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Clinical Trial Results:
An Open Label Study of the Safety, Efficacy and Pharmacokinetics of Glycerol Phenylbutyrate (GPB; RAVICTI®) in Pediatric Subjects under Two Years of Age with Urea Cycle Disorders (UCDs)

Summary
EudraCT number	2016-003460-38
Trial protocol	Outside EU/EEA
Global end of trial date	17 Jul 2017

Results information
Results version number	v1(current)
This version publication date	24 Feb 2018
First version publication date	24 Feb 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

HPN-100-009

ISRCTN number

US NCT number

NCT02246218

WHO universal trial number (UTN)

Sponsor organisation name

Horizon Therapeutics, LLC

Sponsor organisation address

150 South Saunders Rd , Lake Forest, IL, United States, 60045

Public contact

Brenda Ranchino, Horizon Therapeutics, LLC, clinicaltrials@horizonpharma.com

Scientific contact

Tom Vescio, MD, Horizon Therapeutics, LLC, clinicaltrials@horizonpharma.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000297-PIP02-12

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

17 Jul 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 Jul 2017

Was the trial ended prematurely?

Main objective of the trial

This is an open-label study consisting of a transition period to RAVICTI, followed by a safety extension period for at least 6 months and up to 24 months of treatment with RAVICTI, depending on age at enrollment. It is designed to capture information important for evaluating safety, pharmacokinetics and efficacy in young children. Subjects who are followed by or referred to the Investigator for management of their UCD. Subjects eligible for this study will include patients ranging from newborn to < 2 years of age with either a diagnosed or clinically suspected UCD.

Protection of trial subjects

The Investigator ensured that each parent/legal guardian was given full and adequate oral and written information about the nature, purpose, and possible risk and benefit of the study. Parents/legal guardians were notified that the subjects were free to discontinue from the study at any time. Parents/legal guardians were given the opportunity to ask questions and allowed time to consider the information provided. Subjects or their caregiver/guardians were informed that medical records will be kept private and no information will be published without their permission.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 Dec 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

United States: 25

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Number of subjects started

Number of subjects completed

Reason: Number of subjects

Enrolled, not dosed: 1

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

RAVICTI: Age 2 Months to <2 Years

Arm description

Subjects age 2 months to < 2 years received RAVICTI Oral Liquid administered just prior to breastfeeding or intake of formula or food. The recommended dosing regimen is 3-6 times per day depending on feeding schedule and at the discretion of the Investigator.

Arm type

Experimental

Investigational medicinal product name

RAVICTI

Investigational medicinal product code

HPN-100

Other name

glycerol phenylbutyrate, GPB

Pharmaceutical forms

Oral liquid

Routes of administration

Oral use

Dosage and administration details

The starting dose of RAVICTI is based on UCD status (newly diagnosed, or already stable on sodium phenylbutyrate [NaPBA] and/or sodium benzoate [NaBz]) and whether a hyperammonemic crisis is present. Subsequently, the dose may be adjusted based on clinical and/or ammonia results, according to an algorithm provided in the protocol.

RAVICTI: Age 0 to <2 Months

Arm description

Subjects age 0 to < 2 months received RAVICTI Oral Liquid administered just prior to breastfeeding or intake of formula or food. The recommended dosing regimen is 3-6 times per day depending on feeding schedule and at the discretion of the Investigator.

Arm type

Experimental

Investigational medicinal product name

RAVICTI

Investigational medicinal product code

HPN-100

Other name

glycerol phenylbutyrate, GPB

Pharmaceutical forms

Oral liquid

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1 ^[1]	RAVICTI: Age 2 Months to <2 Years	RAVICTI: Age 0 to <2 Months
Started	10	16
Completed	6	10
Not completed	4	6
Stopping Rule: Liver Transplant	2	4
Adverse event	1	1
Lost to follow-up	1	-
Withdrawal by parent/guardian	-	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: One subject enrolled in the study and prior to taking study drug the parents decided not to be dosed.

Baseline characteristics

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Reporting group title

RAVICTI: Age 2 Months to <2 Years

Reporting group description

Reporting group title

RAVICTI: Age 0 to <2 Months

Reporting group description

Reporting group values	RAVICTI: Age 2 Months to <2 Years	RAVICTI: Age 0 to <2 Months	Total
Number of subjects	10	16	26
Age categorical
Units: Subjects
Age Continuous
Units: months
arithmetic mean (standard deviation)	9.87 ± 5.529	0.83 ± 0.697	-
Gender categorical
Units: Subjects
Female	5	7	12
Male	5	9	14

End points

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Reporting group title

RAVICTI: Age 2 Months to <2 Years

Reporting group description

Reporting group title

RAVICTI: Age 0 to <2 Months

Reporting group description

Primary: Percentage of Subjects With Successful Transition to RAVICTI With Controlled Ammonia (i.e. No Clinical Symptoms and Ammonia < 100 µmol/L): Cohort of 2 Months to <2 Years Subjects

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End point title

Percentage of Subjects With Successful Transition to RAVICTI With Controlled Ammonia (i.e. No Clinical Symptoms and Ammonia < 100 µmol/L): Cohort of 2 Months to <2 Years Subjects ^[1] ^[2]

End point description

The percentage of subjects with successful transition is based on Investigator response to the question, "Has transition to 100% RAVICTI been successful with controlled ammonia?" For subjects 2 months of age and older, after a minimum of 24 hours of ammonia monitoring following the first full dose of RAVICTI alone, the subject was effectively transitioned when following conditions were met: no signs and symptoms of hyperammonemia; ammonia level less than 100 μmol/L (without normalization of ammonia, ie, without conversion of values from local laboratories with varying normal ranges to standardized values); and eligible for discharge per Investigator judgment. Safety Population: all enrolled subjects who received any amount of study medication.

End point type

Primary

End point timeframe

Up to Day 4

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics are presented, per protocol.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: percentage of subjects
number (not applicable)	100

No statistical analyses for this end point

Primary: Percentage of Subjects With Successful Transition to RAVICTI With Controlled Ammonia (i.e. No Clinical Symptoms and Ammonia < 100 μmol/L): Cohort of 0 Months to <2 Months Subjects

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End point title

Percentage of Subjects With Successful Transition to RAVICTI With Controlled Ammonia (i.e. No Clinical Symptoms and Ammonia < 100 μmol/L): Cohort of 0 Months to <2 Months Subjects ^[3] ^[4]

End point description

The percentage of subjects with successful transition is based on Investigator response to the question, "Has transition to 100% RAVICTI been successful with controlled ammonia?" For subjects 0 to <2 months of age, after a minimum of 24 hours of ammonia monitoring following the first full dose of RAVICTI alone, the subject was effectively transitioned when following conditions were met: no signs and symptoms of hyperammonemia; ammonia level less than 100 μmol/L (without normalization of ammonia, ie, without conversion of values from local laboratories with varying normal ranges to standardized values); and eligible for discharge per Investigator judgment. Safety Population: all enrolled subjects who received any amount of study medication.

End point type

Primary

End point timeframe

Up to Day 4

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics are presented, per protocol.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16
Units: percentage of subjects
number (not applicable)	100

No statistical analyses for this end point

Secondary: Rate of Hyperammonemic Crises (HACs): Cohort of 2 Months to <2 Years Subjects

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End point title

Rate of Hyperammonemic Crises (HACs): Cohort of 2 Months to <2 Years Subjects ^[5]

End point description

HAC is defined as having signs and symptoms consistent with hyperammonemia (such as but not limited to frequent vomiting, nausea, headache, lethargy, irritability, combativeness, and/or somnolence) associated with high blood ammonia and requiring medical intervention. Rate of HACs per 6 months during the safety extension was calculated as sum of (number of HAC) / sum of (days during first 6 months starting on Day 8 or number days on RAVICTI, whichever is less) across all subjects in the corresponding group. Safety Population: all enrolled subjects who received any amount of study medication.

End point type

Secondary

End point timeframe

Day 8 through up to Month 6

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	9 ^[6]
Units: rate ratio
number (not applicable)	0.005

Notes
[6] - subjects with an assessment

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Deaths, and Discontinuations Due to TEAEs: Cohort of 2 Months to <2 Years Subjects

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Deaths, and Discontinuations Due to TEAEs: Cohort of 2 Months to <2 Years Subjects ^[7]

End point description

An adverse event (AE) is any untoward medical occurrence, whether or not the event is considered related to the study drug. A serious AE is any AE that: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. TEAEs are defined as AEs with an onset date on or after the first dose of study medication until study discontinuation. The Investigator assessed the causal relationship of each TEAE to the study drug as not related, possibly related, or probably related. Safety Population: all enrolled subjects who received any amount of study medication.

End point type

Secondary

End point timeframe

From the first dose of study treatment through 30 days after the final dose (mean [SD] duration of treatment was 9.13 [6.838] months).

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: subjects
≥ 1 TEAE	10
≥ 1 Related TEAE	4
≥ 1 Serious TEAE	6
≥ 1 Serious Related TEAE	0
Fatal Outcome TEAE	1
≥ 1 TEAE Leading to Study Discontinuation	1

No statistical analyses for this end point

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Subjects

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End point title

Amino Acid Assessment: Baseline and Change from Baseline in Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Subjects ^[8]

End point description

Safety Population: all enrolled subjects who received any amount of study medication and had an assessment.

End point type

Secondary

End point timeframe

Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10 ^[9]
Units: μmol/L
arithmetic mean (standard deviation)
Baseline; n=7	122.43 ± 118.620
Day 7 change from Baseline; n=6	-54.50 ± 92.626
Month 2 change from Baseline; n=5	7.80 ± 25.646
Month 3 change from Baseline; n=3	-16.33 ± 39.209
Month 4 change from Baseline; n=4	-13.00 ± 39.590
Month 5 change from Baseline; n=4	0.25 ± 13.426
Month 6 change from Baseline; n=5	-2.20 ± 34.463
Month 9 change from Baseline; n=3	30.80 ± 17.092
Month 12 change from Baseline; n=3	22.20 ± 23.506
Month 15 change from Baseline; n=1	39.00 ± 00000
Month 24 change from Baseline; n=2	48.00 ± 53.740

Notes
[9] - n=subjects with an assessment at given time point; 00000=not applicable (1 subject assessed).

No statistical analyses for this end point

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Glutamine Up to Month 24: Cohort of 2 Months to <2 Years Subjects

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End point title

Amino Acid Assessment: Baseline and Change from Baseline in Glutamine Up to Month 24: Cohort of 2 Months to <2 Years Subjects ^[10]

End point description

Safety Population: all enrolled subjects who received any amount of study medication and had an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10 ^[11]
Units: μmol/L
arithmetic mean (standard deviation)
Baseline; n=7	750.43 ± 309.000
Day 7 change from Baseline; n=6	-184.33 ± 168.657
Month 2 change from Baseline; n=5	-174.60 ± 318.249
Month 3 change from Baseline; n=3	-374.00 ± 425.903
Month 4 change from Baseline; n=4	-252.75 ± 323.852
Month 5 change from Baseline; n=4	-370.25 ± 377.222
Month 6 change from Baseline; n=5	-113.20 ± 519.710
Month 9 change from Baseline; n=3	-446.53 ± 360.457
Month 12 change from Baseline; n=3	-450.50 ± 386.699
Month 15 change from Baseline; n=1	-149.00 ± 00000
Month 24 change from Baseline; n=2	195.00 ± 554.372

Notes
[11] - n=subjects with an assessment at given time point; 00000=not applicable (1 subject assessed).

No statistical analyses for this end point

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Sum of Glutamine and Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Subjects

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End point title

Amino Acid Assessment: Baseline and Change from Baseline in Sum of Glutamine and Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Subjects ^[12]

End point description

Safety Population: all enrolled subjects who received any amount of study medication and had an assessment.

End point type

Secondary

End point timeframe

Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10 ^[13]
Units: μmol/L
arithmetic mean (standard deviation)
Baseline; n=7	872.86 ± 381.005
Day 7 change from Baseline; n=6	-238.83 ± 203.567
Month 2 change from Baseline; n=5	-166.80 ± 332.421
Month 3 change from Baseline; n=3	-390.33 ± 462.292
Month 4 change from Baseline; n=4	-265.75 ± 339.015
Month 5 change from Baseline; n=4	-370.00 ± 379.884
Month 6 change from Baseline; n=5	-115.40 ± 546.796
Month 9 change from Baseline; n=3	-415.73 ± 365.419
Month 12 change from Baseline; n=3	-428.30 ± 404.351
Month 15 change from Baseline; n=1	-110.00 ± 00000
Month 24 change from Baseline; n=2	243.00 ± 608.112

Notes
[13] - n=subjects with an assessment at given time point; 00000=not applicable (1 subject assessed).

No statistical analyses for this end point

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Isoleucine Up to Month 24: Cohort of 2 Months to <2 Years Subjects

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End point title

Amino Acid Assessment: Baseline and Change from Baseline in Isoleucine Up to Month 24: Cohort of 2 Months to <2 Years Subjects ^[14]

End point description

Safety Population: all enrolled subjects who received any amount of study medication and had an assessment.

End point type

Secondary

End point timeframe

Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10 ^[15]
Units: μmol/L
arithmetic mean (standard deviation)
Baseline; n=7	54.86 ± 19.497
Day 7 change from Baseline; n=6	2.67 ± 19.159
Month 2 change from Baseline; n=5	4.20 ± 45.861
Month 3 change from Baseline; n=3	-25.67 ± 16.743
Month 4 change from Baseline; n=4	-20.25 ± 20.353
Month 5 change from Baseline; n=4	-20.00 ± 36.341
Month 6 change from Baseline; n=5	-16.40 ± 12.137
Month 9 change from Baseline; n=3	-6.73 ± 13.342
Month 12 change from Baseline; n=3	-13.33 ± 15.885
Month 15 change from Baseline; n=1	-18.00 ± 00000
Month 24 change from Baseline; n=2	1.50 ± 10.607

Notes
[15] - n=subjects with an assessment at given time point; 00000=not applicable (1 subject assessed).

No statistical analyses for this end point

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Leucine Up to Month 24: Cohort of 2 Months to <2 Years Subjects

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End point title

Amino Acid Assessment: Baseline and Change from Baseline in Leucine Up to Month 24: Cohort of 2 Months to <2 Years Subjects ^[16]

End point description

Safety Population: all enrolled subjects who received any amount of study medication and had an assessment.

End point type

Secondary

End point timeframe

Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10 ^[17]
Units: μmol/L
arithmetic mean (standard deviation)
Baseline; n=7	90.86 ± 29.249
Day 7 change from Baseline; n=6	-0.83 ± 32.762
Month 2 change from Baseline; n=5	9.80 ± 65.975
Month 3 change from Baseline; n=3	-33.00 ± 25.239
Month 4 change from Baseline; n=4	-31.25 ± 24.771
Month 5 change from Baseline; n=4	-39.50 ± 61.136
Month 6 change from Baseline; n=5	-25.40 ± 13.594
Month 9 change from Baseline; n=3	-19.13 ± 39.322
Month 12 change from Baseline; n=3	-34.37 ± 23.283
Month 15 change from Baseline; n=1	-40.00 ± 00000
Month 24 change from Baseline; n=2	-1.50 ± 31.820

Notes
[17] - n=subjects with an assessment at given time point; 00000=not applicable (1 subject assessed).

No statistical analyses for this end point

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Valine Up to Month 24: Cohort of 2 Months to <2 Years Subjects

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End point title

Amino Acid Assessment: Baseline and Change from Baseline in Valine Up to Month 24: Cohort of 2 Months to <2 Years Subjects ^[18]

End point description

Safety Population: all enrolled subjects who received any amount of study medication and had an assessment.

End point type

Secondary

End point timeframe

Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 24

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10 ^[19]
Units: μmol/L
arithmetic mean (standard deviation)
Baseline; n=7	171.43 ± 42.887
Day 7 change from Baseline; n=6	4.00 ± 24.133
Month 2 change from Baseline; n=5	40.60 ± 90.057
Month 3 change from Baseline; n=3	-27.33 ± 37.018
Month 4 change from Baseline; n=4	-31.50 ± 29.760
Month 5 change from Baseline; n=4	-56.00 ± 75.939
Month 6 change from Baseline; n=5	-21.60 ± 18.202
Month 9 change from Baseline; n=3	-11.90 ± 71.753
Month 12 change from Baseline; n=3	-48.87 ± 51.644
Month 15 change from Baseline; n=1	-46.00 ± 0000
Month 24 change from Baseline; n=2	5.00 ± 55.154

Notes
[19] - n=subjects with an assessment at given time point; 00000=not applicable (1 subject assessed).

No statistical analyses for this end point

Secondary: Assessment of Growth and Development: Baseline and Change from Baseline in Body Mass Index (BMI) Z-Score Up to Month 24: Cohort of 2 Months to <2 Years Subjects

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End point title

Assessment of Growth and Development: Baseline and Change from Baseline in Body Mass Index (BMI) Z-Score Up to Month 24: Cohort of 2 Months to <2 Years Subjects ^[20]

End point description

To assess any effect of study drug treatment on growth, Z-scores were calculated to express the deviation from a reference population for BMI. The Z-scores are based on the World Health Organization's Child Growth Standards charts. Negative Z-scores indicate lower than typical for age and gender while positive scores indicate higher than typical for age and gender. Safety Population: all enrolled subjects who received any amount of study medication and had an assessment.

End point type

Secondary

End point timeframe

Baseline, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10 ^[21]
Units: z-score
arithmetic mean (standard deviation)
Baseline; n=10	0.8107 ± 2.17017
Month 1 change from Baseline; n=9	-0.2385 ± 0.77830
Month 2 change from Baseline; n=7	-0.0249 ± 0.74861
Month 3 change from Baseline; n=7	0.1815 ± 0.86056
Month 4 change from Baseline; n=7	0.4434 ± 0.94854
Month 5 change from Baseline; n=6	0.1484 ± 0.76293
Month 6 change from Baseline; n=7	0.2497 ± 0.80923
Month 9 change from Baseline; n=5	0.6407 ± 0.98695
Month 12 change from Baseline; n=4	0.4164 ± 0.80674
Month 15 change from Baseline; n=2	-0.2997 ± 0.16959
Month 18 change from Baseline; n=1	-0.2038 ± 00000
Month 24 change from Baseline; n=4	0.5581 ± 1.23993

Notes
[21] - n=subjects with an assessment at given time point; 00000=not applicable (1 subject assessed).

No statistical analyses for this end point

Secondary: Assessment of Growth and Development: Baseline and Change from Baseline in Body Surface Area (BSA) Z-Score Up to Month 24: Cohort of 2 Months to <2 Years Subjects

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End point title

Assessment of Growth and Development: Baseline and Change from Baseline in Body Surface Area (BSA) Z-Score Up to Month 24: Cohort of 2 Months to <2 Years Subjects ^[22]

End point description

To assess any effect of study drug treatment on growth, Z-scores were calculated to express the deviation from a reference population for BSA. The Z-scores are based on weight-for-length charts. Negative Z-scores indicate lower than typical for age and gender while positive scores indicate higher than typical for age and gender. Safety Population: all enrolled subjects who received any amount of study medication and had an assessment.

End point type

Secondary

End point timeframe

Baseline, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10 ^[23]
Units: z-score
arithmetic mean (standard deviation)
Baseline; n=10	0.7143 ± 2.14922
Month 1 change from Baseline; n=9	-0.2105 ± 0.74135
Month 2 change from Baseline; n=7	-0.0704 ± 0.70393
Month 3 change from Baseline; n=7	0.1065 ± 0.70165
Month 4 change from Baseline; n=7	0.3365 ± 0.77672
Month 5 change from Baseline; n=6	0.1043 ± 0.56747
Month 6 change from Baseline; n=7	0.1842 ± 0.62205
Month 9 change from Baseline; n=5	0.4875 ± 0.86137
Month 12 change from Baseline; n=4	0.2944 ± 0.75133
Month 15 change from Baseline; n=2	-0.3661 ± 0.00932
Month 18 change from Baseline; n=1	-0.2214 ± 00000
Month 24 change from Baseline; n=4	0.4310 ± 1.13140

Notes
[23] - n=subjects with an assessment at given time point; 00000=not applicable (1 subject assessed).

No statistical analyses for this end point

Secondary: Plasma Phenylbutyrate/Phenylbutyric Acid (PBA) Maximum Plasma Concentration (Cmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

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End point title

Plasma Phenylbutyrate/Phenylbutyric Acid (PBA) Maximum Plasma Concentration (Cmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[24]

End point description

Pharmacokinetic (PK) Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: μg/mL
arithmetic mean (standard deviation)	42.44 ± 36.715

No statistical analyses for this end point

Secondary: Plasma PBA Minimum Plasma Concentration (Cmin) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Plasma PBA Minimum Plasma Concentration (Cmin) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[25]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: μg/mL
arithmetic mean (standard deviation)	1.697 ± 2.254

No statistical analyses for this end point

Secondary: Plasma PBA Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC[0-last]) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Plasma PBA Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC[0-last]) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[26]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: μg*hr/mL
arithmetic mean (standard deviation)	280.936 ± 293.553

No statistical analyses for this end point

Secondary: Plasma PBA Time to Cmax (Tmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Plasma PBA Time to Cmax (Tmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[27]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: hours
arithmetic mean (standard deviation)	8.383 ± 4.564

No statistical analyses for this end point

Secondary: Plasma Phenylacetate/Phenylacetic Acid (PAA) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Plasma Phenylacetate/Phenylacetic Acid (PAA) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[28]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: μg/mL
arithmetic mean (standard deviation)	36.52 ± 31.784

No statistical analyses for this end point

Secondary: Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[29]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: μg/mL
arithmetic mean (standard deviation)	4.197 ± 6.434

No statistical analyses for this end point

Secondary: Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[30]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: μg*hr/mL
arithmetic mean (standard deviation)	246.126 ± 238.547

No statistical analyses for this end point

Secondary: Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[31]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: hours
arithmetic mean (standard deviation)	7.422 ± 7.351

No statistical analyses for this end point

Secondary: Plasma phenylacetylglutamine (PAGN) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Plasma phenylacetylglutamine (PAGN) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[32]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: μg/mL
arithmetic mean (standard deviation)	62.45 ± 27.281

No statistical analyses for this end point

Secondary: Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[33]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: μg/mL
arithmetic mean (standard deviation)	20.62 ± 14.529

No statistical analyses for this end point

Secondary: Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[34]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: μg*hr/mL
arithmetic mean (standard deviation)	583.835 ± 285.241

No statistical analyses for this end point

Secondary: Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[35]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: hours
arithmetic mean (standard deviation)	6.573 ± 7.181

No statistical analyses for this end point

Secondary: Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[36]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 0.5 and 1.5 hours, 1.5 and 2.5 hours, 4 and 6 hours, 7.5 and 8.5 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10 ^[37]
Units: μg/mL
arithmetic mean (standard deviation)
Hour 0; n=6	3273 ± 1993
0.5 to 1.5 hours; n=6	4140 ± 4399
1.5 to 2.5 hours; n=9	3145 ± 5045
4 to 6 hours; n=9	5202 ± 4547
7.5 to 8.5 hours; n=8	3950 ± 3068
12 to 24 hours; n=9	7561 ± 6956

Notes
[37] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Subjects ^[38]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Day 7, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, End of Trial

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: μg/mL
arithmetic mean (standard deviation)
Day 7; n=8	8859 ± 10500
Month 1; n=8	6274 ± 4802
Month 2; n=5	7386 ± 6419
Month 3; n=6	11456 ± 14471
Month 4; n=3	21416 ± 33695
Month 5; n=5	6129 ± 8024
Month 6; n=3	5347 ± 3153
Month 9; n=3	9357 ± 7286
Month 12; n=3	2580 ± 286
Month 15; n=1	6400 ± 00000
Month 18; n=1	5250 ± 00000
End of trial; n=3	25333 ± 21324

No statistical analyses for this end point

Secondary: Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[39]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: μg/mL
arithmetic mean (standard deviation)
Hour 0; n=3	18.78 ± 27.33
0.5 to 1.5 hours; n=4	6.50 ± 3.39
1.5 to 2.5 hours; n=4	7.29 ± 4.10
4 to 6 hours; n=6	2.60 ± 2.18
7.5 to 8.5 hours; n=4	4.48 ± 4.38
12 to 24 hours; n=4	4.31 ± 2.33

No statistical analyses for this end point

Secondary: Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Subjects

Top of page

End point title

Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Subjects ^[40]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Day 7, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 15, Month 18, End of Trial

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 2 Months to <2 Years
Number of subjects analysed	10
Units: μg/mL
arithmetic mean (standard deviation)
Day 7; n=2	5.82 ± 2.21
Month 1; n=6	4.44 ± 4.61
Month 2; n=3	3.69 ± 1.82
Month 3; n=2	4.65 ± 0.49
Month 4; n=1	7.14 ± 00000
Month 5; n=2	3.27 ± 1.96
Month 6; n=1	1.59 ± 00000
Month 9; n=3	4.10 ± 1.65
Month 15; n=1	2.04 ± 00000
Month 18; n=1	1.64 ± 00000
End of trial; n=3	7.0 ± 5.16

No statistical analyses for this end point

Secondary: Rate of HACs: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Rate of HACs: Cohort of 0 Months to <2 Months Subjects ^[41]

End point description

End point type

Secondary

End point timeframe

Day 8 through up to Month 6

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16
Units: rate ratio
number (not applicable)	0.003

No statistical analyses for this end point

Secondary: Number of Subjects With TEAEs, Serious TEAEs, Deaths, and Discontinuations Due to TEAEs: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Number of Subjects With TEAEs, Serious TEAEs, Deaths, and Discontinuations Due to TEAEs: Cohort of 0 Months to <2 Months Subjects ^[42]

End point description

An AE is any untoward medical occurrence, whether or not the event is considered related to the study drug. A serious AE is any AE that: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. TEAEs are defined as AEs with an onset date on or after the first dose of study medication until study discontinuation. The Investigator assessed the causal relationship of each TEAE to the study drug as not related, possibly related, or probably related. Safety Population: all enrolled subjects who received any amount of study medication.

End point type

Secondary

End point timeframe

From the first dose of study treatment through 30 days after the final dose (mean [SD] duration of treatment was 10.67 [6.142] months).

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16
Units: subjects
≥ 1 TEAE	16
≥ 1 Related TEAE	10
≥ 1 Serious TEAE	11
≥ 1 Serious Related TEAE	0
Fatal Outcome TEAE	0
≥ 1 TEAE Leading to Study Discontinuation	1

No statistical analyses for this end point

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Amino Acid Assessment: Baseline and Change from Baseline in Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Subjects ^[43]

End point description

Safety Population: all enrolled subjects who received any amount of study medication and had an assessment.

End point type

Secondary

End point timeframe

Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16 ^[44]
Units: μmol/L
arithmetic mean (standard deviation)
Baseline; n=15	84.97 ± 52.086
Day 7 change from Baseline; n=14	26.81 ± 76.417
Month 2 change from Baseline; n=14	25.16 ± 64.474
Month 3 change from Baseline; n=14	50.05 ± 73.988
Month 4 change from Baseline; n=11	18.77 ± 67.561
Month 5 change from Baseline; n=10	57.43 ± 98.550
Month 6 change from Baseline; n=8	43.65 ± 140.985
Month 9 change from Baseline; n=8	33.41 ± 150.273
Month 12 change from Baseline; n=4	8.75 ± 97.329
Month 15 change from Baseline; n=4	25.75 ± 62.660
Month 18 change from Baseline; n=2	2.50 ± 21.920
Month 24 change from Baseline; n=8	16.10 ± 95.461

Notes
[44] - n=subjects with an assessment at given time point.

No statistical analyses for this end point

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Glutamine Up to Month 24: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Amino Acid Assessment: Baseline and Change from Baseline in Glutamine Up to Month 24: Cohort of 0 Months to <2 Months Subjects ^[45]

End point description

Safety Population: all enrolled subjects who received any amount of study medication and had an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16 ^[46]
Units: μmol/L
arithmetic mean (standard deviation)
Baseline; n=15	508.83 ± 337.175
Day 7 change from Baseline; n=14	21.04 ± 260.500
Month 2 change from Baseline; n=14	-27.62 ± 379.796
Month 3 change from Baseline; n=14	-15.09 ± 352.471
Month 4 change from Baseline; n=11	-113.98 ± 230.855
Month 5 change from Baseline; n=10	-99.82 ± 305.674
Month 6 change from Baseline; n=8	-138.16 ± 349.269
Month 9 change from Baseline; n=8	-56.08 ± 269.288
Month 12 change from Baseline; n=4	-181.50 ± 118.604
Month 15 change from Baseline; n=4	-103.75 ± 328.583
Month 18 change from Baseline; n=2	-184.00 ± 80.610
Month 24 change from Baseline; n=8	-219.93 ± 279.815

Notes
[46] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Sum of Glutamine and Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Amino Acid Assessment: Baseline and Change from Baseline in Sum of Glutamine and Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Subjects ^[47]

End point description

Safety Population: all enrolled subjects who received any amount of study medication and had an assessment.

End point type

Secondary

End point timeframe

Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16 ^[48]
Units: μmol/L
arithmetic mean (standard deviation)
Baseline; n=15	593.80 ± 333.657
Day 7 change from Baseline; n=14	47.85 ± 230.343
Month 2 change from Baseline; n=14	-2.46 ± 402.919
Month 3 change from Baseline; n=14	34.96 ± 371.522
Month 4 change from Baseline; n=11	-95.21 ± 238.136
Month 5 change from Baseline; n=10	-42.39 ± 288.782
Month 6 change from Baseline; n=8	-94.51 ± 297.378
Month 9 change from Baseline; n=8	-22.66 ± 318.034
Month 12 change from Baseline; n=4	-172.75 ± 210.202
Month 15 change from Baseline; n=4	-78.00 ± 297.410
Month 18 change from Baseline; n=2	-181.50 ± 102.530
Month 24 change from Baseline; n=8	-203.83 ± 255.810

Notes
[48] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Isoleucine Up to Month 24: Cohort of 0 Months to <2 Month Subjects

Top of page

End point title

Amino Acid Assessment: Baseline and Change from Baseline in Isoleucine Up to Month 24: Cohort of 0 Months to <2 Month Subjects ^[49]

End point description

Safety Population: all enrolled subjects who received any amount of study medication and had an assessment.

End point type

Secondary

End point timeframe

Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16 ^[50]
Units: μmol/L
arithmetic mean (standard deviation)
Baseline; n=15	142.68 ± 222.694
Day 7 change from Baseline; n=14	-49.09 ± 198.730
Month 2 change from Baseline; n=14	-1.62 ± 233.754
Month 3 change from Baseline; n=14	-20.46 ± 216.885
Month 4 change from Baseline; n=11	-67.32 ± 173.564
Month 5 change from Baseline; n=10	-75.45 ± 221.845
Month 6 change from Baseline; n=8	-35.94 ± 78.367
Month 9 change from Baseline; n=8	-73.09 ± 245.051
Month 12 change from Baseline; n=4	-178.50 ± 335.538
Month 15 change from Baseline; n=4	-139.50 ± 359.287
Month 18 change from Baseline; n=2	1.00 ± 45.255
Month 24 change from Baseline; n=8	-55.31 ± 217.209

Notes
[50] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Leucine Up to Month 24: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Amino Acid Assessment: Baseline and Change from Baseline in Leucine Up to Month 24: Cohort of 0 Months to <2 Months Subjects ^[51]

End point description

Safety Population: all enrolled subjects who received any amount of study medication and had an assessment.

End point type

Secondary

End point timeframe

Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16 ^[52]
Units: μmol/L
arithmetic mean (standard deviation)
Baseline; n=15	133.67 ± 253.829
Day 7 change from Baseline; n=14	-81.91 ± 273.127
Month 2 change from Baseline; n=14	-60.80 ± 278.083
Month 3 change from Baseline; n=14	-51.66 ± 269.558
Month 4 change from Baseline; n=11	-82.82 ± 224.269
Month 5 change from Baseline; n=10	-118.55 ± 311.125
Month 6 change from Baseline; n=8	-11.85 ± 40.693
Month 9 change from Baseline; n=8	-115.09 ± 338.186
Month 12 change from Baseline; n=4	-249.50 ± 483.776
Month 15 change from Baseline; n=4	-195.75 ± 496.313
Month 18 change from Baseline; n=2	6.00 ± 62.225
Month 24 change from Baseline; n=8	-82.54 ± 228.107

Notes
[52] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Valine Up to Month 24: Cohort of 0 Months to <2 Months Subjects

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End point title

Amino Acid Assessment: Baseline and Change from Baseline in Valine Up to Month 24: Cohort of 0 Months to <2 Months Subjects ^[53]

End point description

Safety Population: all enrolled subjects who received any amount of study medication and had an assessment.

End point type

Secondary

End point timeframe

Baseline, Day 7, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16 ^[54]
Units: μmol/L
arithmetic mean (standard deviation)
Baseline; n=15	181.49 ± 257.948
Day 7 change from Baseline; n=14	-63.96 ± 290.312
Month 2 change from Baseline; n=14	-39.04 ± 297.634
Month 3 change from Baseline; n=14	-23.86 ± 290.128
Month 4 change from Baseline; n=11	-74.41 ± 233.538
Month 5 change from Baseline; n=10	-98.67 ± 326.300
Month 6 change from Baseline; n=8	2.64 ± 77.843
Month 9 change from Baseline; n=8	-90.40 ± 355.316
Month 12 change from Baseline; n=4	-238.25 ± 506.435
Month 15 change from Baseline; n=4	-137.00 ± 519.042
Month 18 change from Baseline; n=2	38.00 ± 67.882
Month 24 change from Baseline; n=8	-72.78 ± 258.710

Notes
[54] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Assessment of Growth and Development: Baseline and Change from Baseline in BMI Z-Score Up to Month 24: Cohort of 0 Months to <2 Months Subjects

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End point title

Assessment of Growth and Development: Baseline and Change from Baseline in BMI Z-Score Up to Month 24: Cohort of 0 Months to <2 Months Subjects ^[55]

End point description

End point type

Secondary

End point timeframe

Baseline, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24

Notes
[55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16 ^[56]
Units: z-score
arithmetic mean (standard deviation)
Baseline; n=16	-0.0544 ± 1.26821
Month 1 change from Baseline; n=16	-0.2158 ± 1.35960
Month 2 change from Baseline; n=15	-0.2598 ± 1.19544
Month 3 change from Baseline; n=15	-0.1617 ± 1.02572
Month 4 change from Baseline; n=12	-0.0264 ± 1.68215
Month 5 change from Baseline; n=11	0.0828 ± 1.14206
Month 6 change from Baseline; n=10	0.0136 ± 1.72106
Month 9 change from Baseline; n=9	0.4614 ± 1.25343
Month 12 change from Baseline; n=6	0.6646 ± 0.95334
Month 15 change from Baseline; n=4	0.6830 ± 0.55703
Month 18 change from Baseline; n=3	0.3308 ± 0.27572
Month 24 change from Baseline; n=10	0.7743 ± 0.64962

Notes
[56] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Assessment of Growth and Development: Baseline and Change from Baseline in BSA Z-Score Up to Month 24: Cohort of 0 Months to <2 Months Subjects

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End point title

Assessment of Growth and Development: Baseline and Change from Baseline in BSA Z-Score Up to Month 24: Cohort of 0 Months to <2 Months Subjects ^[57]

End point description

End point type

Secondary

End point timeframe

Baseline, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16 ^[58]
Units: z-score
arithmetic mean (standard deviation)
Baseline; n=16	-0.1980 ± 2.11774
Month 1 change from Baseline; n=16	0.2336 ± 1.95603
Month 2 change from Baseline; n=15	0.2006 ± 1.72135
Month 3 change from Baseline; n=15	0.2684 ± 1.37517
Month 4 change from Baseline; n=12	0.2372 ± 2.30831
Month 5 change from Baseline; n=11	0.1810 ± 1.70024
Month 6 change from Baseline; n=10	0.2902 ± 2.05956
Month 9 change from Baseline; n=9	0.1679 ± 1.32407
Month 12 change from Baseline; n=6	0.1308 ± 0.50371
Month 15 change from Baseline; n=4	0.1595 ± 0.75833
Month 18 change from Baseline; n=3	0.1050 ± 0.73521
Month 24 change from Baseline; n=10	0.7341 ± 1.35582

Notes
[58] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Plasma PBA Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Plasma PBA Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[59]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16
Units: μg/mL
arithmetic mean (standard deviation)	46.2 ± 49.8

No statistical analyses for this end point

Secondary: Plasma PBA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

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End point title

Plasma PBA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects ^[60]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	7 ^[61]
Units: μg/mL
arithmetic mean (standard deviation)	4.8 ± 4.2

Notes
[61] - subjects with an evaluable assessment

No statistical analyses for this end point

Secondary: Plasma PBA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Plasma PBA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[62]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16
Units: μg*hr/mL
arithmetic mean (standard deviation)	374.53 ± 390.48

No statistical analyses for this end point

Secondary: Plasma PBA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Plasma PBA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[63]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16
Units: hours
arithmetic mean (standard deviation)	9.39 ± 7.41

No statistical analyses for this end point

Secondary: Plasma PAA Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Plasma PAA Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[64]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16
Units: μg/mL
arithmetic mean (standard deviation)	115.3 ± 102.0

No statistical analyses for this end point

Secondary: Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[65]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	10 ^[66]
Units: μg/mL
arithmetic mean (standard deviation)	98.98 ± 122.07

Notes
[66] - subjects with an evaluable assessment

No statistical analyses for this end point

Secondary: Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[67]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16
Units: μg*hr/mL
arithmetic mean (standard deviation)	1321.18 ± 1220.52

No statistical analyses for this end point

Secondary: Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[68]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16
Units: hours
arithmetic mean (standard deviation)	9.85 ± 9.26

No statistical analyses for this end point

Secondary: Plasma PAGN Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Plasma PAGN Cmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[69]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[69] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16
Units: μg/mL
arithmetic mean (standard deviation)	102.1 ± 48.6

No statistical analyses for this end point

Secondary: Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[70]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	13 ^[71]
Units: μg/mL
arithmetic mean (standard deviation)	69.39 ± 54.03

Notes
[71] - subjects with an evaluable assessment

No statistical analyses for this end point

Secondary: Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[72]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[72] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16
Units: μg*hr/mL
arithmetic mean (standard deviation)	1384.12 ± 1141.03

No statistical analyses for this end point

Secondary: Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[73]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Hour 0 and between 4 and 6 hours, 8 hours, and between 12 and 24 hours after the first dose of the day on Day 1 for stable subjects and on Day 2 for subjects in HAC

Notes
[73] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16
Units: hours
arithmetic mean (standard deviation)	11.72 ± 8.24

No statistical analyses for this end point

Secondary: Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[74]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Notes
[74] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16 ^[75]
Units: μg/mL
arithmetic mean (standard deviation)
Hour 0; n=6	3530.43 ± 3600.4
0.5 to 1.5 hours; n=8	1828 ± 2862
1.5 to 2.5 hours; n=9	1746 ± 1464
4 to 6 hours; n=11	2260 ± 1472
7.5 to 8.5 hours; n=14	3530.43 ± 3600.4
12 to 24 hours; n=16	4404 ± 3766

Notes
[75] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 0 Months to <2 Months Subjects ^[76]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Day 7, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, End of Trial

Notes
[76] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16 ^[77]
Units: μg/mL
arithmetic mean (standard deviation)
Day 7; n=10	4643 ± 2506
Month 1; n=11	4517 ± 2485
Month 2; n=12	4116 ± 3137
Month 3; n=9	7037 ± 4493
Month 4; n=9	2826 ± 1543
Month 5; n=8	6973 ± 3682
Month 6; n=3	5883 ± 3128
Month 9; n=7	7006 ± 4289
Month 12; n=3	5847 ± 2992
Month 15; n=4	3915 ± 2584
End of trial; n=8	6939 ± 6581

Notes
[77] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 0 Months to <2 Months Subjects ^[78]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Notes
[78] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16 ^[79]
Units: μg/mL
arithmetic mean (standard deviation)
Hour 0; n=3	11.1 ± 10.4
0.5 to 1.5 hours; n=4	46.2 ± 58.6
1.5 to 2.5 hours; n=4	62.5 ± 42.8
4 to 6 hours; n=9	34.6 ± 56.2
7.5 to 8.5 hours; n=11	22.8 ± 25.3
12 to 24 hours; n=12	35.2 ± 51.0

Notes
[79] - n=subjects with an assessment at given time point

No statistical analyses for this end point

Secondary: Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 0 Months to <2 Months Subjects

Top of page

End point title

Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 0 Months to <2 Months Subjects ^[80]

End point description

PK Evaluable Population: all subjects from the safety population with individual concentration-time profiles that allow computation of meaningful PK parameter values.

End point type

Secondary

End point timeframe

Day 7, Month 1, Month 2, Month 3, Month 4, Month 5, Month 6, Month 9, Month 12, Month 15, End of Trial

Notes
[80] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for each cohort are presented as separate endpoints.

End point values	RAVICTI: Age 0 to <2 Months
Number of subjects analysed	16 ^[81]
Units: μg/mL
arithmetic mean (standard deviation)
Day 7; n=9	23.7 ± 31.2
Month 1; n=8	14.6 ± 17.2
Month 2; n=8	12.3 ± 13.3
Month 3; n=7	14.4 ± 10.7
Month 4; n=6	6.4 ± 7.1
Month 5; n=6	13.2 ± 14.0
Month 6; n=1	5.5 ± 00000
Month 9; n=7	11.8 ± 8.5
Month 12; n=3	6.0 ± 3.8
Month 15; n=2	4.9 ± 0.3
End of trial; n=5	11.6 ± 9.0

Notes
[81] - n=subjects with an assessment at given time point; 00000=not applicable (1 subject assessed).

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From the first dose of study treatment through 30 days after the final dose (mean [SD] duration of treatment was 9.13 [6.838] months for Cohort of 2 Months to <2 Years Subjects and 10.67 [6.142] months for Cohort of 0 Months to <2 Months Subjects).

Adverse event reporting additional description

TEAEs (defined as AEs with an onset date on or after the first dose of study medication until study discontinuation) are presented.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

RAVICTI: Age 2 Months to <2 Years

Reporting group description

Reporting group title

RAVICTI: Age 0 to <2 Months

Reporting group description

Serious adverse events	RAVICTI: Age 2 Months to <2 Years	RAVICTI: Age 0 to <2 Months
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 10 (60.00%)	11 / 16 (68.75%)
number of deaths (all causes)	1	0
number of deaths resulting from adverse events
Investigations
Ammonia increased
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cyanosis
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Lethargy
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Pneumatosis intestinalis
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Vomiting
subjects affected / exposed	0 / 10 (0.00%)	2 / 16 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Apnoeic attack
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Asthma
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Status asthmaticus
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Croup infectious
subjects affected / exposed	1 / 10 (10.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 10 (10.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	2 / 10 (20.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Rhinovirus infection
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Medical device site infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tracheitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperammonaemia
subjects affected / exposed	3 / 10 (30.00%)	5 / 16 (31.25%)
occurrences causally related to treatment / all	0 / 7	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Feeding disorder
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	RAVICTI: Age 2 Months to <2 Years	RAVICTI: Age 0 to <2 Months
Total subjects affected by non serious adverse events
subjects affected / exposed	8 / 10 (80.00%)	16 / 16 (100.00%)
Vascular disorders
Venous thrombosis limb
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	2	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	2 / 10 (20.00%)	2 / 16 (12.50%)
occurrences all number	2	3
Catheter site rash
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Device occlusion
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Drug withdrawal syndrome
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Medical device site haemorrhage
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Immune system disorders
Seasonal allergy
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 10 (20.00%)	4 / 16 (25.00%)
occurrences all number	2	5
Rhinorrhoea
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Apnoea
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Nasal congestion
subjects affected / exposed	1 / 10 (10.00%)	2 / 16 (12.50%)
occurrences all number	1	2
Respiratory disorder
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Oropharyngeal pain
subjects affected / exposed	0 / 10 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Pneumothorax
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Tachypnoea
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Use of accessory respiratory muscles
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Irritability
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Investigations
Amino acid level decreased
subjects affected / exposed	1 / 10 (10.00%)	1 / 16 (6.25%)
occurrences all number	1	1
Ammonia increased
subjects affected / exposed	1 / 10 (10.00%)	1 / 16 (6.25%)
occurrences all number	1	1
Carbon dioxide decreased
subjects affected / exposed	1 / 10 (10.00%)	1 / 16 (6.25%)
occurrences all number	1	2
Hepatic enzyme increased
subjects affected / exposed	0 / 10 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Alanine aminotransferase increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Amino acid level increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Anion gap increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Blood bicarbonate decreased
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Blood urea decreased
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Body height below normal
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Platelet count increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Transaminases increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Weight decreased
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Injury, poisoning and procedural complications
Stoma site reaction
subjects affected / exposed	1 / 10 (10.00%)	1 / 16 (6.25%)
occurrences all number	1	1
Tibia fracture
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Arthropod bite
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Congenital, familial and genetic disorders
Dacryostenosis congenital
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Plagiocephaly
subjects affected / exposed	0 / 10 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Nervous system disorders
Gross motor delay
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Lethargy
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Tremor
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 10 (10.00%)	3 / 16 (18.75%)
occurrences all number	1	3
Neutropenia
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Thrombocytopenia
subjects affected / exposed	0 / 10 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Thrombocytosis
subjects affected / exposed	0 / 10 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Leukocytosis
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Lymphocytosis
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Microcytic anaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Ear and labyrinth disorders
Excessive cerumen production
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Eye disorders
Eye discharge
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Ocular hyperaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Gastrointestinal disorders
Vomiting
subjects affected / exposed	4 / 10 (40.00%)	5 / 16 (31.25%)
occurrences all number	5	12
Diarrhoea
subjects affected / exposed	1 / 10 (10.00%)	5 / 16 (31.25%)
occurrences all number	1	6
Teething
subjects affected / exposed	1 / 10 (10.00%)	3 / 16 (18.75%)
occurrences all number	1	3
Constipation
subjects affected / exposed	2 / 10 (20.00%)	2 / 16 (12.50%)
occurrences all number	2	2
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 10 (0.00%)	6 / 16 (37.50%)
occurrences all number	0	6
Flatulence
subjects affected / exposed	0 / 10 (0.00%)	3 / 16 (18.75%)
occurrences all number	0	3
Dysphagia
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Post-tussive vomiting
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Hepatobiliary disorders
Hepatic calcification
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	2 / 10 (20.00%)	5 / 16 (31.25%)
occurrences all number	3	6
Nail ridging
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Dermatitis diaper
subjects affected / exposed	1 / 10 (10.00%)	6 / 16 (37.50%)
occurrences all number	1	6
Eczema
subjects affected / exposed	1 / 10 (10.00%)	1 / 16 (6.25%)
occurrences all number	1	2
Red man syndrome
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Seborrhoeic dermatitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Renal and urinary disorders
Vesicoureteric reflux
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Nephrolithiasis
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Torticollis
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	4 / 10 (40.00%)	5 / 16 (31.25%)
occurrences all number	6	7
Gastroenteritis
subjects affected / exposed	1 / 10 (10.00%)	1 / 16 (6.25%)
occurrences all number	2	2
Urinary tract infection
subjects affected / exposed	1 / 10 (10.00%)	2 / 16 (12.50%)
occurrences all number	1	2
Viral infection
subjects affected / exposed	1 / 10 (10.00%)	1 / 16 (6.25%)
occurrences all number	1	1
Nasopharyngitis
subjects affected / exposed	2 / 10 (20.00%)	4 / 16 (25.00%)
occurrences all number	2	7
Croup infectious
subjects affected / exposed	1 / 10 (10.00%)	1 / 16 (6.25%)
occurrences all number	1	2
Otitis media
subjects affected / exposed	2 / 10 (20.00%)	1 / 16 (6.25%)
occurrences all number	2	1
Conjunctivitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Pharyngitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Pneumonia
subjects affected / exposed	1 / 10 (10.00%)	0 / 16 (0.00%)
occurrences all number	1	0
Sinusitis
subjects affected / exposed	1 / 10 (10.00%)	1 / 16 (6.25%)
occurrences all number	2	1
Ear infection
subjects affected / exposed	0 / 10 (0.00%)	3 / 16 (18.75%)
occurrences all number	0	3
Oral candidiasis
subjects affected / exposed	0 / 10 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Respiratory syncytial virus infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Angular cheilitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Candida infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Gastrointestinal viral infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Lower respiratory tract infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Otitis media acute
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Rhinovirus infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Metabolism and nutrition disorders
Hypophagia
subjects affected / exposed	2 / 10 (20.00%)	1 / 16 (6.25%)
occurrences all number	3	1
Metabolic acidosis
subjects affected / exposed	2 / 10 (20.00%)	2 / 16 (12.50%)
occurrences all number	2	2
Hyperammonaemia
subjects affected / exposed	0 / 10 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	3
Dehydration
subjects affected / exposed	0 / 10 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	4
Decreased appetite
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Feeding disorder of infancy or early childhood
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Protein deficiency
subjects affected / exposed	0 / 10 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

13 Jul 2015

• It was clarified that the total daily RAVICTI dose should remain the same when making changes to dose or dosing regimen. • The section describing how urine PAGN measurements could be used to help guide RAVICTI dose adjustment was updated to reflect that the final analysis of urine PAGN concentration data was to be based on age and BSA, rather than RAVICTI dose. • The density of RAVICTI Oral Liquid used in the study was corrected from 1.1 g/L to 1.1 g/mL. • It was indicated that at early termination, a PK sample was to be collected as close to the last dose of RAVICTI as possible and that the Medical Monitor was to be contacted for guidance when early termination procedures could not be conducted as scheduled. • It was clarified that liver transplantation was not to be considered an AE when performed for the treatment of stable underlying UCDs. • It was clarified that the DSMB met at least every 6 months, beginning 6 months after the first subject was enrolled, rather than every 6 to 8 months as previously stated. • It was clarified that single blood samples were used for PK PBA analysis in addition to PAA and PAGN, and added a Day 3 collection time for subjects <2 months of age presenting in hyperammonemic crisis. • It was clarified that single urine samples were used for urinary creatinine PK analysis, in addition to PAA and PAGN, and added a Day 3 collection time for subjects <2 months of age presenting in hyperammonemic crisis. • It was added that the single PK urine and blood samples were analyzed as outlined in the dosing algorithm guidance in Appendix B of the protocol, and that the results of all PK samples may have been provided to the DSMB, Sponsor, and Investigators when available. • A planned analysis when the database was locked for the 2 months to <2 years old cohort was added, in order to meet the PMR requirement.

13 Jul 2015

(continued) • It was added that the Investigator must maintain adequate and accurate records of study data and provide a list of such source data. • It was clarified that although an algorithm was provided as guidance to the Investigator for the use of ammonia and PK in future dose adjustment, the algorithm was not intended to be used in lieu of clinical judgment, i.e., Investigators was not to defer clinical decision making until the PK results were received. • Administrative changes were made related to the change in ownership from Hyperion Therapeutics, Inc. to Horizon Therapeutics, Inc. throughout the protocol (subsequently became Horizon Therapeutics, LLC).

23 Aug 2016

• Because samples could not be consistently obtained when dose adjustments were needed on an outpatient basis, and the PK results could not be delivered in a timely manner to guide dosing, the following changes were made: o The objectives of characterizing the PK of RAVICTI were revised to omit examining the utility of ammonia, urinary PAGN, and plasma PAA and PAGN as dosing biomarkers. o It was clarified that the PK results would be used to examine the study drug absorption and metabolism but would not be used to provide information on management of individualized dosing. Additionally, Investigators were to use their clinical judgment and consider the subject’s status if the allowable blood volume limit was reached per their institutional guideline. o It was specified that blood and urinary metabolite levels would not be used to guide dose adjustments. Rather, dose adjustment would be individualized at the discretion of the Investigator and according to the needs of each subject and accounting for the subject’s expected level of growth and development, BSA, and ammonia control. o All language that PAA, PAGN, and/or urinary PAGN were to be used to help guide study drug dosing was removed. o It was specified that the dose adjustment algorithm was to be driven by ammonia control and other clinical considerations. o Language regarding PK sample collection prior to dose adjustment was removed. • Outpatient ammonia monitoring after 48 hours inpatient following the first study drug dose was allowed. At least 48 hours monitoring after the first full dose of RAVICTI had to occur in an inpatient setting, and if the subject was discharged after 48 hours but prior to 72 hours of monitoring, the subject was to return at approximately the 60- and 72-hour mark for evaluation and plasma ammonia measurement.

23 Aug 2016

(continued) • It was clarified that although it was preferred to measure height (length), weight, and head circumference twice (and an average calculated), failure to obtain second value would not constitute a protocol deviation. • Collection of the date and time of PK sample collection was added to ensure the most informative analysis of PK results. • All GPB sample collection was removed because these samples were obtained for select sites only and in less than a third of subjects prior to the amendment. It was unlikely that the subjects yet to enroll, who all would be less than 2 months of age, would yield additional samples. • A section was added that specified any of remaining subjects enrolled who entered the study at age birth to <1 month of age (rather than 1 month to <2 months of age as originally planned) would undergo thorough PK assessment when they were age 1 month to <2 months, as well as in the transition period, to facilitate completion of the study. Enrollment of additional subjects between 1-2 months of age could have been challenging because it may have required the subject to switch therapies or delay treatment. Therefore the remaining enrollment included any otherwise eligible subject <2 months of age at the time of consent. • A section was added that a product complaint form would be provided to each site, and any product complaint would be reported to the Sponsor using the form. • The total enrollment was increased from 24 to 26 subjects based on over enrollment of the 2 months to 2 years cohort by 2 subjects. Information on enrollment to date was added, and allowed completion of enrollment with any mix of subjects <2 months of age without losing the opportunity to get the needed data from 1 month to <2 months of age.

23 Aug 2016

(continued) • The Per-Protocol population (all subjects from the Safety population with at least 80% compliance with study drug and no major protocol violations) was removed from the analysis plans because it was not possible to precisely determine compliance in the study. • It was clarified that the planned interim analysis for the 2 months to 2 years old cohort conducted to meet the PMR milestone from FDA was completed prior to Protocol Amendment 2. The interim analysis was conducted after the subjects in this cohort completed the Month 3 assessments, the data for that age group were locked, and a CSR was generated. Data subsequently gathered from this age group was included in an addendum to that CSR. There were no other planned interim analyses.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: An Open Label Study of the Safety, Efficacy and Pharmacokinetics of Glycerol Phenylbutyrate (GPB; RAVICTI®) in Pediatric Subjects under Two Years of Age with Urea Cycle Disorders (UCDs)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects With Successful Transition to RAVICTI With Controlled Ammonia (i.e. No Clinical Symptoms and Ammonia < 100 µmol/L): Cohort of 2 Months to <2 Years Subjects

Primary: Percentage of Subjects With Successful Transition to RAVICTI With Controlled Ammonia (i.e. No Clinical Symptoms and Ammonia < 100 µmol/L): Cohort of 2 Months to <2 Years Subjects

Primary: Percentage of Subjects With Successful Transition to RAVICTI With Controlled Ammonia (i.e. No Clinical Symptoms and Ammonia < 100 μmol/L): Cohort of 0 Months to <2 Months Subjects

Primary: Percentage of Subjects With Successful Transition to RAVICTI With Controlled Ammonia (i.e. No Clinical Symptoms and Ammonia < 100 μmol/L): Cohort of 0 Months to <2 Months Subjects

Secondary: Rate of Hyperammonemic Crises (HACs): Cohort of 2 Months to <2 Years Subjects

Secondary: Rate of Hyperammonemic Crises (HACs): Cohort of 2 Months to <2 Years Subjects

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Deaths, and Discontinuations Due to TEAEs: Cohort of 2 Months to <2 Years Subjects

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Deaths, and Discontinuations Due to TEAEs: Cohort of 2 Months to <2 Years Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Glutamine Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Glutamine Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Sum of Glutamine and Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Sum of Glutamine and Glutamate Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Isoleucine Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Isoleucine Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Leucine Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Leucine Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Valine Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Valine Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Assessment of Growth and Development: Baseline and Change from Baseline in Body Mass Index (BMI) Z-Score Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Assessment of Growth and Development: Baseline and Change from Baseline in Body Mass Index (BMI) Z-Score Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Assessment of Growth and Development: Baseline and Change from Baseline in Body Surface Area (BSA) Z-Score Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Assessment of Growth and Development: Baseline and Change from Baseline in Body Surface Area (BSA) Z-Score Up to Month 24: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma Phenylbutyrate/Phenylbutyric Acid (PBA) Maximum Plasma Concentration (Cmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma Phenylbutyrate/Phenylbutyric Acid (PBA) Maximum Plasma Concentration (Cmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PBA Minimum Plasma Concentration (Cmin) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PBA Minimum Plasma Concentration (Cmin) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PBA Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC[0-last]) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PBA Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC[0-last]) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PBA Time to Cmax (Tmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PBA Time to Cmax (Tmax) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma Phenylacetate/Phenylacetic Acid (PAA) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma Phenylacetate/Phenylacetic Acid (PAA) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PAA Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PAA AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PAA Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma phenylacetylglutamine (PAGN) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma phenylacetylglutamine (PAGN) Cmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PAGN Cmin on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PAGN AUC(0-last) on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Plasma PAGN Tmax on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Assessment of Urinary PAGN Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Subjects

Secondary: Assessment of Urinary PAGN Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Subjects

Secondary: Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Assessment of Urinary PAA Concentrations on the First Full Day of RAVICTI Dosing: Cohort of 2 Months to <2 Years Subjects

Secondary: Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Subjects

Secondary: Assessment of Urinary PAA Concentrations Up to End of Trial: Cohort of 2 Months to <2 Years Subjects

Secondary: Rate of HACs: Cohort of 0 Months to <2 Months Subjects

Secondary: Rate of HACs: Cohort of 0 Months to <2 Months Subjects

Secondary: Number of Subjects With TEAEs, Serious TEAEs, Deaths, and Discontinuations Due to TEAEs: Cohort of 0 Months to <2 Months Subjects

Secondary: Number of Subjects With TEAEs, Serious TEAEs, Deaths, and Discontinuations Due to TEAEs: Cohort of 0 Months to <2 Months Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Glutamine Up to Month 24: Cohort of 0 Months to <2 Months Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Glutamine Up to Month 24: Cohort of 0 Months to <2 Months Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Sum of Glutamine and Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Sum of Glutamine and Glutamate Up to Month 24: Cohort of 0 Months to <2 Months Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Isoleucine Up to Month 24: Cohort of 0 Months to <2 Month Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Isoleucine Up to Month 24: Cohort of 0 Months to <2 Month Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Leucine Up to Month 24: Cohort of 0 Months to <2 Months Subjects

Secondary: Amino Acid Assessment: Baseline and Change from Baseline in Leucine Up to Month 24: Cohort of 0 Months to <2 Months Subjects

Clinical Trial Results:
An Open Label Study of the Safety, Efficacy and Pharmacokinetics of Glycerol Phenylbutyrate (GPB; RAVICTI®) in Pediatric Subjects under Two Years of Age with Urea Cycle Disorders (UCDs)