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

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ClinicalTrials.gov Identifier: NCT02323529
Recruitment Status : Completed
First Posted : December 23, 2014
Last Update Posted : November 11, 2015
Sponsor:
Information provided by (Responsible Party):
Swedish Orphan Biovitrum

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.

Condition or disease Intervention/treatment Phase
Hereditary Tyrosinemia, Type I Drug: Nitisinone Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : December 2014
Actual Primary Completion Date : September 2015
Actual Study Completion Date : September 2015


Arm Intervention/treatment
Experimental: Nitisinone treatment group
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.
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.
Other Name: Orfadin




Primary Outcome Measures :
  1. Minimum serum concentration (Cmin) of nitisinone [ Time Frame: 4 weeks ]
    Sample collected immediately before administration of morning dose


Secondary Outcome Measures :
  1. Maximum serum concentration (Cmax) of nitisinone [ Time Frame: 4 weeks ]
    Sample collected 3-4 hours post dose

  2. Cmax/Cmin ratio of nitisinone [ Time Frame: 4 weeks ]
  3. Number of patients with Serum succinylacetone (s-SA) above lower limit of quantification (LLOQ) [ Time Frame: 4 weeks ]
  4. Minimum serum concentration (Cmin) of nitisinone at possible occurence of s-SA above lower limit of quantification (LLOQ) [ Time Frame: 4 weeks ]
    Cmin of nitisinone will be listed for patients with s-SA above LLOQ

  5. Number of patients with at least one adverse event [ Time Frame: 4 weeks ]
    Total and by system organ class and preferred term (MedDRA)

  6. Number of patients with at least one serious adverse events [ Time Frame: 4 weeks ]
    Total and by system organ class and preferred term (MedDRA)

  7. Number of patients with at least one study drug related adverse events [ Time Frame: 4 weeks ]
    Total and by system organ class and preferred term (MedDRA)

  8. Number of patients with at least one non-serious adverse event [ Time Frame: 4 weeks ]
    Total and by system organ class and preferred term (MedDRA)

  9. Number of patients with at least one adverse event leading to study discontinuation [ Time Frame: 4 weeks ]
    Total and by system organ class and preferred term (MedDRA)

  10. Serum-tyrosine (µmol/L) [ Time Frame: 4 weeks ]
    Descriptive statistics of s-tyrosine

  11. Serum-alpha fetoprotein (µg/L) [ Time Frame: 4 weeks ]
    Descriptive statistics of s-alpha fetoprotein



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02323529


Locations
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Belgium
Swedish Orphan Biovitrum Investigational Site
Brussels, Belgium
Denmark
Swedish Orphan Biovitrum Investigational Site
Copenhagen, Denmark
France
Swedish Orphan Biovitrum Investigational Site
Lyon, France
Germany
Swedish Orphan Biovitrum Investigational Site
Giessen, Germany
Swedish Orphan Biovitrum Investigational Site
Reutlingen, Germany
Sweden
Swedish Orphan Biovitrum Investigational site
Gothenburg, Sweden
Sponsors and Collaborators
Swedish Orphan Biovitrum
Investigators
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Study Director: Anders Bröijersén, MD Swedish Orphan Biovitrum

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Responsible Party: Swedish Orphan Biovitrum
ClinicalTrials.gov Identifier: NCT02323529     History of Changes
Other Study ID Numbers: Sobi.NTBC-003
First Posted: December 23, 2014    Key Record Dates
Last Update Posted: November 11, 2015
Last Verified: November 2015
Keywords provided by Swedish Orphan Biovitrum:
Orfadin
Nitisinone
NTBC
Additional relevant MeSH terms:
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Tyrosinemias
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Nitisinone
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action