Efficacy and Safety Dose Finding Study of Givinostat to Treat Polyarticular Course Juvenile Idiopathic Arthritis
Condition: Polyarticular Course Juvenile Idiopathic Arthritis
MeSH terms: Arthritis; Arthritis, Juvenile
Intervention: Givinostat
Intervention description: 1.0 mg/kg daily (0.5 mg/kg twice a day) in fed condition 1.5 mg/kg daily (0.75 mg/kg twice a day) in fed condition
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 2 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: poly JIA

Summary:

      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.
    

Eligibility criteria:

        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