<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/NCT02997748</url>
  </required_header>
  <id_info>
    <org_study_id>04-AnIt-16</org_study_id>
    <nct_id>NCT02997748</nct_id>
  </id_info>
  <brief_title>Remote Ischemic Preconditioning After Cardiac Surgery</brief_title>
  <acronym>RIPCRenal</acronym>
  <official_title>Remote Ischemic Preconditioning to Prevent Acute Kidney Injury in High Risk Patients After Cardiac Surgery (RIPCRenal)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital Muenster</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Else Kröner Fresenius Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital Muenster</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Acute kidney injury (AKI) is a well-recognized complication after cardiac surgery with&#xD;
      cardiopulmonary bypass (CPB). The aim of this study is to reduce the incidence of AKI by&#xD;
      implementing remote ischemic preconditioning and to evaluate the dose-response relationship&#xD;
      using the biomarkers urinary [TIMP-2] *[IGFBP7] in high risk patients undergoing cardiac&#xD;
      surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Acute kidney injury (AKI) complicates 7-19% of cardiac surgical procedures. The investigators&#xD;
      recently found that remote ischemic preconditioning (RIPC) using transient external&#xD;
      compression of the upper arm prior to cardiac surgery was effective for reducing the&#xD;
      occurrence of AKI (37.5% compared to 52.5% with sham; absolute risk reduction (ARR),15%; 95%&#xD;
      CI, 2.56% to 27.44%; P=0.02). Fewer patients treated with RIPC received renal replacement&#xD;
      therapy (RRT) (5.8% versus 15.8%; ARR, 10%; 95% CI, 2.25% to 17.75%; P=0.01). Moreover, the&#xD;
      investigators found that the effectiveness of this intervention was strongly associated with&#xD;
      the release of cell-cycle arrest biomarkers into the urine. Patients with urinary tissue&#xD;
      inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7&#xD;
      ([TIMP-2]•[IGFBP7]) ≥ 0.5 (ng/ml)(ng/ml)/1000 before surgery had a significantly reduced rate&#xD;
      of AKI compared to patients with lower urinary [TIMP-2]•[IGFBP7] concentration (relative risk&#xD;
      (RR), 67%; 95% CI, 53% to 83%, P&lt;0.001) whereas the biomarker concentrations after surgery&#xD;
      predicted AKI as previously shown. This effect makes sense because cell-cycle arrest is&#xD;
      thought to be part of the protective mechanisms endothelial cells use when exposed to stress.&#xD;
      Stimulating these responses with RIPC should reduce AKI. Importantly, only 56% of patients&#xD;
      treated with RIPC achieved an increase in urine [TIMP-2]•[IGFBP7] to ≥ 0.5, and only in this&#xD;
      group was the intervention effective-patients that did not achieve this level showed no&#xD;
      benefit.&#xD;
&#xD;
      Our goal is to eventually design and conduct a Bayesian 2-stage adaptive design sequence&#xD;
      trial to evaluate the effectiveness of RIPC to prevent AKI in patients undergoing cardiac&#xD;
      surgery. The dimensions of dose include duration, intensity and number of cycles. However,&#xD;
      before this trial can be designed we need to answer 4 questions: i. Do baseline urinary&#xD;
      [TIMP-2]•[IGFBP7] levels predict AKI (enrichment)? ii. Do [TIMP-2]•[IGFBP7] changes elicited&#xD;
      by RIPC predict protection (RIPC efficacy measure)? iii. Is there a dose-response&#xD;
      relationship between RIPC &quot;dose&quot; and [TIMP-2]•[IGFBP7]? iv. Is a dose-escalation RIPC&#xD;
      protocol where doses are increased for non-responders, feasible and safe within the&#xD;
      anesthesia workflow for cardiac surgery cases (practical)?&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>December 2016</start_date>
  <completion_date type="Anticipated">September 2019</completion_date>
  <primary_completion_date type="Anticipated">June 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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in urinary [TIMP-2]*[IGFBP7]</measure>
    <time_frame>within 12 hours after CPB</time_frame>
    <description>Biomarkers will be measured at different time points after to evaluate the effect of RIPC on [TIMP-2]*[IGFBP7]</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>AKI within 72 hours</measure>
    <time_frame>72 h</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dialysis within 7 days of surgery</measure>
    <time_frame>7 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause-mortality at 90 days</measure>
    <time_frame>90 d</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dialysis at day 90</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Renal recovery at day 90</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MAKE 90</measure>
    <time_frame>90 days</time_frame>
    <description>major adverse kidney events</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Anticipated">180</enrollment>
  <condition>Cardiac Surgery, Aortocoronary Bypass</condition>
  <arm_group>
    <arm_group_label>Observational group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>No intervention, standard care</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham RIPC</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Three cycles of 5- min upper limb sham ischemia</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RIPC-Group 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three cycles of 5- min upper limb ischemia</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RIPC-Group 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three cycles of 7-min upper limb ischemia</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RIPC-Group 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three cycles of 10-min upper limb ischemia</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RIPC-Group 4</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three Cycles of 5-min upper limb ischemia. If there is no response this will be followed by 2 cycles of 10-min upper-limb ischemia</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Remote ischemic preconditioning (RIPC)</intervention_name>
    <description>3 cycles or more cycles of 5 to 10-min inflation of a blood-pressure cuff to 200 mm HG (or at least to a pressure 50 mmHG higher than the systolic arterial pressure) to one upper arm followed by 5 min reperfusion with the cuff deflated. In Non-Responder two additional cycles of 10 min cuff inflation will be performed in arm 6.</description>
    <arm_group_label>RIPC-Group 1</arm_group_label>
    <arm_group_label>RIPC-Group 2</arm_group_label>
    <arm_group_label>RIPC-Group 3</arm_group_label>
    <arm_group_label>RIPC-Group 4</arm_group_label>
    <arm_group_label>Sham RIPC</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients who are scheduled to undergo cardiac surgery with cardiopulmonary bypass&#xD;
&#xD;
          -  Cleveland Clinic Score &gt;=6&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Acute myocardial infarction up to 7 days before surgery&#xD;
&#xD;
          -  Age &lt; 18 years&#xD;
&#xD;
          -  Off-pump cardiac surgery&#xD;
&#xD;
          -  Preexisting AKI&#xD;
&#xD;
          -  Chronic kidney disease (GFR &lt; 30 ml/min)&#xD;
&#xD;
          -  Kidney transplantation within the last 12 months&#xD;
&#xD;
          -  Peripheral arterial occlusive disease&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Hepatorenal syndrome&#xD;
&#xD;
          -  Sulfonamide or thiazide medication within the last 7 days&#xD;
&#xD;
          -  Participation in another interventional trial&#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>Melanie Meersch</last_name>
    <role>Study Chair</role>
    <affiliation>University Hospital Muenster</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Melanie Meersch, MD</last_name>
    <phone>+49-251-8347282</phone>
    <email>aki@anit.uni-muenster.de</email>
  </overall_contact>
  <location>
    <facility>
      <name>University Hospital Muenster</name>
      <address>
        <city>Muenster</city>
        <zip>D-48149</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alexander Zarbock, PhD, MD</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>December 15, 2016</study_first_submitted>
  <study_first_submitted_qc>December 15, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 20, 2016</study_first_posted>
  <last_update_submitted>January 29, 2018</last_update_submitted>
  <last_update_submitted_qc>January 29, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 30, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>acute kidney injury</keyword>
  <keyword>cardiac surgery</keyword>
  <keyword>Remote ischemic preconditioning</keyword>
  <keyword>[TIMP-2]*[IGFBP7]</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acute Kidney Injury</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/NCT02997748
org study id: 04-AnIt-16
nct id: NCT02997748
lead sponsor: 
collaborator: 
has dmc: Yes
Acute kidney injury (AKI) is a well-recognized complication after cardiac surgery with
      cardiopulmonary bypass (CPB). The aim of this study is to reduce the incidence of AKI by
      implementing remote ischemic preconditioning and to evaluate the dose-response relationship
      using the biomarkers urinary [TIMP-2] *[IGFBP7] in high risk patients undergoing cardiac
      surgery.
Acute kidney injury (AKI) complicates 7-19% of cardiac surgical procedures. The investigators
      recently found that remote ischemic preconditioning (RIPC) using transient external
      compression of the upper arm prior to cardiac surgery was effective for reducing the
      occurrence of AKI (37.5% compared to 52.5% with sham; absolute risk reduction (ARR),15%; 95%
      CI, 2.56% to 27.44%; P=0.02). Fewer patients treated with RIPC received renal replacement
      therapy (RRT) (5.8% versus 15.8%; ARR, 10%; 95% CI, 2.25% to 17.75%; P=0.01). Moreover, the
      investigators found that the effectiveness of this intervention was strongly associated with
      the release of cell-cycle arrest biomarkers into the urine. Patients with urinary tissue
      inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7
      ([TIMP-2]•[IGFBP7]) ≥ 0.5 (ng/ml)(ng/ml)/1000 before surgery had a significantly reduced rate
      of AKI compared to patients with lower urinary [TIMP-2]•[IGFBP7] concentration (relative risk
      (RR), 67%; 95% CI, 53% to 83%, P<0.001) whereas the biomarker concentrations after surgery
      predicted AKI as previously shown. This effect makes sense because cell-cycle arrest is
      thought to be part of the protective mechanisms endothelial cells use when exposed to stress.
      Stimulating these responses with RIPC should reduce AKI. Importantly, only 56% of patients
      treated with RIPC achieved an increase in urine [TIMP-2]•[IGFBP7] to ≥ 0.5, and only in this
      group was the intervention effective-patients that did not achieve this level showed no
      benefit.

      Our goal is to eventually design and conduct a Bayesian 2-stage adaptive design sequence
      trial to evaluate the effectiveness of RIPC to prevent AKI in patients undergoing cardiac
      surgery. The dimensions of dose include duration, intensity and number of cycles. However,
      before this trial can be designed we need to answer 4 questions: i. Do baseline urinary
      [TIMP-2]•[IGFBP7] levels predict AKI (enrichment)? ii. Do [TIMP-2]•[IGFBP7] changes elicited
      by RIPC predict protection (RIPC efficacy measure)? iii. Is there a dose-response
      relationship between RIPC "dose" and [TIMP-2]•[IGFBP7]? iv. Is a dose-escalation RIPC
      protocol where doses are increased for non-responders, feasible and safe within the
      anesthesia workflow for cardiac surgery cases (practical)?
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Change in urinary [TIMP-2]*[IGFBP7]
time frame: within 12 hours after CPB
description: Biomarkers will be measured at different time points after to evaluate the effect of RIPC on [TIMP-2]*[IGFBP7]
measure: AKI within 72 hours
time frame: 72 h
measure: Dialysis within 7 days of surgery
time frame: 7 days
measure: All-cause-mortality at 90 days
time frame: 90 d
measure: Dialysis at day 90
time frame: 90 days
measure: Renal recovery at day 90
time frame: 90 days
measure: MAKE 90
time frame: 90 days
description: major adverse kidney events
arm group label: Observational group
arm group type: No Intervention
description: No intervention, standard care
arm group label: Sham RIPC
arm group type: Sham Comparator
description: Three cycles of 5- min upper limb sham ischemia
arm group label: RIPC-Group 1
arm group type: Experimental
description: Three cycles of 5- min upper limb ischemia
arm group label: RIPC-Group 2
arm group type: Experimental
description: Three cycles of 7-min upper limb ischemia
arm group label: RIPC-Group 3
arm group type: Experimental
description: Three cycles of 10-min upper limb ischemia
arm group label: RIPC-Group 4
arm group type: Experimental
description: Three Cycles of 5-min upper limb ischemia. If there is no response this will be followed by 2 cycles of 10-min upper-limb ischemia
intervention type: Procedure
intervention name: Remote ischemic preconditioning (RIPC)
description: 3 cycles or more cycles of 5 to 10-min inflation of a blood-pressure cuff to 200 mm HG (or at least to a pressure 50 mmHG higher than the systolic arterial pressure) to one upper arm followed by 5 min reperfusion with the cuff deflated. In Non-Responder two additional cycles of 10 min cuff inflation will be performed in arm 6.
arm group label: RIPC-Group 1
arm group label: RIPC-Group 2
arm group label: RIPC-Group 3
arm group label: RIPC-Group 4
arm group label: Sham RIPC
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Melanie Meersch
role: Study Chair
affiliation: University Hospital Muenster
last name: Melanie Meersch, MD
phone: +49-251-8347282
email: aki@anit.uni-muenster.de
facility: 
status: Recruiting
contact: 
country: Germany
responsible party type: Sponsor
mesh term: Acute Kidney Injury
sharing ipd: No