Trial Outcomes & Findings for Trial of Angiotensin Converting Enzyme Inhibition in Infants With Single Ventricle--Pediatric Heart Network (NCT NCT00113087)

Results Overview

Weight-for-age z-score at 14 months of age. In primary analysis outcome is defined as predicted mean of weight z-score at age 14 months based on longitudinal modeling(and adjusted for baseline values)

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

230 participants

Primary outcome timeframe

Measured at baseline, 2 weeks after starting study drug, just prior to the Glenn surgery, 7 days after restarting drug following the Glenn surgery, at 10 months of age, and at 14 months of age

Results posted on

2010-09-28

Participant Flow

Participant milestones

Participant milestones
Measure	Enalapril ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo Placebo suspension
Overall Study STARTED	115	115
Overall Study COMPLETED	91	94
Overall Study NOT COMPLETED	24	21

Reasons for withdrawal

Reasons for withdrawal
Measure	Enalapril ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo Placebo suspension
Overall Study Death or Transplant	14	16
Overall Study Family or MD withdrew subject	10	5

Baseline Characteristics

Trial of Angiotensin Converting Enzyme Inhibition in Infants With Single Ventricle--Pediatric Heart Network

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Enalapril n=115 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=115 Participants Placebo suspension	Total n=230 Participants Total of all reporting groups
Age, Categorical <=18 years	115 Participants n=5 Participants	115 Participants n=7 Participants	230 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age Continuous	20.1 days STANDARD_DEVIATION 8.9 • n=5 Participants	20.7 days STANDARD_DEVIATION 9.1 • n=7 Participants	20.4 days STANDARD_DEVIATION 9.0 • n=5 Participants
Sex: Female, Male Female	40 Participants n=5 Participants	28 Participants n=7 Participants	68 Participants n=5 Participants
Sex: Female, Male Male	75 Participants n=5 Participants	87 Participants n=7 Participants	162 Participants n=5 Participants
Race/Ethnicity, Customized White	96 participants n=5 Participants	89 participants n=7 Participants	185 participants n=5 Participants
Race/Ethnicity, Customized Black/African-American	12 participants n=5 Participants	20 participants n=7 Participants	32 participants n=5 Participants
Race/Ethnicity, Customized Asian	4 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants
Race/Ethnicity, Customized Other	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment United States	104 participants n=5 Participants	105 participants n=7 Participants	209 participants n=5 Participants
Region of Enrollment Canada	11 participants n=5 Participants	10 participants n=7 Participants	21 participants n=5 Participants

PRIMARY outcome

Timeframe: Measured at baseline, 2 weeks after starting study drug, just prior to the Glenn surgery, 7 days after restarting drug following the Glenn surgery, at 10 months of age, and at 14 months of age

Population: ITT, no imputation

Weight-for-age z-score at 14 months of age. In primary analysis outcome is defined as predicted mean of weight z-score at age 14 months based on longitudinal modeling(and adjusted for baseline values)

Outcome measures

Outcome measures
Measure	Enalapril n=91 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=94 Participants Placebo suspension
Weight-for-age Z-score at 14 Months of Age	-0.62 standard deviation Standard Error 0.13	-0.42 standard deviation Standard Error 0.13

SECONDARY outcome

Timeframe: Measured at baseline, 2 weeks after starting study drug, just prior to the Glenn surgery, 7 days after restarting drug following the Glenn surgery, at 10 months of age, and at 14 months of age

Height-for-age z-score at 14 months of age. In primary analysis outcome is defined as predicted mean of height z-score at age 14 months based on longitudinal modeling (adjusted bor baseline value)

Outcome measures

Outcome measures
Measure	Enalapril n=91 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=94 Participants Placebo suspension
Height-for-age Z-score	-1.00 standard deviation Standard Error 0.13	-0.86 standard deviation Standard Error 0.13

SECONDARY outcome

Timeframe: Measured at baseline, 2 weeks after starting study drug, just prior to the Glenn surgery, 7 days after restarting drug following the Glenn surgery, at 10 months of age, and at 14 months of age

Population: ITT, no imputation

Head circumference-for-age z-score at 14 months of age.In primary analysis outcome is defined as predicted mean of Head circumference z-score at age 14 months based on longitudinal modeling(and adjusted for baseline values)

Outcome measures

Outcome measures
Measure	Enalapril n=91 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=94 Participants Placebo suspension
Head Circumference-for-age Z-score	-0.55 standard deviation Standard Error 0.17	0.09 standard deviation Standard Error 0.17

SECONDARY outcome

Timeframe: Just prior to the pre-Glenn surgery

Population: Intention-to-treat analysis of participants measured just prior to the Glenn surgery

Class I is defined as having no limitations or symptoms of heart failure. Classes II to IV include increasing degrees of growth failure, prolonged feeding time, tachypnea, diaphoresis, and in older children, dyspnea on exercise.

Outcome measures

Outcome measures
Measure	Enalapril n=96 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=102 Participants Placebo suspension
Number of Participants With Ross Heart Failure Class I	53 Participants	56 Participants

SECONDARY outcome

Timeframe: Measured at 14 months of age

Population: Intention-to-treat analysis of participants completing the final study visit (target visit window age 14 months)

Class I is defined as having no limitations or symptoms of heart failure. Classes II to IV include increasing degrees of growth failure, prolonged feeding time, tachypnea, diaphoresis, and in older children, dyspnea on exercise.

Outcome measures

Outcome measures
Measure	Enalapril n=91 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=94 Participants Placebo suspension
Number of Participants With Ross Heart Failure Class I	72 participants	77 participants

SECONDARY outcome

Timeframe: Measured just prior to the Glenn surgery

Population: ITT analysis, no imputation

B-Type Natriuretic Peptide (BNP) level.

Outcome measures

Outcome measures
Measure	Enalapril n=83 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=90 Participants Placebo suspension
B-Type Natriuretic Peptide	79 pg/ml Interval 30.0 to 182.0	84 pg/ml Interval 36.0 to 196.0

SECONDARY outcome

Timeframe: at the time of the 14 month visit

Population: ITT, no imputation

B-type natriuretic peptide (BNP) level.

Outcome measures

Outcome measures
Measure	Enalapril n=69 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=65 Participants Placebo suspension
B-type Natriuretic Peptide Level	25 pg/ml Interval 13.0 to 35.0	39 pg/ml Interval 21.0 to 86.0

SECONDARY outcome

Timeframe: at 14 months of age

Population: ITT, no imputation

Neurodevelopmental status (PDI): the Bayley Scales of Infant Development: Psychomotor Development index z-score .

Outcome measures

Outcome measures
Measure	Enalapril n=86 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=83 Participants Placebo suspension
Neurodevelopmental Status (PDI): the Bayley Scales of Infant Development,Psychomotor Development Index Z-score	-1.29 standard deviation Standard Deviation 1.19	-1.32 standard deviation Standard Deviation 1.22

SECONDARY outcome

Timeframe: at 14 months of age

Population: ITT, not imputation

Neurodevelopmental status(MDI):Bayley Scales of infant development, Mental Developmental Index z-score .

Outcome measures

Outcome measures
Measure	Enalapril n=87 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=83 Participants Placebo suspension
Neurodevelopmental Status(MDI): Bayley Scales of Infant Development, Mental Developmental Index Z-score	-0.26 standard deviation Standard Deviation 0.91	-0.33 standard deviation Standard Deviation 1.02

SECONDARY outcome

Timeframe: at 14 months of age

Population: ITT, no imputation

Functional status II (Revised) Total Score. Scale ranges up to 100.00, the higher the better. The score presents an instrument for assessing health status for children surviving long term with chronic physcial disorders.

Outcome measures

Outcome measures
Measure	Enalapril n=89 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=89 Participants Placebo suspension
Neurodevelopmental Status (FSII)	96.4 units on a scale Interval 89.0 to 100.0	96.4 units on a scale Interval 86.0 to 100.0

SECONDARY outcome

Timeframe: at 14 months of age

Population: ITT, no imputation

MacArthur-Bates Communicative Development inventory( Words and Gestures)-Phrases Understood z-score.

Outcome measures

Outcome measures
Measure	Enalapril n=90 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=87 Participants Placebo suspension
MacArthur-Bates Inventory -Phrases Understood	-0.48 standard deviation Standard Deviation 1.11	-0.92 standard deviation Standard Deviation 1.17

SECONDARY outcome

Timeframe: at 14 months of age

Population: ITT, no imputation

MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Understood z-score.

Outcome measures

Outcome measures
Measure	Enalapril n=90 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=87 Participants Placebo suspension
MacArthur-Bates Inventory -Words Understood	-0.46 standard deviation Standard Deviation 0.91	-0.82 standard deviation Standard Deviation 0.83

SECONDARY outcome

Timeframe: at 14 months of age

Population: ITT, no imputation

MacArthur-Bates Communicative Development inventory( Words and Gestures)-Total Gestures z-score.

Outcome measures

Outcome measures
Measure	Enalapril n=90 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=87 Participants Placebo suspension
MacArthur-Bates Inventory -Total Gestures	-0.86 standard deviation Standard Deviation 1.07	-1.31 standard deviation Standard Deviation 0.97

SECONDARY outcome

Timeframe: at 14 months of age

Population: ITT, no imputation

MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Produced z-score.

Outcome measures

Outcome measures
Measure	Enalapril n=90 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=87 Participants Placebo suspension
MacArthur-Bates Inventory -Words Produced	-0.60 standard deviation Interval -0.72 to 0.41	-0.63 standard deviation Interval -0.75 to 0.42

SECONDARY outcome

Timeframe: just before the Glenn surgery

Population: ITT, no imputation

Two-dimensional echocardiography endpoint -Total Ejection Fraction (%) per Core Laboratory assessment. Ejection Fraction % is defined as the percentage of the stroke volume (i.e. difference between end-diastolic and end-systolic volumes) in a ventricle relative to end-diastolic volume.

Outcome measures

Outcome measures
Measure	Enalapril n=94 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=95 Participants Placebo suspension
Ejection Fraction (%)	57.9 percent (of end diastolic volume) Standard Deviation 9.8	56.6 percent (of end diastolic volume) Standard Deviation 10.2

SECONDARY outcome

Timeframe: at 14 months of age

Population: ITT, no imputation

Two-dimensional echocardiography endpoint -Total Ejection Fraction (%) per Core Laboratory assessment. Ejection Fraction (%) is defined as percentage of stroke volume of a ventricle (i.e. the difference between end diastolic and end systolic volumes)relative to end diastolic volume.

Outcome measures

Outcome measures
Measure	Enalapril n=87 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=91 Participants Placebo suspension
Ejection Fraction (%)	59.3 percent (of end diastolic volume) Standard Deviation 9.6	57.9 percent (of end diastolic volume) Standard Deviation 10.4

SECONDARY outcome

Timeframe: just before the Glenn surgery

Population: ITT, no imputation

Two-dimensional echocardiography endpoint - Total Ventricular mass (g) per Core Laboratory assessment.

Outcome measures

Outcome measures
Measure	Enalapril n=93 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=94 Participants Placebo suspension
Ventricular Mass	25.5 g Standard Deviation 9.2	28.1 g Standard Deviation 10.6

SECONDARY outcome

Timeframe: At 14 months of age

Population: ITT, no imputation

Two-Dimensional Echocardiography endpoint-Total Ventricular mass (g) per Core Laboratory assessment. Range from 15.60 to 70.40

Outcome measures

Outcome measures
Measure	Enalapril n=87 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=89 Participants Placebo suspension
Ventricular Mass	31.4 g Standard Deviation 10.3	34.4 g Standard Deviation 11.4

SECONDARY outcome

Timeframe: just before the Glenn surgery

Population: ITT, no imputation

Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.

Outcome measures

Outcome measures
Measure	Enalapril n=92 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=92 Participants Placebo suspension
Ventricular Mass Z-score	4.0 standard deviation Standard Deviation 2.9	4.9 standard deviation Standard Deviation 3.3

SECONDARY outcome

Timeframe: at 14 months of age

Population: ITT, no imputation

Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.

Outcome measures

Outcome measures
Measure	Enalapril n=87 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=89 Participants Placebo suspension
Ventricular Mass Z-score	2.5 standard deviation Standard Deviation 2.3	3.1 standard deviation Standard Deviation 2.5

SECONDARY outcome

Timeframe: just before the Glenn surgery

Population: ITT, no imputation

Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.

Outcome measures

Outcome measures
Measure	Enalapril n=94 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=95 Participants Placebo suspension
End-diastolic Volume	24.1 ml Standard Deviation 10.1	23.2 ml Standard Deviation 9.0

SECONDARY outcome

Timeframe: at 14 months of age

Population: ITT, no imputation

Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.

Outcome measures

Outcome measures
Measure	Enalapril n=87 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=91 Participants Placebo suspension
End-diastolic Volume	29.2 ml Standard Deviation 10.0	30.7 ml Standard Deviation 11.3

SECONDARY outcome

Timeframe: just before the Glenn surgery

Population: ITT, no imputation

Two-dimensional echocardiography endpoint -total End diastolic volume z-score per Core Laboratory assessment.

Outcome measures

Outcome measures
Measure	Enalapril n=93 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=93 Participants Placebo suspension
End Diastolic Volume Z-score	2.3 standard deviation Standard Deviation 2.5	2.1 standard deviation Standard Deviation 2.5

SECONDARY outcome

Timeframe: at 14 months of age

Population: ITT, no imputation

Two-dimensional echocardiography endpoint -total end-diastolic volume z-score per Core Laboratory assessment.

Outcome measures

Outcome measures
Measure	Enalapril n=87 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=91 Participants Placebo suspension
End-diastolic Volume Z-score	1.1 standard deviation Standard Deviation 2.1	1.3 standard deviation Standard Deviation 2.4

SECONDARY outcome

Timeframe: Measured just before the Glenn surgery

Population: Intention-to-treat analysis of participants completing the pre-Glenn visit

Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.

Outcome measures

Outcome measures
Measure	Enalapril n=93 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=94 Participants Placebo suspension
Ventricular Mass to Volume Ratio	1.15 g/ml Standard Deviation 0.43	1.31 g/ml Standard Deviation 0.50

SECONDARY outcome

Timeframe: Measured at 14 months of age

Population: Intention-to-treat analysis of participants completing the final study visit (target visit window age 14 months)

Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.

Outcome measures

Outcome measures
Measure	Enalapril n=87 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=89 Participants Placebo suspension
Ventricular Mass to Volume Ratio	1.14 g/ml Standard Deviation 0.38	1.20 g/ml Standard Deviation 0.44

SECONDARY outcome

Timeframe: just before the Glenn surgery

Population: ITT, no imputation

Ventricular filling pressure measured by catherization

Outcome measures

Outcome measures
Measure	Enalapril n=58 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=63 Participants Placebo suspension
Ventricular Filling Pressure	10.9 mmHg Standard Deviation 3.6	11.1 mmHg Standard Deviation 4.0

SECONDARY outcome

Timeframe: just before the pre-Glenn surgery

Population: ITT, no imputation

Number of participants with Moderate to severe AV valve regurgitation.

Outcome measures

Outcome measures
Measure	Enalapril n=98 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=98 Participants Placebo suspension
Number of Participants With Moderate to Severe AV Valve Regurgitation	20 participants	32 participants

SECONDARY outcome

Timeframe: at age 14 months

Population: ITT, no imputation

Number of participants with moderate to severe AV valve regurgitation.

Outcome measures

Outcome measures
Measure	Enalapril n=90 Participants ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=93 Participants Placebo suspension
Number of Participants With Moderate to Severe AV Valve Regurgitation	11 participants	22 participants

Adverse Events

Enalapril

Serious events: 88 serious events

Other events: 77 other events

Deaths: 0 deaths

Placebo

Serious events: 87 serious events

Other events: 70 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Lynn Sleeper

New England Research Institute

Phone: 617-972-3235

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Enalapril n=115 participants at risk ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=115 participants at risk Placebo suspension
Cardiac disorders Cardiac general	25.2% 29/115 • Number of events 37 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	16.5% 19/115 • Number of events 24 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Infections and infestations Infection	31.3% 36/115 • Number of events 55 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	30.4% 35/115 • Number of events 44 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Nervous system disorders Neurology	3.5% 4/115 • Number of events 4 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	5.2% 6/115 • Number of events 6 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Respiratory, thoracic and mediastinal disorders Pulmonary/Upper Respiratory	27.0% 31/115 • Number of events 41 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	30.4% 35/115 • Number of events 49 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Vascular disorders Vascular	19.1% 22/115 • Number of events 30 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	18.3% 21/115 • Number of events 26 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Ear and labyrinth disorders auditory/ear	0.00% 0/115 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Blood and lymphatic system disorders blood/bone marrow	3.5% 4/115 • Number of events 4 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	1.7% 2/115 • Number of events 2 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Cardiac disorders cardiac arrhythmia	3.5% 4/115 • Number of events 5 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	4.3% 5/115 • Number of events 6 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Blood and lymphatic system disorders coagulation	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.00% 0/115 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
General disorders constitutional symptoms	1.7% 2/115 • Number of events 2 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	2.6% 3/115 • Number of events 3 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Cardiac disorders death	4.3% 5/115 • Number of events 5 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	3.5% 4/115 • Number of events 4 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Skin and subcutaneous tissue disorders dermatology/skin	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Gastrointestinal disorders gastrointestinal	17.4% 20/115 • Number of events 27 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	15.7% 18/115 • Number of events 26 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Metabolism and nutrition disorders growth and development	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	4.3% 5/115 • Number of events 5 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Blood and lymphatic system disorders hemorrhage/bleeding	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	1.7% 2/115 • Number of events 2 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Blood and lymphatic system disorders lymphatics	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.00% 0/115 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Metabolism and nutrition disorders metabolic/laboratory	2.6% 3/115 • Number of events 3 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.00% 0/115 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Musculoskeletal and connective tissue disorders musculoskeletal/soft issue	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	1.7% 2/115 • Number of events 3 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Renal and urinary disorders renal/genitourinary	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.87% 1/115 • Number of events 2 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Surgical and medical procedures surgery/intra-operative injury	0.00% 0/115 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	2.6% 3/115 • Number of events 3 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Congenital, familial and genetic disorders syndromes	0.00% 0/115 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.

Measure	Enalapril n=115 participants at risk ACE (Angiotensin-converting enzyme) inhibitor enalapril, initial dose 0.1 mg/kg/day; Uptitrated as tolerated to target dose of 0.4 mg/kg/day given in two divided doses	Placebo n=115 participants at risk Placebo suspension
Cardiac disorders Cardiac General	15.7% 18/115 • Number of events 23 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	10.4% 12/115 • Number of events 15 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Nervous system disorders Neurology	4.3% 5/115 • Number of events 6 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	5.2% 6/115 • Number of events 9 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Respiratory, thoracic and mediastinal disorders Pulmonary/upper respiratory	17.4% 20/115 • Number of events 28 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	19.1% 22/115 • Number of events 25 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Vascular disorders Vascular	6.1% 7/115 • Number of events 7 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	4.3% 5/115 • Number of events 5 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Infections and infestations infection	33.0% 38/115 • Number of events 66 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	28.7% 33/115 • Number of events 64 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Immune system disorders allergy/immunology	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	1.7% 2/115 • Number of events 3 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Ear and labyrinth disorders auditory/ear	0.00% 0/115 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Blood and lymphatic system disorders blood/bone marrow	1.7% 2/115 • Number of events 2 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	2.6% 3/115 • Number of events 3 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Cardiac disorders cardiac arrhythmia	8.7% 10/115 • Number of events 12 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	4.3% 5/115 • Number of events 6 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Blood and lymphatic system disorders coagulation	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
General disorders constitutional symptoms	7.0% 8/115 • Number of events 8 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	2.6% 3/115 • Number of events 4 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Skin and subcutaneous tissue disorders dermatology/skin	2.6% 3/115 • Number of events 3 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	7.0% 8/115 • Number of events 9 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Endocrine disorders endocrine	1.7% 2/115 • Number of events 2 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.00% 0/115 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Gastrointestinal disorders gastrointestinal	16.5% 19/115 • Number of events 27 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	13.9% 16/115 • Number of events 24 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Blood and lymphatic system disorders hemorrhage/bleeding	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Hepatobiliary disorders hepatobillary	1.7% 2/115 • Number of events 2 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.00% 0/115 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Metabolism and nutrition disorders metabolic/laboratory	6.1% 7/115 • Number of events 8 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	7.8% 9/115 • Number of events 9 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Renal and urinary disorders renal/genitourinary	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Surgical and medical procedures surgery/intra-operative injury	1.7% 2/115 • Number of events 2 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.00% 0/115 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Metabolism and nutrition disorders growth and development	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.00% 0/115 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.
Musculoskeletal and connective tissue disorders musculoskeletal/soft tissue	0.87% 1/115 • Number of events 2 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.	0.87% 1/115 • Number of events 1 • Randomization to 14 months of age All serious AE counts by body system are presented. The total count of affected by SAE is based on all reported SAEs. All other AE counts by body system are presented. The total count of affected by "other AE" is based on all reported AEs other than serious.