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CompletedNCT03335488Updated Jul 1, 2024Results posted

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

A Phase 4 interventional study of RAVICTI and NaPBA in Urea Cycle Disorder, sponsored by Amgen. Completed at 11 sites in 4 countries. Open to participants aged Up to 99 Years. Per ClinicalTrials.gov, last updated 2024-07-01.

Sponsored by Amgen · Phase 4, Interventional, and Treatment

Phase
Phase 4
Study type
Interventional
Enrollment
16
Allocation
Randomized
Ages
Up to 99 Years
Sex
All
01

Study summary

This is a randomized, controlled, open-label parallel arm study to assess the safety, tolerability, pharmacokinetics and ammonia control, of RAVICTI® as compared to Sodium phenylbutyrate (NaPBA) in urea cycle disorder subjects not currently or previously chronically treated with phenylacetic acid (phenylacetate; PAA) prodrugs. The study design will include: 1) Baseline Period; 2) Initial Treatment Period; 3) a RAVICTI only Transition Period 4) a RAVICTI only Maintenance Period; and 5) a RAVICTI only Safety Extension Period. The study will run for approximately 25 weeks.

Read the detailed description

Study acquired from Horizon in 2024.

02

Conditions studied

  • Urea Cycle Disorder

Keywords

  • Urea
  • Hyperammonemic crisis (HAC)
03

Who can participate

Ages eligible
Up to 99 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Signed informed consent given by the subject or the subject's parent/legal guardian for those under 18 years of age or the age of consent by local regulation.
  • Male and female subjects with a suspected or confirmed UCD diagnosis of any subtype, except n-acetylglutamate synthetase (NAGS) deficiency.
  • Suspected diagnosis is defined as having experienced a hyperammonemic crisis (HAC) or a documented high ammonia of >=100 µmol/L

  • Confirmed diagnosis is determined via enzymatic, biochemical, or genetic testing.

    • Requires nitrogen-binding agents according to the judgment of the Investigator
    • Birth and older.
    • All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception from signing the informed consent throughout the study and for 30 days after the last dose of study drug. Acceptable forms of contraception are (oral, injected, implanted or transdermal), tubal ligation, intrauterine device, hysterectomy, vasectomy, or double barrier methods. Abstinence is an acceptable form of birth control, though appropriate contraception must be used if the subject becomes sexually active.

Exclusion criteria

Exclusion Criteria:

  • Subject has received chronic treatment with an oral phenylbutyrate (RAVICTI, NaPBA, Pheburane, or other) longer than 14 consecutive days within one year prior to enrollment.

  • Temporary use of NaPBA for acute management of a hyperammonemic crisis in the past is acceptable.

    • Any concomitant illness (e.g., malabsorption or clinically significant liver or bowel disease) which would preclude the subject's safe participation, as judged by the Investigator.
    • Has undergone liver transplantation, including hepatocellular transplant.
    • Subjects on sodium benzoate (NaBz) at Baseline will be excluded if they are viewed by the Investigator as being unable to undergo NaBz transition to a PAA prodrug during the Initial Treatment Period.
    • Known hypersensitivity to phenylbutyric acid (PBA) or any excipients of the NaPBA/PBA formulations.
    • Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed at the Baseline Visit prior to the start of study drug.
04

Study design

Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
16 participants (actual)

Study arms

  • Experimental
    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.

    Drug: RAVICTI

  • Active comparator
    NaPBA -> RAVICTI

    Initial Treatment Period: NaPBA dosing based on participants disease and treatment status at entry to the study. 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.

    Drug: NaPBA

Interventions

  • DrugRAVICTI

    RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose

    Also known as: Glycerol phenylbutyrate, GPB, HPN-100

  • DrugNaPBA

    * 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

    Also known as: Sodium phenylbutyrate

05

What researchers measure

Primary outcomes

  1. Rate of Treatment Success (Percentage of Participants Defined as Treatment Success at Week 4) During the Initial Treatment Period

    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.

    Time frame: Week 4

Secondary outcomes

  1. Rate of Drug Discontinuations (Percentage of Participants Who Discontinued Study Drug) Due to Any Reason in the Initial Treatment Period

    Time frame: Baseline through Week 4

  2. Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period

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

  3. Plasma Ammonia Area Under the Curve (AUC) 0 to 8h at the End of the Initial Treatment Period

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

  4. Peak Plasma Concentration (Cmax) of Ammonia at the End of the Initial Treatment Period

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

06

Results

Posted Jul 10, 2023

Participant flow

Initial Treatment Period
Participant flow — Initial Treatment Period
MilestoneRAVICTI -> RAVICTINaPBA -> RAVICTI
Started115
Completed115
Not completed00
Transition Period
Participant flow — Transition Period
MilestoneRAVICTI -> RAVICTINaPBA -> RAVICTI
Started05
Completed05
Not completed00
Maintenance Period
Participant flow — Maintenance Period
MilestoneRAVICTI -> RAVICTINaPBA -> RAVICTI
Started115
Completed105
Not completed10
Withdrew: Withdrawal by parent/guardian10
Safety Extension Period
Participant flow — Safety Extension Period
MilestoneRAVICTI -> RAVICTINaPBA -> RAVICTI
Started105
Completed85
Not completed20
Withdrew: Adverse event10
Withdrew: Did not return to study visit10

Outcome measures

PrimaryRate of Treatment Success (Percentage of Participants Defined as Treatment Success at Week 4) During the Initial Treatment Period

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.

Time frame:
Week 4
Reported as:
Number · percentage of participants
Rate of Treatment Success (Percentage of Participants Defined as Treatment Success at Week 4) During the Initial Treatment Period
percentage of participantsRAVICTINaPBA
Rate of Treatment Success (Percentage of Participants Defined as Treatment Success at Week 4) During the Initial Treatment Period81.880.0
Statistical analysis
  • RAVICTI vs NaPBA · Fisher Exact · p = 1.0000 · Odds ratio (or): 1.1 · 95% CI 0.0 to 28.1
SecondaryRate of Drug Discontinuations (Percentage of Participants Who Discontinued Study Drug) Due to Any Reason in the Initial Treatment Period
Time frame:
Baseline through Week 4
Reported as:
Number · percentage of participants
Rate of Drug Discontinuations (Percentage of Participants Who Discontinued Study Drug) Due to Any Reason in the Initial Treatment Period
percentage of participantsRAVICTINaPBA
Rate of Drug Discontinuations (Percentage of Participants Who Discontinued Study Drug) Due to Any Reason in the Initial Treatment Period00
SecondaryChange From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period
Time frame:
Baseline, Initial Treatment Period Week 1, Week 2, Week 3, Week 4 (0, 4, 8 hours post dose)
Reported as:
Mean · µmol/L
Change From Baseline in Fasting Plasma Ammonia Levels During the Initial Treatment Period
µmol/LRAVICTINaPBA
Week 16.5 ± 21.160.0 ± 10.12
Week 225.5 ± 59.88-10.4 ± 10.17
Week 37.4 ± 35.91-10.9 ± 6.40
Week 4: 0 hour2.1 ± 15.52-0.3 ± 8.49
Week 4: 4 hours postdose2.6 ± 23.49-1.1 ± 8.68
Week 4: 8 hours postdose23.4 ± 62.09-0.7 ± 7.37
Statistical analysis
  • RAVICTI vs NaPBA · Wilcoxon rank sum test · p = 0.8464
  • RAVICTI vs NaPBA · Wilcoxon rank sum test · p = 0.1040
  • RAVICTI vs NaPBA · Wilcoxon rank sum test · p = 0.0979
  • RAVICTI vs NaPBA · Wilcoxon rank sum test · p = 0.9808
  • RAVICTI vs NaPBA · Wilcoxon rank sum test · p = 0.8329
  • RAVICTI vs NaPBA · Wilcoxon rank sum test · p = 0.2544
SecondaryPlasma Ammonia Area Under the Curve (AUC) 0 to 8h at the End of the Initial Treatment Period
Time frame:
Week 4: hour 0 (predose), and hours 4 and 8 postdose
Reported as:
Mean · µmol*h /L
Plasma Ammonia Area Under the Curve (AUC) 0 to 8h at the End of the Initial Treatment Period
µmol*h /LRAVICTINaPBA
Plasma Ammonia Area Under the Curve (AUC) 0 to 8h at the End of the Initial Treatment Period331.8 ± 342.79258.9 ± 153.35
Statistical analysis
  • RAVICTI vs NaPBA · t-test · p = 0.8579 (P-value is from a t-test comparing log-transformed RAVICTI vs NaPBA values.)
SecondaryPeak Plasma Concentration (Cmax) of Ammonia at the End of the Initial Treatment Period
Time frame:
Week 4: hour 0 (predose), and hours 4 and 8 postdose
Reported as:
Mean · µmol/L
Peak Plasma Concentration (Cmax) of Ammonia at the End of the Initial Treatment Period
µmol/LRAVICTINaPBA
Peak Plasma Concentration (Cmax) of Ammonia at the End of the Initial Treatment Period60.2 ± 78.4738.1 ± 18.91
Statistical analysis
  • RAVICTI vs NaPBA · t-test · p = 0.7155 (P-value is from a t-test comparing log-transformed RAVICTI vs NaPBA values.)

Adverse events

Collected over 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.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Initial Treatment Period: RAVICTI0/11 (0%)2/11 (18.2%)6/11 (54.5%)
Initial Treatment Period: NaPBA0/5 (0%)0/5 (0%)2/5 (40%)
Transition Period: RAVICTI0/5 (0%)1/5 (20%)1/5 (20%)
Maintenance and Safety Periods Combined0/16 (0%)3/16 (18.8%)8/16 (50%)
Most frequent serious events
Most frequent serious events
EventInitial Treatment Period: RAVICTIInitial Treatment Period: NaPBATransition Period: RAVICTIMaintenance and Safety Periods Combined
PyrexiaGeneral disorders0/110/51/51/16
Hyperammonaemic crisisMetabolism and nutrition disorders2/110/50/52/16
NeutropeniaBlood and lymphatic system disorders1/110/50/51/16
HyperammonaemiaMetabolism and nutrition disorders1/110/50/51/16
Bone marrow failureBlood and lymphatic system disorders0/110/50/51/16
Most frequent other events
Showing 10 of 38
Most frequent other events
EventInitial Treatment Period: RAVICTIInitial Treatment Period: NaPBATransition Period: RAVICTIMaintenance and Safety Periods Combined
ThrombocytopeniaBlood and lymphatic system disorders0/111/50/50/16
HypoacusisEar and labyrinth disorders0/111/50/50/16
Vision blurredEye disorders0/111/50/50/16
Abdominal painGastrointestinal disorders0/111/50/51/16
DysphagiaGastrointestinal disorders0/111/50/50/16
NauseaGastrointestinal disorders0/111/50/50/16
FatigueGeneral disorders0/111/50/50/16
Fibula fractureInjury, poisoning and procedural complications0/111/50/50/16
Ligament sprainInjury, poisoning and procedural complications0/111/50/50/16
Alanine aminotransferase increasedInvestigations0/110/51/50/16

Baseline characteristics

Age, Customized
Age, Customized(Participants)RAVICTI -> RAVICTINaPBA -> RAVICTITotal
< 2 months101
2 months - < 2 years404
2 years - 12 years134
> 12 - 16 years000
>= 17 years527
Sex: Female, Male
Sex: Female, Male(Participants)RAVICTI -> RAVICTINaPBA -> RAVICTITotal
Female437
Male729
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)RAVICTI -> RAVICTINaPBA -> RAVICTITotal
Hispanic or Latino426
Not Hispanic or Latino7310
Unknown or Not Reported000
Race (NIH/OMB)
Race (NIH/OMB)(Participants)RAVICTI -> RAVICTINaPBA -> RAVICTITotal
American Indian or Alaska Native000
Asian000
Native Hawaiian or Other Pacific Islander000
Black or African American000
White10515
More than one race101
Unknown or Not Reported000
07

Study locations

11 sites
  • University of Florida (UF) - Shands Hospital
    Gainesville, Florida 32610-0214, United States
  • Mount Sinai School of Medicine
    New York, New York 10029, United States
  • University Hospitals Case Medical Center
    Cleveland, Ohio 44106-6005, United States
  • Children's Hospital of Pittsburgh of UPMC
    Pittsburgh, Pennsylvania 15224, United States
  • University of Texas, Southwestern Medical Centre
    Dallas, Texas 753908565, United States
  • University of Utah
    Salt Lake City, Utah 84132, United States
  • Azienda Ospedaliera Universitaria Di Padova, U.O.C. Malattie Metaboliche Ereditarie, Dipartimento della Salute della Donna e del Bambino
    Padua, Veneto 35128, Italy
  • Bambino Gesù Children's Research Hospital
    Rome, 00165, Italy
  • Hospital Materno-Infantil (HRU Carlos Haya)
    Málaga, Andalucia 29006, Spain
  • Hospital Universitario de Cruces
    Barakaldo, Vizcaya 48903, Spain
  • Universitätsspital, Inselspital Bern
    Bern, 3010, Switzerland
08

References and documents

Study documents

  • Study protocol · Sep 23, 2022
  • Statistical analysis plan · Dec 19, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

Supporting information: Study protocol, Sap, Icf, Csr

09

Registry details

Key details

Study ID
NCT03335488
Lead sponsor
Amgen
Responsible party
Sponsor
First posted
Nov 7, 2017
Start date
Feb 20, 2018
Primary completion
Jul 5, 2022
Completion
Dec 20, 2022
Results posted
Jul 10, 2023
Last update
Jul 1, 2024

Study contacts

MD
study director · Amgen

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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