<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/NCT01713257</url>
  </required_header>
  <id_info>
    <org_study_id>CNN-TOP-2010-01</org_study_id>
    <nct_id>NCT01713257</nct_id>
  </id_info>
  <brief_title>Study of Arginine Free IED in Critically Ill Patients.</brief_title>
  <acronym>ROSIED</acronym>
  <official_title>A Comparative Randomized Controlled Study of Arginine Free Immunoenhancing Diet and Isocaloric, Isonitrogenous Formula in Critically Ill Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Thai Otsuka Pharmaceutical Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Thai Otsuka Pharmaceutical Co., Ltd.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study intends to investigate the clinical outcomes of a new immunoenhancing formula&#xD;
      which composed arginine free compare to isonitrogenous, isocaloric standard formula in ICU&#xD;
      patients.The study design is multicenter, double-blind randomized controlled study with 3&#xD;
      periods of Screening, Run-in and Randomization period.&#xD;
&#xD;
      Primary Objective: To evaluate the clinical outcomes of immunoenhancing diet (IED) arginine&#xD;
      free in medical-surgical ICU patients.&#xD;
&#xD;
      Secondary Objective: To evaluate the immunologic effects and safety of IED arginine free&#xD;
      formula.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      It is accepted that nutrition support is essential in the treatment of critically ill&#xD;
      patients. It is also reasonable to initiate nutrition support therapy as soon as possible.&#xD;
      Although malnutrition is most frequently associated with a risk for immune dysfunction, it&#xD;
      can affect all organ systems. Thus, ICU patients are in need of immunonutrients&#xD;
      supplementation. An additional strategy to maximize the benefits is to consider using&#xD;
      products supplemented with specific nutrients that modulate the immune system, improve wound&#xD;
      healing, and reduce oxidative stress. The lower incidence of infectious complications may&#xD;
      follow in shorter lengths of both intensive care units (ICU) and hospital stays. Many studies&#xD;
      have concentrated on nutrients to stimulate the function of cellular immunity in these&#xD;
      patients. These nutrients include arginine, glutamine and omega-3 fatty acid which has direct&#xD;
      effect on T lymphocytes and macrophage. Enteral formulas designed as immune-enhancing diets&#xD;
      (IED) contain supplemental amounts of L-arginine, L-glutamine, nucleotides and the long chain&#xD;
      polyunsaturated fatty acids: eicosapentaenoic acid (EPA), docosahexanoic acid (DHA) and&#xD;
      arachidonic acid (ARA) in addition to nutrient substrates essential for general nutrition and&#xD;
      metabolism. These formulas vary considerably in composition of these four primary substrates.&#xD;
      They introduce the immune cell function augmentation, inflammation regulation and infections&#xD;
      minimization. Glutamine, a conditional-essential amino acid, an essential energy source, a&#xD;
      precursor for protein synthesis and donates nitrogen for the synthesis of purines,&#xD;
      pyrimidines, nucleotides, amino sugars, and glutathione antioxidant.&#xD;
&#xD;
      Glutamine also plays an important role in enhancing immune cell function with no elevation in&#xD;
      proinflammatory cytokine production. The lower levels of glutamine have been associated with&#xD;
      impaired tissue healing, immune dysfunction and increased mortality.&#xD;
&#xD;
      Omega-3 fatty acid (n-3 fatty acid or omega-3 fatty acid) directly affects the function of&#xD;
      monocyte by membrane characteristic alteration, prostaglandin E2 (PGE2) synthesis that has&#xD;
      the action of macrophage phagocytosis, IL-1 and superoxide synthesis. Moreover, omega-3 fatty&#xD;
      acid reduces cellular immune response reaction by compete arachidonic acid resulting in less&#xD;
      inflammation.&#xD;
&#xD;
      Arginine is considered a nutrient that enhances the immune response. Studies have shown&#xD;
      arginine-supplemented immune formulas in helping decrease protein catabolism, improve&#xD;
      nitrogen balance, enhance wound healing and wound strength resulted in less infection and&#xD;
      shorter hospitalization days. Arginine has also been shown to support the immune system by&#xD;
      enhancing lymphocyte proliferation and phagocytosis. Arginine may provide some benefits.&#xD;
      However, recent meta-analysis conducted in a subgroup of critically ill patients by Heyland&#xD;
      and colleagues revealed that arginine may be harmful to some group especially septic patients&#xD;
      by stimulating nitric oxide (NO) production.&#xD;
&#xD;
      Based on these scientific rationales, it is recommended that arginine should not be used in&#xD;
      critically ill patients who are clearly septic. And many evidences exist for supplementation&#xD;
      with antioxidant and immunonutrition in the critically ill. Glutamine and fish oil/borage oil&#xD;
      should be considered. These result in the development of immune-enhancing diet (IED) without&#xD;
      arginine. In addition, two types of lipids are added into the formula to further modulate&#xD;
      immune response. First, fish oil as a source of omega-3 fatty acids and borage oil as a&#xD;
      source of docosahexanoic acid (DHA), a unique omega-6 fatty acid (n-6 fatty acid). Both n-3&#xD;
      and n-6 fatty acids are polyunsaturated fatty acids (PUFAs) and are essential fatty acids&#xD;
      (EFA). Therefore, immune-enhancing diet composes of L-glutamine, eicosapentaenoic acid (EPA),&#xD;
      docosahexanoic acid (DHA), antioxidant vitamins and trace minerals such as vitamin A, vitamin&#xD;
      E, vitamin C, selenium and betacarotene.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2011</start_date>
  <completion_date type="Actual">October 2012</completion_date>
  <primary_completion_date type="Actual">October 2012</primary_completion_date>
  <phase>Phase 4</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>Supportive Care</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Development of new organ failure</measure>
    <time_frame>10 days</time_frame>
    <description>Development of new organ failure: cardiovascular, respiratory, renal, hematologic, hepatic, neurologic Clinical outcomes: Change of SOFA score or MODS</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Immunologic parameters</measure>
    <time_frame>10 days</time_frame>
    <description>Immunologic: IL6, IL10, TNF-alpha Hospitalization day parameters: length of stay 28-day mortality Safety and tolerance; Nutritional parameters: caloric intake, body weight, nitrogen balance, serum albumin, electrolytes, minerals, serum chemistries GI complications: vomiting, diarrhea, constipation, abdominal distension, aspiration Infection complications (other than baseline): wound infection, pneumonia, urinary tract infection, intra-abdominal abscess and bacteremia</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">172</enrollment>
  <condition>Critical Illness</condition>
  <arm_group>
    <arm_group_label>Immunoenhancing diet</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Immunoenhancing diet feeding until Day 10 or the day of discharge if earlier than Day 10. The goal of caloric intake is 25 kcal/kg/day and protein 1.2 g/kg/day.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Isocaloric, isonitrogenous diet</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Enteral feeding until Day 10 or the day of discharge if earlier than Day 10. The goal of caloric intake is 25 kcal/kg/day and protein 1.2 g/kg/day.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Immunoenhancing diet</intervention_name>
    <description>Enteral feeding until Day 10 or the day of discharge if earlier than Day 10. The goal of caloric intake is 25 kcal/kg/day and protein 1.2 g/kg/day.</description>
    <arm_group_label>Immunoenhancing diet</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Isocaloric, isonitrogenous diet</intervention_name>
    <description>Enteral feeding until Day 10 or the day of discharge if earlier than Day 10. The goal of caloric intake is 25 kcal/kg/day and protein 1.2 g/kg/day.</description>
    <arm_group_label>Isocaloric, isonitrogenous diet</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. ICU patients requiring mechanical ventilation or APACHE II score equal or more than 10&#xD;
&#xD;
          2. Patients arrived at ICU within 24 hours before feeding&#xD;
&#xD;
          3. Anticipated tube feeding for at least 5 days&#xD;
&#xD;
          4. Age of 18 years and older&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Inability to be fed via the gastrointestinal tract&#xD;
&#xD;
          2. Allergic to whey protein isolate (WPI), soy protein isolate, glutamine, fish oil or&#xD;
             any components in study formulas&#xD;
&#xD;
          3. Hemodynamically unstable, requiring significant dose of vasopressor or inotropes&#xD;
             infusion (Dopamine or dobutamine &gt; 5 microgram/kg/min or noradrenaline &gt; 0.1&#xD;
             microgram/kg/min)&#xD;
&#xD;
          4. Known insulin dependent diabetes mellitus&#xD;
&#xD;
          5. Cerebral hemorrhage or severe head injury (Glasgow Coma Scale Score ≤ 8)&#xD;
&#xD;
          6. Active bleeding requiring ongoing blood transfusion&#xD;
&#xD;
          7. Platelet count &lt; 30,000/mm3 or INR &gt; 5&#xD;
&#xD;
          8. Pre-existing incurable disease (uncontrolled cancer, terminal disease, patient's legal&#xD;
             representative not committed to full support)&#xD;
&#xD;
          9. On chemotherapy, radiation therapy within the previous 6 months or immunosuppressive&#xD;
             regimen (including prednisolone or aspirin at least 7 days consecutively within the&#xD;
             previous 4 weeks) or on other investigational drugs&#xD;
&#xD;
         10. Any genetic immune or autoimmune disorder; known HIV-positive patients&#xD;
&#xD;
         11. Severe chronic liver disease (Child- Pugh score of 11-15)&#xD;
&#xD;
         12. Renal failure requiring renal replacement therapy&#xD;
&#xD;
         13. Pregnancy or lactation&#xD;
&#xD;
         14. Unable to obtain inform consent from patient or his/her legal representative&#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>Assist.Prof.Boonsong Pajanasoontorn, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Faculty of Medicine, Khon Kaen University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Kaweesak Chittawatanarat, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Faculty of Medicine, Chiang Mai University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Burapat Sangthong, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Surgery, Faculty of Medicine, Songklanagarind University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Rungsun Bhurayanontachai, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Medicine, Faculty of Medicine, Songklanakarind University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Assoc.Prof.Kaweesak Chittawatanarat</name>
      <address>
        <city>Muang</city>
        <state>Chiang Mai</state>
        <zip>50200</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Assoc.Prof.Boonsong Pachanasoonthorn</name>
      <address>
        <city>Muang</city>
        <state>Khonkaen</state>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Songklanakarind Hospital</name>
      <address>
        <city>Haad Yai</city>
        <state>Songkla</state>
        <zip>90110</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Thailand</country>
  </location_countries>
  <verification_date>October 2012</verification_date>
  <study_first_submitted>October 22, 2012</study_first_submitted>
  <study_first_submitted_qc>October 22, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 24, 2012</study_first_posted>
  <last_update_submitted>October 22, 2012</last_update_submitted>
  <last_update_submitted_qc>October 22, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 24, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Critically ill patients</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Critical Illness</mesh_term>
  </condition_browse>
  <!-- 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/NCT01713257
org study id: CNN-TOP-2010-01
nct id: NCT01713257
lead sponsor: 
has dmc: Yes
This study intends to investigate the clinical outcomes of a new immunoenhancing formula
      which composed arginine free compare to isonitrogenous, isocaloric standard formula in ICU
      patients.The study design is multicenter, double-blind randomized controlled study with 3
      periods of Screening, Run-in and Randomization period.

      Primary Objective: To evaluate the clinical outcomes of immunoenhancing diet (IED) arginine
      free in medical-surgical ICU patients.

      Secondary Objective: To evaluate the immunologic effects and safety of IED arginine free
      formula.
It is accepted that nutrition support is essential in the treatment of critically ill
      patients. It is also reasonable to initiate nutrition support therapy as soon as possible.
      Although malnutrition is most frequently associated with a risk for immune dysfunction, it
      can affect all organ systems. Thus, ICU patients are in need of immunonutrients
      supplementation. An additional strategy to maximize the benefits is to consider using
      products supplemented with specific nutrients that modulate the immune system, improve wound
      healing, and reduce oxidative stress. The lower incidence of infectious complications may
      follow in shorter lengths of both intensive care units (ICU) and hospital stays. Many studies
      have concentrated on nutrients to stimulate the function of cellular immunity in these
      patients. These nutrients include arginine, glutamine and omega-3 fatty acid which has direct
      effect on T lymphocytes and macrophage. Enteral formulas designed as immune-enhancing diets
      (IED) contain supplemental amounts of L-arginine, L-glutamine, nucleotides and the long chain
      polyunsaturated fatty acids: eicosapentaenoic acid (EPA), docosahexanoic acid (DHA) and
      arachidonic acid (ARA) in addition to nutrient substrates essential for general nutrition and
      metabolism. These formulas vary considerably in composition of these four primary substrates.
      They introduce the immune cell function augmentation, inflammation regulation and infections
      minimization. Glutamine, a conditional-essential amino acid, an essential energy source, a
      precursor for protein synthesis and donates nitrogen for the synthesis of purines,
      pyrimidines, nucleotides, amino sugars, and glutathione antioxidant.

      Glutamine also plays an important role in enhancing immune cell function with no elevation in
      proinflammatory cytokine production. The lower levels of glutamine have been associated with
      impaired tissue healing, immune dysfunction and increased mortality.

      Omega-3 fatty acid (n-3 fatty acid or omega-3 fatty acid) directly affects the function of
      monocyte by membrane characteristic alteration, prostaglandin E2 (PGE2) synthesis that has
      the action of macrophage phagocytosis, IL-1 and superoxide synthesis. Moreover, omega-3 fatty
      acid reduces cellular immune response reaction by compete arachidonic acid resulting in less
      inflammation.

      Arginine is considered a nutrient that enhances the immune response. Studies have shown
      arginine-supplemented immune formulas in helping decrease protein catabolism, improve
      nitrogen balance, enhance wound healing and wound strength resulted in less infection and
      shorter hospitalization days. Arginine has also been shown to support the immune system by
      enhancing lymphocyte proliferation and phagocytosis. Arginine may provide some benefits.
      However, recent meta-analysis conducted in a subgroup of critically ill patients by Heyland
      and colleagues revealed that arginine may be harmful to some group especially septic patients
      by stimulating nitric oxide (NO) production.

      Based on these scientific rationales, it is recommended that arginine should not be used in
      critically ill patients who are clearly septic. And many evidences exist for supplementation
      with antioxidant and immunonutrition in the critically ill. Glutamine and fish oil/borage oil
      should be considered. These result in the development of immune-enhancing diet (IED) without
      arginine. In addition, two types of lipids are added into the formula to further modulate
      immune response. First, fish oil as a source of omega-3 fatty acids and borage oil as a
      source of docosahexanoic acid (DHA), a unique omega-6 fatty acid (n-6 fatty acid). Both n-3
      and n-6 fatty acids are polyunsaturated fatty acids (PUFAs) and are essential fatty acids
      (EFA). Therefore, immune-enhancing diet composes of L-glutamine, eicosapentaenoic acid (EPA),
      docosahexanoic acid (DHA), antioxidant vitamins and trace minerals such as vitamin A, vitamin
      E, vitamin C, selenium and betacarotene.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Supportive Care
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Development of new organ failure
time frame: 10 days
description: Development of new organ failure: cardiovascular, respiratory, renal, hematologic, hepatic, neurologic Clinical outcomes: Change of SOFA score or MODS
measure: Immunologic parameters
time frame: 10 days
description: Immunologic: IL6, IL10, TNF-alpha Hospitalization day parameters: length of stay 28-day mortality Safety and tolerance; Nutritional parameters: caloric intake, body weight, nitrogen balance, serum albumin, electrolytes, minerals, serum chemistries GI complications: vomiting, diarrhea, constipation, abdominal distension, aspiration Infection complications (other than baseline): wound infection, pneumonia, urinary tract infection, intra-abdominal abscess and bacteremia
arm group label: Immunoenhancing diet
arm group type: Experimental
description: Immunoenhancing diet feeding until Day 10 or the day of discharge if earlier than Day 10. The goal of caloric intake is 25 kcal/kg/day and protein 1.2 g/kg/day.
arm group label: Isocaloric, isonitrogenous diet
arm group type: Active Comparator
description: Enteral feeding until Day 10 or the day of discharge if earlier than Day 10. The goal of caloric intake is 25 kcal/kg/day and protein 1.2 g/kg/day.
intervention type: Dietary Supplement
intervention name: Immunoenhancing diet
description: Enteral feeding until Day 10 or the day of discharge if earlier than Day 10. The goal of caloric intake is 25 kcal/kg/day and protein 1.2 g/kg/day.
arm group label: Immunoenhancing diet
intervention type: Dietary Supplement
intervention name: Isocaloric, isonitrogenous diet
description: Enteral feeding until Day 10 or the day of discharge if earlier than Day 10. The goal of caloric intake is 25 kcal/kg/day and protein 1.2 g/kg/day.
arm group label: Isocaloric, isonitrogenous diet
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Assist.Prof.Boonsong Pajanasoontorn, MD
role: Principal Investigator
affiliation: Faculty of Medicine, Khon Kaen University
last name: Kaweesak Chittawatanarat, M.D.
role: Principal Investigator
affiliation: Faculty of Medicine, Chiang Mai University
last name: Burapat Sangthong, M.D.
role: Principal Investigator
affiliation: Department of Surgery, Faculty of Medicine, Songklanagarind University
last name: Rungsun Bhurayanontachai, M.D.
role: Principal Investigator
affiliation: Department of Medicine, Faculty of Medicine, Songklanakarind University
facility: 
facility: 
facility: 
country: Thailand
responsible party type: Sponsor
mesh term: Critical Illness