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Nutrition and Exercise in Critical Illness (NEXIS)

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ClinicalTrials.gov Identifier: NCT03021902
Recruitment Status : Recruiting
First Posted : January 16, 2017
Last Update Posted : February 11, 2019
Sponsor:
Collaborators:
University of Vermont
Johns Hopkins University
Information provided by (Responsible Party):
Daren K. Heyland, Clinical Evaluation Research Unit at Kingston General Hospital

Tracking Information
First Submitted Date  ICMJE December 21, 2016
First Posted Date  ICMJE January 16, 2017
Last Update Posted Date February 11, 2019
Actual Study Start Date  ICMJE September 28, 2017
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 12, 2017)
Physical functioning [ Time Frame: Hospital discharge (up to 26 weeks after randomization) ]
6-minute walk distance
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 7, 2019)
  • Overall strength-upper extremity [ Time Frame: Hospital discharge (up to 26 weeks after randomization) ]
    MRC Sum-score
  • Overall strength-lower extremity [ Time Frame: Hospital discharge (up to 26 weeks after randomization) ]
    MRC Sum-score
  • Quadriceps force-lower extremity strength [ Time Frame: Hospital discharge (up to 26 weeks after randomization) ]
    Hand held dynamometry
  • Distal strength-hand grip strength [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Hand held dynamometry
  • Overall Physical Functional status - Short Physical Performance Battery [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Short Physical Performance Battery
  • Overall Physical Functional status - Functional Status Score - ICU [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Functional Status Score - ICU
  • Mortality [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • Length of ventilation [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • ICU stay [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • Hospital stay [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • ICU readmission [ Time Frame: Hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • Re-intubation [ Time Frame: Hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • Hospital-acquired infections [ Time Frame: Hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • Discharge location (e.g. home vs. rehab) [ Time Frame: Hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • Body composition - Ultrasound [ Time Frame: Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization) ]
    Ultrasound of quadriceps
  • Body composition - CT - Chest when clinically available [ Time Frame: Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization) ]
    Chest CT
  • Body composition - CT - Abdominal Scan when clinically available [ Time Frame: Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization) ]
    Abdominal CT scan at 3rd lumbar vertebra
  • Health-related quality of life - SF-36 [ Time Frame: Telephone survey at 6 months ]
    36-Item Short Form Health Survey (SF-36)
  • Health-related quality of life - EQ-5D-5L [ Time Frame: Telephone survey at 6 months ]
    EuroQol Group standardized measure of health status (EQ-5D-5L)
  • Physical functioning - Katz ADL [ Time Frame: Hospital discharge (proxy) and telephone survey at 6 months ]
    Katz Index of Independence in Activities of Daily Living (Katz ADL)
  • Physical functioning - Lawton IADL [ Time Frame: Telephone survey at 6 months ]
    Lawton Instrument Activities of Daily Living Scale (Lawton IADL)
  • Physical functioning/participation - return to work [ Time Frame: Telephone survey at 6 months ]
    Return to baseline work/activity
  • Physical functioning/participation - living location [ Time Frame: Telephone survey at 6 months ]
    Living location
  • Mental and Cognitive Functioning - MoCA-BLIND [ Time Frame: Telephone survey at 6 months ]
    MoCA-BLIND
  • Mental and Cognitive Functioning - HADS [ Time Frame: Telephone survey at 6 months ]
    Hospital Anxiety and Depression Scale
  • Mental and Cognitive Functioning - IES-R [ Time Frame: Telephone survey at 6 months ]
    Impact of Events Scale
  • Health Care Resource Utilization [ Time Frame: Telephone survey at 6 months ]
    Admission to ICU, hospital, rehabilitation & nursing facility
  • Body composition - DEXA Scan [ Time Frame: Hospital Discharge ]
    Whole Body DEXA Scan
  • Body Composition - Heavy water [ Time Frame: Enrolllment, During ICU stay ]
    Fat-free and fat mass can be measured with D2O in body fluids using gas chromatography-tandem mass spectrometry.
  • Plasma and muscle protein synthesis - Heavy water [ Time Frame: Enrolllment, During ICU stay ]
    Muscle protein synthesis will be analyzed with chromatography and mass spectrometry techniques.
  • NEXIS FLAME - Circulating inflammatory mediators [ Time Frame: Enrollment, Days 3,5,and 8 ]
    Blood IL-17, IL-23, IL-6, TNFα, CXCK1, CXCL5, CXCL8, CCL2, SP-D, KL-6, vWF, and leukocyte counts with differential
  • NEXIS FLAME - Lung Inflammation [ Time Frame: Enrollment, Day 5 ]
    Bronchoalveolar lavage neutrophil counts, IL-17A, CXCL5, and protein
  • NEXIS FLAME - Muscle area [ Time Frame: Enrollment, Day 5 ]
    Single muscle fiber cross-sectional area (CSA), UPS expression, MuRF1 expression, myosin protein content (all from vastus lateralis sampling)
  • NEXIS FLAME - Muscle inflammation [ Time Frame: Enrollment, Day 5 ]
    Muscle macrophages (CD45+, CD206+)
Original Secondary Outcome Measures  ICMJE
 (submitted: January 12, 2017)
  • Overall strength-upper extremity [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    MRC Sum-score
  • Overall strength-lower extremity [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    MRC Sum-score
  • Quadriceps force-lower extremity strength [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Hand held dynamometry
  • Distal strength-hand grip strength [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Hand held dynamometry
  • Physical Functional status - Short Physical Performance Battery [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Short Physical Performance Battery
  • Physical Functional status - Family Satisfaction Survey - ICU [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Family Satisfaction Survey-ICU
  • Mortality [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • Length of ventilation [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • ICU stay [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • Hospital stay [ Time Frame: ICU and hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • ICU readmission [ Time Frame: Hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • Re-intubation [ Time Frame: Hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • Hospital-acquired infections [ Time Frame: Hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • Discharge location (e.g. home vs. rehab) [ Time Frame: Hospital discharge (up to 26 weeks after randomization) ]
    Chart review
  • Body composition - Ultrasound [ Time Frame: Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization) ]
    Ultrasound of quadriceps
  • Body composition - CT [ Time Frame: Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization) ]
    Abdominal CT scan at 3rd lumbar vertebra
  • Body composition (subset of 50 patients) [ Time Frame: Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization) ]
    Deuterium studies
  • Protein synthesis/breakdown (50 patient subset) [ Time Frame: Enrollment and ICU discharge (up to 26 weeks after randomization) ]
    Stable isotope tracer
  • Health-related quality of life - SF-36 [ Time Frame: Telephone survey at 6 months ]
    36-Item Short Form Health Survey (SF-36)
  • Health-related quality of life - EQ-5D-5L [ Time Frame: Telephone survey at 6 months ]
    EuroQol Group standardized measure of health status (EQ-5D-5L)
  • Physical functioning - Katz ADL [ Time Frame: Telephone survey at 6 months ]
    Katz Index of Independence in Activities of Daily Living (Katz ADL)
  • Physical functioning - Lawton IADL [ Time Frame: Telephone survey at 6 months ]
    Lawton Instrument Activities of Daily Living Scale (Lawton IADL)
  • Physical functioning/participation - return to work [ Time Frame: Telephone survey at 6 months ]
    Return to baseline work/activity
  • Physical functioning/participation - living location [ Time Frame: Telephone survey at 6 months ]
    Living location
  • Health Care Resource Utilization [ Time Frame: Telephone survey at 6 months ]
    Admission to ICU, hospital, rehabilitation & nursing facility
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nutrition and Exercise in Critical Illness
Official Title  ICMJE Nutrition and Exercise in Critical Illness (The NEXIS Trial): A Randomized Trial of Combined Cycle Ergometry and Amino Acids in the ICU
Brief Summary This study proposes a novel early intervention combining Intravenous (IV) amino acids plus in-bed cycle ergometry exercise to improve physical outcomes in critically ill patients. The investigators hypothesize that this innovative approach will improve short-term physical functioning outcomes (primary outcome), as well as amino acid metabolism, body composition, and patient-reported outcomes at 6-month follow-up.
Detailed Description

The evaluation of a combination of exercise and protein supplementation in intensive care unit (ICU) patients is novel and potentially very important. For instance, outside of the ICU, in other clinical conditions, the combination of protein supplementation and exercise improves protein synthesis, muscle mass, and muscle strength compared to protein or exercise alone.[63-70] Hence, an opportunity exists to improve ICU patients' physical outcomes via evaluating the combination of optimized protein intake and early exercise in the ICU setting.

The proposed intervention and hypothesis: The investigators propose a multi-centered Phase II RCT, with blinded outcomes assessment, of a combination of intravenous (IV) amino acid supplementation and early in-bed cycle ergometry exercise versus usual care in ICU patients requiring mechanical ventilation. The investigators hypothesize that this novel combined intervention will: (1) improve physical functioning at hospital discharge; (2) reduce muscle wasting with improved amino acid metabolism and protein synthesis in-hospital; and (3) improve health-related quality of life, physical functioning, and healthcare resource utilization at 6 months after enrollment. Preliminary data show feasibility and safety of IV amino acids and the proposed exercise intervention. The investigators have chosen a primary outcome that correlates well with long-term outcomes including mortality, hospitalization, and quality of life. [54] If this Phase II trial is positive, investigators will seek funding for a Phase III RCT to demonstrate sustained improvements with a longer-term patient-centered primary outcome and to examine the feasibility, and facilitators/barriers of delivery of this intervention by ICU nurses, physical therapists, and others. If proven effective, this combined intervention has potential to revolutionize care of ICU patients and have a major public health impact on the growing number of ICU survivors.

Objectives: To demonstrate that the innovative combination of amino acid supplementation plus early in-bed cycle ergometry exercise improves physical outcomes of ICU patients.

Specific Aims of Full Phase II RCT:

  1. Short-term performance-based physical function outcomes. To determine if a combined IV amino acid supplementation and in-bed cycle ergometry exercise intervention, compared to usual care, improves in hospital muscle strength and performance-based physical functioning outcomes in critically ill patients, using a primary endpoint of six-minute walk distance (6MWD) at hospital discharge.
  2. Body composition. To determine if the combined intervention, compared to usual care, improves amino acid utilization and decreases muscle wasting in ICU patients (secondary endpoints).
  3. Patient-reported outcomes and health care utilization at 6 months. To determine if the combined intervention, compared to usual care, improves physical functioning, health-related quality of life, and healthcare utilization at 6 months after study enrollment (secondary endpoints).

NEXIS Flame mechanisitic Ancillary sub study:

In the proposed sub-study, the addition of bronchoaveloar lavages, blood sampling and muscle sampling measures during the participant's ICU stay will provide the ability to examine the effects of the NEXIS intervention on inflammation as a possible mechanism for improved muscle weakness.

Specific Aims of the NEXIS FLAME mechanistic ancillary study:

  1. To determine if the NEXIS intervention attenuates the release of IL-17 and related cytokines to reduce systemic inflammation in humans.
  2. To determine if the NEXIS intervention reduces lung injury and neutrophilic lung inflammation in humans.
  3. To determine if the NEXIS intervention attenuates skeletal muscle fiber atrophy via down regulation of muscle proteolytic pathways.
  4. To determine if the NEXIS intervention, and exercise specifically, reduces the content of inflammatory cells in skeletal muscle.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Acute Respiratory Failure
Intervention  ICMJE
  • Drug: IV amino acids
    IV amino acids delivered by continuous infusion, such that the total enteral and IV protein will be between 2.0-2.5 g/kg/day as a combination of amino acid infusion plus standard feeding.
    Other Name: Clinisol 15% (Baxter) - sulfite-free (Amino Acid) Injection
  • Device: In-bed cycle ergometry exercise

    In-bed cycle ergometry exercise delivered in 45-minute sessions once-daily 5 days per week according to a detailed specific protocol that includes a safety check in combination with vigorous verbal encouragement from trained research staff delivering the intervention to promote active cycling.

    Cycling is protocolized to provide graduated increases in resistance during each session and between daily sessions. Cycling will continue through ICU discharge or 21 calendar days after randomization. The intervention will specifically occur during ICU stay.

    Other Name: MotoMed Letto II Cycle Ergometer
Study Arms  ICMJE
  • Experimental: IV amino acid + in-bed cycle ergometry
    Beginning within 96 hours of initiation of mechanical ventilation, participants will receive the combined intervention that includes IV amino acids supplementation and in-bed cycle ergometry exercise
    Interventions:
    • Drug: IV amino acids
    • Device: In-bed cycle ergometry exercise
  • No Intervention: Usual care
    Participants randomized to the usual care arm will receive usual care protein and exercise.
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 12, 2017)
142
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2022
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. ≥18 years old.
  2. Requiring mechanical ventilation with actual or expected total duration of mechanical ventilation ≥ 48 hours.
  3. Expected ICU stay ≥ 4 days after enrollment (to permit adequate exposure to the proposed intervention).

Exclusion Criteria:

  1. >96 continuous hours of mechanical ventilation before enrollment.
  2. Expected death or withdrawal of life-sustaining treatments within this hospitalization.
  3. No expectation for any nutritional intake within the subsequent 72 hours.
  4. Severe chronic liver disease (MELD score ≥20) or acute fulminant hepatitis.
  5. Documented allergy to the amino acid intervention.
  6. Metabolic disorders involving impaired nitrogen utilization
  7. Not ambulating independently prior to illness that lead to ICU admission (use of gait aid permitted).
  8. Pre-existing primary systemic neuromuscular disease (e.g. Guillain Barre).
  9. Neuromuscular blocker infusion (eligible once infusion discontinued if other inclusion criteria met).
  10. Intracranial or spinal process affecting motor function
  11. Pre-existing cognitive impairment or language barrier that prohibits outcomes assessment.
  12. Patients in hospital >5 days prior to ICU admission
  13. Lower extremity impairments that prevent cycling (e.g. amputation, knee/hip injury).
  14. Remaining intubated for airway protection only
  15. Weight ≥150kg
  16. Physician declines patient enrollment
  17. Insufficient IV access
  18. Pregnant
  19. Incarcerated
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Daren K Heyland, MD, MSc 613-548-3232 ext 4847 dkh2@queensu.ca
Contact: John Clarke, MSc 613-549-6666 ext 4847 clarkej1@kgh.kari.net
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03021902
Other Study ID Numbers  ICMJE The NEXIS Trial
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: There is no plan to share IPD.
Responsible Party Daren K. Heyland, Clinical Evaluation Research Unit at Kingston General Hospital
Study Sponsor  ICMJE Clinical Evaluation Research Unit at Kingston General Hospital
Collaborators  ICMJE
  • University of Vermont
  • Johns Hopkins University
Investigators  ICMJE
Principal Investigator: Daren K Heyland, MD, MSc Queen's University
Principal Investigator: Renee D Stapleton, MD, PhD University of Vermont
Principal Investigator: Dale M Needham, MD, PhD Johns Hopkins University
PRS Account Clinical Evaluation Research Unit at Kingston General Hospital
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP