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Study of Sacubitril/ValsarTan on MyocardIal OxygenatioN and Fibrosis in Heart Failure With Preserved Ejection Fraction (PRISTINE-HF)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04128891
Recruitment Status : Not yet recruiting
First Posted : October 16, 2019
Last Update Posted : October 16, 2019
Information provided by (Responsible Party):
Joseph Selvanayagam, Flinders University

Brief Summary:
To assess the effect of ARNI on myocardial deoxygenation at stress and myocardial fibrosis, and correlate this to changes in myocardial systolic and diastolic function in HFpEF patients.

Condition or disease Intervention/treatment Phase
Heart Failure With Preserved Ejection Fraction Drug: Sacubitril-Valsartan Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: PRospectIve Study of Sacubitril/ValsarTan on MyocardIal OxygenatioN and Fibrosis in PatiEnts With Heart Failure and Preserved Ejection Fraction
Estimated Study Start Date : February 1, 2020
Estimated Primary Completion Date : February 1, 2022
Estimated Study Completion Date : February 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure
Drug Information available for: Valsartan

Arm Intervention/treatment
Experimental: Sacubitril/Valsartan
30 participants to be administered Sacubitril/Valsartan (Entresto) tablets, minimum dose of 49/51mg or maximum dose of 97/103 mg twice daily for the duration of the study (two years).
Drug: Sacubitril-Valsartan
Cardiomagnetic Resonance Imaging
Other Name: Valsartan

Active Comparator: Valsartan
30 participants to be administered Valsartan tablets, minimum dose 80 mg or maximum dose of 160 mg twice daily for the duration of the study (two years).
Drug: Sacubitril-Valsartan
Cardiomagnetic Resonance Imaging
Other Name: Valsartan

Primary Outcome Measures :
  1. • To study the effects of Sacubitril/Valsartan on microvascular function and ischaemia in HFpEF patients. [ Time Frame: 12 Months ]
    The HFpEF participants on Sacubitril/valsartan with improvement in microvascular function and ischaemia, as assessed by OS-CMR at rest and stress (ΔSI: signal intensity change, at baseline and at 12 months).

Secondary Outcome Measures :
  1. 2.1 Incidence of microvascular dysfunction in HFpEF [ Time Frame: 12 Months ]
    The proportion of HFpEF patients with microvascular dysfunction, as assessed by OS-CMR ΔSI.

  2. 2.2 Extent of myocardial fibrosis in HFpEF [ Time Frame: 12 Months ]
    Baseline assessment of myocardial fibrosis in HFpEF patients and assess the response to Sacubitril/Valsartan by measuring changes in myocardial ECV

  3. 2.3 Assessment of left ventricular diastolic function in HFpEF [ Time Frame: 12 Months ]
    Baseline echocardiographic assessment of left ventricular diastolic function in HFpEF patients and assess the response to Sacubitril/Valsartan.

  4. 2.4 New York Heart Association (NYHA) class [ Time Frame: 12 Months ]
    Baseline evaluation of NYHA class and change in NYHA class at 12 months following Sacubitril/Valsartan therapy.

  5. 2.5 Functional assessment [ Time Frame: 12 Months ]
    Baseline computation of functional status by 6-minute walk test and evaluate the response to Sacubitril/Valsartan therapy

  6. 2.6 Number of heart failure related hospitalisations [ Time Frame: 12 Months ]
    The number of HFpEF patients admitted with heart failure during the study period.

  7. 2.7 Cardiac mortality [ Time Frame: 12 Months ]
    Cardiac mortality during the study period

  8. 2.8 All-cause mortality. [ Time Frame: 12 Months ]
    All-cause mortality during the study period.

Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Written informed consent will be obtained before any assessment is performed
  2. ≥ 40 years of age, male or female
  3. LVEF ≥45% by echocardiography during the screening period
  4. Symptom(s) of heart failure requiring treatment with diuretic(s) for at least 30 days prior to screening visit
  5. Current symptom(s) of heart failure (NYHA functional class II to IV)
  6. Structural heart disease evidenced by at least 1 of the following echocardiography findings:

    1. Left atrial (LA) enlargement defined by at least 1 of the following: LA width (diameter) ≥3.8 cm or LA length ≥5.0 cm or LA area ≥20 cm2 or LA volume ≥55 ml or LA volume index ≥29 ml/m2
    2. Left ventricular hypertrophy defined by septal thickness or posterior wall thickness ≥1.2 cm
  7. Elevated NT-proBNP (atleast 1 of the following)

    1. NT-proBNP >300 pg/ml for patients not in atrial fibrillation or >900 pg/ml for patients in atrial fibrillation during initial screening
    2. Heart failure hospitalization (defined as heart failure listed as the major reason for hospitalization) within 9 months prior to screening visit and NT-proBNP >200 pg/ml for patients not in atrial fibrillation or >600 pg/ml for patients in atrial fibrillation during initial screening

Exclusion Criteria:

  1. Any prior echocardiographic measurement of LVEF <45%
  2. Acute coronary syndrome (including myocardial infarction), cardiac surgery, other major cardiovascular surgery, or percutaneous coronary intervention within 3 months
  3. Known unrevascularized epicardial coronary artery disease (> 50% stenosis in any major epicardial coronary artery)
  4. Current acute decompensated heart failure requiring augmented therapy with intravenous diuretic agents, vasodilator agents, and/or inotropic drugs
  5. Patients who require treatment with 2 or more of the following: an angiotensin converting enzyme inhibitor, an angiotensin receptor blocker, or a renin inhibitor
  6. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes
  7. Patients with a known history of angioedema
  8. Probable alternative diagnoses that in the opinion of the investigator could account for the patient's heart failure symptoms such as significant pulmonary disease (including primary pulmonary hypertension), anaemia, or obesity. Specifically, patients with the following are excluded:

    1. Severe pulmonary disease including chronic obstructive pulmonary disease (i.e., requiring home oxygen therapy, chronic oral steroid therapy or hospitalized for pulmonary decompensation within 12 months) or
    2. Haemoglobin <10 g/dl, or
    3. Body mass index >40 kg/m2
  9. Patients with any of the following:

    1. Systolic blood pressure (SBP) ≥180 mm Hg at entry, or
    2. SBP >150 mm Hg and <180 mm Hg at entry unless the patient is receiving 3 or more antihypertensive drugs.
    3. SBP <110 mm Hg at entry
  10. Current participation in another investigational drug or device.
  11. Patients with history of any dilated cardiomyopathy, including peripartum cardiomyopathy, chemotherapy-induced cardiomyopathy, or viral myocarditis
  12. Evidence of right-sided heart failure in the absence of left-sided structural heart disease
  13. Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy
  14. Clinically significant congenital heart disease that could be the cause of the patient's symptoms and signs of heart failure
  15. Presence of hemodynamically significant valvular heart disease in the opinion of the investigator
  16. Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within the 3 months
  17. Carotid artery disease or valvular heart disease likely to require surgical or percutaneous intervention during the trial
  18. Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or atrial flutter with a resting ventricular rate >110 beats per minute
  19. Patients with a cardiac resynchronization therapy device
  20. Patients with prior major organ transplant or intent to transplant (i.e., on transplant list)
  21. Any surgical or medical condition that in the opinion of the investigator may place the patient at higher risk from his/her participation in the study or is likely to prevent the patient from complying with the requirements of the study or completing the study
  22. Any surgical or medical condition that might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including but not limited to any of the following: any history of pancreatic injury, pancreatitis, or evidence of impaired pancreatic function/injury within the past 5 years
  23. Evidence of hepatic disease as determined by any 1 of the following: SGOT (AST) or SGPT (ALT) values exceeding 3× the upper limit of normal, bilirubin >1.5 mg/dl at entry
  24. Patients with severe renal impairment of the following: eGFR <30 ml/min/1.73 m2 as calculated by the Modification in Diet in Renal Disease (MDRD) formula at entry
  25. Presence of known functionally significant bilateral renal artery stenosis
  26. Patients with serum potassium >5.2 mmol/l (mEq/l) at entry
  27. History or presence of any other disease with a life expectancy of <3 years
  28. History of noncompliance to medical regimens and patients who are considered potentially unreliable
  29. History or evidence of drug or alcohol abuse within the past 12 months
  30. Persons directly involved in the execution of this protocol
  31. History of malignancy of any organ system (other than localized basal or squamous cell carcinoma of the skin or localized prostate cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
  32. Pregnant or nursing (lactating) women
  33. Women of child-bearing potential
  34. Contraindications to CMR (claustrophobia, implanted medical devices like pacemakers / defibrillators, cochlear implants, intracranial clips, iron fragments in eyes, inability to lie flat for the scanning period)
  35. Contraindications to Gadolinium (eGFR <30 ml/min/1.73 m2 as calculated by the MDRD formula at entry or previous know serious allergy)
  36. Contraindications to Adenosine (second or third-degree atrioventricular block, asthma, concurrent dipyridamole use)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04128891

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Contact: Professor Selvanayagam 0984045619 ext 65619
Contact: Tonia Bromley 0984042852 ext 62852

Sponsors and Collaborators
Flinders University
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Principal Investigator: Carmine De Pasquale, Assoc Prof Flinders Medical Centre
Principal Investigator: Majo Joseph, Doctor Flinders Medical Centre
Principal Investigator: Rajiv Ananthakrishna, Doctor Flinders Medical Centre
Principal Investigator: Michael Stokes, Doctor Royal Adelaide Hospital
Principal Investigator: Sean Lal, Doctor Royal Prince Alfred
Principal Investigator: David Kaye, Professor Baker Institute/ Alfred Hospital

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Responsible Party: Joseph Selvanayagam, Professor, Flinders University Identifier: NCT04128891    
Other Study ID Numbers: FlindersU
First Posted: October 16, 2019    Key Record Dates
Last Update Posted: October 16, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
LCZ 696
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action