Adalimumab for the treatment of perianal fistulas in Crohnâ¤*s disease more effective alone or combined to ciprofloxacin (ADAFI study)

Perianal fistulas in Crohn*s disease rarely heal spontaneously; medical or
surgical treatment is often required. The main medical therapies include
antibiotics, azathioprine or 6-mercaptopurine, and infliximab. The efficacy of
antibiotics for the treatment of Crohn*s fistulas has only been tested in
uncontrolled studies, which have suggested a short-term benefit of both
ciprofloxacin and metronidazole either alone or in combination. However, drug
discontinuation or dose reduction often led to disease relapse. Ciprofloxacin
is often preferred to metronidazole because it is associated with fewer side
effects (1-6).
Clinical trials have shown that chimeric monoclonal antibody to TNF, infliximab
is effective for the induction and maintenance therapy of patients with
perianal fistulas in Crohn*s disease (7,8). However, the use of infliximab is
associated with the formation of antibodies to infliximab, which can lead to
allergic reactions and a reduced response. A combination of ciprofloxacin and
infliximab seems to be more effective than infliximab alone (9).
Adalimumab (D2E7, Humira; Abbott laboratories, Chicago, IL) is a recombinant
human immunoglobulin G1 (IgG1) monoclonal antibody that binds with high
affinity and specificity to human soluble TNF. A recent randomised trial showed
that adalimumab was superior to a placebo for induction of remission in
patients with moderate to severe Crohn*s disease naive to anti-TNF therapy
(10). Open-label studies have found adalimumab to be well tolerated and
beneficial in patients who have previously lost there response to, or cannot
tolerate infliximab (11-13). There is only one small open label study available
focusing on the use of adalimumab in the treatment of perianal fistulas in
Crohn*s disease. In this study 64% of patients showed a partial or complete
closure of all fistulas (14).

To assess whether a combination of ciprofloxacin and adalimumab is more
effective than adalimumab alone.

3. DESIGN OF THE STUDY

3.1 Setting
Principal centers:
· Department of Gastroenterology & Hepatology, Erasmus MC Rotterdam, The
Netherlands
Others:
· Multiple centers in The Netherlands will participate in this study.


3.2 Number of patients
146 patients will be included, with 73 patients in each treatment group.


3.3 Design (type of trial)
Multicenter, randomized, double-blind study with two arms.

Medication, dosage and duration
- Group A receive Adalimumab 160 mg at day 0, 80 mg at week 2, 40 mg at week 4
and every 14 days thereafter by subcutaneous injection combined with oral
Ciprofloxacin 2 X 500 mg.
- Group B receive Adalimumab 160 mg at day 0, 80 mg at week 2, 40 mg at week 4
and every 14 days thereafter by subcutaneous injection combined with oral
Placebo 2 x 500 mg.
Combination therapy will be given for a total treatment period of 12 weeks.
After 12 weeks treatment will be continued with subcutaneously Adalimumab only.

Patients need to come 3 times extra to the hosptial compared to patients not in
this study.