Efficacy and Safety Dose Finding Study of Givinostat to Treat Polyarticular Course Juvenile Idiopathic Arthritis

A Multicenter, Open Label, Dose Finding Study to Evaluate Efficacy and Safety of Givinostat Administered in Two Different Doses in Patients With Poly JIA Not Adequately Responding to the Standard Treatment.

The present study has been designed in order to evaluate the efficacy and safety of two doses of Givinostat in subjects with polyarticular course JIA

Givinostat ready-to-use suspension especially intended for paediatric administration, will be administered orally at different daily doses.

Patients with an established diagnosis of one of the following JIA forms (Polyarticular JIA rheumatoid factor positive or negative, Oligoarticular extended JIA, Systemic JIA without active systemic features) will be enrolled.

The treatment regimen will remain unchanged for 12 weeks and the clinical response will by assessed by applying the ACR Pediatric response criteria. Patients achieving at least an ACR Pediatric 30 response will continue receiving the assigned dose for 12 further weeks.

After the end of study (week 24) responder patients will be allowed to extend the treatment until they maintain a clinical benefit.

Non-clinical data on Givinostat, support a potent anti-inflammatory mechanism of action which can potentially slow the arthritic destructive process. This rationale seems to be confirmed by the preliminary evidences collected in a previous Phase II clinical trial conducted in children and young adults with systemic JIA.

The present protocol is aimed at collecting new information on safety and efficacy of two doses of Givinostat for the treatment of JIA.

Inclusion Criteria:

• patients of both genders, aged 2 to 17 years, with established diagnosis of polyarticular course Juvenile Idiopathic Arthritis (see before for specific subtypes) according to ILAR (International League Against Rheumatism) criteria (Petty RE et al., 2004) for at least six months before the study entry
• age at polyarticular JIA diagnosis < 16 years
• active disease for at least 6 months prior to enrolment as defined by the following criteria:
• presence of at least 5 active joints (those with swelling or, in the absence of swelling, limited range of motion accompanied by pain/tenderness)
• inadequate response to, or intolerance to, at least one biologic agent such as, but not limited to, etanercept, infliximab, and adalimumab.
• maximum allowed steroid dose 0.2 mg/kg/day or 10 mg/day (whichever is lower) of prednisone or equivalent
• in case of concomitant methotrexate treatment, it has to be on a stable dose ≤15 mg/m2 weekly for at least 1 month before patient's enrolment
• other disease-modifying anti-rheumatic drugs possibly previously introduced have to be discontinued for a period of at least five half-lives
• concomitant nonsteroidal anti-inflammatory drugs, if any, on a stable dose for at least four weeks before patient's enrolment

Exclusion Criteria:

• patient with fever related to JIA or other systemic features of JIA during 12 months before entering the study
• active bacterial or mycotic infection requiring antimicrobial treatment
• episode of macrophage activation syndrome in the last 6 months
• a baseline prolongation of QT/QTc interval, use of concomitant medications that prolong the QT/QTc interval or history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) (Appendix C)
• clinically significant cardiovascular disease
• clinically significant illness i.e. any condition (including laboratory abnormalities) that in the opinion of the Investigator places the patient to unacceptable risk for adverse outcome if he/she were to participate in the study
• psychiatric illness/social situations that would limit compliance with study medication and protocol requirements
• inherited metabolic diseases
• presence of malignancy
• pregnancy or lactation
• positive blood test for HIV
• active EBV infection, active B and/or C hepatitis
• platelet count <100x109/L
• absolute neutrophil count <1.5x109/L
• serum creatinine >2xULN (Upper limit of normal).
• total serum bilirubin >1.5xULN.
• serum AST/ALT > 3xULN.
• congenital heart and/or central nervous system disorders