<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/NCT02252770</url>
  </required_header>
  <id_info>
    <org_study_id>H-33236</org_study_id>
    <nct_id>NCT02252770</nct_id>
  </id_info>
  <brief_title>Nitric Oxide Supplementation in Argininosuccinic Aciduria</brief_title>
  <official_title>Nitric Oxide Supplementation as a Therapeutic Intervention in Argininosuccinic Aciduria</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Baylor College of Medicine</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a study involving a dietary supplement. Patients with argininosuccinic aciduria will&#xD;
      be randomly assigned to receive either a nitric oxide dietary supplement or placebo for 2&#xD;
      weeks, and then crossed-over to receive the other treatment for two weeks.&#xD;
&#xD;
      The investigators expect to see that : 1) Patients with ASA will have a decreased ability for&#xD;
      their arteries to dilate due to nitric oxide deficiency, 2) Treatment of ASA with the nitric&#xD;
      oxide supplement will improve the ability of their arteries to dilate, and 3) Through the&#xD;
      testing of subjects' fibroblasts (cells in connective tissue that produce collagen and other&#xD;
      fibers), the investigators hope to predict which patients may respond NO supplementation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators will perform a double blind, randomized, placebo-controlled, crossover&#xD;
      study of NO supplementation in ASA patients assessing endothelial function and blood pressure&#xD;
      as primary endpoints, and markers of nitric oxide production as exploratory endpoints.&#xD;
&#xD;
      Subjects will receive a nitrite-restricted diet prior to the start and during the trial&#xD;
      period. The dietary protein prescriptions will not be altered. After screening, informed&#xD;
      consent, subjects will undergo study procedures at the Clinical Research Center (CRC) at&#xD;
      Texas Children's Hospital, Houston, TX.&#xD;
&#xD;
      Safety laboratories will be performed. Fibroblast and lymphoblast cultures will be&#xD;
      established for subsequent studies.A baseline assessment of the vascular endothelial NO&#xD;
      production and function will be assessed using FMD of brachial artery using standard&#xD;
      techniques (1). Subjects will be randomized to receive either dietary nitric oxide supplement&#xD;
      or placebo for 2 weeks, and then crossed-over to receive the other treatment for two weeks.&#xD;
      The Investigational Pharmacy Services at Texas Children's Hospital will assign the initial&#xD;
      treatment group randomly in a 1:1 ratio using established randomization procedures. Following&#xD;
      randomization, subjects will be receive either Neo40® 40 mg/kg/day in two divided doses) or&#xD;
      placebo for 14 days. This dose is the dietary supplemental dose and was well-tolerated in the&#xD;
      investigators proof of concept treatment subject as well as other clinical studies in&#xD;
      cardiovascular disease. Subjects will return on day 14 to the CRC where they will undergo&#xD;
      assessment of FMD of the brachial artery, repeated BP measurements, and assay of NO status.&#xD;
      The subjects will then be crossed over to receive the alternative treatment and the study&#xD;
      procedures will be repeated in identical fashion to the initial arm.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">May 2018</completion_date>
  <primary_completion_date type="Actual">May 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>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Vascular endothelial function as assessed by FMD of brachial artery</measure>
    <time_frame>2 weeks</time_frame>
    <description>The primary outcome measures will be vascular endothelial function as assessed by the flow mediated dilatation (FMD) of the brachial artery measured by Doppler ultrasound.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">12</enrollment>
  <condition>Argininosuccinic Aciduria</condition>
  <condition>Argininosuccinate Lyase Deficiency</condition>
  <condition>Urea Cycle Disorders</condition>
  <arm_group>
    <arm_group_label>Nitric oxide supplement arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>During this arm, subjects will receive a lozenge with nitric oxide supplement</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Arm</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>During this arm, subjects will receive placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Nitric oxide supplement</intervention_name>
    <description>Each active comparator supplement is an all natural nitric oxide supplement. Subjects will take one lozenge twice a day.</description>
    <arm_group_label>Nitric oxide supplement arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo will not contain nitric oxide supplement.</description>
    <arm_group_label>Placebo Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  A confirmed diagnosis of ASA based on biochemical, enzymatic, or genetic testing&#xD;
&#xD;
          -  Capable of completing study procedures&#xD;
&#xD;
          -  History of compliance with diet and treatment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  An active infection (viral or bacterial), any condition(s) that may precipitate a&#xD;
             metabolic decompensation&#xD;
&#xD;
          -  A hypersensitivity to nitrite&#xD;
&#xD;
          -  A serum creatinine &gt; 1.5 times above the normal&#xD;
&#xD;
          -  A clinical or laboratory abnormality of Grade 3 or greater according to the CTCAE V4.0&#xD;
             (except elevations of AST or ALT which are a part of the disease) which in the view of&#xD;
             the Investigator compromises safety&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>8 Years</minimum_age>
    <maximum_age>64 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sandesh CS Nagamani, MD, FACMG</last_name>
    <role>Principal Investigator</role>
    <affiliation>Baylor College of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Texas Children's Hospital</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.bcm.edu/people/view/b22371a1-ffed-11e2-be68-080027880ca6</url>
    <description>Sandesh CS Nagamani</description>
  </link>
  <link>
    <url>http://www.bcm.edu/departments/molecular-and-human-genetics</url>
    <description>Baylor College of Medicine, Department of Molecular and Human Genetics</description>
  </link>
  <reference>
    <citation>Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R; International Brachial Artery Reactivity Task Force. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002 Jan 16;39(2):257-65. doi: 10.1016/s0735-1097(01)01746-6. Erratum In: J Am Coll Cardiol 2002 Mar 20;39(6):1082.</citation>
    <PMID>11788217</PMID>
  </reference>
  <reference>
    <citation>Nagamani SC, Campeau PM, Shchelochkov OA, Premkumar MH, Guse K, Brunetti-Pierri N, Chen Y, Sun Q, Tang Y, Palmer D, Reddy AK, Li L, Slesnick TC, Feig DI, Caudle S, Harrison D, Salviati L, Marini JC, Bryan NS, Erez A, Lee B. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am J Hum Genet. 2012 May 4;90(5):836-46. doi: 10.1016/j.ajhg.2012.03.018. Epub 2012 Apr 26.</citation>
    <PMID>22541557</PMID>
  </reference>
  <reference>
    <citation>Nagamani SC, Lee B, Erez A. Optimizing therapy for argininosuccinic aciduria. Mol Genet Metab. 2012 Sep;107(1-2):10-4. doi: 10.1016/j.ymgme.2012.07.009. Epub 2012 Jul 20.</citation>
    <PMID>22841516</PMID>
  </reference>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>September 25, 2014</study_first_submitted>
  <study_first_submitted_qc>September 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 30, 2014</study_first_posted>
  <last_update_submitted>January 14, 2020</last_update_submitted>
  <last_update_submitted_qc>January 14, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 18, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Baylor College of Medicine</investigator_affiliation>
    <investigator_full_name>Sandesh Chakravarthy Sreenath Nagamani</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>ASA</keyword>
  <keyword>ASLD</keyword>
  <keyword>UCD</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Urea Cycle Disorders, Inborn</mesh_term>
    <mesh_term>Argininosuccinic Aciduria</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nitric Oxide</mesh_term>
  </intervention_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/NCT02252770
org study id: H-33236
nct id: NCT02252770
lead sponsor: 
has dmc: No
This is a study involving a dietary supplement. Patients with argininosuccinic aciduria will
      be randomly assigned to receive either a nitric oxide dietary supplement or placebo for 2
      weeks, and then crossed-over to receive the other treatment for two weeks.

      The investigators expect to see that : 1) Patients with ASA will have a decreased ability for
      their arteries to dilate due to nitric oxide deficiency, 2) Treatment of ASA with the nitric
      oxide supplement will improve the ability of their arteries to dilate, and 3) Through the
      testing of subjects' fibroblasts (cells in connective tissue that produce collagen and other
      fibers), the investigators hope to predict which patients may respond NO supplementation.
The investigators will perform a double blind, randomized, placebo-controlled, crossover
      study of NO supplementation in ASA patients assessing endothelial function and blood pressure
      as primary endpoints, and markers of nitric oxide production as exploratory endpoints.

      Subjects will receive a nitrite-restricted diet prior to the start and during the trial
      period. The dietary protein prescriptions will not be altered. After screening, informed
      consent, subjects will undergo study procedures at the Clinical Research Center (CRC) at
      Texas Children's Hospital, Houston, TX.

      Safety laboratories will be performed. Fibroblast and lymphoblast cultures will be
      established for subsequent studies.A baseline assessment of the vascular endothelial NO
      production and function will be assessed using FMD of brachial artery using standard
      techniques (1). Subjects will be randomized to receive either dietary nitric oxide supplement
      or placebo for 2 weeks, and then crossed-over to receive the other treatment for two weeks.
      The Investigational Pharmacy Services at Texas Children's Hospital will assign the initial
      treatment group randomly in a 1:1 ratio using established randomization procedures. Following
      randomization, subjects will be receive either Neo40® 40 mg/kg/day in two divided doses) or
      placebo for 14 days. This dose is the dietary supplemental dose and was well-tolerated in the
      investigators proof of concept treatment subject as well as other clinical studies in
      cardiovascular disease. Subjects will return on day 14 to the CRC where they will undergo
      assessment of FMD of the brachial artery, repeated BP measurements, and assay of NO status.
      The subjects will then be crossed over to receive the alternative treatment and the study
      procedures will be repeated in identical fashion to the initial arm.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Vascular endothelial function as assessed by FMD of brachial artery
time frame: 2 weeks
description: The primary outcome measures will be vascular endothelial function as assessed by the flow mediated dilatation (FMD) of the brachial artery measured by Doppler ultrasound.
arm group label: Nitric oxide supplement arm
arm group type: Active Comparator
description: During this arm, subjects will receive a lozenge with nitric oxide supplement
arm group label: Placebo Arm
arm group type: Placebo Comparator
description: During this arm, subjects will receive placebo
intervention type: Dietary Supplement
intervention name: Nitric oxide supplement
description: Each active comparator supplement is an all natural nitric oxide supplement. Subjects will take one lozenge twice a day.
arm group label: Nitric oxide supplement arm
intervention type: Dietary Supplement
intervention name: Placebo
description: Placebo will not contain nitric oxide supplement.
arm group label: Placebo Arm
criteria: 
gender: All
minimum age: 8 Years
maximum age: 64 Years
healthy volunteers: No
last name: Sandesh CS Nagamani, MD, FACMG
role: Principal Investigator
affiliation: Baylor College of Medicine
facility: 
country: United States
url: http://www.bcm.edu/people/view/b22371a1-ffed-11e2-be68-080027880ca6
description: Sandesh CS Nagamani
url: http://www.bcm.edu/departments/molecular-and-human-genetics
description: Baylor College of Medicine, Department of Molecular and Human Genetics
citation: Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R; International Brachial Artery Reactivity Task Force. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002 Jan 16;39(2):257-65. doi: 10.1016/s0735-1097(01)01746-6. Erratum In: J Am Coll Cardiol 2002 Mar 20;39(6):1082.
PMID: 11788217
citation: Nagamani SC, Campeau PM, Shchelochkov OA, Premkumar MH, Guse K, Brunetti-Pierri N, Chen Y, Sun Q, Tang Y, Palmer D, Reddy AK, Li L, Slesnick TC, Feig DI, Caudle S, Harrison D, Salviati L, Marini JC, Bryan NS, Erez A, Lee B. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am J Hum Genet. 2012 May 4;90(5):836-46. doi: 10.1016/j.ajhg.2012.03.018. Epub 2012 Apr 26.
PMID: 22541557
citation: Nagamani SC, Lee B, Erez A. Optimizing therapy for argininosuccinic aciduria. Mol Genet Metab. 2012 Sep;107(1-2):10-4. doi: 10.1016/j.ymgme.2012.07.009. Epub 2012 Jul 20.
PMID: 22841516
responsible party type: Principal Investigator
investigator affiliation: Baylor College of Medicine
investigator full name: Sandesh Chakravarthy Sreenath Nagamani
investigator title: Assistant Professor
mesh term: Urea Cycle Disorders, Inborn
mesh term: Argininosuccinic Aciduria
mesh term: Nitric Oxide