Efficacy and Safety of Once Daily Dosing Compared to Twice Daily Dosing of Nitisinone in HT-1

Hereditary Tyrosinemia, Type I Clinical Trial

— HT-1  

Official title:

Open-label, Multicentre, Multiple-dose Trial to Evaluate Pharmacokinetics, Efficacy and Safety of Once Daily Dosing Compared to Twice Daily Dosing of Orfadin in Patients Diagnosed With Hereditary Tyrosinemia Type 1

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02323529
• Other study ID #: Sobi.NTBC-003
• Status: Completed
• Phase: Phase 3
• First received: December 18, 2014
• Last updated: November 10, 2015
• Start date: December 2014
• Est. completion date: September 2015

Study information

• Verified date: November 2015
• Source: Swedish Orphan Biovitrum
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: Danish Health and Medicines AuthoritySweden: Medical Products AgencyGermany: Federal Institute for Drugs and Medical DevicesFrance: Agence Nationale de Sécurité du Médicament et des produits de santéBelgium: Federal Agency for Medicines and Health Products, FAMHP
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to look at the steady-state serum concentrations of nitisinone when switching from twice daily and once daily dosing.

Description:

Nitisinone (Orfadin) is used in the treatment of hereditary tyrosinemia type 1(HT-1), an inborn error of metabolism. The clinical study that forms the basis for licensing of nitisinone in the treatment of HT-1 used twice daily dosing. This became the recommended dosing frequency of nitisinone stated in the Summary of Product Characteristics. Later on, when the half-life became know (around 50 hours in adults), many physicians started to use once daily dosing. The suitability of once daily dosing and especially of switching patients from twice to once daily dosing has not been documented. The aim with this study is therefore to investigate the effect on nitisinone serum concentrations (Cmax and Cmin) and possible clinical consequences of a lower dosing frequency.

This one-way crossover study consists of three periods; Screening period, Treatment period 1 and Treatment period 2. The study starts with a screening period (Visit 1-1b) that may be up to 6 weeks long. This is followed by two treatment periods of at least 4 weeks each. During Treatment period 1 (Visits 2-3), the patient will take Orfadin twice daily. During Treatment period 2 (Visits 4-5), the patient will take Orfadin once daily. The dose of nitisinone in the study will be the same as the one prescribed at completed screening visit. Dose will be 1-2 mg/kg body weight. The total treatment period will be at least 8 weeks.

At least 20 patients with a minimum of 3 patients in each of the following age groups will be included; infants (< 2 years), children (2-<12 years), adolescents (12-<18 years) and adults (≥18 years).

Determination of succinylacetone (SA) in blood (serum/plasma) and/or urine will be performed both locally and at a central Good Laboratory Practice certified laboratory (Dry Blood Spot sample). The purpose of the local sample is to provide the investigator with more or less immediate results to determine if a dose adjustment is needed before the patient enters either of the two treatment periods. Results from samples analyzed at the central laboratory, including determination of nitisinone, will be used in the evaluation of pharmacokinetics, efficacy and safety during the two treatment periods.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: September 2015
• Est. primary completion date: September 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Male and female patients of all ages diagnosed with HT-1.

• Patients currently well-controlled, as judged by the investigator, on twice daily (or more frequent) dosing with Orfadin.

• Stable lab values, including liver values <2 ULN (ALP, ALT, AST, bilirubin, INR).

• Women of childbearing potential willing to use adequate contraception

• Signed informed consent/assent.

Exclusion Criteria:

• Patients who have been previously treated with once daily Orfadin, even if later converted to twice daily dosing.

• Any medical condition which in the opinion of the investigator makes the patient unsuitable for inclusion.

• Enrollment in another concurrent clinical interventional study within three months prior to inclusion in this study.

• Pregnant women.

• Lactating women.

• Previous liver transplantation.

• Patients who have recently (past 4 weeks prior to inclusion) started any new medication for a previously undiagnosed illness/disease.

• Known hepatitis B, hepatitis C or HIV infection.

• Foreseeable inability to cooperate with given instructions or study procedures.

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hereditary Tyrosinemia, Type I
• Tyrosinemias

Intervention

Drug:
• Nitisinone
All patients in the study will first be put on twice daily dosing of nitisinone for 4 weeks. This will then be followed by once daily dosing of nitisinone for 4 weeks. The dose of nitisinone in the study will be the same as the one prescribed at completed screening visit. Dose will be 1-2 mg/kg body weight.

Locations

Country	Name	City	State
Belgium	Swedish Orphan Biovitrum Investigational Site	Brussels
Denmark	Swedish Orphan Biovitrum Investigational Site	Copenhagen
France	Swedish Orphan Biovitrum Investigational Site	Lyon
Germany	Swedish Orphan Biovitrum Investigational Site	Giessen
Germany	Swedish Orphan Biovitrum Investigational Site	Reutlingen
Sweden	Swedish Orphan Biovitrum Investigational site	Gothenburg

Sponsors (1)

Lead Sponsor	Collaborator
Swedish Orphan Biovitrum

Countries where clinical trial is conducted

Belgium,  Denmark,  France,  Germany,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Minimum serum concentration (Cmin) of nitisinone	Sample collected immediately before administration of morning dose	4 weeks	No
Secondary	Maximum serum concentration (Cmax) of nitisinone	Sample collected 3-4 hours post dose	4 weeks	No
Secondary	Cmax/Cmin ratio of nitisinone		4 weeks	No
Secondary	Number of patients with Serum succinylacetone (s-SA) above lower limit of quantification (LLOQ)		4 weeks	No
Secondary	Minimum serum concentration (Cmin) of nitisinone at possible occurence of s-SA above lower limit of quantification (LLOQ)	Cmin of nitisinone will be listed for patients with s-SA above LLOQ	4 weeks	No
Secondary	Number of patients with at least one adverse event	Total and by system organ class and preferred term (MedDRA)	4 weeks	No
Secondary	Number of patients with at least one serious adverse events	Total and by system organ class and preferred term (MedDRA)	4 weeks	No
Secondary	Number of patients with at least one study drug related adverse events	Total and by system organ class and preferred term (MedDRA)	4 weeks	No
Secondary	Number of patients with at least one non-serious adverse event	Total and by system organ class and preferred term (MedDRA)	4 weeks	No
Secondary	Number of patients with at least one adverse event leading to study discontinuation	Total and by system organ class and preferred term (MedDRA)	4 weeks	No
Secondary	Serum-tyrosine (µmol/L)	Descriptive statistics of s-tyrosine	4 weeks	No
Secondary	Serum-alpha fetoprotein (µg/L)	Descriptive statistics of s-alpha fetoprotein	4 weeks	No