<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/NCT04440085</url>
  </required_header>
  <id_info>
    <org_study_id>RaGuS</org_study_id>
    <nct_id>NCT04440085</nct_id>
  </id_info>
  <brief_title>RaGuS Trial by Postoperative Patients</brief_title>
  <acronym>RaGuS</acronym>
  <official_title>RANDOMIZED CASE-CONTROLLED TRIAL ASSESSING MIDODRINE (GUTRON®) IN POSTOPERATIVE VASOPLEGIC PATIENTS</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bürgerspital Solothurn</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Bürgerspital Solothurn</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Vasoplegic syndrome is characterized clinically by reduced systemic vascular resistance and&#xD;
      normal or increased cardiac output. It is principally observed in cardiovascular and&#xD;
      orthopedic interventions and is characterized by a systemic inflammatory response with the&#xD;
      inability of the vascular endothelial muscles to contract and a resistance to the action of&#xD;
      vasoactive drugs. This event extends the length of stay in the critical care area due to the&#xD;
      need of vasoactive drugs.&#xD;
&#xD;
      The investigators aim to assess the standardized application of midodrine in postoperative&#xD;
      patients without sepsis and need of vasoactive drugs in order to reduce the length of stay in&#xD;
      critical care area and for extension in hospital.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Midodrine is an alpha 1 receptor agonist used usually in cases of hypotension helping to&#xD;
      increase blood pressure. The main indication is orthostatic hypotension but there are other&#xD;
      clinical conditions where this medicament is often used like hypotension by dialysis,&#xD;
      hepatorenal syndrome and after carotid artery stenting.&#xD;
&#xD;
      Vasoplegic syndrome coul be interpreted as a variant of orthostatic hypotension that happens&#xD;
      usually after surgical interventions. It produces a loss of systemic vascular resistance due&#xD;
      to inflammatory reaction without any signs of infection.&#xD;
&#xD;
      The investigators aim to conduct a randomized, double-blind, single-center,&#xD;
      placebo-controlled study of midodrine in patients who present postoperative vasoplegia with&#xD;
      no active signs of sepsis but need of vasoactive drugs (Noradrenalin).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">September 14, 2020</start_date>
  <completion_date type="Anticipated">September 14, 2021</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2020</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>Randomized, double-blind, single-center, placebo-controlled study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time</measure>
    <time_frame>aproximately 2 days</time_frame>
    <description>Hours from initiation of treatment with midodrine to discharge from critical care area</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Length of stay</measure>
    <time_frame>aproximately 7 days</time_frame>
    <description>days in critical care area and hospital</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vasopresors</measure>
    <time_frame>aproximately 2 days</time_frame>
    <description>Noradrenalin needed doses</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fluid balance</measure>
    <time_frame>aproximately 2 days</time_frame>
    <description>cumulative fluid balance in mililiter</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Vasoplegic Syndrome</condition>
  <condition>Sirs Due to Noninfectious Process Without Organ Dysfunction</condition>
  <condition>Orthostatic Hypotension</condition>
  <arm_group>
    <arm_group_label>Intervention group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Midodrine will be administered every 8 hours, increasing the dose gradually until a maximum of 30 mg a day is reached. It will be given orally in the following sequence: 2.5 mg - 5 mg - 7.5 mg - 10 mg. The target standard perfusion pressure for all the patients will be a mean arterial pressure (MAP) &gt; 65 mmHg, with unchanged dose of midodrine after target pressure is reached. If the pressure continues to increase, the same sequence will be followed for dose de-escalation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>By placebo group will be followed the same strategy.The target standard perfusion pressure for all the patients will be a mean arterial pressure (MAP) &gt; 65 mmHg, with unchanged dose of placebo after target pressure is reached. If the pressure continues to increase, the same sequence will be followed for dose de-escalation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midodrine Hydrochloride</intervention_name>
    <description>All patients become standard care resuscitation treatment using liquids and vasoactive drugs in order to get a median arterial pressure ≥ 65 mmHg. Midodrine will be administered according to the evolution of the patient's mean pressure.</description>
    <arm_group_label>Intervention group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>All patients become standard care resuscitation treatment using liquids and vasoactive drugs in order to get a median arterial pressure ≥ 65 mmHg. Placebo will be administered according to the evolution of the patient's mean pressure.</description>
    <arm_group_label>Control group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Over 18 years of age&#xD;
&#xD;
          -  Need of vasoactive drugs after three hours from arrival and adequate volume recovery.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Signs of infection (anamnesis or pro-calcitonin &gt; 0.2 with leukocytosis, CRP and/or&#xD;
             fever)&#xD;
&#xD;
          -  Serum lactate &gt; 2mmol/l&#xD;
&#xD;
          -  Mechanical ventilation&#xD;
&#xD;
          -  Therapeutic restrictions or comfort measures at arrival&#xD;
&#xD;
          -  &quot;de novo&quot; or acute on chronic heart failure (Reduction of known ejection fraction for&#xD;
             more than 20 percent, signs of acute lung edema)&#xD;
&#xD;
          -  Pregnant&#xD;
&#xD;
          -  Patients with digoxin treatment or history of glaucoma.&#xD;
&#xD;
          -  History of midodrine allergy, pheochromocytoma, thyrotoxicosis, tachyarrhythmias or&#xD;
             ventricular fibrillation.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marcos Delgado, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Bürgerspital Solothurn</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Marcos Delgado, MD</last_name>
    <phone>+4132627</phone>
    <phone_ext>3820</phone_ext>
    <email>marcos.delgado@spital.so.ch</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>René Fahrner, MD</last_name>
    <phone>+4132627</phone>
    <phone_ext>3398</phone_ext>
    <email>r.fahrner@web.de</email>
  </overall_contact_backup>
  <results_reference>
    <citation>Tchen S, Sullivan JB. Clinical utility of midodrine and methylene blue as catecholamine-sparing agents in intensive care unit patients with shock. J Crit Care. 2020 Jun;57:148-156. doi: 10.1016/j.jcrc.2020.02.011. Epub 2020 Feb 19.</citation>
    <PMID>32145658</PMID>
  </results_reference>
  <results_reference>
    <citation>Shaefi S, Mittel A, Klick J, Evans A, Ivascu NS, Gutsche J, Augoustides JGT. Vasoplegia After Cardiovascular Procedures-Pathophysiology and Targeted Therapy. J Cardiothorac Vasc Anesth. 2018 Apr;32(2):1013-1022. doi: 10.1053/j.jvca.2017.10.032. Epub 2017 Oct 27.</citation>
    <PMID>29223724</PMID>
  </results_reference>
  <results_reference>
    <citation>Jans O, Mehlsen J, Kjaersgaard-Andersen P, Husted H, Solgaard S, Josiassen J, Lunn TH, Kehlet H. Oral Midodrine Hydrochloride for Prevention of Orthostatic Hypotension during Early Mobilization after Hip Arthroplasty: A Randomized, Double-blind, Placebo-controlled Trial. Anesthesiology. 2015 Dec;123(6):1292-300. doi: 10.1097/ALN.0000000000000890.</citation>
    <PMID>26492477</PMID>
  </results_reference>
  <results_reference>
    <citation>Smits M, Lin S, Rahme J, Bailey M, Bellomo R, Hardidge A. Blood Pressure and Early Mobilization After Total Hip and Knee Replacements: A Pilot Study on the Impact of Midodrine Hydrochloride. JB JS Open Access. 2019 May 14;4(2):e0048. doi: 10.2106/JBJS.OA.18.00048. eCollection 2019 Apr-Jun.</citation>
    <PMID>31334462</PMID>
  </results_reference>
  <results_reference>
    <citation>Levine AR, Meyer MJ, Bittner EA, Berg S, Kalman R, Stanislaus AB, Ryan C, Ball SA, Eikermann M. Oral midodrine treatment accelerates the liberation of intensive care unit patients from intravenous vasopressor infusions. J Crit Care. 2013 Oct;28(5):756-62. doi: 10.1016/j.jcrc.2013.05.021. Epub 2013 Jul 8.</citation>
    <PMID>23845791</PMID>
  </results_reference>
  <results_reference>
    <citation>Cardenas-Garcia JL, Whitson MR, Healy K, Koenig S, Narasimhan M, Mayo P: Safety of oral midrodrine as a mehtod of weaning from intravenous vasoactive medication in the medical intensive care unit. Chest 2014, 146(4):224A.</citation>
  </results_reference>
  <results_reference>
    <citation>Rizvi MS, Nei AM, Gajic O, Mara KC, Barreto EF. Continuation of Newly Initiated Midodrine Therapy After Intensive Care and Hospital Discharge: A Single-Center Retrospective Study. Crit Care Med. 2019 Aug;47(8):e648-e653. doi: 10.1097/CCM.0000000000003814.</citation>
    <PMID>31107279</PMID>
  </results_reference>
  <results_reference>
    <citation>Whitson MR, Mo E, Nabi T, Healy L, Koenig S, Narasimhan M, Mayo PH. Feasibility, Utility, and Safety of Midodrine During Recovery Phase From Septic Shock. Chest. 2016 Jun;149(6):1380-3. doi: 10.1016/j.chest.2016.02.657. Epub 2016 Mar 4.</citation>
    <PMID>26953217</PMID>
  </results_reference>
  <results_reference>
    <citation>Anstey MH, Wibrow B, Thevathasan T, Roberts B, Chhangani K, Ng PY, Levine A, DiBiasio A, Sarge T, Eikermann M. Midodrine as adjunctive support for treatment of refractory hypotension in the intensive care unit: a multicenter, randomized, placebo controlled trial (the MIDAS trial). BMC Anesthesiol. 2017 Mar 21;17(1):47. doi: 10.1186/s12871-017-0339-x.</citation>
    <PMID>28327122</PMID>
  </results_reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 13, 2020</study_first_submitted>
  <study_first_submitted_qc>June 18, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 19, 2020</study_first_posted>
  <last_update_submitted>June 18, 2020</last_update_submitted>
  <last_update_submitted_qc>June 18, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 19, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Bürgerspital Solothurn</investigator_affiliation>
    <investigator_full_name>Marcos Delgado</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <keyword>Midodrine</keyword>
  <keyword>Vasoplegic syndrome</keyword>
  <keyword>Noradrenaline</keyword>
  <keyword>SIRS</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypotension, Orthostatic</mesh_term>
    <mesh_term>Hypotension</mesh_term>
    <mesh_term>Vasoplegia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Midodrine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>We have decided for the Trial not to share the participant Information.</ipd_description>
  </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/NCT04440085
org study id: RaGuS
nct id: NCT04440085
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Vasoplegic syndrome is characterized clinically by reduced systemic vascular resistance and
      normal or increased cardiac output. It is principally observed in cardiovascular and
      orthopedic interventions and is characterized by a systemic inflammatory response with the
      inability of the vascular endothelial muscles to contract and a resistance to the action of
      vasoactive drugs. This event extends the length of stay in the critical care area due to the
      need of vasoactive drugs.

      The investigators aim to assess the standardized application of midodrine in postoperative
      patients without sepsis and need of vasoactive drugs in order to reduce the length of stay in
      critical care area and for extension in hospital.
Midodrine is an alpha 1 receptor agonist used usually in cases of hypotension helping to
      increase blood pressure. The main indication is orthostatic hypotension but there are other
      clinical conditions where this medicament is often used like hypotension by dialysis,
      hepatorenal syndrome and after carotid artery stenting.

      Vasoplegic syndrome coul be interpreted as a variant of orthostatic hypotension that happens
      usually after surgical interventions. It produces a loss of systemic vascular resistance due
      to inflammatory reaction without any signs of infection.

      The investigators aim to conduct a randomized, double-blind, single-center,
      placebo-controlled study of midodrine in patients who present postoperative vasoplegia with
      no active signs of sepsis but need of vasoactive drugs (Noradrenalin).
allocation: Randomized
intervention model: Sequential Assignment
intervention model description: Randomized, double-blind, single-center, placebo-controlled study
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Time
time frame: aproximately 2 days
description: Hours from initiation of treatment with midodrine to discharge from critical care area
measure: Length of stay
time frame: aproximately 7 days
description: days in critical care area and hospital
measure: Vasopresors
time frame: aproximately 2 days
description: Noradrenalin needed doses
measure: Fluid balance
time frame: aproximately 2 days
description: cumulative fluid balance in mililiter
arm group label: Intervention group
arm group type: Active Comparator
description: Midodrine will be administered every 8 hours, increasing the dose gradually until a maximum of 30 mg a day is reached. It will be given orally in the following sequence: 2.5 mg - 5 mg - 7.5 mg - 10 mg. The target standard perfusion pressure for all the patients will be a mean arterial pressure (MAP) > 65 mmHg, with unchanged dose of midodrine after target pressure is reached. If the pressure continues to increase, the same sequence will be followed for dose de-escalation.
arm group label: Control group
arm group type: Placebo Comparator
description: By placebo group will be followed the same strategy.The target standard perfusion pressure for all the patients will be a mean arterial pressure (MAP) > 65 mmHg, with unchanged dose of placebo after target pressure is reached. If the pressure continues to increase, the same sequence will be followed for dose de-escalation.
intervention type: Drug
intervention name: Midodrine Hydrochloride
description: All patients become standard care resuscitation treatment using liquids and vasoactive drugs in order to get a median arterial pressure ≥ 65 mmHg. Midodrine will be administered according to the evolution of the patient's mean pressure.
arm group label: Intervention group
intervention type: Drug
intervention name: Placebo
description: All patients become standard care resuscitation treatment using liquids and vasoactive drugs in order to get a median arterial pressure ≥ 65 mmHg. Placebo will be administered according to the evolution of the patient's mean pressure.
arm group label: Control group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Marcos Delgado, MD
role: Principal Investigator
affiliation: Bürgerspital Solothurn
last name: Marcos Delgado, MD
phone: +4132627
phone ext: 3820
email: marcos.delgado@spital.so.ch
last name: René Fahrner, MD
phone: +4132627
phone ext: 3398
email: r.fahrner@web.de
citation: Tchen S, Sullivan JB. Clinical utility of midodrine and methylene blue as catecholamine-sparing agents in intensive care unit patients with shock. J Crit Care. 2020 Jun;57:148-156. doi: 10.1016/j.jcrc.2020.02.011. Epub 2020 Feb 19.
PMID: 32145658
citation: Shaefi S, Mittel A, Klick J, Evans A, Ivascu NS, Gutsche J, Augoustides JGT. Vasoplegia After Cardiovascular Procedures-Pathophysiology and Targeted Therapy. J Cardiothorac Vasc Anesth. 2018 Apr;32(2):1013-1022. doi: 10.1053/j.jvca.2017.10.032. Epub 2017 Oct 27.
PMID: 29223724
citation: Jans O, Mehlsen J, Kjaersgaard-Andersen P, Husted H, Solgaard S, Josiassen J, Lunn TH, Kehlet H. Oral Midodrine Hydrochloride for Prevention of Orthostatic Hypotension during Early Mobilization after Hip Arthroplasty: A Randomized, Double-blind, Placebo-controlled Trial. Anesthesiology. 2015 Dec;123(6):1292-300. doi: 10.1097/ALN.0000000000000890.
PMID: 26492477
citation: Smits M, Lin S, Rahme J, Bailey M, Bellomo R, Hardidge A. Blood Pressure and Early Mobilization After Total Hip and Knee Replacements: A Pilot Study on the Impact of Midodrine Hydrochloride. JB JS Open Access. 2019 May 14;4(2):e0048. doi: 10.2106/JBJS.OA.18.00048. eCollection 2019 Apr-Jun.
PMID: 31334462
citation: Levine AR, Meyer MJ, Bittner EA, Berg S, Kalman R, Stanislaus AB, Ryan C, Ball SA, Eikermann M. Oral midodrine treatment accelerates the liberation of intensive care unit patients from intravenous vasopressor infusions. J Crit Care. 2013 Oct;28(5):756-62. doi: 10.1016/j.jcrc.2013.05.021. Epub 2013 Jul 8.
PMID: 23845791
citation: Cardenas-Garcia JL, Whitson MR, Healy K, Koenig S, Narasimhan M, Mayo P: Safety of oral midrodrine as a mehtod of weaning from intravenous vasoactive medication in the medical intensive care unit. Chest 2014, 146(4):224A.
citation: Rizvi MS, Nei AM, Gajic O, Mara KC, Barreto EF. Continuation of Newly Initiated Midodrine Therapy After Intensive Care and Hospital Discharge: A Single-Center Retrospective Study. Crit Care Med. 2019 Aug;47(8):e648-e653. doi: 10.1097/CCM.0000000000003814.
PMID: 31107279
citation: Whitson MR, Mo E, Nabi T, Healy L, Koenig S, Narasimhan M, Mayo PH. Feasibility, Utility, and Safety of Midodrine During Recovery Phase From Septic Shock. Chest. 2016 Jun;149(6):1380-3. doi: 10.1016/j.chest.2016.02.657. Epub 2016 Mar 4.
PMID: 26953217
citation: Anstey MH, Wibrow B, Thevathasan T, Roberts B, Chhangani K, Ng PY, Levine A, DiBiasio A, Sarge T, Eikermann M. Midodrine as adjunctive support for treatment of refractory hypotension in the intensive care unit: a multicenter, randomized, placebo controlled trial (the MIDAS trial). BMC Anesthesiol. 2017 Mar 21;17(1):47. doi: 10.1186/s12871-017-0339-x.
PMID: 28327122
responsible party type: Principal Investigator
investigator affiliation: Bürgerspital Solothurn
investigator full name: Marcos Delgado
investigator title: Principal investigator
mesh term: Hypotension, Orthostatic
mesh term: Hypotension
mesh term: Vasoplegia
mesh term: Midodrine
sharing ipd: No
ipd description: We have decided for the Trial not to share the participant Information.