E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
MedDRA Classification |
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 |
To evaluate the long-term safety of HPN 100 and its control of blood ammonia in pediatric subjects with urea cycle disorders (UCDs) |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male and female patients 6–17 years old
• Signed informed consent by patient’s legally acceptable representative and assent by patient, 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; if not on a stable dose of NaPBA at the initial screening visit, patients may have been converted to a stable dose of NaPBA during the screening period and enrolled as long as they were on a stable dose of NaPBA for 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 have agreed to use an acceptable method of contraception throughout the study. Appropriate contraceptive methods included hormonal contraceptives (oral, injected, implanted, or transdermal), tubal ligation, intrauterine device, hysterectomy, vasectomy, or double barrier methods. Abstinence was an acceptable form of birth control, though appropriate contraception must have been used if the patient became sexually active. |
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E.4 | Principal exclusion criteria |
• Screening ammonia level of ≥ 100 μmol/L or signs and symptoms indicative of hyperammonemia; patients may have been rescreened after their ammonia was controlled, at the discretion of the investigator
• History of 4 or more hyperammonemic events (defined as clinical symptoms associated with ammonia of ≥ 100 μmol/L) 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 have increased 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), aspartate aminotransferase (AST), or gamma glutamyl transpeptidase (GGT) in a clinically stable patient
• Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may have put the patient 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
• 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, patients on sodium benzoate who were otherwise eligible to participate may have been 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Blood ammonia levels
• Number and causes of hyperammonemic events
• Quality of life assessed by the SF-15 (pediatric) questionnaire
• Neuropsychological testing
• Plasma metabolite levels |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | No |
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA 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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 1 |