Replacing protein via enteral nutrition in a stepwise approach in critically ill patients: the REPLENISH randomized clinical trial protocol

Background Protein intake is recommended in critically ill patients to mitigate the negative effects of critical illness-induced catabolism and muscle wasting. However, the optimal dose of enteral protein remains unknown. We hypothesize that supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition formula to achieve high amount of enteral protein (range 2–2.4 g/kg/day) given from ICU day 5 until ICU discharge or ICU day 90 as compared to no supplemental enteral protein to achieve moderate amount enteral protein (0.8–1.2 g/kg/day) would reduce all-cause 90-day mortality in adult critically ill mechanically ventilated patients. Methods The REPLENISH (Replacing Protein Via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients) trial is an open-label, multicenter randomized clinical trial. Patients will be randomized to the supplemental protein group or the control group. Patients in both groups will receive the primary enteral formula as per the treating team, which includes a maximum protein 1.2 g/kg/day. The supplemental protein group will receive, in addition, supplemental protein at 1.2 g/kg/day starting the fifth ICU day. The control group will receive the primary formula without supplemental protein. The primary outcome is 90-day all-cause mortality. Other outcomes include functional and quality of life assessments at 90 days. The trial will enroll 2502 patients. Discussion The study has been initiated in September 2021. Interim analysis is planned at one third and two thirds of the target sample size. The study is expected to be completed by the end of 2025. Trial registration ClinicalTrials.gov Identifier: NCT04475666. Registered on July 17, 2020. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-023-07507-6.


Replacing Protein via Enteral Nutrition in a Stepwise Approach in Critically Ill
Patients   Table 2: Randomized controlled trials examining the association of protein intake and outcomes in critically ill patients.

Introduction
The acute phase of critical illness is characterized by a severe proinflammatory response, insulin resistance, gastrointestinal injury and a catabolic state with proteolysis primarily occurring in the skeletal muscles. 1,2 The amino acids released into the circulation from muscles are likely used for tissue repair and synthesis of acute phase proteins and other inflammatory mediators. The resulting protein catabolism may be associated with immunosuppression, 3 poor wound healing 4 and ICU-acquired weakness, which are associated with increased mortality and delayed recovery. 5 Higher protein intake has been thought to mitigate the negative protein catabolic state by increasing the availability of exogenous amino acids. It has been demonstrated that protein breakdown is more pronounced in the early phase of illness which then subsides gradually during the recovery phase. 6 The timing of the switch from the acute phase to the recovery phase of critical illness is probably variable, but may occur at the end the week of critical illness. 6,7  These guidelines are also however largely based on weak evidence and mostly from observational studies that suggested that outcomes are improved with higher protein intake.

Observational studies
Observational studies showing better outcome with more protein: Weijs et al. studying 886 patients showed that ICU patients with 1.2-1.5 g/kg/d delivered protein had reduced 28-day mortality. 24 Allingstrup et al showed a stepwise dose-dependent improvement in survival when protein delivery was higher. 25 Nicolo et al found an improvement in survival when patients received >80% of the protein target. 26 Moreover, Compher et al showed that the mortality risk decreased by 6.6% with each 10% increase in protein intake. 27 An observational study demonstrated that the achievement of >90% of target protein intake in early phase of illness was associated with improved ICU outcomes in mechanically ventilated critically ill patients. 28  Observational studies showing better outcome with less protein: There are data suggesting that higher protein intake in early phase of critical illness may actually cause harm, which may be related to inhibition of autophagy and increased ureagenesis. 30,31 Evidence suggests that higher protein delivery in the first week of critical illness might actually be associated with greater muscle wasting 32 and delayed recovery. 33 A pre-planned analysis of the PEPaNIC trial found that higher protein delivery in the first week of critical illness was associated with higher risk of infections and lower risk of earlier live weaning from MV and earlier live ICU discharge. 34 The PROTINVENT (Timing of PROTein INtake and clinical outcomes of adult critically ill patients on prolonged mechanical VENTilation) retrospective study suggested that although an overall low protein intake was associated with the highest mortality risk, high protein intake during the first 3 to 5 ICU days was associated with increased long-term mortality. 35 Furthermore, amino acid infusion may increase amino acid catabolism in the liver, mediated by increased glucagon, without preventing muscle wasting. 36 Observational studies showing no difference in outcome with more or less protein: The Permissive Underfeeding versus Target Enteral Feeding in Adult Critically Ill Patients trial (PermiT) was a randomized controlled trial of restricted caloric intake compared with standard feeding while targeting the full recommended amount of protein in both groups. 37 There was no difference in the primary outcome of mortality in the 2 groups. 37 A subsequent secondary analysis of this trial using propensity score adjustment demonstrated no difference in outcomes among patients who received lower (0.6 ± 0.2 g/kg/day) versus higher protein intake (1.0 ± 0.2 g/kg/day), although the difference in protein between the two groups was moderate. 38

Randomized controlled trials
There is scarce evidence from randomized controlled trials that compared higher versus lower protein doses in ICU patients. A meta-analysis of 5 RCTs showed that there was no difference in mortality with the use of higher vs. lower protein. 39 Doig et al randomized 474 adult ICU patients expected to remain in the ICU for >2 days to receive a daily supplement of up to 100 g of IV amino acids or standard care and found no difference in the primary outcome (mean duration of renal dysfunction) and no difference in mortality (or other secondary or tertiary outcomes), although there was a trend towards increased use of renal replacement therapy in patients receiving amino acid therapy (5.5% versus 10.5%, p=0.062). 40 Ferrie et al included 119 patients requiring parenteral nutrition and randomized them to receive 0.8 or 1.2 g/kg parenteral amino acids as part of their nutritional regimen. 41 They found that the patients receiving higher amino acids had less fatigue, greater forearm muscle thickness by ultrasound and better nitrogen balance at day 3, but there was no difference in mortality or length of stay. 41 Rugeles et al. compared hyperproteic (1.4 g/kg/day) hypocaloric with isocaloric (0.76 g/kg/day protein) enteral feeding found significant improvement in SOFA scores at 48 hours in the hyperproteic group. 42 In another study, the same group of investigators administered 1.7 g/kg/day of protein with normocaloric and hypocaloric regimens and did not find any significant differences between the two groups. 43 11 There was no difference in the duration renal failure between the two groups. But it did increase the GFR and urine output in the intervention group.

Geukers -
The effect of short-term high versus normal protein intake on whole-body protein synthesis and balance in children following cardiac surgery: a randomized double-blind controlled clinical trial/2015. 46 28 children with Congenital heart defect in the preoperative phase of surgical repair Inclusion criteria age 3-24 months with CHD Exclusion trisomy 21 evidence of infection with a fever of more than 35.5 o and positive blood culture mechanically ventilated patients. Patients on inotropes not able to tolerate tube feeding Postoprerative use of medication Patients were randomized to receive protein of 2 g/kg/24 h in the control group and 5 g/kg/24 h in the intervention group. Both the groups received glucose of 6 mg/kg/min Valine kinetics and fractional albumin synthesis rate were measured There was no difference in the fractional albumin synthesis rate between the two groups. There is increased oxidation and BUN in the High protein group compared to normal protein. Patients were randomized to receive either 0.8g/kg or 1.2g/kg of amino acids. Outcomes measured were Handgrip, Chalder fatigue score and USG for muscle thickness.

Ferrie -
Handgrip strength was not different between the two groups except in high amino acid group on the 7 th day. They also had less fatigue and more forearm muscles. However, there was no difference in mortality or LOS.

EGDN group
We estimated nutritional requirements by indirect calorimetry and 24-h urinary urea aiming at covering 100% of requirements from the first full trial day using enteral and parenteral nutrition.

Standard of care group
We aimed at providing 25 kcal/kg/day by enteral nutrition The EGDN group had less negative energy (p < 0.001) and protein (p < 0.001) balances in the ICU as compared to the standard of care group. The PCS score at 6 months did not differ between the two groups (mean difference 0.0, 95% CI −5.9 to 5.8, p = 0.99); neither did mortality, rates of organ failures, serious adverse reactions or infections in the ICU, length of ICU or hospital stay, or days alive without life support at 90 days.

Ongoing studies
A number of trials are ongoing which will likely help further understand the optimal protein requirement in different phases of critical illness, in different subgroups and in nutritionally high-risk patients. 49 Below is summary of the major ongoing randomized controlled trials addressing protein intake;

NEXIS (Nutrition and Exercise in Critical Illness: A Randomized Trial of Combined Cycle
Ergometry and Amino Acids in the ICU) Trial. 50 This trial is funded by National Institute of Health and evaluates the effect of early bedside cycling and intravenous amino acids to a maximum of 2.5 g/kg/day on the physical recovery of the ICU patients. The physical recovery is evaluated by a 6-minute walk test. Other outcomes include muscle mass, muscle strength, functional capacity and quality of life. The sample size is 142 patients.
EFFORT (The Effect of Higher Protein Dosing in Critically Ill Patients) trial. 51 This trial is a large, multicenter, pragmatic, registry-based, randomized clinical trial of 4000 nutritionally high-risk critically ill patients who are randomly allocated to a higher dose of protein (≥2.2 g/kg/day) or usual care (≤1.2 g/kg/day). The primary outcome for this trial is 60-day mortality.
Secondary outcomes include time-to-discharge-alive, nutritional adequacy, hospital mortality, readmission to ICU and hospital, and duration of mechanical ventilation, ICU stay, and hospital stay..

TARGET-Protein
Trial. 52 This is a prospective, blinded, parallel group, randomized feasibility trial which will enroll patients from ICUs participating in TARGET-The Augmented versus Routine approach to Giving Energy Trial. 53 Patients will receive two liquid nutrient formulae in a blinded fashion with different amounts of protein but similar calories.

(Replacing Protein via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients Trial,
ClinicalTrials.gov Identifier: NCT03480555). 54 This randomized trial compared high protein (target 1.8 -2.2 g of protein/kg/day ) to low protein (target 0.8 -1.0 g of protein/kg/day) intake in adult, medical-surgical critically ill patients. Patients received moderate amount of protein and energy till day 5 and then they are randomized on day 5. This feasibility pilot study with sample size of 40 patients was conducted at 3 sites in Saudi Arabia and showed the feasibility of enrolling subjects and achieving separation in protein intake enterally.
However, the difference was in the range of 0.6-0.7 g/kg/day ( Figure 1). Consequently, we revised the way the protein was administered in this trial to achieve larger separation. In addition, we revised the eligibility criteria, based on recent guidelines and ongoing trials. We also, revised the caloric intake during the intervention to be consistent with current guidelines. We also removed some of the functional outcomes which were found difficult to implement.

Rationale for the REPLENISH trial
With the current state of evidence, the optimal amount of protein intake in critically ill patients remains largely unclear and is considered a high priority for research. 2 Interpretation of current studies is complicated by the small sample size, presence of confounders, like increased energy intake in the high protein group in some studies 55

Objectives
In adult critically ill patients, does the addition of supplemental enteral protein (1.2 g/kg/day) added to standard formula to achieve high amount of enteral protein (range 2-2.4 g/kg/day) given from ICU day 5 until ICU discharge up to ICU day 90 as compared to no supplemental enteral protein to achieve moderate amount enteral protein (0.8-1.2 g/kg/day), given in conjunction with similar amounts of stepwise caloric administration in the two groups, reduce all-cause 90-day mortality.

Study design
This is an open label, multicenter, multinational randomized-controlled trial.

Screening:
Subjects will be screened on ICU calendar day 4, up to the morning of ICU calendar day 5.
The ICU admission calendar day is considered ICU day 1.

Study setting
The REPLENISH Trial will be centrally coordinated by Intensive care department, King 3. The patient is on invasive mechanical ventilation and unlikely to be discharged from ICU next day.

Exclusion criteria
1) Lack of commitment to full life support or brain death. Patients with "Do Not Resuscitate" order but with commitment to ongoing life support can be enrolled.
2) Patients on any amount of parenteral nutrition (PN) in ICU at the time of screening, whether PN is used alone or in combination with enteral nutrition. Non-nutritional calories (dextrose, propofol, citrate) not considered as PN.
3) Patients who received an average protein of more than 0.8g/kg/day in the first 4 ICU days.
4) Patients being fed entirely through oral routei.e. those who are eating.
8) Patients with hepatic encephalopathy or Child C liver cirrhosis 9) Inherited defect of amino acid metabolism.
10) Allergies to protein supplement

Recruitment strategy
As per standard practice, the research team will approach the patient if he/she is able to provide informed consent. If not, the surrogate decision maker (SDM) will be approached for consent according to national law. Because both feeding strategies are within the standard of care and because enrollment needs to be done early in order to initiate the feeding strategy, deferred consent can be used if the SDM is not readily available and if legal. If no SDM is present at bedside, the research staff will try to reach him/her by telephone to obtain consent by telephone or will enroll and obtain deferred consent. Consent should be obtained as soon as possible after enteral feeding starting. To facilitate enrollment during weekends, patients can be enrolled anytime in the first 4 calendar days as long as the eligibility criteria are met. The patient will only start the intervention if all inclusion criteria and no exclusion criteria are present on ICU day 4 (or on the morning of day 5).
Once the written informed consent is signed, the patient will be enrolled in the study. In case of deferred consent, written consent should be obtained as soon as possible. Patient can withdraw from the study anytime without any effect on the treatment. The research coordinator will be maintaining a screening log of eligible patients who are not randomized.

Randomization method
The randomization system will be a 24 x 7 web-based system ensuring allocation of trial participants 1:1 to intervention and control using permuted variable block sizes and stratification by suspected or confirmed COVID-19, trial site and by the use or not of renal replacement therapy at the time of randomization (i.e. the patient at the time of randomization requires intermittent dialysis or continuous renal replacement therapy, whether or not he/she is actually connected to the machine at that time)

Coenrollment
Co-enrollment in other RCTs is permitted after approval by both trial steering committees.

Calories
Until ICU calendar day 4, the prescription of energy will be left to the discretion of the treating teams. If desired, energy expenditure can be determined using the predictive equations or indirect calorimetry, based on the practice at individual sites. Between days 5-90, the energy target is 70 to 100% of calculated or measured caloric requirements. Caloric intake will be calculated taking into consideration IV dextrose, citrate and propofol. Caloric intake will include the administered protein in the primary formula.

Pre-randomization (ICU calender day 1-4)
Until ICU day 4, protein requirement will be provided according to the local practice as long as no intravenous amino acids are given and the average protein intake in the first 4 days does not exceed 0.8 g/kg/day.

Post-randomization (ICU day 5-ICU discharge)
On ICU day 4 (or the morning of day 5), patients will be randomized to;

Standard protein group:
The subjects randomized to this group will receive standard prescription without supplemental proteins (maximum1.2 g/kg/day) from the enteral formula. No supplemental protein will be allowed.
For patients with BMI <30, we will use pre-ICU actual BW for or if unavailable, we will use weight on ICU admission. For patients with BMI >=30, we will use adjusted body weight. 58

Replenish protein group:
The subjects randomized to this group will receive the standard amount of proteins

The enteral feeding protocol:
Each ICU will use their own enteral feeding protocol.
The use of prokinetics and type of feeding tube (large-bore nasogastric tube or small-bore nasogastric tube with or without guide wire) is left to the treating team. Patients included in the trial in both arms will receive vitamins as per local practice.

Randomization
Patients will be randomized on ICU day 4 up to the morning of day 5 into one of the two intervention arms. The intervention starts on ICU day 5. A list of random blocks will be computer-generated and based on variable block procedure. Randomization will be stratified by suspected or confirmed COVID-19 and then by site and the use of renal replacement therapy at the time of randomization (intermittent hemodialysis or continuous renal replacement therapy).

Allocation
Patient allocation will follow a computer-based concealed process generated by the bioinformatics and research consulting services at King Abdullah International Research Centre (KAIMRC), Riyadh, Saudi Arabia.

Duration of the intervention
The allocated diet and protein supplement will continue until meeting any of the following criteria: death, ICU discharge or day 90 in ICU, premature stopping of feeding due to brain death or palliative care plan whichever comes first, initiation and tolerating of full oral feeding for more than 24 hour (ie. Treating physicians feel that enteral nutrition is no longer required). In these situations, the allocated protocol will no longer be followed but outcome data will be collected. Upon discharge from the ICU, feeding will be at the discretion of ward clinicians.

Blinding:
This is an open-label study.

Management of potential risks to participants
a. Adminstration of enteral feeding is a standard practice in ICUs and is not considered to pose any special safety issues. The two levels of protein intake under study (high versus low) are within the recommended ranges of administered protein supplementation to ICU patients by most Clinical Practice Guidelines.
b. Monitoring the kidney and liver functions will be done during the study period as per local standards.

I. Primary outcome:
90 day-all-cause mortality

III. Safety outcomes
All patients will have a safety evaluation during the intervention period till day 90 in ICU a. Major safety outcomes will be recorded as one or more of the following 3: 1. New episode of stage 2 or higher AKI by KDIGO criteria after enrollment defined by increase in creatinine 2.0 to 2.9 multiplied by baseline SCr or urine output <0.5 ml/kg/hr for ≥ 12 hours

4.
Glucose and insulin data.

7.
Use of invasive mechanical ventilation (y/n)

(Optional)
At a subset of participating sites upon their willingness the following data will be collected. These will be ordered by request for the study patients and will be optional. In case of labs which have multiple readings in a day, worst values will be recorded.

Frequency and duration of follow-up
Patients will be followed daily until discharge from ICU up to a maximum of 90 days. Hospital discharge date and 90-day outcomes will be documented from the chart or registries or, if need, by telephonic interview from the patient or next of kin if the patient is discharged alive. 90 day follow up will include vital status, date of death if the patient is dead and Functional assessment using SARC-F screen and EuroQoL (EQ)-5D-5L) if the patient is alive at that day.

Study compliance
Several measures will be taken to ensure optimal compliance with the study protocols. Before launching the study, ICU physicians, nurses and dietitians will attend training sessions, which include mock scenarios about protocols implementation with special emphasis on adjustment of feeding to achieve the caloric intake as per protocol. Follow-up training sessions will be conducted periodically to provide feedback. The Study Steering Committee will meet frequently at the initial stages of the study and as needed thereafter to ensure the correct implementation of the protocols. The adherence to the protocol and data quality will be monitored by the coordinating site on regular basis, at least every three months. Feedback will be provided to each site to further improve adherence to nutritional targets

Data management and statistical analysis
Data will be entered via a secure web-based database hosted at KAIMRC, all of which will only be accessible to the study investigators. The database will be password protected and data will be de-identified. Only the data manager, the statistician and the trial SC will have access to all data. Each site will be assigned an identification code. Sites using the paper copy of the data sheets will keep them in a secured cabinet specified specifically for the study. Several procedures to ensure data quality and protocol standardization will also help to minimize bias. These include: 1) a training session will be held for all Research Coordinators from participating centers prior to study commencement to ensure consistency in procedures; 2) A detailed study Instruction Manual will outline each step of the protocol.

Sample size
We anticipate a baseline risk of 90-day mortality 30% and absolute risk reduction of 5% with the protein intervention. The baseline risk was estimated based on a similar cohort from the Significance level. Final analysis of the primary outcome will be based on two-sided alpha (α) of 0.05 and power (1-β) = 0.80.

Sample size calculation:
Based on these assumptions, we need 1251 patients in each group, 2502 in both groups.

Statistical methods
The analyses will be done in the intention-to-treat population defined as all randomised patients for whom there is consent for the use of data. Baseline characteristics will be summarized as numbers and percentages (categorical variables), whereas the continuous variables will be summarized as medians and IQRs or means and SD.
We will compare the proportions for the primary and secondary outcomes between patients randomized to standard versus Replenish group. We will calculate the relative risk reduction, absolute risk reduction and the number needed to treat to prevent one death. We will present the primary result with a 2-sided p-value (5% level of significance) and 95% confidence intervals (CI) and the secondary results with adjusted CIs. Detailed statistical analysis plan will be developed and published before the last patient is enrolled.
Each component of the composite outcomes, e.g. SAEs and use of life support, will be reported in a supplement to the primary publication, but any differences between these single components will not analysed.

Interim analysis
In making decision to recommend termination of the study, the Data Safety Monitoring Board shall be guided by a formal stopping rule based on the primary endpoint of 90-day mortality and on the rates of serious adverse events. The interim test statistics shall be primary outcome analysis. It is planned that two equally spaced formal interim analyses will be performed during the monitoring of the study (when 33% and 67% of the sample size has been achieved). The trial may be stopped for safety (based on mortality) (p<0.01) or effectiveness (<0.001) or if there is other compelling evidence that trial participants are being harmed. There will be no plans to terminate the trial for futility. We will account for alpha spending by O'Brien Fleming method and the final significance level will be 0.048 65 .

Subgroup analyses
The following a priori subgroups will be analysed: Medical vs postoperative vs truama patients.
SOFA day 4 stratified a value of 9 Specific diagnoses: sepsis vs not and head injury vs not.
Patients on vasopressors vs those who are not.

REPLENISH-COVID module (substudy)
In view of the current pandemic, COVID-19 patients will constitute a dominant subgroup. In sites which will allow enrolling these patients who meet the criteria for the study, we will be doing a subgroup analysis that will evaluate the interaction between addition of supplemental Following labs will be ordered on day 1, which will be optional for the sites participating in the substudy;  Lactate (mmol/L)  Ferritin (ng/mL)  IL-6 (pg/mL)  procalcitonin

Safety analyses
The issue of the safety of critically ill patients is a prime concern in this randomized trial.
Several measures are taken to minimize, observe and document any potential safety concerns. First, any unexpected safety concerns will be reported immediately to the Steering Committee. Second, an Independent Data Safety Monitoring Board will be monitoring the safety of the trial (See below). Third, interim analysis will be conducted after recruiting one thirds and two thirds of the total patient number. Since we are not comparing investigational drugs, devices, or procedures and the study is being conducted in ICUs most of the adverse or serious adverse events occur as part of the participants natural disease process. As such, only adverse events that are definitively related to research procedures will be reported as per usual guidelines. As the occurrence of serious adverse events is a trial outcome, these will be continuously reported to the coordinating site and will be part of the 2 formal interim analyses.

Loss-to-follow up
Patients will be followed post ICU discharge (without further intervention) to document hospital vital status. In occasional randomized patients, the study may be withdrawn by the patient, family, clinical doctor or investigator. In such cases, the patient's data will be included in the group to which they were allocated as per the intention to treat principle and the reason of withdrawal will be documented. If the patient or the family make the withdrawal these will be asked for permission to continue trial data registration. This is done to obtain as much data as possible and produce the most valid trial result.

Steering committee
The study Steering Committee members will be responsible for overseeing the conduct of the trial, for upholding or modifying study procedures as needed, addressing challenges with protocol implementation, formulating the analysis plan, reviewing and interpreting the data, and preparing the manuscript. This will be achieved through meetings (in-person or by conference calls) at least quarter yearly. All other committees will report directly to the Steering Committee.

Data monitoring committee
Data and safety monitoring boards (DSMB) should provide an independent opinion on the safety and/or efficacy of a product. According to the FDA guidelines, "An independent DMC is a committee whose members are considered to be independent of those sponsoring, organizing, and conducting the trial" 66 . Independence is critical for the committee and should be incorporated in all aspects of the operations, functions and reporting of the board.
Independence is commonly defined as those who would have no influence in the conduct of the trial or who would not be influenced in any way by the outcome or stopping of a study 67 .
The goal of the DSMB correlates to promote ethical research practices, enhance transparency and completeness, hold companies responsible, and to achieve new levels of corporate excellence. The investigators propose contracting an independent DSMB free of financial COIs related to the topic.

Study centers and participating sites
The Steering Committee will be responsible for overall management of study, providing central guidance and support to participating centers for protocol adherence. For this trial, we will approach sites from different counties. Presently the following sites have already expressed their interest their particapation. Before launching the trial, each clinical site will provide the Coordinating Centre with a copy of their ethics approval letter.

Informed consent
All consecutive eligible patients or their SDM should be approached for participation in the trial. If the patient is unable to provide consent within the time window allowed by the protocol, the research team could also enroll eligible patients and obtain consent subsequently as per local IRB recommendations under a deferred consent model. The objectives of the study and its potential risks and benefits will be explained to the patient or his/her surrogate decision maker by the in-charge research coordinator or a physician who is a part of the research team in a simple and an understandable manner.

Confidentiality
Information about study participants will be kept confidential and will be managed in accordance with the following rules:  All study-related information will be stored securely.
 All study participant information will be accessible only to study personnel.
 All paper and electronic CRFs will be identified only by a coded participant number. Beneprotein, Nestle: one packet (one 7 g serving) contains: 25 Kcal, 6 grams of proteins, 0 grams of CHO and 0 grams of fat. EuroQoL (EQ)-5D-5L

Pre-morbid functional assessment evaluated by EuroQoL (EQ)-5D-5L)
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