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.

INTERVENTION: Trade Name: Orfadin Product Name: Orfadin Pharmaceutical Form: Capsule CONDITION: Alkaptonuria (AKU) ‐ a serious, autosomal recessive, multisystem disorder. ; MedDRA version: 16.0 Level: PT Classification code 10001689 Term: Alkaptonuria System Organ Class: 10010331 ‐ Congenital, familial and genetic disorders Therapeutic area: Body processes [G] ‐ Metabolic Phenomena [G03] PRIMARY OUTCOME: Main Objective: 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. Primary end point(s): u‐HGA24 after 12 months. Secondary Objective: • 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. Timepoint(s) of evaluation of this end point: Visit 3 (month 12) SECONDARY OUTCOME: Secondary 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. Timepoint(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) 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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 140 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range