Dose Response Study of Nitisinone in Alkaptonuria (SONIA1)

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.

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.

Study Overview

• Status: Completed
• Conditions: Alkaptonuria
• Intervention / Treatment: Drug: Nitisinone

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Merseyside
    • Liverpool, Merseyside, United Kingdom, L7 8XP
      • Royal Liverpool Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

A subject must fulfil the following criteria in order to be included in the study:

1. Diagnosis of alkaptonuria verified by 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 obtained.

Exclusion criteria

The presence of any of the following will exclude a subject from inclusion in the study:

1. Non-alkaptonuria causes of ochronosis.
2. Currently pregnant or lactating.
3. Known allergy to nitisinone or any of the constituents of the investigational product.
4. Use of a protein-restricted diet
5. Dietary habits or use of homeopathic therapies that interfere with tyrosine catabolism.
6. Current keratopathy, contact lens use or uncontrolled glaucoma.
7. Current malignancy.
8. Uncontrolled hypertension (blood pressure greater than 180 systolic or greater than 95 diastolic).
9. Electrocardiogram changes indicative of myocardial infarction, arrhythmia, tachycardia, bradycardia, left bundle branch block.
10. Chest radiographic abnormalities, including an infiltrative, mass, congestive heart failure, embolism, atelectasis.
11. Serum potassium < 3.0 mmol/L.
12. eGFR < 60 mL/min.
13. Any hepatic enzymes greater than 3 x upper limit of normal.
14. Haemoglobin < 10.0 g/dL.
15. Platelets less than 100 x 109/L.
16. WBC less than 3.0 x 109/L.
17. ESR greater than 100 mm/h.
18. History of alcohol or drug abuse.
19. Participation in another clinical trial within 3 months of randomisation.
20. Treatment with nitisinone within 3 months of randomisation
21. Psychiatric illness or neurological disease that interferes with compliance or communication with health care personnel.
22. Any other medical condition which in the opinion of the investigator makes the subject unsuitable for inclusion.
23. Foreseeable inability to cooperate with given instructions or study procedures.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: no treatment; comparrator
Experimental: Nitisinone 1mg; interventional	Drug: Nitisinone; doses 1, 2, 4 & 8 mg plus no treatment arm
Experimental: Nitisinone 2mg; interventional	Drug: Nitisinone; doses 1, 2, 4 & 8 mg plus no treatment arm
Experimental: Nitisinone 4mg; interventional	Drug: Nitisinone; doses 1, 2, 4 & 8 mg plus no treatment arm
Experimental: Nitisinone 8mg; interventional	Drug: Nitisinone; doses 1, 2, 4 & 8 mg plus no treatment arm

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Liverpool
• Collaborators: Liverpool University Hospitals NHS Foundation Trust
• Investigators: Principal Investigator: L Ranganath, Royal Liverpool & Broadgreen University Hospitals NHS Truts

Publications and helpful links

General Publications

• Milan AM, Hughes AT, Davison AS, Khedr M, Rovensky J, Psarelli EE, Cox TF, Rhodes NP, Gallagher JA, Ranganath LR. Quantification of the flux of tyrosine pathway metabolites during nitisinone treatment of Alkaptonuria. Sci Rep. 2019 Jul 11;9(1):10024. doi: 10.1038/s41598-019-46033-x.
• Ranganath LR, Milan AM, Hughes AT, Dutton JJ, Fitzgerald R, Briggs MC, Bygott H, Psarelli EE, Cox TF, Gallagher JA, Jarvis JC, van Kan C, Hall AK, Laan D, Olsson B, Szamosi J, Rudebeck M, Kullenberg T, Cronlund A, Svensson L, Junestrand C, Ayoob H, Timmis OG, Sireau N, Le Quan Sang KH, Genovese F, Braconi D, Santucci A, Nemethova M, Zatkova A, McCaffrey J, Christensen P, Ross G, Imrich R, Rovensky J. Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment. Ann Rheum Dis. 2016 Feb;75(2):362-7. doi: 10.1136/annrheumdis-2014-206033. Epub 2014 Dec 4.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: April 5, 2013
• First Submitted That Met QC Criteria: April 5, 2013
• First Posted (Estimate): April 10, 2013

Study Record Updates

• Last Update Posted (Estimate): June 11, 2014
• Last Update Submitted That Met QC Criteria: June 10, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Amino Acid Metabolism, Inborn Errors; Alkaptonuria; Ochronosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nitisinone
• Other Study ID Numbers: UoL000928