<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/NCT01683981</url>
  </required_header>
  <id_info>
    <org_study_id>f-91-138</org_study_id>
    <nct_id>NCT01683981</nct_id>
  </id_info>
  <brief_title>Exercise Capacity and Quality of Life in Patients With PPH Receiving Short Term Oral L-Citrulline Malate</brief_title>
  <official_title>Exercise Capacity and Quality of Life in Patients With Idiopathic Pulmonary Hypertension and Eisenmenger Syndrome Receiving Short Term Oral L-Citrulline Malate</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Masih Daneshvari Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Masih Daneshvari Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Due to vasodilatory properties of the NO, one of the therapeutic approaches for IPAH is oral&#xD;
      use of nitric oxide precursors (10). Efficacy of L-arginine is well-documented in the current&#xD;
      literature but there is paucity of data with regard to L-citrulline- malate. Hence, this&#xD;
      study will evaluate therapeutic efficacy of L-citrulline- malate in two categories of&#xD;
      patients with pulmonary hypertension (IPAH, and Eisenmeger syndrome). This randomized&#xD;
      clinical trial utilizes 6-minute walk, pro BNP levels and the echocardiographic indexes an&#xD;
      indicator of functional improvement of the patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pulmonary vascular tone is maintained by the action of vasoprotective compounds including&#xD;
      nitric oxide (NO)(1).NO can be synthesized endogenously in the body via L-arginine and&#xD;
      NOS-independent mechanism from the anion nitrite (NO2-)(2,3).Nitric oxide (NO) causes cyclic&#xD;
      guanosine monophosphate-mediated vasodilatation of the pulmonary vasculature. Endogenous NO&#xD;
      is also produced from the metabolism of citrulline; an amino acid generated by the urea cycle&#xD;
      (4). NO is critical for normal development of the pulmonary vasculature and loss of this&#xD;
      vasodilator factor and subsequent endothelial dysfunction is proposed as one of the possible&#xD;
      explanations for development of pulmonary hypertension (1).&#xD;
&#xD;
      From a clinical standpoint, pulmonary hypertension is a common complication of chronic&#xD;
      obstructive pulmonary disease (COPD).Its presence is associated with shorter survival and&#xD;
      worse clinical outcome. In a setting of COPD, pulmonary hypertension tends to be of moderate&#xD;
      severity and progresses slowly. Recent investigations have demonstrated endothelial&#xD;
      dysfunction and changes in the expression of endothelial-derived mediators that regulate&#xD;
      vascular tone and cell growth in the pulmonary arteries of patients with mild disease(5).&#xD;
      Pulmonary vascular involvement from congenital heart disease like Eisenmeger syndrome is&#xD;
      another important category of patients with PAH. In this congenital disease pulmonary&#xD;
      vascular involvement follows a period in which pulmonary resistance is low and pulmonary&#xD;
      blood flow is high (6, 7, 8). Finally, Idiopathic pulmonary hypertension (IPAH) is the third&#xD;
      category of these patients. IPAH has unknown etiology and is characterized by progressive&#xD;
      obliteration of small and medium size pulmonary arteries; elevation in pulmonary arterial&#xD;
      pressure, and an increase in pulmonary vascular resistance. Presence of these pathologies&#xD;
      eventually leads to right heart failure and death (9).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>August 2012</start_date>
  <completion_date type="Anticipated">August 2013</completion_date>
  <primary_completion_date type="Anticipated">August 2013</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>the change in exercise capacity</measure>
    <time_frame>2 weeks</time_frame>
    <description>The primary measure of efficacy was the change in exercise capacity, as measured by the total distance walked in six minutes, from baseline to week 2. (15)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>changes in mean pulmonary-artery pressure</measure>
    <time_frame>2 weeks</time_frame>
    <description>changes in mean pulmonary-artery pressure from baseline to week 2.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>change in the quality of life</measure>
    <time_frame>2 weeks</time_frame>
    <description>change in the quality of life from baseline to week 2</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">25</enrollment>
  <condition>Idiopathic Pulmonary Arterial Hypertension</condition>
  <condition>Eisenmenger Syndrome</condition>
  <arm_group>
    <arm_group_label>L-Citrulline, Exercise Capacity</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>L-Citrulline malate, 1gr, oral, divided 3 times a day,for 2 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>L-Citrulline Malate</intervention_name>
    <description>3 gr per day, oral, for 2 weeks</description>
    <arm_group_label>L-Citrulline, Exercise Capacity</arm_group_label>
    <other_name>Stimol</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  all patients less than 70 years old,&#xD;
&#xD;
          -  patients with a six-minute walking distance of more than 100 meters (m),&#xD;
&#xD;
          -  a mean pulmonary arterial pressure (PAP) ≥ 25 mmHg at rest as assessed by right heart&#xD;
             catheterization(RHC) (11,12).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  all patients more than 70 years old,&#xD;
&#xD;
          -  patients with a six-minute walking distance of less than 100 meters (m), active&#xD;
             pulmonary or extra pulmonary infection,&#xD;
&#xD;
          -  serious coronaropathy and/ or ventricular dysfunction,&#xD;
&#xD;
          -  significant renal illness and/or hepatitis,&#xD;
&#xD;
          -  detected immunosuppressive illnesses,&#xD;
&#xD;
          -  carrier of known neoplasias,&#xD;
&#xD;
          -  pregnancy,&#xD;
&#xD;
          -  lack of family support,&#xD;
&#xD;
          -  psychosocial problems,&#xD;
&#xD;
          -  drug or alcohol abuse, and&#xD;
&#xD;
          -  noncompliance with established medical protocol.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>15 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>babak sharif kashani, cardiologist</last_name>
    <role>Principal Investigator</role>
    <affiliation>Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Science, Tehran, Iran.</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Paritash Tahmaseb pour, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>MD</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>babak sharif kashani, Cardiologist</last_name>
    <phone>0098-02188883114</phone>
    <email>sharifk@nritld.ac.ir</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>paritash tahmasebpour, MD</last_name>
    <phone>0098-09125037861</phone>
    <email>paritash_t@yahoo.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>MasihDH</name>
      <address>
        <city>Tehran</city>
        <zip>021</zip>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>babak sharif kashani, cardiologist</last_name>
      <phone>0098-02188883114</phone>
      <email>sharifk@nritld.ac.ir</email>
    </contact>
    <contact_backup>
      <last_name>paritash tahmasebpour, MD</last_name>
      <phone>0098-09125037861</phone>
      <email>paritash_t@yahoo.com</email>
    </contact_backup>
    <investigator>
      <last_name>babak sharif kashani, cardiologist</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Iran, Islamic Republic of</country>
  </location_countries>
  <verification_date>September 2012</verification_date>
  <study_first_submitted>September 1, 2012</study_first_submitted>
  <study_first_submitted_qc>September 11, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 12, 2012</study_first_posted>
  <last_update_submitted>August 8, 2013</last_update_submitted>
  <last_update_submitted_qc>August 8, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 12, 2013</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Masih Daneshvari Hospital</investigator_affiliation>
    <investigator_full_name>babak sharif kashani</investigator_full_name>
    <investigator_title>Head of Cardiology Department of NRITLD, Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Idiopathic Pulmonary Arterial Hypertension</keyword>
  <keyword>Eisenmenger Syndrome</keyword>
  <keyword>Exercise Capacity</keyword>
  <keyword>Quality of Life</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulmonary Arterial Hypertension</mesh_term>
    <mesh_term>Familial Primary Pulmonary Hypertension</mesh_term>
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Eisenmenger Complex</mesh_term>
    <mesh_term>Syndrome</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/NCT01683981
org study id: f-91-138
nct id: NCT01683981
lead sponsor: 
has dmc: Yes
Due to vasodilatory properties of the NO, one of the therapeutic approaches for IPAH is oral
      use of nitric oxide precursors (10). Efficacy of L-arginine is well-documented in the current
      literature but there is paucity of data with regard to L-citrulline- malate. Hence, this
      study will evaluate therapeutic efficacy of L-citrulline- malate in two categories of
      patients with pulmonary hypertension (IPAH, and Eisenmeger syndrome). This randomized
      clinical trial utilizes 6-minute walk, pro BNP levels and the echocardiographic indexes an
      indicator of functional improvement of the patients.
Pulmonary vascular tone is maintained by the action of vasoprotective compounds including
      nitric oxide (NO)(1).NO can be synthesized endogenously in the body via L-arginine and
      NOS-independent mechanism from the anion nitrite (NO2-)(2,3).Nitric oxide (NO) causes cyclic
      guanosine monophosphate-mediated vasodilatation of the pulmonary vasculature. Endogenous NO
      is also produced from the metabolism of citrulline; an amino acid generated by the urea cycle
      (4). NO is critical for normal development of the pulmonary vasculature and loss of this
      vasodilator factor and subsequent endothelial dysfunction is proposed as one of the possible
      explanations for development of pulmonary hypertension (1).

      From a clinical standpoint, pulmonary hypertension is a common complication of chronic
      obstructive pulmonary disease (COPD).Its presence is associated with shorter survival and
      worse clinical outcome. In a setting of COPD, pulmonary hypertension tends to be of moderate
      severity and progresses slowly. Recent investigations have demonstrated endothelial
      dysfunction and changes in the expression of endothelial-derived mediators that regulate
      vascular tone and cell growth in the pulmonary arteries of patients with mild disease(5).
      Pulmonary vascular involvement from congenital heart disease like Eisenmeger syndrome is
      another important category of patients with PAH. In this congenital disease pulmonary
      vascular involvement follows a period in which pulmonary resistance is low and pulmonary
      blood flow is high (6, 7, 8). Finally, Idiopathic pulmonary hypertension (IPAH) is the third
      category of these patients. IPAH has unknown etiology and is characterized by progressive
      obliteration of small and medium size pulmonary arteries; elevation in pulmonary arterial
      pressure, and an increase in pulmonary vascular resistance. Presence of these pathologies
      eventually leads to right heart failure and death (9).
allocation: N/A
intervention model: Single Group Assignment
masking: None (Open Label)
measure: the change in exercise capacity
time frame: 2 weeks
description: The primary measure of efficacy was the change in exercise capacity, as measured by the total distance walked in six minutes, from baseline to week 2. (15)
measure: changes in mean pulmonary-artery pressure
time frame: 2 weeks
description: changes in mean pulmonary-artery pressure from baseline to week 2.
measure: change in the quality of life
time frame: 2 weeks
description: change in the quality of life from baseline to week 2
arm group label: L-Citrulline, Exercise Capacity
arm group type: Experimental
description: L-Citrulline malate, 1gr, oral, divided 3 times a day,for 2 weeks
intervention type: Drug
intervention name: L-Citrulline Malate
description: 3 gr per day, oral, for 2 weeks
arm group label: L-Citrulline, Exercise Capacity
other name: Stimol
criteria: 
gender: All
minimum age: 15 Years
maximum age: 70 Years
healthy volunteers: No
last name: babak sharif kashani, cardiologist
role: Principal Investigator
affiliation: Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Science, Tehran, Iran.
last name: Paritash Tahmaseb pour, MD
role: Principal Investigator
affiliation: MD
last name: babak sharif kashani, Cardiologist
phone: 0098-02188883114
email: sharifk@nritld.ac.ir
last name: paritash tahmasebpour, MD
phone: 0098-09125037861
email: paritash_t@yahoo.com
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Iran, Islamic Republic of
responsible party type: Principal Investigator
investigator affiliation: Masih Daneshvari Hospital
investigator full name: babak sharif kashani
investigator title: Head of Cardiology Department of NRITLD, Associate Professor
mesh term: Pulmonary Arterial Hypertension
mesh term: Familial Primary Pulmonary Hypertension
mesh term: Hypertension
mesh term: Eisenmenger Complex
mesh term: Syndrome