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

July 20, 2023 updated by: Horizon Therapeutics, LLC

A Randomised, Controlled, Open-Label Parallel Arm Study of Safety, PK and Ammonia Control of RAVICTI® (Glycerol Phenylbutyrate) Oral Liquid and Sodium Phenylbutyrate in Phenylbutyrate Treatment Naïve Patients With Urea Cycle Disorders

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

16

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 99 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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:

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose
Other Names:
  • Glycerol phenylbutyrate
  • GPB
  • HPN-100
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.

  • 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
Other Names:
  • Sodium phenylbutyrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of Treatment Success (Percentage of Participants Defined as Treatment Success at Week 4) During the Initial Treatment Period
Time Frame: Week 4

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.
Week 4

Secondary Outcome Measures

Outcome Measure
Time Frame
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
Baseline through Week 4
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)
Baseline, Initial Treatment Period Week 1, Week 2, Week 3, Week 4 (0, 4, 8 hours post dose)
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
Week 4: hour 0 (predose), and hours 4 and 8 postdose
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
Week 4: hour 0 (predose), and hours 4 and 8 postdose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Director: Denise Coughlan, Horizon Therapeutics, LLC

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 20, 2018

Primary Completion (Actual)

July 5, 2022

Study Completion (Actual)

December 20, 2022

Study Registration Dates

First Submitted

October 18, 2017

First Submitted That Met QC Criteria

November 3, 2017

First Posted (Actual)

November 7, 2017

Study Record Updates

Last Update Posted (Actual)

July 27, 2023

Last Update Submitted That Met QC Criteria

July 20, 2023

Last Verified

July 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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