<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/NCT04475861</url>
  </required_header>
  <id_info>
    <org_study_id>201702332A3</org_study_id>
    <nct_id>NCT04475861</nct_id>
  </id_info>
  <brief_title>Metabolomics and Wound Healing in Diabetes</brief_title>
  <official_title>Metabolomics and Wound Healing in Diabetes-Mechanisms and Clinical Value of Arginine Supplement in Patients With Diabetic Foot Ulcers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Chang Gung Memorial Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Science and Technology, Taiwan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Chang Gung Memorial Hospital</source>
  <oversight_info>
    <has_dmc>No</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 dysfunction of wound healing in diabetes involves multiple healing processes by&#xD;
      diminished inflammatory responses and delayed deposition of matrix components, wound&#xD;
      remodeling, and closure. Furthermore, hyperglycemia increases the infection susceptibility of&#xD;
      wounds. In Taiwan, we have data demonstrating the nutrition status associated the outcome of&#xD;
      diabetic foot ulcer (DFU) acute treatment and value of serum arginine level (in preliminary&#xD;
      metabolomics study) to predict one-year healing of DFUs. The arginine has the beneficial&#xD;
      effects on wound healing by the action of its metabolites, including vasodilatation,&#xD;
      bactericide, growth factors recruitment and collage formation. Nevertheless, its supplement&#xD;
      and mechanism in patients with diabetes is still remains unproven. This study aims at (1)&#xD;
      defining the effects of arginine supplement, on top of the traditional treatment and risk&#xD;
      reduction, on healing outcomes of patients with DFUs, (2) studying the modes of action of&#xD;
      arginine supplements in diabetes, and (3) verifying the metabolomics factors and their&#xD;
      association with wound healing prospects in patients with DFUs. A total of 120 patients with&#xD;
      chronic diabetic foot ulcer will be enrolled and survey in 3 years. Along with standard of&#xD;
      care, patients will receive, in a randomized fashion, either arginine (treatment group) or&#xD;
      whey protein (control group) 5 g per day supplement for 4 weeks. The wound status will be&#xD;
      collected with features in wound size, tissue perfusion, and infection status before and&#xD;
      after treatment. Nutritional surveys, nitrogen balance as well as various molecular studies&#xD;
      such as metabolomics analysis and neutrophil-to-lymphocyte ratio will be performed to study&#xD;
      the association between the molecules of nutrients and the healing&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The dysfunction of wound healing in diabetes involves multiple healing processes by&#xD;
      diminished inflammatory responses and delayed deposition of matrix components, wound&#xD;
      remodeling, and closure. Furthermore, hyperglycemia increases the infection susceptibility of&#xD;
      wounds. The wounds noted at distal limb of body, the diabetic foot ulcers, have more&#xD;
      significant impacts clinically and socioeconomically compare to those injuries from surgery&#xD;
      or pressure sores.&#xD;
&#xD;
        1. Urge for Novel treatments in patients with diabetic foot ulcers:&#xD;
&#xD;
           1.1. Facts: Diabetic foot ulcer (DFU) is a major complication of diabetes that can lead&#xD;
           to limb loss and premature death. According to a report from the International Diabetes&#xD;
           Federation in 2017, DFU is also the most common cause of hospitalization for patients&#xD;
           with diabetes.&#xD;
&#xD;
           In Taiwan, 1% of patients with diabetes are admitted to hospital for the treatment of&#xD;
           DFU annually. However, considering that the lower-extremity amputation (LEA) rate is&#xD;
           around 30%,the treatment outcomes are obviously unsatisfactory.&#xD;
&#xD;
           1.2. Standard treatment for DFU 1.2.1 In 2016, we formed a Taiwan national working group&#xD;
           on diabetic foot under the authorization of Diabetes Association of the Republic of&#xD;
           China and subsequently published a Diabetic foot guideline in Taiwan in 2017 (ISBN&#xD;
           978-986-82436-8-2). In addition, I also participated in the writing of a clinical foot&#xD;
           care guideline released 2017 by International Diabetes Federation . 1.2.2 These two most&#xD;
           updated guidelines detail the diagnosis, management and prevention for patients with&#xD;
           DFUs with specifically focused on (1) infection, (2) peripheral artery diseases, (3)&#xD;
           wound care and surgical intervention, and (4) off-loading and risks reduction.&#xD;
           Suggestions for the appropriate medications for patients with various clinical&#xD;
           characteristics were also provided. Nevertheless, in addition to treating acute&#xD;
           infections and limb ischemia, the optimum healing of a foot ulcer requires treating the&#xD;
           complex biological and molecular events of cell migration and proliferation, and of&#xD;
           extracellular matrix deposition, remodeling, and tissue microcirculation. This is why&#xD;
           the prognosis for patients with DFU is still unsatisfactory, worldwide. Novel treatments&#xD;
           are therefore needed to provide better tissue healing in patients with diabetes.&#xD;
           Unfortunately, recent results of well-designed novel treatments for patients with DFU&#xD;
           have been disappointing.&#xD;
&#xD;
        2. The role of nutrition in wound healing The relationship between nutrition and wound&#xD;
           healing, whether after injury or surgical intervention, has been recognized for&#xD;
           centuries and adequate carbohydrate, fat and protein intake is known to be necessary for&#xD;
           healing to take place. Wound failure, as reflected by wound infections and/or delayed&#xD;
           healing, significantly contributes to the financial burden imposed on health care&#xD;
           systems worldwide.&#xD;
&#xD;
           2.1. Molecular pathogenesis of diabetic wound healing In healthy individuals, the wound&#xD;
           healing requires maintenance of multiple signals (cytokines and chemokines) released by&#xD;
           keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. During&#xD;
           wound-induced hypoxia, VEGF released by macrophages, fibroblasts, and epithelial cells&#xD;
           induces nitric oxide synthase (NOS) resulting in an increase in nitric oxide (NO)&#xD;
           levels.&#xD;
&#xD;
           2.2. Role of nutrition in wound healing in patients with diabetes Studies have shown&#xD;
           that changes in energy, carbohydrate, protein, fat, vitamin, and mineral metabolism&#xD;
           affect the healing process12. Loss of protein due to protein-calorie malnutrition, the&#xD;
           most common form of malnutrition, leads to decreased wound tensile strength, decreased&#xD;
           T-cell function, decreased phagocytic activity, and decreased complement and antibody&#xD;
           levels,ultimately diminishing the body's ability to defend the wound against infection.&#xD;
&#xD;
           Furthermore, wounding increases metabolic rates, catecholamine levels, loss of total&#xD;
           body water, and cellular protein turnover, resulting in an overall state of catabolism.&#xD;
&#xD;
           Patients with diabetes have a significantly impaired ability to heal wounds, and&#xD;
           therefore, exhibit increased complication rates compared with their euglycemic&#xD;
           counterparts. The mechanisms at work are multifactorial and need to be further&#xD;
           verified.Recent evidence has shown that patients with diabetes exhibit a diminished&#xD;
           early inflammatory response and inhibition of fibroblast and endothelial cell&#xD;
           activities. Subsequently, when inflammatory cells eventually arrive at the site of&#xD;
           injury, they initiate a prolonged inflammatory phase that results in delayed deposition&#xD;
           of matrix components, wound remodeling, and closure. Furthermore, hyperglycemia&#xD;
           interferes with the cellular transport of ascorbic acid into fibroblasts and leukocytes&#xD;
           and decreases leukocyte chemotaxis. In addition, patients with diabetes are more&#xD;
           susceptible to infection2 because of decreased host resistance and phagocytosis ability.&#xD;
&#xD;
        3. Preliminary data highlights the role of L-arginine in wound healing in patients with DFU&#xD;
           In our diabetic foot center, we have consistently observed that a lower serum albumin&#xD;
           level is an independent risk factor for lower-extremity amputation (LEA) . Furthermore,&#xD;
           we identified an association between nutritional status and treatment outcomes in&#xD;
           patients with limb-threatening DFU. Using the Mini Nutritional Assessment (MNA) and&#xD;
           Geriatric Nutritional Risk Index (GNRI) tools, we confirmed a high prevalence of&#xD;
           nutritional problems among these patients. We further identified that the nutritional&#xD;
           status of the patients was an independent predictor for acute treatment outcomes.&#xD;
&#xD;
      More recently, we analyzed the effect of metabolomic molecules and clinical and wound&#xD;
      characteristics on the 1-year outcomes of wound healing in patients with limb-threatening&#xD;
      foot ulcer.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    no participants enrolled&#xD;
  </why_stopped>
  <start_date type="Anticipated">October 31, 2018</start_date>
  <completion_date type="Anticipated">June 18, 2025</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2018</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>Health Services Research</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>PEDIS</measure>
    <time_frame>up to 1 months</time_frame>
    <description>Wound assessment was recorded using the PEDIS system</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Diabetes Mellitus, Type 2</condition>
  <condition>Infection</condition>
  <arm_group>
    <arm_group_label>L-arginine supplements</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The enrolled subjects will then be randomized into two groups. Study Group: will take a supplementation pill containing 5 g L-arginine (0.5g/ pill, GNC, USA) All the food intake of the subjects during the 4 weeks of the study will be recorded and supervised by responsible dietitians.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>nutritional supports</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>The enrolled subjects will then be randomized into two groups. Control group: will take a supplementation pill containing 5 g whey protein (5g/ pack, Santosa,Taiwan).&#xD;
All the food intake of the subjects during the 4 weeks of the study will be recorded and supervised by responsible dietitians.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>L-arginine supplements and nutritional supports</intervention_name>
    <description>The enrolled subjects will then be randomized into two groups. The subjects will receive either L-arginine (the study group) or another amino acid supplement (the control group), with 60 patients in each group. All the food intake of the subjects during the 4 weeks of the study will be recorded and supervised by responsible dietitians.</description>
    <arm_group_label>L-arginine supplements</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. are men or non-pregnant women, aged ≥ 40 years or ≤ 80 years&#xD;
&#xD;
          2. have a history of foot ulcers for more than 1 month&#xD;
&#xD;
          3. have a serum albumin level ≤ 4.0 or an ABI level ≤ 1&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Have active malignancy&#xD;
&#xD;
          2. Have acute gastrointestinal surgery&#xD;
&#xD;
          3. are receiving dialysis&#xD;
&#xD;
          4. have heart failure (NYHA Fc ≥ 3), liver cirrhosis (Child class &gt; B), or myocardial&#xD;
             infarction in the past 3 months,&#xD;
&#xD;
          5. have wounds complicated with persistent osteomyelitis or Charcot deformity&#xD;
&#xD;
          6. are receiving hydroxyurea or steroid treatment&#xD;
&#xD;
          7. have alcohol abuse, any mental or physiological condition that may interfere with&#xD;
             dietary intake, and those who are unable to follow orders or cooperate.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Chang Gung Memorial Hospital</name>
      <address>
        <city>Taipei</city>
        <zip>333</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>September 18, 2018</study_first_submitted>
  <study_first_submitted_qc>July 16, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 17, 2020</study_first_posted>
  <last_update_submitted>July 16, 2020</last_update_submitted>
  <last_update_submitted_qc>July 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 17, 2020</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>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT04475861
org study id: 201702332A3
nct id: NCT04475861
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The dysfunction of wound healing in diabetes involves multiple healing processes by
      diminished inflammatory responses and delayed deposition of matrix components, wound
      remodeling, and closure. Furthermore, hyperglycemia increases the infection susceptibility of
      wounds. In Taiwan, we have data demonstrating the nutrition status associated the outcome of
      diabetic foot ulcer (DFU) acute treatment and value of serum arginine level (in preliminary
      metabolomics study) to predict one-year healing of DFUs. The arginine has the beneficial
      effects on wound healing by the action of its metabolites, including vasodilatation,
      bactericide, growth factors recruitment and collage formation. Nevertheless, its supplement
      and mechanism in patients with diabetes is still remains unproven. This study aims at (1)
      defining the effects of arginine supplement, on top of the traditional treatment and risk
      reduction, on healing outcomes of patients with DFUs, (2) studying the modes of action of
      arginine supplements in diabetes, and (3) verifying the metabolomics factors and their
      association with wound healing prospects in patients with DFUs. A total of 120 patients with
      chronic diabetic foot ulcer will be enrolled and survey in 3 years. Along with standard of
      care, patients will receive, in a randomized fashion, either arginine (treatment group) or
      whey protein (control group) 5 g per day supplement for 4 weeks. The wound status will be
      collected with features in wound size, tissue perfusion, and infection status before and
      after treatment. Nutritional surveys, nitrogen balance as well as various molecular studies
      such as metabolomics analysis and neutrophil-to-lymphocyte ratio will be performed to study
      the association between the molecules of nutrients and the healing
The dysfunction of wound healing in diabetes involves multiple healing processes by
      diminished inflammatory responses and delayed deposition of matrix components, wound
      remodeling, and closure. Furthermore, hyperglycemia increases the infection susceptibility of
      wounds. The wounds noted at distal limb of body, the diabetic foot ulcers, have more
      significant impacts clinically and socioeconomically compare to those injuries from surgery
      or pressure sores.

        1. Urge for Novel treatments in patients with diabetic foot ulcers:

           1.1. Facts: Diabetic foot ulcer (DFU) is a major complication of diabetes that can lead
           to limb loss and premature death. According to a report from the International Diabetes
           Federation in 2017, DFU is also the most common cause of hospitalization for patients
           with diabetes.

           In Taiwan, 1% of patients with diabetes are admitted to hospital for the treatment of
           DFU annually. However, considering that the lower-extremity amputation (LEA) rate is
           around 30%,the treatment outcomes are obviously unsatisfactory.

           1.2. Standard treatment for DFU 1.2.1 In 2016, we formed a Taiwan national working group
           on diabetic foot under the authorization of Diabetes Association of the Republic of
           China and subsequently published a Diabetic foot guideline in Taiwan in 2017 (ISBN
           978-986-82436-8-2). In addition, I also participated in the writing of a clinical foot
           care guideline released 2017 by International Diabetes Federation . 1.2.2 These two most
           updated guidelines detail the diagnosis, management and prevention for patients with
           DFUs with specifically focused on (1) infection, (2) peripheral artery diseases, (3)
           wound care and surgical intervention, and (4) off-loading and risks reduction.
           Suggestions for the appropriate medications for patients with various clinical
           characteristics were also provided. Nevertheless, in addition to treating acute
           infections and limb ischemia, the optimum healing of a foot ulcer requires treating the
           complex biological and molecular events of cell migration and proliferation, and of
           extracellular matrix deposition, remodeling, and tissue microcirculation. This is why
           the prognosis for patients with DFU is still unsatisfactory, worldwide. Novel treatments
           are therefore needed to provide better tissue healing in patients with diabetes.
           Unfortunately, recent results of well-designed novel treatments for patients with DFU
           have been disappointing.

        2. The role of nutrition in wound healing The relationship between nutrition and wound
           healing, whether after injury or surgical intervention, has been recognized for
           centuries and adequate carbohydrate, fat and protein intake is known to be necessary for
           healing to take place. Wound failure, as reflected by wound infections and/or delayed
           healing, significantly contributes to the financial burden imposed on health care
           systems worldwide.

           2.1. Molecular pathogenesis of diabetic wound healing In healthy individuals, the wound
           healing requires maintenance of multiple signals (cytokines and chemokines) released by
           keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. During
           wound-induced hypoxia, VEGF released by macrophages, fibroblasts, and epithelial cells
           induces nitric oxide synthase (NOS) resulting in an increase in nitric oxide (NO)
           levels.

           2.2. Role of nutrition in wound healing in patients with diabetes Studies have shown
           that changes in energy, carbohydrate, protein, fat, vitamin, and mineral metabolism
           affect the healing process12. Loss of protein due to protein-calorie malnutrition, the
           most common form of malnutrition, leads to decreased wound tensile strength, decreased
           T-cell function, decreased phagocytic activity, and decreased complement and antibody
           levels,ultimately diminishing the body's ability to defend the wound against infection.

           Furthermore, wounding increases metabolic rates, catecholamine levels, loss of total
           body water, and cellular protein turnover, resulting in an overall state of catabolism.

           Patients with diabetes have a significantly impaired ability to heal wounds, and
           therefore, exhibit increased complication rates compared with their euglycemic
           counterparts. The mechanisms at work are multifactorial and need to be further
           verified.Recent evidence has shown that patients with diabetes exhibit a diminished
           early inflammatory response and inhibition of fibroblast and endothelial cell
           activities. Subsequently, when inflammatory cells eventually arrive at the site of
           injury, they initiate a prolonged inflammatory phase that results in delayed deposition
           of matrix components, wound remodeling, and closure. Furthermore, hyperglycemia
           interferes with the cellular transport of ascorbic acid into fibroblasts and leukocytes
           and decreases leukocyte chemotaxis. In addition, patients with diabetes are more
           susceptible to infection2 because of decreased host resistance and phagocytosis ability.

        3. Preliminary data highlights the role of L-arginine in wound healing in patients with DFU
           In our diabetic foot center, we have consistently observed that a lower serum albumin
           level is an independent risk factor for lower-extremity amputation (LEA) . Furthermore,
           we identified an association between nutritional status and treatment outcomes in
           patients with limb-threatening DFU. Using the Mini Nutritional Assessment (MNA) and
           Geriatric Nutritional Risk Index (GNRI) tools, we confirmed a high prevalence of
           nutritional problems among these patients. We further identified that the nutritional
           status of the patients was an independent predictor for acute treatment outcomes.

      More recently, we analyzed the effect of metabolomic molecules and clinical and wound
      characteristics on the 1-year outcomes of wound healing in patients with limb-threatening
      foot ulcer.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Health Services Research
masking: Single (Participant)
measure: PEDIS
time frame: up to 1 months
description: Wound assessment was recorded using the PEDIS system
arm group label: L-arginine supplements
arm group type: Experimental
description: The enrolled subjects will then be randomized into two groups. Study Group: will take a supplementation pill containing 5 g L-arginine (0.5g/ pill, GNC, USA) All the food intake of the subjects during the 4 weeks of the study will be recorded and supervised by responsible dietitians.
arm group label: nutritional supports
arm group type: No Intervention
description: The enrolled subjects will then be randomized into two groups. Control group: will take a supplementation pill containing 5 g whey protein (5g/ pack, Santosa,Taiwan).
All the food intake of the subjects during the 4 weeks of the study will be recorded and supervised by responsible dietitians.
intervention type: Dietary Supplement
intervention name: L-arginine supplements and nutritional supports
description: The enrolled subjects will then be randomized into two groups. The subjects will receive either L-arginine (the study group) or another amino acid supplement (the control group), with 60 patients in each group. All the food intake of the subjects during the 4 weeks of the study will be recorded and supervised by responsible dietitians.
arm group label: L-arginine supplements
criteria: 
gender: All
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: No
facility: 
country: Taiwan
responsible party type: Sponsor
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
sharing ipd: Undecided