Study of Efficacy and Safety of LCZ696 in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction

NCT02468232 | Completed Phase 3 Results DMC

• 1 other identifier: CLCZ696B1301
• Study Type: interventional
• Target: 225
• Locations: 1 country
• Sites: 49

Brief Summary

The purpose of this study was to assess the effect of LCZ696 at a target dose of 200 mg b.i.d. compared to enalapril 10 mg b.i.d., in addition to the background heart failure (HF) treatment, on delaying time to first occurrence of either cardiovascular (CV) death or HF hospitalization events in Japanese patients with stable chronic heart failure (CHF), New York Heart Association (NYHA) classes II-IV and reduced ejection fraction (left ventricular ejection fraction (LVEF) ≤ 35%).

Conditions

Heart Failure With Reduced Ejection Fraction (HF-rEF)

Keywords

chronic heart failure; cardiovascular death; hospitalization; outcome study; worsening heart failure; NT-proBNP; NYHA; KCCQ; HF-rEF

Outcome Measures

Primary Outcomes (2)

• Number of Participants Who Had CEC (Clinical Endpoint Committee) Confirmed Composite Endpoints

  Composite endpoint is defined as either cardiovascular (CV) death or heart failure (HF) hospitalization in Japanese patients with chronic heart failure (CHF) and reduced ejection fraction. The composite endpoint events occurred on and after End-of-study (EOS) declaration were reported by investigators but those events were not required to be adjudicated by Clinical Endpoint Committee (CEC) and not included in the efficacy analysis.

  up to 40 months

• Exposure-adjusted Incident Rate (EAIR) of CEC Confirmed Composite Endpoints

  Composite endpoint is defined as either cardiovascular (CV) death or heart failure (HF) hospitalization in Japanese patients with chronic heart failure (CHF) and reduced ejection fraction. EAIR = n/T where n = Total number of events included in the analysis. T (100 patient years) = total up-to-event/censoring duration-time summarized over participants in the respective treatment group. The composite endpoint events occurred on and after EOS declaration were reported by investigators but those events were not required to be adjudicated by CEC and not included in the efficacy analysis.

  up to 40 months

Secondary Outcomes (25)

• Key Secondary: Change From Baseline to the Pre-defined Time-points in Log-transformed Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)

  Baseline, Weeks 4, 8 and Month 6

• Key Secondary: Number of Participants With CEC-confirmed First Triple Composite Endpoint (Cardiovascular (CV) Death, Heart Failure (HF) Hospitalization, or Worsening of HF in Outpatients)

  up to 40 months

• Key Secondary: EAIR of CEC-confirmed First Triple Composite Endpoint (Cardiovascular (CV) Death, Heart Failure (HF) Hospitalization, or Worsening of HF in Outpatients)

  up to 40 months

• Key Secondary: Number of Participants by Changes in New York Heart Association (NYHA) Classification From Baseline at Predefined Timepoints

  Baseline, Weeks 4, 8 and Month 6

• Key Secondary: Change From Baseline in Clinical Summary Score for Heart Failure Symptoms and Physical Limitations Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ).

  Baseline, Week 8 and Month 6

Study Arms (2)

LCZ696

EXPERIMENTAL

Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.

Drug: LCZ696; Drug: Placebo to Enalapril

Enalapril

ACTIVE COMPARATOR

Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.

Drug: Enalapril; Drug: Placebo to LCZ696

Interventions

LCZ696 DRUG

The target dose during the study was LCZ696 200 mg bid given orally. LCZ696 was supplied as 50 mg, 100 mg and 200 mg film-coated tablets.

LCZ696

Enalapril DRUG

The target dose during the study was enalapril 10 mg bid given orally. Enalapril was provided as 2.5 mg, 5 mg, and 10 mg tablets.

Enalapril

Placebo to LCZ696 DRUG

LCZ696 Placebo 50 mg, 100 mg and 200 mg film-coated tablets

Enalapril

Placebo to Enalapril DRUG

Enalapril Placebo 2.5 mg, 5 mg and 10 mg tablets

LCZ696

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent must be obtained before any assessment is performed.
• Outpatients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction:
• LVEF ≤ 35% at Visit 1 (any local measurement, made within the past 6 months using echocardiography, MUGA, CT scanning, MRI or ventricular angiography is also acceptable, provided no subsequent measurement above 35%)
• NT-proBNP ≥ 600 pg/ml at Visit 1 OR NT-proBNP ≥ 400 pg/ml at Visit 1 and a hospitalization for HF within the last 12 months (according to central laboratory measurements)
• Patients must be on an ACEI or an ARB at a stable dose for at least 4 weeks before Visit 1.
• Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to Visit 1 (reason should be documented if patients reported contraindications or intolerance).
• 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, and should be stable for at least 4 weeks prior to Visit 1. Other evidence-based therapy for HF should also be considered e.g. cardiac resynchronization therapy and an implantable cardioverter-defibrillator in selected patients, as recommended by guidelines.

You may not qualify if:

• History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes, ACEIs, ARBs, NEP inhibitors as well as known or suspected contraindications to the study drugs.
• Previous documented history of intolerance to ACEIs or ARBs.
• Known history of angioedema.
• Requirement of treatment with both ACEIs and ARBs.
• Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy).
• Symptomatic hypotension and/or a SBP \< 100 mmHg at screening or \< 95 mmHg at the end of run-in.
• Estimated GFR \< 30 mL/min/1.73 m2 as measured by the Japanese formula at screening, or the end of run-in or \> 35% decline in eGFR between screening and end of run-in (according to local measurements).
• Serum potassium \> 5.2 mmol/L (mEq/L) at screening or \> 5.4 mmol/L (mEq/L) at the end of run-in (according to local measurements).
• 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.
• Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1.
• Symptomatic bradycardia or second (except asymptomatic Wenckebach block) or third degree heart block without a pacemaker.
• Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation.
• Presence of other hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic and sub-aortic stenosis.
• Presence of bilateral renal artery stenosis.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (49)

Novartis Investigative Site

Nagoya, Aichi-ken, 453-8511, Japan

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Seto, Aichi-ken, 489-8642, Japan

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Chikushino-shi, Fukuka, 818-8516, Japan

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Fukuoka, Fukuoka, 810-0001, Japan

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Fukuoka, Fukuoka, 812-8582, Japan

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Iizuka, Fukuoka, 820-8505, Japan

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Kurume, Fukuoka, 830-8577, Japan

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Fukushima, Fukushima, 960 1295, Japan

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Kōriyama, Fukushima, 963-8052, Japan

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Maebashi, Gunma, 371 8511, Japan

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Hatsukaichi, Hiroshima, 738 8503, Japan

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Asahikawa, Hokkaido, 078-8211, Japan

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Otaru, Hokkaido, 047-8510, Japan

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Sapporo, Hokkaido, 060 8648, Japan

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Amagasaki, Hyōgo, 660 8550, Japan

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Takarazuka, Hyōgo, 665-0873, Japan

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Morioka, Iwate, 020 0066, Japan

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Takamatsu, Kagawa-ken, 760 8557, Japan

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Kawasaki, Kanagawa, 211-8533, Japan

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Kawasaki, Kanagawa, 216-8511, Japan

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Yokohama, Kanagawa, 227-8501, Japan

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Kumamoto, Kumamoto, 860-8556, Japan

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Kyoto, Kyoto, 607-8062, Japan

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Uji, Kyoto, 611-0042, Japan

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Sendai, Miyagi, 980 8574, Japan

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Miyazaki, Miyazaki, 880-2102, Japan

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Saku, Nagano, 3850051, Japan

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Kashihara, Nara, 634 8522, Japan

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Ōita, Oita Prefecture, 870-0192, Japan

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Okayama, Okayama-ken, 700-8558, Japan

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Kishiwada, Osaka, 596-0042, Japan

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Osaka, Osaka, 530-8480, Japan

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Osaka, Osaka, 559-0012, Japan

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Takatsuki, Osaka, 569-1096, Japan

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Toyonaka, Osaka, 560-8565, Japan

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Tokorozawa, Saitama, 359-1141, Japan

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Kusatsu, Shiga, 525 8585, Japan

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Shizuoka, Shizuoka, 420-8630, Japan

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Shimotsuke, Tochigi, 329-0498, Japan

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Bunkyo-ku, Tokyo, 113-8603, Japan

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Chiyoda-ku, Tokyo, 101-8309, Japan

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Chuo Ku, Tokyo, 104-8560, Japan

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Hachiōji, Tokyo, 192-0918, Japan

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Itabashi-ku, Tokyo, 173-8610, Japan

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Shinagawa-ku, Tokyo, 142-8666, Japan

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Yonago, Tottori, 683-8504, Japan

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Shūnan, Yamaguchi, 745-8522, Japan

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Kofu, Yamanashi, 400-8506, Japan

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Saitama, 330 8503, Japan

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MeSH Terms

Interventions

sacubitril and valsartan sodium hydrate drug combination; Enalapril

Intervention Hierarchy (Ancestors)

Dipeptides; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Clinical Disclosure Office
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 8, 2015
• First Posted: June 10, 2015
• Study Start: June 15, 2015
• Primary Completion: February 8, 2019
• Study Completion: February 18, 2021
• Last Updated: December 8, 2023
• Results First Posted: December 8, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share

Locations

JP (49)