<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/NCT03234543</url>
  </required_header>
  <id_info>
    <org_study_id>Pro20160001420</org_study_id>
    <nct_id>NCT03234543</nct_id>
  </id_info>
  <brief_title>Remote Ischemic Conditioning in Abdominal Surgery</brief_title>
  <official_title>Remote Ischemic Conditioning (RIC) to Decrease Post-Operative Complications After Major Abdominal Surgery - A Phase IIa Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rutgers, The State University of New Jersey</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rutgers, The State University of New Jersey</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 phase II randomized (1:1) controlled trial will examine the effects of remote ischemic&#xD;
      conditioning (RIC) on the outcomes of major abdominal surgery. One hundred subjects will be&#xD;
      enrolled at a single institution - University Hospital - Newark. The study population are&#xD;
      patients undergoing major abdominal surgery (anticipated to be &gt;/= 2 hrs long with a hospital&#xD;
      stay &gt;/= 2 days). Subjects in the treatment group will receive lower limb ischemic&#xD;
      conditioning at 3 different time points: before surgery, POD 1 and POD 2. The primary outcome&#xD;
      is the 30-day comprehensive complications index (CCI). Key secondary outcomes are changes in&#xD;
      systemic inflammatory markers in peripheral blood and 30-day mortality.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      STUDY GOALS AND OBJECTIVES:&#xD;
&#xD;
        1. To obtain preliminary data regarding postoperative complications in subjects undergoing&#xD;
           abdominal surgery and receiving remote limb ischemic or sham conditioning.&#xD;
&#xD;
        2. To test whether remote limb ischemic conditioning (RIC) decreases systemic inflammatory&#xD;
           response in patients undergoing major abdominal surgery.&#xD;
&#xD;
      HYPOTHESiS:&#xD;
&#xD;
      The central hypothesis of the research is that pre- and post-operative RIC in patients&#xD;
      undergoing major abdominal surgery would decrease the systemic inflammatory response to major&#xD;
      abdominal surgery and decrease postoperative complications.&#xD;
&#xD;
      STUDY DESIGN:&#xD;
&#xD;
      A prospective, randomized, double - masked clinical trial of RIC will be conducted in adult&#xD;
      patients undergoing major abdominal surgery at University Hospital in Newark, NJ.&#xD;
      Participants will be randomized into two groups: RIC and No RIC. RIC will be induced at three&#xD;
      time points - the first after anesthesia induction but before commencement of surgery, and&#xD;
      the second and the third on post-operative days 1 and 2, respectively. The RIC intervention&#xD;
      consists of 5 minutes of inflation of a pneumatic tourniquet placed mid-thigh followed by 5&#xD;
      minutes of deflation, repeated for 3 cycles. The pressure used will be 250 mmHg for the&#xD;
      pre-operative intervention. Subsequent tourniquet pressures will be 50 mmHg above the&#xD;
      patient's systolic blood pressure. The No RIC group will receive a sham intervention at all&#xD;
      the same time points. The thigh tourniquet will be inflated to only 20 mmHg. A Doppler probe&#xD;
      will be used to assess pedal arterial flow in both groups. Blood samples will be collected at&#xD;
      baseline, 1hr after skin closure, and 1hr after interventions 2 and 3.&#xD;
&#xD;
      STUDY POPULATION:&#xD;
&#xD;
      Adults (&gt; 18 years of age) of both sexes scheduled for elective major abdominal surgery at&#xD;
      University Hospital will be considered for inclusion. Major abdominal surgery is defined as&#xD;
      peritoneal, retroperitoneal and pelvic surgery expected to last &gt;/= 120 minutes (from&#xD;
      incision to closure) with an expected hospital stay &gt;/= 2 days. A list of surgeries&#xD;
      considered for inclusion is included as Appendix A. Additional operations will be considered&#xD;
      for inclusion if the study team and primary surgical team both agree that the procedure is a&#xD;
      major abdominal surgery and that the duration of surgery is likely to be &gt; 2 hours.&#xD;
&#xD;
      RISKS AND BENEFITS&#xD;
&#xD;
        1. Risks to Subjects During inflation of the tourniquet in awake patients (post-op), there&#xD;
           is a risk of pain secondary to tourniquet inflation. The investigators believe this risk&#xD;
           is small, and if it occurs, the patient will have the option to discontinue the&#xD;
           intervention.&#xD;
&#xD;
           There is a theoretical risk of injury to the limb receiving the RIC stimulus. However,&#xD;
           such occurrences have not been reported to date in other clinical studies.&#xD;
&#xD;
           During collection of blood samples, there is a theoretical risk of bleeding from the&#xD;
           venipuncture site; however this risk is no greater than routine blood draw. The amount&#xD;
           of blood drawn for study purposes will be small (less than 50 mL total anticipated).&#xD;
&#xD;
        2. Benefits to Subjects The anticipated benefit to subjects is fewer complications after&#xD;
           major abdominal surgery. However, no such benefit may accrue. In addition, the study is&#xD;
           expected to provide valuable information regarding how RIC might modulate stress&#xD;
           response to major surgery.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Enrolling by invitation</last_known_status>
  <start_date type="Actual">October 8, 2017</start_date>
  <completion_date type="Anticipated">June 15, 2020</completion_date>
  <primary_completion_date type="Anticipated">June 15, 2019</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>A prospective, randomized, double - masked clinical trial of RIC will be conducted in adult patients undergoing major abdominal surgery at University Hospital in Newark, NJ. Participants will be randomized into two groups: RIC and No RIC.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Care Provider, Outcomes Assessor)</masking>
    <masking_description>The study will be conducted in a double-masked fashion. Investigative team member/s that will carry out randomization and administer the intervention will not be involved in evaluation of clinical and laboratory outcomes. The primary surgical team, nurses, and any consulting services caring for the patient will be unaware of the group assignment. Other care providers will not be informed of the group assignment. Outcome assessors will not be involved in randomization and administration of the RIC intervention. Adequate steps are in place to mask the outcome assessors (clinical and laboratory) from knowing group assignment.&#xD;
Subjects will be masked from recognizing which group they are in in the following manner: a) Subjects will not be informed of the group assignment throughout their participation in the study; b) subjects randomized to No RIPC will have a tourniquet placed on the thigh and inflated.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Comprehensive Complication Index</measure>
    <time_frame>30 days after surgery</time_frame>
    <description>The CCI, a validated and scaled score of all surgical complications (range 0 [no complications] to 100 [death]) will be computed for each subject using the publically available website, http://www.assessurgery.com/.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Completion all three interventions</measure>
    <time_frame>Up to 3 days</time_frame>
    <description>Proportions of subjects completing all three research interventions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital days</measure>
    <time_frame>Up to 30 days</time_frame>
    <description>Number of days to discharge from the hospital after surgery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>30-day mortality</measure>
    <time_frame>Up to 30 days</time_frame>
    <description>Proportions of patients dying within 30 days after surgery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma complement levels (C2, C4b, C5, C5a, and C5b-9)</measure>
    <time_frame>Up to 3 days</time_frame>
    <description>Measured at baseline, an hour after skin closure, completion of second and third research intervention</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma cytokines levels (TNF-a, IL - 1, 6, 8 and 10)</measure>
    <time_frame>Up to 3 days</time_frame>
    <description>Plasma cytokine levels at baseline, an hour after skin closure, completion of second and third research intervention</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma acute phase reactant proteins (CRP, alpha-1- acid glycoprotein, FGN, and haptoglobin)</measure>
    <time_frame>Up to 3 days</time_frame>
    <description>Measured at baseline, an hour after skin closure, completion of second and third research intervention</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peripheral blood leukocyte gene expression profiles determined by RNA sequencing.</measure>
    <time_frame>Up to 3 days</time_frame>
    <description>Measured at baseline, an hour after skin closure, completion of second and third research intervention</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Laparotomy</condition>
  <condition>Laparoscopy</condition>
  <condition>Retroperitoneal Disease</condition>
  <condition>Pelvis Disease</condition>
  <condition>Pancreatic Diseases</condition>
  <condition>Liver Diseases</condition>
  <condition>Gastrointestinal Disease</condition>
  <condition>Urologic Diseases</condition>
  <condition>Complication of Surgical Procedure</condition>
  <arm_group>
    <arm_group_label>Remote Ischemic Conditioning</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The RIC intervention consists of 5 minutes of inflation of a pneumatic tourniquet placed mid-thigh followed by 5 minutes of deflation, repeated for 3 cycles. The pressure used will be 250 mmHg for the pre-operative intervention. Subsequent tourniquet pressures will be 50 mmHg above the patient's systolic blood pressure.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>No Remote Ischemic Conditioning</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>The No RIC group will receive a sham intervention at all the same time points. The thigh tourniquet will be inflated to only 20 mmHg (to mask the intervention from the subject).</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Remote ischemic conditioning</intervention_name>
    <description>Placement of blood pressure cuff to lower extremity in order to induce temporary and reversible ischemia.</description>
    <arm_group_label>Remote Ischemic Conditioning</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>No Remote ischemic conditioning</intervention_name>
    <description>Placement of blood pressure cuff to lower extremity with minimal inflation without inducing ischemia.</description>
    <arm_group_label>No Remote Ischemic Conditioning</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adults (&gt; 18 years of age)&#xD;
&#xD;
          2. Both genders&#xD;
&#xD;
          3. Undergoing major abdominal surgery as above&#xD;
&#xD;
          4. Elective surgeries&#xD;
&#xD;
          5. Both outpatients and in-hospital patients&#xD;
&#xD;
          6. Post-op length of stay expected to be at least 2 days by the primary surgical service&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Subjects with lower extremity paralysis&#xD;
&#xD;
          2. Lower extremity amputees&#xD;
&#xD;
          3. Known, documented peripheral arterial disease&#xD;
&#xD;
          4. Body mass index &gt; 45&#xD;
&#xD;
          5. Pregnancy&#xD;
&#xD;
          6. Trauma patients&#xD;
&#xD;
          7. Organ transplant recipients&#xD;
&#xD;
          8. Prior major surgery during current hospitalization (for instance, a patient undergoing&#xD;
             re-laparotomy for a complication from a previous procedure)&#xD;
&#xD;
          9. Patient taking sulfonylureas or nitrates prior to or during admission (listed in&#xD;
             Appendix B)&#xD;
&#xD;
             a. These subjects are excluded because sulfonylureas are shown to abrogate the RIC&#xD;
             effect whereas nitrates are shown to mimic the RIC effect in animal models.&#xD;
&#xD;
         10. Non-elective surgeries (urgent or emergent surgeries)&#xD;
&#xD;
         11. General surgical procedures with no planned intra-abdominal component&#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>Baburao Koneru, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rutgers-NJMS</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospital</name>
      <address>
        <city>Newark</city>
        <state>New Jersey</state>
        <zip>07101</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Slankamenac K, Graf R, Barkun J, Puhan MA, Clavien PA. The comprehensive complication index: a novel continuous scale to measure surgical morbidity. Ann Surg. 2013 Jul;258(1):1-7. doi: 10.1097/SLA.0b013e318296c732.</citation>
    <PMID>23728278</PMID>
  </reference>
  <reference>
    <citation>Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13. doi: 10.1097/01.sla.0000133083.54934.ae.</citation>
    <PMID>15273542</PMID>
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    <citation>Lausevic Z, Lausevic M, Trbojevic-Stankovic J, Krstic S, Stojimirovic B. Predicting multiple organ failure in patients with severe trauma. Can J Surg. 2008 Apr;51(2):97-102.</citation>
    <PMID>18377749</PMID>
  </reference>
  <reference>
    <citation>Kvarnstrom AL, Sarbinowski RT, Bengtson JP, Jacobsson LM, Bengtsson AL. Complement activation and interleukin response in major abdominal surgery. Scand J Immunol. 2012 May;75(5):510-6. doi: 10.1111/j.1365-3083.2012.02672.x.</citation>
    <PMID>22229650</PMID>
  </reference>
  <reference>
    <citation>Kvarnstrom A, Sokolov A, Swartling T, Kurlberg G, Mollnes TE, Bengtsson A. Alternative pathway activation of complement in laparoscopic and open rectal surgery. Scand J Immunol. 2012 Jul;76(1):49-53. doi: 10.1111/j.1365-3083.2012.02702.x.</citation>
    <PMID>22486843</PMID>
  </reference>
  <reference>
    <citation>Birnbaum Y, Hale SL, Kloner RA. Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation. 1997 Sep 2;96(5):1641-6. doi: 10.1161/01.cir.96.5.1641.</citation>
    <PMID>9315559</PMID>
  </reference>
  <reference>
    <citation>Leung CH, Caldarone CA, Wang F, Venkateswaran S, Ailenberg M, Vadasz B, Wen XY, Rotstein OD. Remote Ischemic Conditioning Prevents Lung and Liver Injury After Hemorrhagic Shock/Resuscitation: Potential Role of a Humoral Plasma Factor. Ann Surg. 2015 Jun;261(6):1215-25. doi: 10.1097/SLA.0000000000000877.</citation>
    <PMID>25185480</PMID>
  </reference>
  <reference>
    <citation>Konstantinov IE, Arab S, Kharbanda RK, Li J, Cheung MM, Cherepanov V, Downey GP, Liu PP, Cukerman E, Coles JG, Redington AN. The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics. 2004 Sep 16;19(1):143-50. doi: 10.1152/physiolgenomics.00046.2004. Epub 2004 Aug 10.</citation>
    <PMID>15304621</PMID>
  </reference>
  <reference>
    <citation>Pang T, Zhao Y, Zhang NR, Jin SQ, Pan SQ. Transient limb ischemia alters serum protein expression in healthy volunteers: complement C3 and vitronectin may be involved in organ protection induced by remote ischemic preconditioning. Oxid Med Cell Longev. 2013;2013:859056. doi: 10.1155/2013/859056. Epub 2013 Dec 2.</citation>
    <PMID>24363825</PMID>
  </reference>
  <reference>
    <citation>Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc Res. 2008 Aug 1;79(3):377-86. doi: 10.1093/cvr/cvn114. Epub 2008 May 2.</citation>
    <PMID>18456674</PMID>
  </reference>
  <reference>
    <citation>Ali ZA, Callaghan CJ, Lim E, Ali AA, Nouraei SA, Akthar AM, Boyle JR, Varty K, Kharbanda RK, Dutka DP, Gaunt ME. Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation. 2007 Sep 11;116(11 Suppl):I98-105. doi: 10.1161/circulationaha.106.679167.</citation>
    <PMID>17846333</PMID>
  </reference>
  <reference>
    <citation>Meng R, Asmaro K, Meng L, Liu Y, Ma C, Xi C, Li G, Ren C, Luo Y, Ling F, Jia J, Hua Y, Wang X, Ding Y, Lo EH, Ji X. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology. 2012 Oct 30;79(18):1853-61. doi: 10.1212/WNL.0b013e318271f76a. Epub 2012 Oct 3.</citation>
    <PMID>23035060</PMID>
  </reference>
  <reference>
    <citation>Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, Wolf B, Goebel U, Schwer CI, Rosenberger P, Haeberle H, Gorlich D, Kellum JA, Meersch M; RenalRIPC Investigators. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA. 2015 Jun 2;313(21):2133-41. doi: 10.1001/jama.2015.4189.</citation>
    <PMID>26024502</PMID>
  </reference>
  <reference>
    <citation>Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, Coburn M, Schaelte G, Boning A, Niemann B, Roesner J, Kletzin F, Strouhal U, Reyher C, Laufenberg-Feldmann R, Ferner M, Brandes IF, Bauer M, Stehr SN, Kortgen A, Wittmann M, Baumgarten G, Meyer-Treschan T, Kienbaum P, Heringlake M, Schon J, Sander M, Treskatsch S, Smul T, Wolwender E, Schilling T, Fuernau G, Hasenclever D, Zacharowski K; RIPHeart Study Collaborators. A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery. N Engl J Med. 2015 Oct 8;373(15):1397-407. doi: 10.1056/NEJMoa1413579. Epub 2015 Oct 5.</citation>
    <PMID>26436208</PMID>
  </reference>
  <reference>
    <citation>Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, Knight R, Kunst G, Laing C, Nicholas J, Pepper J, Robertson S, Xenou M, Clayton T, Yellon DM; ERICCA Trial Investigators. Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery. N Engl J Med. 2015 Oct 8;373(15):1408-17. doi: 10.1056/NEJMoa1413534. Epub 2015 Oct 5.</citation>
    <PMID>26436207</PMID>
  </reference>
  <reference>
    <citation>Gonzalez NR, Hamilton R, Bilgin-Freiert A, Dusick J, Vespa P, Hu X, Asgari S. Cerebral hemodynamic and metabolic effects of remote ischemic preconditioning in patients with subarachnoid hemorrhage. Acta Neurochir Suppl. 2013;115:193-8. doi: 10.1007/978-3-7091-1192-5_36.</citation>
    <PMID>22890668</PMID>
  </reference>
  <reference>
    <citation>Li S, Ma C, Shao G, Esmail F, Hua Y, Jia L, Qin J, Ren C, Luo Y, Ding Y, Borlongan CV, Ji X. Safety and Feasibility of Remote Limb Ischemic Preconditioning in Patients With Unilateral Middle Cerebral Artery Stenosis and Healthy Volunteers. Cell Transplant. 2015;24(9):1901-11. doi: 10.3727/096368914X683520. Epub 2014 Jul 30.</citation>
    <PMID>25198862</PMID>
  </reference>
  <reference>
    <citation>Bilgin-Freiert A, Dusick JR, Stein NR, Etchepare M, Vespa P, Gonzalez NR. Muscle microdialysis to confirm sublethal ischemia in the induction of remote ischemic preconditioning. Transl Stroke Res. 2012 Jun;3(2):266-72. doi: 10.1007/s12975-012-0153-1. Epub 2012 Apr 10.</citation>
    <PMID>24323782</PMID>
  </reference>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>July 25, 2017</study_first_submitted>
  <study_first_submitted_qc>July 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>February 22, 2019</last_update_submitted>
  <last_update_submitted_qc>February 22, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 25, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Rutgers, The State University of New Jersey</investigator_affiliation>
    <investigator_full_name>Baburao Koneru, MD, MPH</investigator_full_name>
    <investigator_title>Professor of Surgery</investigator_title>
  </responsible_party>
  <keyword>Abdominal Surgery</keyword>
  <keyword>Pre-conditioning</keyword>
  <keyword>Remote Ischemic Conditioning</keyword>
  <keyword>Post-Operative Complications</keyword>
  <keyword>Acute Phase Response</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Gastrointestinal Diseases</mesh_term>
    <mesh_term>Digestive System Diseases</mesh_term>
    <mesh_term>Pancreatic Diseases</mesh_term>
    <mesh_term>Urologic Diseases</mesh_term>
    <mesh_term>Postoperative Complications</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>May 22, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/43/NCT03234543/ICF_002.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>September 8, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/43/NCT03234543/SAP_003.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>September 8, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/43/NCT03234543/Prot_004.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03234543
org study id: Pro20160001420
nct id: NCT03234543
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This phase II randomized (1:1) controlled trial will examine the effects of remote ischemic
      conditioning (RIC) on the outcomes of major abdominal surgery. One hundred subjects will be
      enrolled at a single institution - University Hospital - Newark. The study population are
      patients undergoing major abdominal surgery (anticipated to be >/= 2 hrs long with a hospital
      stay >/= 2 days). Subjects in the treatment group will receive lower limb ischemic
      conditioning at 3 different time points: before surgery, POD 1 and POD 2. The primary outcome
      is the 30-day comprehensive complications index (CCI). Key secondary outcomes are changes in
      systemic inflammatory markers in peripheral blood and 30-day mortality.
STUDY GOALS AND OBJECTIVES:

        1. To obtain preliminary data regarding postoperative complications in subjects undergoing
           abdominal surgery and receiving remote limb ischemic or sham conditioning.

        2. To test whether remote limb ischemic conditioning (RIC) decreases systemic inflammatory
           response in patients undergoing major abdominal surgery.

      HYPOTHESiS:

      The central hypothesis of the research is that pre- and post-operative RIC in patients
      undergoing major abdominal surgery would decrease the systemic inflammatory response to major
      abdominal surgery and decrease postoperative complications.

      STUDY DESIGN:

      A prospective, randomized, double - masked clinical trial of RIC will be conducted in adult
      patients undergoing major abdominal surgery at University Hospital in Newark, NJ.
      Participants will be randomized into two groups: RIC and No RIC. RIC will be induced at three
      time points - the first after anesthesia induction but before commencement of surgery, and
      the second and the third on post-operative days 1 and 2, respectively. The RIC intervention
      consists of 5 minutes of inflation of a pneumatic tourniquet placed mid-thigh followed by 5
      minutes of deflation, repeated for 3 cycles. The pressure used will be 250 mmHg for the
      pre-operative intervention. Subsequent tourniquet pressures will be 50 mmHg above the
      patient's systolic blood pressure. The No RIC group will receive a sham intervention at all
      the same time points. The thigh tourniquet will be inflated to only 20 mmHg. A Doppler probe
      will be used to assess pedal arterial flow in both groups. Blood samples will be collected at
      baseline, 1hr after skin closure, and 1hr after interventions 2 and 3.

      STUDY POPULATION:

      Adults (> 18 years of age) of both sexes scheduled for elective major abdominal surgery at
      University Hospital will be considered for inclusion. Major abdominal surgery is defined as
      peritoneal, retroperitoneal and pelvic surgery expected to last >/= 120 minutes (from
      incision to closure) with an expected hospital stay >/= 2 days. A list of surgeries
      considered for inclusion is included as Appendix A. Additional operations will be considered
      for inclusion if the study team and primary surgical team both agree that the procedure is a
      major abdominal surgery and that the duration of surgery is likely to be > 2 hours.

      RISKS AND BENEFITS

        1. Risks to Subjects During inflation of the tourniquet in awake patients (post-op), there
           is a risk of pain secondary to tourniquet inflation. The investigators believe this risk
           is small, and if it occurs, the patient will have the option to discontinue the
           intervention.

           There is a theoretical risk of injury to the limb receiving the RIC stimulus. However,
           such occurrences have not been reported to date in other clinical studies.

           During collection of blood samples, there is a theoretical risk of bleeding from the
           venipuncture site; however this risk is no greater than routine blood draw. The amount
           of blood drawn for study purposes will be small (less than 50 mL total anticipated).

        2. Benefits to Subjects The anticipated benefit to subjects is fewer complications after
           major abdominal surgery. However, no such benefit may accrue. In addition, the study is
           expected to provide valuable information regarding how RIC might modulate stress
           response to major surgery.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: A prospective, randomized, double - masked clinical trial of RIC will be conducted in adult patients undergoing major abdominal surgery at University Hospital in Newark, NJ. Participants will be randomized into two groups: RIC and No RIC.
primary purpose: Prevention
masking: Triple (Participant, Care Provider, Outcomes Assessor)
masking description: The study will be conducted in a double-masked fashion. Investigative team member/s that will carry out randomization and administer the intervention will not be involved in evaluation of clinical and laboratory outcomes. The primary surgical team, nurses, and any consulting services caring for the patient will be unaware of the group assignment. Other care providers will not be informed of the group assignment. Outcome assessors will not be involved in randomization and administration of the RIC intervention. Adequate steps are in place to mask the outcome assessors (clinical and laboratory) from knowing group assignment.
Subjects will be masked from recognizing which group they are in in the following manner: a) Subjects will not be informed of the group assignment throughout their participation in the study; b) subjects randomized to No RIPC will have a tourniquet placed on the thigh and inflated.
measure: Comprehensive Complication Index
time frame: 30 days after surgery
description: The CCI, a validated and scaled score of all surgical complications (range 0 [no complications] to 100 [death]) will be computed for each subject using the publically available website, http://www.assessurgery.com/.
measure: Completion all three interventions
time frame: Up to 3 days
description: Proportions of subjects completing all three research interventions
measure: Hospital days
time frame: Up to 30 days
description: Number of days to discharge from the hospital after surgery
measure: 30-day mortality
time frame: Up to 30 days
description: Proportions of patients dying within 30 days after surgery
measure: Plasma complement levels (C2, C4b, C5, C5a, and C5b-9)
time frame: Up to 3 days
description: Measured at baseline, an hour after skin closure, completion of second and third research intervention
measure: Plasma cytokines levels (TNF-a, IL - 1, 6, 8 and 10)
time frame: Up to 3 days
description: Plasma cytokine levels at baseline, an hour after skin closure, completion of second and third research intervention
measure: Plasma acute phase reactant proteins (CRP, alpha-1- acid glycoprotein, FGN, and haptoglobin)
time frame: Up to 3 days
description: Measured at baseline, an hour after skin closure, completion of second and third research intervention
measure: Peripheral blood leukocyte gene expression profiles determined by RNA sequencing.
time frame: Up to 3 days
description: Measured at baseline, an hour after skin closure, completion of second and third research intervention
arm group label: Remote Ischemic Conditioning
arm group type: Experimental
description: The RIC intervention consists of 5 minutes of inflation of a pneumatic tourniquet placed mid-thigh followed by 5 minutes of deflation, repeated for 3 cycles. The pressure used will be 250 mmHg for the pre-operative intervention. Subsequent tourniquet pressures will be 50 mmHg above the patient's systolic blood pressure.
arm group label: No Remote Ischemic Conditioning
arm group type: Sham Comparator
description: The No RIC group will receive a sham intervention at all the same time points. The thigh tourniquet will be inflated to only 20 mmHg (to mask the intervention from the subject).
intervention type: Procedure
intervention name: Remote ischemic conditioning
description: Placement of blood pressure cuff to lower extremity in order to induce temporary and reversible ischemia.
arm group label: Remote Ischemic Conditioning
intervention type: Procedure
intervention name: No Remote ischemic conditioning
description: Placement of blood pressure cuff to lower extremity with minimal inflation without inducing ischemia.
arm group label: No Remote Ischemic Conditioning
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Baburao Koneru, MD, MPH
role: Principal Investigator
affiliation: Rutgers-NJMS
facility: 
country: United States
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responsible party type: Principal Investigator
investigator affiliation: Rutgers, The State University of New Jersey
investigator full name: Baburao Koneru, MD, MPH
investigator title: Professor of Surgery
mesh term: Liver Diseases
mesh term: Gastrointestinal Diseases
mesh term: Digestive System Diseases
mesh term: Pancreatic Diseases
mesh term: Urologic Diseases
mesh term: Postoperative Complications
sharing ipd: No
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