Clinical trial NCT00570661: Open Label, Multicentre Trial to Assess Safety and Efficacy of ITF2357 in Active Systemic Juvenile Idiopathic Arthritis
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Active Systemic
Onset Juvenile Idiopathic Arthritis
Lead sponsor: Italfarmaco
Sponsor class: INDUSTRY
First posted: 2007-12-11
Enrollment: 17
Sex: ALL
Minimum age (years): 2
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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.
2. 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
3. Age at enrolment between 2 and 25 years
4. Age at first SOJIA diagnosis \< 16 years
5. 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
6. In case of concomitant methotrexate treatment, it has to be on stable dose \>= 10mg/m2 weekly for al least 4 weeks before pt enrollment
7. 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
8. Other disease-modifying anti-rheumatic drugs possibly previously introduced have to be discontinued for a period of at least five half lives
9. Concomitant nonsteroidal anti-inflammatory drugs, if any, on a stable dose for at least four weeks before patient's enrolment
10. Female of childbearing potential, using safe contraceptive measures
11. Signed written informed consent before starting any study procedure

Exclusion Criteria:

1. Ongoing clinical relevant viral infection (eg.: Herpes Zoster, Ebstein barr, CMV, Systemic fungal infections or history of recurrent serious bacterial infection)
2. History of macrophage activation syndrome
3. 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
4. Psychiatric illness/social situations that would limit compliance with study medication and protocol requirements
5. Congenital heart and/or central nervous system disorders
6. Inherited metabolic diseases
7. Positive serological testing for anti HCV, anti HIV and HBsAg (to be performed at screening)
8. Pregnant or lactating women
9. Presence of malignancy
10. Any previous evidence, irrespective of its severity, of coronary disease, cardiac rhythm abnormalities or congestive heart failure
11. QTc interval \> 450 msec at screening evaluation
12. Serum magnesium and potassium below the LLN at screening
13. Unavoidable concomitant treatment with any drug known for potential risk of causing Torsades de Pointes

Primary outcomes:
measure: Number of Patients Completing Week 12 of Treatment
timeFrame: At week 12
Secondary outcomes:
measure: JIA Outcome Core Set Variables - Patient Global Assessment
timeFrame: 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.
measure: JIA Outcome Core Set Variables - Physician Global Assessment
timeFrame: 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.
measure: JIA Outcome Core Set Variables - Number of Joints With Active Arthritis
timeFrame: 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.
measure: JIA Outcome Core Set Variables - Number of Joints With Limitation
timeFrame: 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.
measure: JIA Outcome Core Set Variables - CHAQ
timeFrame: 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.
measure: JIA Outcome Core Set Variables - ESR
timeFrame: 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.
measure: Overall SFS Results - Sum of First Five Variables and Sum of Last Five Variables
timeFrame: 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.
measure: Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Temperature
timeFrame: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
measure: Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Typical SOJIA Rash
timeFrame: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
measure: Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Lymphadenopathy
timeFrame: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
measure: Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Hepatomegaly and/or Splenomegaly
timeFrame: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
measure: Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Serositis
timeFrame: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
measure: Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Erythrocyte Sedimentation Rate (ESR)
timeFrame: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
measure: Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - C-reactive Protein (CRP)
timeFrame: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
measure: Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - White Blood Cell (WBC)
timeFrame: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
measure: Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Haemoglobin (Hb)
timeFrame: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
measure: Number of Patients With Presence or Absence of Each Item for Modified Systemic Feature Score (SFS) - Thrombocytes
timeFrame: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
measure: Number of Patients With JIA Plus SFS Clinical Improvement
timeFrame: At weeks 2, 4, 6, 8, 10 and 12.
measure: Number of Patients With Sufficient Therapeutic Response at Week 4 to Continue Treatment
timeFrame: At week 4
Other outcomes:
Locations:
city: Bucharest
country: Romania
facility: Clinica Institute Fundeni.Pediatric Clinic 258 Sos. Fundeni,
city: Bucharest
country: Romania
facility: Clinical Emergency Children Hospital "M.S. Curie" Paediatric Clinic no. I 20 Ctin. Brancoveanu Bvd., 041451 Bucharest 4th district
city: Niš
country: Serbia
facility: University Clinical Centre NisClinic of Paediatrics Department for Rheumatology Bul Dr Zoran Djindjica
state: Nis
city: Belgrade
country: Serbia
facility: Mother and Child Health Institute "Dr. Vukan Cupic" Clinic of Paediatrics Radoja Dakica
state: Novi Belgrade
city: Belgrade
country: Serbia
facility: Institute of Rheumatology Belgrade Resavska
Study officials:
affiliation: Institute of Rheumatology Belgrade
name: Nemanja Damjanov, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vojinovic J, Damjanov N, D'Urzo C, Furlan A, Susic G, Pasic S, Iagaru N, Stefan M, Dinarello CA. Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2011 May;63(5):1452-8. doi: 10.1002/art.30238.
citation: Vojinovic J, Damjanov N. HDAC inhibition in rheumatoid arthritis and juvenile idiopathic arthritis. Mol Med. 2011 May-Jun;17(5-6):397-403. doi: 10.2119/molmed.2011.00030. Epub 2011 Feb 4.