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

NCT02678312 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: CLCZ696B23192015-004207-22
• Study Type: interventional
• Target: 393
• Locations: 29 countries
• Sites: 98

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.

Conditions

Pediatric Heart Failure

Keywords

Pediatric Heart failure,; systemic left ventricle,; reduced ejection fraction

Outcome Measures

Primary Outcomes (11)

• Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Maximum Drug Concentration in Plasma (Cmax)

  The analyses of Cmax was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s).

  Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2

• Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Time to Maximum Plasma Concentration (Tmax)

  The analyses of Tmax was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s).

  Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2

• Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)

  The analyses of AUCinf was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s).

  Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2

• Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Number of Participants With Area Under the Plasma Concentration-time Curve From Time Zero to Last (AUClast)

  As prespecified in protocol and SAP the analysis of this outcome measure was done based on dose of LCZ696 administered within the different age groups.

  Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2

• Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, and Valsartan): Clearance From Plasma (CL/F)

  The analyses was based on plasma concentrations of two sacubitril/valsartan analytes (AHU377 (sacubitril), and valsartan). The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s). CL/F was not estimated for LBQ657 as it is a metabolite.

  Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2

• Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril): Time Required to Drug Concentration to Decrease by Half (T 1/2)

  The analyses of T1/2 was based on plasma concentrations of sacubitril. The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s). T1/2 for other analytes of LCZ696 (LBQ657 and Valsartan) was not estimable due to the short sample collection timeframe.

  Age group 1: Pre-dose and 0.5, 1, 2, 4, 8, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2; Age groups 2 and 3: Pre-dose and 1, 2, 4, 10, optional 24 hours post-dose on Day 1 of Period 1 and 2

• Part 1: Pharmacodynamics (PD) of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma B-type Natriuretic Peptide (BNP)

  Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included plasma BNP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed.

  Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2

• Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma N-terminal Pro-brain Natriuretic Peptide (NTproBNP)

  Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included plasma NTproBNP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed.

  Baseline (0 hrs pre dose) and optional 24 hrs post dosing on Day 1 of Period 1 and Period 2

• Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma Cyclic Guanosine Monophosphate (cGMP)

  Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included plasma cGMP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed.

  Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2

• Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Urine cGMP

  Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included urine cGMP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed.

  Baseline (0 hrs pre dose), 4 to 8 hrs post dose on Day 1 of Period 1 and Period 2

• Part 2: Percentage of Participants With Worst Event in Each Category Based on Global Ranking

  Global ranking is based on 5 categories ranking worst to best outcome:Category 1:Death; United Network for Organ Sharing(UNOS)status 1A listing for heart transplant or equivalent; ventricular assist device(VAD)/extracorporeal membrane oxygenation(ECMO)/mechanical ventilation/intra-aortic balloon pump requirement for life support at end of study. Category 2:Worsening HF(WHF);defined by signs and symptoms of WHF that requires an intensification of HF therapy. Category 3:Worsened; worse New York Heart Association(NYHA)/Ross or worse Patient Global Impression of Severity(PGIS); and further ranking by Pediatric Quality of Life Inventory(PedsQL)physical functioning domain.Category 4:Unchanged; unchanged NYHA/Ross and unchanged PGIS; and further ranking by PedsQL physical functioning domain. Category 5:Improved; improved NYHA/Ross or improved PGIS(neither can be worse);and further ranking by PedsQL physical functioning domain. Participants with worst event in each category are reported here.

  Up to 52 weeks

Secondary Outcomes (12)

• Part 1: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)

  From first dose to 30 days after last dose of study drug in Part 1

• Part 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)

  From first dose to 30 days after last dose of study drug in Part 2 (up to 56 weeks)

• Part 2: Exposure-adjusted Incidence Rate of Category 1 or Category 2 Event

  52 weeks

• Part 2: Percentage of Participants With Change From Baseline in New York Heart Association (NYHA)/Ross Functional Class

  Baseline, Week 4, 12, 24, 36, and 52

• Part 2: Percentage of Participants With Change From Baseline in Patient Global Impression of Severity (PGIS) Score

  Baseline, Week 4, 12, 24, 36, and 52

Study Arms (3)

Part 1: LCZ696 open label

EXPERIMENTAL

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.

Drug: LCZ696; Drug: Enalapril

Part 2: Enalapril

ACTIVE COMPARATOR

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.

Drug: Enalapril; Drug: Placebo of LCZ696

Part 2: LCZ696

EXPERIMENTAL

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.

Drug: LCZ696; Drug: Placebo of Enalapril

Interventions

LCZ696 DRUG

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

Part 1: LCZ696 open label; Part 2: LCZ696

Enalapril DRUG

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

Part 1: LCZ696 open label; Part 2: Enalapril

Placebo of LCZ696 DRUG

Part 2: Enalapril

Placebo of Enalapril DRUG

Part 2: LCZ696

Eligibility Criteria

• Age: 1 Month - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (98)

Novartis Investigative Site

Loma Linda, California, 92354, United States

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Los Angeles, California, 90027, United States

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Los Angeles, California, 90095, United States

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Palo Alto, California, 94304, United States

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San Diego, California, 92123, United States

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Aurora, Colorado, 80045, United States

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Gainesville, Florida, 32610, United States

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Miami, Florida, 33136, United States

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St. Petersburg, Florida, 33701, United States

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Atlanta, Georgia, 30322, United States

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Indianapolis, Indiana, 46202, United States

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Boston, Massachusetts, 02115, United States

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Ann Arbor, Michigan, 48109-5238, United States

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Minneapolis, Minnesota, 55455, United States

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Rochester, Minnesota, 55905, United States

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St Louis, Missouri, 63110, United States

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New York, New York, 10029, United States

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New York, New York, 10032, United States

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Charlotte, North Carolina, 28203, United States

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Cleveland, Ohio, 44195, United States

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Philadelphia, Pennsylvania, 19104 4399, United States

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Pittsburgh, Pennsylvania, 15224, United States

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Dallas, Texas, 75235, United States

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Salt Lake City, Utah, 84113, United States

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Seattle, Washington, 98105, United States

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Ramos Mejía, Buenos Aires, B1704ETD, Argentina

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Salta, Salta Province, A4406BPF, Argentina

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Innsbruck, 6020, Austria

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Sofia, 1309, Bulgaria

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Edmonton, Alberta, T6G 1C9, Canada

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Toronto, Ontario, M5G 1X8, Canada

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Guangzhou, Guangdong, 510623, China

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Beijing, 100037, China

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Shanghai, 200062, China

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Shanghai, 200127, China

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Zagreb, 10000, Croatia

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Prague, 150 06, Czechia

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Helsinki, 00290, Finland

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Montpellier, 34295 CEDEX 5, France

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Paris, 75015, France

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Pessac, 33600, France

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Berlin, 13353, Germany

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Erlangen, 91054, Germany

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Freiburg im Breisgau, 79106, Germany

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Heidelberg, 69120, Germany

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Leipzig, 04289, Germany

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Stuttgart, 70174, Germany

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Budapest, H 1096, Hungary

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Ahmedabad, Gujarat, 380 060, India

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Kochi, Kerala, 682041, India

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New Delhi, National Capital Territory of Delhi, 110 060, India

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New Delhi, National Capital Territory of Delhi, 110076, India

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Beersheba, 84101, Israel

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Bergamo, BG, 24127, Italy

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Bologna, BO, 40138, Italy

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Florence, FI, 50132, Italy

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Milan, MI, 20162, Italy

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Padua, PD, 35128, Italy

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Roma, RM, 00165, Italy

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Torino, TO, 10126, Italy

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Napoli, 80131, Italy

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Ōbu, Aichi-ken, 474 8710, Japan

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Sapporo, Hokkaido, 060 8648, Japan

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Ōmura, Nagasaki, 856-8562, Japan

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Bunkyo Ku, Tokyo, 113 8655, Japan

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Setagaya-ku, Tokyo, 157-8535, Japan

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Shinjuku Ku, Tokyo, 162 8666, Japan

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Toyama, Toyama, 930-0194, Japan

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Saitama, 330 8777, Japan

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Amman, JOR, 11183, Jordan

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Beirut, Lebanon

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El Achrafîyé, 166830, Lebanon

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Gdansk, 80-952, Poland

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Warsaw, 04 730, Poland

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Carnaxide, Lisbon District, 2799 523, Portugal

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Coimbra, 3000 075, Portugal

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Lisbon, 1169 024, Portugal

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Moscow, 125412, Russia

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Saint Petersburg, 197341, Russia

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Riyadh, 11211, Saudi Arabia

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Singapore, 229899, Singapore

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Yangsan, Gyeongsangnam-do, 50612, South Korea

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Seoul, 03080, South Korea

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Seoul, 03722, South Korea

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Seoul, 06351, South Korea

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Córdoba, Andalusia, 14004, Spain

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Barcelona, Catalonia, 08035, Spain

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Barcelona, Catalonia, 08950, Spain

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Novartis Investigative Site

Madrid, 28009, Spain

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Madrid, 28046, Spain

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Lausanne, 1011, Switzerland

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Kaohsiung City, 83301, Taiwan

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Taipei, 10041, Taiwan

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Bangkoknoi, Bangkok, 10700, Thailand

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Bangkok, 10400, Thailand

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Ankara, 06490, Turkey (Türkiye)

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Izmir, 35040, Turkey (Türkiye)

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Novartis Investigative Site

Konak, 35210, Turkey (Türkiye)

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Related Publications (2)

• 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.

  PMID: 39319469 DERIVED

• 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.

  PMID: 36601956 DERIVED

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: Study Director
• Organization: Novartis Pharmaceuticals

trialandresults.registries@novartis.com

862-778-8300

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 4, 2016
• First Posted: February 9, 2016
• Study Start: November 3, 2016
• Primary Completion: January 3, 2022
• Study Completion: January 3, 2022
• Last Updated: February 10, 2023
• Results First Posted: February 10, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will share

Locations

IT (8); SG (1); JO (1); RU (2); FR (3); CA (2); AU (1); PT (3); SA (1); HU (1); CN (4); TW (2); LE (2); IN (4); TH (2); AR (2); ES (5); IL (1); CH (1); BU (1); CZ (1); PL (2); KR (4); CR (1); JP (8); TU (3); US (25); FI (1); DE (6)