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Trial record 5 of 10 for:    "Tyrosinemia type 1"

Bioequivalence Study of Two Oral Nitisinone Formulations to Treat Hereditary Tyrosinemia (HT-1)

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ClinicalTrials.gov Identifier: NCT02750345
Recruitment Status : Completed
First Posted : April 25, 2016
Results First Posted : October 17, 2016
Last Update Posted : June 14, 2017
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
Cycle Pharmaceuticals Ltd.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Condition Hereditary Tyrosinemia, Type I
Interventions Drug: Nitisinone
Drug: Nitisinone Baked Tablet
Drug: Orfadin
Enrollment 24
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Sequence TP 1 - TP 2 - Reference Sequence TP 1 - Reference - TP 2 Sequence TP 2 - TP 1 - Reference Sequence TP 2 - Reference - TP 1 Sequence Reference - TP 1 - TP 2 Sequence Reference - TP 2 - TP 1
Hide Arm/Group Description

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.

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.

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.

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.

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.

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.

Period Title: Intervention 1
Started 4 4 4 4 4 4
Completed 4 4 4 4 3 4
Not Completed 0 0 0 0 1 0
Reason Not Completed
Adverse Event             0             0             0             0             1             0
Period Title: Intervention 2
Started 4 4 4 4 3 4
Completed 4 4 4 4 3 4
Not Completed 0 0 0 0 0 0
Period Title: Intervention 3
Started 4 4 4 4 3 4
Completed 4 4 4 4 3 4
Not Completed 0 0 0 0 0 0
Arm/Group Title All Study Participants
Hide Arm/Group Description Grouped by all participants as this is how overall data has been collected.
Overall Number of Baseline Participants 24
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants
<=18 years
0
   0.0%
Between 18 and 65 years
24
 100.0%
>=65 years
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants
Female
3
  12.5%
Male
21
  87.5%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 24 participants
Black 16
Caucasian 7
Mixed Race 1
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
South Africa Number Analyzed 24 participants
24
1.Primary Outcome
Title Maximum Observed Plasma Concentration (Cmax)
Hide Description [Not Specified]
Time Frame 0 - 120 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Test Product 1 Test Product 2 Reference Product
Hide Arm/Group Description:
10 mg Nitisinone Tablet
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
ORFADIN®, 10 mg hard capsule
Overall Number of Participants Analyzed 23 23 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
1277.77
(17.8%)
1272.34
(16.6%)
1339.79
(17.3%)
2.Primary Outcome
Title Area Under the Plasma Concentration Versus Time Curve (AUC(0-120))
Hide Description [Not Specified]
Time Frame 0 - 120 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Treatment Period 1 Treatment Period 2 Reference Product
Hide Arm/Group Description:
10 mg Nitisinone Tablet
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
ORFADIN®, 10 mg hard capsule
Overall Number of Participants Analyzed 23 23 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hr*ng/mL
77874.13
(19.3%)
77295.02
(20.00%)
78672.56
(17.4%)
3.Secondary Outcome
Title Area Under the Plasma Concentration Versus Time Curve (AUC(0-72))
Hide Description [Not Specified]
Time Frame 0 - 72 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Treatment Period 1 Treatment Period 2 Reference Product
Hide Arm/Group Description:
10 mg Nitisinone Tablet
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
ORFADIN®, 10 mg hard capsule
Overall Number of Participants Analyzed 23 23 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hr*ng/mL
57838.41
(20.0%)
57497.79
(18.7%)
59013.52
(15.7%)
4.Secondary Outcome
Title Area Under the Plasma Concentration Versus Time Curve, With Extrapolation to Infinity (AUC(0-∞))
Hide Description [Not Specified]
Time Frame 0 - 120 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Treatment Period 1 Treatment Period 2 Reference Product
Hide Arm/Group Description:
10 mg Nitisinone Tablet
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
ORFADIN®, 10 mg hard capsule
Overall Number of Participants Analyzed 23 23 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hr*ng/mL
104495.96
(26.6%)
105117.79
(25.4%)
106892.31
(23.9%)
5.Secondary Outcome
Title Time to Maximum Observed Plasma Concentration (Tmax)
Hide Description [Not Specified]
Time Frame 0 - 120 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Treatment Period 1 Treatment Period 2 Reference Product
Hide Arm/Group Description:
10 mg Nitisinone Tablet
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
ORFADIN®, 10 mg hard capsule
Overall Number of Participants Analyzed 23 23 23
Median (Full Range)
Unit of Measure: hr
3.5
(1 to 4)
4.0
(2 to 10)
2.5
(0.5 to 10)
6.Secondary Outcome
Title Terminal Elimination Rate Constant (λz)
Hide Description [Not Specified]
Time Frame 0 - 120 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Treatment Period 1 Treatment Period 2 Reference Product
Hide Arm/Group Description:
10 mg Nitisinone Tablet
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
ORFADIN®, 10 mg hard capsule
Overall Number of Participants Analyzed 23 23 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 1/hr
0.012
(15.8%)
0.011
(20.1%)
0.012
(21.1%)
7.Secondary Outcome
Title Apparent Terminal Elimination Half-life (t1/2)
Hide Description [Not Specified]
Time Frame 0 - 120 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Treatment Period 1 Treatment Period 2 Reference Product
Hide Arm/Group Description:
10 mg Nitisinone Tablet
Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH)
ORFADIN®, 10 mg hard capsule
Overall Number of Participants Analyzed 23 23 23
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hr
58.668
(15.8%)
60.780
(20.1%)
59.904
(21.1%)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Test Product 1 Test Product 2 Reference Product
Hide Arm/Group Description 10 mg Nitisinone Tablet Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) ORFADIN®, 10 mg hard capsule
All-Cause Mortality
Test Product 1 Test Product 2 Reference Product
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Test Product 1 Test Product 2 Reference Product
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/23 (0.00%)   0/23 (0.00%)   0/24 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Test Product 1 Test Product 2 Reference Product
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/23 (13.04%)   1/23 (4.35%)   1/24 (4.17%) 
Gastrointestinal disorders       
Vomit  0/23 (0.00%)  0/23 (0.00%)  1/24 (4.17%) 
General disorders       
Fatigue  1/23 (4.35%)  0/23 (0.00%)  0/24 (0.00%) 
Infections and infestations       
Flu  0/23 (0.00%)  1/23 (4.35%)  0/24 (0.00%) 
Cold  1/23 (4.35%)  0/23 (0.00%)  0/24 (0.00%) 
Nervous system disorders       
Headache  1/23 (4.35%)  0/23 (0.00%)  0/24 (0.00%) 
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: James Price
Organization: Cycle Pharmaceuticals Ltd
Phone: +44 1223 803638
EMail: james.price@cyclepharma.com
Layout table for additonal information
Responsible Party: Cycle Pharmaceuticals Ltd.
ClinicalTrials.gov Identifier: NCT02750345     History of Changes
Other Study ID Numbers: CT-003
PXL227430 ( Other Identifier: PAREXEL )
First Submitted: April 21, 2016
First Posted: April 25, 2016
Results First Submitted: October 14, 2016
Results First Posted: October 17, 2016
Last Update Posted: June 14, 2017