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

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00113087
• Collaborator: Pediatric Heart Network (Other)
• Enrollment: 230
• Locations: 9
• Arms: 2
• Duration (Months): 59
• Patients Per Site: 25.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy and safety of administering an angiotensin converting enzyme inhibitor (ACE-I) (enalapril) to infants with a functional single ventricle. The study will also compare the effect of ACE-I therapy to placebo on somatic growth and compare the effect of ACE-I therapy to placebo on signs and symptoms of heart failure, neurodevelopmental and functional status, ventricular geometry, function, and atrioventricular (AV) valve regurgitation. In addition, the study will determine the relationship between genetic polymorphisms linked to ventricular hypertrophy (enlarged heart) and the response to ACE-I therapy and compare the incidence of adverse events in subjects treated with ACE-I with those in subjects treated with placebo.

Condition or Disease	Intervention/Treatment	Phase
Heart Defects, Congenital; Heart Failure, Congestive	Drug: Enalapril; Drug: Placebo	Phase 3

Detailed Description

BACKGROUND:

Growth impairment is common in infants and children with congenital heart disease, most often in the presence of congestive heart failure and/or cyanosis. Growth failure is noted in many infants with a single ventricle who manifest both cyanosis and heart failure that commonly persist after palliative surgery. Whether this impairment is related to persistent or progressive abnormalities in cardiac structure and function is not known. ACE-Is are widely used in the treatment of infants with severe congestive heart failure to improve cardiac function and somatic growth. The ability of an ACE-I to improve somatic growth in infants with a single ventricle has not been previously studied.

This study has been approved by the Institutional Review Boards/Research Ethics Boards of all participating clinical centers:

Hospital for Sick Children, Toronto, Canada

Children's Hospital Boston, Boston, MA

Columbia College of Physicians and Surgeons, New York, NY

Children's Hospital of Philadelphia, Philadelphia, PA

Duke University Medical Center, Durham, NC

Brody School of Medicine at East Carolina University, Greenville, NC

Wake Forest Baptist Medical Center, Winston Salem, NC

Medical University of South Carolina, Charleston, SC

Primary Children's Medical Center, Salt Lake City, UT

Children's Hospital of Wisconsin, Milwaukee, WI

Cincinnati Children's Hospital Medical Center, Cincinnati, OH

DESIGN NARRATIVE:

This is a prospective, randomized, double-blind, placebo-controlled trial of ACE-I in infants with a single ventricle. After stratification by ventricular anatomy, neonates will be randomly assigned to receive enalapril or placebo and then followed for 14 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 230 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Trial of ACE Inhibition in Infants With Single Ventricle (A Trial Conducted by the Pediatric Heart Network)
• Study Start Date: Aug 1, 2003
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Enalapril Enalapril (angiotensin converting enzyme inhibitor)	Drug: Enalapril; Enalapril to target dose of .4mg/kg/day divided to twice per day (BID)
Placebo Comparator: Placebo Placebo (Ora-Plus and Ora-Sweet)	Drug: Placebo; Participants will receive placebo

Outcome Measures

Primary Outcome Measures

1. Weight-for-age Z-score at 14 Months of Age [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]

   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)

Secondary Outcome Measures

1. Height-for-age Z-score [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)

2. Head Circumference-for-age Z-score [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]

   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)

3. Number of Participants With Ross Heart Failure Class I [Just prior to the pre-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.

4. Number of Participants With Ross Heart Failure Class I [Measured at 14 months of age]

   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.

5. B-Type Natriuretic Peptide [Measured just prior to the Glenn surgery]

   B-Type Natriuretic Peptide (BNP) level.

6. B-type Natriuretic Peptide Level [at the time of the 14 month visit]

   B-type natriuretic peptide (BNP) level.

7. Neurodevelopmental Status (PDI): the Bayley Scales of Infant Development,Psychomotor Development Index Z-score [at 14 months of age]

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

8. Neurodevelopmental Status(MDI): Bayley Scales of Infant Development, Mental Developmental Index Z-score [at 14 months of age]

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

9. Neurodevelopmental Status (FSII) [at 14 months of age]

   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.

10. MacArthur-Bates Inventory -Phrases Understood [at 14 months of age]

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

11. MacArthur-Bates Inventory -Words Understood [at 14 months of age]

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

12. MacArthur-Bates Inventory -Total Gestures [at 14 months of age]

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

13. MacArthur-Bates Inventory -Words Produced [at 14 months of age]

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

14. Ejection Fraction (%) [just before the Glenn surgery]

    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.

15. Ejection Fraction (%) [at 14 months of age]

    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.

16. Ventricular Mass [just before the Glenn surgery]

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

17. Ventricular Mass [At 14 months of age]

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

18. Ventricular Mass Z-score [just before the Glenn surgery]

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

19. Ventricular Mass Z-score [at 14 months of age]

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

20. End-diastolic Volume [just before the Glenn surgery]

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

21. End-diastolic Volume [at 14 months of age]

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

22. End Diastolic Volume Z-score [just before the Glenn surgery]

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

23. End-diastolic Volume Z-score [at 14 months of age]

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

24. Ventricular Mass to Volume Ratio [Measured just before the Glenn surgery]

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

25. Ventricular Mass to Volume Ratio [Measured at 14 months of age]

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

26. Ventricular Filling Pressure [just before the Glenn surgery]

    Ventricular filling pressure measured by catherization

27. Number of Participants With Moderate to Severe AV Valve Regurgitation [just before the pre-Glenn surgery]

    Number of participants with Moderate to severe AV valve regurgitation.

28. Number of Participants With Moderate to Severe AV Valve Regurgitation [at age 14 months]

    Number of participants with moderate to severe AV valve regurgitation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 45 Days
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Less than or equal to 45 days of age

• Age greater than 1 week if born at 35 weeks gestation

• Single ventricle physiology

• Stable systemic and pulmonary blood flow

• Planned Glenn shunt surgery (or variant known as hemi-Fontan)

Exclusion Criteria:

• Birth weight less than or equal to 2.5 kg if gestational age is greater than or equal to 38 weeks

• Birth weight less than the 10th percentile for gestational age if gestational age is 35 to 37 weeks

• Less than 35 weeks gestation

• Anatomic diagnosis of pulmonary atresia with intact ventricular septum

• Less than 3 days after palliative cardiac surgical procedure, if performed

• Aortic oxygen saturation less than 65%

• Current mechanical ventilatory support

• Current intravenous inotropic support

• Creatinine greater than 1.0 mg/dL

• Absolute neutrophil count less than 1,000 cells/mL

• Chromosomal or recognizable phenotypic syndrome of noncardiac congenital abnormalities associated with growth failure (e.g., Trisomy 21, Noonan's syndrome, Turner's syndrome)

• Prior ACE inhibitor use for greater than 7 consecutive days

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Boston	Boston	Massachusetts	United States	02115
2	Columbia College of Physicians and Surgeons	New York	New York	United States	10032
3	Duke University Medical Center	Durham	North Carolina	United States	27710
4	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
5	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
6	Medical University of South Carolina	Charleston	South Carolina	United States	29425
7	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
8	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
9	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8

Sponsors and Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)
• Pediatric Heart Network

Investigators

• Principal Investigator: Page Anderson, MD, Duke University Medical Center, Durham, NC
• Principal Investigator: Daphne Hsu, MD, The Children's Hospital at Montefiore, NYC, NY
• Principal Investigator: Brian McCrindle, MD, The Hospital for Sick Children
• Principal Investigator: LuAnn Minich, MD, Primary Children's Hospital, Salt Lake City, UT
• Principal Investigator: Jane Newburger, MD, Children's Hospital Boston, Boston, MA
• Principal Investigator: J. Philip Saul, MD, Medical University of South Carolina
• Principal Investigator: Lynn Sleeper, Sc.D., New England Research Institute, Watertown, MA
• Principal Investigator: Victoria Vetter, MD, Children's Hospital of Philadelphia, Philadelphia, PA
• Principal Investigator: Woodrow Benson, MD, Cincinnati Children's Medical Center, Cincinnati, OH

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00113087
• Other Study ID Numbers: 177; U01HL068270; U01HL068279; U01HL068281; U01HL068285; U01HL068288; U01HL068290; U01HL068292; U01HL068269
• First Posted: Jun 6, 2005
• Last Update Posted: Sep 28, 2010
• Last Verified: Sep 1, 2009

• Additional relevant MeSH terms: Heart Failure; Univentricular Heart; Heart Defects, Congenital; Congenital Abnormalities; Enalapril

Study Results

Participant Flow

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Period Title: Overall Study
STARTED	115	115
COMPLETED	91	94
NOT COMPLETED	24	21

Baseline Characteristics

Arm/Group Title	Enalapril	Placebo	Total
Arm/Group Description	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 suspension	Total of all reporting groups
Overall Participants	115	115	230
Age (Count of Participants)
<=18 years	115 100%	115 100%	230 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	20.1 (8.9)	20.7 (9.1)	20.4 (9.0)
Sex: Female, Male (Count of Participants)
Female	40 34.8%	28 24.3%	68 29.6%
Male	75 65.2%	87 75.7%	162 70.4%
Race/Ethnicity, Customized (participants) [Number]
White	96 83.5%	89 77.4%	185 80.4%
Black/African-American	12 10.4%	20 17.4%	32 13.9%
Asian	4 3.5%	3 2.6%	7 3%
Other	3 2.6%	3 2.6%	6 2.6%
Region of Enrollment (participants) [Number]
United States	104 90.4%	105 91.3%	209 90.9%
Canada	11 9.6%	10 8.7%	21 9.1%

Outcome Measures

1. Primary Outcome

Title	Weight-for-age Z-score at 14 Months of Age
Description	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)
Time Frame	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

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	91	94
Least Squares Mean (Standard Error) [standard deviation]	-0.62 (0.13)	-0.42 (0.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments

2. Secondary Outcome

Title	Height-for-age Z-score
Description	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)
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	91	94
Least Squares Mean (Standard Error) [standard deviation]	-1.00 (0.13)	-0.86 (0.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.42
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Head Circumference-for-age Z-score
Description	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)
Time Frame	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

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	91	94
Least Squares Mean (Standard Error) [standard deviation]	-0.55 (0.17)	0.09 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.64
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Participants With Ross Heart Failure Class I
Description	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.
Time Frame	Just prior to the pre-Glenn surgery

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	96	102
Number [Participants]	53 46.1%	56 48.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	Fisher Exact
	Comments

5. Secondary Outcome

Title	Number of Participants With Ross Heart Failure Class I
Description	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.
Time Frame	Measured at 14 months of age

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	91	94
Number [participants]	72 62.6%	77 67%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	Fisher Exact
	Comments

6. Secondary Outcome

Title	B-Type Natriuretic Peptide
Description	B-Type Natriuretic Peptide (BNP) level.
Time Frame	Measured just prior to the Glenn surgery

Outcome Measure Data

Analysis Population Description

ITT analysis, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	83	90
Median (Inter-Quartile Range) [pg/ml]	79	84

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.74
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	B-type Natriuretic Peptide Level
Description	B-type natriuretic peptide (BNP) level.
Time Frame	at the time of the 14 month visit

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	69	65
Median (Inter-Quartile Range) [pg/ml]	25	39

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Secondary Outcome

Title	Neurodevelopmental Status (PDI): the Bayley Scales of Infant Development,Psychomotor Development Index Z-score
Description	Neurodevelopmental status (PDI): the Bayley Scales of Infant Development: Psychomotor Development index z-score .
Time Frame	at 14 months of age

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	86	83
Mean (Standard Deviation) [standard deviation]	-1.29 (1.19)	-1.32 (1.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.86
	Comments
	Method	t-test, 2 sided
	Comments

9. Secondary Outcome

Title	Neurodevelopmental Status(MDI): Bayley Scales of Infant Development, Mental Developmental Index Z-score
Description	Neurodevelopmental status(MDI):Bayley Scales of infant development, Mental Developmental Index z-score .
Time Frame	at 14 months of age

Outcome Measure Data

Analysis Population Description

ITT, not imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	87	83
Mean (Standard Deviation) [standard deviation]	-0.26 (0.91)	-0.33 (1.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.60
	Comments
	Method	t-test, 2 sided
	Comments

10. Secondary Outcome

Title	Neurodevelopmental Status (FSII)
Description	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.
Time Frame	at 14 months of age

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	89	89
Median (Inter-Quartile Range) [units on a scale]	96.4	96.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.60
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

11. Secondary Outcome

Title	MacArthur-Bates Inventory -Phrases Understood
Description	MacArthur-Bates Communicative Development inventory( Words and Gestures)-Phrases Understood z-score.
Time Frame	at 14 months of age

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	90	87
Mean (Standard Deviation) [standard deviation]	-0.48 (1.11)	-0.92 (1.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	t-test, 2 sided
	Comments

12. Secondary Outcome

Title	MacArthur-Bates Inventory -Words Understood
Description	MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Understood z-score.
Time Frame	at 14 months of age

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	90	87
Mean (Standard Deviation) [standard deviation]	-0.46 (0.91)	-0.82 (0.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	t-test, 2 sided
	Comments

13. Secondary Outcome

Title	MacArthur-Bates Inventory -Total Gestures
Description	MacArthur-Bates Communicative Development inventory( Words and Gestures)-Total Gestures z-score.
Time Frame	at 14 months of age

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	90	87
Mean (Standard Deviation) [standard deviation]	-0.86 (1.07)	-1.31 (0.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	t-test, 2 sided
	Comments

14. Secondary Outcome

Title	MacArthur-Bates Inventory -Words Produced
Description	MacArthur-Bates Communicative Development inventory( Words and Gestures)-Words Produced z-score.
Time Frame	at 14 months of age

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	90	87
Median (Inter-Quartile Range) [standard deviation]	-0.60	-0.63

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

15. Secondary Outcome

Title	Ejection Fraction (%)
Description	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.
Time Frame	just before the Glenn surgery

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	94	95
Mean (Standard Deviation) [percent (of end diastolic volume)]	57.9 (9.8)	56.6 (10.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	t-test, 2 sided
	Comments

16. Secondary Outcome

Title	Ejection Fraction (%)
Description	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.
Time Frame	at 14 months of age

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	87	91
Mean (Standard Deviation) [percent (of end diastolic volume)]	59.3 (9.6)	57.9 (10.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments
	Method	t-test, 2 sided
	Comments

17. Secondary Outcome

Title	Ventricular Mass
Description	Two-dimensional echocardiography endpoint - Total Ventricular mass (g) per Core Laboratory assessment.
Time Frame	just before the Glenn surgery

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	93	94
Mean (Standard Deviation) [g]	25.5 (9.2)	28.1 (10.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	t-test, 2 sided
	Comments

18. Secondary Outcome

Title	Ventricular Mass
Description	Two-Dimensional Echocardiography endpoint-Total Ventricular mass (g) per Core Laboratory assessment. Range from 15.60 to 70.40
Time Frame	At 14 months of age

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	87	89
Mean (Standard Deviation) [g]	31.4 (10.3)	34.4 (11.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	t-test, 2 sided
	Comments

19. Secondary Outcome

Title	Ventricular Mass Z-score
Description	Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.
Time Frame	just before the Glenn surgery

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	92	92
Mean (Standard Deviation) [standard deviation]	4.0 (2.9)	4.9 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	t-test, 2 sided
	Comments

20. Secondary Outcome

Title	Ventricular Mass Z-score
Description	Two-dimensional echocardiography endpoint -Total Ventricular mass z-score per Core Laboratory assessment.
Time Frame	at 14 months of age

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	87	89
Mean (Standard Deviation) [standard deviation]	2.5 (2.3)	3.1 (2.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	t-test, 2 sided
	Comments

21. Secondary Outcome

Title	End-diastolic Volume
Description	Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.
Time Frame	just before the Glenn surgery

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	94	95
Mean (Standard Deviation) [ml]	24.1 (10.1)	23.2 (9.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.49
	Comments
	Method	t-test, 2 sided
	Comments

22. Secondary Outcome

Title	End-diastolic Volume
Description	Two-Dimensional Echocardiography endpoint - Total End-diastolic volume (ml) per Core Laboratory assessment.
Time Frame	at 14 months of age

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	87	91
Mean (Standard Deviation) [ml]	29.2 (10.0)	30.7 (11.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.35
	Comments
	Method	t-test, 2 sided
	Comments

23. Secondary Outcome

Title	End Diastolic Volume Z-score
Description	Two-dimensional echocardiography endpoint -total End diastolic volume z-score per Core Laboratory assessment.
Time Frame	just before the Glenn surgery

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	93	93
Mean (Standard Deviation) [standard deviation]	2.3 (2.5)	2.1 (2.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.62
	Comments
	Method	t-test, 2 sided
	Comments

24. Secondary Outcome

Title	End-diastolic Volume Z-score
Description	Two-dimensional echocardiography endpoint -total end-diastolic volume z-score per Core Laboratory assessment.
Time Frame	at 14 months of age

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	87	91
Mean (Standard Deviation) [standard deviation]	1.1 (2.1)	1.3 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments
	Method	t-test, 2 sided
	Comments

25. Secondary Outcome

Title	Ventricular Mass to Volume Ratio
Description	Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.
Time Frame	Measured just before the Glenn surgery

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	93	94
Mean (Standard Deviation) [g/ml]	1.15 (0.43)	1.31 (0.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	t-test, 2 sided
	Comments

26. Secondary Outcome

Title	Ventricular Mass to Volume Ratio
Description	Two-Dimensional Echocardiography endpoint -Ventricular Mass to Volume ratio per Core Laboratory assessment.
Time Frame	Measured at 14 months of age

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	87	89
Mean (Standard Deviation) [g/ml]	1.14 (0.38)	1.20 (0.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	t-test, 2 sided
	Comments

27. Secondary Outcome

Title	Ventricular Filling Pressure
Description	Ventricular filling pressure measured by catherization
Time Frame	just before the Glenn surgery

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	58	63
Mean (Standard Deviation) [mmHg]	10.9 (3.6)	11.1 (4.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.81
	Comments
	Method	t-test, 2 sided
	Comments

28. Secondary Outcome

Title	Number of Participants With Moderate to Severe AV Valve Regurgitation
Description	Number of participants with Moderate to severe AV valve regurgitation.
Time Frame	just before the pre-Glenn surgery

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	98	98
Number [participants]	20 17.4%	32 27.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Fisher Exact
	Comments

29. Secondary Outcome

Title	Number of Participants With Moderate to Severe AV Valve Regurgitation
Description	Number of participants with moderate to severe AV valve regurgitation.
Time Frame	at age 14 months

Outcome Measure Data

Analysis Population Description

ITT, no imputation

Arm/Group Title	Enalapril	Placebo
Arm/Group Description	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 suspension
Measure Participants	90	93
Number [participants]	11 9.6%	22 19.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enalapril, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Randomization to 14 months of age
Adverse Event Reporting Description	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.
Arm/Group Title	Enalapril		Placebo
Arm/Group Description	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 suspension
All Cause Mortality
	Enalapril		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Enalapril		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	88/115 (76.5%)		87/115 (75.7%)
Blood and lymphatic system disorders
blood/bone marrow	4/115 (3.5%)	4	2/115 (1.7%)	2
coagulation	1/115 (0.9%)	1	0/115 (0%)	0
hemorrhage/bleeding	1/115 (0.9%)	1	2/115 (1.7%)	2
lymphatics	1/115 (0.9%)	1	0/115 (0%)	0
Cardiac disorders
Cardiac general	29/115 (25.2%)	37	19/115 (16.5%)	24
cardiac arrhythmia	4/115 (3.5%)	5	5/115 (4.3%)	6
death	5/115 (4.3%)	5	4/115 (3.5%)	4
Congenital, familial and genetic disorders
syndromes	0/115 (0%)	0	1/115 (0.9%)	1
Ear and labyrinth disorders
auditory/ear	0/115 (0%)	0	1/115 (0.9%)	1
Gastrointestinal disorders
gastrointestinal	20/115 (17.4%)	27	18/115 (15.7%)	26
General disorders
constitutional symptoms	2/115 (1.7%)	2	3/115 (2.6%)	3
Infections and infestations
Infection	36/115 (31.3%)	55	35/115 (30.4%)	44
Metabolism and nutrition disorders
growth and development	1/115 (0.9%)	1	5/115 (4.3%)	5
metabolic/laboratory	3/115 (2.6%)	3	0/115 (0%)	0
Musculoskeletal and connective tissue disorders
musculoskeletal/soft issue	1/115 (0.9%)	1	2/115 (1.7%)	3
Nervous system disorders
Neurology	4/115 (3.5%)	4	6/115 (5.2%)	6
Renal and urinary disorders
renal/genitourinary	1/115 (0.9%)	1	1/115 (0.9%)	2
Respiratory, thoracic and mediastinal disorders
Pulmonary/Upper Respiratory	31/115 (27%)	41	35/115 (30.4%)	49
Skin and subcutaneous tissue disorders
dermatology/skin	1/115 (0.9%)	1	1/115 (0.9%)	1
Surgical and medical procedures
surgery/intra-operative injury	0/115 (0%)	0	3/115 (2.6%)	3
Vascular disorders
Vascular	22/115 (19.1%)	30	21/115 (18.3%)	26
Other (Not Including Serious) Adverse Events
	Enalapril		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/115 (67%)		70/115 (60.9%)
Blood and lymphatic system disorders
blood/bone marrow	2/115 (1.7%)	2	3/115 (2.6%)	3
coagulation	1/115 (0.9%)	1	1/115 (0.9%)	1
hemorrhage/bleeding	1/115 (0.9%)	1	1/115 (0.9%)	1
Cardiac disorders
Cardiac General	18/115 (15.7%)	23	12/115 (10.4%)	15
cardiac arrhythmia	10/115 (8.7%)	12	5/115 (4.3%)	6
Ear and labyrinth disorders
auditory/ear	0/115 (0%)	0	1/115 (0.9%)	1
Endocrine disorders
endocrine	2/115 (1.7%)	2	0/115 (0%)	0
Gastrointestinal disorders
gastrointestinal	19/115 (16.5%)	27	16/115 (13.9%)	24
General disorders
constitutional symptoms	8/115 (7%)	8	3/115 (2.6%)	4
Hepatobiliary disorders
hepatobillary	2/115 (1.7%)	2	0/115 (0%)	0
Immune system disorders
allergy/immunology	1/115 (0.9%)	1	2/115 (1.7%)	3
Infections and infestations
infection	38/115 (33%)	66	33/115 (28.7%)	64
Metabolism and nutrition disorders
metabolic/laboratory	7/115 (6.1%)	8	9/115 (7.8%)	9
growth and development	1/115 (0.9%)	1	0/115 (0%)	0
Musculoskeletal and connective tissue disorders
musculoskeletal/soft tissue	1/115 (0.9%)	2	1/115 (0.9%)	1
Nervous system disorders
Neurology	5/115 (4.3%)	6	6/115 (5.2%)	9
Renal and urinary disorders
renal/genitourinary	1/115 (0.9%)	1	1/115 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary/upper respiratory	20/115 (17.4%)	28	22/115 (19.1%)	25
Skin and subcutaneous tissue disorders
dermatology/skin	3/115 (2.6%)	3	8/115 (7%)	9
Surgical and medical procedures
surgery/intra-operative injury	2/115 (1.7%)	2	0/115 (0%)	0
Vascular disorders
Vascular	7/115 (6.1%)	7	5/115 (4.3%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT 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.