Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LCZ696 Followed by a 52-week, Double-blind Study of LCZ696 Compared With Enalapril in Pediatric Patients With Heart Failure

NCT ID: NCT02678312

Last Updated: 2023-02-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 393 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-11-03
• Study Completion Date: 2022-01-03

Brief Summary

This study consists of two parts (Part 1 and Part 2). The purpose of Part 1 is to evaluate the way the body absorbs, distributes, metabolizes and removes the drug LCZ696. This will help determine the proper dose of LCZ696 for Part 2 of the study.

The purpose for Part 2 is to compare the effectiveness and safety of LCZ696 with enalapril in a double-blind manner, in pediatric heart failure patients over 52 weeks of treatment.

Detailed Description

This study consists of two parts (Part 1 and Part 2). The purpose of Part 1 is to evaluate the way the body absorbs, distributes, metabolizes and removes the drug LCZ696. This will help determine the proper dose of LCZ696 for Part 2 of the study.

The purpose for Part 2 is to compare the effectiveness and safety of LCZ696 with enalapril in a double-blind manner, in pediatric heart failure patients over 52 weeks of treatment.

Conditions

Pediatric Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Part 1: LCZ696 open label

LCZ696 open label: For Age Groups 1 and 2, either 1) 0.8 mg/kg or 2) 3.1 mg/kg or both. For Age Group 3, either 1) 0.4 mg/kg or 2) 1.6 mg/kg or both. After LCZ696 PK assessment, patients will be maintained on open-label Enalapril provided locally by the study site, or standard of care also provided locally by the study site, for heart failure treatment, if patient intended to participate in Part 2.

Group Type: EXPERIMENTAL

LCZ696

Intervention Type: DRUG

LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules)

Enalapril

Intervention Type: DRUG

Enalapril tablets: 2.5 mg, 5 mg, 10 mg dosage strengths

Part 2: Enalapril

The target dose for enalapril is 0.2 mg/kg bid (0.4 mg/kg total daily dose) with a maximum dose of 10 mg bid (20 mg total daily dose). Administered in a double-blind fashion.

Group Type: ACTIVE_COMPARATOR

Enalapril

Intervention Type: DRUG

Enalapril tablets: 2.5 mg, 5 mg, 10 mg dosage strengths

Placebo of LCZ696

Intervention Type: DRUG

Part 2: LCZ696

LCZ696 3.125 mg granules and adult formulation (50, 100, 200 mg) can be given based on patient weight. Administered in a double-blind fashion.

Group Type: EXPERIMENTAL

LCZ696

Intervention Type: DRUG

LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules)

Placebo of Enalapril

Intervention Type: DRUG

LCZ696

Intervention Type: DRUG

LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules), tablets: 50 mg, 100 mg, 200 mg dosage strengths

Interventions

LCZ696

LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules)

Intervention Type: DRUG

Enalapril

Enalapril tablets: 2.5 mg, 5 mg, 10 mg dosage strengths

Intervention Type: DRUG

Placebo of LCZ696

Intervention Type: DRUG

Placebo of Enalapril

Intervention Type: DRUG

LCZ696

LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules), tablets: 50 mg, 100 mg, 200 mg dosage strengths

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Chronic heart failure (CHF) resulting from left ventricular systolic dysfunction, and receiving chronic HF therapy (if not newly diagnosed)
• New York Heart Association (NYHA) classification II-IV (older children: 6 to <18 years old) or Ross CHF classification II-IV (younger children: < 6 years old)
• Systemic left ventricular ejection fraction ≤ 45% or fractional shortening ≤22.5%
• For Part 1 study: Patients must be treated with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARB) prior to screening. Patients in Group 1 and 2 must be currently treated with the dose equivalent of at least enalapril 0.2 mg/kg prior to the LCZ696 3.1 mg/kg administration. Group 3 patients will participate in LCZ696 0.8 mg/kg and not LCZ696 3.1 mg/kg.
• Biventricular physiology with systemic left ventricle

Exclusion Criteria

• Patient with single ventricle or systemic right ventricle
• Patients listed for heart transplantation (as United Network for Organ Sharing status 1A) or hospitalized waiting for transplant (while on inotropes or with ventricular assist device)
• Sustained or symptomatic dysrhythmias uncontrolled with drug or device therapy
• Patients that have had cardiovascular surgery or percutaneous intervention to palliate or correct congenital cardiovascular malformations within 3 months of the screening visit. Patients anticipated to undergo corrective heart surgery during the 12 months after entry into Part 2
• Patients with unoperated obstructive or severe regurgitant valvular (aortic, pulmonary, or tricuspid) disease, or significant systemic ventricular outflow obstruction or aortic arch obstruction
• Patients with restrictive or hypertrophic cardiomyopathy
• Active myocarditis
• Renal vascular hypertension (including renal artery stenosis)
• Moderate-to severe obstructive pulmonary disease
• Serum potassium > 5.3 mmol/L
• History of angioedema
• Allergy or hypersensitivity to ACEI / ARB

• Minimum Eligible Age: 1 Month
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Novartis Investigative Site

Loma Linda, California, United States

Novartis Investigative Site

Los Angeles, California, United States

Novartis Investigative Site

Los Angeles, California, United States

Novartis Investigative Site

Palo Alto, California, United States

Novartis Investigative Site

San Diego, California, United States

Novartis Investigative Site

Aurora, Colorado, United States

Novartis Investigative Site

Gainesville, Florida, United States

Novartis Investigative Site

Miami, Florida, United States

Novartis Investigative Site

St. Petersburg, Florida, United States

Novartis Investigative Site

Atlanta, Georgia, United States

Novartis Investigative Site

Indianapolis, Indiana, United States

Novartis Investigative Site

Boston, Massachusetts, United States

Novartis Investigative Site

Ann Arbor, Michigan, United States

Novartis Investigative Site

Minneapolis, Minnesota, United States

Novartis Investigative Site

Rochester, Minnesota, United States

Novartis Investigative Site

St Louis, Missouri, United States

Novartis Investigative Site

New York, New York, United States

Novartis Investigative Site

New York, New York, United States

Novartis Investigative Site

Charlotte, North Carolina, United States

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Cleveland, Ohio, United States

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Philadelphia, Pennsylvania, United States

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Pittsburgh, Pennsylvania, United States

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Dallas, Texas, United States

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Salt Lake City, Utah, United States

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Seattle, Washington, United States

Novartis Investigative Site

Ramos Mejía, Buenos Aires, Argentina

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Salta, Salta Province, Argentina

Novartis Investigative Site

Innsbruck, , Austria

Novartis Investigative Site

Sofia, , Bulgaria

Novartis Investigative Site

Edmonton, Alberta, Canada

Novartis Investigative Site

Toronto, Ontario, Canada

Novartis Investigative Site

Guangzhou, Guangdong, China

Novartis Investigative Site

Beijing, , China

Novartis Investigative Site

Shanghai, , China

Novartis Investigative Site

Shanghai, , China

Novartis Investigative Site

Zagreb, , Croatia

Novartis Investigative Site

Prague, , Czechia

Novartis Investigative Site

Helsinki, , Finland

Novartis Investigative Site

Montpellier, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Pessac, , France

Novartis Investigative Site

Berlin, , Germany

Novartis Investigative Site

Erlangen, , Germany

Novartis Investigative Site

Freiburg im Breisgau, , Germany

Novartis Investigative Site

Heidelberg, , Germany

Novartis Investigative Site

Leipzig, , Germany

Novartis Investigative Site

Stuttgart, , Germany

Novartis Investigative Site

Budapest, , Hungary

Novartis Investigative Site

Ahmedabad, Gujarat, India

Novartis Investigative Site

Kochi, Kerala, India

Novartis Investigative Site

New Delhi, National Capital Territory of Delhi, India

Novartis Investigative Site

New Delhi, National Capital Territory of Delhi, India

Novartis Investigative Site

Beersheba, , Israel

Novartis Investigative Site

Bergamo, BG, Italy

Novartis Investigative Site

Bologna, BO, Italy

Novartis Investigative Site

Florence, FI, Italy

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Padua, PD, Italy

Novartis Investigative Site

Roma, RM, Italy

Novartis Investigative Site

Torino, TO, Italy

Novartis Investigative Site

Napoli, , Italy

Novartis Investigative Site

Ōbu, Aichi-ken, Japan

Novartis Investigative Site

Sapporo, Hokkaido, Japan

Novartis Investigative Site

Ōmura, Nagasaki, Japan

Novartis Investigative Site

Bunkyo Ku, Tokyo, Japan

Novartis Investigative Site

Setagaya-ku, Tokyo, Japan

Novartis Investigative Site

Shinjuku Ku, Tokyo, Japan

Novartis Investigative Site

Toyama, Toyama, Japan

Novartis Investigative Site

Saitama, , Japan

Novartis Investigative Site

Amman, JOR, Jordan

Novartis Investigative Site

Beirut, , Lebanon

Novartis Investigative Site

El Achrafîyé, , Lebanon

Novartis Investigative Site

Gdansk, , Poland

Novartis Investigative Site

Warsaw, , Poland

Novartis Investigative Site

Carnaxide, Lisbon District, Portugal

Novartis Investigative Site

Coimbra, , Portugal

Novartis Investigative Site

Lisbon, , Portugal

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Saint Petersburg, , Russia

Novartis Investigative Site

Riyadh, , Saudi Arabia

Novartis Investigative Site

Singapore, , Singapore

Novartis Investigative Site

Yangsan, Gyeongsangnam-do, South Korea

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Córdoba, Andalusia, Spain

Novartis Investigative Site

Barcelona, Catalonia, Spain

Novartis Investigative Site

Barcelona, Catalonia, Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Lausanne, , Switzerland

Novartis Investigative Site

Kaohsiung City, , Taiwan

Novartis Investigative Site

Taipei, , Taiwan

Novartis Investigative Site

Bangkoknoi, Bangkok, Thailand

Novartis Investigative Site

Bangkok, , Thailand

Novartis Investigative Site

Ankara, , Turkey (Türkiye)

Novartis Investigative Site

Izmir, , Turkey (Türkiye)

Novartis Investigative Site

Konak, , Turkey (Türkiye)

Countries

United States; Argentina; Austria; Bulgaria; Canada; China; Croatia; Czechia; Finland; France; Germany; Hungary; India; Israel; Italy; Japan; Jordan; Lebanon; Poland; Portugal; Russia; Saudi Arabia; Singapore; South Korea; Spain; Switzerland; Taiwan; Thailand; Turkey (Türkiye)

References

Shaddy R, Burch M, Kantor PF, Solar-Yohay S, Garito T, Zhang S, Kocun M, Mao C, Cilliers A, Wang X, Canter C, Rossano J, Wallis G, Menteer J, Daou L, Kusa J, Tokel K, Dilber D, Xu Z, Xiao T, Halnon N, Daly KP, Bock MJ, Zuckerman W, Singh TP, Chakrabarti M, Levitas A, Senni M, Grutter G, Kim GB, Song J, Lee HD, Chen CK, Sanchez-de-Toledo J, Law Y, Wanitkun S, Cui Y, Anjos R, Mese T, Bonnet D; PANORAMA-HF Investigators. Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial. Circulation. 2024 Nov 26;150(22):1756-1766. doi: 10.1161/CIRCULATIONAHA.123.066605. Epub 2024 Sep 25.

Reference Type: DERIVED

PMID: 39319469 (View on PubMed)

Shaddy R, Burch M, Kantor PF, Solar-Yohay S, Garito T, Zhang S, Kocun M, Bonnet D. Baseline Characteristics of Pediatric Patients With Heart Failure Due to Systemic Left Ventricular Systolic Dysfunction in the PANORAMA-HF Trial. Circ Heart Fail. 2023 Mar;16(3):e009816. doi: 10.1161/CIRCHEARTFAILURE.122.009816. Epub 2023 Jan 5.

Reference Type: DERIVED

PMID: 36601956 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan: Original Statistical Analysis Plan (SAP)

View Document

Document Type: Statistical Analysis Plan: Statistical Analysis Plan (SAP) for China Sub-CSR

View Document

Other Identifiers

2015-004207-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CLCZ696B2319

Identifier Type: -

Identifier Source: org_study_id