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

Primary Purpose

Urea Cycle Disorder

Status

Completed

Phase

Phase 4

Locations

International

Study Type

Interventional

Intervention

RAVICTI

NaPBA

About this trial

This is an interventional treatment trial for Urea Cycle Disorder focused on measuring Urea, Hyperammonemic crisis (HAC)

Eligibility Criteria

undefined - 99 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 NAGS deficiency.
Suspected diagnosis is defined as having experienced a 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 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 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.

Sites / Locations

University of Florida (UF) - Shands Hospital
Mount Sinai School of Medicine
University Hospitals Case Medical Center
Children's Hospital of Pittsburgh of UPMC
University of Texas, Southwestern Medical Centre
University of Utah
Azienda Ospedaliera Universitaria Di Padova, U.O.C. Malattie Metaboliche Ereditarie, Dipartimento della Salute della Donna e del Bambino
Bambino Gesù Children's Research Hospital
Hospital Materno-Infantil (HRU Carlos Haya)
Hospital Universitario de Cruces
Universitätsspital, Inselspital Bern

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

RAVICTI -> RAVICTI

NaPBA -> RAVICTI

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

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

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

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

Full Information

NCT ID

NCT03335488

First Posted

October 18, 2017

Last Updated

July 20, 2023

Sponsor

Horizon Therapeutics, LLC

1. Study Identification

Unique Protocol Identification Number

NCT03335488

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Completed

Study Start Date

February 20, 2018 (Actual)

Primary Completion Date

July 5, 2022 (Actual)

Study Completion Date

December 20, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Horizon Therapeutics, LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Urea Cycle Disorder

Keywords

Urea, Hyperammonemic crisis (HAC)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

Randomized, Controlled, Open-Label Parallel Arm study

Masking

None (Open Label)

Allocation

Randomized

Enrollment

16 (Actual)

8. Arms, Groups, and Interventions

Arm Title

RAVICTI -> RAVICTI

Arm Type

Experimental

Arm Description

Arm Title

NaPBA -> RAVICTI

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

RAVICTI

Other Intervention Name(s)

Glycerol phenylbutyrate, GPB, HPN-100

Intervention Description

RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose

Intervention Type

Drug

Intervention Name(s)

NaPBA

Other Intervention Name(s)

Sodium phenylbutyrate

Intervention Description

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

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Week 4

Secondary Outcome Measure Information:

Title

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

Title

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)

Title

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

Title

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

10. Eligibility

Sex

All

Maximum Age & Unit of Time

99 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Denise Coughlan

Organizational Affiliation

Horizon Therapeutics, LLC

Official's Role

Study Director

Facility Information:

Facility Name

University of Florida (UF) - Shands Hospital

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610-0214

Country

United States

Facility Name

Mount Sinai School of Medicine

City

New York

State/Province

New York

ZIP/Postal Code

10029

Country

United States

Facility Name

University Hospitals Case Medical Center

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44106-6005

Country

United States

Facility Name

Children's Hospital of Pittsburgh of UPMC

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15224

Country

United States

Facility Name

University of Texas, Southwestern Medical Centre

City

Dallas

State/Province

Texas

ZIP/Postal Code

753908565

Country

United States

Facility Name

University of Utah

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84132

Country

United States

Facility Name

Azienda Ospedaliera Universitaria Di Padova, U.O.C. Malattie Metaboliche Ereditarie, Dipartimento della Salute della Donna e del Bambino

City

Padua

State/Province

Veneto

ZIP/Postal Code

35128

Country

Italy

Facility Name

Bambino Gesù Children's Research Hospital

City

Rome

ZIP/Postal Code

00165

Country

Italy

Facility Name

Hospital Materno-Infantil (HRU Carlos Haya)

City

Málaga

State/Province

Andalucia

ZIP/Postal Code

29006

Country

Spain

Facility Name

Hospital Universitario de Cruces

City

Barakaldo

State/Province

Vizcaya

ZIP/Postal Code

48903

Country

Spain

Facility Name

Universitätsspital, Inselspital Bern

City

Bern

ZIP/Postal Code

3010

Country

Switzerland

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Learn more about this trial

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

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