E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Alkaptonuria (AKU) - a serious, autosomal recessive, multisystem disorder |
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E.1.1.1 | Medical condition in easily understood language |
Alkaptonuria (AKU) - a serious, autosomal recessive, multisystem disorder. Also, known as 'black bone' disease. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the effect of different doses of once daily nitisinone on 24-hour urinary homogentisic acid excretion (u-HGA24) in patients with alkaptonuria after 4-weeks treatment. |
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E.2.2 | Secondary objectives of the trial |
• To investigate the effect of different doses of once daily nitisinone on plasma homogentisic acid concentration (p-HGA)
and plasma tyrosine concentration (p-Tyr) in patients with alkaptonuria.
• To determine the pharmacokinetics (PK) of nitisinone at steady state and to test for PK dose-proportionality.
• To describe the relationship between PK variables of nitisinone, u-HGA24, p-HGA and p-Tyr.
• To assess the safety of nitisinone at doses relevant for the treatment of alkaptonuria.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Diagnosis of AKU verified by previously documented elevated urinary homogentisic acid excretion.
2. Age ≥18 years.
3. Willing and able to visit the investigational site for study visits.
4. Signed written informed consent given.
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E.4 | Principal exclusion criteria |
1. Currently pregnant or lactating.
2. Female patient of child-bearing potential not using a reliable method of contraception.
3. Known allergy to nitisinone or any of the constituents of the investigational product.
4. Current keratopathy or uncontrolled glaucoma.
5. Current malignancy.
6. Uncontrolled hypertension (blood pressure greater than 180 mmHg systolic or greater than 95 mmHg diastolic).
7. Unstable cardiovascular disease.
8. Serum potassium < 3.0 mmol/L.
9. eGFR < 60 mL/min.
10. ALT > 3 x upper limit of normal.
11. Hemoglobin < 10.0 g/dL.
12. Platelets < 100 x 109/L.
13. White blood count < 3.0 x 109/L.
14. History of alcohol or drug abuse.
15. Participation in another clinical study within 3 months of randomization.
16. Treatment with nitisinone within 60 days of randomization.
17. Psychiatric illness or neurological disease that interferes with compliance or communication with health care personnel.
18. Any other medical condition which in the opinion of the investigator makes the patient unsuitable for inclusion.
19. Foreseeable inability to cooperate with given instructions or study procedures. |
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E.5 End points |
E.5.1 | Primary end point(s) |
u-HGA24 after 4 weeks of treatment with nitisinone. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
A follow-up phone call will take place 2 weeks (+/- 3 days) after the Final Visit. The patient will be questioned about concomitant medication and adverse events. |
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E.5.2 | Secondary end point(s) |
• u-HGA24 after 1, 2 and 3 weeks of treatment with nitisinone.
• Proportion of patients achieving normal levels of u-HGA24 at weeks 1, 2, 3 and 4.
• p-HGA and p-Tyr at Weeks 1, 2, 3, and 4.
• 24-hour plasma HGA and plasma tyrosine profiles at baseline and Week 4.
• Nitisinone steady-state pharmacokinetic variables.
• Adverse events, clinical chemistry and haematology, vital signs, ECG. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Visit 2: The 24-hour urine collection will be done at home. Patients should begin collection in the morning, immediately after taking the daily dose of study medication. Collection ends the following morning at the same time.
Visit 3: As for Visit 1. The patient will take the last dose of study medication immediately before the 24-hour collection period begins.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
No treatment control group |
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E.8.2.4 | Number of treatment arms in the trial | 5 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS and one follow-up telephone call. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |