<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/NCT03832660</url>
  </required_header>
  <id_info>
    <org_study_id>252015</org_study_id>
    <nct_id>NCT03832660</nct_id>
  </id_info>
  <brief_title>Sacubitril/Valsartan vs Lifestyle in Hypertrophic Cardiomyopathy</brief_title>
  <acronym>SILICOFCM</acronym>
  <official_title>Clinical and Genetic Determinants of Disease Progression and Response to Sacubitril/Valsartan vs Lifestyle (Physical Activity and Dietary Nitrate) in Patients With Hypertrophic Cardiomyopathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Newcastle University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Azienda Ospedaliero-Universitaria Careggi</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital Regensburg</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institute for Cardiovascular Diseases of Vojvodina</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Belgrade</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Newcastle University</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>
      The overall aim of this project is to establish potential benefits of a novel lifestyle&#xD;
      (physical activity and dietary nitrate) and pharmacological (angiotensin receptor neprilysin&#xD;
      inhibitor) interventions in patients with hypertrophic cardiomyopathy (HCM). HCM is the most&#xD;
      common genetic cardiovascular disease with a broad spectrum of disease severity. Angiotensin&#xD;
      receptor neprilysin inhibitor reduces death, hospitalisation, and may improve cardiac&#xD;
      function and exercise tolerance in heart failure. Exercise training is associated with a&#xD;
      significant increase in exercise tolerance, but appear to have limited effect on measures of&#xD;
      cardiac morphology or function in patients with HCM. Dietary supplementation with inorganic&#xD;
      nitrate (i.e. concentrated nitrate-rich beetroot juice) improves exercise capacity,&#xD;
      vasodilatation and cardiac output reserves while reduces arterial wave reflections, which are&#xD;
      linked to left ventricular diastolic dysfunction and remodelling. Using a five-centre, open&#xD;
      label, three-arm, pilot design, the present study will evaluate the effect of lifestyle&#xD;
      (physical activity and dietary supplementation with inorganic nitrate) and pharmacological&#xD;
      (angiotensin receptor neprilysin inhibitor sacubitril / valsartan) interventions in patients&#xD;
      with HCM. The Aim is to examine whether these interventions improve functional capacity,&#xD;
      clinical phenotypic characteristics, and quality of life in patients with HCM.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background and Rationale for the Study:&#xD;
&#xD;
      Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiac disease, affecting&#xD;
      one in 500 individuals. The predominant cause is mutation of genes that encode protein&#xD;
      components of the cardiac sarcomere. The mechanisms that lead from a sarcomere gene mutation&#xD;
      to phenotypic expression of HCM are poorly understood, which impedes the search for a&#xD;
      treatment that can disrupt the pathophysiological process.&#xD;
&#xD;
      The clinical diagnosis of HCM is based on hypertrophy of the left ventricle that cannot be&#xD;
      explained by extrinsic factors such as increased afterload. The course of the disease is&#xD;
      highly variable, ranging from an asymptomatic, benign course with a normal life expectancy to&#xD;
      a progressive disease characterised by angina, heart failure, atrial fibrillation, stroke,&#xD;
      malignant arrhythmia, syncope, or sudden cardiac death. Disease progression can relate to&#xD;
      increasing left ventricular hypertrophy and fibrosis leading to worsening of diastolic (and&#xD;
      occasionally systolic) function, increased left ventricular end-diastolic pressure, and left&#xD;
      atrial enlargement. No medical treatment has been reliably shown to halt or reverse disease&#xD;
      progression. Clinical trials demonstrated limited or no effect of angiotensin receptor&#xD;
      blockers or late sodium current inhibitor on disease progression, cardiac structure and&#xD;
      function, exercise tolerance and quality of life in patients with HCM. Accordingly, treatment&#xD;
      recommendations are focused on the alleviation of symptoms, prevention of thromboembolic&#xD;
      events, and implantation of prophylactic implantable cardioverter defibrillators in patients&#xD;
      at high risk of sudden cardiac death.&#xD;
&#xD;
      Lifestyle interventions including physical activity and dietary nitrate supplementation are&#xD;
      safe and can improve symptoms and signs in patients with heart failure. Exercise training is&#xD;
      associated with a significant increase in exercise tolerance, but appear to have limited&#xD;
      effect on measures of cardiac morphology or function in patients with HCM. Dietary&#xD;
      supplementation with inorganic nitrate (i.e. concentrated nitrate-rich beetroot juice)&#xD;
      improves exercise capacity, vasodilatation and cardiac output reserves while reduces arterial&#xD;
      wave reflections, which are linked to a left ventricular diastolic dysfunction and&#xD;
      remodelling.&#xD;
&#xD;
      Angiotensin receptor neprilysin inhibitor (ARNI) is a novel treatment shown to reduce&#xD;
      mortality and hospitalisation in heart failure with reduced ejection fraction, while there is&#xD;
      an ongoing trial to evaluate its effect on heart failure with preserved ejection fraction.&#xD;
      Recent preliminary data suggest that ARNI improves left ventricular wall motion and exercise&#xD;
      tolerance, while reduces markers of left ventricular wall stress. The impact of ARNI on&#xD;
      parameters of cardiac function and remodeling has not been previously described in heart&#xD;
      failure. Several trials are ongoing aiming provide mechanistic insight on the effect of ARNI&#xD;
      in heart failure. The effect of ARNI has not been evaluated in patients with HCM.&#xD;
&#xD;
      Despite both lifestyle and ARNI interventions may have potential positive effect, no study so&#xD;
      far has evaluated their effect on exercise tolerance, cardiac remodelling and quality of life&#xD;
      in patients with HCM.&#xD;
&#xD;
      Aim and Objectives:&#xD;
&#xD;
      The aim of the project is to identify clinical and genetic markers of disease progression and&#xD;
      response to lifestyle and pharmacological interventions in patients with hypertrophic&#xD;
      cardiomyopathy. Specifically, the project will examine whether i) Lifestyle intervention&#xD;
      incorporating physical activity and dietary supplementation with inorganic nitrate, and ii)&#xD;
      Angiotensin receptor neprilysin inhibitor, improve functional capacity, clinical phenotypic&#xD;
      characteristics, and quality of life in patients with HCM.&#xD;
&#xD;
      Study Design and Methods:&#xD;
&#xD;
      The Investigators propose to study at least 240 patients across five centres using an open&#xD;
      label, three-arm trial designed to evaluate the effect of lifestyle (physical activity and&#xD;
      dietary supplementation with inorganic nitrate) and pharmacological intervention (angiotensin&#xD;
      receptor neprilysin inhibitor sacubitril / valsartan) in patients with HCM who are currently&#xD;
      not participating in any drug trial or a regular exercise regimen (i.e. ≤ minutes of&#xD;
      exercise, ≤ 1 day per week for the previous 3 months). All patients will be administered a&#xD;
      pre-screening questionnaire in order to determine eligibility and will be randomized into a&#xD;
      intervention or a standard (control) care group in the 2:1 ratio. This will be a&#xD;
      collaborative effort with investigators from Germany - University Hospital Regensburg (Dr&#xD;
      Lars Maier), Italy - Azienda Ospedaliero Universitaria Careggi Florence (Dr Iacopo Olivotto),&#xD;
      Serbia - Institute of Cardiovascular Diseases of Vojvodina (Dr Lazar Velicki), Serbia -&#xD;
      University of Belgrade Faculty of Medicine (Drs Arsen Ristic and Dejana Popovic) and United&#xD;
      Kingdom - University of Newcastle (Drs Djordje Jakovljevic and Guy MacGowan). Investigator&#xD;
      will secure their own Ethics Committee / Institutional Review Board approvals. Target number&#xD;
      is at least 45 patients at each centre.&#xD;
&#xD;
      Recruitment procedures:&#xD;
&#xD;
      Potentially eligible patients will be identified through the Cardiology clinics of the&#xD;
      participating centres. Patients will be identified and contacted by the member of the study&#xD;
      research team. An information sheet will be mailed out upon request. Consent forms will be&#xD;
      signed by the participant and countersigned by a member of the study team during the first&#xD;
      research visit.&#xD;
&#xD;
      Interventions:&#xD;
&#xD;
      Duration of the lifestyle and pharmacological interventions is four months.&#xD;
&#xD;
      Lifestyle Intervention:&#xD;
&#xD;
      The lifestyle intervention will consist of two integrated components i.e. physical activity&#xD;
      and dietary supplementation with inorganic nitrate.&#xD;
&#xD;
      The first component of the lifestyle intervention is physical activity component is a&#xD;
      validated home-based exercise intervention aiming to increase daily physical activity level&#xD;
      by at least 2000 steps/day from baseline (e.g. walking for approximately 30 minutes), at&#xD;
      least 5-7 days per week, as this increment in daily physical activity was associated with a&#xD;
      10% lower risk of a cardiovascular events in high risk patients.&#xD;
&#xD;
      To control for exercise intensity patients will be instructed to use standardised Borg Scale&#xD;
      (0-20) to rate perceived exertion aiming for achieving the levels between 11 - 13&#xD;
      (easy-light-to somewhat hard). The exercise prescription will be progressed individually as&#xD;
      conditioning takes place, with the emphasis placed on volume of activity i.e. duration before&#xD;
      intensity. Targets will be set by participants, but the Investigators will present potential&#xD;
      health benefits of increasing physical activity by 2000 steps per day at least five days per&#xD;
      week (≥150 minutes per week). No strength training or burst activity will be prescribed and&#xD;
      all activities will fall well within the recommended national guidelines for recreational&#xD;
      exercise. Patients will be counselled to hydrate adequately during exercise, and to be alert&#xD;
      to warning signs and symptoms that should prompt them to stop exercising and contact the&#xD;
      research team. All patients will be provided with pedometers and asked to complete a daily&#xD;
      physical activity diary which will be reviewed and discussed on a weekly basis (telephone&#xD;
      call) with the member of the research team. All study patients will keep an exercise log and&#xD;
      be provided with pedometers.&#xD;
&#xD;
      The second component of the lifestyle intervention is a dietary supplementation with&#xD;
      inorganic nitrate. A single dose of inorganic nitrate given in the form of concentrated&#xD;
      nitrate-rich beetroot juice (NO3-, BEET IT Sport, James White Drinks Ltd., Ipswich, UK)&#xD;
      containing 6 mmol of NO3- in 70 ml bottle. Instructions will be provided for&#xD;
      self-administration of the nutritional intervention and patients will be asked to consume&#xD;
      beetroot juice each morning with the breakfast for 4 months.&#xD;
&#xD;
      The EPIC Food Frequency Questionnaire (FFQ) will be administered at baseline and the FETA&#xD;
      software used to extract dietary (energy and nutrient) information. Adherence to the&#xD;
      intervention will be tracked by completion of activity logs, weekly telephone follow-ups,&#xD;
      pedometers, and self-reported diaries.&#xD;
&#xD;
      Pharmacological Intervention (Angiotensin receptor neprilysin inhibitor sacubitril /&#xD;
      valsartan):&#xD;
&#xD;
      Patients who meet the study inclusion/exclusion criteria, after signing the informed consent,&#xD;
      will be invited to the screening visit. Patients previously receiving angiotensin-converting&#xD;
      enzyme inhibitor or angiotensin receptor blocker therapy will require a 36-hour washout&#xD;
      period before initiation of sacubitril/valsartan to reduce the risk of angioedema.&#xD;
&#xD;
      The treatment period begins on day 1 with initial dosing of sacubitril/valsartan, followed by&#xD;
      uptitration every 2 to 4 weeks, according to the prescribing information, to the target dose&#xD;
      of 97/103 mg twice daily. The 3 doses of sacubitril/valsartan available throughout the study&#xD;
      are 24/26 mg (dose level 1), 49/51 mg (dose Level 2), and 97/103 mg (dose Level 3), each&#xD;
      taken by mouth twice daily.&#xD;
&#xD;
      Doses may be adjusted based on overall safety and tolerability. If necessary, dose&#xD;
      adjustments or elimination of concomitant medications is made to alleviate adverse effects.&#xD;
      If adverse effects are not alleviated or it is not possible to adjust concomitant&#xD;
      medications, the study treatment may be down-titrated by 1 dose level-or, at the lowest dose,&#xD;
      temporarily withdrawn-for 1 to 4 weeks. The patient may then be reassessed and the study&#xD;
      treatment further down-titrated every 1 to 4 weeks until the patient is deemed stable. Once&#xD;
      stability is achieved, the patient is re-challenged with up-titration to the target dose. If&#xD;
      the patient discontinues the study medication, the patient is advised to return to the clinic&#xD;
      for an end-of-study visit. Patients undergo treatment for four months.&#xD;
&#xD;
      Control group / Usual Care Patients with HCM typically do not receive exercise and/or&#xD;
      nutritional therapies. The choice of a usual care (no intervention) comparator in this pilot&#xD;
      study is therefore reflective of the situation for the vast majority of patients with HCM. In&#xD;
      this study, the intervention and control group will receive usual medical management for HCM&#xD;
      according to national and local guidelines. Patients in the control group will also be&#xD;
      provided with activity logs, weekly telephone follow-ups, pedometers, and self-reported&#xD;
      diaries but will be asked not to change their physical activity and dietary habits during the&#xD;
      study.&#xD;
&#xD;
      Research Visits Eligible patients will attend the Clinical Research Facilities of five&#xD;
      participating centres for the total of 5 visits i.e. two at baseline (Visit 1 and Visit 2),&#xD;
      and two at 4-month (Visit 3 and Visit 4) when the assessments performed during Visits 1 and 3&#xD;
      (detailed below) will be repeated.&#xD;
&#xD;
      Patients will be given new activity logs at the end of 4-month protocol period and these logs&#xD;
      will be reviewed 3 months later (7 months after study initiation) during the follow-up visit&#xD;
      (Visit 5) During this visit patients will be asked to complete quality of life&#xD;
      questionnaires. Additionally, physical activity will be reviewed and patients will be asked&#xD;
      to repeat cardiopulmonary exercise test.&#xD;
&#xD;
      Patients will be contacted via email, telephone or spoken to in person to discuss the project&#xD;
      and will be taken through the information sheet to ensure they understand the nature of the&#xD;
      study.&#xD;
&#xD;
      The following testing will be performed at study initiation and termination:&#xD;
&#xD;
        1. Bloods, body composition, electrocardiography, cardiac autonomic function, arterial&#xD;
           stiffness.&#xD;
&#xD;
        2. Cardiopulmonary exercise testing in combination with echocardiography.&#xD;
&#xD;
        3. Cardiac magnetic resonance imaging in patients without implantable devices.&#xD;
&#xD;
        4. Quality of life, Anxiety and Depression, and Food Frequency questionnaires.&#xD;
&#xD;
      Funding: This project has received funding from the European Union's Horizon 2020 Research&#xD;
      and Innovation Programme under Grant Agreement no. 777204.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 3, 2019</start_date>
  <completion_date type="Actual">June 30, 2022</completion_date>
  <primary_completion_date type="Actual">May 15, 2022</primary_completion_date>
  <phase>Phase 2</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>Peak Oxygen Consumption (ml/kg/min)</measure>
    <time_frame>4 months</time_frame>
    <description>Change in exercise tolerance i.e. peak oxygen consumption and anaerobic threshold post intervention</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Left ventricular mass (grams)</measure>
    <time_frame>4 months</time_frame>
    <description>The size of the left ventricle</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LVOT obstruction</measure>
    <time_frame>4 months</time_frame>
    <description>Degree of left ventricular outflow tract obstruction.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LVEF (%)</measure>
    <time_frame>4 months</time_frame>
    <description>Left ventricular ejection fraction</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minnesota Living with Heart Failure questionnaire</measure>
    <time_frame>4 months</time_frame>
    <description>Quality of Life (score range from 0 to 105)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SF36 questionnaire</measure>
    <time_frame>4 months</time_frame>
    <description>Quality of Life RAND 36-Item Health Survey (score range from 0 to 100)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>E/A ratio</measure>
    <time_frame>4 months</time_frame>
    <description>Early to late filling ratio</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">168</enrollment>
  <condition>Hypertrophic Cardiomyopathy</condition>
  <arm_group>
    <arm_group_label>Lifestyle</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Lifestyle intervention will consist of two integrated components i.e. physical activity and dietary supplementation with inorganic nitrate. The physical activity component aims to increase daily physical activity level by at least 2000 steps/day from baseline (e.g. walking for approximately 30 minutes), at least 5-7 days per week. The second component of the lifestyle intervention is a dietary supplementation with inorganic nitrate. A single dose of inorganic nitrate given in the form of concentrated nitrate-rich beetroot juice (NO3-, BEET IT Sport, James White Drinks Ltd., Ipswich, UK) containing 6 mmol of NO3- in 70 ml bottle.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sacubitril/Valsartan</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Sacubitril / Valsartan as a pharmacological agent shall be studied to verify its effects on cardiac morphology and physiology of hypertrophic cardiomyopathy patients.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Usual Care</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>The participants in control group do not undertake lifestyle or sacubitril / valsartan intervention.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Lifestyle</intervention_name>
    <description>A 4-month lifestyle intervention will consist of two integrated components i.e. physical activity and dietary supplementation with inorganic nitrate. The physical activity component aims to increase daily physical activity level by at least 2000 steps/day from baseline (e.g. walking for approximately 30 minutes), at least 5-7 days per week. The second component of the lifestyle intervention is a dietary supplementation with inorganic nitrate. A single dose of inorganic nitrate given in the form of concentrated nitrate-rich beetroot juice (NO3-, BEET IT Sport, James White Drinks Ltd., Ipswich, UK) containing 6 mmol of NO3- in 70 ml bottle.</description>
    <arm_group_label>Lifestyle</arm_group_label>
    <other_name>Physical acitivity and dietary nitrate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sacubitril/Valsartan</intervention_name>
    <description>Angiotensin receptor neprilysin inhibitor Sacubitril / Valsartan: The treatment period begins on day 1 with initial dosing of sacubitril/valsartan, followed by uptitration every 2 to 4 weeks to the target dose of 97/103 mg twice daily. 3 doses of sacubitril/valsartan available throughout the study are 24/26 mg, 49/51 mg, and 97/103 mg, each taken by mouth twice daily. If the patient discontinues the study medication, the patient is advised to return to the clinic for an end-of-study visit. Patients undergo treatment for 4 months.</description>
    <arm_group_label>Sacubitril/Valsartan</arm_group_label>
    <other_name>Pharmacological</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Confirmed diagnosis of obstructive and/or non-obstructive hypertrophic cardiomyopathy.&#xD;
&#xD;
          -  Agreement to be a participant in the study protocol and willing/able to return for&#xD;
             follow-up.&#xD;
&#xD;
          -  Able to provide written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Less than 3 months post septal reduction therapy (surgery or catheter based&#xD;
             intervention)&#xD;
&#xD;
          -  Clinical decompensation in the previous 3 months, defined as New York Heart&#xD;
             Association class IV congestive heart failure symptoms.&#xD;
&#xD;
          -  Resting blood pressure greater than 180/100 mm Hg.&#xD;
&#xD;
          -  Systolic blood pressure lower than 100 mmHg&#xD;
&#xD;
          -  Hypotensive response to exercise testing (≥20 mmHg decrease of systolic blood pressure&#xD;
             from baseline blood pressure or an initial increase in systolic blood pressure&#xD;
             followed by a decrease of systolic blood pressure ≥20 mmHg).&#xD;
&#xD;
          -  Use of angiotensin converting Enzyme inhibitors or angiotensin receptor blockers.&#xD;
&#xD;
          -  Resting left ventricular outflow tract gradient &gt; 50 mm Hg.&#xD;
&#xD;
          -  Left ventricular ejection fraction of less than 50% by echocardiography.&#xD;
&#xD;
          -  Implanted pacemaker or cardiodefibrilator in the last 3 months or scheduled.&#xD;
&#xD;
          -  Renal insufficiency with a glomerular filtration rate of less than 30 mL/min per&#xD;
             1.73m2.&#xD;
&#xD;
          -  Present or planned pregnancy.&#xD;
&#xD;
          -  Life expectancy less than 12 months.&#xD;
&#xD;
          -  Body mass index &gt;40 kg/m2.&#xD;
&#xD;
          -  A history of exercise induced syncope or ventricular arrhythmias.&#xD;
&#xD;
          -  Inability to exercise due to orthopaedic or other non-cardiovascular limitations.&#xD;
&#xD;
          -  Use of other investigational drugs at the time of enrolment.&#xD;
&#xD;
          -  Any surgical or medical condition that in the opinion of the investigator may place&#xD;
             the patient at higher risk from his/her participation in the study or is likely to&#xD;
             prevent the patient from complying with the requirements of the study or completing&#xD;
             the study.&#xD;
&#xD;
          -  History or presence of any other disease with a life expectancy of &lt;3 years&#xD;
&#xD;
          -  History of noncompliance to medical regimens and patients who are considered&#xD;
             potentially unreliable.&#xD;
&#xD;
          -  History or evidence of drug or alcohol abuse within the past 12 months.&#xD;
&#xD;
          -  History of malignancy of any organ system (other than localized basal or squamous cell&#xD;
             carcinoma of the skin or localized prostate cancer), treated or untreated, within the&#xD;
             past 2 years, regardless of whether there is evidence of local recurrence or&#xD;
             metastases.&#xD;
&#xD;
          -  Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained&#xD;
             ventricular tachycardia and AF or atrial flutter with a resting ventricular rate &gt;110&#xD;
             beats per minute.&#xD;
&#xD;
          -  Participation in competitive or organized sport activities (such as football,&#xD;
             basketball, rugby, hockey, etc), burst activity (such as sprinting, racket sports,&#xD;
             etc) or heavy isometric exercise (such as body building or bench-pressing) or&#xD;
             opposition of refraining from the same for the duration of the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dr Djordje G Jakovljevic</last_name>
    <role>Principal Investigator</role>
    <affiliation>Newcastle University Faculty of Medical Sciences, Clinical Research Facility, Newcastle upun Tyne Hospitals NHS Foundation Trust</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospital Regensburg</name>
      <address>
        <city>Regensburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliero Universitaria Careggi Florence</name>
      <address>
        <city>Florence</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Belgrade Faculty of Medicine</name>
      <address>
        <city>Belgrade</city>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institute of Cardiovascular Diseases of Vojvodina</name>
      <address>
        <city>Sremska Kamenica</city>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Newcastle University, Faculty of Medical Sciences, Clinical Research Facility, Royal Victoria Infirmary; Newcastle upon Tyne Hospitals NHS Foundation Trust</name>
      <address>
        <city>Newcastle Upon Tyne</city>
        <state>England</state>
        <zip>NE2</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
    <country>Italy</country>
    <country>Serbia</country>
    <country>United Kingdom</country>
  </location_countries>
  <results_reference>
    <citation>Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation. 1995 Aug 15;92(4):785-9. doi: 10.1161/01.cir.92.4.785.</citation>
    <PMID>7641357</PMID>
  </results_reference>
  <results_reference>
    <citation>Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med. 2008 May 1;358(18):1899-908. doi: 10.1056/NEJMoa075463. Epub 2008 Apr 9.</citation>
    <PMID>18403758</PMID>
  </results_reference>
  <results_reference>
    <citation>Force T, Bonow RO, Houser SR, Solaro RJ, Hershberger RE, Adhikari B, Anderson ME, Boineau R, Byrne BJ, Cappola TP, Kalluri R, LeWinter MM, Maron MS, Molkentin JD, Ommen SR, Regnier M, Tang WH, Tian R, Konstam MA, Maron BJ, Seidman CE. Research priorities in hypertrophic cardiomyopathy: report of a Working Group of the National Heart, Lung, and Blood Institute. Circulation. 2010 Sep 14;122(11):1130-3. doi: 10.1161/CIRCULATIONAHA.110.950089. No abstract available.</citation>
    <PMID>20837938</PMID>
  </results_reference>
  <results_reference>
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    <PMID>24361242</PMID>
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    <citation>Mulligan AA, Luben RN, Bhaniani A, Parry-Smith DJ, O'Connor L, Khawaja AP, Forouhi NG, Khaw KT; EPIC-Norfolk FFQ Study. A new tool for converting food frequency questionnaire data into nutrient and food group values: FETA research methods and availability. BMJ Open. 2014 Mar 27;4(3):e004503. doi: 10.1136/bmjopen-2013-004503.</citation>
    <PMID>24674997</PMID>
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  <verification_date>November 2022</verification_date>
  <study_first_submitted>February 1, 2019</study_first_submitted>
  <study_first_submitted_qc>February 4, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 6, 2019</study_first_posted>
  <last_update_submitted>November 23, 2022</last_update_submitted>
  <last_update_submitted_qc>November 23, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 28, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Newcastle University</investigator_affiliation>
    <investigator_full_name>Djordje Jakovljevic</investigator_full_name>
    <investigator_title>Senior Lecturer/Associate Professor in Cardiovascular Ageing and Heart Failure</investigator_title>
  </responsible_party>
  <keyword>Lifestyle</keyword>
  <keyword>ARNI</keyword>
  <keyword>Exercise tolerance</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiomyopathies</mesh_term>
    <mesh_term>Cardiomyopathy, Hypertrophic</mesh_term>
    <mesh_term>Hypertrophy</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Valsartan</mesh_term>
    <mesh_term>Sacubitril and valsartan sodium hydrate drug combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Anonymised individual patient data will be shared between the partners of the SILICOFCM project.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_time_frame>January 2022, for five years</ipd_time_frame>
    <ipd_access_criteria>Data will be available upon request to a principal investigator.</ipd_access_criteria>
    <ipd_url>http://silicofcm.eu</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>September 14, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/60/NCT03832660/Prot_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03832660
org study id: 252015
nct id: NCT03832660
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The overall aim of this project is to establish potential benefits of a novel lifestyle
      (physical activity and dietary nitrate) and pharmacological (angiotensin receptor neprilysin
      inhibitor) interventions in patients with hypertrophic cardiomyopathy (HCM). HCM is the most
      common genetic cardiovascular disease with a broad spectrum of disease severity. Angiotensin
      receptor neprilysin inhibitor reduces death, hospitalisation, and may improve cardiac
      function and exercise tolerance in heart failure. Exercise training is associated with a
      significant increase in exercise tolerance, but appear to have limited effect on measures of
      cardiac morphology or function in patients with HCM. Dietary supplementation with inorganic
      nitrate (i.e. concentrated nitrate-rich beetroot juice) improves exercise capacity,
      vasodilatation and cardiac output reserves while reduces arterial wave reflections, which are
      linked to left ventricular diastolic dysfunction and remodelling. Using a five-centre, open
      label, three-arm, pilot design, the present study will evaluate the effect of lifestyle
      (physical activity and dietary supplementation with inorganic nitrate) and pharmacological
      (angiotensin receptor neprilysin inhibitor sacubitril / valsartan) interventions in patients
      with HCM. The Aim is to examine whether these interventions improve functional capacity,
      clinical phenotypic characteristics, and quality of life in patients with HCM.
Background and Rationale for the Study:

      Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiac disease, affecting
      one in 500 individuals. The predominant cause is mutation of genes that encode protein
      components of the cardiac sarcomere. The mechanisms that lead from a sarcomere gene mutation
      to phenotypic expression of HCM are poorly understood, which impedes the search for a
      treatment that can disrupt the pathophysiological process.

      The clinical diagnosis of HCM is based on hypertrophy of the left ventricle that cannot be
      explained by extrinsic factors such as increased afterload. The course of the disease is
      highly variable, ranging from an asymptomatic, benign course with a normal life expectancy to
      a progressive disease characterised by angina, heart failure, atrial fibrillation, stroke,
      malignant arrhythmia, syncope, or sudden cardiac death. Disease progression can relate to
      increasing left ventricular hypertrophy and fibrosis leading to worsening of diastolic (and
      occasionally systolic) function, increased left ventricular end-diastolic pressure, and left
      atrial enlargement. No medical treatment has been reliably shown to halt or reverse disease
      progression. Clinical trials demonstrated limited or no effect of angiotensin receptor
      blockers or late sodium current inhibitor on disease progression, cardiac structure and
      function, exercise tolerance and quality of life in patients with HCM. Accordingly, treatment
      recommendations are focused on the alleviation of symptoms, prevention of thromboembolic
      events, and implantation of prophylactic implantable cardioverter defibrillators in patients
      at high risk of sudden cardiac death.

      Lifestyle interventions including physical activity and dietary nitrate supplementation are
      safe and can improve symptoms and signs in patients with heart failure. Exercise training is
      associated with a significant increase in exercise tolerance, but appear to have limited
      effect on measures of cardiac morphology or function in patients with HCM. Dietary
      supplementation with inorganic nitrate (i.e. concentrated nitrate-rich beetroot juice)
      improves exercise capacity, vasodilatation and cardiac output reserves while reduces arterial
      wave reflections, which are linked to a left ventricular diastolic dysfunction and
      remodelling.

      Angiotensin receptor neprilysin inhibitor (ARNI) is a novel treatment shown to reduce
      mortality and hospitalisation in heart failure with reduced ejection fraction, while there is
      an ongoing trial to evaluate its effect on heart failure with preserved ejection fraction.
      Recent preliminary data suggest that ARNI improves left ventricular wall motion and exercise
      tolerance, while reduces markers of left ventricular wall stress. The impact of ARNI on
      parameters of cardiac function and remodeling has not been previously described in heart
      failure. Several trials are ongoing aiming provide mechanistic insight on the effect of ARNI
      in heart failure. The effect of ARNI has not been evaluated in patients with HCM.

      Despite both lifestyle and ARNI interventions may have potential positive effect, no study so
      far has evaluated their effect on exercise tolerance, cardiac remodelling and quality of life
      in patients with HCM.

      Aim and Objectives:

      The aim of the project is to identify clinical and genetic markers of disease progression and
      response to lifestyle and pharmacological interventions in patients with hypertrophic
      cardiomyopathy. Specifically, the project will examine whether i) Lifestyle intervention
      incorporating physical activity and dietary supplementation with inorganic nitrate, and ii)
      Angiotensin receptor neprilysin inhibitor, improve functional capacity, clinical phenotypic
      characteristics, and quality of life in patients with HCM.

      Study Design and Methods:

      The Investigators propose to study at least 240 patients across five centres using an open
      label, three-arm trial designed to evaluate the effect of lifestyle (physical activity and
      dietary supplementation with inorganic nitrate) and pharmacological intervention (angiotensin
      receptor neprilysin inhibitor sacubitril / valsartan) in patients with HCM who are currently
      not participating in any drug trial or a regular exercise regimen (i.e. ≤ minutes of
      exercise, ≤ 1 day per week for the previous 3 months). All patients will be administered a
      pre-screening questionnaire in order to determine eligibility and will be randomized into a
      intervention or a standard (control) care group in the 2:1 ratio. This will be a
      collaborative effort with investigators from Germany - University Hospital Regensburg (Dr
      Lars Maier), Italy - Azienda Ospedaliero Universitaria Careggi Florence (Dr Iacopo Olivotto),
      Serbia - Institute of Cardiovascular Diseases of Vojvodina (Dr Lazar Velicki), Serbia -
      University of Belgrade Faculty of Medicine (Drs Arsen Ristic and Dejana Popovic) and United
      Kingdom - University of Newcastle (Drs Djordje Jakovljevic and Guy MacGowan). Investigator
      will secure their own Ethics Committee / Institutional Review Board approvals. Target number
      is at least 45 patients at each centre.

      Recruitment procedures:

      Potentially eligible patients will be identified through the Cardiology clinics of the
      participating centres. Patients will be identified and contacted by the member of the study
      research team. An information sheet will be mailed out upon request. Consent forms will be
      signed by the participant and countersigned by a member of the study team during the first
      research visit.

      Interventions:

      Duration of the lifestyle and pharmacological interventions is four months.

      Lifestyle Intervention:

      The lifestyle intervention will consist of two integrated components i.e. physical activity
      and dietary supplementation with inorganic nitrate.

      The first component of the lifestyle intervention is physical activity component is a
      validated home-based exercise intervention aiming to increase daily physical activity level
      by at least 2000 steps/day from baseline (e.g. walking for approximately 30 minutes), at
      least 5-7 days per week, as this increment in daily physical activity was associated with a
      10% lower risk of a cardiovascular events in high risk patients.

      To control for exercise intensity patients will be instructed to use standardised Borg Scale
      (0-20) to rate perceived exertion aiming for achieving the levels between 11 - 13
      (easy-light-to somewhat hard). The exercise prescription will be progressed individually as
      conditioning takes place, with the emphasis placed on volume of activity i.e. duration before
      intensity. Targets will be set by participants, but the Investigators will present potential
      health benefits of increasing physical activity by 2000 steps per day at least five days per
      week (≥150 minutes per week). No strength training or burst activity will be prescribed and
      all activities will fall well within the recommended national guidelines for recreational
      exercise. Patients will be counselled to hydrate adequately during exercise, and to be alert
      to warning signs and symptoms that should prompt them to stop exercising and contact the
      research team. All patients will be provided with pedometers and asked to complete a daily
      physical activity diary which will be reviewed and discussed on a weekly basis (telephone
      call) with the member of the research team. All study patients will keep an exercise log and
      be provided with pedometers.

      The second component of the lifestyle intervention is a dietary supplementation with
      inorganic nitrate. A single dose of inorganic nitrate given in the form of concentrated
      nitrate-rich beetroot juice (NO3-, BEET IT Sport, James White Drinks Ltd., Ipswich, UK)
      containing 6 mmol of NO3- in 70 ml bottle. Instructions will be provided for
      self-administration of the nutritional intervention and patients will be asked to consume
      beetroot juice each morning with the breakfast for 4 months.

      The EPIC Food Frequency Questionnaire (FFQ) will be administered at baseline and the FETA
      software used to extract dietary (energy and nutrient) information. Adherence to the
      intervention will be tracked by completion of activity logs, weekly telephone follow-ups,
      pedometers, and self-reported diaries.

      Pharmacological Intervention (Angiotensin receptor neprilysin inhibitor sacubitril /
      valsartan):

      Patients who meet the study inclusion/exclusion criteria, after signing the informed consent,
      will be invited to the screening visit. Patients previously receiving angiotensin-converting
      enzyme inhibitor or angiotensin receptor blocker therapy will require a 36-hour washout
      period before initiation of sacubitril/valsartan to reduce the risk of angioedema.

      The treatment period begins on day 1 with initial dosing of sacubitril/valsartan, followed by
      uptitration every 2 to 4 weeks, according to the prescribing information, to the target dose
      of 97/103 mg twice daily. The 3 doses of sacubitril/valsartan available throughout the study
      are 24/26 mg (dose level 1), 49/51 mg (dose Level 2), and 97/103 mg (dose Level 3), each
      taken by mouth twice daily.

      Doses may be adjusted based on overall safety and tolerability. If necessary, dose
      adjustments or elimination of concomitant medications is made to alleviate adverse effects.
      If adverse effects are not alleviated or it is not possible to adjust concomitant
      medications, the study treatment may be down-titrated by 1 dose level-or, at the lowest dose,
      temporarily withdrawn-for 1 to 4 weeks. The patient may then be reassessed and the study
      treatment further down-titrated every 1 to 4 weeks until the patient is deemed stable. Once
      stability is achieved, the patient is re-challenged with up-titration to the target dose. If
      the patient discontinues the study medication, the patient is advised to return to the clinic
      for an end-of-study visit. Patients undergo treatment for four months.

      Control group / Usual Care Patients with HCM typically do not receive exercise and/or
      nutritional therapies. The choice of a usual care (no intervention) comparator in this pilot
      study is therefore reflective of the situation for the vast majority of patients with HCM. In
      this study, the intervention and control group will receive usual medical management for HCM
      according to national and local guidelines. Patients in the control group will also be
      provided with activity logs, weekly telephone follow-ups, pedometers, and self-reported
      diaries but will be asked not to change their physical activity and dietary habits during the
      study.

      Research Visits Eligible patients will attend the Clinical Research Facilities of five
      participating centres for the total of 5 visits i.e. two at baseline (Visit 1 and Visit 2),
      and two at 4-month (Visit 3 and Visit 4) when the assessments performed during Visits 1 and 3
      (detailed below) will be repeated.

      Patients will be given new activity logs at the end of 4-month protocol period and these logs
      will be reviewed 3 months later (7 months after study initiation) during the follow-up visit
      (Visit 5) During this visit patients will be asked to complete quality of life
      questionnaires. Additionally, physical activity will be reviewed and patients will be asked
      to repeat cardiopulmonary exercise test.

      Patients will be contacted via email, telephone or spoken to in person to discuss the project
      and will be taken through the information sheet to ensure they understand the nature of the
      study.

      The following testing will be performed at study initiation and termination:

        1. Bloods, body composition, electrocardiography, cardiac autonomic function, arterial
           stiffness.

        2. Cardiopulmonary exercise testing in combination with echocardiography.

        3. Cardiac magnetic resonance imaging in patients without implantable devices.

        4. Quality of life, Anxiety and Depression, and Food Frequency questionnaires.

      Funding: This project has received funding from the European Union's Horizon 2020 Research
      and Innovation Programme under Grant Agreement no. 777204.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Peak Oxygen Consumption (ml/kg/min)
time frame: 4 months
description: Change in exercise tolerance i.e. peak oxygen consumption and anaerobic threshold post intervention
measure: Left ventricular mass (grams)
time frame: 4 months
description: The size of the left ventricle
measure: LVOT obstruction
time frame: 4 months
description: Degree of left ventricular outflow tract obstruction.
measure: LVEF (%)
time frame: 4 months
description: Left ventricular ejection fraction
measure: Minnesota Living with Heart Failure questionnaire
time frame: 4 months
description: Quality of Life (score range from 0 to 105)
measure: SF36 questionnaire
time frame: 4 months
description: Quality of Life RAND 36-Item Health Survey (score range from 0 to 100)
measure: E/A ratio
time frame: 4 months
description: Early to late filling ratio
arm group label: Lifestyle
arm group type: Active Comparator
description: Lifestyle intervention will consist of two integrated components i.e. physical activity and dietary supplementation with inorganic nitrate. The physical activity component aims to increase daily physical activity level by at least 2000 steps/day from baseline (e.g. walking for approximately 30 minutes), at least 5-7 days per week. The second component of the lifestyle intervention is a dietary supplementation with inorganic nitrate. A single dose of inorganic nitrate given in the form of concentrated nitrate-rich beetroot juice (NO3-, BEET IT Sport, James White Drinks Ltd., Ipswich, UK) containing 6 mmol of NO3- in 70 ml bottle.
arm group label: Sacubitril/Valsartan
arm group type: Active Comparator
description: Sacubitril / Valsartan as a pharmacological agent shall be studied to verify its effects on cardiac morphology and physiology of hypertrophic cardiomyopathy patients.
arm group label: Usual Care
arm group type: No Intervention
description: The participants in control group do not undertake lifestyle or sacubitril / valsartan intervention.
intervention type: Behavioral
intervention name: Lifestyle
description: A 4-month lifestyle intervention will consist of two integrated components i.e. physical activity and dietary supplementation with inorganic nitrate. The physical activity component aims to increase daily physical activity level by at least 2000 steps/day from baseline (e.g. walking for approximately 30 minutes), at least 5-7 days per week. The second component of the lifestyle intervention is a dietary supplementation with inorganic nitrate. A single dose of inorganic nitrate given in the form of concentrated nitrate-rich beetroot juice (NO3-, BEET IT Sport, James White Drinks Ltd., Ipswich, UK) containing 6 mmol of NO3- in 70 ml bottle.
arm group label: Lifestyle
other name: Physical acitivity and dietary nitrate
intervention type: Drug
intervention name: Sacubitril/Valsartan
description: Angiotensin receptor neprilysin inhibitor Sacubitril / Valsartan: The treatment period begins on day 1 with initial dosing of sacubitril/valsartan, followed by uptitration every 2 to 4 weeks to the target dose of 97/103 mg twice daily. 3 doses of sacubitril/valsartan available throughout the study are 24/26 mg, 49/51 mg, and 97/103 mg, each taken by mouth twice daily. If the patient discontinues the study medication, the patient is advised to return to the clinic for an end-of-study visit. Patients undergo treatment for 4 months.
arm group label: Sacubitril/Valsartan
other name: Pharmacological
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Dr Djordje G Jakovljevic
role: Principal Investigator
affiliation: Newcastle University Faculty of Medical Sciences, Clinical Research Facility, Newcastle upun Tyne Hospitals NHS Foundation Trust
facility: 
facility: 
facility: 
facility: 
facility: 
country: Germany
country: Italy
country: Serbia
country: United Kingdom
citation: Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation. 1995 Aug 15;92(4):785-9. doi: 10.1161/01.cir.92.4.785.
PMID: 7641357
citation: Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med. 2008 May 1;358(18):1899-908. doi: 10.1056/NEJMoa075463. Epub 2008 Apr 9.
PMID: 18403758
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responsible party type: Principal Investigator
investigator affiliation: Newcastle University
investigator full name: Djordje Jakovljevic
investigator title: Senior Lecturer/Associate Professor in Cardiovascular Ageing and Heart Failure
mesh term: Cardiomyopathies
mesh term: Cardiomyopathy, Hypertrophic
mesh term: Hypertrophy
mesh term: Valsartan
mesh term: Sacubitril and valsartan sodium hydrate drug combination
sharing ipd: Yes
ipd description: Anonymised individual patient data will be shared between the partners of the SILICOFCM project.
ipd info type: Study Protocol
ipd time frame: January 2022, for five years
ipd access criteria: Data will be available upon request to a principal investigator.
ipd url: http://silicofcm.eu
provided document: 