Hereditary Tyrosinemia, Type IPhase 3HT-1NCT02323529
Efficacy and Safety of Once Daily Dosing Compared to Twice Daily Dosing of Nitisinone in HT-1
A Phase 3 study testing Nitisinone in people with Hereditary Tyrosinemia, Type I, run by Swedish Orphan Biovitrum at 6 sites in 5 countries.
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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Hereditary Tyrosinemia, Type I
- What is being tested?
- Nitisinone
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 6 sitesin 5 countries
- Study dates
- Dec 2014to Sep 2015
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 9Show fewer
- 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.
Trial locations and contacts
6 sites in 5 countries.
6 sites in 5 countries
Germany2 sites
Swedish Orphan Biovitrum Investigational Site
Giessen
Swedish Orphan Biovitrum Investigational Site
Reutlingen
About this study
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
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.
Read the 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
- Being tested
- Nitisinone
- Keywords
- Orfadin, Nitisinone, NTBC
- Medical subject headings
- Tyrosinemias
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NitisinoneDrug
Also called Orfadin
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.
| Study group | Role | What they receive |
|---|---|---|
| Nitisinone treatment group | Experimental | 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. Receives: Drug: Nitisinone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Minimum serum concentration (Cmin) of nitisinone
Sample collected immediately before administration of morning dose
Measured: 4 weeks
Secondary outcomes (11)
Maximum serum concentration (Cmax) of nitisinone
Sample collected 3-4 hours post dose
Measured: 4 weeks
Cmax/Cmin ratio of nitisinone
Measured: 4 weeks
Number of patients with Serum succinylacetone (s-SA) above lower limit of quantification (LLOQ)
Measured: 4 weeks
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
Measured: 4 weeks
Number of patients with at least one adverse event
Total and by system organ class and preferred term (MedDRA)
Measured: 4 weeks
Number of patients with at least one serious adverse events
Total and by system organ class and preferred term (MedDRA)
Measured: 4 weeks
Number of patients with at least one study drug related adverse events
Total and by system organ class and preferred term (MedDRA)
Measured: 4 weeks
Number of patients with at least one non-serious adverse event
Total and by system organ class and preferred term (MedDRA)
Measured: 4 weeks
Number of patients with at least one adverse event leading to study discontinuation
Total and by system organ class and preferred term (MedDRA)
Measured: 4 weeks
Serum-tyrosine (µmol/L)
Descriptive statistics of s-tyrosine
Measured: 4 weeks
Serum-alpha fetoprotein (µg/L)
Descriptive statistics of s-alpha fetoprotein
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Dec 2014 (estimated)
- Study startDec 2014
- Primary completionSep 2015
- Study completionSep 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hereditary Tyrosinemia, Type IStudies of the same condition, open and under way.
- More trials run by Swedish Orphan BiovitrumThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- Swedish Orphan Biovitrum
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Anders Bröijersén, MD, Study director, Swedish Orphan Biovitrum
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02323529
- Sponsor's protocol ID
- Sobi.NTBC-003
- Acronym
- HT-1
- Status last verified
- Nov 2015
- First submitted
- 18 Dec 2014
- Last updated
- 11 Nov 2015
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 11 Nov 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02323529
- Acronym / sponsor ID
- HT-1 / Sobi.NTBC-003
- Conditions
- Hereditary Tyrosinemia, Type I
- Keywords
- Orfadin, Nitisinone, NTBC
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Swedish Orphan BiovitrumIndustry (pharma, biotech, devices)
- Study start
- Dec 2014
- Primary completion
- Sep 2015 (actual)
- Study completion
- Sep 2015 (actual)
- First posted
- 23 Dec 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Nitisinone treatment group | Experimental | Drug: NitisinoneAll 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. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NitisinoneAlso: OrfadinAll 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. | Drug | Nitisinone treatment group |
Primary outcome
Minimum serum concentration (Cmin) of nitisinone
Time frame: 4 weeks
Sample collected immediately before administration of morning dose
11 secondary outcomes
Maximum serum concentration (Cmax) of nitisinone
Time frame: 4 weeks
Cmax/Cmin ratio of nitisinone
Time frame: 4 weeks
Number of patients with Serum succinylacetone (s-SA) above lower limit of quantification (LLOQ)
Time frame: 4 weeks
Minimum serum concentration (Cmin) of nitisinone at possible occurence of s-SA above lower limit of quantification (LLOQ)
Time frame: 4 weeks
Number of patients with at least one adverse event
Time frame: 4 weeks
Number of patients with at least one serious adverse events
Time frame: 4 weeks
Number of patients with at least one study drug related adverse events
Time frame: 4 weeks
Number of patients with at least one non-serious adverse event
Time frame: 4 weeks
Number of patients with at least one adverse event leading to study discontinuation
Time frame: 4 weeks
Serum-tyrosine (µmol/L)
Time frame: 4 weeks
Serum-alpha fetoprotein (µg/L)
Time frame: 4 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Nov 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anders Bröijersén, MD study director
Swedish Orphan Biovitrum
6 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Nitisinone in people with Hereditary Tyrosinemia, Type I, run by Swedish Orphan Biovitrum at 6 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Nov 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Germany, Belgium, Denmark, France, Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Minimum serum concentration (Cmin) of nitisinone (time frame: 4 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Nov 2015.