Trial Outcomes & Findings for Bioequivalence Study of Two Oral Nitisinone Formulations to Treat Hereditary Tyrosinemia (HT-1) (NCT NCT02750345)
NCT ID: NCT02750345
Last Updated: 2017-06-14
Results Overview
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
24 participants
Primary outcome timeframe
0 - 120 hours post-dose
Results posted on
2017-06-14
Participant Flow
Participant milestones
| Measure |
Sequence TP 1 - TP 2 - Reference
Subjects will receive a single 10 mg tablet of Nitisinone (Test Product 1 (TP 1)) in treatment period 1, 10 mg tablet of Nitisinone Baked Tablet (Test Product 2 (TP 2)) in treatment period 2, and 10 mg hard capsule of Orfadin (Reference) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.
Nitisinone: A single oral dose of Nitisinone 10 mg Tablet will be administered.
Nitisinone Baked Tablet: A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Orfadin: A single oral dose of Orfadin 10 mg hard capsule will be administered.
|
Sequence TP 1 - Reference - TP 2
Subjects will receive a single 10 mg tablet of Nitisinone (Test Product 1) in treatment period 1, 10 mg hard capsule of Orfadin (Reference) in treatment period 2, and 10 mg tablet of Nitisinone Baked Tablet (Test Product 2) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.
Nitisinone: A single oral dose of Nitisinone 10 mg Tablet will be administered.
Nitisinone Baked Tablet: A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Orfadin: A single oral dose of Orfadin 10 mg hard capsule will be administered.
|
Sequence TP 2 - TP 1 - Reference
Subjects will receive a single 10 mg tablet of Nitisinone Baked Tablet (Test Product 2) in treatment period 1, 10 mg tablet of Nitisinone (Test Product 1) in treatment period 2, and 10 mg hard capsule of Orfadin (Reference) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.
Nitisinone: A single oral dose of Nitisinone 10 mg Tablet will be administered.
Nitisinone Baked Tablet: A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Orfadin: A single oral dose of Orfadin 10 mg hard capsule will be administered.
|
Sequence TP 2 - Reference - TP 1
Subjects will receive a single 10 mg tablet of Nitisinone Baked Tablet (Test Product 2) in treatment period 1, 10 mg hard capsule of Orfadin (Reference) in treatment period 2, and 10 mg tablet of Nitisinone (Test Product 1) in treatment period 3, and under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.
Nitisinone: A single oral dose of Nitisinone 10 mg Tablet will be administered.
Nitisinone Baked Tablet: A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Orfadin: A single oral dose of Orfadin 10 mg hard capsule will be administered.
|
Sequence Reference - TP 1 - TP 2
Subjects will receive a single 10 mg hard capsule of Orfadin (Reference) in treatment period 1, 10 mg tablet of Nitisinone (Test Product 1) in treatment period 2, and 10 mg tablet of Nitisinone Baked Tablet (Test Product 2) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.
Nitisinone: A single oral dose of Nitisinone 10 mg Tablet will be administered.
Nitisinone Baked Tablet: A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Orfadin: A single oral dose of Orfadin 10 mg hard capsule will be administered.
|
Sequence Reference - TP 2 - TP 1
Subjects will receive a single 10 mg hard capsule of Orfadin (Reference) in treatment period 1, 10 mg tablet of Nitisinone Baked Tablet (Test Product 2) in treatment period 2, and 10 mg tablet of Nitisinone (Test Product 1) in treatment period 3, and under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.
Nitisinone: A single oral dose of Nitisinone 10 mg Tablet will be administered.
Nitisinone Baked Tablet: A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Orfadin: A single oral dose of Orfadin 10 mg hard capsule will be administered.
|
|---|---|---|---|---|---|---|
|
Intervention 1
STARTED
|
4
|
4
|
4
|
4
|
4
|
4
|
|
Intervention 1
COMPLETED
|
4
|
4
|
4
|
4
|
3
|
4
|
|
Intervention 1
NOT COMPLETED
|
0
|
0
|
0
|
0
|
1
|
0
|
|
Intervention 2
STARTED
|
4
|
4
|
4
|
4
|
3
|
4
|
|
Intervention 2
COMPLETED
|
4
|
4
|
4
|
4
|
3
|
4
|
|
Intervention 2
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
0
|
|
Intervention 3
STARTED
|
4
|
4
|
4
|
4
|
3
|
4
|
|
Intervention 3
COMPLETED
|
4
|
4
|
4
|
4
|
3
|
4
|
|
Intervention 3
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
0
|
Reasons for withdrawal
| Measure |
Sequence TP 1 - TP 2 - Reference
Subjects will receive a single 10 mg tablet of Nitisinone (Test Product 1 (TP 1)) in treatment period 1, 10 mg tablet of Nitisinone Baked Tablet (Test Product 2 (TP 2)) in treatment period 2, and 10 mg hard capsule of Orfadin (Reference) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.
Nitisinone: A single oral dose of Nitisinone 10 mg Tablet will be administered.
Nitisinone Baked Tablet: A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Orfadin: A single oral dose of Orfadin 10 mg hard capsule will be administered.
|
Sequence TP 1 - Reference - TP 2
Subjects will receive a single 10 mg tablet of Nitisinone (Test Product 1) in treatment period 1, 10 mg hard capsule of Orfadin (Reference) in treatment period 2, and 10 mg tablet of Nitisinone Baked Tablet (Test Product 2) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.
Nitisinone: A single oral dose of Nitisinone 10 mg Tablet will be administered.
Nitisinone Baked Tablet: A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Orfadin: A single oral dose of Orfadin 10 mg hard capsule will be administered.
|
Sequence TP 2 - TP 1 - Reference
Subjects will receive a single 10 mg tablet of Nitisinone Baked Tablet (Test Product 2) in treatment period 1, 10 mg tablet of Nitisinone (Test Product 1) in treatment period 2, and 10 mg hard capsule of Orfadin (Reference) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.
Nitisinone: A single oral dose of Nitisinone 10 mg Tablet will be administered.
Nitisinone Baked Tablet: A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Orfadin: A single oral dose of Orfadin 10 mg hard capsule will be administered.
|
Sequence TP 2 - Reference - TP 1
Subjects will receive a single 10 mg tablet of Nitisinone Baked Tablet (Test Product 2) in treatment period 1, 10 mg hard capsule of Orfadin (Reference) in treatment period 2, and 10 mg tablet of Nitisinone (Test Product 1) in treatment period 3, and under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.
Nitisinone: A single oral dose of Nitisinone 10 mg Tablet will be administered.
Nitisinone Baked Tablet: A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Orfadin: A single oral dose of Orfadin 10 mg hard capsule will be administered.
|
Sequence Reference - TP 1 - TP 2
Subjects will receive a single 10 mg hard capsule of Orfadin (Reference) in treatment period 1, 10 mg tablet of Nitisinone (Test Product 1) in treatment period 2, and 10 mg tablet of Nitisinone Baked Tablet (Test Product 2) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.
Nitisinone: A single oral dose of Nitisinone 10 mg Tablet will be administered.
Nitisinone Baked Tablet: A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Orfadin: A single oral dose of Orfadin 10 mg hard capsule will be administered.
|
Sequence Reference - TP 2 - TP 1
Subjects will receive a single 10 mg hard capsule of Orfadin (Reference) in treatment period 1, 10 mg tablet of Nitisinone Baked Tablet (Test Product 2) in treatment period 2, and 10 mg tablet of Nitisinone (Test Product 1) in treatment period 3, and under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.
Nitisinone: A single oral dose of Nitisinone 10 mg Tablet will be administered.
Nitisinone Baked Tablet: A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Orfadin: A single oral dose of Orfadin 10 mg hard capsule will be administered.
|
|---|---|---|---|---|---|---|
|
Intervention 1
Adverse Event
|
0
|
0
|
0
|
0
|
1
|
0
|
Baseline Characteristics
Bioequivalence Study of Two Oral Nitisinone Formulations to Treat Hereditary Tyrosinemia (HT-1)
Baseline characteristics by cohort
| Measure |
All Study Participants
n=24 Participants
Grouped by all participants as this is how overall data has been collected.
|
|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=5 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
24 Participants
n=5 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=5 Participants
|
|
Sex: Female, Male
Female
|
3 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
21 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Black
|
16 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Caucasian
|
7 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Mixed Race
|
1 Participants
n=5 Participants
|
|
Region of Enrollment
South Africa
|
24 participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 0 - 120 hours post-dosePopulation: All subjects for whom the primary pk parameters Cmax and AUC (0-120) could be calculated for at least two treatment periods (where one of which is the reference product), and who had no major protocol deviations thought to impact on the analysis of pk data were included in the statistical pk analysis for the study.
Outcome measures
| Measure |
Test Product 1
n=23 Participants
10 mg Nitisinone Tablet
|
Test Product 2
n=23 Participants
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
|
Reference Product
n=23 Participants
ORFADIN®, 10 mg hard capsule
|
|---|---|---|---|
|
Maximum Observed Plasma Concentration (Cmax)
|
1277.77 ng/mL
Geometric Coefficient of Variation 17.8
|
1272.34 ng/mL
Geometric Coefficient of Variation 16.6
|
1339.79 ng/mL
Geometric Coefficient of Variation 17.3
|
PRIMARY outcome
Timeframe: 0 - 120 hours post-dosePopulation: All subjects for whom the primary Pk parameters Cmax and AUC (0-120) could be calculated for at least 2 treatment periods (where one of the treatment includes the reference product), and who had no major protocol deviations thought to impact the analysis of the pk data were included for the statistical pk analysis for the study.
Outcome measures
| Measure |
Test Product 1
n=23 Participants
10 mg Nitisinone Tablet
|
Test Product 2
n=23 Participants
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
|
Reference Product
n=23 Participants
ORFADIN®, 10 mg hard capsule
|
|---|---|---|---|
|
Area Under the Plasma Concentration Versus Time Curve (AUC(0-120))
|
77874.13 hr*ng/mL
Geometric Coefficient of Variation 19.3
|
77295.02 hr*ng/mL
Geometric Coefficient of Variation 20.00
|
78672.56 hr*ng/mL
Geometric Coefficient of Variation 17.4
|
SECONDARY outcome
Timeframe: 0 - 72 hours post-dosePopulation: All subjects for whom the primary pk parameters Cmax and AUC (0-120) could be calculated for at least 2 treatment periods (where one of the treatment periods must be the reference product), and who had no major protocol deviations thought to impact on the analysis of the pk data were included in the statistical pk analysis for the study.
Outcome measures
| Measure |
Test Product 1
n=23 Participants
10 mg Nitisinone Tablet
|
Test Product 2
n=23 Participants
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
|
Reference Product
n=23 Participants
ORFADIN®, 10 mg hard capsule
|
|---|---|---|---|
|
Area Under the Plasma Concentration Versus Time Curve (AUC(0-72))
|
57838.41 hr*ng/mL
Geometric Coefficient of Variation 20.0
|
57497.79 hr*ng/mL
Geometric Coefficient of Variation 18.7
|
59013.52 hr*ng/mL
Geometric Coefficient of Variation 15.7
|
SECONDARY outcome
Timeframe: 0 - 120 hours post-dosePopulation: All subjects for whom the primary pk parameters Cmax and AUC (0-120) could be calculated for at least 2 treatment periods (where one of which is the reference product), and who had no major protocol deviations thought to impact on the analysis of pk data were included in the statistical pk analysis for the study
Outcome measures
| Measure |
Test Product 1
n=23 Participants
10 mg Nitisinone Tablet
|
Test Product 2
n=23 Participants
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
|
Reference Product
n=23 Participants
ORFADIN®, 10 mg hard capsule
|
|---|---|---|---|
|
Area Under the Plasma Concentration Versus Time Curve, With Extrapolation to Infinity (AUC(0-∞))
|
104495.96 hr*ng/mL
Geometric Coefficient of Variation 26.6
|
105117.79 hr*ng/mL
Geometric Coefficient of Variation 25.4
|
106892.31 hr*ng/mL
Geometric Coefficient of Variation 23.9
|
SECONDARY outcome
Timeframe: 0 - 120 hours post-dosePopulation: All subjects for whom the primary pk parameters Cmax and AUC (0-120) could be calculated for at least 2 treatment periods (where one of which must be the reference product), and who had no major protocol deviations thought to impact on the analysis of pk data were included in the statistical analysis for the study.
Outcome measures
| Measure |
Test Product 1
n=23 Participants
10 mg Nitisinone Tablet
|
Test Product 2
n=23 Participants
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
|
Reference Product
n=23 Participants
ORFADIN®, 10 mg hard capsule
|
|---|---|---|---|
|
Time to Maximum Observed Plasma Concentration (Tmax)
|
3.5 hr
Interval 1.0 to 4.0
|
4.0 hr
Interval 2.0 to 10.0
|
2.5 hr
Interval 0.5 to 10.0
|
SECONDARY outcome
Timeframe: 0 - 120 hours post-dosePopulation: All subjects for whom the primary pk parameters Cmax and AUC (0-120) could be calculated for at least 2 treatment periods (where one of which must be the reference product), and who had no major protocol deviations thought to impact on the analysis of pk data were included in the statistical pk analysis for the study
Outcome measures
| Measure |
Test Product 1
n=23 Participants
10 mg Nitisinone Tablet
|
Test Product 2
n=23 Participants
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
|
Reference Product
n=23 Participants
ORFADIN®, 10 mg hard capsule
|
|---|---|---|---|
|
Terminal Elimination Rate Constant (λz)
|
0.012 1/hr
Geometric Coefficient of Variation 15.8
|
0.011 1/hr
Geometric Coefficient of Variation 20.1
|
0.012 1/hr
Geometric Coefficient of Variation 21.1
|
SECONDARY outcome
Timeframe: 0 - 120 hours post-dosePopulation: All subjects for whom the primary pk parameters Cmax and AUC (0-120) could be calculated for at least 2 treatment periods (where one of which must be the reference product), and who had no major protocol deviations thought to impact on the analysis of pk data were included in the statistical pk analysis for the study.
Outcome measures
| Measure |
Test Product 1
n=23 Participants
10 mg Nitisinone Tablet
|
Test Product 2
n=23 Participants
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
|
Reference Product
n=23 Participants
ORFADIN®, 10 mg hard capsule
|
|---|---|---|---|
|
Apparent Terminal Elimination Half-life (t1/2)
|
58.668 hr
Geometric Coefficient of Variation 15.8
|
60.780 hr
Geometric Coefficient of Variation 20.1
|
59.904 hr
Geometric Coefficient of Variation 21.1
|
Adverse Events
Test Product 1
Serious events: 0 serious events
Other events: 3 other events
Deaths: 0 deaths
Test Product 2
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Reference Product
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Test Product 1
n=23 participants at risk
10 mg Nitisinone Tablet
|
Test Product 2
n=23 participants at risk
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
|
Reference Product
n=24 participants at risk
ORFADIN®, 10 mg hard capsule
|
|---|---|---|---|
|
Infections and infestations
Flu
|
0.00%
0/23
|
4.3%
1/23
|
0.00%
0/24
|
|
Gastrointestinal disorders
Vomit
|
0.00%
0/23
|
0.00%
0/23
|
4.2%
1/24
|
|
Nervous system disorders
Headache
|
4.3%
1/23
|
0.00%
0/23
|
0.00%
0/24
|
|
Infections and infestations
Cold
|
4.3%
1/23
|
0.00%
0/23
|
0.00%
0/24
|
|
General disorders
Fatigue
|
4.3%
1/23
|
0.00%
0/23
|
0.00%
0/24
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place