Personalised Prospective Comparison of ARni With ArB in Patients With Natriuretic Peptide eLEvation

• Status: Active, not recruiting
• Trial end date: 2021-06-11
• Target enrollment: 0
• Participant gender: All

Summary

Sacubitril-valsartan, an Angiotensin Receptor Blocker-Neprilysin Inhibitor (ARNI), currently marketed for the management of heart failure, has been shown to reduce cardiovascular morbidity and mortality in stage C heart failure with reduced ejection fraction. In stage C HFpEF, sacubitril-valsartan has also been shown to reduce left atrial volume index measured using echocardiography over a 9 month timeframe. The PARABLE study investigates the hypothesis that sacubitril-valsartan can provide benefits in terms of left atrial structure and function as well as left ventricular structure and function in asymptomatic (stage A/B HFpEF) patients. This is a prospective, randomised, double-blind, double-dummy, phase II study design. The patient population will have hypertension and/or diabetes together with preserved ejection fraction, elevated natriuretic peptide (NP) and abnormal left atrial volume index (LAVI, > 28 mL/m2).

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Mark Ledwidge; The Heartbeat Trust
• Collaborators: Novartis Ireland Ltd; The Heartbeat Trust
• Treatments: LCZ 696; Sacubitril and valsartan sodium hydrate drug combination; Valsartan

Criteria

Inclusion Criteria:

1. Age > 40yrs with cardiovascular risk factor(s) including at least one of:

1. History of hypertension (medicated for greater than one month);

2. History of diabetes;

2. Elevated NP: Elevated NP: BNP between 20 and 280pg/ml or NT-proBNP values between 100 pg/ml and 1,000 pg/ml within 6 months prior to screening or at screening

3. LAVI > 28 mL/m2 obtained during Doppler Echocardiography within 6 months prior to screening or at screening

4. Subjects must give written informed consent to participate in the study and before any study related assessments are performed.

Exclusion Criteria:

1. A history of heart failure.

2. Asymptomatic left ventricular systolic dysfunction defined as LVEF <50% on most recent measurement.

3. Systolic blood pressure <100mmHg

4. Persistent atrial fibrillation.

5. History of hypersensitivity, allergy or intolerance to LCZ696, ARB or neprilysin therapy or to any of the excipients or other contraindication to their use.

6. Previous history of intolerance to recommended target doses for ARBs

7. Subjects who require treatment with both an ACE inhibitor and an ARB

8. Presence of haemodynamically significant mitral and /or aortic valve disease.

9. Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic stenosis.

10. Conditions that are expected to compromise survival over the study period.

11. Serum potassium level > 5.2 mmol/L at screening.

12. Severe renal insufficiency (eGFR <30 mL per minute per 1.73 m2).

13. Hepatic dysfunction (Any LFT > 3 times the upper limit of normal (ULN))

14. Concomitant use of aliskiren

15. History of angioedema.

16. History or evidence of drug or alcohol abuse within the last 12 months

17. Malignancy or presence of any other disease with a life expectancy of < 2 years

18. Women who are pregnant, breast-feeding, or women of child bearing potential not using estro-progestative oral or intra-uterine contraception or implants, or women using estro-progestative oral or intra-uterine contraception or implants but who consider stopping it during the planned duration of the study. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. (Contraception must be continued for one week following discontinuation of study drug).

19. Concomitant participation in other intervention trials

20. Participation in any investigational drug trial within one month of visit 1.

21. Refusal to provide informed consent

22. Subjects with contraindications to MRI

1. Brain aneurysm clip

2. Implanted neural stimulator

3. Implanted cardiac pacemaker or defibrillator

4. Cochlear implant

5. Ocular foreign body (e.g. metal shavings)

6. Other implanted medical devices: (e.g. Swan-Ganz catheter)

7. Insulin pump

8. Metal shrapnel or bullet.

23. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including but not limited to any of the following:

1. History of major gastrointestinal tract surgery including gastrectomy, gastroenterostomy, or bowel resection.

2. Inflammatory bowel disease during the 12 months prior to Visit 1.

3. Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase.

4. Evidence of hepatic disease as determined by any one of the following: SGOT or SGPT values exceeding 3 x ULN at Visit 1, a history of hepatic encephalopathy, a history of oesophageal varices, or a history of portocaval shunt.