E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
hereditary tyrosinemia type 1 |
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E.1.1.1 | Medical condition in easily understood language |
hereditary tyrosinemia type 1 |
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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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10069462 |
E.1.2 | Term | Tyrosinemia type I |
E.1.2 | System Organ Class | 100000004850 |
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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 evaluate the steady-state exposure to nitisinone during once and twice daily dosing of Orfadin |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of Orfadin during once daily dosing.
- To evaluate the safety of Orfadin during once and twice daily dosing. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female patients of all ages diagnosed with HT-1.
2. Patients currently well-controlled, as judged by the investigator, on twice daily (or more frequent) dosing with Orfadin.
3. Stable lab values, including liver values <2 ULN (ALP, ALT, AST, bilirubin, INR).
4. Women of childbearing potential willing to use adequate contraception
5. Signed informed consent/assent. |
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E.4 | Principal exclusion criteria |
1. Patients who have been previously treated with once daily Orfadin, even if later converted to twice daily dosing.
2. Any medical condition which in the opinion of the investigator makes the patient unsuitable for inclusion.
3. Enrollment in another concurrent clinical interventional study within three months prior to inclusion in this study.
4. Pregnant women.
5. Lactating women.
6. Previous liver transplantation
7. Patients who have recently (past 4 weeks prior to inclusion) started any new medication for a previously undiagnosed illness/disease.
8. Known hepatitis B, hepatitis C or HIV infection.
9. Foreseeable inability to cooperate with given instructions or study procedures. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Minimum (Cmin) serum concentrations of nitisinone after at least 4 weeks of treatment on each dosage regimen. Cmin = concentration in the sample taken immediately before dosing. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
D1, after 4w + 10 days on 2x daily dosing with IMP - predose, after 4w + 10 days on 1x daily dosing with IMP - predose
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E.5.2 | Secondary end point(s) |
- maximum (Cmax) serum concentrations of nitisinone and the Cmax/Cmin ratio, after at least 4 weeks of treatment on each dosage regimen. Cmax = concentration in a sample taken any time from 3 to 4 hours after dosing.
- Serum succinylacetone (s-SA) after at least 4 weeks of treatment.
- Serum concentration of nitisinone, Cmin at possible occurrence of s-SA above lower limit of quantitation (LLOQ).
-Safety and tolerability assessments; including Adverse Events (AEs), routine clinical chemistry tests including serum alpha fetoprotein (s-AFP), hepatic and renal function, coagulation and serum tyrosine. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- maximum (Cmax) serum concentrations of nitisinone and the Cmax/Cmin ratio: after 4w + 10 days on 2x daily dosing with IMP - 3-4 hrs postdose, 4w + 10 days on 1x daily dosing with IMP - 3-4 hrs postdose
- sSA, serum concentration of nitisinone, Cmin at possible occurrence of s-SA above lower limit of quantitation (LLOQ) and laboratory safety:
D1, after 4w+10 days on 2x daily dosing with IMP, after 4w + 10 days on 1x daily dosing with IMP
AEs: D1 - last study visit |
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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 | 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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |