Dose Response Study of Nitisinone in Alkaptonuria

Study Overview
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Brief Summary
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SONIA 1 is an international, multicentre, randomised, open-label, no-treatment controlled, parallel group, dose-response study to investigate the effect of once daily nitisinone on 24-hour urinary homogentisic acid excretion in patients with alkaptonuria after 4-weeks treatment. They study will identify the optimal dose to decrease urine homogentisic acid to near normal levels.

Official Title
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An International, Multicentre, Randomised, Open-label, No-treatment Controlled, Parallel-group, Dose-response Study to Investigate the Effect of Once Daily Nitisinone on 24-hour Urinary Homogentisic Acid Excretion in Patients With Alkaptonuria After 4 Weeks Treatment.

Conditions
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Alkaptonuria

Intervention / Treatment
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* Drug: Nitisinone


Participation Criteria
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Eligibility Criteria
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Inclusion criteria A subject must fulfil the following criteria in order to be included in the study: Diagnosis of alkaptonuria verified by documented elevated urinary homogentisic acid excretion. Age ≥18 years. Willing and able to visit the investigational site for study visits. Signed written informed consent obtained. Exclusion criteria The presence of any of the following will exclude a subject from inclusion in the study: Non-alkaptonuria causes of ochronosis. Currently pregnant or lactating. Known allergy to nitisinone or any of the constituents of the investigational product. Use of a protein-restricted diet Dietary habits or use of homeopathic therapies that interfere with tyrosine catabolism. Current keratopathy, contact lens use or uncontrolled glaucoma. Current malignancy. Uncontrolled hypertension (blood pressure greater than 180 systolic or greater than 95 diastolic). Electrocardiogram changes indicative of myocardial infarction, arrhythmia, tachycardia, bradycardia, left bundle branch block. Chest radiographic abnormalities, including an infiltrative, mass, congestive heart failure, embolism, atelectasis. Serum potassium < 3.0 mmol/L. eGFR < 60 mL/min. Any hepatic enzymes greater than 3 x upper limit of normal. Haemoglobin < 10.0 g/dL. Platelets less than 100 x 109/L. WBC less than 3.0 x 109/L. ESR greater than 100 mm/h. History of alcohol or drug abuse. Participation in another clinical trial within 3 months of randomisation. Treatment with nitisinone within 3 months of randomisation Psychiatric illness or neurological disease that interferes with compliance or communication with health care personnel. Any other medical condition which in the opinion of the investigator makes the subject unsuitable for inclusion. Foreseeable inability to cooperate with given instructions or study procedures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: no treatment<br>comparrator | |
| Experimental: Nitisinone 1mg<br>interventional | Drug: Nitisinone<br>* doses 1, 2, 4 & 8 mg plus no treatment arm<br>|
| Experimental: Nitisinone 2mg<br>interventional | Drug: Nitisinone<br>* doses 1, 2, 4 & 8 mg plus no treatment arm<br>|
| Experimental: Nitisinone 4mg<br>interventional | Drug: Nitisinone<br>* doses 1, 2, 4 & 8 mg plus no treatment arm<br>|
| Experimental: Nitisinone 8mg<br>interventional | Drug: Nitisinone<br>* doses 1, 2, 4 & 8 mg plus no treatment arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| dose of nitisinone that decreases urinary homogentisic acid to near normal |  | 4 weeks |