Exercise capacity study of LCZ696 vs. enalapril in patients with chronic heart failure and reduced ejection fraction

• Register: EUCTR
• Last refreshed on: 15 September 2020
• Main ID: EUCTR2015-004632-35-DE
• Date of registration: 24/02/2016
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma GmbH
• Public title: Exercise capacity study of LCZ696 vs. enalapril in patients with chronic heart failure and reduced ejection fraction
• Scientific title: A randomized, double-blind, active-controlled study to assess the effect of LCZ696 compared with enalapril to improve exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF).
• Date of first enrolment: 04/05/2016
• Target sample size: 200
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-004632-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: yes; Other trial design description: double-dummy; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Germany

Contacts

• Name: Medizinischer Infoservice (MCC)
• Affiliation: Novartis Pharma GmbH

• Name: Medizinischer Infoservice (MCC)
• Affiliation: Novartis Pharma GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
1. Patients must give written informed consent before any assessment is performed and must be willing and capable to comply with all study procedures.
2. Outpatients = 18 years of age, male or female.
3. Patients with a diagnosis of CHF NYHA class III and reduced ejection fraction:
• LVEF = 40% at Visit 1 (any local measurement, made within the past 6 months using echocardiography, MUGA, CT scanning, MRI or ventricular angiography is acceptable, provided no subsequent measurement above 40%)
4. Reduced ability to exercise, evidenced by VO2peak = 18 ml/min per kg
5. Patients must be on an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks before Visit 1
• For this protocol doses of other ACEIs considered to be equivalent to enalapril 10 mg/d include benazepril 20 mg/d, captopril 100 mg/d, cilazapril 2.5 mg/d, fosinopril 20 mg/d, lisinopril 10 mg/d, moexipril 7.5 mg/d, perindopril 4 mg/d, quinapril 20 mg/d, ramipril 5 mg/d, trandolapril 2 mg/d, and zofenopril 30 mg/d.
• For this protocol doses of ARBs considered to be equivalent to enalapril 10 mg/d include candesartan 16 mg/d, eprosartan 400 mg/d, irbesartan 150 mg/d, losartan 50 mg/d, olmesartan 10 mg/d, telmisartan 40 mg/d, and valsartan 160 mg/d.
6. Patients must be treated for CHF according to local guideline recommendations and should be stable on treatment and dose for at least 4 weeks prior to Visit 1. Treatment according to guideline should include:
• A ß-blocker, unless contraindicated or not tolerated, (reason should be documented for patients not on CHF target doses per local guidelines, or in absence of that medication).
• An aldosterone antagonist should also be considered in all patients, taking account of renal function, serum potassium and tolerability. If given, the dose of aldosterone antagonist should be optimized according to guideline recommendations and patient tolerability.
• Ivabradine should also be considered in all patients with heart rates above 70 beats per minute. If given, the dose of ivabradine should be optimized according to guideline recommendations and patient tolerability.
• Other evidence-based therapy for heart failure should also be considered e.g. cardiac resynchronization therapy and an implantable cardioverter-defibrillator in selected patients, as recommended by guidelines.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 100
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 100

Exclusion criteria:
1. Use of other investigational drugs at the time of enrolment, or within 30 days or 5 half-lives of enrolment, whichever is longer
2. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs
3. Previous history of intolerance to recommended target doses of ACEIs or ARBs
4. Known history of angioedema
5. Requirement of treatment with both ACEIs and ARBs
6. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy)
7. Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 (screening) or at Visit 3 (randomization)
8. Estimated GFR < 30 mL/min/1.73m2 as measured by the simplified MDRD formula at Visit 1 (screening), or Visit 3 (randomization)
9. Serum potassium > 5.2 mmol/L at Visit 1 (screening) or Visit 3 (randomization)
10. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 months prior to Visit 1
11. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after Visit 1.
12. Implantation of a cardiac resynchronization therapy pacemaker (CRT-P) or a cardiac resynchronization therapy defibrillator (CRT-D) or upgrading of an existing conventional pacemaker or an implantable cardioverter defibrillator (ICD) to CRT device within 3 months prior Visit 1 or intent to implant such a device. Also, patients who had implantation of a conventional pacemaker or an ICD or had a revision of a pacemaker or other device leads within 1 month before Visit 1 are excluded.
13. Heart transplant or ventricular assistance device (VAD) or intent to transplant within the 14 week study duration (on transplant list with high urgency (HU) status) or to implant a VAD.
14. History or current diagnosis of severe pulmonary disease, including chronic obstructive pulmonary disease (COPD).
15. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 months prior to Visit 1
16. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1
17. Symptomatic bradycardia or second or third degree heart block without a pacemaker
18. Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation
19. Presence of other hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic and sub-aortic stenosis
20. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs
21. Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 2 x ULN at Visit 1, severe hepatic insufficiency (classification Child-Pugh C), biliary cirrhosis, cholestasis (current or anamnestic evidence), history of hepatic encephalopathy, history of esophageal varices, or history of portocaval shunt
22. Active treatment with cholestyramine or colestipol resins
23. Presence of any other disease with a life expectancy of < 5 years
24. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

chronic heart failure and reduced ejection fraction
MedDRA version: 20.0 Level: LLT Classification code 10008502 Term: CHF System Organ Class: 100000004849

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Trade Name: Entresto
Product Name: LCZ696, 50 mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sacubitril/valsartan
CAS Number: 936623-90-4
Current Sponsor code: LCZ696
Other descriptive name: LCZ696
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50 (24 mg/26 mg)-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Entresto
Product Name: LCZ696, 100 mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sacubitril/valsartan
CAS Number: 936623-90-4
Current Sponsor code: LCZ696
Other descriptive name: LCZ696
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100 (49 mg/51 mg)-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Entresto
Product Name: LCZ696, 200 mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sacubitril/valsartan
CAS Number: 936623-90-4
Current Sponsor code: LCZ696
Other descriptive name: LCZ696
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200 (97 mg/103mg)-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Enalapril
Product Name: enalapril, 2.5 mg
Pharmaceutical Form: Tablet
INN or Proposed INN: ENALAPRIL
CAS Number: 75847-73-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Trade Name: EnaHexal
Product Name: enalapril, 5 mg
Pharmaceutical Form: Tablet
INN or Proposed INN: ENALAPRIL
CAS Number: 75847-73-3
Concentration

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: 3 months

Main Objective: The primary objective of this study is to demonstrate the superiority of LCZ696 200 mg bid compared to enalapril 10 mg bid in improving exercise tolerance (VO2peak, adjusted to body weight) as assessed by cardiopulmonary exercise testing (CPET) in patients with stable chronic heart failure (NYHA class III) and reduced ejection fraction (LVEF = 40%) after 3 months treatment.

Secondary Objective: Secondary objectives of this study are

To demonstrate the superiority LCZ696 versus enalapril regarding improvement of exercise tolerance (VO2peak, adjusted to body weight) as assessed by cardiopulmonary exercise testing (CPET) in patients with chronic heart failure after 6 weeks treatment.

To compare LCZ696 versus enalapril on the following CPET parameters:
? Change of VE/VCO2 slope after 6 weeks and 3 months
? Change in exercise capacity (Watt) at VAT after 6 weeks and 3 months
? Rate of perceived exertion during exercise (Borg Scale) after 3 months

To assess the safety and tolerability of LCZ696 in patients with stable chronic heart failure with NYHA class III and reduced ejection fraction (LVEF = 40%)

Primary end point(s): The primary endpoint is change of VO2peak compared to baseline measurements (adjusted to body weight) after 3 months of treatment.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 6 weeks + 3 months

Secondary end point(s): Secondary objectives of this study are

To demonstrate the superiority LCZ696 versus enalapril regarding improvement of exercise tolerance (VO2peak, adjusted to body weight) as assessed by cardiopulmonary exercise testing (CPET) in patients with chronic heart failure after 6 weeks treatment.

To compare LCZ696 versus enalapril on the following CPET parameters:
? Change of VE/VCO2 slope after 6 weeks and 3 months
? Change in exercise capacity (Watt) at VAT after 6 weeks and 3 months
? Rate of perceived exertion during exercise (Borg Scale) after 3 months

To assess the safety and tolerability of LCZ696 in patients with stable chronic heart failure with NYHA class III and reduced ejection fraction (LVEF = 40%)

Secondary ID(s)

CLCZ696BDE01

Source(s) of Monetary Support

Novartis Pharma GmbH

Ethics review

Status: Approved
Approval date: 04/05/2016
Contact: