Multicentre, controlled, randomised, investigator-blinded, comparative study of oral Mesalazine 4g per day Once daily versus 4g per day in Two divided doses in patients with active Ulcerative colitiS (MOTUS study)

Ulcerative colitis (UC), an inflammatory bowel disease (IBD), is a chronic
condition of unknown origin. Ulcerative colitis is a relapsing and remitting
disease characterised by acute non-infectious inflammation of the colorectal
mucosa (14) (Ghosh S., Shand A., Fergusson A. 2000). The estimated incidence of
UC is in Europe of 8 new cases per year for 105 inhabitants and 4/105 in
France. The estimated prevalence is 21 to 243/105 in Europe and 60/105 in
France. Active episodes of UC are marked by passing of blood and mucus,
diarrhoea and abdominal pain presenting as urgency and tenesmus (1) (Baumgart
and Sandborn 2007). In the most severe forms, systemic signs comprising fever,
anorexia and weight loss may occur. Approximately 60% of the patients have a
mild form, 25% a moderate form and 15% a severe disease. It is estimated that
approximately one of every two patients with UC will experience a relapse
within one year and the cumulative probability of relapse is 80% within 2 years
and 95% within 10 years (2) (Carter, Lobo et al. 2004).
In this disease, involvement of the rectal mucosa is a constant feature while
the inflammation spreads to higher levels in continuous and retrograde fashion,
with no sparing of mucosa from the anorectal junction. Hence, UC may be divided
in proctitis, proctosigmoiditis, left-sided colitis (the proximal limit being
below the splenic flexure), extensive colitis (involving the transverse colon),
or pancolitis.
The aim of the treatment is to induce remission and then maintain it. Several
therapeutic drug classes are used in UC: aminosalicylate derivatives,
corticosteroids, immunosuppressants and anti-TNF* agents. Aminosalicylate
derivatives are the chief therapy for mild to moderate episodes of UC and for
maintenance treatment (27) (Marteau, Seksik et al. 2004). Rectal administration
of salicylate-type drugs constitutes the treatment of choice in proctitis,
proctosigmoiditis, and left-sided ulcerative colitis (4, 24, 25), (Cohen,
Woseth et al. 2000; Marshall and Irvine 1995; Marshall and Irvine 2000). Oral
mesalazine constitutes the treatment of choice in inducing remission of mild to
moderate episodes of extensive forms (16,32) ( Hanauer 2004; Sutherland and
MacDonald 2006).
The optimum dose of mesalazine for induction therapy in order to achieve
remission is between 3 and 4 g/d by the oral route and 1 g/d by topical
administration (enema) (31) (Riley 1998). The time required to achieve
remission in active episodes of UC with oral mesalazine is approximately 8
weeks. The rapidity of action of mesalazine in alleviating symptoms of active
UC may be increased by supplementing oral treatment with topical therapy
comprising mesalazine enema for the first 4 weeks. A randomised controlled
study by Marteau et al demonstrated that combined 4g/d oral mesalazine for 8
weeks and 1g/d topical mesalazine during the initial 4 weeks is superior to
oral therapy alone in terms of remission rates at 8 weeks (64% vs 43%, p=0.03)
and in terms of time to cessation of rectal bleeding (p=0.0025) (26) (Marteau,
Probert et al. 2005). Several consensus conferences have recommended a
combination of both oral and topical treatment, either after a delay (27)
(Marteau, Seksik et al. 2004), either immediately (33) (ECCO 2008).
A key element in therapeutic response in UC is treatment compliance. In daily
practice, compliance of UC patients with 5-ASA treatment appears mediocre,
particularly in maintenance therapy. In a study of 94 patients with UC in
clinical remission, only 40% effectively continued to take their treatment at
the prescribed dosage (19) (Kane, Cohen et al. 2001). Poor or non-existent
compliance affects not only treatment response but also disease progression.
Indeed, the same author detected an increased risk (5-fold greater) of
recurrence in non-compliant patients compared with their compliant counterparts
(relative risk: 5.5; confidence interval: 2.3-13.0; p<0.001) (18) (Kane, Huo et
al. 2003). This issue of treatment compliance with salicylates is thus of
crucial importance not only as regards maintenance treatment of UC in remission
but also for the treatment of active episodes of the disease. For these
reasons, any means of increasing patient compliance with mesalazine therapy are
extremely welcome (10) (Evans and Spelman 1983).

An inverse relationship has been found between the number of daily doses
prescribed and treatment compliance (3) (Claxton, Cramer et al. 2001). Thus,
reduction to a single daily dose of mesalazine is a major factor likely to
significantly increase treatment compliance. A non-inferiority study showed
that at an identical dose of 4 g/d mesalazine, the efficacy of mesalazine given
2 or 4 times daily is identical with regard to active UC and that the dose
frequency was described as optimal in 78% in the twice daily group compared to
26% in the 4 times daily group (11) (Farup, Hinterleitner et al. 2001).
However, reduction of the dosage to twice-daily intake may not be sufficient to
improve compliance. In a very recent study, (7) Dignass et al compared a once
daily versus a twice daily regimen of patient receiving 2g/d of mesalazine for
the maintenance of remission in ulcerative colitis. The authors showed that the
once daily regimen was not only equally effective to the twice daily regimen
but was also superior in terms of remission rates at 12 months. The compliance
assessed with a patient questionnaire was higher in the once daily group (7)
(Dignass, Vermeire UEGW 2007). In addition, it was recently demonstrated that
QD slow release mesalazine was efficacious in active UC (17, 22) (Kamm,
Sandborn et al. 2007; Lichtenstein, Kamm et al. 2007).
Moreover, a very recent double-blind, double-dummy, randomised study (21)
(Kruis W., Gorelov A. et al 2007) compared a once daily versus a three-time
daily regimen of 3g/d of mesalazine for the induction of remission in
ulcerative colitis. The once daily group showed slightly (though not
significant) better efficacy in nearly all endpoints at 8 weeks.
These results are supported by a pharmacokinetic study comparing the
bioavailability in the intestinal mucosa of mesalazine or its main metabolite
(N-acetyl-mesalazine) in a single dose of 4 g and 2 g twice-daily regimen (13)
(Gandia, Idier et al. 2007).
In addition, it should be pointed out that the safety and tolerability of these
regimens is acceptable. In the Marteau trial combining 4g/d oral mesalazine for
8 weeks and 1g/d topical mesalazine during the initial 4 weeks in patient with
active UC, the occurrence of adverse events was comparable for the 4+1g/d group
and the 4g/d group (34% vs 50% respectively). The majority of these adverse
events were mild or moderate and the most common were diarrhoea, headache,
vomiting, and abdominal pain. During the study period, there were no relevant
changes in serum creatinine, urinary protein, urinary haemoglobin, platelet,
white blood cells or red blood cells count whatever the treatment group.
Elevation of hepatic enzymes was seen in 1 patient/71 of the 4+1/d group and in
3 patients/56 of the 4g/d group (26) (Marteau, Probert et al. 2005).
In the pharmacokinetic study comparing mesalazine in a single dose of 4 g with
2 g twice-daily for 8 days, 3 subjects/30 healthy volunteers reported headache,
nausea and asthenia. These AE were all mild or moderate and resolved
spontaneously. There were no major changes in vital signs, ECG, renal, hepatic
or pancreatic functions. Under the study conditions, both regimens were safe
and well tolerated. (13) (Gandia, Idier et al. 2007).
In conclusion, while standard treatment of mild to moderate active episodes of
extensive UC using mesalazine is effective in a significant number of patients,
response rate and disease progression under treatment is determined by
compliance of patients with their therapy. Reducing the dosing rate to a single
daily dose for 8 weeks constitutes a simple method of improving treatment
compliance but it is necessary to demonstrate at least equivalent efficacy
compared to the twice daily dosing.

Primary objective:
To demonstrate that mesalazine po 4g per day once daily (QD.) is non-inferior
to the reference regimen, mesalazine 4g per day in two divided doses (BID.) (2g
x 2 per day), in patients with active ulcerative colitis treated for 8 weeks,
in terms of remission evaluated with the UC-DAI score and defined as * 1. Both
groups (4g QD and 2gx2) will receive an enema containing 1g of mesalazine at
bedtime during the initial 4 weeks.
Secondary objectives:
To compare the following between the two groups:
• Compliance
• Clinical remission at week 4 and week 8
• Clinical variables improvement (stool frequency and bloody stools) at week 4,
8 and 12 separately
• Treatment failure rates at W4 and W8
• Time to remission according patient*s diary (normal stool frequency and
cessation of bleeding)
• Time to cessation of bleeding
• Improvement at week 4 and 8 based on UC-DAI score
• Endoscopic assessment at W0 and W8
• Acceptability of the treatment
• Safety
• Proportion of patients staying in clinical remission at week 12.

METHODOLOGY
Multicentre, controlled, investigator-blinded design, randomised,
parallel-group study.
The randomisation will be done centrally, based on a central computer-generated
randomisation scheme.
The patients will be treated for 8 weeks, with clinical evaluations at
baseline, week 4, 8 and 12 and endoscopic evaluations (sigmoidoscopy) at
baseline and week 8.
400 patients.

Mesalazine (orally) 4 grams once daily or 2 grams twice daily.

Risk: AEs of mesalazine (i.e. diarrhoea, nausea, pain in stomach, headache,
vomiting and skin rash) and (small) risk of endoscopy.
Burden: 5 visitsin in 12 weeks. Diary during 12 weeks. Total amount of blood to
be drawn approx. 30 ml.
Physical examination 2x, preganancy test (if relevant) 1x, blood tests 2x,
endoscopy 2x, VAS 2x.