, as assessed by muscle histology
Timepoint [9] 344345 0
day 0 (prior to commencement of intervention) and on the day of extubation (prior to extubation) or on day 7 (whichever comes earlier)
Secondary outcome [10] 344346 0
Markers of muscle proteolysis (ratio of protein to DNA), as assessed by muscle histology
Timepoint [10] 344346 0
day 0 (prior to commencement of intervention) and on the day of extubation (prior to extubation) or on day 7 (whichever comes earlier)
Secondary outcome [11] 344347 0
Presence or absence of an inflammatory infiltrate in muscle, as assessed by muscle histology
Timepoint [11] 344347 0
day 0 (prior to commencement of intervention) and on the day of extubation (prior to extubation) or on day 7 (whichever comes earlier)
Secondary outcome [12] 344348 0
Muscle necrosis, as assessed by muscle histology
Timepoint [12] 344348 0
day 0 (prior to commencement of intervention) and on the day of extubation (prior to extubation) or on day 7 (whichever comes earlier)
Secondary outcome [13] 344349 0
Muscle mitochondrial content, as assessed by muscle histology
Timepoint [13] 344349 0
day 0 (prior to commencement of intervention) and on the day of extubation (prior to extubation) or on day 7 (whichever comes earlier)
Secondary outcome [14] 344350 0
Handgrip strength, assessed using a calibrated dynamometer
Timepoint [14] 344350 0
At the conclusion of the intervention period, at ICU discharge and at 7 days after ICU discharge (PFIT-s will not be conducted 7 days after ICU discharge)
Secondary outcome [15] 344368 0
Physical function, as assessed by the Physical Function ICU Test-scored (PFIT-s)
Timepoint [15] 344368 0
At the conclusion of the intervention period and at ICU discharge
Secondary outcome [16] 344375 0
ICU mortality
Timepoint [16] 344375 0
One month after ICU discharge
Secondary outcome [17] 344376 0
Health related quality of life, as assessed by the short form-36 (SF-36 survey)
Timepoint [17] 344376 0
7 days after ICU discharge, 1 month after ICU discharge

Eligibility
Key inclusion criteria
a. Aged 18 years or over
b. Receiving invasive mechanical ventilation and expected to remain mechanically ventilated until the day after tomorrow
c. Arterial or central venous line in situ
d. Receiving or suitable to receive EN
e. Expected to be receiving EN in the ICU until at least the day after tomorrow
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a. Death during ICU admission deemed to be inevitable
b. Pregnancy
c. Lower limbs amputated
d. Spinal cord injury
e. Presented with primary neuromuscular pathology
f. Presented with disseminated cancer
g. Bleeding diathesis (corrected INR > 1.5 and/or APTT > 50), or receiving anticoagulants beyond that required for venous thromboembolism prophylaxis or antiplatelet drugs other than aspirin
h. Received > 72 hours of EN or PN during this ICU admission
i. Intolerant of EN (gastric residual volume > 300mL)
j. Already been admitted to ICU for > 96 hours during this hospitalization
k. Previously enrolled in this study
l. Requirement for specific nutritional therapy as determined by the treating doctor or dietitian

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)
The randomisation sequence will be generated, and study arm allocation will be assigned by a designated research coordinator who is not involved in the study. The randomisation sequence will be concealed from the staff enrolling and consenting participants to prevent selection bias. The randomisation sequence will be protected by an electronic password known only to the designated research coordinator. All treating staff, staff involved in study procedures or analysis of muscle biopsies, patients and families will be blinded to treatment allocation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a computerised random number generator (https://www.randomizer.org)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Plasma glycine concentrations will be presented as area under the curve (AUC), calculated using the trapezoidal rule. Individual patient AUC glycine data will be analysed using a linear regression model incorporating the 3 study arms as well as age and illness severity (APACHE II score).
All other secondary outcomes will provide crucial mechanistic understanding. Analysis of covariance (ANCOVA) will be conducted to assess the effect of exogenous glycine on quadriceps myofibre cross-sectional area and on ultrasound-derived muscle layer thickness across 2 time periods (Days 0 and 7), with covariate adjustment including each baseline measure (to control for individual differences) and any baseline variables that were associated with outcome or imbalanced between treatment group. Pearson’s correlation coefficient will be used to explore the relationship between all measurements and plasma glycine levels, as well as between the measurements and patient outcome (survival, length of stay, ventilation hours). A P value of < 0.05 will be considered significant for all tests.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
9/04/2018
Actual
21/05/2018
Date of last participant enrolment
Anticipated
29/07/2022
Actual
27/07/2022
Date of last data collection
Anticipated
30/06/2024
Actual
Sample size
Target
30
Accrual to date
Final
29
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 10001 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 19327 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 298644 0
Hospital
Name [1] 298644 0
Royal Melbourne Hospital
Country [1] 298644 0
Australia
Funding source category [2] 298647 0
University
Name [2] 298647 0
University of Melbourne
Country [2] 298647 0
Australia
Primary sponsor type
Hospital
Name
Royal Melbourne Hospital
Address
300 Grattan St, Parkville VIC 3050
Country
Australia
Secondary sponsor category [1] 298187 0
None
Name [1] 298187 0
Address [1] 298187 0
Country [1] 298187 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299604 0
Human Research Ethics Committee (HREC)
Ethics committee address [1] 299604 0
Ethics committee country [1] 299604 0
Australia
Date submitted for ethics approval [1] 299604 0
28/11/2017
Approval date [1] 299604 0
02/03/2018
Ethics approval number [1] 299604 0
HREC/17/MH/421

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80998 0
Dr Yasmine Ali Abdelhamid
Address 80998 0
The Royal Melbourne Hospital, 300 Grattan St, Parkville VIC 3050
Country 80998 0
Australia
Phone 80998 0
+61 (0) 3 93427000
Fax 80998 0
Email 80998 0
[email protected]
Contact person for public queries
Name 80999 0
Yasmine Ali Abdelhamid
Address 80999 0
The Royal Melbourne Hospital, 300 Grattan St, Parkville VIC 3050
Country 80999 0
Australia
Phone 80999 0
+61 (0) 3 93427000
Fax 80999 0
Email 80999 0
[email protected]
Contact person for scientific queries
Name 81000 0
Yasmine Ali Abdelhamid
Address 81000 0
The Royal Melbourne Hospital, 300 Grattan St, Parkville VIC 3050
Country 81000 0
Australia
Phone 81000 0
+61 (0) 3 93427000
Fax 81000 0
Email 81000 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
No IPD will be shared at this stage.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseProtein supplementation in critical illness: why, when and how?.2023https://dx.doi.org/10.1097/MCO.0000000000000912
N.B. These documents automatically identified may not have been verified by the study sponsor.