Trial Outcomes & Findings for Study of Glycerol Phenylbutyrate & Sodium Phenylbutyrate in Phenylbutyrate Naïve Patients With Urea Cycle Disorders (UCDs) (NCT NCT03335488)

Last Updated: 2024-07-01

Results Overview

A participant was considered a Treatment Success for the assigned treatment arm if the participant had not experienced an unprovoked hyperammonemic crisis (HAC) (i.e., a HAC that cannot be attributed to one or more specific precipitating factors such as infection, intercurrent illness, diet noncompliance, treatment noncompliance, etc.) on the assigned treatment and had met at least 2 of the following 3 criteria: * Had absolute values at the 3 time points (pre-dose, after dose at 4 hours and 8 hours) of plasma ammonia levels which do not exceed ULN at the Week 4(End of Initial Treatment Period visit) * Had normal (≤ ULN) glutamine levels at the Week 4 (End of Initial Treatment Period visit at the time point Zero Hour. * Had normal (≤ ULN) essential amino acids including branched chain amino acid levels (threonine, phenylalanine, methionine, lysine, leucine, isoleucine, histidine, valine) at the End of Initial Treatment Period visit at time point Zero Hour.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

16 participants

Primary outcome timeframe

Week 4

Results posted on

2024-07-01

Participant Flow

In the Initial Treatment Period (approximately 28 days), eligible participants were randomized to one of two treatment arms: RAVICTI or NaPBA. For all Initial Treatment Period NaPBA participants and RAVICTI participants who were treatment failures, a Transition Period (7 days ± 2 days) with RAVICTI followed. All participants received RAVICTI in the Maintenance Period (8 Weeks) and the Safety Extension Period (12 Weeks).

Participant milestones

Participant milestones
Measure	RAVICTI -> RAVICTI Initial Treatment, Maintenance, Safety Extension Periods: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.	NaPBA -> RAVICTI Initial Treatment Period: NaPBA dosing based on participants disease and treatment status at entry to the study: * NaPBA in patients weighing \< 20 Kg - 600 mg/Kg, maximum total daily dose * NaPBA in patients weighing \> 20 Kg - 13 g/m2, maximum total daily dose. Transition, Maintenance, Safety Extension Periods: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.
Initial Treatment Period STARTED	11	5
Initial Treatment Period COMPLETED	11	5
Initial Treatment Period NOT COMPLETED	0	0
Transition Period STARTED	0	5
Transition Period COMPLETED	0	5
Transition Period NOT COMPLETED	0	0
Maintenance Period STARTED	11	5
Maintenance Period COMPLETED	10	5
Maintenance Period NOT COMPLETED	1	0
Safety Extension Period STARTED	10	5
Safety Extension Period COMPLETED	8	5
Safety Extension Period NOT COMPLETED	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	RAVICTI -> RAVICTI Initial Treatment, Maintenance, Safety Extension Periods: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.	NaPBA -> RAVICTI Initial Treatment Period: NaPBA dosing based on participants disease and treatment status at entry to the study: * NaPBA in patients weighing \< 20 Kg - 600 mg/Kg, maximum total daily dose * NaPBA in patients weighing \> 20 Kg - 13 g/m2, maximum total daily dose. Transition, Maintenance, Safety Extension Periods: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.
Maintenance Period Withdrawal by Parent/Guardian	1	0
Safety Extension Period Adverse Event	1	0
Safety Extension Period Did Not Return to Study Visit	1	0

Baseline Characteristics

Study of Glycerol Phenylbutyrate & Sodium Phenylbutyrate in Phenylbutyrate Naïve Patients With Urea Cycle Disorders (UCDs)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	RAVICTI -> RAVICTI n=11 Participants Initial Treatment, Maintenance, Safety Extension Periods: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.	NaPBA -> RAVICTI n=5 Participants Initial Treatment Period: NaPBA dosing based on participants disease and treatment status at entry to the study: NaPBA in patients weighing \< 20 Kg - 600 mg/Kg, maximum total daily dose NaPBA in patients weighing \> 20 Kg - 13 g/m2, maximum total daily dose. Transition, Maintenance, Safety Extension Periods: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.	Total n=16 Participants Total of all reporting groups
Age, Customized < 2 months	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Age, Customized 2 months - < 2 years	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants
Age, Customized 2 years - 12 years	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Age, Customized > 12 - 16 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized >= 17 years	5 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	2 Participants n=7 Participants	9 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants n=5 Participants	3 Participants n=7 Participants	10 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	10 Participants n=5 Participants	5 Participants n=7 Participants	15 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 4

Population: Modified Intent-to-Treat Population: all participants from the Safety population with no major eligibility violations and participants who had ammonia data post-randomization.

Outcome measures

Outcome measures
Measure	RAVICTI n=11 Participants Initial Treatment Period: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.	NaPBA n=5 Participants Initial Treatment Period: NaPBA dosing based on participants disease and treatment status at entry to the study: NaPBA in patients weighing \< 20 Kg - 600 mg/Kg, maximum total daily dose NaPBA in patients weighing \> 20 Kg - 13 g/m2, maximum total daily dose.
Rate of Treatment Success (Percentage of Participants Defined as Treatment Success at Week 4) During the Initial Treatment Period	81.8 percentage of participants	80.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline through Week 4

Population: Modified Intent-to-Treat Population: all participants from the Safety population with no major eligibility violations and participants who had ammonia data post-randomization.

Outcome measures

Outcome measures
Measure	RAVICTI n=11 Participants Initial Treatment Period: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.	NaPBA n=5 Participants Initial Treatment Period: NaPBA dosing based on participants disease and treatment status at entry to the study: NaPBA in patients weighing \< 20 Kg - 600 mg/Kg, maximum total daily dose NaPBA in patients weighing \> 20 Kg - 13 g/m2, maximum total daily dose.
Rate of Drug Discontinuations (Percentage of Participants Who Discontinued Study Drug) Due to Any Reason in the Initial Treatment Period	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Initial Treatment Period Week 1, Week 2, Week 3, Week 4 (0, 4, 8 hours post dose)

Population: Modified Intent-to-Treat Population: all participants from the Safety population with no major eligibility violations and participants who had ammonia data post-randomization. Participants with an assessment at given time point.

Outcome measures

Outcome measures
Measure	RAVICTI n=11 Participants Initial Treatment Period: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.	NaPBA n=5 Participants Initial Treatment Period: NaPBA dosing based on participants disease and treatment status at entry to the study: NaPBA in patients weighing \< 20 Kg - 600 mg/Kg, maximum total daily dose NaPBA in patients weighing \> 20 Kg - 13 g/m2, maximum total daily dose.
Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period Week 1	6.5 µmol/L Standard Deviation 21.16	0.0 µmol/L Standard Deviation 10.12
Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period Week 2	25.5 µmol/L Standard Deviation 59.88	-10.4 µmol/L Standard Deviation 10.17
Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period Week 3	7.4 µmol/L Standard Deviation 35.91	-10.9 µmol/L Standard Deviation 6.40
Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period Week 4: 0 hour	2.1 µmol/L Standard Deviation 15.52	-0.3 µmol/L Standard Deviation 8.49
Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period Week 4: 4 hours postdose	2.6 µmol/L Standard Deviation 23.49	-1.1 µmol/L Standard Deviation 8.68
Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period Week 4: 8 hours postdose	23.4 µmol/L Standard Deviation 62.09	-0.7 µmol/L Standard Deviation 7.37

SECONDARY outcome

Timeframe: Week 4: hour 0 (predose), and hours 4 and 8 postdose

Outcome measures

Outcome measures
Measure	RAVICTI n=10 Participants Initial Treatment Period: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.	NaPBA n=5 Participants Initial Treatment Period: NaPBA dosing based on participants disease and treatment status at entry to the study: NaPBA in patients weighing \< 20 Kg - 600 mg/Kg, maximum total daily dose NaPBA in patients weighing \> 20 Kg - 13 g/m2, maximum total daily dose.
Plasma Ammonia Area Under the Curve (AUC) 0 to 8h at the End of the Initial Treatment Period	331.8 µmol*h /L Standard Deviation 342.79	258.9 µmol*h /L Standard Deviation 153.35

SECONDARY outcome

Timeframe: Week 4: hour 0 (predose), and hours 4 and 8 postdose

Outcome measures

Outcome measures
Measure	RAVICTI n=11 Participants Initial Treatment Period: RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose. Dosing will be based on participants disease and treatment status at entry to the study.	NaPBA n=5 Participants Initial Treatment Period: NaPBA dosing based on participants disease and treatment status at entry to the study: NaPBA in patients weighing \< 20 Kg - 600 mg/Kg, maximum total daily dose NaPBA in patients weighing \> 20 Kg - 13 g/m2, maximum total daily dose.
Peak Plasma Concentration (Cmax) of Ammonia at the End of the Initial Treatment Period	60.2 µmol/L Standard Deviation 78.47	38.1 µmol/L Standard Deviation 18.91

Adverse Events

Initial Treatment Period: RAVICTI

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Initial Treatment Period: NaPBA

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Transition Period: RAVICTI

Serious events: 1 serious events

Other events: 1 other events

Deaths: 0 deaths

Maintenance and Safety Periods Combined

Serious events: 3 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Initial Treatment Period: RAVICTI n=11 participants at risk RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose for up to 28 days.	Initial Treatment Period: NaPBA n=5 participants at risk Initial Treatment Period: NaPBA for up to 28 days dosing based on participants disease and treatment status at entry to the study: NaPBA in patients weighing \< 20 Kg - 600 mg/Kg, maximum total daily dose NaPBA in patients weighing \> 20 Kg - 13 g/m2, maximum total daily dose.	Transition Period: RAVICTI n=5 participants at risk RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose for 7 days ± 2 days	Maintenance and Safety Periods Combined n=16 participants at risk RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose in the Maintenance Period (8 Weeks) and the Safety Extension Period (12 Weeks)
Blood and lymphatic system disorders Bone marrow failure	0.00% 0/11 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	0.00% 0/5 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	0.00% 0/5 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	6.2% 1/16 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.
Blood and lymphatic system disorders Neutropenia	9.1% 1/11 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	0.00% 0/5 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	0.00% 0/5 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	6.2% 1/16 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.
General disorders Pyrexia	0.00% 0/11 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	0.00% 0/5 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	20.0% 1/5 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	6.2% 1/16 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.
Metabolism and nutrition disorders Hyperammonaemia	9.1% 1/11 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	0.00% 0/5 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	0.00% 0/5 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	6.2% 1/16 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.
Metabolism and nutrition disorders Hyperammonaemic crisis	18.2% 2/11 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	0.00% 0/5 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	0.00% 0/5 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.	12.5% 2/16 • All-cause mortality: from enrollment through the end of study up to 25 weeks plus 30 days. Adverse events: from the first dose through the last dose of study drug in a given period, plus 30 days from the last dose taken, regardless of period. Overall mean time on treatment for the Initial Treatment Period was 30.7 days (RAVICTI) and 26.0 days (NaPBA), for the Transition Period was 8.0 days, for the Maintenance Period was 54.4 days, and for the Safety Extension Period was 84.6 days.

Other adverse events

Additional Information

Horizon Therapeutics, LLC

Phone: 866-479-6742

Email: [email protected]

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