Sacubitril/Valsartan vs Lifestyle in Hypertrophic Cardiomyopathy
Condition: Hypertrophic Cardiomyopathy
MeSH terms: Cardiomyopathies; Cardiomyopathy, Hypertrophic; Hypertrophy
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Lifestyle; Sacubitril/Valsartan
Intervention type(s): Behavioral; Drug
Intervention description(s): 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.; 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.
Other intervention name(s): Physical acitivity and dietary nitrate; Pharmacological
Intervention MeSH terms: Valsartan; Sacubitril and valsartan sodium hydrate drug combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Lifestyle; ARNI; Exercise tolerance