| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients (asymptomatic) with cardiovascular risk factors for heart failure including either hypertension and/or type II diabetes, with elevated levels of natriuretic peptide (brain natriuretic peptide (BNP) between 20 and 280pg/ml or NT-proBNP values between 100 pg/ml and 1,000 pg/ml) and left atrial volume index (LAVI) > 28 mL/m2.
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| E.1.1.1 | Medical condition in easily understood language |
| Patients at increased risk of developing heart failure |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess the impact of LCZ696 (ARNI) versus angiotensin receptor blocker (ARB) (valsartan) on left ventricular diastolic function over 18 months.
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| E.2.2 | Secondary objectives of the trial |
1. To assess the impact of LCZ696 versus valsartan therapy on atrial and ventricular structure and function over 9 and 18 months.
2. To assess the impact of LCZ696 versus valsartan therapy on cardiovascular and non-cardiovascular adverse events, including prior to and post onset of Covid19 pandemic. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PARABLE. Nine-month follow-up study. 17 April 2019.
The overall objective of the nine-month follow-up study is to evaluate if the treatment effects observed during the 18-month PARABLE study persist nine-months after study drug discontinuation.
All PARABLE participants that completed the 18-month follow-up period, and did not discontinue the study drug prematurely, will be eligible for inclusion in the follow-up study.
The difference in the following parameters at 18 months (study drug discontinuation) and 27 months (follow-up timepoint) will be determined:
1. Left ventricular function using Doppler Echocardiography (average E/e’)
2. Left atrial volume index (Doppler Echocardiography LAV)/BSA*
3. Measures of vascular compliance (ABPM pulse pressure)
4. Change in log transformed NT-proBNP
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| E.3 | Principal inclusion criteria |
Age > 40yrs with cardiovascular risk factor(s) including at least one of:
a. History of hypertension (medicated for greater than one month);
b. History of diabetes;
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
LAVI > 28 mL/m2 obtained during Doppler Echocardiography within 6 months prior to screening
Subjects must give written informed consent to participate in the study and before any study related assessments are performed
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| E.4 | Principal 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 (AST or ALT > 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
a) Brain aneurysm clip
b) Implanted neural stimulator
c) Implanted cardiac pacemaker or defibrillator
d) Cochlear implant
e) Ocular foreign body (e.g. metal shavings)
f) Other implanted medical devices: (e.g. Swan-Ganz catheter)
g) Insulin pump
h) 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:
a) History of major gastrointestinal tract surgery including gastrectomy, gastroenterostomy, or bowel resection.
b) Inflammatory bowel disease during the 12 months prior to Visit 1.
c) Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase.
d) 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in left atrial volume index (LAVI) measured by Cardiac Magnetic Resonance Imaging (cMRI) over 18 months |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. Left ventricular function using Doppler Echocardiography (average E/e’) between baseline and 18 months
2. Left atrial volume index (Doppler Echocardiography LAV)/BSA* between baseline and 9 months
3. Left atrial function measured as total cMRI LAEF ((LAVimax-LAVimin)/LAVimax) over 18 months
4. Left atrial function measured as cMRI left atrial stroke volume index (LAVmax-LAVmin)/BSA*, or LAVimax-LAVimin over 18 months
5. Left ventricular structure (cMRI LVMi indexed to BSA*) over 18 months
6. Left ventricular function (cMRI LVEF) over 18 months
7. Measures of vascular compliance (ABPM pulse pressure) between baseline and 18 months
8. Change in log transformed NT-proBNP between baseline and 18 months
9. Time to first all cardiovascular death and major adverse cardiac events (MACE) requiring hospitalisation over 18 months. MACE includes arrthymia (including atrial fibrillation/flutter), transient ischaemic attack, stroke, valvular heart disease, myocardial infarction, peripheral or pulmonary thrombosis/embolus or heart failure
*BSA calculated using the DuBois formula
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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