Clinical trial NCT00737789: Mesalazine 4g Once Daily Versus 4g in Two Divided Doses in Active Ulcerative Colitis.
Official title: Multicentre, Controlled, Randomised, Investigator-Blinded, Comparative Study of Oral Mesalazine 4g Once Daily Versus Mesalazine 4g in Two Divided Doses in Patients With Active Ulcerative Colitis.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ulcerative Colitis
Lead sponsor: Ferring Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2008-08-20
Enrollment: 206
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to demonstrate that mesalazine 4g orally 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 (UC) treated for 8 weeks, in terms of remission evaluated with the Ulcerative Colitis Disease Activity Index (UC-DAI) score and defined as less than or equal to 1. Both groups (4g QD and 2gx2) received an enema containing 1g of mesalazine at bedtime during the initial 4 weeks.

Participants in remission at week 8 received an additional 4 weeks of maintenance therapy with 2g oral mesalazine once a day. Participants who did not achieve remission at Week 8 completed the study at week 8.

Detailed description: A key element in therapeutic response in UC is treatment compliance. In daily practice, compliance of UC patients with 5-Amino Salicylic Acid (5-ASA) treatment appears mediocre, particularly in maintenance therapy. Poor or non-existent compliance affects not only treatment response but also disease progression.

An inverse relationship has been found between the number of daily doses prescribed and treatment compliance. Thus, reduction to a single daily dose of mesalazine is a major factor likely to significantly increase treatment compliance.

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 which is the reference regimen. This study was designed to show that mesalazine 4g once daily is at least as effective as mesalazine 4g in two divided doses per day in patients with mild to moderate ulcerative colitis after 8 weeks of treatment with a better compliance. To improve remission, both groups received an enema during the first 4 weeks, as usually done in current practice.

Eligibility criteria: Inclusion Criteria:

Patients will be included if they comply with the following inclusion criteria determined at baseline, prior to first drug administration:

* Aged over 18 years.
* Newly diagnosed or relapsing mild to moderate ulcerative colitis with disease extension beyond rectum (of at least 12-18 cm from the anorectal junction). All patients must have had at least one total colonoscopy in their disease history (within the previous 5 years).
* Disease activity will be assessed on the 15 days before inclusion and according to ulcerative colitis disease activity index (UC-DAI) score. The UC-DAI score will be from 3 to 8 (mild: 3-5 or moderate: 6-8).
* Men or non pregnant women.
* Women with childbearing potential must be using a contraceptive method judged effective by the investigator.
* Oral maintenance treatment with azathioprine or 6-mercaptopurine (taken for at least 6 months at stable dose and continued at the same dose throughout the study) is permitted.
* Informed consent given.

Exclusion Criteria:

The patients will not be included in the study if one of the following exclusion criteria is fulfilled at baseline, prior to first drug administration:

* Proctitis (less than 12-18 cm from the anorectal junction).
* Previous colonic surgery.
* Previously failed to respond to steroids within the previous year.
* Non-response to rectal 5-Amino Salicylic Acid (5-ASA) therapy or to oral 5-ASA therapy at a dose \> 3g/day for induction of remission within the previous year.
* Current relapse lasting more than 6 weeks (for patient recently diagnosed the period of 6 weeks runs from the endoscopic diagnosis)(from what patient says).
* Severe/fulminant ulcerative colitis.
* Evidence of other forms of inflammatory bowel disease or infectious disease.
* Allergy to aspirin or salicylate derivatives.
* The following treatment will be forbidden during the study (if present at selection, a wash-out will be necessary):
* Loperamide and other antidiarrheal agents, mucilages, antibiotics: 1 week wash-out.
* Oral steroids: 4 weeks wash-out.
* Rectal steroids: 2 weeks wash-out
* Repeated treatment (\> 3days of use) of non steroidal anti-inflammatory drugs (NSAID) oral or rectal route: 1 week wash-out (aspirin ≤ 325 mg/day used for cardioprotection is allowed).
* Sulfasalazine \> 4g/day or mesalazine or 4-ASA at a higher dose than what is permitted in the local formulary or standard care for maintenance treatment: 4 weeks wash-out
* Immunomodulating/suppressing drugs: 3 month for wash out (except for patients maintained on azathioprine or 6-mercaptopurine -see above).
* Known significant hepatic or renal function abnormalities.
* Moderate/severe abnormal renal, hepatic or blood count tests defined as: creatinine plasma value \> 1.5 x Upper Limit of Normal (ULN) or white blood cells \< 3500/mm˄3 or \> 15000/mm˄3 or Platelets \< 100000/mm˄3 or \> 800000/mm˄3 or aspartate aminotransferase/alanine Aminotransferase (ASAT/ALAT) \> 3 x ULN or Gamma glutamyl transpeptidase (GGT)/Alkaline Phosphatase's \> 3 x ULN (Primary Sclerosing Cholangitis is not an exclusion criteria).
* History or physical examination findings indicative of active alcohol or drug abuse,
* Pregnancy or breast-feeding,
* History of disease, including mental/emotional disorder, that might interfere with their participation in the study,
* Participation in another clinical study in the last 3 months.
* Inability to comply with the protocol requirements.
* Inability to fill in the diary cards.

Primary outcomes:
measure: Primary efficacy criterion: remission after 8 weeks of treatment, defined on the basis of the UC-DAI score less than or equal to 1
timeFrame: 12 weeks
Secondary outcomes:
measure: Compliance
timeFrame: Week 8
measure: Clinical remission
timeFrame: At week 4, week 8 and week 12
measure: Treatment failure is defined as need of other treatment (ie steroids, immunosuppressive or immunomodulating drugs) than those allowed by the protocol, as judged by investigator. Treatment failure will be counted as non-remission.
timeFrame: At week 4 and week 8
measure: Clinical variables (stool frequency and bloody stools)
timeFrame: At week 4, 8 and 12 separately
measure: Time to remission according to patient's diary (normal stool frequency and cessation of bleeding)
timeFrame: At week 4 and week 8
measure: Time to cessation of bleeding
timeFrame: At week 4, week 8 and week 12
measure: Improvement - based on UC-DAI score
timeFrame: At week 4 and 8
measure: Endoscopic assessment
timeFrame: At week 0 and week 8
measure: Safety
timeFrame: At week 0, week 4, week 8 and week 12
Other outcomes:
Locations:
city: Aalst
country: Belgium
facility: O.L.Vrouwziekenhuis Campus Aalst
city: Brussels
country: Belgium
facility: Saint Luc University Hospital
city: Brussels
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Bruxelles
country: Belgium
facility: C.H.U. Saint-Pierre
city: Edegem
country: Belgium
facility: U.Z. Antwerpen
city: Leuven
country: Belgium
facility: University Hospital Gasthuisberg
city: Agen
country: France
facility: Clinique Esquirol-St Hilaire
city: Albi
country: France
facility: Investigational site
city: Amiens
country: France
facility: Investigational site
city: Avignon
country: France
facility: Centre Hospitalier Avignon
city: BETHUNE Cedex
country: France
facility: Centre Hospitalier Bethune
city: Bourgoin-jallieu
country: France
facility: Investigational site
city: Brest
country: France
facility: Investigational site
city: Bruges
country: France
facility: Clinique Jean-Villar
city: CAEN Cedex 4
country: France
facility: Clinique Saint Martin - 18 rue Rocquemonts
city: CAEN Cedex 4
country: France
facility: Clinique Saint Martin
city: Caluire Et Cuire
country: France
facility: Investigational site
city: Carcassonne
country: France
facility: Investigational site
city: Castelnau Le Lez
country: France
facility: Clinique du Parc
city: Chambray les Tours
country: France
facility: Investigational site
city: Clermont-ferrand
country: France
facility: Centre Médical République
city: Clichy
country: France
facility: Investigational site
city: Cornebarrieu
country: France
facility: Clinique des Cèdres
city: Creteil
country: France
facility: Centre Hospitalier Intercommunal
city: Dunkerque
country: France
facility: Investigational site
city: Grenoble Cedex 09
country: France
facility: Centre Hospitalier Universitaire Albert MICHALON
city: Grenoble
country: France
facility: Investigational site
city: Hazebroucq
country: France
facility: Investigational site
city: Irigny
country: France
facility: Investigational site
city: Istres
country: France
facility: Investigational site
city: Lagny
country: France
facility: Centre Hospitalier Lagny
city: Le Mans
country: France
facility: Investigational site
city: Lille
country: France
facility: Investigational site - 23 bis, place Sébastol
city: Lille
country: France
facility: Investigational site - 60 rue Jean Bart
city: Lyon
country: France
facility: Clinique de la Sauvegarde
city: Marseille
country: France
facility: Investigational site - 186 avenue de la Rose
city: Marseille
country: France
facility: Investigational site - 23 Cours Gouffé
city: Miramas
country: France
facility: Investigational site
city: Montfermeil
country: France
facility: CH Le raincy-Montfermeil
city: Nancy
country: France
facility: Investigational site
city: Nice
country: France
facility: Hôpital L'Archet 2
city: Paris
country: France
facility: Investigational site - 127 boulevard St Germain
city: Paris
country: France
facility: Investigational site - 72 rue Archeveau
city: Paris
country: France
facility: Investigational site - 91 rue Caulaincourt
city: Perpignan
country: France
facility: Investigational site
city: Pessac
country: France
facility: Clinique Saint Martin
city: Pierre-benite
country: France
facility: Hôpital de Lyon Sud
city: Reims
country: France
facility: Investigational site
city: Saint Gregoire
country: France
facility: Centre Hospitalier Privé
city: Saint Priest
country: France
facility: Investigational site - 140 avenue Lwoff
city: Saint Quentin
country: France
facility: Investigational site
city: Strasbourg
country: France
facility: Investigational site
city: Toulouse
country: France
facility: Clinique Saint Jean Languedoc - 20 route de Revel
city: Toulouse
country: France
facility: Clinique Saint Jean-Languedoc
city: Venissieux
country: France
facility: Groupe Hospitalier les Portes du Sud
city: Verquigneul
country: France
facility: Centre FUTURA MEDICA
city: Den Haag
country: Netherlands
facility: Haga Ziekenhuis, loc.Rode Kruis
city: Haarlem
country: Netherlands
facility: Kennemer Gasthuis, loc. EG
city: Hengelo
country: Netherlands
facility: Streekziekenhuis Midden Twente
city: Lelystad
country: Netherlands
facility: IJsselmeer Ziekenhuis Loc. Lelystad, Poli MDL
city: Maastricht
country: Netherlands
facility: Mumc / Azm
city: Tilburg
country: Netherlands
facility: TweeSteden Ziekenhuis
city: Zwolle
country: Netherlands
facility: Isala Klinieken, loc. Sophia
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Newcastle
country: United Kingdom
facility: Royal Victoria Infirmary
Study officials:
affiliation: Ferring Pharmaceuticals
name: Clinical Development Support
role: STUDY_DIRECTOR
References:
citation: Flourie B, Hagege H, Tucat G, Maetz D, Hebuterne X, Kuyvenhoven JP, Tan TG, Pierik MJ, Masclee AA, Dewit O, Probert CS, Aoucheta D; MOTUS study investigators. Randomised clinical trial: once- vs. twice-daily prolonged-release mesalazine for active ulcerative colitis. Aliment Pharmacol Ther. 2013 Apr;37(8):767-75. doi: 10.1111/apt.12266. Epub 2013 Mar 4.