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

• ClinicalTrials.gov Identifier: NCT03335488
• Recruitment Status: Recruiting
• First Posted: November 7, 2017
• Last Update Posted: January 19, 2021
• Sponsor: Horizon Therapeutics, LLC
• Information provided by (Responsible Party): Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics, LLC )

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 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.

Condition or disease	Intervention/treatment	Phase
Urea Cycle Disorder	Drug: RAVICTI; Drug: NaPBA	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, Controlled, Open-Label Parallel Arm study
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: February 20, 2018
• Estimated Primary Completion Date: September 2022
• Estimated Study Completion Date: March 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1, RAVICTI; Used for Baseline, Treatment, Transition, Maintenance, and Safety. 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.	Drug: RAVICTI; RAVICTI, Oral Liquid Product 17.5 mL maximum total daily dose; Other Names: Glycerol phenylbutyrate; GPB; HPN-100
Active Comparator: Arm 2, NaPBA (sodium phenylbutyrate); Used for Baseline and Treatment. Sodium Phenylbutyrate (NaPBA). 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	Drug: NaPBA; 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 Name: Sodium phenylbutyrate

Outcome Measures

Primary Outcome Measures :

1. Rate of Treatment Success [ Time Frame: Week 4 ]

   A subject will be considered a Treatment Success for the assigned treatment arm if the subject has 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 has met at least 2 of the following 3 criteria:

   • Has 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)
   • Has normal (≤ ULN) glutamine levels at the Week 4 (End of Initial Treatment Period visit at the time point Zero Hour.
   • Has 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 :

1. Annualized Rate of Hyperammonemic Crisis (HAC) [ Time Frame: Week 25 ]
   Hyperammonemic Crisis (HAC) will be captured throughout the study.
2. Amino Acid Assessment [ Time Frame: Day 1, Week 1, 2, 3, 4, 5, 9, 13, 17, 21, 25 ]
   The amino acid panel will include ornithine, aspartic acid, serine, threonine, glutamic acid, asparagine, proline, glutamine, alanine, glycine, valine, citrulline, methionine, cystine, leucine, isoleucine, phenylalanine, tyrosine, lysine, arginine, taurine, phosphoserine, phosphoethanolamine, alpha-aminobutyric acid, 1-methylhistidine, histidine, 3-methylhistidine, and argininosuccinate.
3. Rate of Drug Discontinuations Due to Any Reasons [ Time Frame: Baseline through Week 4 ]
4. Rate of Drug Discontinuations Due to Adverse Events [ Time Frame: Baseline through Week 25 ]
5. Palatability of Study Drug (Hedonic Scale) [ Time Frame: Week 4 , Week 5 (End of transition period for participant on NaPBA arm) ]
   The Hedonic scale is a validated scale developed to assess palatability of medications. Participants (or parents or caregivers) are asked to rate the palatability of RAVICTI (glycerol phenylbutyrate) Oral Liquid and NaPBA based on the participant's reactions. There are 5 smiley faces to choose from. Happy face = likes very much through sad face = dislikes very much.
6. Clinical Global Impression (CGI) Scales Severity (Investigator Only) [ Time Frame: Baseline, Week 13 and 25 ]
   Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of rating, relative to clinician's past experience with patient's who have the same diagnosis. Rating scale is 1 = normal not ill to 7 = extremely ill.
7. Clinical Global Impression (CGI) Scales Improvement (Investigator Only) [ Time Frame: Baseline, Week 13 and 25 ]
   The CGI improvement scale is a 7 point scale that shows improvement. This scale requires the investigator to assess how much of the participant's illness has improved or worsened relative to a Baseline state. 1= very much improved to 7= very much worse.
8. Neuropsychological Checklists Child Behavior (CBCL) [ Time Frame: Baseline, Week 13 and 25 ]
   CBCL is a questionnaire by which parents rate a child's problem behaviors and competencies. The preschool checklist (CBCL/1.5 to 5) is intended for use with children aged 18 months to 5 years. The school-age version (CBCL/6-18) is for children aged 6 to 18 years. It is used as a diagnostic tool for a variety of behavioral and emotional problems.
9. Neuropsychological Checklist Adult Behavior (ABCL) [ Time Frame: Baseline, Week 13 and 25 ]
   The ABCL is a questionnaire used to obtain information about the individual's adaptive functioning and problems. It is intended for use with adults aged 19 to 59 years. This is a diagnostic tool for a variety of behavioral and emotional problems. It is completed by an observer who knows the individual well.
10. Neuropsychological Assessment Adult Self Report (ASR) [ Time Frame: Baseline, Week 13 and 25 ]
    Assessment adult self report (ASR) is a questionnaire used to obtain information about the individual's adaptive functioning and problems. It will be completed by those participants able to self-complete the form.
11. EQ-5D-5L Health Status Quality of Life [ Time Frame: Baseline,Week 4, 13 and 25 ]
    The EQ-5D-5L provides a simple descriptive profile and a single index value for health status that can be used in the clinical and economic evaluation of health care as well as in population health surveys. It is designed for self-completion by participants or caregivers of subjects aged ≥12 years. There are 5 values, mobility, self care, usual activities, pain/discomfort, anxiety/depression. The questionnaire includes 5 levels, no problems, slight problems, moderate problems, severe problems, and extreme problems which are used for assessment.
12. Plasma Concentration of Phenylbutyric Acid (PBA) [ Time Frame: Week 4 ]
    Blood samples will be collected for the assessment of the plasma level of PBA and plasma concentration levels will be summarized using descriptive statistics.
13. Plasma Concentration of Phenylacetic Acid (PAA) [ Time Frame: Week 4 ]
    Blood samples will be collected for the assessment of the plasma level of PAA and plasma concentration levels will be summarized using descriptive statistics.
14. Plasma Concentration of Phenylacetylglutamine (PAGN) [ Time Frame: Week 4 ]
    Blood samples will be collected for the assessment of plasma level of PAGN and plasma concentration levels will be summarized using descriptive statistics.
15. Urinary Excretion of Phenylacetylglutamine (PAGN) [ Time Frame: Week 4 ]
    Urine samples will be collected at hours 0 and 8 for the assessment of urinary excretion of PAGN.
16. Rate of Adverse Events [ Time Frame: Baseline through Week 25 and 30 days post last dose for SAEs ]
    Treatment Emergent Adverse Events will be summarized by treatment received.
17. Drug preference (NaPBA arm only) [ Time Frame: Week 5 ]
    Measures which drug is preferred. Participant is queried directly however for younger children, the parent or legal guardian can report on behalf of the child if more appropriate.
18. Plasma Ammonia Level [ Time Frame: Day 1, Week 1, 2, 3, 4, 5, 9, 13, 17, 21, 25 ]
    Plasma ammonia will be analyzed on Day 1, Week 1, 2, 3, 4, 5, 9, 13, 17, 21, 25.

Eligibility Criteria

• Ages Eligible for Study: up to 99 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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.

Contacts and Locations

Contacts

Contact: HorizonTherapeutics; 866-479-6742; clinicaltrials@horizontherapeutics.com

Locations

United States, Florida

University of Florida (UF) - Shands Hospital; Recruiting

Gainesville, Florida, United States, 32610-0214

Contact: Roberto Zori, MD 352-273-7763 zorirt@peds.ufl.edu

Principal Investigator: Roberto Zori, MD

United States, New York

Mount Sinai School of Medicine; Recruiting

New York, New York, United States, 10029

Contact: George Diaz, M.D., PhD. 212-241-0858 George.Diaz@mssm.edu

Principal Investigator: George Diaz, M.D., PhD.

United States, Ohio

University Hospitals Case Medical Center; Recruiting

Cleveland, Ohio, United States, 44106-6005

Contact: Dr. Jirair Bedoyan, MD 216-844-7124 Jirair.Bedoyan@UHhospitals.org

Principal Investigator: Dr. Jirair Bedoyan, MD

United States, Pennsylvania

Children's Hospital of Pittsburgh of UPMC; Recruiting

Pittsburgh, Pennsylvania, United States, 15224

Contact: Dr. Gerard Vockley, MD, PhD 412-692-7530 Jennifer.baker@chp.edu

Contact: Jennifer Baker 412-692-7530 Jennifer.baker@chp.edu

Principal Investigator: Dr. Gerard Vockley, MD, PhD

United States, Texas

University of Texas, Southwestern Medical Centre; Recruiting

Dallas, Texas, United States, 753908565

Contact: Markey McNutt, MD, PhD 214-648-1814 Markey.McNutt@UTSouthwestern.edu

Principal Investigator: Markey McNutt, MD, PhD

United States, Utah

University of Utah; Recruiting

Salt Lake City, Utah, United States, 84132

Contact: Dr. Nicola Longo, M.D., PhD. 801-587-3605 Nicola.Longo@hsc.utah.edu

Contact: Carrie Bailey 801 587 3605 Carrie.Bailey@hsc.utah.edu

Principal Investigator: Dr. Nicola Longo, M.D., PhD.

Belgium

Cliniques Universitaires Saint-Luc; Withdrawn

Brussels, Belgium, 1200

Italy

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

Padua, Veneto, Italy, 35128

Contact: Alberto Burlina, MD +39 049 821 3569 alberto.burlina@unipd.it

Principal Investigator: Alberto Burlina, MD

Bambino Gesù Children's Research Hospital; Recruiting

Rome, Italy, 00165

Contact: Diego Martinelli, MD, PhD +39 06/68592275 diego.martinelli@opbg.net

Principal Investigator: Dr. Diego Martinelli, MD, PhD

Spain

Hospital Materno-Infantil (HRU Carlos Haya); Recruiting

Málaga, Andalucia, Spain, 29006

Contact: Dr. Javier Blasco-Alonso, MD 34 951 29 21 91 javierblascoalonso@yahoo.es

Contact: Almudena Frias 34 951 29 21 91

Principal Investigator: Dr. Javier Blasco-Alonso

Hospital Clinico Universitario de Santiago; Withdrawn

Santiago de Compostela, Galicia, Spain, 15706

Hospital Universitario de Cruces; Completed

Barakaldo, Vizcaya, Spain, 48903

Switzerland

Universitätsspital, Inselspital Bern; Completed

Bern, Switzerland, 3010

University Children's Hospital; Withdrawn

Zurich, Switzerland, 75, 8032

Sponsors and Collaborators

Horizon Therapeutics, LLC

Investigators

• Study Director: Colleen Canavan, BS; Horizon Therapeutics, LLC

More Information

• Responsible Party: Horizon Therapeutics, LLC
• ClinicalTrials.gov Identifier: NCT03335488
• Other Study ID Numbers: HPN-100-021; 2015-000075-27 ( EudraCT Number )
• First Posted: November 7, 2017
• Last Update Posted: January 19, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics, LLC ):

Urea; Hyperammonemic crisis (HAC)

Additional relevant MeSH terms:

Urea Cycle Disorders, Inborn; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; 4-phenylbutyric acid; Glycerol; Cryoprotective Agents; Protective Agents; Physiological Effects of Drugs; Antineoplastic Agents