Bioavailability Food-Effect Study of an Oral Nitisinone Formulation to Treat Hereditary Tyrosinemia (HT-1)

Brief Title

Bioavailability Food-Effect Study of an Oral Nitisinone Formulation to Treat Hereditary Tyrosinemia (HT-1)

Official Title

A Single Center, Single-Dose, Open-Label, Randomized Study to Compare the Bioavailability of an Oral Test Formulation Containing Nitisinone 10 mg in at Least 16 Healthy Male and Female Subjects Under Fasting and Fed Conditions

Brief Summary

      The purpose of this study is to compare the bioavailability of the Test Product, Nitisinone
      10 mg Tablet, under fasting and fed conditions (food-effect).

Detailed Description

      The specific aim is to conduct a randomized, single dose, two-period crossover
      bioavailability study in at least 16 healthy male and female subjects at a single study
      center to evaluate the in vivo performance of Test Product, Nitisinone 10 mg Tablet, under
      fasting and fed conditions.

      The study in healthy male and female volunteers is designed to establish a pharmacokinetic
      (PK) profile under fed and fasting conditions for the orally administered Test Product,
      Nitisinone 10 mg Tablets.

      A total of 20 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 receive the Test Product under fasting or fed 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).

Study Phase

Phase 1

Study Type


Primary Outcome

Maximum Observed Plasma Concentration (Cmax)

Secondary Outcome

 Area Under the Plasma Concentration Versus Time Curve (AUC(0-72))


Hereditary Tyrosinemia, Type I



Study Arms / Comparison Groups

 Treatment Sequence A (Fed) - B (Fasted)
Description:  Subjects will receive a single 10 mg tablet of Nitisinone in treatment period 1 under fed conditions, and 10 mg tablet of Nitisinone in treatment period 2 under fasting conditions. Each treatment period will be separated by at least 23 calendar days of washout period.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

November 2015

Completion Date

January 2016

Primary Completion Date

December 2015

Eligibility 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

          -  Written consent given for participation in the study.

          -  Subjects must be willing to consume the meal prescribed with administration of the IMP
             in full and within the required time.

        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 investigational medicinal product (IMP)
             except if this will not affect the outcome of the study in the opinion of the

        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

          -  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

          -  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).




18 Years - 55 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers


André Nell, , 

Location Countries

South Africa

Location Countries

South Africa

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

Cycle Pharmaceuticals Ltd.



Study Sponsor

André Nell, Principal Investigator, +27 51 410 3046

Verification Date

February 2017