E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Urea Cycle Disorders (UCDs) |
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E.1.1.1 | Medical condition in easily understood language |
Genetic disease that affects how the body gets rid of waste from excess protein in the diet |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10013373 |
E.1.2 | Term | Disorders of urea cycle metabolism |
E.1.2 | System Organ Class | 100000161833 |
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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 |
To assess the safety, tolerability, pharmacokinetics (PK) and ammonia control of RAVICTI and NaPBA in UCD subjects not currently treated with phenylacetic acid (also referred to as phenylacetate; PAA) prodrugs. |
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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 |
• Signed informed consent given by the subject or the subject’s parent/legal guardian for those under 18 years of age or the age of consent by local regulation • Male and female subjects with a suspected or confirmed UCD diagnosis of any subtype, except NAGS deficiency - Suspected diagnosis is defined as having experienced an HAC or a documented high ammonia of ≥100 µmol/L - Confirmed diagnosis is determined via enzymatic, biochemical, or genetic testing • Requires nitrogen binding agents according to the judgment of the Investigator • ≥ 2 months of age and older • All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception from signing the informed consent throughout the duration of the study and for 30 days after the last dose of study drug. 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. |
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E.4 | Principal exclusion criteria |
• Subject has received chronic treatment with an oral phenylbutyrate (RAVICTI, NaPBA, Pheburane, or other) longer than 14 consecutive days within one year prior to enrollment - Temporary use of oral PBA for acute management of a hyperammonemic crisis in the past is acceptable. • Any concomitant illness (e.g. malabsorption or clinically significant liver or bowel disease) which would preclude the subject’s safe participation, as judged by the Investigator • Have undergone liver transplantation, including hepatocellular transplant • Subjects on NaBz at Baseline will be excluded if they are viewed by the Investigator as being unable to undergo NaBz transition to a PAA prodrug during the Initial Treatment Period • Known hypersensitivity to PBA or any excipients of the NaPBA/PBA formulations • Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed at the Baseline Visit prior to the start of study drug.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is the Rate of Treatment Success: Efficacy |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The efficacy endpoint will be evaluated during the Initial Treatment Period |
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E.5.2 | Secondary end point(s) |
1) Efficacy a) Initial Treatment Period Endpoints (RAVICTI vs NaPBA) • Drug discontinuation due to any reason b) Transition, Maintenance, and Safety Extension Periods (RAVICTI) • Control of plasma ammonia • Annualized rate of HAC
2) Safety and Tolerability • Assessment of AEs • Standard clinical laboratory tests • Amino acid panel • Rate of drug discontinuation due to AEs
3) Clinical Outcome Assessments • Rate of treatment success in the Initial Treatment Period • Subject preference for study drug (Arm 2 after exposure to both RAVICTI and NaPBA) • Palatability of study drug (Hedonic Scale) • Changes in CGI scales (Investigator) • Neuropsychological assessments: CBCL or ABCL or ASR • EQ-5D-5L health status quality of life assessment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) Initial Treatment Period (RAVICTI vs NaPBA) • Drug discontinuation due to any reason • Amino acid panel • Standard clinical laboratory tests • Assessment of AEs • Rate of Treatment Success • EQ-5D-5L health status quality of life assessment
b) Transition, Maintenance, and Safety Extension Periods (RAVICTI) • Control of plasma ammonia • Annualized rate of HAC • Amino acid panel • Standard clinical laboratory tests • Neuropsychological assessments: CBCL or ABCL or ASR • EQ-5D-5L health status quality of life assessment • Subject preference for study drug (Arm 2 after exposure to both RAVICTI and NaPBA) • Assessment of AEs • Changes in CGI scales (Investigator) • Palatability of study drug (Hedonic Scale) • Rate of drug discontinuation due to AEs |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 | No |
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 |
Austria |
Belgium |
Italy |
Spain |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |