<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/NCT02200822</url>
  </required_header>
  <id_info>
    <org_study_id>ZOL-STOP-CRT</org_study_id>
    <nct_id>NCT02200822</nct_id>
  </id_info>
  <brief_title>Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding CRT Patients</brief_title>
  <acronym>STOP-CRT</acronym>
  <official_title>Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding Patients to Cardiac Resynchronization Therapy: the STOP-CRT Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hasselt University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ziekenhuis Oost-Limburg</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hasselt University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of this study is to demonstrate that in patients with&#xD;
      recuperated/normalized left ventricular function, defined as an ejection fraction (EF) ≥ 50%,&#xD;
      after implantation of cardiac resynchronization therapy, device treatment is sufficient and&#xD;
      neurohumoral blocker therapy can safely be withdrawn&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>July 2014</start_date>
  <completion_date type="Actual">February 2019</completion_date>
  <primary_completion_date type="Actual">February 2019</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>Factorial Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>a &gt; 15% increase in left ventricular end systolic volume</measure>
    <time_frame>at 12 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>- Incidence of HF related hospitalizations defined as admission to hospital / presentation to emergency room with need for parental therapy</measure>
    <time_frame>at 12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All cause mortality</measure>
    <time_frame>at 12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VO2 max change</measure>
    <time_frame>at 12 months</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>&gt;15% increase in left ventricular end systolic volume</measure>
    <time_frame>6 and 24 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>&gt; 15% decrease in left ventricular ejection fraction</measure>
    <time_frame>at 6, 12 and 24 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>mean blood pressure change</measure>
    <time_frame>at 6, 12 and 24 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>HF symptoms change (dyspnea visual analogue scale (VAS), New York Heart Association (NYHA) class, questionnaire &quot;Minnesota living with Heart Failure&quot;)</measure>
    <time_frame>at 6, 12 and 24 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>incidence of heart rhythm events (sustained ventricular tachycardia (VT), atrial fibrillation, ventricular fibrillation)</measure>
    <time_frame>at 6, 12 and 24 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>heart rate variability</measure>
    <time_frame>at 6, 12 and 24 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>urinary catecholamine concentration</measure>
    <time_frame>at 6, 12 and 24 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>change in myocardial contractility (force frequence relationship, left ventricular pre-ejection time, iso-volumetric contraction time, dP/dt)</measure>
    <time_frame>at 6, 12 and 24 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>change in diastolic filling pattern</measure>
    <time_frame>at 6, 12 and 24 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>plasma concentrations of plasma renin activity and aldosterone</measure>
    <time_frame>at 6, 12 and 24 months</time_frame>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">80</enrollment>
  <condition>Heart Failure (HF)</condition>
  <arm_group>
    <arm_group_label>non-intervention arm</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>continuation of neurohumoral blocker therapy based on maximum tolerated guideline recommended dose (this group is the control arm for as well withdrawal of beta blocker therapy as withdrawal of RAAS blocker therapy)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>withdrawal of beta blockers</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Intervention arm with systematic withdrawal of beta blocker therapy at a reverse sequence of guideline recommended uptitration.&#xD;
(this group is the experimental arm for beta blocker withdrawal. This group receives no intervention with regards to the withdrawal of RAAS blockade). Per 2 weeks:&#xD;
bisoprolol: 10mg/d → 5 mg/d → 2,5 mg/d → 1,25 mg/d stop&#xD;
metoprolol: 200 mg/d → 100 mg/d → 50 mg/d → 25 mg/d → stop&#xD;
nebivolol: 10mg/d → 5 mg/d → 2,5 mg/d → 1,25 mg/d stop&#xD;
carvedilol: 50 mg bid → 25 mg bid → 12,5 mg bid → 6,25 mg bid → stop</description>
  </arm_group>
  <arm_group>
    <arm_group_label>withdrawal of RAAS blockers</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>intervention arm with systematic withdrawal of spironolactone followed by withdrawal of ACE-I/ARB at a reverse sequence of guideline recommended uptitration (this group receives no intervention regarding the withdrawal of beta blockers. This group is the experimental arm for withdrawal of RAAS blockers)&#xD;
first spironolactone/eplerenone: per two weeks: 25 mg/d→12,5 mg/d → stop&#xD;
after 2 weeks stop spironolactone/eplerenone start withdrawal of ACE-I/ARB per two weeks:&#xD;
captopril: 50 mg tid→25 mg tid→12,5 mg tid→6,25 mg tid→stop&#xD;
enalapril: 10 mg bid→5 mg bid→2,5 mg bid→1,25 mg bid→stop&#xD;
lisinopril: 20 mg/d→10 mg/d→5 mg/d→2,5 mg/d→stop&#xD;
ramipril: 10 mg/d→5 mg/d→2,5 mg/d→1,25 mg/d→stop&#xD;
candesartan: 32 mg/d→16 mg/d→8 mg/d→4 m/d→stop&#xD;
valsartan: 160 mg bid→80 mg bid→40 mg bid→20 mg bid→stop</description>
  </arm_group>
  <arm_group>
    <arm_group_label>withdrawal of RAAS - and beta blockers</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>intervention arm with systematic withdrawal of spironolactone, secondly ACE-I/ARB and finally beta blockers. (this group is the experimental group for both study interventions (withdrawal of beta blockers and RAAS blockers)&#xD;
First: spironolactone/eplerenone cfr reduction schedule supra&#xD;
After 2 weeks of stop spironolactone withdrawal of ACE-I or ARB cfr reduction schedule supra&#xD;
After 2 weeks of stop ACE-I/ARB withdrawal of beta blocker cfr reduction schedule supra</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>beta blockers</intervention_name>
    <arm_group_label>withdrawal of RAAS - and beta blockers</arm_group_label>
    <arm_group_label>withdrawal of beta blockers</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>RAAS blockers</intervention_name>
    <description>RAAS blockers (combination of ACE-I/ARB and a mineralocorticoid receptor antagonist)</description>
    <arm_group_label>withdrawal of RAAS - and beta blockers</arm_group_label>
    <arm_group_label>withdrawal of RAAS blockers</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ≥18 years&#xD;
&#xD;
          -  CRT implantation&#xD;
&#xD;
               -  based on class I recommendations of ESC (European society of CArdiology)&#xD;
                  guidelines:&#xD;
&#xD;
               -  Left bundle branch block (LBBB) with QRS duration &gt;150 ms and left ventricular&#xD;
                  ejection fraction (LVEF) ≤35% who remained NYHA functional class II, III and&#xD;
                  ambulatory IV despite adequate medical treatment&#xD;
&#xD;
               -  LBBB with QRS duration 120-150 ms and LVEF ≤ 35% who remain in NYHA functional&#xD;
                  class II, III and ambulatory IV despite adequate medical treatment&#xD;
&#xD;
          -  At the moment of inclusion: ≥ 6 months after implantation&#xD;
&#xD;
          -  At the moment of inclusion: normalised LVEF (≥ 50%), LVIDD/BSA (left ventricular&#xD;
             internal diastolic diameter indexed to body surface area) ≤3.2 cm/m²(woman) en ≤3.1&#xD;
             cm/m² (men) or LVDV/BSA (left ventricular diastolic volume indexed to body surface&#xD;
             area) ≤75 ml/m² (women) or ≤75 ml/m² (men)&#xD;
&#xD;
          -  euvolemic clinical state and functioning in NYHA class I&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  contraindication for withdrawal of ACE-I/ARB such as diabetic nephropathy and&#xD;
             proteinuria &gt; 1g / 24 h&#xD;
&#xD;
          -  severe ventricular arrythmia (sustained VT or ventricular fibrillation) occuring at&#xD;
             the time LV function was normalized&#xD;
&#xD;
          -  ischemic cardiomyopathy with evidence of scarring (scarring on MRI or severe&#xD;
             hypokinesia/akinesia in &gt;1 LV wall segment on echocardiography)&#xD;
&#xD;
          -  known severe coronary atherosclerosis (stenosis ≥ 80%)&#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>Petra Nijst, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ziekenhuis Oost-Limburg</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ziekenhuis Oost Limburg</name>
      <address>
        <city>Genk</city>
        <state>Limburg</state>
        <zip>3600</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <verification_date>July 2019</verification_date>
  <study_first_submitted>July 24, 2014</study_first_submitted>
  <study_first_submitted_qc>July 24, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 25, 2014</study_first_posted>
  <last_update_submitted>July 30, 2019</last_update_submitted>
  <last_update_submitted_qc>July 30, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 1, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hasselt University</investigator_affiliation>
    <investigator_full_name>Wilfried Mullens, MD PhD</investigator_full_name>
    <investigator_title>MD PhD</investigator_title>
  </responsible_party>
  <keyword>neurohumoral blocker therapy</keyword>
  <keyword>renin-angiotensin-aldosterone system (RAAS)</keyword>
  <keyword>RAAS-blocker</keyword>
  <keyword>beta blocker</keyword>
  <keyword>spironolactone</keyword>
  <keyword>angiotensin converting enzyme inhibitor (ACE-I)</keyword>
  <keyword>angiotensin receptor blocker (ARB)</keyword>
  <keyword>cardiac resynchronization therapy (CRT)</keyword>
  <keyword>heart failure</keyword>
  <keyword>dyssynchrony</keyword>
  <keyword>left bundle branch block</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adrenergic beta-Antagonists</mesh_term>
  </intervention_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/NCT02200822
org study id: ZOL-STOP-CRT
nct id: NCT02200822
lead sponsor: 
collaborator: 
has dmc: Yes
The primary objective of this study is to demonstrate that in patients with
      recuperated/normalized left ventricular function, defined as an ejection fraction (EF) ≥ 50%,
      after implantation of cardiac resynchronization therapy, device treatment is sufficient and
      neurohumoral blocker therapy can safely be withdrawn
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: a > 15% increase in left ventricular end systolic volume
time frame: at 12 months
measure: - Incidence of HF related hospitalizations defined as admission to hospital / presentation to emergency room with need for parental therapy
time frame: at 12 months
measure: All cause mortality
time frame: at 12 months
measure: VO2 max change
time frame: at 12 months
measure: >15% increase in left ventricular end systolic volume
time frame: 6 and 24 months
measure: > 15% decrease in left ventricular ejection fraction
time frame: at 6, 12 and 24 months
measure: mean blood pressure change
time frame: at 6, 12 and 24 months
measure: HF symptoms change (dyspnea visual analogue scale (VAS), New York Heart Association (NYHA) class, questionnaire "Minnesota living with Heart Failure")
time frame: at 6, 12 and 24 months
measure: incidence of heart rhythm events (sustained ventricular tachycardia (VT), atrial fibrillation, ventricular fibrillation)
time frame: at 6, 12 and 24 months
measure: heart rate variability
time frame: at 6, 12 and 24 months
measure: urinary catecholamine concentration
time frame: at 6, 12 and 24 months
measure: change in myocardial contractility (force frequence relationship, left ventricular pre-ejection time, iso-volumetric contraction time, dP/dt)
time frame: at 6, 12 and 24 months
measure: change in diastolic filling pattern
time frame: at 6, 12 and 24 months
measure: plasma concentrations of plasma renin activity and aldosterone
time frame: at 6, 12 and 24 months
arm group label: non-intervention arm
arm group type: No Intervention
description: continuation of neurohumoral blocker therapy based on maximum tolerated guideline recommended dose (this group is the control arm for as well withdrawal of beta blocker therapy as withdrawal of RAAS blocker therapy)
arm group label: withdrawal of beta blockers
arm group type: Active Comparator
description: Intervention arm with systematic withdrawal of beta blocker therapy at a reverse sequence of guideline recommended uptitration.
(this group is the experimental arm for beta blocker withdrawal. This group receives no intervention with regards to the withdrawal of RAAS blockade). Per 2 weeks:
bisoprolol: 10mg/d → 5 mg/d → 2,5 mg/d → 1,25 mg/d stop
metoprolol: 200 mg/d → 100 mg/d → 50 mg/d → 25 mg/d → stop
nebivolol: 10mg/d → 5 mg/d → 2,5 mg/d → 1,25 mg/d stop
carvedilol: 50 mg bid → 25 mg bid → 12,5 mg bid → 6,25 mg bid → stop
arm group label: withdrawal of RAAS blockers
arm group type: Active Comparator
description: intervention arm with systematic withdrawal of spironolactone followed by withdrawal of ACE-I/ARB at a reverse sequence of guideline recommended uptitration (this group receives no intervention regarding the withdrawal of beta blockers. This group is the experimental arm for withdrawal of RAAS blockers)
first spironolactone/eplerenone: per two weeks: 25 mg/d→12,5 mg/d → stop
after 2 weeks stop spironolactone/eplerenone start withdrawal of ACE-I/ARB per two weeks:
captopril: 50 mg tid→25 mg tid→12,5 mg tid→6,25 mg tid→stop
enalapril: 10 mg bid→5 mg bid→2,5 mg bid→1,25 mg bid→stop
lisinopril: 20 mg/d→10 mg/d→5 mg/d→2,5 mg/d→stop
ramipril: 10 mg/d→5 mg/d→2,5 mg/d→1,25 mg/d→stop
candesartan: 32 mg/d→16 mg/d→8 mg/d→4 m/d→stop
valsartan: 160 mg bid→80 mg bid→40 mg bid→20 mg bid→stop
arm group label: withdrawal of RAAS - and beta blockers
arm group type: Active Comparator
description: intervention arm with systematic withdrawal of spironolactone, secondly ACE-I/ARB and finally beta blockers. (this group is the experimental group for both study interventions (withdrawal of beta blockers and RAAS blockers)
First: spironolactone/eplerenone cfr reduction schedule supra
After 2 weeks of stop spironolactone withdrawal of ACE-I or ARB cfr reduction schedule supra
After 2 weeks of stop ACE-I/ARB withdrawal of beta blocker cfr reduction schedule supra
intervention type: Drug
intervention name: beta blockers
arm group label: withdrawal of RAAS - and beta blockers
arm group label: withdrawal of beta blockers
intervention type: Drug
intervention name: RAAS blockers
description: RAAS blockers (combination of ACE-I/ARB and a mineralocorticoid receptor antagonist)
arm group label: withdrawal of RAAS - and beta blockers
arm group label: withdrawal of RAAS blockers
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Petra Nijst, MD
role: Principal Investigator
affiliation: Ziekenhuis Oost-Limburg
facility: 
country: Belgium
responsible party type: Principal Investigator
investigator affiliation: Hasselt University
investigator full name: Wilfried Mullens, MD PhD
investigator title: MD PhD
mesh term: Heart Failure
mesh term: Adrenergic beta-Antagonists