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

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.

• Givinostat (Drug): 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

Primary outcomes

• ACR Pediatric Response Level (ACRPRL) 30 After 12 Weeks of Treatment [12 weeks of treatment]: ACR Pediatric variables include: Physician's Global Assessment of disease activity on a 0-100 mm visual analogue scale from 0 mm = no disease activity to 100 mm = very severe disease activity; Parent's or patient's Global Assessment of Patient's overall well-being on a 100 mm VAS from 0 mm = very well to 100 mm = very poor; Functional ability: Childhood Health Assessment Questionnaire; Number of joints with active arthritis using the ACR definition (any joint with swelling, or in the absence of swelling, limitation of motion accompanied by pain/tenderness not due to bone deformity); Number of joints with limitation of motion; Laboratory measure of inflammation: C-reactive protein (mg/L) Patients were considered as responders if they achieve at least an ACR Pediatric Criteria level 30 of response, defined as a 30% improvement as compared to baseline in at least 3 of the 6 variables listed above, with no more than 1 variable worsening by > than 30%

Secondary outcomes

• ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 [at week12]: ACR Pediatric variables include: Physician's Global Assessment of disease activity on a 0- 100 mm visual analogue scale from 0 mm = no disease activity to 100 mm = very severe disease activity; Parent's or patient's Global Assessment of Patient's overall well-being on a 100 mm VAS from 0 mm = very well to 100 mm = very poor; Functional ability: Childhood Health Assessment Questionnaire; Number of joints with active arthritis using the ACR definition (any joint with swelling, or in the absence of swelling, limitation of motion accompanied by pain/tenderness not due to bone deformity); Number of joints with limitation of motion; Laboratory measure of inflammation: C-reactive protein (mg/L) Patients were considered as responders if they achieve at least an ACR Pediatric Criteria level 50, 70, 90 and 100 of response, defined as a 50%, 70%, 90% and 100% improvement as compared to baseline in at least 3 of the 6 variables listed above, with no more than 1 variable worsening by > than 30%

Sex: All, ages: 2 Years to 17 Years

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

Participant flow

Outcome results

• ACR Pediatric Response Level (ACRPRL) 30 After 12 Weeks of Treatment (Primary), Number, participants: Low Dose Discontinued 0; Low Dose Throughout 1; Switched Dose 3; High Dose Throughout 2; High Dose Discontinued 1
• ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 (Secondary), Number, participants: Low Dose Discontinued 0; Low Dose Throughout 1; Switched Dose 1; High Dose Throughout 2; High Dose Discontinued 1

Adverse events

Time frame: Planned treatment duration was 24 weeks overall (12 weeks + 12 weeks). The mean (SD) duration of treatment was 131.9 (55.9) days overall, with a median duration of 170 days.

Other adverse events by term

• Francesco Zulian, MD, Principal investigator, Azienda Ospedaliera-Università di Padova - Unità di Reumatologia Pediatrica