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

Brief Title

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

Brief 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.

Study Phase

Phase 3

Study Type


Primary Outcome

Minimum serum concentration (Cmin) of nitisinone

Secondary Outcome

 Maximum serum concentration (Cmax) of nitisinone


Hereditary Tyrosinemia, Type I



Study Arms / Comparison Groups

 Nitisinone treatment group
Description:  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.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

December 2014

Completion Date

September 2015

Primary Completion Date

September 2015

Eligibility Criteria

        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.




N/A - N/A

Accepts Healthy Volunteers



Anders Bröijersén, MD, , 

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party


Study Sponsor

Swedish Orphan Biovitrum

Study Sponsor

Anders Bröijersén, MD, Study Director, Swedish Orphan Biovitrum

Verification Date

November 2015