Intra-erythrocyte Dexamethasone Versus Placebo in Patients With Steroid-dependent Crohn's Disease

Multicenter, Randomized, Double-blind, Parallel-group Study of Intra-erythrocyte Dexamethasone Versus Placebo in Patients With Steroid-dependent Crohn's Disease

Primary objective:

Assessment of the efficacy of EryDex vs PLACEBO in maintaining patients with steroid-dependent Crohn's disease in clinical remission throughout 12 months without oral steroids.

Secondary objectives:

1. safety of EryDex
2. emergence of new adverse effects from steroids or disappearance of those possibly pre-existing in the various subgroups of patients;
3. duration of the period of remission;
4. evaluation of the hypophysis-adrenal function;
5. study of plasma concentrations of dexamethasone;
6. effect of therapy on the metabolism of calcium and on indexes of inflammation;
7. assessing the quality of life;
8. rate of surgical resection
9. evaluation of the indirect costs of care.

This was a multicenter, randomized, double-blind, PLACEBO-controlled, parallel-group study comparing EryDex versus PLACEBO. Patients with steroid-dependent Crohn's disease were enrolled and randomized to undergo 12 infusions of intraerythrocyte dexamethasone (EryDex), or PLACEBO. A balanced (1:1) randomization between the two treatment groups (EryDex / PLACEBO) was employed.

At the time of randomization, study patients were stratified at each study site according to their previous therapy with AZT/6MP/MTX (never treated with AZT/6MP/MTX or intolerant/resistant to the therapy with AZT/6MP/MTX). The treatment was planned to be performed with 12 monthly infusions of EryDex or PLACEBO.

Patients were followed-up after completion of the treatment for 6 months in patients regularly completing the study and 3 months in patients discontinuing from the study prematurely. The evaluation of the primary and secondary objectives was to be done at the 12th month of study (one month after the last study drug infusion), or upon relapse.

Inclusion Criteria:

1. Male and female subjects;
2. Age > 18 years;
3. Patients with steroid-dependent Crohn's disease, documented in the medical history, having suffered from at least one episode of relapse (CDAI > 150) in the last 12 months. Patients should have been in clinical remission (CDAI < 150) for at least four weeks, on stable therapy with at least 10 mg of methylprednisolone (or equivalent), or been on steroidal tapering after a recent relapse. Patients with intolerance or resistance to AZT/6-MP/MTX were eligible;
4. Patients willing and able to give written informed consent.

Exclusion Criteria:

1. Patients with Crohn's disease with intestinal sub-occlusion, or suspect of abdominal abscess, or with active perianal disease, or with clinically active disease at randomization (CDAI ≥150);

2. Patients already on therapy with immunosuppressant agents (AZT, 6-MP, MTX) for less than 4 months;

3. Patients having received therapy with infliximab (or other anti-TNF) in the previous 3 months;

4. Investigational treatments in the previous 3 months prior to randomization;

5. Pregnant women, or women who were not using valid birth-control measures, except those in surgical menopause; breast feeding;

6. Non collaborating subjects or those unable to be compliant with the treatment and the study schedules;

7. Severe concomitant diseases such as :

   1. patients with inadequate "bone marrow reserve": WBC < 3000 /mm3; PLTs < 75000 /mm3; Hb < 8 g/dl
   2. liver disease with total bilirubin ≥ 3 times the upper limit of normal (ULN), AST (GOT) ≥ 3x ULN, alkaline phosphatase ≥ 3x ULN
   3. renal disease with serum creatinine ≥ 3 mg/dl
   4. serious cardiac, allergic, lung, neurological diseases, neoplastic or pre-neoplastic disease
   5. diseases (other than Crohn's) requiring chronic steroid treatment;

8. Elective surgery already scheduled at the start of the study (NB: patients having undergone previous surgery for Crohn's disease could be enrolled, if the patient had fully recovered and had been in remission for at least 4 weeks);

9. Chronic use of alcohol; drug addiction;

10. Subjects with contra-indication to the use of steroids (i.e. systemic fungal infections);

11. Evidence of clostridium difficilis in the stools.