Urea Cycle DisordersPhase 2NCT00551200
Dose-Escalation Safety Study of HPN-100 to Treat Urea Cycle Disorders
A Phase 2 study testing HPN-100 and BUPHENYL® in people with Urea Cycle Disorders, run by Amgen at 2 sites in United States.
Trial summary
The purpose of this study is to determine whether HPN-100 is safe and tolerable in subjects with Urea Cycle Disorders. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Urea Cycle Disorders
- What is being tested?
- HPN-100 and BUPHENYL®
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 2 sitesUnited States
- Study dates
- Oct 2007to Dec 2008
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male and female patients at least 18 years old
- Signed written informed consent by patient or patient's representative
- Diagnosis of urea cycle enzyme deficiency confirmed via enzymatic or genetic testing
- Currently treated with Buphenyl® TID for a minimum of 2 weeks prior to Visit 1
- Able to perform study activities (including the ability to collect all urine in the clinic, i.e., no patients in diapers)
- Negative pregnancy test for all females of childbearing potential. All females of childbearing potential must agree to use an acceptable method of contraception throughout the study
Who cannot join
- Use of any investigational drug within 30 days of Buphenyl® Visit 1
- Active infection (viral or bacterial) or any other condition that may increase ammonia levels
- Laboratory values outside the normal range that are determined to be clinically significant by the investigator
- Any clinical or laboratory abnormality of Grade 3 or greater severity according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (or for conditions not covered by the CTCAE, a severe or life-threatening toxicity); except that Grade 3 elevations in liver enzymes are allowed in an otherwise clinically stable patient
- Use of any medication known to significantly affect renal clearance (e.g., probenecid) or to increase protein catabolism (e.g., corticosteroids), or other medication (e.g., valproate) known to increase ammonia levels, within the 24 hours prior to Visit 1
- Preexisting QTc interval prolongation (> 450 msec for males or > 460 msec for females)
Show all 10Show fewer
- Other severe chronic medical conditions
- Known hypersensitivity to PAA, PBA, or benzoate
- Creatinine levels equal to or greater than 1.5 × ULN
- Liver transplant
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Baylor College of Medicine
Houston, Texas, 77030
University of Minnesota
Minneapolis, Minnesota, 55455
About this study
Official title: A Phase 2, Open-Label, Switch-Over, Dose-Escalation Study of the Safety and Tolerability of HPN-100 Compared to Buphenyl® (Sodium Phenylbutyrate) in Patients With Urea Cycle Disorders
The purpose of this study is to determine whether HPN-100 is safe and tolerable in subjects with Urea Cycle Disorders.
Read the detailed description
When protein is broken down in the body, nitrogen is formed. In healthy individuals, the body combines this nitrogen with other molecules to create a harmless substance called urea, which is excreted in the urine. Patients with Urea Cycle Disorders (UCD) are unable to create as much urea from nitrogen, and therefore, toxic levels of nitrogen can accumulate in the body, causing harm. To treat these patients, doctors usually have the patient consume less protein and supplement certain amino acids that may be lacking. A drug called Buphenyl® is sometimes prescribed as an adjunctive treatment for the chronic maintenance of UCD patients in order to keep ammonia levels down. Some issues with Buphenyl® include a high pill burden (up to 40 pills per day), bad taste and odor, and high sodium content. Like Buphenyl®, HPN-100 provides an alternate way for the body to dispose of nitrogen, other than through the urea cycle. Unlike Buphenyl®, HPN-100 is an odorless, tasteless, concentrated oil that does not contain large amounts of sodium.
Study acquired from Horizon in 2024.
- Conditions
- Urea Cycle Disorders
- Being tested
- HPN-100, BUPHENYL®
- Keywords
- Buphenyl, Sodium Phenylbutyrate, Urea Cycle Disorder, UCD
- Medical subject headings
- Urea Cycle Disorders, Inborn
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HPN-100Drug
Subjects will be taking prescribed dose of Buphenyl® TID (not to exceed 20g/day) at least two weeks prior to enrollment. Subjects will take prescribed dose of Buphenyl® TID for first week of study, and then switch over to HPN-100 TID during a dose-escalation phase. The dose of HPN-100 will be increased and the dose of Buphenyl® will be decreased each week by 50 mg/kg until entire daily dose of phenylbutyrate is HPN-100. Target HPN-100 dose will contain the same amount of phenylbutyrate as the subject's prescribed daily dose of Buphenyl®. Subject will take HPN-100 alone for one week and then switch back to previous dose of Buphenyl for the last week of the study.
BUPHENYL®Drug
Also called Sodium Phenylbutyrate, NaPBA
BUPHENYL® (sodium phenylbutyrate) tablets and powder have been approved for marketing in the United States since 1996 as an adjunctive therapy in the long-term management of patients with UCDs involving deficiencies of CPS, OTC, or ASS.
| Study group | Role | What they receive |
|---|---|---|
| BUPHENYL® to HPN-100 vs. HPN-100 | Active comparator | Buphenyl treatment for one week was followed by dose escalation to HPN-100. Dose of Buphenyl was gradually decreased while HPN-100 dose was gradually increased until subject reached dosing of 100% HPN-100. HPN-100 at 100% of the dose was given for 1 week before subject was switched back to original Buphenyl treatment. Receives: Drug: HPN-100; Drug: BUPHENYL® |
What is being measured
The primary outcome is the main question the study is designed to answer.
Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve)
Data were collected at pre-first dose and at 30 minutes and 1, 2, 4, 5, 6, 8, 10, 12, and 24 hours post first dose.
Measured: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation
Number of Subjects Experienced Adverse Events
Measured: during the period on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)
Number of Subjects Experienced Serious Adverse Events
Measured: during the period subjects on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)
Secondary outcomes (2)
Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites)
measured AUC0-24 (Area under the curve from time 0 (pre-dose) to 24 hours) for each metabolite in plasma. Data were collected at 30 minutes and 1, 2, 4, 5, 6, 8, 10, 12, and 24 hours post-first dose.
Measured: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone)
Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question)
Measured: End of Study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Oct 2007 (estimated)
- Study startOct 2007
- Primary completionJul 2008
- Study completionDec 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Urea Cycle DisordersStudies of the same condition, open and under way.
- More trials run by AmgenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- 14 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amgen
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- MD, Study director, Amgen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00551200
- Sponsor's protocol ID
- UP1204-003 (HPN-100-003)
- Status last verified
- Jun 2024
- First submitted
- 26 Oct 2007
- Last updated
- 10 Jul 2024
- Results posted
- Yes, on ClinicalTrials.gov
- 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
Shih VE. Alternative-pathway therapy for hyperammonemia. N Engl J Med. 2007 May 31;356(22):2321-2. doi: 10.1056/NEJMe078075. No abstract available.
PubMed 17538092Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med. 2007 May 31;356(22):2282-92. doi: 10.1056/NEJMoa066596.
PubMed 17538087Mokhtarani 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 24144944Diaz 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
Study at a glance
From the registry record, last updated by the sponsor on 10 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2, Open-Label, Switch-Over, Dose-Escalation Study of the Safety and Tolerability of HPN-100 Compared to Buphenyl® (Sodium Phenylbutyrate) in Patients With Urea Cycle Disorders
- ClinicalTrials.gov ID
- NCT00551200
- Acronym / sponsor ID
- UP1204-003 (HPN-100-003)
- Conditions
- Urea Cycle Disorders
- Keywords
- Buphenyl, Sodium Phenylbutyrate, Urea Cycle Disorder, UCD
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 14 participants (actual)
- Lead sponsor
- AmgenIndustry (pharma, biotech, devices)
- Study start
- Oct 2007
- Primary completion
- Jul 2008 (actual)
- Study completion
- Dec 2008 (actual)
- First posted
- 30 Oct 2007 (estimated)
- Results
- Posted 12 May 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine whether HPN-100 is safe and tolerable in subjects with Urea Cycle Disorders.
Detailed description
When protein is broken down in the body, nitrogen is formed. In healthy individuals, the body combines this nitrogen with other molecules to create a harmless substance called urea, which is excreted in the urine. Patients with Urea Cycle Disorders (UCD) are unable to create as much urea from nitrogen, and therefore, toxic levels of nitrogen can accumulate in the body, causing harm. To treat these patients, doctors usually have the patient consume less protein and supplement certain amino acids that may be lacking. A drug called Buphenyl® is sometimes prescribed as an adjunctive treatment for the chronic maintenance of UCD patients in order to keep ammonia levels down. Some issues with Buphenyl® include a high pill burden (up to 40 pills per day), bad taste and odor, and high sodium content. Like Buphenyl®, HPN-100 provides an alternate way for the body to dispose of nitrogen, other than through the urea cycle. Unlike Buphenyl®, HPN-100 is an odorless, tasteless, concentrated oil that does not contain large amounts of sodium.
Study acquired from Horizon in 2024.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| BUPHENYL® to HPN-100 vs. HPN-100 | Active comparator | Drug: HPN-100, Drug: BUPHENYL®Buphenyl treatment for one week was followed by dose escalation to HPN-100. Dose of Buphenyl was gradually decreased while HPN-100 dose was gradually increased until subject reached dosing of 100% HPN-100. HPN-100 at 100% of the dose was given for 1 week before subject was switched back to original Buphenyl treatment. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Male and female patients at least 18 years old
- Signed written informed consent by patient or patient's representative
- Diagnosis of urea cycle enzyme deficiency confirmed via enzymatic or genetic testing
- Currently treated with Buphenyl® TID for a minimum of 2 weeks prior to Visit 1
- Able to perform study activities (including the ability to collect all urine in the clinic, i.e., no patients in diapers)
Key exclusion criteria (10 listed)
- Use of any investigational drug within 30 days of Buphenyl® Visit 1
- Active infection (viral or bacterial) or any other condition that may increase ammonia levels
- Laboratory values outside the normal range that are determined to be clinically significant by the investigator
- Any clinical or laboratory abnormality of Grade 3 or greater severity according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (or for conditions not covered by the CTCAE, a severe or life-threatening toxicity); except that Grade 3 elevations in liver enzymes are allowed in an otherwise clinically stable patient
- Use of any medication known to significantly affect renal clearance (e.g., probenecid) or to increase protein catabolism (e.g., corticosteroids), or other medication (e.g., valproate) known to increase ammonia levels, within the 24 hours prior to Visit 1
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HPN-100Subjects will be taking prescribed dose of Buphenyl® TID (not to exceed 20g/day) at least two weeks prior to enrollment. Subjects will take prescribed dose of Buphenyl® TID for first week of study, and then switch over to HPN-100 TID during a dose-escalation phase. The dose of HPN-100 will be increased and the dose of Buphenyl® will be decreased each week by 50 mg/kg until entire daily dose of phenylbutyrate is HPN-100. Target HPN-100 dose will contain the same amount of phenylbutyrate as the subject's prescribed daily dose of Buphenyl®. Subject will take HPN-100 alone for one week and then switch back to previous dose of Buphenyl for the last week of the study. | Drug | BUPHENYL® to HPN-100 vs. HPN-100 |
| BUPHENYL®Also: Sodium Phenylbutyrate, NaPBABUPHENYL® (sodium phenylbutyrate) tablets and powder have been approved for marketing in the United States since 1996 as an adjunctive therapy in the long-term management of patients with UCDs involving deficiencies of CPS, OTC, or ASS. | Drug | BUPHENYL® to HPN-100 vs. HPN-100 |
Primary outcome
Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve)
Time frame: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation
Data were collected at pre-first dose and at 30 minutes and 1, 2, 4, 5, 6, 8, 10, 12, and 24 hours post first dose.
Number of Subjects Experienced Adverse Events
Time frame: during the period on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)
Number of Subjects Experienced Serious Adverse Events
Time frame: during the period subjects on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)
2 secondary outcomes
Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites)
Time frame: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone)
Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question)
Time frame: End of Study
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jul 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 17538092Shih VE. Alternative-pathway therapy for hyperammonemia. N Engl J Med. 2007 May 31;356(22):2321-2. doi: 10.1056/NEJMe078075. No abstract available.
- Background: PubMed 17538087Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med. 2007 May 31;356(22):2282-92. doi: 10.1056/NEJMoa066596.
- Derived from this study: PubMed 24144944Mokhtarani 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.
- Derived from this study: PubMed 22961727Diaz 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.
- Click here to read an overview of Urea Cycle DisordersLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
MD study director
Amgen
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing HPN-100 and BUPHENYL® in people with Urea Cycle Disorders, run by Amgen at 2 sites in United States.
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 6 inclusion and 10 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 10 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 2 sites in United States. 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 12 May 2015). 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?
Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve) (time frame: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation). The study lists 3 primary outcomes in all. 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 NCT00551200, which also lists 4 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 10 Jul 2024.