Thalidomide in Pediatric Inflammatory Bowel Diseases.
Condition: Inflammatory Bowel Diseases; Crohn's Disease; Ulcerative Colitis
MeSH terms: Crohn Disease; Colitis; Colitis, Ulcerative; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer
Study type: Interventional
Phase: Phase 3

Summary: 
      Several open-label studies reported thalidomide efficacy in inducing clinical remission and
      steroid tapering in refractory Inflammatory Bowel diseases (IBD), both in adults and in
      children.

      This is a randomized placebo controlled (RCT) double blind study, to evaluate the efficacy of
      thalidomide in inducing clinical remission at 8 weeks in refractory IBD patients aged 2-20
      years.

      The primary hypotheses of the study is that thalidomide would be more effective than placebo
      in inducing clinical remission.

      The RCT phase is followed by a open-label phase, to further evaluate efficacy and safety of
      thalidomide in thalidomide responders, with a total follow up of one year.
    

Detailed description: 
      Inflammatory bowel diseases (IBD) are particularly debilitating. They present
      chronic-recurrent symptoms which often seriously affects the patient's quality of life, acute
      complications which may need surgical interventions and long-term risks as evolution in
      cancer for ulcerative colitis.

      Although onset is most common in the third decade of life, more than one third of IBD cases
      are diagnosed before age sixteen, and these younger patients, especially with Crohn's
      disease, are increasing in Western countries. Recent studies in the United Kingdom, Sweden
      and the United States report an incidence of 5-7 new cases of IBD every year per 100,000
      subjects < 16 years of age, with an increasing trend over the last two decades.

      IBD-related morbidity causes special concern in childhood-onset cases, since the disease can
      compromise height and weight development. This is even worsened in patients with poor disease
      control, which need steroid treatment in multiple courses and/or for a long period of time.

      There are various drugs and treatments available for the management of IBD, but some
      patients, during the course of the illness, become resistant to conventional treatment, or
      develop serious adverse effects to immunosuppressive drugs.

      A particular challenge is represented by those patients (especially children) who fail to
      respond to conventional treatment, or are steroid-dependent, or suffer from serious side
      effects from steroids use.

      Thalidomide was first marketed in the early 1960s as a sedative drug and sadly gained
      notoriety because of its teratogenic effect. After few years from this tragedy, thalidomide
      was rediscovered both as an immunomodulator and as an anti-inflammatory drug, with anti tumor
      necrosis factor-alfa properties.

      Thalidomide is now approved for the treatment of multiple myeloma and erythema nodosum
      leprorum. It has also been tested, with beneficial effects, in a variety of inflammatory
      diseases, especially those involving the skin and mucous membranes: recurrent aphthous
      stomatitis, oral and oesophageal ulcers in HIV, oral and genital ulcers and intestinal
      symptoms in Behcet's syndrome, graft versus host disease, skin manifestations in systemic
      lupus erythematosus, sarcoidosis, and tuberculosis. In these diseases, especially in those
      cases resistant to conventional treatments, thalidomide seems to have a promising role as a
      secondary therapeutic option.

      The safety and efficacy of thalidomide in IBD has been recently evaluated in several
      open-label studies both adults and children, some of which with a long-term follow up. A
      total of approximately 200 patients with steroid-resistant or steroid-dependent IBD were
      treated with thalidomide. Overall, the drug was effective in inducing clinical remission in
      20-70% of patients (average of 40%). 60-100% patients (average of 70%) had some clinical
      response. Steroid-tapering was possible in 60-100% of cases.

      The most frequent side effect of thalidomide in IBD cases was neuropathy, which mainly
      reported as cumulative dose-dependent. Other possible side effects are constipation,
      sedation, dermatitis, mood disturbance, vertigo, cephalea, hypertension, hormonal
      alterations.

      In the experience of our center, thalidomide was effective in achieving clinical remission in
      several children, adolescents, and young adults with intractable IBD. From 1998 to 2004
      twenty-eight patients with refractory moderate-severe IBD (19 CD, 9 UC) received thalidomide
      1.5-2.5 mg/kg/day. Remission was achieved with thalidomide in 21 of 28 (75%) patients (17
      with CD, 4 with UC). Mean duration of remission was 34.5 months. Sixteen of 20 (80%) patients
      suspended steroids. Reversible neuropathy occurred in seven of 28 (25%) patients, but only
      with cumulative doses over 28 g. Other side effects requiring thalidomide suspension were
      vertigo/somnolence (one case), and agitation/ hallucinations (one case).

      The aim of this study is to evaluate the efficacy of thalidomide therapy in children,
      adolescents and young adults with refractory Crohn's disease (CD) and ulcerative colitis
      (UD), with a total follow up of one year.

      The study is divided in two phases:

        -  Phase I: randomized placebo controlled double blind study, to evaluate efficacy of
           thalidomide in refractory IBD patients, at 8 weeks.

        -  Phase II: open-label study, to evaluate efficacy and safety of thalidomide in patients
           responders to Thalidomide in Phase I, with a total follow up of one year.

      Analysis will be stratified for Crohn's disease and ulcerative colitis. Given the hypotheses
      that thalidomide will be effective in inducing clinical remission at 8 weeks in 60% of
      patients with Crohn's disease, and 55% of patients with ulcerative colitis, compared to 20%
      of patients with placebo, with a significance of 0.05% and a power of 80%, estimated needed
      sample size is of 124 patients.
    

Intervention name(s): Thalidomide; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Thalidomide 1.5-2.5 mg/kg/die once a day, at evening.; placebo capsules
Other intervention name(s): Thalidomide PHARMION; Thalidomid CELGENE
Intervention MeSH terms: Thalidomide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Inflammatory bowel diseases.; Crohn disease.; Ulcerative, colitis.; Randomised controlled trial.; Therapy.; Thalidomide.; Children.