Mesalazine 4g Once Daily Versus 4g in Two Divided Doses in Active Ulcerative Colitis.

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.

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.

Study Overview

• Status: Completed
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Drug: Mesalazine slow-release granules; Drug: Mesalazine liquid enema

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.

• Study Type: Interventional
• Enrollment (Actual): 206
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium
    • O.L.Vrouwziekenhuis Campus Aalst
  • Brussels, Belgium
    • Universitair Ziekenhuis Brussel
  • Brussels, Belgium
    • Saint Luc University Hospital
  • Bruxelles, Belgium
    • C.H.U. Saint-Pierre
  • Edegem, Belgium
    • U.Z. Antwerpen
  • Leuven, Belgium
    • University Hospital Gasthuisberg
• France
  • Agen, France
    • Clinique Esquirol-St Hilaire
  • Albi, France
    • Investigational Site
  • Amiens, France
    • Investigational Site
  • Avignon, France
    • Centre Hospitalier Avignon
  • BETHUNE Cedex, France
    • Centre Hospitalier Béthune
  • Bourgoin-jallieu, France
    • Investigational Site
  • Brest, France
    • Investigational Site
  • Bruges, France
    • Clinique Jean-Villar
  • CAEN Cedex 4, France
    • Clinique Saint Martin - 18 rue Rocquemonts
  • CAEN Cedex 4, France
    • Clinique Saint Martin
  • Caluire Et Cuire, France
    • Investigational Site
  • Carcassonne, France
    • Investigational Site
  • Castelnau Le Lez, France
    • Clinique du Parc
  • Chambray les Tours, France
    • Investigational Site
  • Clermont-ferrand, France
    • Centre Médical République
  • Clichy, France
    • Investigational Site
  • Cornebarrieu, France
    • Clinique des Cèdres
  • Creteil, France
    • Centre Hospitalier Intercommunal
  • Dunkerque, France
    • Investigational Site
  • Grenoble, France
    • Investigational Site
  • Grenoble Cedex 09, France
    • Centre Hospitalier Universitaire Albert MICHALON
  • Hazebroucq, France
    • Investigational Site
  • Irigny, France
    • Investigational Site
  • Istres, France
    • Investigational Site
  • Lagny, France
    • Centre Hospitalier Lagny
  • Le Mans, France
    • Investigational Site
  • Lille, France
    • Investigational site - 23 bis, place Sébastol
  • Lille, France
    • Investigational site - 60 rue Jean Bart
  • Lyon, France
    • Clinique De La Sauvegarde
  • Marseille, France
    • Investigational site - 186 avenue de la Rose
  • Marseille, France
    • Investigational site - 23 Cours Gouffé
  • Miramas, France
    • Investigational Site
  • Montfermeil, France
    • CH Le raincy-Montfermeil
  • Nancy, France
    • Investigational Site
  • Nice, France
    • Hopital L'Archet 2
  • Paris, France
    • Investigational site - 127 boulevard St Germain
  • Paris, France
    • Investigational site - 72 rue Archeveau
  • Paris, France
    • Investigational site - 91 rue Caulaincourt
  • Perpignan, France
    • Investigational Site
  • Pessac, France
    • Clinique Saint Martin
  • Pierre-benite, France
    • Hôpital de Lyon Sud
  • Reims, France
    • Investigational Site
  • Saint Gregoire, France
    • Centre Hospitalier Prive
  • Saint Priest, France
    • Investigational site - 140 avenue Lwoff
  • Saint Quentin, France
    • Investigational Site
  • Strasbourg, France
    • Investigational Site
  • Toulouse, France
    • Clinique Saint Jean Languedoc - 20 route de Revel
  • Toulouse, France
    • Clinique Saint Jean-Languedoc
  • Venissieux, France
    • Groupe hospitalier les Portes du Sud
  • Verquigneul, France
    • Centre Futura Medica
• Netherlands
  • Den Haag, Netherlands
    • Haga Ziekenhuis, loc.Rode Kruis
  • Haarlem, Netherlands
    • Kennemer Gasthuis, loc. EG
  • Hengelo, Netherlands
    • Streekziekenhuis Midden Twente
  • Lelystad, Netherlands
    • IJsselmeer Ziekenhuis Loc. Lelystad, Poli MDL
  • Maastricht, Netherlands
    • Mumc / Azm
  • Tilburg, Netherlands
    • TweeSteden Ziekenhuis
  • Zwolle, Netherlands
    • Isala Klinieken, loc. Sophia
• United Kingdom
  • Bristol, United Kingdom
    • Bristol Royal Infirmary
  • Cambridge, United Kingdom
    • Addenbrooke's Hospital
  • Newcastle, United Kingdom
    • Royal Victoria Infirmary

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Mesalazine once/day; Participants received 4g oral Mesalazine once a day (2 sachets of prolonged release granules) for 8 weeks during the induction period. In addition, participants received a liquid enema of 1g Mesalazine once a day at bedtime for the first 4 weeks. Participants who were in remission at Week 8 received oral mesalazine 2g once daily (1 sachet/day) for an additional 4 weeks (maintenance period).	Drug: Mesalazine slow-release granules; Mesalazine 2g Sachet prolonged release granules, administered orally.; Other Names: Pentasa; Drug: Mesalazine liquid enema; 1g mesalazine liquid enema, administered topically once a day in the evening.
ACTIVE_COMPARATOR: Mesalazine twice/day; Participants received oral mesalazine 4 g per day in two divided doses (1 sachet prolonged release granules twice a day) for 8 weeks during the induction period. In addition, participants received a liquid enema of 1g Mesalazine once a day at bedtime for the first 4 weeks. Participants who were in remission at Week 8 received oral Mesalazine 2g (one sachet) once a day for an additional 4 weeks (maintenance period).	Drug: Mesalazine slow-release granules; Mesalazine 2g Sachet prolonged release granules, administered orally.; Other Names: Pentasa; Drug: Mesalazine liquid enema; 1g mesalazine liquid enema, administered topically once a day in the evening.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Primary efficacy criterion: remission after 8 weeks of treatment, defined on the basis of the UC-DAI score less than or equal to 1	12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Compliance	Week 8
Clinical remission	At week 4, week 8 and week 12
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.	At week 4 and week 8
Clinical variables (stool frequency and bloody stools)	At week 4, 8 and 12 separately
Time to remission according to patient's diary (normal stool frequency and cessation of bleeding)	At week 4 and week 8
Time to cessation of bleeding	At week 4, week 8 and week 12
Improvement - based on UC-DAI score	At week 4 and 8
Endoscopic assessment	At week 0 and week 8
Safety	At week 0, week 4, week 8 and week 12

Collaborators and Investigators

• Sponsor: Ferring Pharmaceuticals

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (ACTUAL): June 1, 2010
• Study Completion (ACTUAL): June 1, 2010

Study Registration Dates

• First Submitted: August 19, 2008
• First Submitted That Met QC Criteria: August 19, 2008
• First Posted (ESTIMATE): August 20, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): March 4, 2015
• Last Update Submitted That Met QC Criteria: March 3, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Mesalamine
• Other Study ID Numbers: Pentasa FE999907 CS06; EudractCT No 2008-000045-59