Efficacy and Safety of HPN-100 for the Treatment of Adults With Urea Cycle Disorders

Urea Cycle Disorders Clinical Trial

Official title:

A Phase 3, Randomized, Double-Blind, Cross-Over, Active-Controlled Study of the Efficacy and Safety of HPN-100, Glyceryl Tri-(4-phenylbutyrate), for the Treatment of Adults With Urea Cycle Disorders (Help UCD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00992459
• Other study ID #: HPN-100-006
• Status: Completed
• Phase: Phase 3
• First received: October 8, 2009
• Last updated: January 13, 2017
• Start date: October 2009
• Est. completion date: September 2010

Study information

• Verified date: September 2015
• Source: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This was a randomized, active-controlled, double-blind, cross-over study designed to enroll subjects with UCDs who are being treated with NaPBA.

Description:

This was a randomized, active-controlled, double-blind, cross-over study designed to enroll subjects with UCDs who are being treated with NaPBA. Subjects were randomly assigned to receive either HPN-100 + NaPBA placebo or NaPBA + HPN 100 placebo for 2 weeks, and then crossed over to receive the other treatment for 2 weeks. Venous ammonia was the primary outcome measure. Subjects were admitted to the clinical research unit for 24 hours of pharmacokinetic (PK) blood and urine sampling (including an overnight stay) at the end of each treatment period, by which time the study drug had reached steady state.

Subjects followed a stable diet throughout the study as prescribed by the investigator and dietician. Throughout the study, diet diaries were completed by the subject and dietary protein intake were assessed by a dietician based on completed dietary diaries and consultation with the subject.

Subjects who completed this study and met the study entry criteria, were offered the opportunity to enroll in the HPN-100 open-label safety protocol (HPN-100-007).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: September 2010
• Est. primary completion date: September 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of UCD (Urea Cycle Disorder) involving deficiencies of Carbamyl phosphate synthetase (CPS), Ornithine transcarbamylase (OTC), or Arginosuccinate (ASS), confirmed via enzymatic, biochemical, or genetic testing

• Adult UCD subjects 18 years of age or older who are being treated with Buphenyl/Sodium phenylbuterate (NaPBA) for their UCD; subjects must be on a stable dose of NaPBA for at least 1 week prior to the Day 1 visit. Subjects who are not receiving NaPBA at the initial screening visit, but who have the potential to benefit from treatment, may start receiving NaPBA during the screening period and be enrolled as long as they are on a stable dose of NaPBA for at least 1 week prior to Day 1.

• No clinical evidence of hyperammonemia associated with an ammonia level of = 100 µmol/L during the 2 weeks preceding screening

• Signed informed consent by subject

• Able to perform and comply with study activities, including blood draws and 24-hour urine samples

• Negative pregnancy test for all females of childbearing potential

• All females of childbearing age and all sexually active males must agree to use an acceptable method of contraception throughout the study. Appropriate contraceptive methods include hormonal contraceptives (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:

• Screening or baseline ammonia level of = 100 µmol/L or signs and symptoms indicative of hyperammonemia during the 2-week period preceding screening or enrollment; subjects may be re-screened after their ammonia is controlled and are stable for at least 14 days, at the discretion of the investigator

• Use of any investigational drug within 30 days of Day 1

• Active infection (viral or bacterial) or any other intercurrent condition (apart from UCD) that may increase ammonia levels

• Any clinical or laboratory abnormality of Grade 3 or greater severity according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0, except Grade 3 elevations in liver enzymes, defined as levels 5-20 times upper limit of normal (ULN) in alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), or gamma glutamyl transpeptidase (GGT) in a clinically stable subject

• Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at increased risk by participating in this study

• Use of any medication known to significantly affect renal clearance (e.g., probenecid) or to increase protein catabolism (e.g., corticosteroids), or other medication known to increase ammonia levels (e.g., valproate), within the 24 hours prior to Day 1 and throughout the study

• Use of sodium benzoate within one week of Day 1

• History of corrected QT interval (QTc) prolongation or QTc interval > 450 msec at screening or baseline

• Known hypersensitivity to phenylacetate (PAA) or phenylbutyrate (PBA)

• Liver transplant, including hepatocellular transplant

• Breastfeeding or lactating females

Related Conditions & MeSH terms

• Disease
• Urea Cycle Disorders
• Urea Cycle Disorders, Inborn

Intervention

Drug:
• HPN-100
HPN-100 is a triglyceride that has a similar mechanism of action as NaPBA. It is a liquid with minimal taste and odor. Three teaspoons of HPN-100 (~17.4mL) delivers equivalent amount of PBA in 40 tablets of NaPBA.
• Buphenyl (NaPBA)
Buphenyl (NaPBA) will be the comparator drug to HPN-100 in this study.

Locations

Country	Name	City	State
Canada	The Hospital for Sick Children	Toronto	Ontario
United States	Denver Children's Hospital	Aurora	Colorado
United States	SNBL-Clinical Pharmacology Center	Baltimore	Maryland
United States	Tufts-New England Medical Center	Boston	Massachusetts
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	University of Florida	Gainesville	Florida
United States	Baylor College of Medicine	Houston	Texas
United States	University of Iowa	Iowa City	Iowa
United States	Long Beach Memorial	Long Beach	California
United States	UCLA	Los Angeles	California
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota Medical Center	Minneapolis	Minnesota
United States	Yale School of Medicine	New Haven	Connecticut
United States	Mount Sinai School of Medicine	New York	New York
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	Oregon Health & Science University	Portland	Oregon
United States	University of Utah	Salt Lake City	Utah
United States	Stanford University	Stanford	California
United States	Westchester Medical Center	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Horizon Pharma Ireland, Ltd., Dublin Ireland

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

Diaz GA, Krivitzky LS, Mokhtarani M, Rhead W, Bartley J, Feigenbaum A, Longo N, Berquist W, Berry SA, Gallagher R, Lichter-Konecki U, Bartholomew D, Harding CO, Cederbaum S, McCandless SE, Smith W, Vockley G, Bart SA, Korson MS, Kronn D, Zori R, Merritt JL 2nd, C S Nagamani S, Mauney J, Lemons C, Dickinson K, Moors TL, Coakley DF, Scharschmidt BF, Lee B. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology. 2013 Jun;57(6):2171-9. doi: 10.1002/hep.26058. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Primary Endpoint Was the 24-hour Area Under the Curve for Blood Ammonia (NH324-hour AUC) on Days 14 and 28.	Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28. Arm A day 14 and Arm B day 28 data were combined as a NaPBA treatment Arm. Arm B day 14 and Arm A day 28 data were combined as a HPN-100 treatment Arm.	pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28
Secondary	Correlation Between Urinary Phenylacetylglutamine (PAGN) Excretion Over 24 Hours (U-PAGN24-hour Excr) and Venous Ammonia - Area Under the Concentration-time Curve From Time 0 (Predose) to 24 Hours (AUC0-24)	The correlation between 24-hour urinary phenylacetylglutamine (PAGN) excretion (U-PAGN24-hour Excr) and venous ammonia AUC0-24 was summarized and the correlation was tested using the Spearman rank-order correlation.	28 Days
Secondary	Maximum Ammonia Values Observed on NaPBA Versus HPN-100	Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28.	pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28
Secondary	Rate (Percentage) of Ammonia Values Above Upper Limit of Normal (ULN) on NaPBA Versus HPN-100	NaPBA treated arm: total 345 blood samples were collected. HPN-100 treated arm: 343 blood samples were collected.	on Day 14 and Day 28
Secondary	Number and Severity of Symptomatic Hyperammonemic Crises	Severity of symptomatic hyperammonemic crises was measured by peak ammonia level (µmol/L) when it is >= 100 µmol/L.	29 Days
Secondary	Rate of Adverse Events in Each Treatment Group		29 Days
Secondary	Cmax for PAA of NaPBA and HPN-100 in Plasma	Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28.	pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28
Secondary	Cmax for PBA of NaPBA and HPN-100 in Plasma	Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28.	pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28
Secondary	Cmax PAGN of NaPBA and HPN-100 in Plasma	Blood samples were collected at pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28.	pre-dose, 2, 4, 8, 12, 16, 20 and 24 hours after first dose on days 14 and 28
Secondary	U-PAGN24-hour Excr of NaPBA and HPN-100		24 hours on Day 14 of each treatments