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The study is primarily being performed in order to demonstrate bioequivalence between the Orfadin (nitisinone) suspension and the marketed capsule formulation. The study will also contain a comparison of the bioavailability of the suspension given with food and on an empty stomach.
This is an open, randomized 3-way crossover study in 12 healthy volunteers. Subjects will receive single oral 30-mg doses of nitisinone as a suspension (fasting and with food) and as hard gelatin capsules (fasting only). There will be a 2-week washout period between the doses.
There will be a screening visit within 3 weeks prior to the first dose. During each treatment period, subjects will be admitted to the clinic from the afternoon on the day before drug administration (i.e., on Day -1) and remain at the clinic until the 48-hour post-dose blood sample has been collected in the morning of Day 3. They will then return for ambulatory visit in the morning of Day 4 (72-hour sample). A follow-up visit will take place 7-14 days after the last dose.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Orfadin capsules, fasting | Active Comparator | Orfadin capsules, single dose, 30 mg |
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| Orfadin suspension, fasting | Experimental | Orfadin suspension 4 mg/mL, single dose 30 mg (7,5 mL) |
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| Orfadin suspension, with food | Experimental | Orfadin suspension 4mg/mL, single dose 30 mg (7,5 mL) |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nitisinone, capsule | Drug |
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| Nitisinone, suspension |
| Measure | Description | Time Frame |
|---|---|---|
| The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) During Fasting Conditions. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. | |
| The Maximum Serum Concentration (Cmax) During Fasting Conditions. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
| Measure | Description | Time Frame |
|---|---|---|
| The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) | Measured for the Orfadin suspension treatments arms- both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
| The Maximum Serum Concentration (Cmax) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Erik Brouwer, MD | Swedish Orphan Biovitrum | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pharmaceutical Research Associates Group B.V (PRA) | Zuidlaren | Netherlands |
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First subject screened: 29 August 2012 Last subject last visit: 25 October 2012.
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| ID | Title | Description |
|---|---|---|
| FG000 | All Treatment Groups | All participants received all study treatments in a randomized fashion. Subjects were allocated to one of the following treatment sequences (2 subjects to each sequence): A B C; B C A; C A B; C B A; A C B; B A C where A=Orfadin capsules, single dose, 30 mg; B=Orfadin suspension, single dose 30 mg, fasting; C=Orfadin suspension, single dose 30 mg, fed |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Drug |
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Measured for the Orfadin suspension treatment arms- both fasting and with food. |
| Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
| AUC From Time Zero to Infinity | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
| Time to Reach C-Max (t-Max) | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
| Terminal Half-life | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
| Oral Clearance (CL/F) | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
| Apparent Volume of Distribution (Vz/F) | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Overall Study | All treatment arms |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||||
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| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) During Fasting Conditions. | Full analysis set was used; subjects with available PK data for at least one of the treatments. | Posted | Geometric Mean | Full Range | uM*h | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
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| Primary | The Maximum Serum Concentration (Cmax) During Fasting Conditions. | Full analysis set was used; subjects with available PK data for at least one of the treatments. | Posted | Geometric Mean | Full Range | nM | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
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| Secondary | The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) | Measured for the Orfadin suspension treatments arms- both fasting and with food. | Full analysis set was used; subjects with available PK data for at least one of the treatments. | Posted | Geometric Mean | Full Range | uM*h | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
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| Secondary | The Maximum Serum Concentration (Cmax) | Measured for the Orfadin suspension treatment arms- both fasting and with food. | Full analysis set was used; subjects with available PK data for at least one of the treatments. | Posted | Geometric Mean | Full Range | nM | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
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| Secondary | AUC From Time Zero to Infinity | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Per-protocol set (bioequivalence) was used for fasted treatment groups and per-protocol set (food effect) for fed treatment group (all subjects with available PK data) | Posted | Geometric Mean | Full Range | h*uM | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
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| Secondary | Time to Reach C-Max (t-Max) | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data) | Posted | Median | Full Range | hours | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
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| Secondary | Terminal Half-life | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data) | Posted | Median | Full Range | hours | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
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| Secondary | Oral Clearance (CL/F) | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data) | Posted | Median | Full Range | L/h | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
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| Secondary | Apparent Volume of Distribution (Vz/F) | Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food. | Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data) | Posted | Median | Full Range | L | Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose. |
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Orfadin Capsules, Fasting | Orfadin capsules, single dose, 30 mg | 0 | 12 | 1 | 12 | ||
| EG001 | Orfadin Suspension, Fasting | Orfadin suspension 4 mg/mL, single dose, 30 mg (7.5 mL) | 0 | 12 | 2 | 12 | ||
| EG002 | Orfadin Suspension, With Food | Orfadin suspension 4 mg/mL, single dose, 30 mg (7.5 mL) | 0 | 12 | 2 | 12 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dyspepsia | Gastrointestinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Catheter site related reaction | General disorders | MedDRA 15.0 | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 15.0 | Systematic Assessment |
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| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 15.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 15.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 15.0 | Systematic Assessment |
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| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 15.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Director | Swedish Orphan Biovitrum | +4686972000 | erik.brouwer@sobi.com |
| ID | Term |
|---|---|
| C077073 | nitisinone |
| D002214 | Capsules |
| D013535 | Suspensions |
| ID | Term |
|---|---|
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
| D003102 | Colloids |
| D045424 | Complex Mixtures |
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