<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/NCT01693354</url>
  </required_header>
  <id_info>
    <org_study_id>MID-INT01</org_study_id>
    <nct_id>NCT01693354</nct_id>
  </id_info>
  <brief_title>Mid-HDF Randomized Controlled Study on Outcome</brief_title>
  <acronym>MILESTONE</acronym>
  <official_title>Mid-dilution Hemodiafiltration International Randomized Prospective Study on Incident Patients Focused on Outcome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>IRCCS Azienda Ospedaliero-Universitaria di Bologna</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>IRCCS Azienda Ospedaliero-Universitaria di Bologna</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine whether mid-dilution hemodiafiltration is effective&#xD;
      in the reduction of the crude mortality risk in patients who have been undergoing renal&#xD;
      replacement treatment for less than 1 year. Patients will be randomized since the beginning&#xD;
      of the study in two groups: standard HF dialysis and mid-dilution HDF.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      It is a matter of fact that in the last decades the Chronic Kidney Disease (CKD) population&#xD;
      has widely changed. In Italy, for example, more than 50% of the incident dialysis patients&#xD;
      are more than 70 year old, with diabetic and hypertension being the major underlying&#xD;
      diseases; moreover a great percentage of the patients starts dialysis with a burden of at&#xD;
      least 1-2 comorbidities [1]. Online hemodiafiltration (online HDF) has been recently&#xD;
      associated with better patient survival in comparison with standard hemodialysis in two large&#xD;
      trials [2,3]; the overall relative risk of mortality was found to be approximately 33% lower&#xD;
      in patients treated with online HDF [2,3]. These impressive results were not obtained anyway&#xD;
      on the whole population, but in a sub-group analysis. A strong correlation was found between&#xD;
      the total convective volume obtained and the mortality risk reduction; HDF was found to be&#xD;
      significantly better than standard hemodialysis when a total convective volume of 19-22&#xD;
      L/session (in 4 hours sessions of post-dilution HDF) was achieved.&#xD;
&#xD;
      These results support the importance of the &quot;adequate convective dose&quot; concept in order to&#xD;
      improve the patient outcomes especially in frail patients, as recently demonstrated by a&#xD;
      large randomised control trial, the MPO study [4], comparing High Flux versus Low Flux&#xD;
      dialysis in patients with plasma albumin levels equal to or less than 4 gr/dl ( as a marker&#xD;
      of patient comorbidities) and, in a post hoc analysis, in diabetic patients [4].&#xD;
&#xD;
      Mid-dilution HDF is a variant of classical HDF combining simultaneous pre- and post.-dilution&#xD;
      in order to maximise middle and large solutes removal.&#xD;
&#xD;
      The MILESTONE study would aim to fully demonstrate for mid-dilution HDF the significant&#xD;
      mortality risk reduction observed in the recent mentioned studies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>September 2012</start_date>
  <completion_date type="Anticipated">September 2018</completion_date>
  <primary_completion_date type="Anticipated">September 2017</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>crude, all-causes mortality</measure>
    <time_frame>5 years</time_frame>
    <description>The primary objective will be assessed by the incidence rate of fatal events</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cardiovascular morbidity</measure>
    <time_frame>5 years</time_frame>
    <description>It will be assessed by taking into consideration:&#xD;
Number of hospital admissions related to non fatal major CV events&#xD;
Length of stay during hospitalization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life and dialysis tolerance evaluated by questionnaire</measure>
    <time_frame>1 year</time_frame>
    <description>It will be assessed by taking into consideration:&#xD;
- Results of the SF-36 questionnaire given to the patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Micro-inflammation evaluation</measure>
    <time_frame>1 year</time_frame>
    <description>It will be assessed by measuring the pre-dialysis serum levels of:&#xD;
IL-6 CR Myoglobin RbP p-cresylsulfate beta2-microglobulin.&#xD;
The hospitals' laboratories will be in charge for the sample collection and analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Nutrition and anaemia management</measure>
    <time_frame>1 year</time_frame>
    <description>It will be assessed by taking in consideration the pre-dialysis serum levels of:&#xD;
Hb albumin iron.&#xD;
ESAs and iron supplementation will be as well noted in apposite CRF.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">500</enrollment>
  <condition>End Stage Renal Disease</condition>
  <arm_group>
    <arm_group_label>HF dialysis</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>HF (high-flux) dialysis is standard hemodialysis treatment performed by using a high permeability dialyzer instead of a low permeability one.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Mid-dilution HDF</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Mid-dilution is a newly developed hemodiafiltration therapy able to allow a simultaneous pre- and post-dilution infusion.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Mid-dilution HDF</intervention_name>
    <description>Mid-dilution HDF is a special, newly developed variant of online HDF which is characterized by a dedicated high-flux hemodialyzer named OLPUR MD able to support simultaneous pre- and post-dilution</description>
    <arm_group_label>Mid-dilution HDF</arm_group_label>
    <other_name>OLPUR MD 220</other_name>
    <other_name>OLPUR MD 190</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>HF dialysis</intervention_name>
    <description>Standard hemodialyzers equipped with high permeability polyphenylene/polyethersulfone membranes</description>
    <arm_group_label>HF dialysis</arm_group_label>
    <other_name>PHYLTHER HF</other_name>
    <other_name>DIAPES HF</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  On a thrice/week RRT for at least 3 months&#xD;
&#xD;
          -  Dialysis vintage &gt; 3 months&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
          -  Blood flow &gt; 300 mL/min&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  On waiting list for living-donor transplant&#xD;
&#xD;
          -  Residual diuresis &gt; 500 mL/day&#xD;
&#xD;
          -  Inability, as judget by the investigator, to follow or understand the protocol&#xD;
             instructions&#xD;
&#xD;
          -  Active neoplastic disease&#xD;
&#xD;
          -  Single needle treatment&#xD;
&#xD;
          -  Patients with expectancy life lower than 6 months&#xD;
&#xD;
          -  Inclusion to other studies&#xD;
&#xD;
          -  Pregnancy&#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>Francisco Maduell, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Hospital Clínic Barcelona, Spain</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Vincenzo Panichi, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>AUSL 12 Viareggio, Italy</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Pedro Aljama, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Hospital Reina Sofia, Cordoba, Spain</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Michel Jadoul, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Cliniques Universitaires Saint-Luc, Brussels, Belgium</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Philippe Brunet, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Hôpital de la Conception, Marseille, France</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Antonio Santoro, MD</last_name>
    <role>Study Chair</role>
    <affiliation>AOSP Bologna, Italy</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cliniques Universitaires Saint-Luc</name>
      <address>
        <city>Brussels</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital de la Conception</name>
      <address>
        <city>Marseille</city>
        <zip>13385</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliero-Universitaria di Bologna</name>
      <address>
        <city>Bologna</city>
        <zip>40138</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínic Barcelona</name>
      <address>
        <city>Barcelona</city>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>France</country>
    <country>Italy</country>
    <country>Spain</country>
  </location_countries>
  <reference>
    <citation>Stel VS, van de Luijtgaarden MW, Wanner C, Jager KJ; on behalf of the European Renal Registry Investigators. The 2008 ERA-EDTA Registry Annual Report-a precis. NDT Plus. 2011 Feb;4(1):1-13. doi: 10.1093/ndtplus/sfq191. Epub 2010 Nov 19.</citation>
    <PMID>21245934</PMID>
  </reference>
  <reference>
    <citation>Grooteman MP, van den Dorpel MA, Bots ML, Penne EL, van der Weerd NC, Mazairac AH, den Hoedt CH, van der Tweel I, Levesque R, Nube MJ, ter Wee PM, Blankestijn PJ; CONTRAST Investigators. Effect of online hemodiafiltration on all-cause mortality and cardiovascular outcomes. J Am Soc Nephrol. 2012 Jun;23(6):1087-96. doi: 10.1681/ASN.2011121140. Epub 2012 Apr 26.</citation>
    <PMID>22539829</PMID>
  </reference>
  <reference>
    <citation>Canaud B, Bragg-Gresham JL, Marshall MR, Desmeules S, Gillespie BW, Depner T, Klassen P, Port FK. Mortality risk for patients receiving hemodiafiltration versus hemodialysis: European results from the DOPPS. Kidney Int. 2006 Jun;69(11):2087-93. doi: 10.1038/sj.ki.5000447.</citation>
    <PMID>16641921</PMID>
  </reference>
  <reference>
    <citation>Locatelli F, Martin-Malo A, Hannedouche T, Loureiro A, Papadimitriou M, Wizemann V, Jacobson SH, Czekalski S, Ronco C, Vanholder R; Membrane Permeability Outcome (MPO) Study Group. Effect of membrane permeability on survival of hemodialysis patients. J Am Soc Nephrol. 2009 Mar;20(3):645-54. doi: 10.1681/ASN.2008060590. Epub 2008 Dec 17.</citation>
    <PMID>19092122</PMID>
  </reference>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>September 6, 2012</study_first_submitted>
  <study_first_submitted_qc>September 24, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 26, 2012</study_first_posted>
  <last_update_submitted>January 12, 2017</last_update_submitted>
  <last_update_submitted_qc>January 12, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 13, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>IRCCS Azienda Ospedaliero-Universitaria di Bologna</investigator_affiliation>
    <investigator_full_name>Antonio Santoro</investigator_full_name>
    <investigator_title>Professor Antonio Santoro MD, Chief of Nephrology</investigator_title>
  </responsible_party>
  <keyword>dialysis</keyword>
  <keyword>mortality</keyword>
  <keyword>cardiovascular stability</keyword>
  <keyword>inflammation</keyword>
  <keyword>quality of life</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Failure, Chronic</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01693354
org study id: MID-INT01
nct id: NCT01693354
lead sponsor: 
has dmc: Yes
The purpose of this study is to determine whether mid-dilution hemodiafiltration is effective
      in the reduction of the crude mortality risk in patients who have been undergoing renal
      replacement treatment for less than 1 year. Patients will be randomized since the beginning
      of the study in two groups: standard HF dialysis and mid-dilution HDF.
It is a matter of fact that in the last decades the Chronic Kidney Disease (CKD) population
      has widely changed. In Italy, for example, more than 50% of the incident dialysis patients
      are more than 70 year old, with diabetic and hypertension being the major underlying
      diseases; moreover a great percentage of the patients starts dialysis with a burden of at
      least 1-2 comorbidities [1]. Online hemodiafiltration (online HDF) has been recently
      associated with better patient survival in comparison with standard hemodialysis in two large
      trials [2,3]; the overall relative risk of mortality was found to be approximately 33% lower
      in patients treated with online HDF [2,3]. These impressive results were not obtained anyway
      on the whole population, but in a sub-group analysis. A strong correlation was found between
      the total convective volume obtained and the mortality risk reduction; HDF was found to be
      significantly better than standard hemodialysis when a total convective volume of 19-22
      L/session (in 4 hours sessions of post-dilution HDF) was achieved.

      These results support the importance of the "adequate convective dose" concept in order to
      improve the patient outcomes especially in frail patients, as recently demonstrated by a
      large randomised control trial, the MPO study [4], comparing High Flux versus Low Flux
      dialysis in patients with plasma albumin levels equal to or less than 4 gr/dl ( as a marker
      of patient comorbidities) and, in a post hoc analysis, in diabetic patients [4].

      Mid-dilution HDF is a variant of classical HDF combining simultaneous pre- and post.-dilution
      in order to maximise middle and large solutes removal.

      The MILESTONE study would aim to fully demonstrate for mid-dilution HDF the significant
      mortality risk reduction observed in the recent mentioned studies.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: crude, all-causes mortality
time frame: 5 years
description: The primary objective will be assessed by the incidence rate of fatal events
measure: Cardiovascular morbidity
time frame: 5 years
description: It will be assessed by taking into consideration:
Number of hospital admissions related to non fatal major CV events
Length of stay during hospitalization
measure: Quality of life and dialysis tolerance evaluated by questionnaire
time frame: 1 year
description: It will be assessed by taking into consideration:
- Results of the SF-36 questionnaire given to the patients
measure: Micro-inflammation evaluation
time frame: 1 year
description: It will be assessed by measuring the pre-dialysis serum levels of:
IL-6 CR Myoglobin RbP p-cresylsulfate beta2-microglobulin.
The hospitals' laboratories will be in charge for the sample collection and analysis
measure: Nutrition and anaemia management
time frame: 1 year
description: It will be assessed by taking in consideration the pre-dialysis serum levels of:
Hb albumin iron.
ESAs and iron supplementation will be as well noted in apposite CRF.
arm group label: HF dialysis
arm group type: Active Comparator
description: HF (high-flux) dialysis is standard hemodialysis treatment performed by using a high permeability dialyzer instead of a low permeability one.
arm group label: Mid-dilution HDF
arm group type: Experimental
description: Mid-dilution is a newly developed hemodiafiltration therapy able to allow a simultaneous pre- and post-dilution infusion.
intervention type: Device
intervention name: Mid-dilution HDF
description: Mid-dilution HDF is a special, newly developed variant of online HDF which is characterized by a dedicated high-flux hemodialyzer named OLPUR MD able to support simultaneous pre- and post-dilution
arm group label: Mid-dilution HDF
other name: OLPUR MD 220
other name: OLPUR MD 190
intervention type: Device
intervention name: HF dialysis
description: Standard hemodialyzers equipped with high permeability polyphenylene/polyethersulfone membranes
arm group label: HF dialysis
other name: PHYLTHER HF
other name: DIAPES HF
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Francisco Maduell, MD
role: Study Chair
affiliation: Hospital Clínic Barcelona, Spain
last name: Vincenzo Panichi, MD, PhD
role: Study Chair
affiliation: AUSL 12 Viareggio, Italy
last name: Pedro Aljama, MD, PhD
role: Study Chair
affiliation: Hospital Reina Sofia, Cordoba, Spain
last name: Michel Jadoul, MD, PhD
role: Study Chair
affiliation: Cliniques Universitaires Saint-Luc, Brussels, Belgium
last name: Philippe Brunet, MD, PhD
role: Study Chair
affiliation: Hôpital de la Conception, Marseille, France
last name: Antonio Santoro, MD
role: Study Chair
affiliation: AOSP Bologna, Italy
facility: 
facility: 
facility: 
facility: 
country: Belgium
country: France
country: Italy
country: Spain
citation: Stel VS, van de Luijtgaarden MW, Wanner C, Jager KJ; on behalf of the European Renal Registry Investigators. The 2008 ERA-EDTA Registry Annual Report-a precis. NDT Plus. 2011 Feb;4(1):1-13. doi: 10.1093/ndtplus/sfq191. Epub 2010 Nov 19.
PMID: 21245934
citation: Grooteman MP, van den Dorpel MA, Bots ML, Penne EL, van der Weerd NC, Mazairac AH, den Hoedt CH, van der Tweel I, Levesque R, Nube MJ, ter Wee PM, Blankestijn PJ; CONTRAST Investigators. Effect of online hemodiafiltration on all-cause mortality and cardiovascular outcomes. J Am Soc Nephrol. 2012 Jun;23(6):1087-96. doi: 10.1681/ASN.2011121140. Epub 2012 Apr 26.
PMID: 22539829
citation: Canaud B, Bragg-Gresham JL, Marshall MR, Desmeules S, Gillespie BW, Depner T, Klassen P, Port FK. Mortality risk for patients receiving hemodiafiltration versus hemodialysis: European results from the DOPPS. Kidney Int. 2006 Jun;69(11):2087-93. doi: 10.1038/sj.ki.5000447.
PMID: 16641921
citation: Locatelli F, Martin-Malo A, Hannedouche T, Loureiro A, Papadimitriou M, Wizemann V, Jacobson SH, Czekalski S, Ronco C, Vanholder R; Membrane Permeability Outcome (MPO) Study Group. Effect of membrane permeability on survival of hemodialysis patients. J Am Soc Nephrol. 2009 Mar;20(3):645-54. doi: 10.1681/ASN.2008060590. Epub 2008 Dec 17.
PMID: 19092122
responsible party type: Principal Investigator
investigator affiliation: IRCCS Azienda Ospedaliero-Universitaria di Bologna
investigator full name: Antonio Santoro
investigator title: Professor Antonio Santoro MD, Chief of Nephrology
mesh term: Kidney Failure, Chronic