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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.

Brief Summary:
The purpose of this study is to determine whether Nitisinone 10 mg Tablets (Test Product 1) and Nitisinone 10 mg Tablets 'Baked' for 6 months @ 40°C/75% RH (Test Product 2) are bioequivalent to the reference product Orfadin 10 mg hard capsules.

Condition or disease Intervention/treatment Phase
Hereditary Tyrosinemia, Type I Drug: Nitisinone Drug: Nitisinone Baked Tablet Drug: Orfadin Phase 1

Detailed Description:

The specific aim is to conduct a randomized, single dose, three-period crossover bioequivalence study in at least 18 healthy male and female subjects at a single study center to evaluate the in vivo performance of two formulations of Nitisinone 10 mg and the reference product Orfadin under fasting.

A total of 24 healthy female and male volunteers (age 18 to 55 years old) will be entered into the study. Volunteers will be determined to be free of significant medical conditions as assessed by medical history, physical examination, and blood and urine tests. Volunteers will be randomly allocated to a treatment sequence, before administration of investigational medicinal product (IMP) under fasting conditions.

There will be a minimum 23 calendar days washout between treatments. Blood samples will be collected at pre-dose (0 hours) and at 15 minutes, 30 minutes, 1 hour, 2 hours, 2 hours and 30 minutes, 3 hours, 3 hours and 30 minutes, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours and 120 hours post-dose (total: 21 samples per treatment period).


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Three-Period Crossover Study to Determine the Bioequivalence of Two Oral Formulations Containing Nitisinone 10 mg Compared to Reference Formulation Orfadin In Healthy Subjects Under Fasting Conditions
Study Start Date : March 2016
Actual Primary Completion Date : May 2016
Actual Study Completion Date : May 2016


Arm Intervention/treatment
Experimental: 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.
Drug: Nitisinone
A single oral dose of Nitisinone 10 mg Tablet will be administered.

Drug: Nitisinone Baked Tablet
A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Other Name: Nitisinone (Baked)

Drug: Orfadin
A single oral dose of Orfadin 10 mg hard capsule will be administered.
Other Name: Nitisinone

Experimental: 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.
Drug: Nitisinone
A single oral dose of Nitisinone 10 mg Tablet will be administered.

Drug: Nitisinone Baked Tablet
A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Other Name: Nitisinone (Baked)

Drug: Orfadin
A single oral dose of Orfadin 10 mg hard capsule will be administered.
Other Name: Nitisinone

Experimental: 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.
Drug: Nitisinone
A single oral dose of Nitisinone 10 mg Tablet will be administered.

Drug: Nitisinone Baked Tablet
A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Other Name: Nitisinone (Baked)

Drug: Orfadin
A single oral dose of Orfadin 10 mg hard capsule will be administered.
Other Name: Nitisinone

Experimental: 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.
Drug: Nitisinone
A single oral dose of Nitisinone 10 mg Tablet will be administered.

Drug: Nitisinone Baked Tablet
A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Other Name: Nitisinone (Baked)

Drug: Orfadin
A single oral dose of Orfadin 10 mg hard capsule will be administered.
Other Name: Nitisinone

Experimental: 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.
Drug: Nitisinone
A single oral dose of Nitisinone 10 mg Tablet will be administered.

Drug: Nitisinone Baked Tablet
A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Other Name: Nitisinone (Baked)

Drug: Orfadin
A single oral dose of Orfadin 10 mg hard capsule will be administered.
Other Name: Nitisinone

Experimental: 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.
Drug: Nitisinone
A single oral dose of Nitisinone 10 mg Tablet will be administered.

Drug: Nitisinone Baked Tablet
A single oral dose of Nitisinone 10 mg Tablet (6 months @ 40°C/75% RH) will be administered.
Other Name: Nitisinone (Baked)

Drug: Orfadin
A single oral dose of Orfadin 10 mg hard capsule will be administered.
Other Name: Nitisinone




Primary Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) [ Time Frame: 0 - 120 hours post-dose ]
  2. Area Under the Plasma Concentration Versus Time Curve (AUC(0-120)) [ Time Frame: 0 - 120 hours post-dose ]

Secondary Outcome Measures :
  1. Area Under the Plasma Concentration Versus Time Curve (AUC(0-72)) [ Time Frame: 0 - 72 hours post-dose ]
  2. Area Under the Plasma Concentration Versus Time Curve, With Extrapolation to Infinity (AUC(0-∞)) [ Time Frame: 0 - 120 hours post-dose ]
  3. Time to Maximum Observed Plasma Concentration (Tmax) [ Time Frame: 0 - 120 hours post-dose ]
  4. Terminal Elimination Rate Constant (λz) [ Time Frame: 0 - 120 hours post-dose ]
  5. Apparent Terminal Elimination Half-life (t1/2) [ Time Frame: 0 - 120 hours post-dose ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male and female subjects, 18 to 55 years (both inclusive) at signing of informed consent.
  • Body Mass Index (BMI) between 18.5 and 30 kg/m2 (inclusive).
  • Body mass not less than 50 kg.
  • Medical history, vital signs, physical examination, standard 12-lead electrocardiogram (ECG) and laboratory investigations must be clinically acceptable or within laboratory reference ranges for the relevant laboratory tests, unless the investigator considers the deviation to be irrelevant for the purpose of the study.
  • Non-smokers.
  • Females, if:

Of childbearing potential, the following conditions are to be met:

  • Negative pregnancy test If this test is positive, the subject will be excluded from the study. In the rare circumstance that a pregnancy is discovered after the subject received IMP, every attempt must be made to follow her to term.
  • Not lactating
  • Abstaining from sexual activity (if this is the usual lifestyle of the subject) or must agree to use an accepted method of contraception, and agree to continue with the same method throughout the study Examples of reliable methods of contraception include non-hormonal intrauterine device, and barrier methods combined with an additional contraceptive method. In this study the concomitant use of hormonal contraceptives is NOT allowed. Other methods, if considered by the investigator as reliable, will be accepted.

    • Written consent given for participation in the study.

Exclusion Criteria:

  • Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional or intellectual problems likely to limit the validity of consent to participate in the study or limit the ability to comply with protocol requirements.
  • Current alcohol use > 21 units of alcohol per week for males and > 14 units of alcohol per week for females.
  • Consumption of more than 5 cups of coffee (or equivalent amounts of caffeine) per day.
  • Regular exposure to substances of abuse (other than alcohol) within the past year.
  • Use of any medication, prescribed or over-the-counter or herbal remedies, within 2 weeks before the first administration of IMP except if this will not affect the outcome of the study in the opinion of the investigator.

In this study the concomitant use of hormonal contraceptives is NOT allowed.

  • Participation in another study with an experimental drug, where the last administration of the previous IMP was within 8 weeks (or within 10 elimination half-lives for chemical entities or 2 elimination half-lives for antibodies or insulin), whichever is the longer) before administration of IMP in this study, at the discretion of the investigator.
  • Treatment within the previous 3 months before the first administration of IMP with any drug with a well-defined potential for adversely affecting a major organ or system.
  • A major illness during the 3 months before commencement of the screening period.
  • History of hypersensitivity or allergy to the IMP or its excipients or any related medication.
  • History of bronchial asthma or any other bronchospastic disease.
  • History of convulsions.
  • History of porphyria.
  • Relevant history or laboratory or clinical findings indicative of acute or chronic disease, likely to influence study outcome.
  • Donation or loss of blood equal to or exceeding 500 mL during the 8 weeks before the first administration of IMP.
  • Diagnosis of hypotension made during the screening period.
  • Diagnosis of hypertension made during the screening period or current diagnosis of hypertension.
  • Resting pulse of > 100 beats per minute or < 40 beats per minute during the screening period, either supine or standing.
  • Positive testing for human immunodeficiency virus (HIV), Hepatitis B and Hepatitis C.
  • Positive urine screen for drugs of abuse. In case of a positive result the urine screen for drugs of abuse may be repeated once at the discretion of the investigator.
  • Positive urine screen for tobacco use.
  • Positive pregnancy test.
  • Female subjects that are pregnant or breastfeeding.
  • Difficulty in swallowing.
  • Any specific investigational product safety concern.
  • Vulnerable subjects, e.g. persons in detention.
  • Subjects with current keratopathy, or other clinically significant abnormalities found by slit-lamp examination (cataracts) at the discretion of the investigator.
  • Concomitant use of medications that are metabolized by CYP2C9 (ibuprofen, diclofenac and indomethacin).

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): NCT02750345


Locations
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South Africa
Bloemfontein Early Phase Clinical Unit, PAREXEL International (South Africa)
Bloemfontein, Free State, South Africa, 9301
Sponsors and Collaborators
Cycle Pharmaceuticals Ltd.
Parexel
Investigators
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Principal Investigator: André Nell +27 51 410 3046

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Responsible Party: Cycle Pharmaceuticals Ltd.
ClinicalTrials.gov Identifier: NCT02750345     History of Changes
Other Study ID Numbers: CT-003
PXL227430 ( Other Identifier: PAREXEL )
First Posted: April 25, 2016    Key Record Dates
Results First Posted: October 17, 2016
Last Update Posted: June 14, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Cycle Pharmaceuticals Ltd.:
HT-1
Tyrosinemia
Nitisinone
Bioavailability
Healthy Volunteer
Food-Effect

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