NCT02323529

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

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

• Status: Completed
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 18 (actual)
• Sponsor: Swedish Orphan Biovitrum · Industry
• Sex: All
• Age: —
• Healthy volunteers: Not accepted

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.

Detailed 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.

Conditions

• Hereditary Tyrosinemia, Type I

Interventions

Type	Name	Description
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.

Timeline

• Start date: 2014-12-01
• Primary completion: 2015-09-01
• Completion: 2015-09-01
• First posted: 2014-12-23
• Last updated: 2015-11-11

Locations

6 sites across 5 countries: Belgium, Denmark, France, Germany, Sweden