The Effect of Higher Protein Dosing in Critically Ill Patients: A Multicenter Randomized Trial (EFFORTcombo)

The primary research question: In critically ill patients with nutrition 'risk factors', what is the effect of providing combined EN/PN to the group prescribed a higher dose (≥2.2 grams/kg/day) of protein/amino acid administration compared to a low group prescribed ≤1.2 gram/kg/day (EN only) on patient's functional recovery as measured by 6-minute walk distance just prior to hospital discharge? The hypothesis: Compared to a control group reflective of usual care prescribing practices and an EN only approach, the administration of a higher dose protein/amino acids using EN and PN to nutritionally high-risk critically ill patients will be associated with improved functional outcome.

Study Overview

• Status: Withdrawn
• Conditions: Critical Illness; Malnutrition; Frailty; Sarcopenia; Nutritional Disorder
• Intervention / Treatment: Drug: OLIMEL 7,6%E / PeriOLIMEL 2,5%E

Detailed Description

Positive, neutral, or negative, the results of the EFFORTcombo study will inform the clinical practice in ICU settings around the world. If positive, because of the pragmatic, multicentre nature of this trial, results will be broadly applicable to all critically ill patients worldwide. If the results are negative, it will be ensured that patients no longer receive high-dose protein/amino acid admixtures or possibly, combined EN/PN.

As it relates to critical care nutrition practice in general, there is a long history of practice-changing initiatives. A process of synthesizing (in the form of evidence-based clinical practice guidelines) and disseminating best practice ideas (in the form of web-based repository of tools and information [see www.criticalcarenutrition.com]) was established.

Over the past several years, this program of research with leaders of the American Society of Parenteral and Enteral Nutrition (ASPEN) and this specific protocol at the annual Clinical Nutrition Week with society leaders, researchers, and the clinical nutrition community at large has been discussed. Partnership with ASPEN will further facilitate both, recruitment initiatives and, importantly, the knowledge translation initiatives. These efforts will increase the likelihood of the uptake of EFFORT results across the world.

This study has both the potential to answer a high-priority clinical question and also transform the new approach in clinical nutrition research. It further represents a unique collaboration between ASPEN, its global partners, and the Clinical Evaluation Research Unit, a methodological support center based in Kingston, Ontario, Canada and managed by Dr. Daren Heyland. If successful, this type of collaboration sets an important precedent for how this community may approach additional research questions related to clinical nutrition. Nested within this larger volunteer-driven registry trial, the aim is to complete a significant sub-study that will establish the role of combined EN/PN in these nutritionally high-risk patients. This protocol pertains to the specifics of this sub-study of combined EN/PN. At the end of the trial, the data from this sub-study will be merged into the results of the overall parent EFFORT Trial (where data points are similar).

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • NRW
    • Aachen, NRW, Germany, 52074
      • University Hospital RWTH Aachen

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:

1. ≥18 years old;
2. Expected to remain mechanically ventilated for an additional 48 hours from screening;

3. And have one or more of the following risk factors that make them at high nutritional risk:

   1. Low (≤25) or High BMI (≥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 >4 days

Exclusion Criteria:

1. >96 continuous hours of mechanical ventilation before enrollment
2. Expected death or withdrawal of life-sustaining treatments within 7 days from screening
3. Pregnancy
4. The responsible clinician feels that the patient either needs low or high protein
5. Absolute contraindication to EN
6. Severe metabolic disorders including electrolyte disorders, uncontrolled hyperglycemia, hyperlipidemia, hypophosphatemia.
7. Severe chronic liver disease (MELD-score >20) or acute fulminant hepatitis.
8. Metabolic disorders involving impaired nitrogen utilization
9. Not ambulating independently prior to illness that lead to ICU admission (use of gait aid permitted)
10. Lower extremity injury or impairments that prevents them walking prior to hospital discharge (e.g. amputation, knee/hip injury)
11. Pre-existing cognitive impairment or language barrier that prohibits outcomes assessment
12. Pre-existing primary severe systemic neuromuscular disease resulting in severe weakness pre-ICU (e.g., Guillain Barre)
13. Intracranial or spinal process affecting motor function
14. Patients in hospital >5 days prior to ICU admission

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; Patients will receive standard care plus OLIMEL 7,6%E or if no central venous access available PeriOLIMEL 2,5%E to reach protein targets: >2.2g/kg/day	Drug: OLIMEL 7,6%E / PeriOLIMEL 2,5%E; OLIMEL 7,6%E will be administered via a central access whereas PeriOLIMEL 2,5%E will be administered peripherally.
No Intervention: Standard Care; Patients will receive standard care (enteral nutrition only) to stay below the protein level: <1.2g/kg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-minute walking distance	measured by performing a 6-minute walking test	at hospital discharge, up to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall strength-upper and lower extremity	MRC sum-score	at hospital discharge, up to 12 weeks
Quadriceps force-lower extremity strength	Hand held dynamometry	ICU and at hospital discharge, up to 12 weeks
Distal strength-hand grip strength	Hand grip dynamometry	ICU and at hospital discharge, up to 12 weeks
Overall Physical Functional status	Walking Impairment Questionnaire	Baseline (questionnaire only) and SPPB & FSS- ICU at ICU and at hospital discharge, up to 12 weeks
Overall Physical Functional status	FSS-ICU	Baseline (questionnaire only) and SPPB & FSS- ICU at ICU and at hospital discharge, up to 12 weeks
Overall Physical Functional status	SPPB	Baseline (questionnaire only) and SPPB & FSS- ICU at ICU and at hospital discharge, up to 12 weeks
Discharge location	Discharge location	at hospital discharge, up to 12 weeks
Body composition	Ultrasound of quadriceps	Enrollment, ICU day 10 and at hospital discharge, up to 12 weeks
Body composition (when clinically available)	Abdominal CT scan at 3rd lumbar vertebra	Only when clinically available, from 2 weeks before enrolment until 2 weeks after enrolment
Health-related quality of life	SF-36	(Telephone) survey at baseline and 6 months
Physical functioning	Katz ADL	(Telephone) survey at hospital discharge, up to 12 weeks and 6 months
Health-related quality of life	EQ-5D-5L	(Telephone) survey at 6 months
Physical functioning	Lawton IADL	(Telephone) survey at 6 months

Collaborators and Investigators

• Sponsor: RWTH Aachen University
• Collaborators: Clinical Evaluation Research Unit at Kingston General Hospital
• Investigators: Principal Investigator: Christian Stoppe, MD, University Hospital RWTH Aachen

Publications and helpful links

General Publications

• Hill A, Heyland DK, Elke G, Schaller SJ, Stocker R, Haberthur C, von Loeffelholz C, Suchner U, Puthucheary ZA, Bear DE, Ney J, Clasen KC, Meybohm P, Lindau S, Laurentius T, Stoppe C. Meeting nutritional targets of critically ill patients by combined enteral and parenteral nutrition: review and rationale for the EFFORTcombo trial. Nutr Res Rev. 2020 Dec;33(2):312-320. doi: 10.1017/S0954422420000165. Epub 2020 Jul 16.

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2020
• Primary Completion (Anticipated): March 1, 2022
• Study Completion (Anticipated): March 1, 2022

Study Registration Dates

• First Submitted: July 3, 2019
• First Submitted That Met QC Criteria: July 8, 2019
• First Posted (Actual): July 9, 2019

Study Record Updates

• Last Update Posted (Actual): October 27, 2022
• Last Update Submitted That Met QC Criteria: October 25, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Disease Attributes; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Muscular Atrophy; Atrophy; Frailty; Sarcopenia; Critical Illness; Malnutrition; Nutrition Disorders
• Other Study ID Numbers: 18-108

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No