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Urea Cycle DisordersPhase 2NCT00947544

Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children With Urea Cycle Disorders

A Phase 2 study testing HPN-100 and NaPBA in people with Urea Cycle Disorders, run by Amgen at 8 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Protocol HPN-100-005 was the first study of HPN-100 in pediatric subjects with urea cycle disorders (UCDs) and was a fixed-sequence, open-label, switch over study of HPN-100 with a long-term (12 month) safety extension designed to assess the safety of HPN-100 and to prospectively assess its ability to control blood… Read more about this study

Who is it for?
Ages 6 to 17 years
Conditions the study is for
Urea Cycle Disorders
What is being tested?
HPN-100 and NaPBA
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
17 participants
Where
8 sitesin 2 countries
Study dates
Mar 2010to Aug 2011
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 6 to 17 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Male and female subjects 6-17 years old.
  • Signed informed consent by subject's legally acceptable representative and assent by subject, as applicable.
  • Diagnosis of urea cycle disorder (enzyme or transporter deficiency) confirmed via enzymatic, biochemical, or genetic testing.
  • On a stable dose of NaPBA for a diagnosis of UCD for at least 1 week prior to the Day 1 visit.
  • Subjects who are not on a stable dose of NaPBA at the initial screening visit may be converted to a stable dose of NaPBA during the screening period and enrolled as long as they are on a stable dose of NaPBA at least 1 week prior to Day 1
  • Able to perform and comply with study activities, including blood draws and urine collections.
  • 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.

Who cannot join

  • Screening ammonia level of ≥100 μmol/L or signs and symptoms indicative of hyperammonemia; subjects may be re-screened after their ammonia is controlled, at the discretion of the investigator.
  • History of 4 or more hyperammonemic events as defined in Section 3.5.1 in the preceding 12 months.
  • Use of any investigational drug within 30 days of Day 1.
  • Active infection (viral or bacterial) or any other condition that may increase ammonia levels.
  • Any clinical or laboratory abnormality of Grade 3 or greater severity according to the CTCAE v3.0, except Grade 3 elevations in liver enzymes, defined as levels 5-20 times ULN in 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.
Show all 12Show fewer
  • 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.
  • History of QTc interval prolongation or QTc interval > 450 msec at screening or baseline.
  • Known hypersensitivity to PAA or PBA.
  • Liver transplant, including hepatocellular transplant.
  • Currently treated with sodium benzoate or Carbaglu® (carglumic acid). At the discretion of the investigator, subjects on sodium benzoate who are otherwise eligible to participate may be switched to 100% NaPBA during the 30 day screening period as part of the study, and at least 7 days prior to Day 1 (Visit 2).
  • Breastfeeding or lactating females.

Trial locations and contacts

8 sites in 2 countries.

8 sites in 2 countries

United States7 sites

  • Baylor College of Medicine

    Houston, Texas, 77030

  • UCLA

    Los Angeles, California, 90095

  • Medical College of Wisconsin

    Milwaukee, Wisconsin, 53226

  • Mount Sinai School of Medicine

    New York, New York, 10029

  • University of Pittsburgh

    Pittsburgh, Pennsylvania, 15201

  • Seattle Children's Hospital

    Seattle, Washington, 98105

  • The George Washington DC Children's National Medical Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

Canada1 site

  • The Hospital for Sick Children

    Toronto, Ontario, M5G1X8

Other trials in Canada

About this study

Official title: A Phase 2, Fixed-Sequence, Open-Label, Switch-Over Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children 6-17 Years of Age With Urea Cycle Disorders, With a Long-Term Safety Extension

Protocol HPN-100-005 was the first study of HPN-100 in pediatric subjects with urea cycle disorders (UCDs) and was a fixed-sequence, open-label, switch over study of HPN-100 with a long-term (12 month) safety extension designed to assess the safety of HPN-100 and to prospectively assess its ability to control blood ammonia as compared with Sodium Phenylbutyrate (NaPBA). Upon DSMB review of the first ten subjects who completed the switch over part of the study, and with DSMB approval, up to an additional 20 subjects were enrolled into the safety extension part of the study. 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 an equivalent amount of PBA to 40 tablets of NaPBA.

Read the detailed description

This was a fixed-sequence, open-label, switch over study of HPN-100 with a long-term (12 month) safety extension part designed to assess the safety of HPN-100 in pediatric subjects and to prospectively assess the ability of HPN-100 to control blood ammonia compared with NaPBA.

For those subjects who participated in the switch over, NaPBA was dosed three times daily (TID) with meals during the first week and the same PBA mole-equivalent dose of HPN-100 during the second week. If there were safety concerns regarding a single-step transition from NaPBA to HPN-100, at the investigator's discretion, the transition could occur in 2 steps such that in the second week, subjects might receive 50% of the PBA equivalent dose as NaPBA and 50% as HPN-100 before receiving 100% of the PBA equivalent dose as HPN-100 in the third week. Serial blood samples were collected for PK and blood ammonia assessments after each drug reached steady state, which was achieved approximately 4 days after initiation of 100% NaPBA or HPN-100 treatment.

The subjects who completed the switch over part of the study, and up to 20 additional subjects, were offered the opportunity to continue in the study by entering the safety extension part of the study to continue receiving open-label HPN-100 for up to 12 months.

Subjects who prematurely terminated the study during the switch-over period after enrollment had safety assessments, including safety labs and a single blood sample drawn for measurement of phenylbutyrate (PBA), the active metabolite phenylacetate (PAA), and the terminal metabolite phenylacetylglutamine (PAGN). Subjects who had enrolled in the safety extension period of the study, either directly or following the switch over, but prematurely terminated the study prior to completing the extension period had Month 12 procedures performed, or at a minimum, had safety assessments including safety labs and ammonia had drawn. The time of day at which the blood sample was drawn was recorded as well as the time since the last dose of medication was taken.

Subjects followed a stable diet throughout the study, as prescribed by the investigator, and dietary compliance was recorded at each study visit for both the switch over and safety extension parts of the study.

Study acquired from Horizon in 2024.

Being tested
HPN-100, NaPBA
Keywords
Urea Cycle Disorder, UCD, GT4P, Buphenyl, hyperammonemia, sodium phenylbutyrate
Medical subject headings
Urea Cycle Disorders, Inborn, Hyperammonemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • HPN-100Drug

    Also called GT4P, Glyceryl tri-(4-phenylbutyrate)

    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 that 40 tablets of NapBA do.

  • NaPBADrug

    Also called GT4P, Glyceryl tri-(4-phenylbutyrate)

    NaPBA tablets for oral administration and NaPBA powder for oral, nasogastric, or gastrostomy tube administration contain the active ingredient sodium phenylbutyrate. NaPBA is a prodrug and is rapidly metabolized to PAA, the metabolically active compound that conjugates with glutamine via acetylation to form PAGN, which is excreted by the kidneys.

Study groups in NCT00947544
Study groupRoleWhat they receive
HPN-100 and NaPBAExperimental1 week of NaPBA treatment followed by 1 week of HPN-100 treatment.
Receives: Drug: HPN-100; Drug: NaPBA

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Rate of Adverse Events During the Switchover Part of the Study Rate of Adverse Events (Number of Participants Showing Adverse Events)

    To evaluate the safety and PK characteristics of HPN-100 compared with sodium phenylbutyrate (NaPBA) in pediatric patients with urea cycle disorders (UCDs)

    Measured: 1 week on each treatment for a total of 2 week.

Secondary outcomes (10)

  1. Number and Causes of Hyperammonemic Events (Safety Extension)

    Number of Subjects with at Least One Hyperammonemic Crisis.

    Hyperammonemic crisis is defined as follows:

    • Clinical symptoms associated with ammonia of ≥ 100 µmol/L

    Measured: 1 year

  2. Blood Ammonia Control

    To evaluate control of blood ammonia by HPN-100 compared with NaPBA in pediatric patients with UCDs.

    Measured: Day 7 (NaPBA) and Day 14 (HPN-100)

  3. NH3 Cmax on NaPBA vs. HPN-100 on the Last Day of Treatment With Each Drug

    blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).

    Measured: Day 7 (NaPBA) and Day 14 (HPN-100)

  4. Average Ammonia Values on NaPBA vs. HPN-100 on the Last Day of Treatment With Each Drug (Switch Over)

    blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).

    Measured: Day 7 (NaPBA) and Day 14 (HPN-100)

  5. Rate (Percentage) of Ammonia Values Above Upper Limit of Normal (ULN) on NaPBA vs. HPN-100

    blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).

    Measured: Day 7 (NaPBA) and Day 14 (HPN-100)

  6. Urinary PAGN 24-hour Excretion Values on NaPBA vs. HPN-100 (Switch Over)

    Urinary PAGN (phenylacetylglutamine) 24-hour excretion. Urine was collect during 0-12 hrs and 12-24 hrs.

    Measured: Day 7 (NaPBA) and Day 14 (HPN-100)

  7. Plasma PAA (Phenylacetate) AUC0-24 Values on NaPBA vs. HPN-100 on on the Last Day of Treatment With Each Drug

    blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).

    Measured: Day 7 (NaPBA) and Day 14 (HPN-100)

  8. Plasma PBA (Phenylbutyrate) AUC0-24 Values on NaPBA vs. HPN-100 on on the Last Day of Treatment With Each Drug

    blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).

    Measured: Day 7 (NaPBA) and Day 14 (HPN-100)

  9. Plasma PAGN AUC0-24 Values on NaPBA vs. HPN-100 on on the Last Day of Treatment With Each Drug

    blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).

    Measured: Day 7 (NaPBA) and Day 14 (HPN-100)

  10. Quality of Life Assessed by the SF-15 Questionnaire

    change from baseline to Month 12.

    The SF 15 questionnaire consists of 15 questions that assess the following:

    • Physical functioning (5 questions)
    • Emotional functioning (4 questions)
    • Social functioning (3 questions)
    • School functioning (3 questions) Items were scored on a 5-point Likert scale from 0 (never) to 4 (almost always) or a 3-point scale (0 [not at all], 2 [sometimes], or 4 [a lot] for the young child self-report). Items were reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, and 4=0. Total score was 0-100 scale (averaged from each functional areas). In the 0-100 scale, 0 is the worst score and 100 is best score.

    Improved quality of life was shown by increased total score from baseline to Month 12.

    Measured: 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Jul 2009 (estimated)
  2. Study startMar 2010
  3. Primary completionAug 2011
  4. Study completionAug 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
17 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00947544
Sponsor's protocol ID
HPN-100-005
Status last verified
Jun 2024
First submitted
24 Jul 2009
Last updated
11 Jul 2024
Data monitoring committee
Yes
Individual data sharing
Yes: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

Publications

  • Mokhtarani M, Diaz GA, Rhead W, Berry SA, Lichter-Konecki U, Feigenbaum A, Schulze A, Longo N, Bartley J, Berquist W, Gallagher R, Smith W, McCandless SE, Harding C, Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS Jr, Dickinson K, Moors T, Norris C, Coakley D, Milikien DA, Nagamani SC, Lemons C, Lee B, Scharschmidt BF. Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio. Mol Genet Metab. 2013 Dec;110(4):446-53. doi: 10.1016/j.ymgme.2013.09.017. Epub 2013 Oct 8.

    PubMed 24144944

  • 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. Epub 2013 Jan 3.

    PubMed 22961727

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing HPN-100 and NaPBA in people with Urea Cycle Disorders, run by Amgen at 8 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 25 Dec 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Rate of Adverse Events During the Switchover Part of the Study Rate of Adverse Events (Number of Participants Showing Adverse Events) (time frame: 1 week on each treatment for a total of 2 week.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00947544, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jul 2024.

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