Bioequivalence Study of Two Nitisinone Formulations Compared to Orfadin

NCT02750709 | Completed Phase 1 Results

• 2 other identifiers: CT-001PXL225418
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine whether Nitisinone 10 mg Tablets (Test Product 1 (TP1)) and Nitisinone 10 mg Tablets High Compritol (Test Product 2 (TP2)) are bioequivalent to the reference product Orfadin 10 mg capsules.

Conditions

Hereditary Tyrosinemia, Type I

Keywords

HT-1; Tyrosinemia; Nitisinone; Bioequivalence; Healthy Volunteer; Orfadin

Outcome Measures

Primary Outcomes (2)

• Maximum Observed Plasma Concentration (Cmax)

  0, 0.25, 0.50, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, 72, 96 and 120 hours

• Area Under the Plasma Concentration Versus Time Curve, From Time Zero to 120 Hours Post-dose (AUC(0-120))

  0, 0.25, 0.50, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, 72, 96 and 120 hours

Secondary Outcomes (5)

• Area Under the Plasma Concentration Versus Time Curve, From Time Zero to 72 Hours Post-dose (AUC(0-72))

  0, 0.25, 0.50, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, 72 hours post-dose

• Area Under the Plasma Concentration Versus Time Curve, With Extrapolation to Infinity (AUC(0-∞)

  0, 0.25, 0.50, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, 72, 96 and 120 hours

• Time to Maximum Observed Plasma Concentration (Tmax)

  0, 0.25, 0.50, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, 72, 96 and 120 hours

• Terminal Elimination Rate Constant (λz)

  0, 0.25, 0.50, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, 72, 96 and 120 hours

• Apparent Terminal Half-life (t1/2)

  0, 0.25, 0.50, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, 72, 96 and 120 hours

Study Arms (6)

Treatment Sequence A (TP 1) - B (TP 2) - C (Reference)

EXPERIMENTAL

Subjects will receive a single 10 mg tablet of Nitisinone 10 mg Tablet (Test Product 1) in treatment period 1, 10 mg tablet of Nitisinone 10 mg Tablet High Compritol (Test Product 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; Drug: Nitisinone 10 mg Tablet High Compritol; Drug: Orfadin

Treatment Sequence A (TP 1) - C (Reference) - B (TP 2)

EXPERIMENTAL

Subjects will receive a single 10 mg tablet of Nitisinone 10 mg 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 10 mg Tablet High Compritol (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; Drug: Nitisinone 10 mg Tablet High Compritol; Drug: Orfadin

Treatment Sequence B (TP 2) - A (TP 1) - C (Reference)

EXPERIMENTAL

Subjects will receive a single 10 mg tablet of Nitisinone 10 mg Tablet High Compritol (Test Product 2) in treatment period 1, 10 mg tablet of Nitisinone 10 mg Tablet (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; Drug: Nitisinone 10 mg Tablet High Compritol; Drug: Orfadin

Treatment Sequence B (TP 2) - C (Reference) - A (TP 1)

EXPERIMENTAL

Subjects will receive a single 10 mg tablet of Nitisinone 10 mg Tablet High Compritol (Test Product 2) in treatment period 1, 10 mg hard capsule of Orfadin (Reference) in treatment period 2, and 10 mg tablet of Nitisinone 10 mg Tablet (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; Drug: Nitisinone 10 mg Tablet High Compritol; Drug: Orfadin

Treatment Sequence C (Reference) - A (TP 1) - B (TP 2)

EXPERIMENTAL

Subjects will receive a single 10 mg hard capsule of Orfadin (Reference) in treatment period 1, 10 mg tablet of Nitisinone 10 mg Tablet (Test Product 1) in treatment period 2, and 10 mg tablet of Nitisinone 10 mg Tablet High Compritol (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; Drug: Nitisinone 10 mg Tablet High Compritol; Drug: Orfadin

Treatment Sequence C (Reference) - B (TP 2) - A (TP 1)

EXPERIMENTAL

Subjects will receive a single 10 mg hard capsule of Orfadin (Reference) in treatment period 1, 10 mg tablet of Nitisinone 10 mg Tablet High Compritol (Test Product 2) in treatment period 2, 10 mg tablet of Nitisinone 10 mg Tablet (Test Product 1) in treatment period 3 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.

Drug: Nitisinone; Drug: Nitisinone 10 mg Tablet High Compritol; Drug: Orfadin

Interventions

Nitisinone DRUG

A single oral dose of Nitisinone 10 mg tablet will be administered in fasted state.

Treatment Sequence A (TP 1) - B (TP 2) - C (Reference); Treatment Sequence A (TP 1) - C (Reference) - B (TP 2); Treatment Sequence B (TP 2) - A (TP 1) - C (Reference); Treatment Sequence B (TP 2) - C (Reference) - A (TP 1); Treatment Sequence C (Reference) - A (TP 1) - B (TP 2); Treatment Sequence C (Reference) - B (TP 2) - A (TP 1)

Nitisinone 10 mg Tablet High Compritol DRUG

A single oral dose of Nitisinone 10 mg High Compritol tablet will be administered in fasted state.

Treatment Sequence A (TP 1) - B (TP 2) - C (Reference); Treatment Sequence A (TP 1) - C (Reference) - B (TP 2); Treatment Sequence B (TP 2) - A (TP 1) - C (Reference); Treatment Sequence B (TP 2) - C (Reference) - A (TP 1); Treatment Sequence C (Reference) - A (TP 1) - B (TP 2); Treatment Sequence C (Reference) - B (TP 2) - A (TP 1)

Orfadin DRUG

A single oral dose of Orfadin 10 mg hard capsule will be administered in fasted state.

Treatment Sequence A (TP 1) - B (TP 2) - C (Reference); Treatment Sequence A (TP 1) - C (Reference) - B (TP 2); Treatment Sequence B (TP 2) - A (TP 1) - C (Reference); Treatment Sequence B (TP 2) - C (Reference) - A (TP 1); Treatment Sequence C (Reference) - A (TP 1) - B (TP 2); Treatment Sequence C (Reference) - B (TP 2) - A (TP 1)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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:
• Not of childbearing potential, e.g., has been surgically sterilized, undergone a hysterectomy, amenorrhea for ≥ 12 months and considered post-menopausal,
• Note: In postmenopausal women, the value of the serum pregnancy test may be slightly increased. This test will be repeated to confirm the results. If there is no increase indicative of pregnancy, the female will be included in the study.
• 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 Investigational Medicinal Product (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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Cycle Pharmaceuticals Ltd.: lead
• Parexel: collaborator

Study Sites (1)

Bloemfontein Early Phase Clinical Unit, PAREXEL International (South Africa)

Bloemfontein, Free State, 9301, South Africa

Location

MeSH Terms

Conditions

Tyrosinemias

Interventions

nitisinone

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: James Price
• Organization: Cycle Pharmaceuticals Ltd

james.price@cyclepharma.com

+44 1223 803638

Study Officials

• André Nell

  Bloemfontein Early Phase Clinical Unit, PAREXEL Internation (South Africa)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 20, 2016
• First Posted: April 25, 2016
• Study Start: October 1, 2015
• Primary Completion: December 1, 2015
• Study Completion: January 1, 2016
• Last Updated: March 15, 2017
• Results First Posted: December 13, 2016

Record last verified: 2017-02

Locations

ZA (1)