<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/NCT03303534</url>
  </required_header>
  <id_info>
    <org_study_id>2016P002507</org_study_id>
    <nct_id>NCT03303534</nct_id>
  </id_info>
  <brief_title>Short-Term Endogenous Hydrogen Sulfide Upregulation</brief_title>
  <official_title>Short-Term Endogenous Hydrogen Sulfide Upregulation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Brigham and Women's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Brigham and Women's 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>
      This research study will compare the impact of dietary restriction pre-operatively before&#xD;
      carotid endarterectomy compared to the standard nutrition that a patient typically eats. The&#xD;
      investigators want to find out how patients comply and generally how well patients do with&#xD;
      this type of dietary restriction before their surgery since animal studies suggest that short&#xD;
      - term dietary restriction may be beneficial before surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary, scientific long term objective is to study any correlation that brief&#xD;
      upregulation of endogenous hydrogen sulfide (H2S) via pre-operative protein calorie&#xD;
      restriction (PCR) in elective major surgery may have biologic effects in humans. In this&#xD;
      study, the investigators plan to evaluate patient compliance and the physiologic response&#xD;
      pre-operative PCR has on patients undergoing carotid endarterectomy surgery. This will be&#xD;
      explored via two primary aims.&#xD;
&#xD;
      The First Aim looks to create a prospective, fast-track, one-year study of 40 vascular&#xD;
      surgery patients undergoing elective carotid artery endarterectomy randomized into two&#xD;
      pre-operative dietary groups: observational group (n=16) and PCR (commercially available&#xD;
      ScandiShake x 3 days, n=24). This pilot study is based on preliminary data balanced with&#xD;
      economic and clinical feasibility considerations. The primary endpoints of this study are: 1)&#xD;
      feasibility of subject compliance with PCR (measured by direct dietary intake data and serum&#xD;
      markers including plasma free amino acids and insulin-like growth factor; thus the 2:3&#xD;
      randomization) and 2) measurement of H2S and standard markers of stress before and after&#xD;
      surgery (including stress hormones, oxidative stress, inflammation and cardiac troponin T&#xD;
      levels). Individual patient's microbiomes,phenotype of circulating blood cells, adipose&#xD;
      tissue (peri-vascular, subcutaneous), and the excised carotid plaque will be characterized to&#xD;
      inform on potential mechanistic links among these and PCR induced H2S upregulation, reduced&#xD;
      peri-operative stress, atherosclerotic plaque stability, and improved outcome (baseline and&#xD;
      peri-procedural clinical datasets will be completed) for future clinical trials. Key&#xD;
      secondary data points include observing endpoints such as carotid restenosis and surgical&#xD;
      complications (cardiac, neurologic, wound, etc) between the two groups, which the&#xD;
      investigators hypothesize will help to inform future trials. This pilot study will elucidate&#xD;
      not only the practicality of pre-operative short term dietary restriction, but also provide&#xD;
      physiologic data to support the long term primary scientific objective stated previously.&#xD;
&#xD;
      The Second Specific Aim is to establish a robust human discovery multi-institutional platform&#xD;
      to capitalize on multiple aspects of this carefully constructed initiative toward long-term&#xD;
      goals such as better understanding and translation of the biologic mechanisms of H2S and PCR.&#xD;
      Data collected in the first aim across institutions will be integrated and made public.This&#xD;
      platform will encourage communication and collaboration among basic scientists, translational&#xD;
      investigators, and clinical communities. This synergy will allow the investigators to define&#xD;
      the mechanisms of H2S and PCR effects, and will also give insights into the human response to&#xD;
      trauma (lipidomics, microbiome, proteins/microRNAs) that regulate the pro-inflammatory&#xD;
      response to injury, and will allow for mechanistic links among these factors ties to surgical&#xD;
      outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 14, 2017</start_date>
  <completion_date type="Actual">June 1, 2018</completion_date>
  <primary_completion_date type="Actual">June 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>
    <intervention_model_description>3:2 randomization to short-term protein calorie restriction diet versus regular meals prior to elective carotid artery endarterectomy</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>subject compliance with PCR</measure>
    <time_frame>three days pre-operatively</time_frame>
    <description>will measure subject compliance via direct dietary intake data by way of written food diary and biologic markers (serum markers including plasma free amino acids and insulin-like growth factor).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>measurement of local and systemic hydrogen sulfide and standard markers of stress peri-procedurally</measure>
    <time_frame>change over 4.5 weeks from baseline</time_frame>
    <description>hydrogen sulfide upregulation has been linked to improved vascular surgery outcomes in rodent models when rodents are pre-operatively on PCR diets</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>fecal microbiome characterization</measure>
    <time_frame>change over 4.5 weeks from baseline</time_frame>
    <description>if PCR and surgery has an impact on patient microbiome or microbiome related metabolites</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Carotid Stenosis</condition>
  <condition>Caloric Restriction</condition>
  <arm_group>
    <arm_group_label>PCR</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>pre-operative protein calorie restricted (PCR) group. participants randomized to this arm will consume scandishake diet (strawberry, caramel, banana cream, vanilla) mixed with almond milk for three days inpatient prior to planned elective carotid endarterectomy. Water is ad libitum for this cohort. Nutritionists will prepare shakes so participants will achieve 30% calorie restriction and severe protein restriction during the three days on the diet.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>control regular diet</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>participants in this cohort are randomized to the control group and will have no dietary restriction three days in patient prior to planned elective carotid endarterectomy</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>ScandiShake</intervention_name>
    <description>weight gain supplement low in protein</description>
    <arm_group_label>PCR</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  consenting adults (men and women)&#xD;
&#xD;
          -  clinical indication for carotid endarterectomy (CEA) as determined by attending&#xD;
             vascular surgeon&#xD;
&#xD;
          -  if symptomatic, patients must be able to safely have surgery timed for PCR&#xD;
             intervention&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  intolerance or allergy to any ingredients in the PCR diet (ScandiShake ingredients or&#xD;
             almond milk/nuts)&#xD;
&#xD;
          -  active infection&#xD;
&#xD;
          -  pregnancy&#xD;
&#xD;
          -  malnutrition determined by serum albumin lower than BWH reference value of 3.5 g/dL&#xD;
&#xD;
          -  active drug dependency or alcoholism that could interfere with protocol adherence&#xD;
&#xD;
          -  active non-cutaneous cancer under treatment with chemotherapeutic&#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>C. Keith Ozaki, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Brigham and Women's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Brigham and Women's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Hine C, Kim HJ, Zhu Y, Harputlugil E, Longchamp A, Matos MS, Ramadoss P, Bauerle K, Brace L, Asara JM, Ozaki CK, Cheng SY, Singha S, Ahn KH, Kimmelman A, Fisher FM, Pissios P, Withers DJ, Selman C, Wang R, Yen K, Longo VD, Cohen P, Bartke A, Kopchick JJ, Miller R, Hollenberg AN, Mitchell JR. Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production. Cell Metab. 2017 Jun 6;25(6):1320-1333.e5. doi: 10.1016/j.cmet.2017.05.003.</citation>
    <PMID>28591635</PMID>
  </reference>
  <reference>
    <citation>Longchamp A, Harputlugil E, Corpataux JM, Ozaki CK, Mitchell JR. Is Overnight Fasting before Surgery Too Much or Not Enough? How Basic Aging Research Can Guide Preoperative Nutritional Recommendations to Improve Surgical Outcomes: A Mini-Review. Gerontology. 2017;63(3):228-237. doi: 10.1159/000453109. Epub 2017 Jan 5.</citation>
    <PMID>28052287</PMID>
  </reference>
  <reference>
    <citation>Longchamp A, Tao M, Bartelt A, Ding K, Lynch L, Hine C, Corpataux JM, Kristal BS, Mitchell JR, Ozaki CK. Surgical injury induces local and distant adipose tissue browning. Adipocyte. 2015 Nov 20;5(2):163-74. doi: 10.1080/21623945.2015.1111971. eCollection 2016 Apr-Jun.</citation>
    <PMID>27386152</PMID>
  </reference>
  <reference>
    <citation>Robertson LT, Trevino-Villarreal JH, Mejia P, Grondin Y, Harputlugil E, Hine C, Vargas D, Zheng H, Ozaki CK, Kristal BS, Simpson SJ, Mitchell JR. Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice. J Nutr. 2015 Aug;145(8):1717-27. doi: 10.3945/jn.114.199380. Epub 2015 Jun 3.</citation>
    <PMID>26041674</PMID>
  </reference>
  <reference>
    <citation>Hine C, Harputlugil E, Zhang Y, Ruckenstuhl C, Lee BC, Brace L, Longchamp A, Trevino-Villarreal JH, Mejia P, Ozaki CK, Wang R, Gladyshev VN, Madeo F, Mair WB, Mitchell JR. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell. 2015 Jan 15;160(1-2):132-44. doi: 10.1016/j.cell.2014.11.048. Epub 2014 Dec 23.</citation>
    <PMID>25542313</PMID>
  </reference>
  <reference>
    <citation>Mauro CR, Tao M, Yu P, Trevino-Villerreal JH, Longchamp A, Kristal BS, Ozaki CK, Mitchell JR. Preoperative dietary restriction reduces intimal hyperplasia and protects from ischemia-reperfusion injury. J Vasc Surg. 2016 Feb;63(2):500-9.e1. doi: 10.1016/j.jvs.2014.07.004. Epub 2014 Aug 8.</citation>
    <PMID>25124359</PMID>
  </reference>
  <reference>
    <citation>Nguyen B, Tao M, Yu P, Mauro C, Seidman MA, Wang YE, Mitchell J, Ozaki CK. Preoperative diet impacts the adipose tissue response to surgical trauma. Surgery. 2013 Apr;153(4):584-93. doi: 10.1016/j.surg.2012.11.001. Epub 2012 Dec 27.</citation>
    <PMID>23274098</PMID>
  </reference>
  <reference>
    <citation>Mitchell JR, Beckman JA, Nguyen LL, Ozaki CK. Reducing elective vascular surgery perioperative risk with brief preoperative dietary restriction. Surgery. 2013 Apr;153(4):594-8. doi: 10.1016/j.surg.2012.09.007. Epub 2012 Dec 4.</citation>
    <PMID>23218877</PMID>
  </reference>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>September 27, 2017</study_first_submitted>
  <study_first_submitted_qc>October 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 6, 2017</study_first_posted>
  <last_update_submitted>June 27, 2018</last_update_submitted>
  <last_update_submitted_qc>June 27, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 28, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Brigham and Women's Hospital</investigator_affiliation>
    <investigator_full_name>C. Keith Ozaki, M.D., F.A.C.S.</investigator_full_name>
    <investigator_title>Attending Surgeon</investigator_title>
  </responsible_party>
  <keyword>inflammation</keyword>
  <keyword>hydrogen sulfide</keyword>
  <keyword>caloric restriction</keyword>
  <keyword>vascular surgery</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carotid Stenosis</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/NCT03303534
org study id: 2016P002507
nct id: NCT03303534
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This research study will compare the impact of dietary restriction pre-operatively before
      carotid endarterectomy compared to the standard nutrition that a patient typically eats. The
      investigators want to find out how patients comply and generally how well patients do with
      this type of dietary restriction before their surgery since animal studies suggest that short
      - term dietary restriction may be beneficial before surgery.
The primary, scientific long term objective is to study any correlation that brief
      upregulation of endogenous hydrogen sulfide (H2S) via pre-operative protein calorie
      restriction (PCR) in elective major surgery may have biologic effects in humans. In this
      study, the investigators plan to evaluate patient compliance and the physiologic response
      pre-operative PCR has on patients undergoing carotid endarterectomy surgery. This will be
      explored via two primary aims.

      The First Aim looks to create a prospective, fast-track, one-year study of 40 vascular
      surgery patients undergoing elective carotid artery endarterectomy randomized into two
      pre-operative dietary groups: observational group (n=16) and PCR (commercially available
      ScandiShake x 3 days, n=24). This pilot study is based on preliminary data balanced with
      economic and clinical feasibility considerations. The primary endpoints of this study are: 1)
      feasibility of subject compliance with PCR (measured by direct dietary intake data and serum
      markers including plasma free amino acids and insulin-like growth factor; thus the 2:3
      randomization) and 2) measurement of H2S and standard markers of stress before and after
      surgery (including stress hormones, oxidative stress, inflammation and cardiac troponin T
      levels). Individual patient's microbiomes,phenotype of circulating blood cells, adipose
      tissue (peri-vascular, subcutaneous), and the excised carotid plaque will be characterized to
      inform on potential mechanistic links among these and PCR induced H2S upregulation, reduced
      peri-operative stress, atherosclerotic plaque stability, and improved outcome (baseline and
      peri-procedural clinical datasets will be completed) for future clinical trials. Key
      secondary data points include observing endpoints such as carotid restenosis and surgical
      complications (cardiac, neurologic, wound, etc) between the two groups, which the
      investigators hypothesize will help to inform future trials. This pilot study will elucidate
      not only the practicality of pre-operative short term dietary restriction, but also provide
      physiologic data to support the long term primary scientific objective stated previously.

      The Second Specific Aim is to establish a robust human discovery multi-institutional platform
      to capitalize on multiple aspects of this carefully constructed initiative toward long-term
      goals such as better understanding and translation of the biologic mechanisms of H2S and PCR.
      Data collected in the first aim across institutions will be integrated and made public.This
      platform will encourage communication and collaboration among basic scientists, translational
      investigators, and clinical communities. This synergy will allow the investigators to define
      the mechanisms of H2S and PCR effects, and will also give insights into the human response to
      trauma (lipidomics, microbiome, proteins/microRNAs) that regulate the pro-inflammatory
      response to injury, and will allow for mechanistic links among these factors ties to surgical
      outcomes.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: 3:2 randomization to short-term protein calorie restriction diet versus regular meals prior to elective carotid artery endarterectomy
primary purpose: Basic Science
masking: None (Open Label)
measure: subject compliance with PCR
time frame: three days pre-operatively
description: will measure subject compliance via direct dietary intake data by way of written food diary and biologic markers (serum markers including plasma free amino acids and insulin-like growth factor).
measure: measurement of local and systemic hydrogen sulfide and standard markers of stress peri-procedurally
time frame: change over 4.5 weeks from baseline
description: hydrogen sulfide upregulation has been linked to improved vascular surgery outcomes in rodent models when rodents are pre-operatively on PCR diets
measure: fecal microbiome characterization
time frame: change over 4.5 weeks from baseline
description: if PCR and surgery has an impact on patient microbiome or microbiome related metabolites
arm group label: PCR
arm group type: Experimental
description: pre-operative protein calorie restricted (PCR) group. participants randomized to this arm will consume scandishake diet (strawberry, caramel, banana cream, vanilla) mixed with almond milk for three days inpatient prior to planned elective carotid endarterectomy. Water is ad libitum for this cohort. Nutritionists will prepare shakes so participants will achieve 30% calorie restriction and severe protein restriction during the three days on the diet.
arm group label: control regular diet
arm group type: No Intervention
description: participants in this cohort are randomized to the control group and will have no dietary restriction three days in patient prior to planned elective carotid endarterectomy
intervention type: Dietary Supplement
intervention name: ScandiShake
description: weight gain supplement low in protein
arm group label: PCR
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: C. Keith Ozaki, M.D.
role: Principal Investigator
affiliation: Brigham and Women's Hospital
facility: 
country: United States
citation: Hine C, Kim HJ, Zhu Y, Harputlugil E, Longchamp A, Matos MS, Ramadoss P, Bauerle K, Brace L, Asara JM, Ozaki CK, Cheng SY, Singha S, Ahn KH, Kimmelman A, Fisher FM, Pissios P, Withers DJ, Selman C, Wang R, Yen K, Longo VD, Cohen P, Bartke A, Kopchick JJ, Miller R, Hollenberg AN, Mitchell JR. Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production. Cell Metab. 2017 Jun 6;25(6):1320-1333.e5. doi: 10.1016/j.cmet.2017.05.003.
PMID: 28591635
citation: Longchamp A, Harputlugil E, Corpataux JM, Ozaki CK, Mitchell JR. Is Overnight Fasting before Surgery Too Much or Not Enough? How Basic Aging Research Can Guide Preoperative Nutritional Recommendations to Improve Surgical Outcomes: A Mini-Review. Gerontology. 2017;63(3):228-237. doi: 10.1159/000453109. Epub 2017 Jan 5.
PMID: 28052287
citation: Longchamp A, Tao M, Bartelt A, Ding K, Lynch L, Hine C, Corpataux JM, Kristal BS, Mitchell JR, Ozaki CK. Surgical injury induces local and distant adipose tissue browning. Adipocyte. 2015 Nov 20;5(2):163-74. doi: 10.1080/21623945.2015.1111971. eCollection 2016 Apr-Jun.
PMID: 27386152
citation: Robertson LT, Trevino-Villarreal JH, Mejia P, Grondin Y, Harputlugil E, Hine C, Vargas D, Zheng H, Ozaki CK, Kristal BS, Simpson SJ, Mitchell JR. Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice. J Nutr. 2015 Aug;145(8):1717-27. doi: 10.3945/jn.114.199380. Epub 2015 Jun 3.
PMID: 26041674
citation: Hine C, Harputlugil E, Zhang Y, Ruckenstuhl C, Lee BC, Brace L, Longchamp A, Trevino-Villarreal JH, Mejia P, Ozaki CK, Wang R, Gladyshev VN, Madeo F, Mair WB, Mitchell JR. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell. 2015 Jan 15;160(1-2):132-44. doi: 10.1016/j.cell.2014.11.048. Epub 2014 Dec 23.
PMID: 25542313
citation: Mauro CR, Tao M, Yu P, Trevino-Villerreal JH, Longchamp A, Kristal BS, Ozaki CK, Mitchell JR. Preoperative dietary restriction reduces intimal hyperplasia and protects from ischemia-reperfusion injury. J Vasc Surg. 2016 Feb;63(2):500-9.e1. doi: 10.1016/j.jvs.2014.07.004. Epub 2014 Aug 8.
PMID: 25124359
citation: Nguyen B, Tao M, Yu P, Mauro C, Seidman MA, Wang YE, Mitchell J, Ozaki CK. Preoperative diet impacts the adipose tissue response to surgical trauma. Surgery. 2013 Apr;153(4):584-93. doi: 10.1016/j.surg.2012.11.001. Epub 2012 Dec 27.
PMID: 23274098
citation: Mitchell JR, Beckman JA, Nguyen LL, Ozaki CK. Reducing elective vascular surgery perioperative risk with brief preoperative dietary restriction. Surgery. 2013 Apr;153(4):594-8. doi: 10.1016/j.surg.2012.09.007. Epub 2012 Dec 4.
PMID: 23218877
responsible party type: Principal Investigator
investigator affiliation: Brigham and Women's Hospital
investigator full name: C. Keith Ozaki, M.D., F.A.C.S.
investigator title: Attending Surgeon
mesh term: Carotid Stenosis
sharing ipd: No