<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03021902</url>
  </required_header>
  <id_info>
    <org_study_id>The NEXIS Trial</org_study_id>
    <nct_id>NCT03021902</nct_id>
  </id_info>
  <brief_title>Nutrition and Exercise in Critical Illness</brief_title>
  <acronym>NEXIS</acronym>
  <official_title>Nutrition and Exercise in Critical Illness (The NEXIS Trial): A Randomized Trial of Combined Cycle Ergometry and Amino Acids in the ICU</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Clinical Evaluation Research Unit at Kingston General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Vermont</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Johns Hopkins University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Clinical Evaluation Research Unit at Kingston General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study proposes a novel early intervention combining Intravenous (IV) amino acids plus&#xD;
      in-bed cycle ergometry exercise to improve physical outcomes in critically ill patients. The&#xD;
      investigators hypothesize that this innovative approach will improve short-term physical&#xD;
      functioning outcomes (primary outcome), as well as amino acid metabolism, body composition,&#xD;
      and patient-reported outcomes at 6-month follow-up.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The evaluation of a combination of exercise and protein supplementation in intensive care&#xD;
      unit (ICU) patients is novel and potentially very important. For instance, outside of the&#xD;
      ICU, in other clinical conditions, the combination of protein supplementation and exercise&#xD;
      improves protein synthesis, muscle mass, and muscle strength compared to protein or exercise&#xD;
      alone.[63-70] Hence, an opportunity exists to improve ICU patients' physical outcomes via&#xD;
      evaluating the combination of optimized protein intake and early exercise in the ICU setting.&#xD;
&#xD;
      The proposed intervention and hypothesis: The investigators propose a multi-centered Phase II&#xD;
      RCT, with blinded outcomes assessment, of a combination of intravenous (IV) amino acid&#xD;
      supplementation and early in-bed cycle ergometry exercise versus usual care in ICU patients&#xD;
      requiring mechanical ventilation. The investigators hypothesize that this novel combined&#xD;
      intervention will: (1) improve physical functioning at hospital discharge; (2) reduce muscle&#xD;
      wasting with improved amino acid metabolism and protein synthesis in-hospital; and (3)&#xD;
      improve health-related quality of life, physical functioning, and healthcare resource&#xD;
      utilization at 6 months after enrollment. Preliminary data show feasibility and safety of IV&#xD;
      amino acids and the proposed exercise intervention. The investigators have chosen a primary&#xD;
      outcome that correlates well with long-term outcomes including mortality, hospitalization,&#xD;
      and quality of life. [54] If this Phase II trial is positive, investigators will seek funding&#xD;
      for a Phase III RCT to demonstrate sustained improvements with a longer-term patient-centered&#xD;
      primary outcome and to examine the feasibility, and facilitators/barriers of delivery of this&#xD;
      intervention by ICU nurses, physical therapists, and others. If proven effective, this&#xD;
      combined intervention has potential to revolutionize care of ICU patients and have a major&#xD;
      public health impact on the growing number of ICU survivors.&#xD;
&#xD;
      Objectives: To demonstrate that the innovative combination of amino acid supplementation plus&#xD;
      early in-bed cycle ergometry exercise improves physical outcomes of ICU patients.&#xD;
&#xD;
      Specific Aims of Full Phase II RCT:&#xD;
&#xD;
        1. Short-term performance-based physical function outcomes. To determine if a combined IV&#xD;
           amino acid supplementation and in-bed cycle ergometry exercise intervention, compared to&#xD;
           usual care, improves in hospital muscle strength and performance-based physical&#xD;
           functioning outcomes in critically ill patients, using a primary endpoint of six-minute&#xD;
           walk distance (6MWD) at hospital discharge.&#xD;
&#xD;
        2. Body composition. To determine if the combined intervention, compared to usual care,&#xD;
           improves amino acid utilization and decreases muscle wasting in ICU patients (secondary&#xD;
           endpoints).&#xD;
&#xD;
        3. Patient-reported outcomes and health care utilization at 6 months. To determine if the&#xD;
           combined intervention, compared to usual care, improves physical functioning,&#xD;
           health-related quality of life, and healthcare utilization at 6 months after study&#xD;
           enrollment (secondary endpoints).&#xD;
&#xD;
      NEXIS Flame mechanisitic Ancillary sub study:&#xD;
&#xD;
      In the proposed sub-study, the addition of bronchoaveloar lavages, blood sampling and muscle&#xD;
      sampling measures during the participant's ICU stay will provide the ability to examine the&#xD;
      effects of the NEXIS intervention on inflammation as a possible mechanism for improved muscle&#xD;
      weakness.&#xD;
&#xD;
      Specific Aims of the NEXIS FLAME mechanistic ancillary study:&#xD;
&#xD;
        1. To determine if the NEXIS intervention attenuates the release of IL-17 and related&#xD;
           cytokines to reduce systemic inflammation in humans.&#xD;
&#xD;
        2. To determine if the NEXIS intervention reduces lung injury and neutrophilic lung&#xD;
           inflammation in humans.&#xD;
&#xD;
        3. To determine if the NEXIS intervention attenuates skeletal muscle fiber atrophy via down&#xD;
           regulation of muscle proteolytic pathways.&#xD;
&#xD;
        4. To determine if the NEXIS intervention, and exercise specifically, reduces the content&#xD;
           of inflammatory cells in skeletal muscle.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 28, 2017</start_date>
  <completion_date type="Anticipated">March 2022</completion_date>
  <primary_completion_date type="Anticipated">March 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Physical functioning</measure>
    <time_frame>Hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>6-minute walk distance</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall strength-upper extremity</measure>
    <time_frame>Hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>MRC Sum-score (Medical Research Council (MRC) Scale for Muscle Strength). Subscales scored 0-5, where 5 is normal. Total score is the sum of the 6 upper extremity subscales.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall strength-lower extremity</measure>
    <time_frame>Hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>MRC Sum-score (Medical Research Council (MRC) Scale for Muscle Strength). Subscales scored 0-5, where 5 is normal. Total score is the sum of the 6 lower extremity subscales.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quadriceps force-lower extremity strength</measure>
    <time_frame>Hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>Hand held dynamometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Distal strength-hand grip strength</measure>
    <time_frame>ICU and hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>Hand held dynamometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Physical Functional status - Short Physical Performance Battery</measure>
    <time_frame>ICU and hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>Short Physical Performance Battery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Physical Functional status - Functional Status Score - ICU</measure>
    <time_frame>ICU and hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>Functional Status Score - ICU 5 items are performed: rolling, transfer from supine to sit, sitting at the edge of bed, transfer from sit to stand, and walking Each task is evaluated using an eight-point ordinal scale ranging from 0 (unable to perform) to 7 (complete independence) Item scores are summed The total score ranges from 0-35, with higher scores indicating better physical functioning.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>ICU and hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>Chart review</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of ventilation</measure>
    <time_frame>ICU and hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>Chart review</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICU stay</measure>
    <time_frame>ICU and hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>Chart review</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital stay</measure>
    <time_frame>ICU and hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>Chart review</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICU readmission</measure>
    <time_frame>Hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>Chart review</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Re-intubation</measure>
    <time_frame>Hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>Chart review</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital-acquired infections</measure>
    <time_frame>Hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>Chart review</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Discharge location (e.g. home vs. rehab)</measure>
    <time_frame>Hospital discharge (up to 26 weeks after randomization)</time_frame>
    <description>Chart review</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body composition - Ultrasound</measure>
    <time_frame>Enrollment, hospital discharge, &amp; ICU discharge (up to 26 weeks after randomization)</time_frame>
    <description>Ultrasound of quadriceps</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body composition - CT - Chest when clinically available</measure>
    <time_frame>Enrollment, hospital discharge, &amp; ICU discharge (up to 26 weeks after randomization)</time_frame>
    <description>Chest CT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body composition - CT - Abdominal Scan when clinically available</measure>
    <time_frame>Enrollment, hospital discharge, &amp; ICU discharge (up to 26 weeks after randomization)</time_frame>
    <description>Abdominal CT scan at 3rd lumbar vertebra</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related quality of life - SF-36</measure>
    <time_frame>Telephone survey at 6 months</time_frame>
    <description>36-Item Short Form Health Survey (SF-36) All items are scored so that a high score defines a more favorable health state.&#xD;
Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100 Items in the same scale are averaged together to create the 8 scale scores. Items that are left blank (missing data) are not taken into account when calculating the scale scores.&#xD;
Scale scores represent the average for all items in the scale that the respondent answered.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related quality of life - EQ-5D-5L</measure>
    <time_frame>Telephone survey at 6 months</time_frame>
    <description>EuroQol Group standardized measure of health status (EQ-5D-5L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical functioning - Katz ADL</measure>
    <time_frame>Hospital discharge (proxy) and telephone survey at 6 months</time_frame>
    <description>Katz Index of Independence in Activities of Daily Living (Katz ADL) Total score where 6 = High (patient independent) 0 = Low (patient very dependent)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical functioning - Lawton IADL</measure>
    <time_frame>Telephone survey at 6 months</time_frame>
    <description>Lawton Instrument Activities of Daily Living Scale (Lawton IADL) A summary score ranges from 0 (low function, dependent) to 8 (high function, independent) for women and 0 through 5 for men to avoid potential gender bias.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical functioning/participation - return to work</measure>
    <time_frame>Telephone survey at 6 months</time_frame>
    <description>Return to baseline work/activity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical functioning/participation - living location</measure>
    <time_frame>Telephone survey at 6 months</time_frame>
    <description>Living location</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mental and Cognitive Functioning - MoCA-BLIND</measure>
    <time_frame>Telephone survey at 6 months</time_frame>
    <description>MoCA-BLIND The total possible score is 22 points; a score of 18 or above is considered normal</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mental and Cognitive Functioning - HADS</measure>
    <time_frame>Telephone survey at 6 months</time_frame>
    <description>Hospital Anxiety and Depression Scale The HADS questionnaire has seven items each for depression and anxiety subscales. Scoring for each item ranges from zero to three, with three denoting highest anxiety or depression level. A total subscale score of &gt;8 points out of a possible 21 denotes considerable symptoms of anxiety or depression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mental and Cognitive Functioning - IES-R</measure>
    <time_frame>Telephone survey at 6 months</time_frame>
    <description>Impact of Events Scale Scoring for each item ranges from 0-4 Total score ranges from 0-88, where a total score of 33 or over signifies the likely presence of PTSD</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health Care Resource Utilization</measure>
    <time_frame>Telephone survey at 6 months</time_frame>
    <description>Admission to ICU, hospital, rehabilitation &amp; nursing facility</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body composition - DEXA Scan</measure>
    <time_frame>At Hospital Discharge</time_frame>
    <description>Whole Body DEXA Scan</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body Composition - Heavy water</measure>
    <time_frame>Enrollment, Days 1-7</time_frame>
    <description>Fat-free and fat mass can be measured with D2O in body fluids using gas chromatography-tandem mass spectrometry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma and muscle protein synthesis - Heavy water</measure>
    <time_frame>Enrollment, Days 1-7</time_frame>
    <description>Muscle protein synthesis will be analyzed with chromatography and mass spectrometry techniques.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NEXIS FLAME - Circulating inflammatory mediators</measure>
    <time_frame>Enrollment, Days 3, 5, and 8</time_frame>
    <description>Blood IL-17, IL-23, IL-6, TNFα, CXCK1, CXCL5, CXCL8, CCL2, SP-D, KL-6, vWF, and leukocyte counts with differential</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NEXIS FLAME - Lung Inflammation</measure>
    <time_frame>Enrollment, Day 5</time_frame>
    <description>Bronchoalveolar lavage neutrophil counts, IL-17A, CXCL5, and protein</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NEXIS FLAME - Muscle area</measure>
    <time_frame>Enrollment, Day 5</time_frame>
    <description>Single muscle fiber cross-sectional area (CSA), UPS expression, MuRF1 expression, myosin protein content (all from vastus lateralis sampling)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NEXIS FLAME - Muscle inflammation</measure>
    <time_frame>Enrollment, Day 5</time_frame>
    <description>Muscle macrophages (CD45+, CD206+)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">142</enrollment>
  <condition>Acute Respiratory Failure</condition>
  <arm_group>
    <arm_group_label>IV amino acid + in-bed cycle ergometry</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Usual care</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Participants randomized to the usual care arm will receive usual care protein and exercise.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>IV amino acids</intervention_name>
    <description>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.</description>
    <arm_group_label>IV amino acid + in-bed cycle ergometry</arm_group_label>
    <other_name>Clinisol 15% (Baxter) - sulfite-free (Amino Acid) Injection</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>In-bed cycle ergometry exercise</intervention_name>
    <description>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.&#xD;
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.</description>
    <arm_group_label>IV amino acid + in-bed cycle ergometry</arm_group_label>
    <other_name>MotoMed Letto II Cycle Ergometer</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. ≥18 years old.&#xD;
&#xD;
          2. Requiring mechanical ventilation with actual or expected total duration of mechanical&#xD;
             ventilation ≥ 48 hours.&#xD;
&#xD;
          3. Expected ICU stay ≥ 4 days after enrollment (to permit adequate exposure to the&#xD;
             proposed intervention).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. &gt;96 continuous hours of mechanical ventilation before enrollment.&#xD;
&#xD;
          2. Expected death or withdrawal of life-sustaining treatments within this&#xD;
             hospitalization.&#xD;
&#xD;
          3. No expectation for any nutritional intake within the subsequent 72 hours.&#xD;
&#xD;
          4. Severe chronic liver disease (MELD score ≥20) or acute fulminant hepatitis.&#xD;
&#xD;
          5. Documented allergy to the amino acid intervention.&#xD;
&#xD;
          6. Metabolic disorders involving impaired nitrogen utilization&#xD;
&#xD;
          7. Not ambulating independently prior to illness that lead to ICU admission (use of gait&#xD;
             aid permitted).&#xD;
&#xD;
          8. Pre-existing primary systemic neuromuscular disease (e.g. Guillain Barre).&#xD;
&#xD;
          9. Neuromuscular blocker infusion (eligible once infusion discontinued if other inclusion&#xD;
             criteria met).&#xD;
&#xD;
         10. Intracranial or spinal process affecting motor function&#xD;
&#xD;
         11. Pre-existing cognitive impairment or language barrier that prohibits outcomes&#xD;
             assessment.&#xD;
&#xD;
         12. Patients in hospital &gt;5 days prior to ICU admission&#xD;
&#xD;
         13. Lower extremity impairments that prevent cycling (e.g. amputation, knee/hip injury).&#xD;
&#xD;
         14. Remaining intubated for airway protection only&#xD;
&#xD;
         15. Weight ≥150kg&#xD;
&#xD;
         16. Physician declines patient enrollment&#xD;
&#xD;
         17. Insufficient IV access&#xD;
&#xD;
         18. Pregnant&#xD;
&#xD;
         19. Incarcerated&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Daren K Heyland, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Queen's University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Renee D Stapleton, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Vermont</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Dale M Needham, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Daren K Heyland, MD, MSc</last_name>
    <phone>403-915-5573</phone>
    <email>dkh2@queensu.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Shawna Froese</last_name>
    <email>Shawna.Froese@queensu.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Kentucky</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40506</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kirby P Mayer, DPT, PhD</last_name>
      <email>kpmaye2@uky.edu</email>
    </contact>
    <contact_backup>
      <last_name>Peter Morris, MD</last_name>
      <email>peter.morris@uky.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins Hospital</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dale M Needham, MD, PhD</last_name>
      <phone>410-955-3467</phone>
      <email>dale.needham@jhmi.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Wake Forest University Baptist Medical Center</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lori Flores</last_name>
      <phone>336-713-0008</phone>
      <email>lflores@wakehealth.edu</email>
    </contact>
    <contact_backup>
      <last_name>Daniel C Files, MD</last_name>
      <phone>336-716-2011</phone>
      <email>dfiles@wakehealth.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Oregon Health &amp; Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Olivia Krol</last_name>
      <email>krolo@ohsu.edu</email>
    </contact>
    <contact_backup>
      <last_name>Akram Khan, MD</last_name>
      <email>khana@ohsu.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>University of Vermont College of Medicine</name>
      <address>
        <city>Burlington</city>
        <state>Vermont</state>
        <zip>05405</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sara S Ardren, PA</last_name>
      <phone>802-656-7953</phone>
      <email>sara.ardren@uvmhealth.org</email>
    </contact>
    <contact_backup>
      <last_name>Renee D Stapleton, MD, PhD</last_name>
      <phone>802-656-7975</phone>
      <email>renee.stapleton@uvm.edu</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Harborview Medical Center</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Burtin C, Clerckx B, Robbeets C, Ferdinande P, Langer D, Troosters T, Hermans G, Decramer M, Gosselink R. Early exercise in critically ill patients enhances short-term functional recovery. Crit Care Med. 2009 Sep;37(9):2499-505. doi: 10.1097/CCM.0b013e3181a38937.</citation>
    <PMID>19623052</PMID>
  </reference>
  <reference>
    <citation>Chan KS, Pfoh ER, Denehy L, Elliott D, Holland AE, Dinglas VD, Needham DM. Construct validity and minimal important difference of 6-minute walk distance in survivors of acute respiratory failure. Chest. 2015 May;147(5):1316-1326. doi: 10.1378/chest.14-1808.</citation>
    <PMID>25742048</PMID>
  </reference>
  <reference>
    <citation>Kho ME, Truong AD, Zanni JM, Ciesla ND, Brower RG, Palmer JB, Needham DM. Neuromuscular electrical stimulation in mechanically ventilated patients: a randomized, sham-controlled pilot trial with blinded outcome assessment. J Crit Care. 2015 Feb;30(1):32-9. doi: 10.1016/j.jcrc.2014.09.014. Epub 2014 Sep 22.</citation>
    <PMID>25307979</PMID>
  </reference>
  <reference>
    <citation>Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, Elke G, Berger MM, Day AG; Canadian Critical Care Trials Group. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013 Apr 18;368(16):1489-97. doi: 10.1056/NEJMoa1212722. Erratum In: N Engl J Med. 2013 May 9;368(19):1853. Dosage error in article text.</citation>
    <PMID>23594003</PMID>
  </reference>
  <reference>
    <citation>National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network; Rice TW, Wheeler AP, Thompson BT, Steingrub J, Hite RD, Moss M, Morris A, Dong N, Rock P. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012 Feb 22;307(8):795-803. doi: 10.1001/jama.2012.137. Epub 2012 Feb 5.</citation>
    <PMID>22307571</PMID>
  </reference>
  <reference>
    <citation>National Heart, Lung, and Blood Institute ARDS Clinical Trials Network; Truwit JD, Bernard GR, Steingrub J, Matthay MA, Liu KD, Albertson TE, Brower RG, Shanholtz C, Rock P, Douglas IS, deBoisblanc BP, Hough CL, Hite RD, Thompson BT. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med. 2014 Jun 5;370(23):2191-200. doi: 10.1056/NEJMoa1401520. Epub 2014 May 18.</citation>
    <PMID>24835849</PMID>
  </reference>
  <reference>
    <citation>Parry SM, Berney S, Koopman R, Bryant A, El-Ansary D, Puthucheary Z, Hart N, Warrillow S, Denehy L. Early rehabilitation in critical care (eRiCC): functional electrical stimulation with cycling protocol for a randomised controlled trial. BMJ Open. 2012 Sep 13;2(5):e001891. doi: 10.1136/bmjopen-2012-001891. Print 2012.</citation>
    <PMID>22983782</PMID>
  </reference>
  <reference>
    <citation>Fan E, Zanni JM, Dennison CR, Lepre SJ, Needham DM. Critical illness neuromyopathy and muscle weakness in patients in the intensive care unit. AACN Adv Crit Care. 2009 Jul-Sep;20(3):243-53. doi: 10.1097/NCI.0b013e3181ac2551.</citation>
    <PMID>19638746</PMID>
  </reference>
  <reference>
    <citation>Dowdy DW, Dinglas V, Mendez-Tellez PA, Bienvenu OJ, Sevransky J, Dennison CR, Shanholtz C, Needham DM. Intensive care unit hypoglycemia predicts depression during early recovery from acute lung injury. Crit Care Med. 2008 Oct;36(10):2726-33. doi: 10.1097/CCM.0b013e31818781f5.</citation>
    <PMID>18766087</PMID>
  </reference>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>December 21, 2016</study_first_submitted>
  <study_first_submitted_qc>January 12, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 16, 2017</study_first_posted>
  <last_update_submitted>August 31, 2021</last_update_submitted>
  <last_update_submitted_qc>August 31, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Clinical Evaluation Research Unit at Kingston General Hospital</investigator_affiliation>
    <investigator_full_name>Daren K. Heyland</investigator_full_name>
    <investigator_title>Director</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Respiratory Insufficiency</mesh_term>
    <mesh_term>Critical Illness</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There is no plan to share IPD.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03021902
org study id: The NEXIS Trial
nct id: NCT03021902
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: Yes
is us export: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Physical functioning
time frame: Hospital discharge (up to 26 weeks after randomization)
description: 6-minute walk distance
measure: Overall strength-upper extremity
time frame: Hospital discharge (up to 26 weeks after randomization)
description: MRC Sum-score (Medical Research Council (MRC) Scale for Muscle Strength). Subscales scored 0-5, where 5 is normal. Total score is the sum of the 6 upper extremity subscales.
measure: Overall strength-lower extremity
time frame: Hospital discharge (up to 26 weeks after randomization)
description: MRC Sum-score (Medical Research Council (MRC) Scale for Muscle Strength). Subscales scored 0-5, where 5 is normal. Total score is the sum of the 6 lower extremity subscales.
measure: Quadriceps force-lower extremity strength
time frame: Hospital discharge (up to 26 weeks after randomization)
description: Hand held dynamometry
measure: Distal strength-hand grip strength
time frame: ICU and hospital discharge (up to 26 weeks after randomization)
description: Hand held dynamometry
measure: Overall Physical Functional status - Short Physical Performance Battery
time frame: ICU and hospital discharge (up to 26 weeks after randomization)
description: Short Physical Performance Battery
measure: Overall Physical Functional status - Functional Status Score - ICU
time frame: ICU and hospital discharge (up to 26 weeks after randomization)
description: Functional Status Score - ICU 5 items are performed: rolling, transfer from supine to sit, sitting at the edge of bed, transfer from sit to stand, and walking Each task is evaluated using an eight-point ordinal scale ranging from 0 (unable to perform) to 7 (complete independence) Item scores are summed The total score ranges from 0-35, with higher scores indicating better physical functioning.
measure: Mortality
time frame: ICU and hospital discharge (up to 26 weeks after randomization)
description: Chart review
measure: Length of ventilation
time frame: ICU and hospital discharge (up to 26 weeks after randomization)
description: Chart review
measure: ICU stay
time frame: ICU and hospital discharge (up to 26 weeks after randomization)
description: Chart review
measure: Hospital stay
time frame: ICU and hospital discharge (up to 26 weeks after randomization)
description: Chart review
measure: ICU readmission
time frame: Hospital discharge (up to 26 weeks after randomization)
description: Chart review
measure: Re-intubation
time frame: Hospital discharge (up to 26 weeks after randomization)
description: Chart review
measure: Hospital-acquired infections
time frame: Hospital discharge (up to 26 weeks after randomization)
description: Chart review
measure: Discharge location (e.g. home vs. rehab)
time frame: Hospital discharge (up to 26 weeks after randomization)
description: Chart review
measure: Body composition - Ultrasound
time frame: Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization)
description: Ultrasound of quadriceps
measure: Body composition - CT - Chest when clinically available
time frame: Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization)
description: Chest CT
measure: Body composition - CT - Abdominal Scan when clinically available
time frame: Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization)
description: Abdominal CT scan at 3rd lumbar vertebra
measure: Health-related quality of life - SF-36
time frame: Telephone survey at 6 months
description: 36-Item Short Form Health Survey (SF-36) All items are scored so that a high score defines a more favorable health state.
Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100 Items in the same scale are averaged together to create the 8 scale scores. Items that are left blank (missing data) are not taken into account when calculating the scale scores.
Scale scores represent the average for all items in the scale that the respondent answered.
measure: Health-related quality of life - EQ-5D-5L
time frame: Telephone survey at 6 months
description: EuroQol Group standardized measure of health status (EQ-5D-5L)
measure: Physical functioning - Katz ADL
time frame: Hospital discharge (proxy) and telephone survey at 6 months
description: Katz Index of Independence in Activities of Daily Living (Katz ADL) Total score where 6 = High (patient independent) 0 = Low (patient very dependent)
measure: Physical functioning - Lawton IADL
time frame: Telephone survey at 6 months
description: Lawton Instrument Activities of Daily Living Scale (Lawton IADL) A summary score ranges from 0 (low function, dependent) to 8 (high function, independent) for women and 0 through 5 for men to avoid potential gender bias.
measure: Physical functioning/participation - return to work
time frame: Telephone survey at 6 months
description: Return to baseline work/activity
measure: Physical functioning/participation - living location
time frame: Telephone survey at 6 months
description: Living location
measure: Mental and Cognitive Functioning - MoCA-BLIND
time frame: Telephone survey at 6 months
description: MoCA-BLIND The total possible score is 22 points; a score of 18 or above is considered normal
measure: Mental and Cognitive Functioning - HADS
time frame: Telephone survey at 6 months
description: Hospital Anxiety and Depression Scale The HADS questionnaire has seven items each for depression and anxiety subscales. Scoring for each item ranges from zero to three, with three denoting highest anxiety or depression level. A total subscale score of >8 points out of a possible 21 denotes considerable symptoms of anxiety or depression.
measure: Mental and Cognitive Functioning - IES-R
time frame: Telephone survey at 6 months
description: Impact of Events Scale Scoring for each item ranges from 0-4 Total score ranges from 0-88, where a total score of 33 or over signifies the likely presence of PTSD
measure: Health Care Resource Utilization
time frame: Telephone survey at 6 months
description: Admission to ICU, hospital, rehabilitation & nursing facility
measure: Body composition - DEXA Scan
time frame: At Hospital Discharge
description: Whole Body DEXA Scan
measure: Body Composition - Heavy water
time frame: Enrollment, Days 1-7
description: Fat-free and fat mass can be measured with D2O in body fluids using gas chromatography-tandem mass spectrometry.
measure: Plasma and muscle protein synthesis - Heavy water
time frame: Enrollment, Days 1-7
description: Muscle protein synthesis will be analyzed with chromatography and mass spectrometry techniques.
measure: NEXIS FLAME - Circulating inflammatory mediators
time frame: Enrollment, Days 3, 5, and 8
description: Blood IL-17, IL-23, IL-6, TNFα, CXCK1, CXCL5, CXCL8, CCL2, SP-D, KL-6, vWF, and leukocyte counts with differential
measure: NEXIS FLAME - Lung Inflammation
time frame: Enrollment, Day 5
description: Bronchoalveolar lavage neutrophil counts, IL-17A, CXCL5, and protein
measure: NEXIS FLAME - Muscle area
time frame: Enrollment, Day 5
description: Single muscle fiber cross-sectional area (CSA), UPS expression, MuRF1 expression, myosin protein content (all from vastus lateralis sampling)
measure: NEXIS FLAME - Muscle inflammation
time frame: Enrollment, Day 5
description: Muscle macrophages (CD45+, CD206+)
arm group label: IV amino acid + in-bed cycle ergometry
arm group type: Experimental
description: 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
arm group label: Usual care
arm group type: No Intervention
description: Participants randomized to the usual care arm will receive usual care protein and exercise.
intervention type: Drug
intervention name: IV amino acids
description: 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.
arm group label: IV amino acid + in-bed cycle ergometry
other name: Clinisol 15% (Baxter) - sulfite-free (Amino Acid) Injection
intervention type: Device
intervention name: In-bed cycle ergometry exercise
description: 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.
arm group label: IV amino acid + in-bed cycle ergometry
other name: MotoMed Letto II Cycle Ergometer
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Daren K Heyland, MD, MSc
role: Principal Investigator
affiliation: Queen's University
last name: Renee D Stapleton, MD, PhD
role: Principal Investigator
affiliation: University of Vermont
last name: Dale M Needham, MD, PhD
role: Principal Investigator
affiliation: Johns Hopkins University
last name: Daren K Heyland, MD, MSc
phone: 403-915-5573
email: dkh2@queensu.ca
last name: Shawna Froese
email: Shawna.Froese@queensu.ca
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Terminated
country: United States
citation: Burtin C, Clerckx B, Robbeets C, Ferdinande P, Langer D, Troosters T, Hermans G, Decramer M, Gosselink R. Early exercise in critically ill patients enhances short-term functional recovery. Crit Care Med. 2009 Sep;37(9):2499-505. doi: 10.1097/CCM.0b013e3181a38937.
PMID: 19623052
citation: Chan KS, Pfoh ER, Denehy L, Elliott D, Holland AE, Dinglas VD, Needham DM. Construct validity and minimal important difference of 6-minute walk distance in survivors of acute respiratory failure. Chest. 2015 May;147(5):1316-1326. doi: 10.1378/chest.14-1808.
PMID: 25742048
citation: Kho ME, Truong AD, Zanni JM, Ciesla ND, Brower RG, Palmer JB, Needham DM. Neuromuscular electrical stimulation in mechanically ventilated patients: a randomized, sham-controlled pilot trial with blinded outcome assessment. J Crit Care. 2015 Feb;30(1):32-9. doi: 10.1016/j.jcrc.2014.09.014. Epub 2014 Sep 22.
PMID: 25307979
citation: Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, Elke G, Berger MM, Day AG; Canadian Critical Care Trials Group. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013 Apr 18;368(16):1489-97. doi: 10.1056/NEJMoa1212722. Erratum In: N Engl J Med. 2013 May 9;368(19):1853. Dosage error in article text.
PMID: 23594003
citation: National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network; Rice TW, Wheeler AP, Thompson BT, Steingrub J, Hite RD, Moss M, Morris A, Dong N, Rock P. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012 Feb 22;307(8):795-803. doi: 10.1001/jama.2012.137. Epub 2012 Feb 5.
PMID: 22307571
citation: National Heart, Lung, and Blood Institute ARDS Clinical Trials Network; Truwit JD, Bernard GR, Steingrub J, Matthay MA, Liu KD, Albertson TE, Brower RG, Shanholtz C, Rock P, Douglas IS, deBoisblanc BP, Hough CL, Hite RD, Thompson BT. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med. 2014 Jun 5;370(23):2191-200. doi: 10.1056/NEJMoa1401520. Epub 2014 May 18.
PMID: 24835849
citation: Parry SM, Berney S, Koopman R, Bryant A, El-Ansary D, Puthucheary Z, Hart N, Warrillow S, Denehy L. Early rehabilitation in critical care (eRiCC): functional electrical stimulation with cycling protocol for a randomised controlled trial. BMJ Open. 2012 Sep 13;2(5):e001891. doi: 10.1136/bmjopen-2012-001891. Print 2012.
PMID: 22983782
citation: Fan E, Zanni JM, Dennison CR, Lepre SJ, Needham DM. Critical illness neuromyopathy and muscle weakness in patients in the intensive care unit. AACN Adv Crit Care. 2009 Jul-Sep;20(3):243-53. doi: 10.1097/NCI.0b013e3181ac2551.
PMID: 19638746
citation: Dowdy DW, Dinglas V, Mendez-Tellez PA, Bienvenu OJ, Sevransky J, Dennison CR, Shanholtz C, Needham DM. Intensive care unit hypoglycemia predicts depression during early recovery from acute lung injury. Crit Care Med. 2008 Oct;36(10):2726-33. doi: 10.1097/CCM.0b013e31818781f5.
PMID: 18766087
responsible party type: Principal Investigator
investigator affiliation: Clinical Evaluation Research Unit at Kingston General Hospital
investigator full name: Daren K. Heyland
investigator title: Director
mesh term: Respiratory Insufficiency
mesh term: Critical Illness
sharing ipd: No
ipd description: There is no plan to share IPD.