xml: <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/NCT06032884</url>
    </required_header>
    <id_info>
      <org_study_id>APHP220811</org_study_id>
      <nct_id>NCT06032884</nct_id>
    </id_info>
    <brief_title>IHD Versus CRRT for Severe Acute Kidney Injury in Critically Ill Patients</brief_title>
    <acronym>ICRAKI</acronym>
    <official_title>Intermittent Hemodialysis Versus Continuous Renal Replacement Therapy for Severe Acute Kidney Injury in Critically Ill Patients</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Assistance Publique - Hôpitaux de Paris</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Assistance Publique - Hôpitaux de Paris</source>
    <oversight_info>
      <has_dmc>Yes</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>
        Intermittent hemodialysis (IHD) and continuous RRT (CRRT) provided as continuous&#xD;
        hemofiltration or hemodiafiltration are the main RRT modalities in ICU. Randomized controlled&#xD;
        trials (RCTs) comparing IHD and CRRT for AKI have not shown an indisputable benefit of one&#xD;
        technique over the other. However, these studies were conducted more than 15 years ago. In&#xD;
        addition, several recent RCTs on RRT initiation strategies have completely modified both&#xD;
        knowledge and practice of RRT initiation.&#xD;
  &#xD;
        The main objective is to evaluate whether IHD is not inferior to CRRT with regard to overall&#xD;
        incidence of a composite outcome of death, persistent renal dysfunction and dialysis&#xD;
        dependency at day 90 in critically ill patients with severe AKI (Major Kidney Event 90, MAKE&#xD;
        90). The primary endpoint will be the proportion of patients who will meet one or more&#xD;
        criteria for a major adverse kidney event 90 days after randomization (MAKE90). The MAKE will&#xD;
        be the composite of death, renal replacement therapy dependence and/or an increase in serum&#xD;
        creatinine above 25% of its basal value.&#xD;
  &#xD;
        This is a non-inferiority multicenter open-label randomized controlled trial with two&#xD;
        parallel groups. Randomization will take place 1:1 to 2 groups: a group receiving IHD and a&#xD;
        group receiving CRRT. Randomization will be stratified according to center, dose of&#xD;
        vasopressor and cumulative fluid balance from ICU admission. Treatment will be initiated and&#xD;
        monitored by the physician responsible for patient. Whatever the group, investigators will&#xD;
        follow recommendations to achieve optimal metabolic control and hemodynamic stability. The&#xD;
        investigators plan to include 1000 patients.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Intermittent hemodialysis (IHD) and continuous RRT (CRRT) provided as continuous&#xD;
        hemofiltration or hemodiafiltration are the main RRT modalities in ICU. Randomized controlled&#xD;
        trials (RCTs) comparing IHD and CRRT for AKI have not shown an indisputable benefit of one&#xD;
        technique over the other. However, these studies were conducted more than 15 years ago. Major&#xD;
        progresses were eventually made leading to much lower mortality rates in recent studies of&#xD;
        RRT for AKI. In addition, an important pitfall of previous studies on RRT modalities is that&#xD;
        the indications for initiating RRT were disputable in the light of present knowledge. Indeed,&#xD;
        these studies included a noticeable proportion of patients who could have recovered without&#xD;
        ever receiving RRT. Three recent RCTs on the timing of RRT for AKI have shown that, in the&#xD;
        absence of immediate life-threatening complication, RRT initiation can be safely delayed,&#xD;
        allowing up to 49% of severe AKI patients to escape RRT. Many such patients who did not&#xD;
        actually require RRT were included in previous studies on modalities. This justifies a&#xD;
        reevaluation of this issue by the performance of a new RCT that takes recent knowledge on RRT&#xD;
        initiation into account.&#xD;
  &#xD;
        The main objective is to evaluate whether IHD is not inferior to CRRT with regard to overall&#xD;
        incidence of a composite outcome of death, persistent renal dysfunction and dialysis&#xD;
        dependency at day 90 in critically ill patients with severe AKI. The primary endpoint will be&#xD;
        the proportion of patients who will meet one or more criteria for a major adverse kidney&#xD;
        event 90 days after randomization (MAKE90). The MAKE will be the composite of death, renal&#xD;
        replacement therapy dependence and/or an increase in serum creatinine above 25% of its basal&#xD;
        value.&#xD;
  &#xD;
        The secondary objectives will address the effect of IHD versus CRRT on:&#xD;
  &#xD;
          1. Survival (at different time points: D28, D60, D90)&#xD;
  &#xD;
          2. Persistence of renal dysfunction (at different time points: D28, D60, D90)&#xD;
  &#xD;
          3. Dialysis dependency (at different time points: D28, D60, D90)&#xD;
  &#xD;
          4. ICU and hospital length of stay&#xD;
  &#xD;
          5. Duration of RRT&#xD;
  &#xD;
          6. Number of organ failure-free days (catecholamine-free days, ventilator-free days,&#xD;
             RRT-free days) at day 28&#xD;
  &#xD;
          7. Estimated renal function at hospital discharge&#xD;
  &#xD;
          8. Occurrence of adverse events (hypotension, bleeding, thrombocytopenia, hypoglycaemia,&#xD;
             hypophosphataemia, hypothermia, cardiac rhythm disorders, air embolism, bloodstream&#xD;
             infection)&#xD;
  &#xD;
          9. Medico-economic aspects&#xD;
  &#xD;
        Another secondary objective will be to assess the ability of plasma and urinary AKI&#xD;
        biomarkers collected at D0 an ICU discharge to predict renal function recovery.&#xD;
  &#xD;
        The secondary endpoints will be:&#xD;
  &#xD;
          1. Time to death; day-28; day-60 and day-90 mortality&#xD;
  &#xD;
          2. Number of patients with more than a 25% increase in serum creatinine from baseline at&#xD;
             different time points: D28, D60, D90&#xD;
  &#xD;
          3. Number of patients with dialysis dependency at different time points: D28, D60, D90&#xD;
  &#xD;
          4. ICU and hospital length of stay&#xD;
  &#xD;
          5. Time until cessation of RRT&#xD;
  &#xD;
          6. Catecholamine-free days, ventilator-free days and RRT free days through day 28.&#xD;
  &#xD;
          7. Estimated glomerular filtration (eGFR) rate at hospital discharge&#xD;
  &#xD;
          8. The number of episodes of adverse events from inclusion until day 28 (or ICU discharge):&#xD;
  &#xD;
               -  Hypotension: systolic arterial pressure &lt; 80 mmHg or a fall &gt; 50 mmHg from baseline&#xD;
                  value&#xD;
  &#xD;
               -  Hemorrhage requiring red blood cell transfusion or surgical procedure&#xD;
  &#xD;
               -  Thrombocytopenia &lt; 100 000 platelets/mm3&#xD;
  &#xD;
               -  Hypoglycaemia: blood glucose concentrations&lt;3.0 mmol/L&#xD;
  &#xD;
               -  Hypophosphataemia: serum phosphate concentration&lt;0.6 mmol/l&#xD;
  &#xD;
               -  Hypothermia: core body temperature &lt;34°C&#xD;
  &#xD;
               -  Cardiac rhythm disorders: ventricular tachycardia or ventricular fibrillation or&#xD;
                  torsade de pointes or new episode of atrial fibrillation requiring medical&#xD;
                  treatment or external electric counter shock&#xD;
  &#xD;
               -  Air embolism&#xD;
  &#xD;
               -  Catheter-related (or unknown origin) bloodstream infection&#xD;
  &#xD;
          9. Incremental cost-effectiveness ratio in € per MAKE-90 averted&#xD;
  &#xD;
        Another secondary endpoint will be the association between the concentration of several&#xD;
        plasma and urinary AKI biomarkers (KIM-1, CCL-14, PENKID, NGAL) collected at D0 and at ICU&#xD;
        discharge and the MAKE-90.&#xD;
  &#xD;
        This is a non-inferiority multicenter open-label randomized controlled trial with two&#xD;
        parallel groups. Randomization will take place 1:1 to 2 groups: a group receiving IHD and a&#xD;
        group receiving CRRT. Randomization will be stratified according to center, dose of&#xD;
        vasopressor and cumulative fluid balance from ICU admission. Treatment will be initiated and&#xD;
        monitored by the physician responsible for patient. Whatever the group, investigators will&#xD;
        follow recommendations to achieve optimal metabolic control and hemodynamic stability.&#xD;
  &#xD;
        IHD group: a central venous access, a biocompatible membrane and bicarbonate dialysate will&#xD;
        be used. In accordance with the management recommendations, the investigators will plan at&#xD;
        least 3 sessions of 4 to 6 hours per week each with blood flow &gt; 200ml/min, dialysate&#xD;
        flow&gt;500ml/min, high sodium concentration (&gt;145 mmol/L) and low temperature (35°C) in the&#xD;
        dialysate. The investigators will recommend urea reduction ratio &gt; 65% for each session.&#xD;
  &#xD;
        CRRT group: a central venous access and a biocompatible membrane will be used. The&#xD;
        investigators will plan continuous treatment with a change of membrane every 72 hours (unless&#xD;
        clotting occurs before). Choice between continuous veno-venous hemodialysis (CVVHD),&#xD;
        continuous veno-venous hemofiltration (CVVHF), or continuous veno-venous hemodiafiltration&#xD;
        (CVVHDF) will be left at physician discretion. The investigators will recommend a minimum&#xD;
        delivered dose of dialysis of 20-25 ml/Kg/h of effluent by filtration and/or diffusion.&#xD;
  &#xD;
        For both groups, anticoagulation will be implemented according to center practice (regional&#xD;
        citrate will be strongly recommended for CVVHDF). The randomly assigned treatment modality&#xD;
        will be unchanged for at least 4 consecutive days unless renal recovery occurs before and&#xD;
        mandates RRT discontinuation. A shift for the other modality will be allowed after this delay&#xD;
        according to clinician decision.&#xD;
  &#xD;
        Discontinuation of RRT will be contemplated when spontaneous diuresis is &gt;500 ml/24h, and&#xD;
        highly recommended if diuresis &gt;1000 ml/24h without diuretic or &gt;2000 ml/24h in patients&#xD;
        receiving diuretics, as in our previous studies (AKIKI and AKIKI2).&#xD;
  &#xD;
        Vital status, need for dialysis and serum creatinine will be collected at day 28, day 60 and&#xD;
        day 90. Patients or their surrogates or the general practitioner (GP) will be contacted by&#xD;
        phone. Prescriptions for plasma creatinine measurements (at D60 and D90) will be provided to&#xD;
        the patient at discharge from the hospital.&#xD;
  &#xD;
        Inclusion criteria&#xD;
  &#xD;
          1. Adults (&gt; or= 18 years old) in ICU&#xD;
  &#xD;
          2. Receiving (or who have received) invasive mechanical ventilation and/or catecholamine&#xD;
             infusion&#xD;
  &#xD;
          3. Availability of both equipment IHD and CRRT (in the investigational center at the time&#xD;
             of inclusion)&#xD;
  &#xD;
          4. One of the 2 following situations 4.a: Either at least one of the 3 following&#xD;
             complications of AKI (whatever the KDIGO stage): persistent severe hyperkalaemia despite&#xD;
             medical treatment, persistent severe metabolic acidosis despite medical treatment or&#xD;
             severe pulmonary edema due to fluid overload despite diuretic therapy 4.b: Or an AKI&#xD;
             stage 3 of KDIGO with one of the 2 following criteria: serum urea concentration&gt;40mmol/L&#xD;
             or persistence of oligo-anuria&gt;3 days&#xD;
  &#xD;
          5. Affiliation of social security system&#xD;
  &#xD;
          6. Written consent obtained from the patients (from a support person, family member or a&#xD;
             close relative if the patient is not able to expressing and sign consent) or inclusion&#xD;
             without initial consent in case of emergency, if the patient is not able to express&#xD;
             his/her consent and in the absence of support person, family member or a close relative&#xD;
  &#xD;
        Non-inclusion criteria&#xD;
  &#xD;
          -  Moribund state (patient likely to die within 24h)&#xD;
  &#xD;
          -  Previous inclusion in the study&#xD;
  &#xD;
          -  Subject deprived of freedom, or under a legal protective measure (example: patients&#xD;
             under guardianship or curatorship)&#xD;
  &#xD;
          -  Subject receiving state medical aid&#xD;
  &#xD;
          -  Pregnancy or breastfeeding woman&#xD;
  &#xD;
          -  Patient included in another research trial on AKI&#xD;
  &#xD;
          -  Advanced chronic kidney disease (CKD) defined by an estimated GFR&lt;20 mL/min/1.73 m2&#xD;
  &#xD;
          -  Presence of a drug overdose or of a dialyzable toxin that necessitates RRT (because IHD&#xD;
             may be preferable in these conditions).• Presence or clinical suspicion of renal&#xD;
             obstruction, rapidly progressive glomerulonephritis, vasculitis, thrombotic&#xD;
             microangiopathy or acute interstitial nephritis&#xD;
  &#xD;
          -  Brain injured patients or other causes of increased intracranial pressure&#xD;
  &#xD;
          -  Fulminant hepatic failure&#xD;
  &#xD;
        The investigators plan to include 1000 participants. Adjusted difference between the&#xD;
        proportions of the two arms, of patients who will meet one or more criteria for a major&#xD;
        adverse kidney event at day 90 (MAKE90), will be estimated with 95% two-sided confidence&#xD;
        interval (95% CI) by the Cochran-Mantel-Haenszel method, stratified by fluid overload and&#xD;
        vasopressor dose. If the upper limit of the 95% CI is &lt; 7.5%,the investigators will conclude&#xD;
        the IHD is not inferior to CRRT. If the 95% confidence interval does not only lie entirely&#xD;
        below 7.5% but also adjusted difference is less than zero, a superiority test will be carried&#xD;
        out using the same method. A subgroup analysis will be done according to fluid overload (≥ 6&#xD;
        liters from admission ICU to randomization) and to vasopressor dose (&gt; 0.5 mcg/kg/min).&#xD;
  &#xD;
        Medico-economic analysis: The cost estimation will be expressed with mean and 95% confidence&#xD;
        intervals obtained by the bootstrapping method. The incremental cost-effectiveness ratio is&#xD;
        defined as the ratio of the difference between mean costs and the difference on the primary&#xD;
        endpoint. It will also be estimated by a mean and the 95% confidence interval using bootstrap&#xD;
        method.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 1, 2023</start_date>
    <completion_date type="Anticipated">September 1, 2025</completion_date>
    <primary_completion_date type="Anticipated">September 1, 2023</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>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Major Adverse Kidney Event 90 days after randomization (MAKE90).</measure>
      <time_frame>90 days after randomization</time_frame>
      <description>The primary endpoint will be the proportion of patients who will meet one or more criteria for a major adverse kidney event 90 days after randomization (MAKE90). The MAKE will be the composite of death, RRT dependence and/or more than a 25% increase in serum creatinine from baseline value. Baseline value of serum creatinine will be determined by either results of a measurement in the 12 months preceding the ICU stay or estimation using the Modification of Diet in Renal Disease (MDRD) study equation assuming that baseline eGFR is 75 ml/min per 1.73m2</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Mortality</measure>
      <time_frame>28,60 and 90 days after randomization</time_frame>
      <description>1/ Time to death; day-28; day-60 and day-90 mortality</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>25% increase in serum creatinine from baseline</measure>
      <time_frame>28, 60 and 90 days after randomization</time_frame>
      <description>Number of patients with more than a 25% increase in serum creatinine from baseline value at different time points: D28, D60, D90</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Dialysis dependency</measure>
      <time_frame>28, 60 and 90 days after randomization</time_frame>
      <description>Number of patients with dialysis dependence at different time points: D28, D60, D90</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>ICU and hospital length of stay</measure>
      <time_frame>ICU discharge until 90 days after randomization</time_frame>
      <description>ICU and hospital length of stay</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Time until RRT cessation</measure>
      <time_frame>90 days after randomization</time_frame>
      <description>Time until cessation of RRT</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Catecholamine free days</measure>
      <time_frame>28 days after randomization</time_frame>
      <description>Catecholamine-free days through day 28</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>ventilator free days</measure>
      <time_frame>28 days after randomization</time_frame>
      <description>ventilator-free days through day 28</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>RRT-free days</measure>
      <time_frame>28 days after randomization</time_frame>
      <description>RRT-free days through day 28.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Estimated GFR at hospital discharge</measure>
      <time_frame>90 days after randomization</time_frame>
      <description>Estimated GFR at hospital discharge (data collected via electronic medical records or from the medical unit in charge of the patient).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Adverse events</measure>
      <time_frame>from inclusion until day 28</time_frame>
      <description>The number of episodes of adverse events from inclusion until day 28 (or ICU discharge if ICU discharge occurs before D28):&#xD;
  Hypotension: systolic arterial pressure &lt; 80 mmHg or a fall &gt; 50 mmHg from baseline value&#xD;
  Hemorrhage requiring red blood cell transfusion or surgical procedure&#xD;
  Thrombocytopenia &lt; 100 000 platelets/mm3&#xD;
  Hypoglycaemia: blood glucose concentrations&lt;3.0 mmol/L&#xD;
  Hypophosphataemia: serum phosphate concentration&lt;0.6 mmol/l&#xD;
  Hypothermia: body temperature &lt;34°C&#xD;
  Cardiac rhythm disorders: ventricular tachycardia or ventricular fibrillation or torsade de pointes or new episode of atrial fibrillation requiring medical treatment or external electric counter shock&#xD;
  Air embolism&#xD;
  Catheter-related (both dialysis and non-dialysis catheters) or of unknown origin bloodstream infection.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>90-day ICER</measure>
      <time_frame>90 days after randomization</time_frame>
      <description>The 90-day Incremental Cost-Effectiveness Ration (ICER) (cost per major kidney event, composite outcome of death, persistent renal dysfunction and dialysis dependency at day 90 or MAKE90), following the definition of the primary clinical endpoint.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">1000</enrollment>
    <condition>Acute Kidney Injury</condition>
    <arm_group>
      <arm_group_label>IHD Group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>A central venous access (uncuffed nontunneled catheter, preferentially in the right jugular vein or femoral vein), a biocompatible membrane and bicarbonate dialysate will be used. The investigators will plan at least 3 sessions of 4 to 6 hours each per week with blood flow &gt; 200ml/min, dialysate flow&gt;500ml/min, high sodium concentration (&gt;145 mmol/L) and low temperature (35°C) in the dialysate. the investigators will recommend urea reduction ratio &gt; 65% for each session.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>CRRT group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>A central venous access (uncuffed nontunneled catheter, preferentially in the right jugular vein or femoral vein) and a biocompatible membrane will be used with a change of membrane every 72 hours (unless clotting occurs before). Choice between continuous veno-venous hemodialysis (CVVHD), continuous veno-venous hemofiltration (CVVHF), or continuous veno-venous hemodiafiltration (CVVHDF) will be left at physician discretion. The investigators will recommend a minimum delivered dose of dialysis of 20-25 ml/Kg/h of effluent by filtration and/or diffusion.</description>
    </arm_group>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>continuous renal replacement therapy (CRRT)</intervention_name>
      <description>renal replacement therapy (RRT).</description>
      <arm_group_label>CRRT group</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Intermittent hemodialysis (IHD)</intervention_name>
      <description>renal replacement therapy (RRT).</description>
      <arm_group_label>IHD Group</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Adults (&gt; or= 18 years old) in ICU&#xD;
  &#xD;
            2. Receiving (or who have received) invasive mechanical ventilation and/or catecholamine&#xD;
               infusion&#xD;
  &#xD;
            3. Availability of both equipment IHD and CRRT (in the investigational center at the time&#xD;
               of inclusion)&#xD;
  &#xD;
            4. One of the 2 following situations 4.a: Either at least one of the 3 following&#xD;
               complications of AKI* (whatever the KDIGO stage): persistent severe hyperkalaemia&#xD;
               despite medical treatment, persistent severe metabolic acidosis despite medical&#xD;
               treatment or severe pulmonary edema due to fluid overload despite diuretic therapy&#xD;
               4.b: Or an AKI stage 3 of KDIGO with one of the 2 following criteria: serum urea&#xD;
               concentration&gt;40mmol/L or persistence of oligo-anuria&gt;3 days&#xD;
  &#xD;
               *Definitions of these complication are provided in the main text (Section 7.1)&#xD;
  &#xD;
            5. Affiliation of social security system&#xD;
  &#xD;
            6. Written consent obtained from the patients (from a support person, family member or a&#xD;
               close relative if the patient is not able to expressing and sign consent) or inclusion&#xD;
               without initial consent in case of emergency, if the patient is not able to express&#xD;
               his/her consent and in the absence of support person, family member or a close&#xD;
               relative&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Moribund state (patient likely to die within 24h)&#xD;
  &#xD;
            -  Previous inclusion in the study&#xD;
  &#xD;
            -  Subject deprived of freedom, or under a legal protective measure (example: patients&#xD;
               under guardianship or curatorship)&#xD;
  &#xD;
            -  Subject receiving state medical aid&#xD;
  &#xD;
            -  Pregnancy or breastfeeding woman&#xD;
  &#xD;
            -  Patient included in another research trial on AKI&#xD;
  &#xD;
            -  Advanced chronic kidney disease (CKD) defined by an estimated GFR&lt;20 mL/min/1.73 m2&#xD;
  &#xD;
            -  Presence of a drug overdose or of a dialyzable toxin that necessitates RRT (because&#xD;
               IHD may be preferable in these conditions).&#xD;
  &#xD;
            -  Presence or clinical suspicion of renal obstruction, rapidly progressive&#xD;
               glomerulonephritis, vasculitis, thrombotic microangiopathy or acute interstitial&#xD;
               nephritis&#xD;
  &#xD;
            -  Brain injured patients or other causes of increased intracranial pressure&#xD;
  &#xD;
            -  Fulminant hepatic failure&#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>Stéphane GAUDRY</last_name>
      <role>Study Director</role>
      <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Stéphane GAUDRY, Pr,MD, PhD</last_name>
      <phone>01.48.95.22.81</phone>
      <email>stephane.gaudry@aphp.fr</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Didier DREYFUSS, Pr,MD, PhD</last_name>
      <email>didier.dreyfuss@aphp.fr</email>
    </overall_contact_backup>
    <verification_date>May 2023</verification_date>
    <study_first_submitted>August 21, 2023</study_first_submitted>
    <study_first_submitted_qc>September 4, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 13, 2023</study_first_posted>
    <last_update_submitted>September 4, 2023</last_update_submitted>
    <last_update_submitted_qc>September 4, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 13, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Acute Kidney Injury</keyword>
    <keyword>Renal Replacement Therapy</keyword>
    <keyword>ICU</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Acute Kidney Injury</mesh_term>
      <mesh_term>Wounds and Injuries</mesh_term>
    </condition_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06032884
  org study id: APHP220811
  nct id: NCT06032884
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  Intermittent hemodialysis (IHD) and continuous RRT (CRRT) provided as continuous
        hemofiltration or hemodiafiltration are the main RRT modalities in ICU. Randomized controlled
        trials (RCTs) comparing IHD and CRRT for AKI have not shown an indisputable benefit of one
        technique over the other. However, these studies were conducted more than 15 years ago. In
        addition, several recent RCTs on RRT initiation strategies have completely modified both
        knowledge and practice of RRT initiation.
  
        The main objective is to evaluate whether IHD is not inferior to CRRT with regard to overall
        incidence of a composite outcome of death, persistent renal dysfunction and dialysis
        dependency at day 90 in critically ill patients with severe AKI (Major Kidney Event 90, MAKE
        90). The primary endpoint will be the proportion of patients who will meet one or more
        criteria for a major adverse kidney event 90 days after randomization (MAKE90). The MAKE will
        be the composite of death, renal replacement therapy dependence and/or an increase in serum
        creatinine above 25% of its basal value.
  
        This is a non-inferiority multicenter open-label randomized controlled trial with two
        parallel groups. Randomization will take place 1:1 to 2 groups: a group receiving IHD and a
        group receiving CRRT. Randomization will be stratified according to center, dose of
        vasopressor and cumulative fluid balance from ICU admission. Treatment will be initiated and
        monitored by the physician responsible for patient. Whatever the group, investigators will
        follow recommendations to achieve optimal metabolic control and hemodynamic stability. The
        investigators plan to include 1000 patients.
  Intermittent hemodialysis (IHD) and continuous RRT (CRRT) provided as continuous
        hemofiltration or hemodiafiltration are the main RRT modalities in ICU. Randomized controlled
        trials (RCTs) comparing IHD and CRRT for AKI have not shown an indisputable benefit of one
        technique over the other. However, these studies were conducted more than 15 years ago. Major
        progresses were eventually made leading to much lower mortality rates in recent studies of
        RRT for AKI. In addition, an important pitfall of previous studies on RRT modalities is that
        the indications for initiating RRT were disputable in the light of present knowledge. Indeed,
        these studies included a noticeable proportion of patients who could have recovered without
        ever receiving RRT. Three recent RCTs on the timing of RRT for AKI have shown that, in the
        absence of immediate life-threatening complication, RRT initiation can be safely delayed,
        allowing up to 49% of severe AKI patients to escape RRT. Many such patients who did not
        actually require RRT were included in previous studies on modalities. This justifies a
        reevaluation of this issue by the performance of a new RCT that takes recent knowledge on RRT
        initiation into account.
  
        The main objective is to evaluate whether IHD is not inferior to CRRT with regard to overall
        incidence of a composite outcome of death, persistent renal dysfunction and dialysis
        dependency at day 90 in critically ill patients with severe AKI. The primary endpoint will be
        the proportion of patients who will meet one or more criteria for a major adverse kidney
        event 90 days after randomization (MAKE90). The MAKE will be the composite of death, renal
        replacement therapy dependence and/or an increase in serum creatinine above 25% of its basal
        value.
  
        The secondary objectives will address the effect of IHD versus CRRT on:
  
          1. Survival (at different time points: D28, D60, D90)
  
          2. Persistence of renal dysfunction (at different time points: D28, D60, D90)
  
          3. Dialysis dependency (at different time points: D28, D60, D90)
  
          4. ICU and hospital length of stay
  
          5. Duration of RRT
  
          6. Number of organ failure-free days (catecholamine-free days, ventilator-free days,
             RRT-free days) at day 28
  
          7. Estimated renal function at hospital discharge
  
          8. Occurrence of adverse events (hypotension, bleeding, thrombocytopenia, hypoglycaemia,
             hypophosphataemia, hypothermia, cardiac rhythm disorders, air embolism, bloodstream
             infection)
  
          9. Medico-economic aspects
  
        Another secondary objective will be to assess the ability of plasma and urinary AKI
        biomarkers collected at D0 an ICU discharge to predict renal function recovery.
  
        The secondary endpoints will be:
  
          1. Time to death; day-28; day-60 and day-90 mortality
  
          2. Number of patients with more than a 25% increase in serum creatinine from baseline at
             different time points: D28, D60, D90
  
          3. Number of patients with dialysis dependency at different time points: D28, D60, D90
  
          4. ICU and hospital length of stay
  
          5. Time until cessation of RRT
  
          6. Catecholamine-free days, ventilator-free days and RRT free days through day 28.
  
          7. Estimated glomerular filtration (eGFR) rate at hospital discharge
  
          8. The number of episodes of adverse events from inclusion until day 28 (or ICU discharge):
  
               -  Hypotension: systolic arterial pressure < 80 mmHg or a fall > 50 mmHg from baseline
                  value
  
               -  Hemorrhage requiring red blood cell transfusion or surgical procedure
  
               -  Thrombocytopenia < 100 000 platelets/mm3
  
               -  Hypoglycaemia: blood glucose concentrations<3.0 mmol/L
  
               -  Hypophosphataemia: serum phosphate concentration<0.6 mmol/l
  
               -  Hypothermia: core body temperature <34°C
  
               -  Cardiac rhythm disorders: ventricular tachycardia or ventricular fibrillation or
                  torsade de pointes or new episode of atrial fibrillation requiring medical
                  treatment or external electric counter shock
  
               -  Air embolism
  
               -  Catheter-related (or unknown origin) bloodstream infection
  
          9. Incremental cost-effectiveness ratio in € per MAKE-90 averted
  
        Another secondary endpoint will be the association between the concentration of several
        plasma and urinary AKI biomarkers (KIM-1, CCL-14, PENKID, NGAL) collected at D0 and at ICU
        discharge and the MAKE-90.
  
        This is a non-inferiority multicenter open-label randomized controlled trial with two
        parallel groups. Randomization will take place 1:1 to 2 groups: a group receiving IHD and a
        group receiving CRRT. Randomization will be stratified according to center, dose of
        vasopressor and cumulative fluid balance from ICU admission. Treatment will be initiated and
        monitored by the physician responsible for patient. Whatever the group, investigators will
        follow recommendations to achieve optimal metabolic control and hemodynamic stability.
  
        IHD group: a central venous access, a biocompatible membrane and bicarbonate dialysate will
        be used. In accordance with the management recommendations, the investigators will plan at
        least 3 sessions of 4 to 6 hours per week each with blood flow > 200ml/min, dialysate
        flow>500ml/min, high sodium concentration (>145 mmol/L) and low temperature (35°C) in the
        dialysate. The investigators will recommend urea reduction ratio > 65% for each session.
  
        CRRT group: a central venous access and a biocompatible membrane will be used. The
        investigators will plan continuous treatment with a change of membrane every 72 hours (unless
        clotting occurs before). Choice between continuous veno-venous hemodialysis (CVVHD),
        continuous veno-venous hemofiltration (CVVHF), or continuous veno-venous hemodiafiltration
        (CVVHDF) will be left at physician discretion. The investigators will recommend a minimum
        delivered dose of dialysis of 20-25 ml/Kg/h of effluent by filtration and/or diffusion.
  
        For both groups, anticoagulation will be implemented according to center practice (regional
        citrate will be strongly recommended for CVVHDF). The randomly assigned treatment modality
        will be unchanged for at least 4 consecutive days unless renal recovery occurs before and
        mandates RRT discontinuation. A shift for the other modality will be allowed after this delay
        according to clinician decision.
  
        Discontinuation of RRT will be contemplated when spontaneous diuresis is >500 ml/24h, and
        highly recommended if diuresis >1000 ml/24h without diuretic or >2000 ml/24h in patients
        receiving diuretics, as in our previous studies (AKIKI and AKIKI2).
  
        Vital status, need for dialysis and serum creatinine will be collected at day 28, day 60 and
        day 90. Patients or their surrogates or the general practitioner (GP) will be contacted by
        phone. Prescriptions for plasma creatinine measurements (at D60 and D90) will be provided to
        the patient at discharge from the hospital.
  
        Inclusion criteria
  
          1. Adults (> or= 18 years old) in ICU
  
          2. Receiving (or who have received) invasive mechanical ventilation and/or catecholamine
             infusion
  
          3. Availability of both equipment IHD and CRRT (in the investigational center at the time
             of inclusion)
  
          4. One of the 2 following situations 4.a: Either at least one of the 3 following
             complications of AKI (whatever the KDIGO stage): persistent severe hyperkalaemia despite
             medical treatment, persistent severe metabolic acidosis despite medical treatment or
             severe pulmonary edema due to fluid overload despite diuretic therapy 4.b: Or an AKI
             stage 3 of KDIGO with one of the 2 following criteria: serum urea concentration>40mmol/L
             or persistence of oligo-anuria>3 days
  
          5. Affiliation of social security system
  
          6. Written consent obtained from the patients (from a support person, family member or a
             close relative if the patient is not able to expressing and sign consent) or inclusion
             without initial consent in case of emergency, if the patient is not able to express
             his/her consent and in the absence of support person, family member or a close relative
  
        Non-inclusion criteria
  
          -  Moribund state (patient likely to die within 24h)
  
          -  Previous inclusion in the study
  
          -  Subject deprived of freedom, or under a legal protective measure (example: patients
             under guardianship or curatorship)
  
          -  Subject receiving state medical aid
  
          -  Pregnancy or breastfeeding woman
  
          -  Patient included in another research trial on AKI
  
          -  Advanced chronic kidney disease (CKD) defined by an estimated GFR<20 mL/min/1.73 m2
  
          -  Presence of a drug overdose or of a dialyzable toxin that necessitates RRT (because IHD
             may be preferable in these conditions).• Presence or clinical suspicion of renal
             obstruction, rapidly progressive glomerulonephritis, vasculitis, thrombotic
             microangiopathy or acute interstitial nephritis
  
          -  Brain injured patients or other causes of increased intracranial pressure
  
          -  Fulminant hepatic failure
  
        The investigators plan to include 1000 participants. Adjusted difference between the
        proportions of the two arms, of patients who will meet one or more criteria for a major
        adverse kidney event at day 90 (MAKE90), will be estimated with 95% two-sided confidence
        interval (95% CI) by the Cochran-Mantel-Haenszel method, stratified by fluid overload and
        vasopressor dose. If the upper limit of the 95% CI is < 7.5%,the investigators will conclude
        the IHD is not inferior to CRRT. If the 95% confidence interval does not only lie entirely
        below 7.5% but also adjusted difference is less than zero, a superiority test will be carried
        out using the same method. A subgroup analysis will be done according to fluid overload (≥ 6
        liters from admission ICU to randomization) and to vasopressor dose (> 0.5 mcg/kg/min).
  
        Medico-economic analysis: The cost estimation will be expressed with mean and 95% confidence
        intervals obtained by the bootstrapping method. The incremental cost-effectiveness ratio is
        defined as the ratio of the difference between mean costs and the difference on the primary
        endpoint. It will also be estimated by a mean and the 95% confidence interval using bootstrap
        method.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Major Adverse Kidney Event 90 days after randomization (MAKE90).
  time frame: 90 days after randomization
  description: The primary endpoint will be the proportion of patients who will meet one or more criteria for a major adverse kidney event 90 days after randomization (MAKE90). The MAKE will be the composite of death, RRT dependence and/or more than a 25% increase in serum creatinine from baseline value. Baseline value of serum creatinine will be determined by either results of a measurement in the 12 months preceding the ICU stay or estimation using the Modification of Diet in Renal Disease (MDRD) study equation assuming that baseline eGFR is 75 ml/min per 1.73m2
  measure: Mortality
  time frame: 28,60 and 90 days after randomization
  description: 1/ Time to death; day-28; day-60 and day-90 mortality
  measure: 25% increase in serum creatinine from baseline
  time frame: 28, 60 and 90 days after randomization
  description: Number of patients with more than a 25% increase in serum creatinine from baseline value at different time points: D28, D60, D90
  measure: Dialysis dependency
  time frame: 28, 60 and 90 days after randomization
  description: Number of patients with dialysis dependence at different time points: D28, D60, D90
  measure: ICU and hospital length of stay
  time frame: ICU discharge until 90 days after randomization
  description: ICU and hospital length of stay
  measure: Time until RRT cessation
  time frame: 90 days after randomization
  description: Time until cessation of RRT
  measure: Catecholamine free days
  time frame: 28 days after randomization
  description: Catecholamine-free days through day 28
  measure: ventilator free days
  time frame: 28 days after randomization
  description: ventilator-free days through day 28
  measure: RRT-free days
  time frame: 28 days after randomization
  description: RRT-free days through day 28.
  measure: Estimated GFR at hospital discharge
  time frame: 90 days after randomization
  description: Estimated GFR at hospital discharge (data collected via electronic medical records or from the medical unit in charge of the patient).
  measure: Adverse events
  time frame: from inclusion until day 28
  description: The number of episodes of adverse events from inclusion until day 28 (or ICU discharge if ICU discharge occurs before D28):
  Hypotension: systolic arterial pressure < 80 mmHg or a fall > 50 mmHg from baseline value
  Hemorrhage requiring red blood cell transfusion or surgical procedure
  Thrombocytopenia < 100 000 platelets/mm3
  Hypoglycaemia: blood glucose concentrations<3.0 mmol/L
  Hypophosphataemia: serum phosphate concentration<0.6 mmol/l
  Hypothermia: body temperature <34°C
  Cardiac rhythm disorders: ventricular tachycardia or ventricular fibrillation or torsade de pointes or new episode of atrial fibrillation requiring medical treatment or external electric counter shock
  Air embolism
  Catheter-related (both dialysis and non-dialysis catheters) or of unknown origin bloodstream infection.
  measure: 90-day ICER
  time frame: 90 days after randomization
  description: The 90-day Incremental Cost-Effectiveness Ration (ICER) (cost per major kidney event, composite outcome of death, persistent renal dysfunction and dialysis dependency at day 90 or MAKE90), following the definition of the primary clinical endpoint.
  arm group label: IHD Group
  arm group type: Experimental
  description: A central venous access (uncuffed nontunneled catheter, preferentially in the right jugular vein or femoral vein), a biocompatible membrane and bicarbonate dialysate will be used. The investigators will plan at least 3 sessions of 4 to 6 hours each per week with blood flow > 200ml/min, dialysate flow>500ml/min, high sodium concentration (>145 mmol/L) and low temperature (35°C) in the dialysate. the investigators will recommend urea reduction ratio > 65% for each session.
  arm group label: CRRT group
  arm group type: Experimental
  description: A central venous access (uncuffed nontunneled catheter, preferentially in the right jugular vein or femoral vein) and a biocompatible membrane will be used with a change of membrane every 72 hours (unless clotting occurs before). Choice between continuous veno-venous hemodialysis (CVVHD), continuous veno-venous hemofiltration (CVVHF), or continuous veno-venous hemodiafiltration (CVVHDF) will be left at physician discretion. The investigators will recommend a minimum delivered dose of dialysis of 20-25 ml/Kg/h of effluent by filtration and/or diffusion.
  intervention type: Procedure
  intervention name: continuous renal replacement therapy (CRRT)
  description: renal replacement therapy (RRT).
  arm group label: CRRT group
  intervention type: Procedure
  intervention name: Intermittent hemodialysis (IHD)
  description: renal replacement therapy (RRT).
  arm group label: IHD Group
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Stéphane GAUDRY
  role: Study Director
  affiliation: Assistance Publique - Hôpitaux de Paris
  last name: Stéphane GAUDRY, Pr,MD, PhD
  phone: 01.48.95.22.81
  email: stephane.gaudry@aphp.fr
  last name: Didier DREYFUSS, Pr,MD, PhD
  email: didier.dreyfuss@aphp.fr
  responsible party type: Sponsor
  mesh term: Acute Kidney Injury
  mesh term: Wounds and Injuries