Open Label, Multicentre Trial to Assess Safety and Efficacy of ITF2357 in Active Systemic Juvenile Idiopathic Arthritis

Study Overview
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Brief Summary
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This study has the following objectives: Primary objective: - To determine the safety and tolerability of oral ITF2357 in patients with active SOJIA with inadequate response or intolerance to standard therapy with oral steroids and methotrexate, with or without previously used biologic agents. Secondary objectives: to evaluate the effect of ITF2357 on disease activity in patients with active SOJIA to investigate the possibility of steroid dose tapering in patients with active SOJIA during ITF2357 treatment to assess the effect of ITF2357 on levels of circulating cytokines to assess the pharmacokinetic properties of ITF2357

Detailed Description
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The present study has been designed in order to evaluate safety and tolerability of ITF2357 in patients with active SOJIA with inadequate response or intolerance to standard therapy with oral steroids and methotrexate, with or without previously used biologic agents, and to have a preliminary evaluation of efficacy of ITF2357 in the treatment of SOJIA. ITF2357 will be administered orally at the daily cumulative dose of 1.5 mg/kg: this dose in children/young adults is considered roughly equivalent to the dose of 1 mg/kg/day in adults, which so far has been proven to be free of any relevant safety concerns both in healthy volunteers and in patients.

Official Title
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Phase II, Open Label, International, Multicentre Clinical Trial to Investigate Safety and Efficacy of Oral ITF2357 in Patients With Active Systemic Onset Juvenile Idiopathic Arthritis (SOJIA)

Conditions
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Active Systemic, Onset Juvenile Idiopathic Arthritis

Intervention / Treatment
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* Drug: ITF2357


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Established diagnosis of Systemic SOJIA according to ILAR criteria for at least six months before the study entry, with inadequate response or intolerance to standard therapy with oral steroids and/or methotrexate, with or without previously used biologic agents. Active disease for at least one month prior to enrolment as defined by the following criteria: Presence of arthritis plus at least one of the following: Fever, defined as a body temperature >= 37,5 C degree at least once a day during at least five consecutive days or presence of typical SOJIA intermittent temperature chart Rash, defined by presence of typical SOJIA salmon pink rash on the trunk and elsewhere during the febrile episodes Serositis (pericarditis, pleuritis, peritonitis) confirmed by ultrasound and/or X-ray exploration or by presence of typical ECG findings in the case of pericarditis Lymphadenopathy, defined by lymph nodes enlargement to 1,5 cm or more localized anywhere within the body, and/or hepatomegaly and/or splenomegaly, confirmed by ultrasound evaluation and established after comparison to age standards for organ size ESR >= 20 mm/h (first hour) and/or CRP >= 10 mg/L. in the absence of arthritis, two definite or one definite and one probable diagnostic criteria plus ESR >=20 mm/h (first hour) and/or CRP >=10 mg/L Age at enrolment between 2 and 25 years Age at first SOJIA diagnosis < 16 years Previously introduced standard treatment of disease with steroids without satisfactory effect and concomitant treatment with oral steroids at a dose equivalent to >= 0,2 mg/kg/day of prednisolone, unmodified for at least four weeks before patient's enrolment In case of concomitant methotrexate treatment, it has to be on stable dose >= 10mg/m2 weekly for al least 4 weeks before pt enrollment Previous treatment with biologics, if any, during at least three months without satisfactory effect or with drug intolerability, discontinued for at least the period specified below before patient's enrolment: Two months for etanercept Six months for infliximab 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 Female of childbearing potential, using safe contraceptive measures Signed written informed consent before starting any study procedure Exclusion Criteria: Ongoing clinical relevant viral infection (eg.: Herpes Zoster, Ebstein barr, CMV, Systemic fungal infections or history of recurrent serious bacterial infection) History of macrophage activation syndrome 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 Congenital heart and/or central nervous system disorders Inherited metabolic diseases Positive serological testing for anti HCV, anti HIV and HBsAg (to be performed at screening) Pregnant or lactating women Presence of malignancy Any previous evidence, irrespective of its severity, of coronary disease, cardiac rhythm abnormalities or congestive heart failure QTc interval > 450 msec at screening evaluation Serum magnesium and potassium below the LLN at screening Unavoidable concomitant treatment with any drug known for potential risk of causing Torsades de Pointes

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ITF2357<br>ITF2357 hard gelatine capsules were administered orally, in fed conditions, at the cumulative daily dose of 1.5 mg/kg achieved by administration of 0.75 mg/kg at 12-hour interval for 4 weeks initially. The doses of 1.5 mg/kg/day were achieved by administration of an appropriate number of capsules of definite strength (dose strengths of 7.5, 10, 12.5, 15, 20 mg and 50 mg). Treatment was further prolonged up to 12 weeks in total if so suggested by the observed benefits and the lack of treatment-limiting toxicity | Drug: ITF2357<br>* ITF2357 orally administered at the cumulative daily dose of 1.5 mg/kg, achieved by administration of different dose strengths identifiable by different colours.<br>* Other names: Givinostat, histone deacetylase inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Completing Week 12 of Treatment | The primary endpoint describes the number of patients who has completed week 12 of treatment with ITF2357, both in the Per protocol (PP) population and in the Intention to treat (ITT) population. ITF2357 hard gelatine capsules were administered orally, in fed conditions, at the cumulative daily dose of 1.5 mg/kg achieved by administration of 0.75 mg/kg at 12-hour interval for 4 weeks initially. The doses of 1.5 mg/kg/day were achieved by administration of an appropriate number of capsules of definite strength. Treatment was further prolonged up to 12 weeks in total if so suggested by the observed benefits and the lack of treatment-limiting toxicity. | At week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| JIA Outcome Core Set Variables - Patient Global Assessment | Patient/parent global Visual Analogue Scale (VAS) is from 0 to 100. The lower the score, the better the outcome. | At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively. | 
| JIA Outcome Core Set Variables - Physician Global Assessment | Physician global Visual Analogue Scale (VAS) is from 0 to 100. The lower the score, the better the outcome. | At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively. | 
| JIA Outcome Core Set Variables - Number of Joints With Active Arthritis | Number of active joints is from 0 to 75. The lower the score, the better the outcome. | At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively. | 
| JIA Outcome Core Set Variables - Number of Joints With Limitation | Number of joints with limited range of motion is from 0 to 75. The lower the score, the better the outcome. | At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively. | 
| JIA Outcome Core Set Variables - CHAQ | The Childhood Health Assessment Questionnaire (CHAQ) is from 0 to 3. For each of 8 section (Dressing and care, Getting up, Eating, Walking, Hygiene, Grasping, Catching, Activities) answers patient is getting 0,1,2 or 3 points (no difficulties, some difficulties, much difficulties, unable to do, respectively). The sum of points is then divided by 8 to get score 0 - 3. The lower the score, the better the outcome. | At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively. | 
| JIA Outcome Core Set Variables - ESR | Measurements of erythrocyte sedimentation rate (ESR) were performed at the local laboratory cooperating with each study site. | At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively. | 
| Overall SFS Results - Sum of First Five Variables and Sum of Last Five Variables | Modified Systemic Feature Score (SFS) variables included: temperature, rash, lymph nodes, liver and spleen size, and clinical evidence of serositis (clinical variables) ESR, CRP, leukocyte count, haemoglobin, thrombocyte count (laboratory variables). Items in both sets of variables were scored as present (1) or not present (0) based on predefined criteria. SFS data were presented as the sum of the first 5 items and the sum of the last 5 items. Each sum could range from a minimum of 0 to a maximum of 5. | At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month follow-up (FU1) in the PP and ITT populations respectively. | 
| Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Temperature | SFS variables included: temperature rash lymph nodes liver and spleen size clinical evidence of serositis (pericarditis, pleuritis or peritonitis) ESR CRP leukocyte count haemoglobin thrombocyte count Temperature was scored as present or not present according to the following criterion: body temperature ≥ 37.5 °C at least once a day during at least five consecutive days or presence of typical SOJIA intermittent temperature chart (patients' temperature chart analysis). | Pre-treatment, Weeks 4, 8, 12, and 1-month follow up | 
| Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Typical SOJIA Rash | SFS variables included: temperature rash lymph nodes liver and spleen size clinical evidence of serositis (pericarditis, pleuritis or peritonitis) ESR CRP leukocyte count haemoglobin thrombocyte count Typical SOJIA is a salmon pink rash on the trunk during the febrile episodes. | Pre-treatment, Weeks 4, 8, 12, and 1-month follow up | 
| Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Lymphadenopathy | SFS variables included: temperature rash lymph nodes liver and spleen size clinical evidence of serositis (pericarditis, pleuritis or peritonitis) ESR CRP leukocyte count haemoglobin thrombocyte count Lymphadenopathy was scored as present or not present according to the following criterion: lymph node (nodes) enlargement to 1.5 cm or more, localized anywhere within the body. | Pre-treatment, Weeks 4, 8, 12, and 1-month follow up | 
| Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Hepatomegaly and/or Splenomegaly | SFS variables included: temperature rash lymph nodes liver and spleen size clinical evidence of serositis (pericarditis, pleuritis or peritonitis) ESR CRP leukocyte count haemoglobin thrombocyte count Hepatomegaly and/or splenomegaly was scored as present if confirmed by ultrasound evaluation and established after comparison to age standards for organ size. | Pre-treatment, Weeks 4, 8, 12, and 1-month follow up | 
| Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Serositis | SFS variables included: temperature rash lymph nodes liver and spleen size clinical evidence of serositis (pericarditis, pleuritis or peritonitis) ESR CRP leukocyte count haemoglobin thrombocyte count Serositis (pericarditis, pleuritis or peritonitis) was scored as present if confirmed by ultrasound and/or X-ray exploration or by the presence of typical ECG findings in the case of pericarditis. | Pre-treatment, Weeks 4, 8, 12, and 1-month follow up | 
| Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Erythrocyte Sedimentation Rate (ESR) | SFS variables included: temperature rash lymph nodes liver and spleen size clinical evidence of serositis (pericarditis, pleuritis or peritonitis) ESR CRP leukocyte count haemoglobin thrombocyte count At the pre-treatment visit ESR was scored as present or not present according to the following criterion: ESR considered as elevated if ≥ 20 mm/h (first hour) At the subsequent visits ESR was scored 0 (Not present) if decreased by at least 30% as compared to pre-treatment value or normalized (< 20 mm/h); score 1 (Present) if increased or decreased less than 30%. | Pre-treatment, Weeks 4, 8, 12, and 1-month follow up | 
| Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - C-reactive Protein (CRP) | SFS variables included: temperature rash lymph nodes liver and spleen size clinical evidence of serositis (pericarditis, pleuritis or peritonitis) ESR CRP leukocyte count haemoglobin thrombocyte count At the pre-treatment visit CRP was scored as present or not present according to the following criterion: CRP considered as elevated if ≥ 10 mg/L. At the subsequent visits CRP was scored 0 (Not present) if decreased by at least 30% compared to pre-treatment value or normalized (< 10 mg/L); score 1 (Present) if increased or decreased less than 30%. | Pre-treatment, Weeks 4, 8, 12, and 1-month follow up | 
| Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - White Blood Cell (WBC) | SFS variables included: temperature rash lymph nodes liver and spleen size clinical evidence of serositis (pericarditis, pleuritis or peritonitis) ESR CRP leukocyte count haemoglobin thrombocyte count At the pre-treatment visit WBC was scored as present or not present according to the following criterion: Leukocyte count considered as elevated if ≥ 12 x 103/μL. At the subsequent visits WBC was scored 0 (Not present) if decreased by 20% compared to pre-treatment value or normalized (< 12x103/μL); score 1 (Present) if increased or decreased less than 20%. | Pre-treatment, Weeks 4, 8, 12, and 1-month follow up | 
| Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Haemoglobin (Hb) | SFS variables included: temperature rash lymph nodes liver and spleen size clinical evidence of serositis (pericarditis, pleuritis or peritonitis) ESR CRP leukocyte count haemoglobin thrombocyte count At the pre-treatment visit Hb was scored as present or not present according to the following criterion: Haemoglobin considered as lowered if below 11g/dL. At the subsequent visits Hb was scored 0 (Not present) if increased by 20% compared to pre-treatment value or normalized (> 11 g/dL); score 1 (Present) if decreased or increased less than 20%. | Pre-treatment, Weeks 4, 8, 12, and 1-month follow up | 
| Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Thrombocytes | SFS variables included: temperature rash lymph nodes liver and spleen size clinical evidence of serositis (pericarditis, pleuritis or peritonitis) ESR CRP leukocyte count haemoglobin thrombocyte count At the pre-treatment visit thrombocyte count was scored as present or not present according to the following criterion: Thrombocyte count considered as increased if ≥ 400x103/μL. At the subsequent visits thrombocyte count was scored 0 (Not present) if decreased by 20% compared to pretreatment value or normalized (< 400x103/μL); score 1 (Present) if increased or decreased less than 20%. | Pre-treatment, Weeks 4, 8, 12, and 1-month follow up | 
| Number of Patients With JIA Plus SFS Clinical Improvement | Clinical improvement at week 2, 4, 6, 8, 10 and 12 was evaluated on the basis of JIA30, JIA50 and JIA70 plus SFS (two points decrease in SFS) as per protocol. Patients were considered as improved and with positive therapeutic response if 3 or more JIA Core Set Variables improved by 30% and no more than one worsened by 30%. JIA50 and JIA70 were defined as an improvement of 3 or more JIA Core Set Variables by 50% and 70%, respectively, and no more than 1 worsened by 30%. Additionally two points decrease in Systemic Feature Score were considered as disease improvement. | At weeks 2, 4, 6, 8, 10 and 12. | 
| Number of Patients With Sufficient Therapeutic Response at Week 4 to Continue Treatment | Therapeutic response at week 4 was considered sufficient by the Investigator if a decrease in Systemic Feature Score of 2 (at least one of the first five variables) and/or JIA30 response (or above: 50 or 70) was obtained. | At week 4 |