E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Urea Cycle Disorder (urea cycle enzyme or transporter deficiency) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10013373 |
E.1.2 | Term | Disorders of urea cycle metabolism |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the safety and tolerability of escalating doses of HPN-100 compared to a constant dose of sodium PBA (European Trade name: AMMONAPS®; United States trade name BUPHENYL®) in adult and pediatric subjects with UCDs. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to assess: • plasma and urine PK characteristics of HPN-100 and sodium phenylbutyrate (sodium PBA) metabolites • preliminary evidence of efficacy (as assessed by venous ammonia levels and urinary excretion of PAGN) • compliance with diet and study drug treatment • subject-reported outcomes of symptoms and drug preference
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male and female subjects ≥ 6 years old • Signed informed consent by subject and/or subject’s legally acceptable representative • Diagnosis of urea cycle disorder (enzyme or transporter deficiency) confirmed via enzymatic, biochemical or genetic testing • Currently being treated with sodium PBA for a diagnosis of UCD for at least one week prior to the screening visit • Able to perform and comply with study activities (including the ability to adhere to 24-hour urine collections both in the clinic and after discharge; i.e., no subjects in diapers) • Willing to maintain a constant diet throughout the study (unless the investigator recommends a change based on safety considerations) • Negative pregnancy test for all females of childbearing potential • All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception throughout the study
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E.4 | Principal exclusion criteria |
• Use of any investigational drug (sodium PBA excepted) within 30 days prior to Day 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 CTCAE v3.0 (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 subject • 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 Day 1 • History of diagnosis with long QT syndrome or QTc interval > 450 msec at screening • Other medical conditions which in the judgment of the investigator preclude entry • Known hypersensitivity to PAA or PBA • Creatinine levels ≥ 1.5 upper limit of normal (ULN) • Liver transplant, including hepatocellular transplant • Currently treated with sodium benzoate or Carbaglu® (carglumic acid)
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of this study is to evaluate the safety and tolerability of escalating doses of HPN-100 compared to a constant dose of sodium PBA (European Trade name: AMMONAPS®; United States trade name BUPHENYL®) in adult and pediatric subjects with UCDs. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Switch-Over Dose Escalation |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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A single pre-dose blood sample will be drawn for measurement of PBA, PBG, PBGN, PAA, PAG, and PAGN. The time of day at which the blood sample is drawn will be recorded as well as the time since the last dose of either HPN-100 or sodium PBA. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |