An open-label, non-randomized, sequential, multicenter study to evaluate the pharmacokinetics, efficacy and safety of once daily dosing compared to twice daily dosing of Orfadin in patients diagnosed with hereditary tyrosinemia type 1

• Register: EUCTR
• Last refreshed on: 22 August 2016
• Main ID: EUCTR2013-004132-29-BE
• Date of registration: 15/10/2014
• Prospective Registration: Yes
• Primary sponsor: Swedish Orphan Biovitrum AB (Publ)
• Public title: An open-label, non-randomized, sequential, multicenter study to evaluate the pharmacokinetics, efficacy and safety of once daily dosing compared to twice daily dosing of Orfadin in patients diagnosed with hereditary tyrosinemia type 1
• Scientific title: An open-label, non-randomized, sequential, multicenter study to evaluate the pharmacokinetics, efficacy and safety of once daily dosing compared to twice daily dosing of Orfadin in patients diagnosed with hereditary tyrosinemia type 1
• Date of first enrolment: 06/11/2014
• Target sample size: 20
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-004132-29
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: yes Other trial design description: sequential If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Belgium, Denmark, Sweden

Contacts

• Name: Karin Becker
• Affiliation: Swedish Orphan Biovitrum AB (Publ)

• Name: Karin Becker
• Affiliation: Swedish Orphan Biovitrum AB (Publ)

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 20
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 5
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

hereditary tyrosinemia type 1
MedDRA version: 17.0 Level: LLT Classification code 10069462 Term: Tyrosinemia type I System Organ Class: 100000004850

Therapeutic area: Body processes [G] - Metabolic Phenomena [G03]

Intervention(s)

Trade Name: Orfadin
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: NITISINONE
CAS Number: 104206-65-7
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2-

Trade Name: Orfadin
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: NITISINONE
CAS Number: 104206-65-7
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Trade Name: Orfadin
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: NITISINONE
CAS Number: 104206-65-7
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

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

Main Objective: To evaluate the steady-state exposure to nitisinone during once and twice daily dosing of Orfadin

Secondary Objective: - To evaluate the efficacy of Orfadin during once daily dosing.
- To evaluate the safety of Orfadin during once and twice daily dosing.

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.

Secondary Outcome(s)

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

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.

Secondary ID(s)

Sobi.NTBC-003

2013-004132-29-SE

Source(s) of Monetary Support

Swedish Orphan Biovitrum AB (Publ)