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    Summary
    EudraCT Number:2013-001633-41
    Sponsor's Protocol Code Number:SONIA2
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-07-19
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2013-001633-41
    A.3Full title of the trial
    An international, multicenter, randomized, evaluator-blinded, no-treatment controlled, parallel-group study to assess the efficacy and safety of once daily nitisinone in patients with alkaptonuria after 12 months of treatment, followed by an additional 36-month treatment period.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of 4 years treatment with nitisinone in patients with Alkaptonuria (AKU).
    A.4.1Sponsor's protocol code numberSONIA2
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Liverpool (UniLiv)
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUniversity of Liverpool
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationClinical Research Governance Team
    B.5.2Functional name of contact pointResearch Support Office
    B.5.3 Address:
    B.5.3.1Street Address3 Brownlow Street
    B.5.3.2Town/ cityLiverpool
    B.5.3.3Post codeL69 3GL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number00441517948373
    B.5.6E-mailsponsor@liv.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Orfadin
    D.2.1.1.2Name of the Marketing Authorisation holderSwedish Orphan Biovitrum
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/02/096
    D.3 Description of the IMP
    D.3.1Product nameOrfadin
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Alkaptonuria (AKU) - a serious, autosomal recessive, multisystem disorder.
    E.1.1.1Medical condition in easily understood language
    Alkaptonuria (AKU) - a serious genetic disease. Also known as 'black bone' disease
    E.1.1.2Therapeutic area Body processes [G] - Metabolic Phenomena [G03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level PT
    E.1.2Classification code 10001689
    E.1.2Term Alkaptonuria
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate that nitisinone is superior compared to no treatment in reducing 24-hour urinary homogentisic acid excretion in patients with alkaptonuria after 12 months.
    E.2.2Secondary objectives of the trial
    • To demonstrate the effect of nitisinone on control of u-HGA24 after 3, 24, 36 and 48 months.
    • To demonstrate the effect of nitisinone on control of serum HGA concentration (s-HGA) in patients with AKU after 3, 12, 24, 36 and 48 months of treatment.
    • To demonstrate the effect of nitisinone on pre-defined clinical parameters.
    • To assess the association between u-HGA24 and change in clinical parameters.
    • To assess predose serum concentrations of nitisinone after 3, 12, 24, 36 and 48 months of treatment.
    • To assess the association between u-HGA24 and predose serum concentrations of nitisinone.
    • To assess the effect of nitisinone on pre-defined measures of health and functional status, as assessed by SF-36, the Health Assessment Questionnaire (HAQ) and Western Ontario and McMaster Universities Arthritis Index (WOMAC).
    • To assess the safety of long-term treatment with nitisinone in patients with AKU.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Diagnosis of AKU.
    2. Any clinical manifestations of AKU, such as clinical ochronosis or chronic back / joint pain.
    3. Age ≥25 years.
    4. Willing and able to visit the investigational site for study visits.
    5. Signed written informed consent given.
    E.4Principal exclusion criteria
    1. Treatment with nitisinone within 3 months of randomization.
    2. Participation in another clinical study within 3 months of randomization.
    3. Known allergy to nitisinone or any of the constituents of the investigational product.
    4. Female patient of child-bearing potential not using a reliable method of contraception.
    5. Currently pregnant or lactating.
    6. Current malignancy.
    7. Uncontrolled hypertension (blood pressure greater than 180 mmHg systolic or greater than 95 mmHg diastolic).
    8. Unstable cardiovascular disease.
    9. Clinically relevant lab abnormalities
    10. History of alcohol or drug abuse.
    11. Psychiatric or somatic illness that interferes with compliance or communication with health care personnel.
    12. Foreseeable inability to cooperate with given instructions or study procedures.
    13. Any other medical condition which in the opinion of the investigator makes the patient unsuitable for inclusion.
    E.5 End points
    E.5.1Primary end point(s)
    u-HGA24 after 12 months.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Visit 3 (month 12)
    E.5.2Secondary end point(s)
    • Clinical AKUSSI scores at 12, 24, 36 and 48 months compared with baseline.
    • Modified AKUSSI scores at 12, 24, 36 and 48 months compared with baseline.
    • Individual cAKUSSI items at 12, 24, 36 and 48 months compared with baseline.
    • Ear cartilage pigmentation at 48 months compared with baseline.
    • Pain scores measured by visual analogue scale (VAS) at 3, 12, 24, 36 and 48 months compared with baseline.
    • Quality of life (QoL) measured by SF36 at 3, 12, 24, 36 and 48 months compared with baseline.
    • Health assessment measured by HAQ at 3, 12, 24, 36 and 48 months compared with baseline.
    • Joint stiffness at 12, 24, 36 and 48 months compared with baseline.
    • Physical function as measured by WOMAC index at 3, 12, 24, 36 and 48 months compared with baseline.
    • Range of joint and spine motion at 12, 24, 36 and 48 months compared with baseline.
    • Predose s-HGA at 3, 12, 24, 36 and 48 months.
    • Predose s-Tyr at 3, 12, 24, 36 and 48 months.
    • Pre-dose serum nitisinone at 3, 12, 24, 36 and 48 months.
    • Adverse events, clinical chemistry and haematology, vital signs, ECG and slit-lamp eye assessments.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Vist 2 (month 3), Visit 3 (month 12), Visit 4 (month 24), Visit 5 (month 36) & Visit 6 (month 48)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    No treatment control group
    E.8.2.4Number of treatment arms in the trial2
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    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
    Month 49, Follow-up Phone Call
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 140
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 140
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Back to usual care
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-09-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-02-15
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