The Efficacy and Safety of ITF2357 in AIS

Brief Title

The Efficacy and Safety of ITF2357 in AIS

Official Title

The Effects and Side Effects of ITS2357 in Autoinflammatory Syndromes

Brief Summary

      Autoinflammatory syndromes (AIS) are a group of disorders characterized by recurrent episodes
      of inflammation.Although for the hereditary autoinflammatory diseases the genetic mutations
      are known it remains largely unclear how these mutations lead to recurrent inflammatory
      attacks. Treatment of the inflammatory symptoms remains a challenge. With beneficial
      responses reported during treatment with simvastatin, etanercept or anakinra in some but not
      all patients. ITF2357 is an orally active histon deacetylase inhibitor with a potent
      anti-inflammatory effect due to inhibition of pro-inflammatory cytokines (IL-1β, TNFα, IFNg,
      IL-6). We expect that ITF2357 is able to modify the clinical symptoms of AIS patients and
      induce clinical complete remission or a reduction in attack duration.
    

Detailed Description

      Rationale: Autoinflammatory syndromes (AIS) are a group of disorders characterized by
      recurrent episodes of inflammation. This occurs in the absence of autoantibodies and antigen
      specific T cells. To date 6 genetically distinct hereditary autoinflammatory syndromes are
      known and more recently other sporadic syndromes, such as the Schnitzler’s syndrome
      (urticaria, periodic fever and paraproteinemia) and Periodic Fever Aphtous stomatitis,
      Pharyngitis and Adenitis (PFAPA) are being recognized as AIS. Amyloidosis is a serious
      complication of chronic or recurrent inflammation seen in some of these syndromes. Although
      for the hereditary autoinflammatory diseases the genetic mutations are known it remains
      largely unclear how these mutations lead to recurrent inflammatory attacks. Symptomatic
      episodes are associated with increased serum concentrations of both pro-inflammatory
      mediators (TNFα, IL-6, IL1β and IFN-g) as well as of the anti-inflammatory compounds (IL-1ra,
      sTNFR p55 and sTNFR p75). In vitro and ex vivo experiments suggest a central role in the
      pathogenesis for IL-1β. The observation that rIL-1ra (anakinra) is highly effective in
      refractory TRAPS, CAPS, HIDS, refractory FMF and SS support this idea. Despite its
      effectiveness daily painful subcutaneous injections and injection site reactions remain a
      problem. ITF2357 is an orally active histon deacetylase inhibitor with a potent
      anti-inflammatory effect due to inhibition of pro-inflammatory cytokines (IL-1β, TNFα, IFNg,
      IL-6). We expect that ITF2357 is able to modify the clinical symptoms of AIS patients and
      induce clinical complete remission or a reduction in attack duration.

      Objective: The primary objective is to asses whether ITF2357 is able to induce clinical
      complete remission in patients with continuous symptoms or reduce attack duration with > 33%
      in periodically symptomatic patients. Secondary objectives are the emergence of adverse
      events and toxicity as well as the influence of ITF2357 on cytokine production and laboratory
      parameters for infection and metabolism.

      Study design: Open Label Pilot Study Study population: AIS patients 18 years or older with
      severe disease

      Intervention: Patients with continuous symptoms will receive 2-3 times a day 50mg (capsule)
      ITF2357 for a total period of 90 days. Patients with periodic symptoms will take ITF2357 (2-3
      times a day 50mg) on 7-14 consecutive days during 6-12 attacks.

      Main study parameters: A clinical complete remission will be regarded as a clinical score
      (CS) < 10 scored on the symptom score list in the absence of a temperature > 38.0°C and
      normalisation of CRP and WBC levels. The end of an attack will be defined as a CS < 20 in the
      absence of a temperature > 38.0°C.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness: All patients will be admitted once at the beginning of the study for 3 days in
      this period there will be performed a daily venipuncture, a history and physical examination
      twice and an ECG once. They will visit the outpatient clinic four times for physical
      examination, history, venipuncture and an ECG. Patients are asked to complete a symptom score
      list on which they can note down the date, number of ITF2357 capsules taken and if present
      co-medication, symptoms, temperature and adverse events. Patients are asked to collect a
      portion of morning urine once a week. ITF2357 showed the following adverse reactions
      asymptomatic trombocytopenia and perhaps increased incidence of mild infections mainly of the
      upper respiratory tract. There were gastrointestinal complaints in the sense of nausea,
      vomiting, abdominal pain and diarrhea.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

clinical complete remission

Secondary Outcome

 side effects

Condition

Autoinflammatory Syndromes

Intervention

ITF2357


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

20

Start Date

September 2006



Eligibility Criteria

        Inclusion Criteria:

          -  Autoinflammatory syndrome (hereditary or acquired)

          -  Age ³18 years

          -  Severe active disease (≥1 attack every eight weeks or continuous symptoms).

        An attack will be defined as:

          -  Temperature of ≥38 ºC not otherwise explained.

          -  At least two other accompanying symptoms (e.g. joint pain, lymphadenopathy, skin
             lesions, abdominal symptoms)

          -  written informed consent obtained

        Exclusion Criteria:

          -  Age < 18 years

          -  Pregnancy and lactation

          -  Increased risk for infection or current infection

          -  Renal failure (GFR<30ml/1.73m2/min)

          -  Pre-existing malignancy
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Jos WM van der Meer, MD PhD, 0031 24 3617276, [email protected]

Location Countries

Netherlands

Location Countries

Netherlands

Administrative Informations


NCT ID

NCT00442182

Organization ID

2006/112



Study Sponsor

Radboud University


Study Sponsor

Jos WM van der Meer, MD PhD, Principal Investigator, Radboud University


Verification Date

February 2007