A randomized controlled withdrawal trial in Crohn's disease patients in long-term remission on mesalazine: the CROWN study

Crohn*s disease (CD) is a chronic inflammatory disorder of the gastrointestinal
tract, characterized by chronicity and frequent recurrences. Maintenance
treatment is directed at prevention of recurrent relapses and a shift toward
stricturing or penetrating disease behavior. A variety of drugs, e.g.
azathioprine, mercaptopurine, methotrexate and infliximab, might all have
efficacy in this respect, but long-term use is hampered by side events and
toxicity. Mesalazine, which has a broad therapeutic window and only a few,
minor side effects, has been used in the maintenance setting as well, although
studies comparing mesalazine and placebo have produced conflicting results. For
this reason, guidelines do not advocate mesalazine as maintenance therapy.
Still, mesalazine is prescribed to a very large number of CD patients, probably
because efficacy is expected in a subgroup of CD patients and immunosuppressive
therapy is considered too aggressive. As the treatment costs of mesalazine in
the Netherlands are approximately ¤30 per month, it can be calculated that the
total costs for this drug are considerable. If mesalazine is prescribed in a
subgroup of CD patients in whom efficacy is highest, the cost/benefit ratio can
be expected to decrease significantly while leading to a substantial reduction
of the total costs.

Primary objectives
1. What is the effect of stopping mesalazine in the maintenance setting of
patients with quiescent CD?
2. Can subgroups of CD patients, for example based on prior treatment (medical
vs. surgical), localization of disease, disease behavior (number of prior
relapses and/or development of complications, such as fistulas or strictures)
be identified, which benefit most from mesalazine maintenance therapy?
3. Is mesalazine cost-effective in a subgroup of CD patients?

Secondary objectives:
1. How does stopping of mesalazine affect quality of life of CD patients?
2. Does compliance to mesalazine affect outcome with regard to disease activity
and quality of life?

The study duration will be 18 months. At baseline patients will be scheduled
for a baseline visit (T=0) and follow up visits at 6 months (T=6), 12 months
(T=12), and 18 months (T=18) of treatment by their treating physician or
investigator. Patients will complete their diary cards during the 7 days
preceding the outpatient clinic visit, necessary for the calculation of the
Crohn*s Disease Activity Index (CDAI).

At T=0, T=6, T=12 and T=18 patient*s interim history (including possible
adverse events), physical examination and a panel of routine blood-tests will
be performed. Furthermore, the CDAI will be calculated and patients will
complete the *online* questionnaires to assess quality of life (IBDQ and
SF-36). At T=0 and T=18 flare up 2 fecal samples will be collected for
assessment of the stool calprotectin level. At T=6 and T=18 a 24-hour urine
collection for 5-ASA and n-acetyl-5-ASA determination will be collected from
patients receiving mesalazine. At T=0 and T=18 a colonoscopy will be scheduled,
but refusal will not be regarded as a reason for exclusion. During colonoscopy
biopsies will be obtained and the Crohn*s Disease Endoscopic Index of Severity
(CDEIS) will be assessed. Finally, patients are requested to fill out
internet-based questionnaires on health care use, work and productivity loss of
paid and unpaid work (SF-HLQ) every month (18 times).

In case patients experience a flare up, an extra visit at the outpatient clinic
will be scheduled. Patients will complete their diary cards during the 3 weeks
preceding the visit. Again, an interim history, physical examination and a
panel of routine blood tests will be performed and 2 fecal samples will be
collected to assess stool calprotectin levels. Furthermore a 24-hour urine
collection for 5-ASA and n-acetyl-5-ASA determination will be collected from
patients receiving mesalazine. In addition, the CDAI will be calculated and
patients will complete the *online* questionnaires to assess quality of life. A
colonoscopy will be performed if indicated.

Patients will be randomized in a 1:1 ratio to 18 months of therapy receiving
either mesalazine or no treatment. In case of mesalazine treatment, patients
will continue their regular treatment. Physicians will be allowed to prescribe
any brand of mesalazine (Asacol®, Pentasa®, Salofalk® or generic mesalazine).
Dosing of Pentasa® and Salofalk® will be 3 gram once daily. Dosing of Asacol®
will be 3.2 gram once daily.

Patients might experience less adverse events after withdrawal from mesalazine
and this consequently might improve their quality of life. On the other hand,
if our assumption is correct and mesalazine is effective in a significant
subgroup of patients, withdrawal of mesalazine might induce a flare in the long
run.
Patients will undergo two colonoscopies. These procedures are generally
considered to be safe, despite a small risk of perforation and
colonoscopy-related bleeding (0.85/1000 and 1.64/1000 respectively in a large
study including 97000 patients)1. Patients will be routinely sedated during
endoscopy using midazolam and pethidine or propofol.
The baseline visit will strictly be a visit for study purposes, but the
follow-up visits at 6, 12, and 18 months will coincide with their usual
outpatient clinic visits. Traveling costs for extra visits will be refunded.
Patients will be asked to collect 2 feces samples the day preceding
study-related visits. Furthermore patients will be asked to collect a urine
sample at 6 and 12 months of treatment. In addition to routine blood withdrawal
during these visits, an additional blood-sample will be taken at baseline. In
case of a flare, an extra visit with blood and feces sampling will be scheduled.
Finally, patients are requested to fill out internet-based questionnaires (IBDQ
and SF-36) 4 times during the study. It will take 10 to 15 minutes to complete
these questionnaires. During the 7 days preceding the visit at the
outpatient-clinic, patients need to fill out an *online* diary card. This will
take 2 minutes. Patients will be able to complete the internet-based
questionnaires and diary cards at home.