<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/NCT04465123</url>
  </required_header>
  <id_info>
    <org_study_id>MED-2563-07080 (2)</org_study_id>
    <nct_id>NCT04465123</nct_id>
  </id_info>
  <brief_title>Early Sequential Nephron Blockade in Acute Heart Failure Patients: A Randomised, Controlled Study</brief_title>
  <acronym>NEB-HF</acronym>
  <official_title>Furosemide With Early Sequential Nephron Blockade Versus Furosemide Alone in Acute Heart Failure Patients With Furosemide-guided Diuretic Resistance: A Double-blinded, Randomized, Placebo-controlled Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Chiang Mai University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Chiang Mai University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study aims to demonstrate the efficacy of sequential nephron blockade by adding&#xD;
      hydrochlorothiazide or spironolactone on intravenous furosemide compared to intravenous&#xD;
      furosemide alone in the treatments of volume overload in patients with acute heart failure&#xD;
      who have diuretic resistance from furosemide stress test.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is a randomised, double-blinded, double-dummy, placebo-controlled study to&#xD;
      demonstrate the efficacy of oral hydrochlorothiazide or spironolactone in combination with&#xD;
      intravenous furosemide compared to intravenous furosemide in combination with placebo. Dosage&#xD;
      of intravenous furosemide will be adjusted according to pre-defined protocol. The primary&#xD;
      outcome is urine volume during 72 hours after randomisation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">August 13, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">July 31, 2022</primary_completion_date>
  <phase>Phase 3</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Urine volume</measure>
    <time_frame>72 hours</time_frame>
    <description>Total urine volume after randomisation</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Urine volume</measure>
    <time_frame>24 and 48 hours</time_frame>
    <description>Total urine volume after randomization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body weight</measure>
    <time_frame>72 hours after randomisation</time_frame>
    <description>Changes of patient's body weight</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of hospital admission</measure>
    <time_frame>During hospital admission period</time_frame>
    <description>Number of days that patients need to stay in the hospital</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Furosemide dose</measure>
    <time_frame>72 hours after randomisation</time_frame>
    <description>Total dosage of intravenous furosemide</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of B-type atrial natriuretic peptide (BNP)</measure>
    <time_frame>72 hours and 7 days after randomisation</time_frame>
    <description>levels of pro-BNP</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with adverse events</measure>
    <time_frame>During hospital admission</time_frame>
    <description>All adverse events during hospital admission</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dyspnea score assessed by visual analogue scale</measure>
    <time_frame>At randomization, and 6, 12, 24, 48 and 72 hours after randomization</time_frame>
    <description>The scale is between 0 and 100. The higher scale represents lower level of dyspnea</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Acute Heart Failure</condition>
  <condition>Acute Kidney Injury</condition>
  <arm_group>
    <arm_group_label>Furosemide with spironolactone or hydrochlorothiazide</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>IV furosemide dosage will be adjusted according to the protocol as follows. Level 1: previous oral furosemide dose ≤80 mg/day; furosemide 80 mg IV bolus every 6 hours Level 2: previous oral furosemide dose 81-160 mg/day; furosemide 160 mg IV bolus every 6 hours Level 3: previous oral furosemide dose &gt;160 mg/day; furosemide 250 mg IV bolus every 6 hours Furosemide dosage will be adjusted to keep urine output between 3,000 and 5,000 ml/day and &gt;600 ml during 6 hours after furosemide administration.&#xD;
If the urine output &lt;3,000 ml/day or &lt;600 ml per 6 hours, furosemide dosage will be increase 1-level up per protocol above.&#xD;
If the urine output &gt;5,000 ml/day, furosemide dosage will be reduced 1-level down per protocol above.&#xD;
Patients will be received spironolactone or hydrochlorothiazide in combination with intravenous furosemide according to patients' serum potassium levels.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Furosemide with placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>IV furosemide dosage will be adjusted according to the pre-defined protocol as shown in the experimental group.&#xD;
Patients will be received spironolactone placebo or hydrochlorothiazide placebo in combination with intravenous furosemide according to patients' serum potassium levels.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Spironolactone or hydrochlorothiazide</intervention_name>
    <description>Patients will be received spironolactone or hydrochlorothiazide in combination with intravenous furosemide according to patients' serum potassium levels.&#xD;
If serum potassium levels ≤4 mEq/L, patients will be received spironolactone 100 mg every 12 hour for 72 hours.&#xD;
If serum potassium levels &gt;4 mEq/L, patients will be received hydrochlorothiazide 50 mg every 12 hour for 72 hours.</description>
    <arm_group_label>Furosemide with spironolactone or hydrochlorothiazide</arm_group_label>
    <other_name>Aldactone</other_name>
    <other_name>HCTZ</other_name>
    <other_name>Thiazide</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Patients will be received spironolactone placebo or hydrochlorothiazide placebo in combination with intravenous furosemide according to patients' serum potassium levels.&#xD;
If serum potassium levels ≤4 mEq/L, patients will be received spironolactone placebo every 12 hour for 72 hours.&#xD;
If serum potassium levels &gt;4 mEq/L, patients will be received hydrochlorothiazide placebo every 12 hour for 72 hours.</description>
    <arm_group_label>Furosemide with placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  Diagnosis of acute heart failure which is defined by 2 of the 3 following features:&#xD;
             ≥2+ leg edema, jugular venous pressure &gt;10 cm from physical examination or central&#xD;
             venous pressure &gt;10 mmHg, and bilateral pulmonary edema or bilateral pleural effusion&#xD;
             from chest radiography&#xD;
&#xD;
          -  Patients consent to participate into the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who receive furosemide ≥500 mg/day or hydrochlorothiazide ≥100 mg/day or&#xD;
             spironolactone ≥100 mg/day or tolvaptan of any doses&#xD;
&#xD;
          -  Patients who have systolic blood pressure &lt;100 mmHg or who need vasoactive drugs&#xD;
             inotropic agents (except dobutamine)&#xD;
&#xD;
          -  Patients with intravascular volume depletion from clinical evaluation&#xD;
&#xD;
          -  Patients with chronic kidney disease stage 5 (estimated glomerular filtration rate &lt;15&#xD;
             ml/min/1.73 m2) or patients who receive maintenance dialysis&#xD;
&#xD;
          -  Patients who require renal replacement therapy at the time of admission&#xD;
&#xD;
          -  Patients whom diagnosed hypertrophic obstructive cardiomyopathy, severe valvular&#xD;
             stenosis or complex congenital heart disease&#xD;
&#xD;
          -  Patients with sepsis or systemic infection&#xD;
&#xD;
          -  Pregnant women&#xD;
&#xD;
          -  Patients who have history of furosemide, spironolactone or hydrochlorothiazide allergy&#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>Kajohnsak Noppakun, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Instructor, Division of Nephrology, Department of Internal Medicine</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Kajohnsak Noppakun, MD</last_name>
    <phone>+66815953465</phone>
    <email>kajohnsak.noppakun@cmu.ac.th</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Tiranun Suriya, RN</last_name>
    <phone>+66818812106</phone>
    <email>tingsuri@hotmail.co.th</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Chiang Mai University Hospital, Faculty of Medicine, Chiang Mai University</name>
      <address>
        <city>Chiang Mai</city>
        <zip>50200</zip>
        <country>Thailand</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kajohnsak Noppakun, MD</last_name>
      <phone>+66815953465</phone>
      <email>kajohnsak.noppakun@cmu.ac.th</email>
    </contact>
    <contact_backup>
      <last_name>Tiranun Suriya, RN</last_name>
      <phone>+66818812106</phone>
      <email>tingsuri@hotmail.co.th</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Thailand</country>
  </location_countries>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>July 6, 2020</study_first_submitted>
  <study_first_submitted_qc>July 6, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 9, 2020</study_first_posted>
  <last_update_submitted>August 16, 2020</last_update_submitted>
  <last_update_submitted_qc>August 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 18, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Chiang Mai University</investigator_affiliation>
    <investigator_full_name>Kajohnsak Noppakun</investigator_full_name>
    <investigator_title>Assistant Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Acute heart failure</keyword>
  <keyword>Diuretic resistance</keyword>
  <keyword>Sequential nephron blockade</keyword>
  <keyword>Diuretic combination</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acute Kidney Injury</mesh_term>
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydrochlorothiazide</mesh_term>
    <mesh_term>Spironolactone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Request for individual participant data (IPD) has to be submitted to the Institutional Review Board (IRB) of Faculty of Medicine, Chiang Mai University, Chiang Mai, THAILAND.</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/NCT04465123
org study id: MED-2563-07080 (2)
nct id: NCT04465123
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study aims to demonstrate the efficacy of sequential nephron blockade by adding
      hydrochlorothiazide or spironolactone on intravenous furosemide compared to intravenous
      furosemide alone in the treatments of volume overload in patients with acute heart failure
      who have diuretic resistance from furosemide stress test.
This study is a randomised, double-blinded, double-dummy, placebo-controlled study to
      demonstrate the efficacy of oral hydrochlorothiazide or spironolactone in combination with
      intravenous furosemide compared to intravenous furosemide in combination with placebo. Dosage
      of intravenous furosemide will be adjusted according to pre-defined protocol. The primary
      outcome is urine volume during 72 hours after randomisation.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Urine volume
time frame: 72 hours
description: Total urine volume after randomisation
measure: Urine volume
time frame: 24 and 48 hours
description: Total urine volume after randomization
measure: Body weight
time frame: 72 hours after randomisation
description: Changes of patient's body weight
measure: Length of hospital admission
time frame: During hospital admission period
description: Number of days that patients need to stay in the hospital
measure: Furosemide dose
time frame: 72 hours after randomisation
description: Total dosage of intravenous furosemide
measure: Levels of B-type atrial natriuretic peptide (BNP)
time frame: 72 hours and 7 days after randomisation
description: levels of pro-BNP
measure: Number of participants with adverse events
time frame: During hospital admission
description: All adverse events during hospital admission
measure: Dyspnea score assessed by visual analogue scale
time frame: At randomization, and 6, 12, 24, 48 and 72 hours after randomization
description: The scale is between 0 and 100. The higher scale represents lower level of dyspnea
arm group label: Furosemide with spironolactone or hydrochlorothiazide
arm group type: Experimental
description: IV furosemide dosage will be adjusted according to the protocol as follows. Level 1: previous oral furosemide dose ≤80 mg/day; furosemide 80 mg IV bolus every 6 hours Level 2: previous oral furosemide dose 81-160 mg/day; furosemide 160 mg IV bolus every 6 hours Level 3: previous oral furosemide dose >160 mg/day; furosemide 250 mg IV bolus every 6 hours Furosemide dosage will be adjusted to keep urine output between 3,000 and 5,000 ml/day and >600 ml during 6 hours after furosemide administration.
If the urine output <3,000 ml/day or <600 ml per 6 hours, furosemide dosage will be increase 1-level up per protocol above.
If the urine output >5,000 ml/day, furosemide dosage will be reduced 1-level down per protocol above.
Patients will be received spironolactone or hydrochlorothiazide in combination with intravenous furosemide according to patients' serum potassium levels.
arm group label: Furosemide with placebo
arm group type: Active Comparator
description: IV furosemide dosage will be adjusted according to the pre-defined protocol as shown in the experimental group.
Patients will be received spironolactone placebo or hydrochlorothiazide placebo in combination with intravenous furosemide according to patients' serum potassium levels.
intervention type: Drug
intervention name: Spironolactone or hydrochlorothiazide
description: Patients will be received spironolactone or hydrochlorothiazide in combination with intravenous furosemide according to patients' serum potassium levels.
If serum potassium levels ≤4 mEq/L, patients will be received spironolactone 100 mg every 12 hour for 72 hours.
If serum potassium levels >4 mEq/L, patients will be received hydrochlorothiazide 50 mg every 12 hour for 72 hours.
arm group label: Furosemide with spironolactone or hydrochlorothiazide
other name: Aldactone
other name: HCTZ
other name: Thiazide
intervention type: Drug
intervention name: Placebo
description: Patients will be received spironolactone placebo or hydrochlorothiazide placebo in combination with intravenous furosemide according to patients' serum potassium levels.
If serum potassium levels ≤4 mEq/L, patients will be received spironolactone placebo every 12 hour for 72 hours.
If serum potassium levels >4 mEq/L, patients will be received hydrochlorothiazide placebo every 12 hour for 72 hours.
arm group label: Furosemide with placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kajohnsak Noppakun, MD
role: Principal Investigator
affiliation: Instructor, Division of Nephrology, Department of Internal Medicine
last name: Kajohnsak Noppakun, MD
phone: +66815953465
email: kajohnsak.noppakun@cmu.ac.th
last name: Tiranun Suriya, RN
phone: +66818812106
email: tingsuri@hotmail.co.th
facility: 
status: Recruiting
contact: 
contact backup: 
country: Thailand
responsible party type: Principal Investigator
investigator affiliation: Chiang Mai University
investigator full name: Kajohnsak Noppakun
investigator title: Assistant Professor of Medicine
mesh term: Acute Kidney Injury
mesh term: Heart Failure
mesh term: Hydrochlorothiazide
mesh term: Spironolactone
sharing ipd: No
ipd description: Request for individual participant data (IPD) has to be submitted to the Institutional Review Board (IRB) of Faculty of Medicine, Chiang Mai University, Chiang Mai, THAILAND.