Polyarticular Course Juvenile Idiopathic Arthritis
Conditions
Keywords
poly JIA
Brief 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.
Detailed description
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.
Interventions
DRUGGivinostat
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
Sponsors
Italfarmaco
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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% |
Countries
Belgium, Czechia, Italy, Romania, Serbia, Slovenia, Spain
Participant flow
Recruitment details
Recruitment period: October 2010 - December 2011. The study was conducted by nine Investigators in five countries across Europe; three Investigators in Italy, two Investigators each in Romania and Serbia, and one Investigator each in Czech Republic and Slovenia
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Treatment Cohort (LDTC): 0.50 mg/kg BID Patient received the dose of 0.50 mg/kg for 12 weeks in fed condition | 10 |
| High Dose Treatment Cohort (HDTC): 0.75 mg/kg BID Patient received the dose of 0.75 mg/kg for 12 weeks in fed condition | 6 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Week 0 to Week 12 | Disease Progression | 1 | 1 |
| Week 0 to Week 12 | Insufficient Response | 0 | 2 |
| Week 13 to Week 24 | Insufficient Response | 0 | 1 |
Baseline characteristics
| Characteristic | Low Dose Treatment Cohort (LDTC): 0.50 mg/kg BID | High Dose Treatment Cohort (HDTC): 0.75 mg/kg BID | Total |
|---|---|---|---|
| Age, Continuous | 11.7 years STANDARD_DEVIATION 5.5 | 9.7 years STANDARD_DEVIATION 5.7 | 10.9 years STANDARD_DEVIATION 5.4 |
| Body Weight | 37.36 kg STANDARD_DEVIATION 15.4 | 37.92 kg STANDARD_DEVIATION 18.59 | 37.57 kg STANDARD_DEVIATION 16.05 |
| Height | 1.388 m STANDARD_DEVIATION 0.204 | 1.365 m STANDARD_DEVIATION 0.277 | 1.379 m STANDARD_DEVIATION 0.225 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 6 Participants | 16 Participants |
| Region of Enrollment Czech Republic | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Italy | 2 participants | 3 participants | 5 participants |
| Region of Enrollment Romania | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Serbia | 5 participants | 1 participants | 6 participants |
| Region of Enrollment Slovenia | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 8 / 8 | 2 / 2 | 4 / 4 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 | 0 / 8 | 0 / 2 | 0 / 4 |
Outcome results
Primary
ACR Pediatric Response Level (ACRPRL) 30 After 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%
Time frame: 12 weeks of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low Dose Discontinued | ACR Pediatric Response Level (ACRPRL) 30 After 12 Weeks of Treatment | ACR Pediatric Response Level 30 | 0 participants |
| Low Dose Discontinued | ACR Pediatric Response Level (ACRPRL) 30 After 12 Weeks of Treatment | No response | 1 participants |
| Low Dose Throughout | ACR Pediatric Response Level (ACRPRL) 30 After 12 Weeks of Treatment | ACR Pediatric Response Level 30 | 1 participants |
| Low Dose Throughout | ACR Pediatric Response Level (ACRPRL) 30 After 12 Weeks of Treatment | No response | 0 participants |
| Switched Dose | ACR Pediatric Response Level (ACRPRL) 30 After 12 Weeks of Treatment | ACR Pediatric Response Level 30 | 3 participants |
| Switched Dose | ACR Pediatric Response Level (ACRPRL) 30 After 12 Weeks of Treatment | No response | 5 participants |
| High Dose Throughout | ACR Pediatric Response Level (ACRPRL) 30 After 12 Weeks of Treatment | No response | 0 participants |
| High Dose Throughout | ACR Pediatric Response Level (ACRPRL) 30 After 12 Weeks of Treatment | ACR Pediatric Response Level 30 | 2 participants |
| High Dose Discontinued | ACR Pediatric Response Level (ACRPRL) 30 After 12 Weeks of Treatment | ACR Pediatric Response Level 30 | 1 participants |
| High Dose Discontinued | ACR Pediatric Response Level (ACRPRL) 30 After 12 Weeks of Treatment | No response | 3 participants |
Secondary
ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12
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%
Time frame: at week12
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low Dose Discontinued | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 50 | 0 participants |
| Low Dose Discontinued | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 70 | 0 participants |
| Low Dose Discontinued | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 90 | 0 participants |
| Low Dose Discontinued | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 100 | 0 participants |
| Low Dose Throughout | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 50 | 1 participants |
| Low Dose Throughout | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 100 | 0 participants |
| Low Dose Throughout | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 70 | 1 participants |
| Low Dose Throughout | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 90 | 0 participants |
| Switched Dose | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 100 | 0 participants |
| Switched Dose | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 70 | 0 participants |
| Switched Dose | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 90 | 0 participants |
| Switched Dose | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 50 | 1 participants |
| High Dose Throughout | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 50 | 2 participants |
| High Dose Throughout | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 70 | 1 participants |
| High Dose Throughout | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 100 | 0 participants |
| High Dose Throughout | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 90 | 0 participants |
| High Dose Discontinued | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 100 | 0 participants |
| High Dose Discontinued | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 90 | 0 participants |
| High Dose Discontinued | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 70 | 0 participants |
| High Dose Discontinued | ACR Pediatric Response Level (ACR 50, 70, 90 and 100) at Week 12 | ACR Pediatric response Level 50 | 1 participants |