<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/NCT04475666</url>
  </required_header>
  <id_info>
    <org_study_id>RC19/414/R</org_study_id>
    <nct_id>NCT04475666</nct_id>
  </id_info>
  <brief_title>Replacing Protein Via Enteral Nutrition in Critically Ill Patients</brief_title>
  <acronym>REPLENISH</acronym>
  <official_title>Replacing Protein Via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients: An International, Multicenter Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>King Abdullah International Medical Research Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>King Abdullah International Medical Research Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigator will investigate the effect of supplemental enteral protein (1.2 g/kg/day)&#xD;
      added to standard formula to achieve high amount of enteral protein (range 2-2.4 g/kg/day)&#xD;
      given from ICU day 5 until ICU discharge up to ICU day 90 as compared to no supplemental&#xD;
      enteral protein to achieve moderate amount enteral protein (0.8-1.2 g/kg/day), given in&#xD;
      conjunction with similar amounts of stepwise caloric administration in the two groups on&#xD;
      all-cause 90-day mortality.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The REPLENISH is a multicentric, international, open label, randomized controlled trial which&#xD;
      will enroll subjects in intensive care unit. Patients will be randomized on day 4 of ICU&#xD;
      admission. Until ICU day 4, protein requirement will be provided according to the local&#xD;
      practice as long as no intravenous amino acids are given and the average protein intake in&#xD;
      the first 4 days does not exceed 0.8 g/kg/day. On ICU day 4, patients will be randomized to&#xD;
      one of the two treatment groups: one with standard prescription without supplemental proteins&#xD;
      (maximum1.2 g/kg/day) from the primary polymeric formula and another group will receive the&#xD;
      standard amount of proteins (maximum 1.2 g/kg/day) from the primary polymeric formula AND&#xD;
      supplemental protein at 1.2 g/kg/day.&#xD;
&#xD;
      Randomization will be stratified by suspected COVID-19 and then by site and the use of renal&#xD;
      replacement therapy at the time of randomization (intermittent hemodialysis or continuous&#xD;
      renal replacement therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 21, 2020</start_date>
  <completion_date type="Anticipated">December 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2025</primary_completion_date>
  <phase>N/A</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>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>90 day-all cause mortality</measure>
    <time_frame>90 days</time_frame>
    <description>Mortality 90 days post randomization</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Days alive at day 90 without life support</measure>
    <time_frame>90 days</time_frame>
    <description>use of vasopressor/inotropic support, invasive mechanical ventilation and/or renal replacement therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Days alive and out of hospital at day 90</measure>
    <time_frame>90 days</time_frame>
    <description>90 day survival after randomization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bacteremia until 2 days of ICU stay</measure>
    <time_frame>until 2 days post ICU.</time_frame>
    <description>Any symptoms of bacteremia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New or progression of Skin Pressure Ulcers</measure>
    <time_frame>ICU stay</time_frame>
    <description>anytime during ICU stay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional assessment at day 90</measure>
    <time_frame>Day 90</time_frame>
    <description>SARC-F screen for sarcopenia and EuroQoL</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Safety outcomes during ICU stay</measure>
    <time_frame>ICU stay</time_frame>
    <description>New episode of stage 2 or higher AKI by KDIGO criteria; 2. Pneumonia defined as episodes of newly confirmed pneumonia according to the modified CDC criteria; 3. Grade IV Acute Gastrointestinal injury (AGI)</description>
  </other_outcome>
  <other_outcome>
    <measure>Minor safety outcomes during ICU stay</measure>
    <time_frame>ICU stay</time_frame>
    <description>Feeding tolerance; Diarrhoea; Refeeding syndrome</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">2502</enrollment>
  <condition>Critical Illness</condition>
  <condition>Nutrition Disorders</condition>
  <arm_group>
    <arm_group_label>Replenish protein group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The subjects randomized to this group will receive the standard amount of proteins (maximum 1.2 g/kg/day) from the primary polymeric formula AND supplemental protein at 1.2 g/kg/day</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard protein group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The subjects randomized to this group will receive standard prescription without supplemental proteins (maximum1.2 g/kg/day) from the primary polymeric formula. No supplemental protein will be allowed</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Replenish protein group</intervention_name>
    <description>For patients with Body mass index(BMI) &lt;30, use pre-ICU actual body weight(BW) for the calculation; if unavailable, use weight on ICU admission. For patients with BMI &gt;=30, use adjusted body weight</description>
    <arm_group_label>Replenish protein group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard protein group</intervention_name>
    <description>For patients with BMI &lt;30, use pre-ICU actual BW for the calculation; if unavailable, use weight on ICU admission. For patients with BMI &gt;=30, use adjusted body weight</description>
    <arm_group_label>Standard protein group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria(on ICU calendar day 4 or the morning of day 5)&#xD;
&#xD;
          1. Age ≥18-years old&#xD;
&#xD;
          2. Patient started on enteral nutrition (EN) via nasogastric/orogastric or duodenal or&#xD;
             percutaneous endoscopic gastrostomy (PEG) or jejunostomy tubes.&#xD;
&#xD;
          3. The patient is on invasive mechanical ventilation and unlikely to be discharged from&#xD;
             ICU next day.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Lack of commitment to full life support or brain death. Patients with &quot;Do Not&#xD;
             Resuscitate&quot; order but with commitment to ongoing life support can be enrolled.&#xD;
&#xD;
          2. Patients on any amount of parenteral nutrition (PN) in ICU at the time of screening,&#xD;
             whether PN is used alone or in combination with enteral nutrition. Non-nutritional&#xD;
             calories (dextrose, propofol, citrate) not considered as PN.&#xD;
&#xD;
          3. Patients who received an average protein of more than 0.8g/kg/day in the first 4 ICU&#xD;
             days.&#xD;
&#xD;
          4. Patients being fed entirely through oral route - i.e. those who are eating.&#xD;
&#xD;
          5. Pregnancy.&#xD;
&#xD;
          6. Burn patients.&#xD;
&#xD;
          7. Prisoners or those undergoing forced treatment.&#xD;
&#xD;
          8. Patients with hepatic encephalopathy or Child C liver cirrhosis&#xD;
&#xD;
          9. Inherited defect of amino acid metabolism.&#xD;
&#xD;
         10. Allergies to protein supplement&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Yaseen M Arabi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>King Saud Bin Abdulaziz University for Health Sciences</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Yaseen M Arabi, MD</last_name>
    <phone>0118011111</phone>
    <phone_ext>18855</phone_ext>
    <email>arabi@ngha.med.sa</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Musharaf Sadat, MBBS</last_name>
    <phone>0118011111</phone>
    <phone_ext>10822</phone_ext>
    <email>sadatmu@ngha.med.sa</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>King Abdulaziz Medical city</name>
      <address>
        <city>Jeddah</city>
        <zip>21423</zip>
        <country>Saudi Arabia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Fahad M Al-Hameed, MD</last_name>
      <phone>00966 12 2266666</phone>
      <phone_ext>22771</phone_ext>
      <email>HameedF@ngha.med.sa</email>
    </contact>
    <contact_backup>
      <last_name>Ohoud Al Orabi, MMedSC</last_name>
      <phone>0096612 2266666</phone>
      <phone_ext>28864</phone_ext>
      <email>alorabioh@NGHA.MED.SA</email>
    </contact_backup>
    <investigator>
      <last_name>Fahad Al-Hameed, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Intensive Care Unit, King Abdulaziz Medical City</name>
      <address>
        <city>Riyadh,</city>
        <zip>11426</zip>
        <country>Saudi Arabia</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>Saudi Arabia</country>
  </location_countries>
  <reference>
    <citation>Liebau F, Wernerman J, van Loon LJ, Rooyackers O. Effect of initiating enteral protein feeding on whole-body protein turnover in critically ill patients. Am J Clin Nutr. 2015 Mar;101(3):549-57. doi: 10.3945/ajcn.114.091934. Epub 2015 Feb 4.</citation>
    <PMID>25733640</PMID>
  </reference>
  <reference>
    <citation>McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, McCarthy MS, Davanos E, Rice TW, Cresci GA, Gervasio JM, Sacks GS, Roberts PR, Compher C; Society of Critical Care Medicine; American Society for Parenteral and Enteral Nutrition. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):159-211. doi: 10.1177/0148607115621863. No abstract available. Erratum In: JPEN J Parenter Enteral Nutr. 2016 Nov;40(8):1200.</citation>
    <PMID>26773077</PMID>
  </reference>
  <reference>
    <citation>Compher C, Chittams J, Sammarco T, Nicolo M, Heyland DK. Greater Protein and Energy Intake May Be Associated With Improved Mortality in Higher Risk Critically Ill Patients: A Multicenter, Multinational Observational Study. Crit Care Med. 2017 Feb;45(2):156-163. doi: 10.1097/CCM.0000000000002083.</citation>
    <PMID>28098623</PMID>
  </reference>
  <reference>
    <citation>Weijs PJ, Looijaard WG, Beishuizen A, Girbes AR, Oudemans-van Straaten HM. Early high protein intake is associated with low mortality and energy overfeeding with high mortality in non-septic mechanically ventilated critically ill patients. Crit Care. 2014 Dec 14;18(6):701. doi: 10.1186/s13054-014-0701-z.</citation>
    <PMID>25499096</PMID>
  </reference>
  <reference>
    <citation>Koekkoek WACK, van Setten CHC, Olthof LE, Kars JCNH, van Zanten ARH. Timing of PROTein INtake and clinical outcomes of adult critically ill patients on prolonged mechanical VENTilation: The PROTINVENT retrospective study. Clin Nutr. 2019 Apr;38(2):883-890. doi: 10.1016/j.clnu.2018.02.012. Epub 2018 Feb 17.</citation>
    <PMID>29486907</PMID>
  </reference>
  <reference>
    <citation>Arabi YM, Aldawood AS, Al-Dorzi HM, Tamim HM, Haddad SH, Jones G, McIntyre L, Solaiman O, Sakkijha MH, Sadat M, Mundekkadan S, Kumar A, Bagshaw SM, Mehta S; PermiT trial group. Permissive Underfeeding or Standard Enteral Feeding in High- and Low-Nutritional-Risk Critically Ill Adults. Post Hoc Analysis of the PermiT Trial. Am J Respir Crit Care Med. 2017 Mar 1;195(5):652-662. doi: 10.1164/rccm.201605-1012OC.</citation>
    <PMID>27589411</PMID>
  </reference>
  <reference>
    <citation>Heyland DK, Patel J, Bear D, Sacks G, Nixdorf H, Dolan J, Aloupis M, Licastro K, Jovanovic V, Rice TW, Compher C. The Effect of Higher Protein Dosing in Critically Ill Patients: A Multicenter Registry-Based Randomized Trial: The EFFORT Trial. JPEN J Parenter Enteral Nutr. 2019 Mar;43(3):326-334. doi: 10.1002/jpen.1449. Epub 2018 Sep 27.</citation>
    <PMID>30260486</PMID>
  </reference>
  <results_reference>
    <citation>Arabi YM, Casaer MP, Chapman M, Heyland DK, Ichai C, Marik PE, Martindale RG, McClave SA, Preiser JC, Reignier J, Rice TW, Van den Berghe G, van Zanten ARH, Weijs PJM. The intensive care medicine research agenda in nutrition and metabolism. Intensive Care Med. 2017 Sep;43(9):1239-1256. doi: 10.1007/s00134-017-4711-6. Epub 2017 Apr 3.</citation>
    <PMID>28374096</PMID>
  </results_reference>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>June 7, 2020</study_first_submitted>
  <study_first_submitted_qc>July 14, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 17, 2020</study_first_posted>
  <last_update_submitted>January 8, 2023</last_update_submitted>
  <last_update_submitted_qc>January 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nutrition Disorders</mesh_term>
    <mesh_term>Critical Illness</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT04475666
org study id: RC19/414/R
nct id: NCT04475666
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The investigator will investigate the effect 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 on
      all-cause 90-day mortality.
The REPLENISH is a multicentric, international, open label, randomized controlled trial which
      will enroll subjects in intensive care unit. Patients will be randomized on day 4 of ICU
      admission. 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. On ICU day 4, patients will be randomized to
      one of the two treatment groups: one with standard prescription without supplemental proteins
      (maximum1.2 g/kg/day) from the primary polymeric formula and another group will receive the
      standard amount of proteins (maximum 1.2 g/kg/day) from the primary polymeric formula AND
      supplemental protein at 1.2 g/kg/day.

      Randomization will be stratified by suspected 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: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: 90 day-all cause mortality
time frame: 90 days
description: Mortality 90 days post randomization
measure: Days alive at day 90 without life support
time frame: 90 days
description: use of vasopressor/inotropic support, invasive mechanical ventilation and/or renal replacement therapy
measure: Days alive and out of hospital at day 90
time frame: 90 days
description: 90 day survival after randomization
measure: Bacteremia until 2 days of ICU stay
time frame: until 2 days post ICU.
description: Any symptoms of bacteremia
measure: New or progression of Skin Pressure Ulcers
time frame: ICU stay
description: anytime during ICU stay
measure: Functional assessment at day 90
time frame: Day 90
description: SARC-F screen for sarcopenia and EuroQoL
measure: Safety outcomes during ICU stay
time frame: ICU stay
description: New episode of stage 2 or higher AKI by KDIGO criteria; 2. Pneumonia defined as episodes of newly confirmed pneumonia according to the modified CDC criteria; 3. Grade IV Acute Gastrointestinal injury (AGI)
measure: Minor safety outcomes during ICU stay
time frame: ICU stay
description: Feeding tolerance; Diarrhoea; Refeeding syndrome
arm group label: Replenish protein group
arm group type: Active Comparator
description: The subjects randomized to this group will receive the standard amount of proteins (maximum 1.2 g/kg/day) from the primary polymeric formula AND supplemental protein at 1.2 g/kg/day
arm group label: Standard protein group
arm group type: Active Comparator
description: The subjects randomized to this group will receive standard prescription without supplemental proteins (maximum1.2 g/kg/day) from the primary polymeric formula. No supplemental protein will be allowed
intervention type: Other
intervention name: Replenish protein group
description: For patients with Body mass index(BMI) <30, use pre-ICU actual body weight(BW) for the calculation; if unavailable, use weight on ICU admission. For patients with BMI >=30, use adjusted body weight
arm group label: Replenish protein group
intervention type: Other
intervention name: Standard protein group
description: For patients with BMI <30, use pre-ICU actual BW for the calculation; if unavailable, use weight on ICU admission. For patients with BMI >=30, use adjusted body weight
arm group label: Standard protein group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Yaseen M Arabi, MD
role: Principal Investigator
affiliation: King Saud Bin Abdulaziz University for Health Sciences
last name: Yaseen M Arabi, MD
phone: 0118011111
phone ext: 18855
email: arabi@ngha.med.sa
last name: Musharaf Sadat, MBBS
phone: 0118011111
phone ext: 10822
email: sadatmu@ngha.med.sa
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
country: Saudi Arabia
citation: Liebau F, Wernerman J, van Loon LJ, Rooyackers O. Effect of initiating enteral protein feeding on whole-body protein turnover in critically ill patients. Am J Clin Nutr. 2015 Mar;101(3):549-57. doi: 10.3945/ajcn.114.091934. Epub 2015 Feb 4.
PMID: 25733640
citation: McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, McCarthy MS, Davanos E, Rice TW, Cresci GA, Gervasio JM, Sacks GS, Roberts PR, Compher C; Society of Critical Care Medicine; American Society for Parenteral and Enteral Nutrition. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):159-211. doi: 10.1177/0148607115621863. No abstract available. Erratum In: JPEN J Parenter Enteral Nutr. 2016 Nov;40(8):1200.
PMID: 26773077
citation: Compher C, Chittams J, Sammarco T, Nicolo M, Heyland DK. Greater Protein and Energy Intake May Be Associated With Improved Mortality in Higher Risk Critically Ill Patients: A Multicenter, Multinational Observational Study. Crit Care Med. 2017 Feb;45(2):156-163. doi: 10.1097/CCM.0000000000002083.
PMID: 28098623
citation: Weijs PJ, Looijaard WG, Beishuizen A, Girbes AR, Oudemans-van Straaten HM. Early high protein intake is associated with low mortality and energy overfeeding with high mortality in non-septic mechanically ventilated critically ill patients. Crit Care. 2014 Dec 14;18(6):701. doi: 10.1186/s13054-014-0701-z.
PMID: 25499096
citation: Koekkoek WACK, van Setten CHC, Olthof LE, Kars JCNH, van Zanten ARH. Timing of PROTein INtake and clinical outcomes of adult critically ill patients on prolonged mechanical VENTilation: The PROTINVENT retrospective study. Clin Nutr. 2019 Apr;38(2):883-890. doi: 10.1016/j.clnu.2018.02.012. Epub 2018 Feb 17.
PMID: 29486907
citation: Arabi YM, Aldawood AS, Al-Dorzi HM, Tamim HM, Haddad SH, Jones G, McIntyre L, Solaiman O, Sakkijha MH, Sadat M, Mundekkadan S, Kumar A, Bagshaw SM, Mehta S; PermiT trial group. Permissive Underfeeding or Standard Enteral Feeding in High- and Low-Nutritional-Risk Critically Ill Adults. Post Hoc Analysis of the PermiT Trial. Am J Respir Crit Care Med. 2017 Mar 1;195(5):652-662. doi: 10.1164/rccm.201605-1012OC.
PMID: 27589411
citation: Heyland DK, Patel J, Bear D, Sacks G, Nixdorf H, Dolan J, Aloupis M, Licastro K, Jovanovic V, Rice TW, Compher C. The Effect of Higher Protein Dosing in Critically Ill Patients: A Multicenter Registry-Based Randomized Trial: The EFFORT Trial. JPEN J Parenter Enteral Nutr. 2019 Mar;43(3):326-334. doi: 10.1002/jpen.1449. Epub 2018 Sep 27.
PMID: 30260486
citation: Arabi YM, Casaer MP, Chapman M, Heyland DK, Ichai C, Marik PE, Martindale RG, McClave SA, Preiser JC, Reignier J, Rice TW, Van den Berghe G, van Zanten ARH, Weijs PJM. The intensive care medicine research agenda in nutrition and metabolism. Intensive Care Med. 2017 Sep;43(9):1239-1256. doi: 10.1007/s00134-017-4711-6. Epub 2017 Apr 3.
PMID: 28374096
responsible party type: Sponsor
mesh term: Nutrition Disorders
mesh term: Critical Illness
sharing ipd: No