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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02678312
Recruitment Status : Completed
First Posted : February 9, 2016
Results First Posted : February 10, 2023
Last Update Posted : February 10, 2023
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Pediatric Heart Failure
Interventions Drug: LCZ696
Drug: Enalapril
Drug: Placebo of LCZ696
Drug: Placebo of Enalapril
Enrollment 393
Recruitment Details 2-Part (Pt) Study: Pt 1 a single dose PK/PD study with 2 dose levels; Pt 2 is a 52-week, double blind, active controlled, randomized, safety & efficacy study. In Pt 1, there were 3 age groups: 6 to <18 yrs, 1 to <6 yrs and 1 month to <1 yr. Each received either a single low dose LCZ696 (Cohort 1), a single high dose LCZ696 (Cohort 2) or both. Cohort S included patients receiving a single low dose after having received a single high dose. The low/high doses for groups 1/2 were 0.8 & 3.1 (mg/kg).
Pre-assignment Details The low and high doses for Group 3 0.4 mg/kg and 1.6 mg/kg, respectively. 26 patients received either one or two single doses of LCZ696 in Pt 1. In Pt 2, patients were randomized to receive either LCZ696 or enalapril. 377 patients were randomized and 375 received study drug (2 did not receive drug). 11 of 26 Pt 1 patients rolled into Pt 2; however, 1 patient had two ID numbers; so only 10 unique patients were in Pt 1 & 2.
Arm/Group Title Part 1: Dose Cohort 1 Part 1: Dose Cohort 2 Part 1: Dose Cohort S Part 2: LCZ696 Part 2: Enalapril
Hide Arm/Group Description Participants received LCZ696 0.4 mg/kg (age group 3 {1 month to < 1 year}) or 0.8 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}), based on age, given as a single oral dose on Day 1 of period 1. Participants received LCZ696 1.6 mg/kg (age group 3 {1 month to < 1 year}) or 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}), based on age, given as a single oral dose on Day 1 of period 2. Participants in the dose cohort 2 who received LCZ696 3.1 mg/kg on Day 1 of period 2 and later received LCZ696 0.8 mg/kg, within period 2. Participants received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks. Participants received enalapril 0.2 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 0.15 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, BID, for 52 weeks.
Period Title: Part 1 Open Label Epoch- Period 1
Started [1] 17 0 0 0 0
Completed 14 0 0 0 0
Not Completed 3 0 0 0 0
Reason Not Completed
Adverse Event             1             0             0             0             0
Lost to Follow-up             1             0             0             0             0
Physician Decision             1             0             0             0             0
[1]
Out of 26 participants enrolled in the Part 1 of the study, 17 were dosed based on their age to receive LCZ696 0.8 mg or 0.4 mg in Period 1.
Period Title: Part 1 Open Label Epoch- Period 2
Started 0 18 [1] 2 [2] 0 0
Completed 0 18 2 0 0
Not Completed 0 0 0 0 0
[1]
Out of 26 participants enrolled in Part 1, 18 participants were dosed in dose cohort 2 to receive LCZ696 1.6 mg or 3.1 mg dose in Period 2. A total of 9 participants who received LCZ696 in Dose cohort 1, received drug further in dose cohort 2 and 9 others received drug directly in Period 2 were included in Dose cohort 2.
[2]
2 participants who were dosed in Dose Cohort 2 at dose level 3.1 mg/kg were then prescribed one dose of study drug at dose level 0.8 mg/kg within period 2 and were therefore grouped under Dose cohort S.
Period Title: Part 2 Double Blind Epoch
Started [1] 0 0 0 187 188
Completed 0 0 0 169 164
Not Completed 0 0 0 18 24
Reason Not Completed
Adverse Event             0             0             0             1             2
Death             0             0             0             8             12
Technical Problems             0             0             0             4             2
Lost to Follow-up             0             0             0             0             2
Subject/guardian Decision             0             0             0             5             6
[1]
Out of 377 participants enrolled in Part 2 of the study, 2 participants in the enalapril arm were randomized in error and did not receive the study medication. Therefore, 375 of 377 randomized participants received study medication.
Arm/Group Title Part 1: Dose Cohort 1 Part 1: Dose Cohort 2 Part 1: Dose Cohort S Part 2: LCZ696 Part 2: Enalapril Total
Hide Arm/Group Description Participants received LCZ696 0.4 mg/kg (age group 3 {1 month to < 1 year}) or 0.8 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}), based on age, given as a single oral dose on Day 1 of period 1. Participants received LCZ696 1.6 mg/kg (age group 3 {1 month to < 1 year}) or 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}), based on age, given as a single oral dose on Day 1 of period 2. Participants in the dose cohort 2 who received LCZ696 3.1 mg/kg on Day 1 of period 2 and later received LCZ696 0.8 mg/kg, within period 2. Participants received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks. Participants received enalapril 0.2 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 0.15 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, BID, for 52 weeks. Total of all reporting groups
Overall Number of Baseline Participants 17 18 2 187 188 412
Hide Baseline Analysis Population Description
Full Analysis Set included all randomized participants who received study drug, with the exception of [2 patients in Part 2] who had not received any study drug, but had been inadvertently randomized into the study (mis-randomized).
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 17 participants 18 participants 2 participants 187 participants 188 participants 412 participants
3.00
(0.30 to 16.00)
2.50
(0.20 to 17.00)
1.55
(1.10 to 2.00)
7.00
(0.50 to 17.00)
8.50
(0.10 to 18.00)
4.51
(0.10 to 18.00)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants 18 participants 2 participants 187 participants 188 participants 412 participants
Female
8
  47.1%
6
  33.3%
0
   0.0%
98
  52.4%
95
  50.5%
207
  50.2%
Male
9
  52.9%
12
  66.7%
2
 100.0%
89
  47.6%
93
  49.5%
205
  49.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants 18 participants 2 participants 187 participants 188 participants 412 participants
Hispanic or Latino
2
  11.8%
1
   5.6%
0
   0.0%
25
  13.4%
15
   8.0%
43
  10.4%
Not Hispanic or Latino
9
  52.9%
10
  55.6%
1
  50.0%
134
  71.7%
125
  66.5%
279
  67.7%
Unknown or Not Reported
6
  35.3%
7
  38.9%
1
  50.0%
28
  15.0%
48
  25.5%
90
  21.8%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 17 participants 18 participants 2 participants 187 participants 188 participants 412 participants
American Indian or Alaska Native
2
  11.8%
1
   5.6%
0
   0.0%
3
   1.6%
2
   1.1%
8
   1.9%
Asian
3
  17.6%
4
  22.2%
0
   0.0%
57
  30.5%
45
  23.9%
109
  26.5%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
3
  17.6%
4
  22.2%
1
  50.0%
23
  12.3%
25
  13.3%
56
  13.6%
White
9
  52.9%
7
  38.9%
0
   0.0%
87
  46.5%
93
  49.5%
196
  47.6%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
2
  11.1%
1
  50.0%
17
   9.1%
23
  12.2%
43
  10.4%
1.Primary Outcome
Title Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Maximum Drug Concentration in Plasma (Cmax)
Hide Description 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).
Time Frame 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
Hide Outcome Measure Data
Hide Analysis Population Description
Part 1 Pharmacokinetic (PK) Set: included all participants who completed Part 1 screening phase; who had received at least one dose of study drug during Part 1, and had at least one available, valid, PK concentration measurement (not flagged for exclusion or considered a protocol deviation from relevant PK data) during Part 1.
Arm/Group Title LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
Hide Arm/Group Description:
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.
Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age 1 month to 1 year were included in this group.
Overall Number of Participants Analyzed 7 8 7 6 4 5
Mean (Standard Deviation)
Unit of Measure: nanograms per milliliter (ng/ml)
Sacubitril 523  (390) 179  (97) 1970  (1666) 549  (298) 124  (80) 433  (181)
LBQ657 1951  (839) 1359  (711) 6707  (1887) 5453  (1032) 632  (89) 2326  (629)
Valsartan 1271  (1011) 1112  (583) 4035  (1678) 4935  (1268) 440  (275) 2487  (1564)
2.Primary Outcome
Title Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Time to Maximum Plasma Concentration (Tmax)
Hide Description 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).
Time Frame 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
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Part 1 PK Set were analyzed.
Arm/Group Title LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
Hide Arm/Group Description:
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.
Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age 1 month to 1 year were included in this group.
Overall Number of Participants Analyzed 7 8 7 6 4 5
Mean (Standard Deviation)
Unit of Measure: hours (hr)
Sacubitril 1.1  (1.3) 1.2  (0.5) 0.8  (0.3) 1.2  (0.4) 1.1  (0.1) 1.0  (0.0)
LBQ657 4.0  (2.0) 2.9  (1.1) 2.9  (1.1) 3.6  (3.2) 2.8  (1.6) 3.6  (0.9)
Valsartan 1.7  (1.1) 2.1  (1.4) 2.6  (1.0) 1.9  (0.4) 1.8  (1.5) 1.8  (1.3)
3.Primary Outcome
Title Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)
Hide Description 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).
Time Frame 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
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Part 1 PK Set were analyzed.
Arm/Group Title LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
Hide Arm/Group Description:
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.
Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age 1 month to 1 year were included in this group.
Overall Number of Participants Analyzed 7 8 7 6 4 5
Mean (Standard Deviation)
Unit of Measure: hr*ng/mL
Sacubitril 690  (410) 494  (286) 3021  (1814) 1214  (684) 270  (182) 1063  (266)
LBQ657 48264  (22939) 31042  (17259) 150440  (49515) 127625  (35634) 15835  (2912) 62377  (16035)
Valsartan 13540  (12962) 11036  (7031) 40733  (21003) 48561  (21163) 3923  (1424) 26170  (16826)
4.Primary Outcome
Title 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)
Hide Description 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.
Time Frame 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
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Part 1 PK Set were analyzed.
Arm/Group Title LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
Hide Arm/Group Description:
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.
Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age 1 month to 1 year were included in this group.
Overall Number of Participants Analyzed 7 8 7 6 4 5
Measure Type: Count of Participants
Unit of Measure: Participants
7 8 7 6 4 5
5.Primary Outcome
Title Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril, and Valsartan): Clearance From Plasma (CL/F)
Hide Description 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.
Time Frame 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
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the Part 1 PK Set were analyzed.
Arm/Group Title LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
Hide Arm/Group Description:
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.
Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age 1 month to 1 year were included in this group.
Overall Number of Participants Analyzed 7 8 7 6 4 5
Mean (Standard Deviation)
Unit of Measure: liter per hour per kilograms (L/hr/kg)
Sacubitril 0.73  (0.35) 1.19  (0.96) 0.63  (0.28) 1.67  (1.01) 1.19  (1.11) 1.67  (1.01)
Valsartan 0.06  (0.05) 0.07  (0.09) 0.06  (0.06) 0.04  (0.01) 0.06  (0.02) 0.05  (0.03)
6.Primary Outcome
Title Part 1: Pharmacokinetics of LCZ696 Analytes (Sacubitril): Time Required to Drug Concentration to Decrease by Half (T 1/2)
Hide Description 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.
Time Frame 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
Hide Outcome Measure Data
Hide Analysis Population Description
Part 1 PK Set. The overall number of participants analyzed is the number of participants with data available for this endpoint. T1/2 could not be determined for participants under the arm LCZ696: 0.4 mg/kg (Age Group 3) as their PK data was inadequate for the T1/2 calculation. As participants were from the age of 1 month to less than 1 year, it was difficult to obtain multiple PK samples.
Arm/Group Title LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
Hide Arm/Group Description:
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.
Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age 1 month to 1 year were included in this group.
Overall Number of Participants Analyzed 6 2 6 4 0 3
Median (Full Range)
Unit of Measure: hours
1.26
(0.95 to 2.36)
1.53
(1.40 to 1.65)
1.34
(1.16 to 1.60)
1.51
(1.34 to 1.70)
1.33
(1.16 to 1.64)
7.Primary Outcome
Title Part 1: Pharmacodynamics (PD) of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma B-type Natriuretic Peptide (BNP)
Hide Description 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.
Time Frame Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2
Hide Outcome Measure Data
Hide Analysis Population Description
Part 1 PD set (PD1) included all participants who completed the Part 1 screening phase and had at least one dose of study drug during Part 1 of the study, at least one available PD measurement during Part 1 of the study and with no protocol deviations with relevant impact on PD data. Overall number of participants analyzed is the number of participants with data available for this endpoint.
Arm/Group Title LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
Hide Arm/Group Description:
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.
Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age 1 month to 1 year were included in this group.
Overall Number of Participants Analyzed 6 6 7 3 3 4
Geometric Mean (95% Confidence Interval)
Unit of Measure: picomoles per liter (pmol/L)
Baseline (0 hrs pre dose) Number Analyzed 6 participants 6 participants 7 participants 3 participants 3 participants 4 participants
100.87
(49.84 to 204.13)
63.80
(8.65 to 470.81)
97.52
(51.59 to 184.32)
120.51
(5.21 to 2787.44)
21.20
(2.14 to 210.41)
129.29
(9.45 to 1768.43)
Change From Baseline (4 hrs post dose) Number Analyzed 6 participants 4 participants 7 participants 1 participants 3 participants 4 participants
1.31
(0.93 to 1.85)
1.60
(0.21 to 11.95)
1.22
(0.94 to 1.58)
0.62 [1] 
(NA to NA)
0.77
(0.56 to 1.05)
1.09
(0.61 to 1.93)
Change From Baseline (8 hrs post dose) Number Analyzed 5 participants 4 participants 1 participants 1 participants 3 participants 2 participants
1.32
(0.92 to 1.88)
1.21
(0.21 to 7.04)
0.97
(0.70 to 1.34)
0.80 [2] 
(NA to NA)
0.59
(0.27 to 1.30)
0.55
(0.15 to 2.02)
[1]
The 95% confidence interval (CI) was not estimable for one participant
[2]
The 95% CI was not estimable for one participant
8.Primary Outcome
Title Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma N-terminal Pro-brain Natriuretic Peptide (NTproBNP)
Hide Description 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.
Time Frame Baseline (0 hrs pre dose) and optional 24 hrs post dosing on Day 1 of Period 1 and Period 2
Hide Outcome Measure Data
Hide Analysis Population Description
Part 1 PD set. The overall number of participants analyzed is the number of participants with data available for this endpoint. Data has not been reported for the arms of LCZ696: 0.8 mg/kg (Age Group 2) and LCZ696: 3.1 mg/kg (Age Group 2) as no participants participated in the optional 24 hrs post-dose assessment.
Arm/Group Title LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
Hide Arm/Group Description:
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.
Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age 1 month to 1 year were included in this group.
Overall Number of Participants Analyzed 7 0 7 0 4 5
Geometric Mean (95% Confidence Interval)
Unit of Measure: picograms per millilitre (pg/mL)
Baseline (0 hrs pre dose) Number Analyzed 7 participants 0 participants 7 participants 0 participants 4 participants 5 participants
2385.34
(1186.13 to 4796.98)
2179.94
(932.77 to 5094.69)
961.76
(125.65 to 7361.70)
5086.37
(683.53 to 37849.47)
Change From Baseline (24 hrs post dose) Number Analyzed 3 participants 0 participants 0 participants 0 participants 2 participants 2 participants
0.74
(0.31 to 1.78)
0.59
(0.00 to 134.25)
0.41
(0.34 to 0.48)
9.Primary Outcome
Title Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Plasma Cyclic Guanosine Monophosphate (cGMP)
Hide Description 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.
Time Frame Baseline (0 hrs pre dose), 4 and 8 hrs post dose on Day 1 of Period 1 and Period 2
Hide Outcome Measure Data
Hide Analysis Population Description
Part 1 PD set. The overall number of participants analyzed is the number of participants with data available for this endpoint.
Arm/Group Title LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
Hide Arm/Group Description:
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.
Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age 1 month to 1 year were included in this group.
Overall Number of Participants Analyzed 7 6 7 4 2 3
Geometric Mean (95% Confidence Interval)
Unit of Measure: nanomoles per litre (nmol/L)
Baseline (0 hrs pre dose) Number Analyzed 7 participants 6 participants 7 participants 4 participants 2 participants 3 participants
18.18
(12.01 to 27.51)
21.41
(12.83 to 35.71)
12.20
(8.13 to 18.32)
24.55
(18.37 to 32.82)
13.38
(0.05 to 3883.59)
22.84
(12.51 to 41.68)
Change From Baseline (4 hrs post dose) Number Analyzed 7 participants 6 participants 7 participants 4 participants 2 participants 3 participants
1.30
(0.89 to 1.90)
0.90
(0.50 to 1.62)
1.54
(1.12 to 2.10)
1.02
(0.52 to 2.01)
0.80
(0.00 to 618.02)
0.78
(0.27 to 2.22)
Change From Baseline (8 hrs post dose) Number Analyzed 7 participants 4 participants 7 participants 4 participants 2 participants 3 participants
1.17
(0.91 to 1.50)
0.92
(0.66 to 1.29)
1.60
(1.10 to 2.31)
0.40
(0.02 to 8.86)
0.79
(0.00 to 230.10)
0.79
(0.29 to 2.18)
10.Primary Outcome
Title Part 1: Pharmacodynamics of LCZ696 Analytes (Sacubitril, LBQ657, and Valsartan): Change From Baseline in Urine cGMP
Hide Description 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.
Time Frame Baseline (0 hrs pre dose), 4 to 8 hrs post dose on Day 1 of Period 1 and Period 2
Hide Outcome Measure Data
Hide Analysis Population Description
Part 1 PD set. The overall number of participants analyzed is the number of participants with data available for this endpoint.
Arm/Group Title LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3)
Hide Arm/Group Description:
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.
Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.
Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age 1 month to 1 year were included in this group.
Overall Number of Participants Analyzed 7 3 6 3 2 5
Geometric Mean (95% Confidence Interval)
Unit of Measure: nmol/L
Baseline (0 hrs pre dose) Number Analyzed 7 participants 3 participants 6 participants 3 participants 1 participants 5 participants
1055.56
(352.98 to 3156.55)
1349.91
(118.48 to 15380.33)
914.57
(311.65 to 2683.88)
1123.69
(75.21 to 16789.03)
485.00 [1] 
(NA to NA)
386.32
(134.04 to 1113.42)
Change From Baseline (4 to 8 hrs post dose) Number Analyzed 7 participants 3 participants 6 participants 3 participants 2 participants 4 participants
1.42
(0.38 to 5.32)
0.80
(0.02 to 27.03)
1.79
(0.65 to 4.96)
2.17
(0.10 to 45.16)
0.92
(0.02 to 51.75)
1.98
(0.51 to 7.63)
[1]
The 95% CI was not estimable for one participant
11.Primary Outcome
Title Part 2: Percentage of Participants With Worst Event in Each Category Based on Global Ranking
Hide Description 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.
Time Frame Up to 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all randomized participants with the exception of those participants who had not been qualified for randomization and had not received study drug but had been inadvertently randomized into the study. A total of 377 participants were randomized in Part 2 of which a total of 375 were analyzed. Two participants who were excluded did not receive study drug and did not qualify for randomization.
Arm/Group Title Part 2: LCZ696 Part 2: Enalapril
Hide Arm/Group Description:
Participants received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks.
Participants received enalapril 0.2 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 0.15 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, BID, for 52 weeks.
Overall Number of Participants Analyzed 187 188
Measure Type: Number
Unit of Measure: percentage of participants
Category 1 10.16 15.96
Category 2 9.63 4.79
Category 3 6.95 5.85
Category 4 20.86 26.60
Category 5 39.57 35.64
Missing 12.83 11.17
12.Secondary Outcome
Title Part 1: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)
Hide Description An adverse event (AE) is any untoward medical occurrence associated with use of a drug in humans, whether considered drug related or not, that occurs after a participant provides informed consent. TEAEs during part 1 are defined as any recorded AE with its start date (recorded or imputed) later than or equal to the date of the first dose of the study drug within part 1 and its start date prior to or equal to the end date of the part 1.
Time Frame From first dose to 30 days after last dose of study drug in Part 1
Hide Outcome Measure Data
Hide Analysis Population Description
Part 1 Safety Analysis Set (SAF1) included all participants who completed the Part 1 screening phase and received at least one dose of study drug during Part 1 of the study.
Arm/Group Title LCZ696: 0.8 mg/kg (Age Group 1) LCZ696: 0.8 mg/kg (Age Group 2) LCZ696: 3.1 mg/kg (Age Group 1) LCZ696: 3.1 mg/kg (Age Group 2) LCZ696: 0.4 mg/kg (Age Group 3) LCZ696: 1.6 mg/kg (Age Group 3) Part 1: Dose Cohort S
Hide Arm/Group Description:
Participants received LCZ696 0.4 mg/kg (age group 3 {1 month to < 1 year}) or 0.8 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}), based on age, given as a single oral dose on Day 1 of period 1.

Participants received LCZ696 0.8 mg/kg, given as a single oral dose on Day 1 of Period 1 in Part 1.

Participants ranging from age of 1 to less than 6 years were included in this group.

Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from the age of 6 to less than 18 years were included in this group.
Participants received LCZ696 3.1 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1. Participants ranging from age of 1 to less than 6 years were included in this group.

Participants received LCZ696 0.4 mg/kg, given as a single oral dose on Day 1 of Period

1 in Part 1. Participants ranging from the age of 1 month to less than 1 year were included in this group.

Participants received LCZ696 1.6 mg/kg, given as a single oral dose on Day 1 of Period 2 in Part 1.

Participants ranging from age 1 month to 1 year were included in this group.

Participants in the dose cohort 2 who received LCZ696 3.1 mg/kg on Day 1 of period 2 and later received LCZ696 0.8 mg/kg, within period 2.
Overall Number of Participants Analyzed 7 6 7 6 4 5 2
Measure Type: Number
Unit of Measure: percentage of participants
28.57 50.00 28.57 50.00 50.00 80.00 50.00
13.Secondary Outcome
Title Part 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)
Hide Description An AE is any untoward medical occurrence associated with use of a drug in humans, whether or not considered drug related, that occurs after a participant provides informed consent. TEAEs during part 2 are defined as any recorded AE with its start date (recorded or imputed) later than or equal to the date of the first dose of the study drug within part 2 and its start date prior to or equal to the end date of part 2.
Time Frame From first dose to 30 days after last dose of study drug in Part 2 (up to 56 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Part 2: Safety Set included randomized participants who received at least one dose of study drug. Participants were analyzed according to the treatment actually received. A total of 377 participants were randomized in Part 2 of which a total of 375 were analyzed. Two participants who were excluded did not receive study drug and did not qualify for randomization.
Arm/Group Title Part 2: LCZ696 Part 2: Enalapril
Hide Arm/Group Description:
Participants received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks.
Participants received enalapril 0.2 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 0.15 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, BID, for 52 weeks.
Overall Number of Participants Analyzed 187 188
Measure Type: Number
Unit of Measure: percentage of participant
88.77 87.77
14.Secondary Outcome
Title Part 2: Exposure-adjusted Incidence Rate of Category 1 or Category 2 Event
Hide Description The exposure adjusted incidence rate is calculated as number of participants with at least one event divided by total participant years across all participants. Category 1: Death; UNOS status 1A listing for heart transplant or equivalent; VAD/ECMO/mechanical ventilation/intra-aortic balloon pump requirement for life support at end of study. Category 2: WHF; defined by signs and symptoms of WHF that requires an intensification of HF therapy.
Time Frame 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all randomized participants with the exception of those participants who had not been qualified for randomization and had not received study drug but had been inadvertently randomized into the study. A total of 377 participants were randomized in Part 2 of which a total of 375 were analyzed. Two participants who were excluded did not receive study drug and did not qualify for randomization.
Arm/Group Title Part 2: LCZ696 Part 2: Enalapril
Hide Arm/Group Description:
Participants received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks.
Participants received enalapril 0.2 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 0.15 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, BID, for 52 weeks.
Overall Number of Participants Analyzed 34 33
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: participant per participant years
20.133
(13.9430 to 28.1344)
20.042
(13.7960 to 28.1464)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: LCZ696, Part 2: Enalapril
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7958
Comments The adjusted hazard ratio and the p-values are based on a Cox proportional hazard model, stratified by modified age group with treatment and NYHA/ROSS class group included as factor.
Method Cox Proportional Hazard
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.0655
Confidence Interval (2-Sided) 95%
0.6589 to 1.7232
Estimation Comments [Not Specified]
15.Secondary Outcome
Title Part 2: Percentage of Participants With Change From Baseline in New York Heart Association (NYHA)/Ross Functional Class
Hide Description NYHA classification is a subjective physician's assessment of participant's functional capacity and symptomatic status and can change frequently over time. NYHA is tool that classifies participants with heart failure into one of four classes according to their degree of symptoms at rest and with activity. Class I: No limitations of physical activity. Class 2: May experience fatigue, palpitations, dyspnea, or angina during moderate exercise but not during rest. Class 3: Symptoms with minimal exertion that interfere with normal daily activity. Class 4: Unable to carry out any physical activity because they typically have symptoms of HF at rest that worsen with any exertion. Participants with change from baseline were classified as improved (shifted from higher to lower class), unchanged (no change in class) or worsened (shifted from lower to higher class).
Time Frame Baseline, Week 4, 12, 24, 36, and 52
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the full analysis set with available data were analyzed. The number analyzed is the number of participants with data available for analyses at specific timepoints. A total of 377 participants were randomized in Part 2 of which a total of 375 were analyzed. Two participants who were excluded did not receive study drug and did not qualify for randomization.
Arm/Group Title Part 2: LCZ696 Part 2: Enalapril
Hide Arm/Group Description:
Participants received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks.
Participants received enalapril 0.2 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 0.15 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, BID, for 52 weeks.
Overall Number of Participants Analyzed 187 188
Measure Type: Number
Unit of Measure: percentage of participants
Change from Baseline at Week 4: Improved Number Analyzed 183 participants 184 participants
14.21 15.67
Change from Baseline at Week 4: Unchanged Number Analyzed 183 participants 184 participants
84.15 82.61
Change from Baseline at Week 4: Worsened Number Analyzed 183 participants 184 participants
1.64 1.63
Change from Baseline at Week 12: Improved Number Analyzed 180 participants 180 participants
23.89 25.56
Change from Baseline at Week 12: Unchanged Number Analyzed 180 participants 180 participants
70.56 67.78
Change from Baseline at Week 12: Worsened Number Analyzed 180 participants 180 participants
5.56 6.67
Change from Baseline at Week 24: Improved Number Analyzed 178 participants 172 participants
26.97 27.91
Change from Baseline at Week 24: Unchanged Number Analyzed 178 participants 172 participants
64.04 63.95
Change from Baseline at Week 24: Worsened Number Analyzed 178 participants 172 participants
8.99 8.14
Change from Baseline at Week 36: Improved Number Analyzed 167 participants 170 participants
29.94 34.12
Change from Baseline at Week 36: Unchanged Number Analyzed 167 participants 170 participants
61.08 58.24
Change from Baseline at Week 36: Worsened Number Analyzed 167 participants 170 participants
8.98 7.65
Change from Baseline at Week 52: Improved Number Analyzed 154 participants 159 participants
37.66 33.96
Change from Baseline at Week 52: Unchanged Number Analyzed 154 participants 159 participants
50.65 56.60
Change from Baseline at Week 52: Worsened Number Analyzed 154 participants 159 participants
11.69 9.43
16.Secondary Outcome
Title Part 2: Percentage of Participants With Change From Baseline in Patient Global Impression of Severity (PGIS) Score
Hide Description PGIS of Heart Failure Symptoms is a 1-item questionnaire to assess the participant's impression of symptoms severity, specifically: shortness of breath, fatigue and swelling. The PGI-S asks the participant to choose one response that best describes how his/her heart failure symptoms, specifically: shortness of breath, fatigue and swelling are now on a 5-point scale, ranging from 'Not at all' (1) to 'Very severe' (5). C1 = none (good), C2 = mild, C3 = moderate, C4 = severe, C5 = very severe (bad). Percentage of participants by change in score are reported. Participants with change from baseline were classified as improved (shifted from higher to score), unchanged (no change in score) or worsened (shifted from lower to higher score).
Time Frame Baseline, Week 4, 12, 24, 36, and 52
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the full analysis set with available data were analyzed. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analyses at specific timepoints. A total of 377 participants were randomized in Part 2 of which a total of 375 were analyzed. Two participants who were excluded did not receive study drug and did not qualify for randomization.
Arm/Group Title Part 2: LCZ696 Part 2: Enalapril
Hide Arm/Group Description:
Participants received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks.
Participants received enalapril 0.2 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 0.15 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, BID, for 52 weeks.
Overall Number of Participants Analyzed 182 188
Measure Type: Number
Unit of Measure: percentage of participants
Change from Baseline at Week 4: Improved Number Analyzed 174 participants 182 participants
27.01 29.67
Change from Baseline at Week 4: Unchanged Number Analyzed 174 participants 182 participants
58.05 59.89
Change from Baseline at Week 4: Worsened Number Analyzed 174 participants 182 participants
14.94 10.44
Change from Baseline at Week 12: Improved Number Analyzed 178 participants 178 participants
30.90 31.46
Change from Baseline at Week 12: Unchanged Number Analyzed 178 participants 178 participants
52.25 55.62
Change from Baseline at Week 12: Worsened Number Analyzed 178 participants 178 participants
16.85 12.92
Change from Baseline at Week 24: Improved Number Analyzed 174 participants 171 participants
33.33 38.01
Change from Baseline at Week 24: Unchanged Number Analyzed 174 participants 171 participants
48.85 48.54
Change from Baseline at Week 24: Worsened Number Analyzed 174 participants 171 participants
17.82 13.45
Change from Baseline at Week 36: Improved Number Analyzed 162 participants 165 participants
33.33 33.94
Change from Baseline at Week 36: Unchanged Number Analyzed 162 participants 165 participants
49.38 52.73
Change from Baseline at Week 36: Worsened Number Analyzed 162 participants 165 participants
17.28 13.33
Change from Baseline at Week 52: Improved Number Analyzed 152 participants 158 participants
35.53 34.81
Change from Baseline at Week 52: Unchanged Number Analyzed 152 participants 158 participants
48.03 47.47
Change from Baseline at Week 52: Worsened Number Analyzed 152 participants 158 participants
16.45 17.72
17.Secondary Outcome
Title Part 1 and Part 2: Population PK of LCZ696 Analytes: Clearance From Plasma (CL)
Hide Description The analyses of CL was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.
Time Frame Part 1: 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 2: Weeks 2, 8, 12, 52
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set included all randomized participants who received study drug, with the exception of [2 patients in Part 2] who had not received any study drug but had been inadvertently randomized into the study (mis-randomized).
Arm/Group Title LCZ696 (Part 1 and 2)
Hide Arm/Group Description:
Participants received LCZ696 0.4 mg/kg (age group 3) or 0.8 mg/kg (age group 1 and 2) on Day 1 of Period 1 and 1.6 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2) on Day 1 of Period 2, based on age, given as a single oral dose in Part 1. Followed by Part 1, participants were enrolled in Part 2 and received LCZ696 2.3 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2), based on age, orally, twice a day (BID) for 52 weeks in Part 2.
Overall Number of Participants Analyzed 203
Mean (Standard Deviation)
Unit of Measure: L/h
Sacubitril Number Analyzed 202 participants
25.93  (19.29)
LBQ657 Number Analyzed 202 participants
0.44  (0.31)
Valsartan Number Analyzed 203 participants
1.97  (1.69)
18.Secondary Outcome
Title Part 1 and Part 2: Population PK of LCZ696 Analytes: Volume of Distribution in Steady State
Hide Description The analyses of volume of distribution was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.
Time Frame Part 1: 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 2: Weeks 2, 8, 12, 52
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set included all randomized participants who received study drug, with the exception of [2 patients in Part 2] who had not received any study drug but had been inadvertently randomized into the study (mis-randomized).
Arm/Group Title LCZ696 (Part 1 and 2)
Hide Arm/Group Description:
Participants received LCZ696 0.4 mg/kg (age group 3) or 0.8 mg/kg (age group 1 and 2) on Day 1 of Period 1 and 1.6 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2) on Day 1 of Period 2, based on age, given as a single oral dose in Part 1. Followed by Part 1, participants were enrolled in Part 2 and received LCZ696 2.3 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2), based on age, orally, twice a day (BID) for 52 weeks in Part 2.
Overall Number of Participants Analyzed 203
Mean (Standard Deviation)
Unit of Measure: L/Kg
Sacubitril Number Analyzed 202 participants
4.67  (5.84)
LBQ657 Number Analyzed 202 participants
0.34  (0.12)
Valsartan Number Analyzed 203 participants
0.68  (0.29)
19.Secondary Outcome
Title Part 1 and Part 2: Population PK of LCZ696 Analytes: Absorption Rate Constant (Ka)
Hide Description The analyses of Ka was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.
Time Frame Part 1: 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 2: Weeks 2, 8, 12, 52
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set included all randomized participants who received study drug, with the exception of [2 patients in Part 2] who had not received any study drug but had been inadvertently randomized into the study (mis-randomized).
Arm/Group Title LCZ696 (Part 1 and 2)
Hide Arm/Group Description:
Participants received LCZ696 0.4 mg/kg (age group 3) or 0.8 mg/kg (age group 1 and 2) on Day 1 of Period 1 and 1.6 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2) on Day 1 of Period 2, based on age, given as a single oral dose in Part 1. Followed by Part 1, participants were enrolled in Part 2 and received LCZ696 2.3 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2), based on age, orally, twice a day (BID) for 52 weeks in Part 2.
Overall Number of Participants Analyzed 203
Mean (Standard Deviation)
Unit of Measure: 1/hour
Sacubitril Number Analyzed 202 participants
1.25  (0.01)
LBQ657 Number Analyzed 202 participants
1.04  (1.34)
Valsartan Number Analyzed 203 participants
1.42  (0.92)
20.Secondary Outcome
Title Part 1 and Part 2: Population PK of LCZ696 Analytes: Time Required to Drug Concentration to Decrease by Half (T 1/2)
Hide Description The analyses of T1/2 was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.
Time Frame Part 1: 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 2: Weeks 2, 8, 12, 52
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set included all randomized participants who received study drug, with the exception of [2 patients in Part 2] who had not received any study drug but had been inadvertently randomized into the study (mis-randomized).
Arm/Group Title LCZ696 (Part 1 and 2)
Hide Arm/Group Description:
Participants received LCZ696 0.4 mg/kg (age group 3) or 0.8 mg/kg (age group 1 and 2) on Day 1 of Period 1 and 1.6 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2) on Day 1 of Period 2, based on age, given as a single oral dose in Part 1. Followed by Part 1, participants were enrolled in Part 2 and received LCZ696 2.3 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2), based on age, orally, twice a day (BID) for 52 weeks in Part 2.
Overall Number of Participants Analyzed 203
Median (Full Range)
Unit of Measure: hours
Sacubitril Number Analyzed 202 participants
8.51
(1.87 to 199.55)
LBQ657 Number Analyzed 202 participants
18.21
(6.08 to 107.47)
Valsartan Number Analyzed 203 participants
7.96
(2.33 to 81.65)
21.Secondary Outcome
Title Part 1 and Part 2: Population PK of LCZ696 Analytes: Maximum Drug Concentration in Plasma at Steady State (Cmax,ss)
Hide Description The analyses of Cmax was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.
Time Frame Part 1: 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 2: Weeks 2, 8, 12, 52
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set included all randomized participants who received study drug, with the exception of [2 patients in Part 2] who had not received any study drug but had been inadvertently randomized into the study (mis-randomized).
Arm/Group Title LCZ696 (Part 1 and 2)
Hide Arm/Group Description:
Participants received LCZ696 0.4 mg/kg (age group 3) or 0.8 mg/kg (age group 1 and 2) on Day 1 of Period 1 and 1.6 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2) on Day 1 of Period 2, based on age, given as a single oral dose in Part 1. Followed by Part 1, participants were enrolled in Part 2 and received LCZ696 2.3 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2), based on age, orally, twice a day (BID) for 52 weeks in Part 2.
Overall Number of Participants Analyzed 203
Mean (Standard Deviation)
Unit of Measure: ng/mL
Sacubitril Number Analyzed 202 participants
1348  (627)
LBQ657 Number Analyzed 202 participants
10153  (3591)
Valsartan Number Analyzed 203 participants
3861  (1770)
22.Secondary Outcome
Title Part 1 and Part 2: Population PK of LCZ696 Analytes: Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss)
Hide Description The analyses of Cmin was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.
Time Frame Part 1: 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 2: Weeks 2, 8, 12, 52
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set included all randomized participants who received study drug, with the exception of [2 patients in Part 2] who had not received any study drug but had been inadvertently randomized into the study (mis-randomized).
Arm/Group Title LCZ696 (Part 1 and 2)
Hide Arm/Group Description:
Participants received LCZ696 0.4 mg/kg (age group 3) or 0.8 mg/kg (age group 1 and 2) on Day 1 of Period 1 and 1.6 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2) on Day 1 of Period 2, based on age, given as a single oral dose in Part 1. Followed by Part 1, participants were enrolled in Part 2 and received LCZ696 2.3 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2), based on age, orally, twice a day (BID) for 52 weeks in Part 2.
Overall Number of Participants Analyzed 203
Mean (Standard Deviation)
Unit of Measure: ng/mL
Sacubitril Number Analyzed 202 participants
63  (141)
LBQ657 Number Analyzed 202 participants
6442  (3474)
Valsartan Number Analyzed 203 participants
1442  (1564)
23.Secondary Outcome
Title Part 1 and Part 2: Population PK of LCZ696 Analytes: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady State (AUCtau,ss)
Hide Description The analyses of AUCtau was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The PK parameters were determined using the non-compartmental method(s). In case of data limitations for estimating PK parameters using non-compartmental methods, a population PK approach was used to estimate exposure of sacubitril/valsartan analytes. The population PK model was developed to describe incoming data from pediatric patients based on an established model developed for the adult population.
Time Frame Part 1: 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 2: Weeks 2, 8, 12, 52
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set included all randomized participants who received study drug, with the exception of [2 patients in Part 2] who had not received any study drug but had been inadvertently randomized into the study (mis-randomized).
Arm/Group Title LCZ696 (Part 1 and 2)
Hide Arm/Group Description:
Participants received LCZ696 0.4 mg/kg (age group 3) or 0.8 mg/kg (age group 1 and 2) on Day 1 of Period 1 and 1.6 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2) on Day 1 of Period 2, based on age, given as a single oral dose in Part 1. Followed by Part 1, participants were enrolled in Part 2 and received LCZ696 2.3 mg/kg (age group 3) or 3.1 mg/kg (age group 1 and 2), based on age, orally, twice a day (BID) for 52 weeks in Part 2.
Overall Number of Participants Analyzed 203
Mean (Standard Deviation)
Unit of Measure: ng/mL*h
Sacubitril 2179  (2241)
LBQ657 98906  (41944)
Valsartan 28672  (19686)
Time Frame Adverse events were collected from first dose of study treatment plus 30 days post treatment up to approximately one year.
Adverse Event Reporting Description

Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.

Of the 26 participants enrolled in Part 1, all 26 participants received at least one dose of study medication. Of the 377 participants enrolled in Part 2, 375 received study medication. 2 participants in the Enalapril arm were mis-randomized in error; therefore, did not receive any medication.

 
Arm/Group Title Part 1: Dose Cohort 1 Part 1: Dose Cohort 2 Part 1: Dose Cohort S Part 2: LCZ696 Part 2: Enalapril
Hide Arm/Group Description Participants received LCZ696 0.4 mg/kg (age group 3 {1 month to < 1 year}) or 0.8 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}), based on age, given as a single oral dose on Day 1 of period 1. Participants received LCZ696 1.6 mg/kg (age group 3 {1 month to < 1 year}) or 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}), based on age, given as a single oral dose on Day 1 of period 2. Participants in the dose cohort 2 who received LCZ696 3.1 mg/kg on Day 1 of period 2 and later received LCZ696 0.8 mg/kg, within period 2. Participants received LCZ696 3.1 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 2.3 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, twice a day (BID) for 52 weeks. Participants received enalapril 0.2 mg/kg (age group 1 {6 to <18 years} and age group 2 {1 to < 6 years}) or 0.15 mg/kg (age group 3 {1 month to < 1 year}), based on age, orally, BID, for 52 weeks.
All-Cause Mortality
Part 1: Dose Cohort 1 Part 1: Dose Cohort 2 Part 1: Dose Cohort S Part 2: LCZ696 Part 2: Enalapril
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/17 (0.00%)   0/18 (0.00%)   0/2 (0.00%)   8/187 (4.28%)   12/188 (6.38%) 
Hide Serious Adverse Events
Part 1: Dose Cohort 1 Part 1: Dose Cohort 2 Part 1: Dose Cohort S Part 2: LCZ696 Part 2: Enalapril
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/17 (11.76%)   1/18 (5.56%)   0/2 (0.00%)   69/187 (36.90%)   62/188 (32.98%) 
Blood and lymphatic system disorders           
Disseminated intravascular coagulation  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Cardiac disorders           
Arrhythmia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  3/188 (1.60%) 
Arrhythmia supraventricular  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Atrial thrombosis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Atrioventricular block complete  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Bradycardia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Cardiac arrest  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  4/188 (2.13%) 
Cardiac disorder  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Cardiac failure  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  24/187 (12.83%)  23/188 (12.23%) 
Cardiac failure acute  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  4/188 (2.13%) 
Cardiac failure congestive  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  4/187 (2.14%)  3/188 (1.60%) 
Cardiac tamponade  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Cardiac ventricular thrombosis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Cardio-respiratory arrest  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Cardiomyopathy  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Congestive cardiomyopathy  1  1/17 (5.88%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Myocarditis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Pulseless electrical activity  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Supraventricular tachycardia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Tachycardia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Ventricular dysfunction  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Ventricular tachycardia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  1/188 (0.53%) 
Congenital, familial and genetic disorders           
Adrenogenital syndrome  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Gastrointestinal disorders           
Abdominal pain upper  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Ascites  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Gastritis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Intestinal haemorrhage  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Intussusception  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Nausea  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Vomiting  1  1/17 (5.88%)  0/18 (0.00%)  0/2 (0.00%)  5/187 (2.67%)  4/188 (2.13%) 
General disorders           
Chest pain  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Death  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Malaise  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Non-cardiac chest pain  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Pyrexia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  4/187 (2.14%)  0/188 (0.00%) 
Sudden death  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Immune system disorders           
Heart transplant rejection  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Infections and infestations           
Appendicitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Bronchiolitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Bronchitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Bronchitis viral  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Gastroenteritis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  1/188 (0.53%) 
Gastroenteritis viral  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Hand-foot-and-mouth disease  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Influenza  1  1/17 (5.88%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  2/188 (1.06%) 
Parainfluenzae virus infection  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Pneumonia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  5/187 (2.67%)  4/188 (2.13%) 
Pneumonia influenzal  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Pneumonia mycoplasmal  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Pneumonia viral  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Pyelonephritis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Pyelonephritis acute  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  1/188 (0.53%) 
Respiratory syncytial virus bronchiolitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Respiratory syncytial virus infection  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Respiratory tract infection  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  1/188 (0.53%) 
Rhinitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Septic shock  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Subcutaneous abscess  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Tonsillitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Upper respiratory tract infection  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  4/187 (2.14%)  0/188 (0.00%) 
Urinary tract infection  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Viral infection  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  1/188 (0.53%) 
Viral sepsis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Viral upper respiratory tract infection  1  0/17 (0.00%)  1/18 (5.56%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Injury, poisoning and procedural complications           
Accidental exposure to product  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Accidental overdose  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Concussion  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Fall  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Investigations           
Anticoagulation drug level above therapeutic  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Blood creatinine increased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Blood urea increased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Cardiac output decreased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Coronavirus test positive  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Human rhinovirus test positive  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Weight decreased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Weight increased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Metabolism and nutrition disorders           
Dehydration  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Electrolyte imbalance  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Feeding intolerance  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  1/188 (0.53%) 
Fluid retention  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Hyperkalaemia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Hypocalcaemia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Hypoglycaemia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Hypophagia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Malnutrition  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Musculoskeletal and connective tissue disorders           
Neck mass  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Pain in extremity  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Pathological fracture  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Nervous system disorders           
Akinesia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Basal ganglia infarction  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Brain injury  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Cerebral infarction  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  1/188 (0.53%) 
Encephalopathy  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Febrile convulsion  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Hemiparesis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Hypoxic-ischaemic encephalopathy  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Juvenile myoclonic epilepsy  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Neuromyopathy  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Partial seizures  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Seizure  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  4/188 (2.13%) 
Status epilepticus  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Syncope  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Psychiatric disorders           
Agitation  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Suicidal ideation  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Renal and urinary disorders           
Acute kidney injury  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Renal artery stenosis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Renal failure  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  1/188 (0.53%) 
Renal impairment  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Respiratory, thoracic and mediastinal disorders           
Acute pulmonary oedema  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Acute respiratory failure  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Asthma  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Cough  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Dyspnoea  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  1/188 (0.53%) 
Dyspnoea exertional  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Epistaxis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Hypoxia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  1/188 (0.53%) 
Orthopnoea  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Pleural effusion  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  1/188 (0.53%) 
Pulmonary oedema  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Respiratory distress  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  1/188 (0.53%) 
Respiratory failure  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  1/188 (0.53%) 
Tachypnoea  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Wheezing  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Skin and subcutaneous tissue disorders           
Angioedema  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Pruritus  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Vascular disorders           
Circulatory collapse  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Haematoma  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Hypotension  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  4/187 (2.14%)  0/188 (0.00%) 
1
Term from vocabulary, MedDRA (24.1)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Part 1: Dose Cohort 1 Part 1: Dose Cohort 2 Part 1: Dose Cohort S Part 2: LCZ696 Part 2: Enalapril
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   6/17 (35.29%)   10/18 (55.56%)   1/2 (50.00%)   161/187 (86.10%)   156/188 (82.98%) 
Blood and lymphatic system disorders           
Anaemia  1  0/17 (0.00%)  2/18 (11.11%)  0/2 (0.00%)  7/187 (3.74%)  5/188 (2.66%) 
Lymphadenopathy  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Cardiac disorders           
Angina pectoris  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  1/188 (0.53%) 
Arrhythmia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Bradycardia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Cardiac failure  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  5/187 (2.67%)  6/188 (3.19%) 
Left ventricular dysfunction  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Palpitations  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  1/188 (0.53%) 
Tachycardia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  4/188 (2.13%) 
Ventricular extrasystoles  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  4/188 (2.13%) 
Ventricular tachycardia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  3/188 (1.60%) 
Congenital, familial and genetic disorders           
Phimosis  1  1/17 (5.88%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  0/188 (0.00%) 
Ear and labyrinth disorders           
Ear pain  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  1/188 (0.53%) 
Eye disorders           
Vision blurred  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  2/188 (1.06%) 
Gastrointestinal disorders           
Abdominal discomfort  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Abdominal distension  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Abdominal pain  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  15/187 (8.02%)  11/188 (5.85%) 
Abdominal pain upper  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  6/187 (3.21%)  9/188 (4.79%) 
Constipation  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  6/187 (3.21%)  7/188 (3.72%) 
Dental caries  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Diarrhoea  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  25/187 (13.37%)  23/188 (12.23%) 
Dyspepsia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Enteritis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Gastrooesophageal reflux disease  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  5/187 (2.67%)  1/188 (0.53%) 
Gingival bleeding  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Mouth ulceration  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Nausea  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  9/187 (4.81%)  9/188 (4.79%) 
Toothache  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  5/187 (2.67%)  2/188 (1.06%) 
Vomiting  1  1/17 (5.88%)  4/18 (22.22%)  1/2 (50.00%)  33/187 (17.65%)  37/188 (19.68%) 
General disorders           
Asthenia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  2/188 (1.06%) 
Chest discomfort  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  1/188 (0.53%) 
Chest pain  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  7/187 (3.74%)  7/188 (3.72%) 
Face oedema  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Fatigue  1  0/17 (0.00%)  1/18 (5.56%)  1/2 (50.00%)  19/187 (10.16%)  14/188 (7.45%) 
Medical device pain  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Non-cardiac chest pain  1  0/17 (0.00%)  1/18 (5.56%)  0/2 (0.00%)  2/187 (1.07%)  1/188 (0.53%) 
Oedema peripheral  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  7/187 (3.74%)  2/188 (1.06%) 
Peripheral swelling  1  0/17 (0.00%)  1/18 (5.56%)  1/2 (50.00%)  0/187 (0.00%)  2/188 (1.06%) 
Pyrexia  1  0/17 (0.00%)  1/18 (5.56%)  0/2 (0.00%)  36/187 (19.25%)  34/188 (18.09%) 
Swelling face  1  0/17 (0.00%)  1/18 (5.56%)  1/2 (50.00%)  1/187 (0.53%)  1/188 (0.53%) 
Hepatobiliary disorders           
Hepatomegaly  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  2/188 (1.06%) 
Infections and infestations           
Acarodermatitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  3/188 (1.60%) 
Atypical pneumonia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Bronchitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  12/187 (6.42%)  8/188 (4.26%) 
COVID-19  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  6/187 (3.21%)  2/188 (1.06%) 
Candida infection  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Ear infection  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  3/188 (1.60%) 
Exanthema subitum  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Gastroenteritis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  9/187 (4.81%)  11/188 (5.85%) 
Gastroenteritis rotavirus  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Gastroenteritis viral  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  2/188 (1.06%) 
Hand-foot-and-mouth disease  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  3/188 (1.60%) 
Influenza  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  11/187 (5.88%)  12/188 (6.38%) 
Nasopharyngitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  29/187 (15.51%)  17/188 (9.04%) 
Oral herpes  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  3/188 (1.60%) 
Otitis media  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  5/187 (2.67%)  3/188 (1.60%) 
Otitis media acute  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  1/188 (0.53%) 
Pharyngitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  6/187 (3.21%)  5/188 (2.66%) 
Pharyngitis streptococcal  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  0/188 (0.00%) 
Pneumonia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  3/188 (1.60%) 
Pneumonia mycoplasmal  1  1/17 (5.88%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  1/188 (0.53%) 
Respiratory syncytial virus infection  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  1/188 (0.53%) 
Respiratory tract infection  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  4/187 (2.14%)  5/188 (2.66%) 
Rhinitis  1  0/17 (0.00%)  1/18 (5.56%)  0/2 (0.00%)  7/187 (3.74%)  10/188 (5.32%) 
Sinusitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  2/188 (1.06%) 
Tonsillitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  3/188 (1.60%) 
Tracheitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Upper respiratory tract infection  1  0/17 (0.00%)  3/18 (16.67%)  1/2 (50.00%)  37/187 (19.79%)  35/188 (18.62%) 
Urinary tract infection  1  0/17 (0.00%)  1/18 (5.56%)  0/2 (0.00%)  1/187 (0.53%)  0/188 (0.00%) 
Viral infection  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  5/187 (2.67%)  4/188 (2.13%) 
Viral upper respiratory tract infection  1  0/17 (0.00%)  1/18 (5.56%)  0/2 (0.00%)  1/187 (0.53%)  3/188 (1.60%) 
Injury, poisoning and procedural complications           
Arthropod bite  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Contusion  1  0/17 (0.00%)  1/18 (5.56%)  0/2 (0.00%)  2/187 (1.07%)  2/188 (1.06%) 
Fall  1  0/17 (0.00%)  1/18 (5.56%)  0/2 (0.00%)  2/187 (1.07%)  5/188 (2.66%) 
Lip injury  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Procedural pain  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  4/188 (2.13%) 
Skin abrasion  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Skin laceration  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Investigations           
Alanine aminotransferase increased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  1/188 (0.53%) 
Aspartate aminotransferase increased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  1/188 (0.53%) 
Blood creatine increased  1  1/17 (5.88%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  0/188 (0.00%) 
Blood creatinine increased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  6/187 (3.21%)  5/188 (2.66%) 
Blood potassium increased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  2/188 (1.06%) 
Blood urea increased  1  1/17 (5.88%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  1/188 (0.53%) 
Blood uric acid increased  1  1/17 (5.88%)  1/18 (5.56%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Body temperature increased  1  0/17 (0.00%)  1/18 (5.56%)  0/2 (0.00%)  0/187 (0.00%)  0/188 (0.00%) 
Glomerular filtration rate decreased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  9/187 (4.81%)  12/188 (6.38%) 
Hepatic enzyme increased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
SARS-CoV-2 test negative  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  6/187 (3.21%)  1/188 (0.53%) 
Weight decreased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  4/188 (2.13%) 
Weight increased  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  2/188 (1.06%) 
Metabolism and nutrition disorders           
Decreased appetite  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  9/187 (4.81%)  1/188 (0.53%) 
Dehydration  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  2/188 (1.06%) 
Hyperglycaemia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Hyperkalaemia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  6/187 (3.21%)  6/188 (3.19%) 
Hypokalaemia  1  0/17 (0.00%)  1/18 (5.56%)  0/2 (0.00%)  4/187 (2.14%)  1/188 (0.53%) 
Iron deficiency  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  3/188 (1.60%) 
Musculoskeletal and connective tissue disorders           
Arthralgia  1  0/17 (0.00%)  1/18 (5.56%)  0/2 (0.00%)  4/187 (2.14%)  1/188 (0.53%) 
Back pain  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  6/187 (3.21%)  3/188 (1.60%) 
Muscle spasms  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Musculoskeletal chest pain  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Myalgia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  1/188 (0.53%) 
Pain in extremity  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  6/187 (3.21%)  3/188 (1.60%) 
Nervous system disorders           
Dizziness  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  23/187 (12.30%)  15/188 (7.98%) 
Headache  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  22/187 (11.76%)  20/188 (10.64%) 
Hypersomnia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Migraine  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  1/188 (0.53%) 
Paraesthesia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Presyncope  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  3/188 (1.60%) 
Syncope  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Psychiatric disorders           
Anxiety  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  5/188 (2.66%) 
Depression  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  1/188 (0.53%) 
Insomnia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  4/187 (2.14%)  3/188 (1.60%) 
Renal and urinary disorders           
Acute kidney injury  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  2/188 (1.06%) 
Polyuria  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Renal failure  1  1/17 (5.88%)  1/18 (5.56%)  0/2 (0.00%)  1/187 (0.53%)  1/188 (0.53%) 
Renal impairment  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  4/187 (2.14%)  2/188 (1.06%) 
Reproductive system and breast disorders           
Balanoposthitis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Dysmenorrhoea  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Respiratory, thoracic and mediastinal disorders           
Asthma  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  2/188 (1.06%) 
Cough  1  0/17 (0.00%)  1/18 (5.56%)  1/2 (50.00%)  36/187 (19.25%)  38/188 (20.21%) 
Dyspnoea  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  6/187 (3.21%)  4/188 (2.13%) 
Dyspnoea exertional  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Epistaxis  1  1/17 (5.88%)  0/18 (0.00%)  0/2 (0.00%)  9/187 (4.81%)  6/188 (3.19%) 
Nasal congestion  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  4/188 (2.13%) 
Oropharyngeal pain  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  9/187 (4.81%)  5/188 (2.66%) 
Pneumothorax  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  1/188 (0.53%) 
Productive cough  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  5/187 (2.67%)  1/188 (0.53%) 
Respiratory disorder  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Rhinitis allergic  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  4/188 (2.13%) 
Rhinorrhoea  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  7/187 (3.74%)  7/188 (3.72%) 
Sleep apnoea syndrome  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  3/188 (1.60%) 
Wheezing  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  2/188 (1.06%) 
Skin and subcutaneous tissue disorders           
Alopecia  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Dermatitis allergic  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Dermatitis contact  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Dry skin  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  0/188 (0.00%) 
Ecchymosis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  1/188 (0.53%) 
Eczema  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  4/187 (2.14%)  1/188 (0.53%) 
Erythema  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  4/187 (2.14%)  1/188 (0.53%) 
Hyperhidrosis  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  3/187 (1.60%)  1/188 (0.53%) 
Ingrowing nail  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Petechiae  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  0/187 (0.00%)  2/188 (1.06%) 
Pruritus  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  2/187 (1.07%)  3/188 (1.60%) 
Rash  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  5/187 (2.67%)  6/188 (3.19%) 
Vascular disorders           
Hypertension  1  0/17 (0.00%)  0/18 (0.00%)  0/2 (0.00%)  1/187 (0.53%)  2/188 (1.06%) 
Hypotension  1  1/17 (5.88%)  2/18 (11.11%)  0/2 (0.00%)  21/187 (11.23%)  22/188 (11.70%) 
1
Term from vocabulary, MedDRA (24.1)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
EMail: trialandresults.registries@novartis.com
Layout table for additonal information
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT02678312    
Other Study ID Numbers: CLCZ696B2319
2015-004207-22 ( EudraCT Number )
First Submitted: February 4, 2016
First Posted: February 9, 2016
Results First Submitted: July 1, 2022
Results First Posted: February 10, 2023
Last Update Posted: February 10, 2023