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Ability to Maintain or Achieve Clinical and Endoscopic Remission With MMX Mesalamine Once Daily in Adults With Ulcerative Colitis

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ClinicalTrials.gov Identifier: NCT01124149
Recruitment Status : Completed
First Posted : May 14, 2010
Results First Posted : December 2, 2013
Last Update Posted : June 12, 2014
Sponsor:
Information provided by (Responsible Party):
Shire

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Ulcerative Colitis
Intervention Drug: MMX mesalamine/ mesalazine
Enrollment 722
Recruitment Details  
Pre-assignment Details Although 639 subjects completed the Acute Phase, 167 were not eligible to enter the Maintenance Phase due to lack of efficacy and 2 others withdrew prior to entering the maintenance Phase and 1 was withdrawn per IVRS prior to entering the Mainenance Phase. Therefore, 469 subjects entered the Maintenance Phase.
Arm/Group Title MMX Mesalamine/ Mesalazine
Hide Arm/Group Description 4.8g/day given QD for 8 weeks in the Acute Phase and 2.4g/day given QD for 12 months in the Maintenance Phase
Period Title: Acute Phase
Started 722
Completed 639
Not Completed 83
Reason Not Completed
Withdrawal by Subject             22
Adverse Event             21
Lack of Efficacy             17
Protocol Violation             14
Lost to Follow-up             2
Prolonged antibiotic therapy             1
Sponsor request             1
UC symptoms not ameliorated             1
Non-compliance             1
Low hemoglobin             1
Travelling to another country             1
Sponsor decision             1
Period Title: Maintenance Phase
Started 469
Completed 373
Not Completed 96
Reason Not Completed
Lack of Efficacy             40
Adverse Event             24
Lost to Follow-up             15
Withdrawal by Subject             10
Protocol Violation             5
Coordinator error             1
Non-compliance             1
Arm/Group Title MMX Mesalamine/ Mesalazine
Hide Arm/Group Description 4.8g/day given QD for 8 weeks in the Acute Phase and 2.4g/day given QD for 12 months in the Maintenance Phase
Overall Number of Baseline Participants 717
Hide Baseline Analysis Population Description
The Safety Population was used. Safety Population defined as all subjects who took at least 1 dose of investigational product during the Acute or Maintenance Phase (n=717).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 717 participants
42.9  (13.97)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 717 participants
>=65 years 51
<=18 years 10
Between 18 and 65 years 656
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 717 participants
Female
308
  43.0%
Male
409
  57.0%
Region of Enrollment   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 717 participants
BELGIUM 22
CANADA 39
COLOMBIA 74
CZECH REPUBLIC 130
FRANCE 2
HUNGARY 30
INDIA 200
IRELAND 9
POLAND 52
ROMANIA 41
SOUTH AFRICA 21
SPAIN 3
UNITED KINGDOM 3
UNITED STATES 96
[1]
Measure Description: All enrolled subjects (n=722).
1.Primary Outcome
Title Percentage of Subjects in Complete Remission at Month 12 of Maintenance Phase
Hide Description

Complete remission was defined as a modified Ulcerative Colitis Disease Activity Index (UC-DAI) <=1 with a score of 0 for rectal bleeding and stool frequency and at least a 1-point reduction in endoscopy score from baseline.

The modified UC-DAI score is the sum of the scores of 4 parameters (stool frequency, rectal bleeding, endoscopy score, and physician global assessment), each scoring between 0 and 3, making 12 the worst score.

Endoscopy score (mucosal appearance) ranges from 0-3 (0 = normal, 1 = mild , 2 = moderate, 3 = severe).

Rectal bleeding is assessed on a scale from 0-3 (0 = no rectal bleeding, 1 = streaks of blood, 2 = obvious blood, 3 = mostly blood).

Stool frequency is assessed on a scale of 0-2 (0 = 0-1 more than normal per day, 1 = 2-3 more than normal per day, 2 = 4 or more than normal per day).

Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Maintenance Phase Efficacy Population included all subjects who, during the Maintenance Phase, took at least 1 dose of investigational product and had at least 1 post-dose efficacy assessment.
Arm/Group Title MMX Mesalamine/ Mesalazine (Complete Remission Acute Phase) MMX Mesalamine/ Mesalazine (Partial Remission Acute Phase)
Hide Arm/Group Description:
Subjects received 4.8g/day given QD for 8 weeks in the Acute Phase and were classified as having complete remission at the end of the Acute Phase. Complete (clinical and endoscopic) remission was defined as a modified UC-DAI <=1 with a score of 0 for rectal bleeding and stool frequency and at least a 1-point reduction in endoscopy score from baseline. These subjects then received 2.4g/day given QD for 12 months in the Maintenance Phase.
Subjects received 4.8g/day given QD for 8 weeks in the Acute Phase and were classified as having partial remission at the end of the Acute Phase. Partial remission was defined as a modified UC-DAI <=3 with a combined stool frequency and rectal bleeding score of <=1 and not in complete remission. These subjects then received 2.4g/day given QD for 12 months in the Maintenance Phase.
Overall Number of Participants Analyzed 182 277
Measure Type: Number
Unit of Measure: percentage of subjects
47.8 26.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MMX Mesalamine/ Mesalazine (Complete Remission Acute Phase), MMX Mesalamine/ Mesalazine (Partial Remission Acute Phase)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.61
Confidence Interval (2-Sided) 95%
1.76 to 3.87
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Subjects in Clinical Remission at Month 12 of Maintenance Phase
Hide Description

Clinical remission was defined as a score of 0 for rectal bleeding and stool frequency.

Rectal bleeding is assessed on a scale from 0-3 (0 = no rectal bleeding, 1 = streaks of blood, 2 = obvious blood, 3 = mostly blood).

Stool frequency is assessed on a scale of 0-2 (0 = 0-1 more than normal per day, 1 = 2-3 more than normal per day, 2 = 4 or more than normal per day).

Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Maintenance Phase Efficacy Population included all subjects who, during the Maintenance Phase, took at least 1 dose of investigational product and had at least 1 post-dose efficacy assessment.
Arm/Group Title MMX Mesalamine/ Mesalazine (Complete Remission Acute Phase) MMX Mesalamine/ Mesalazine (Partial Remission Acute Phase)
Hide Arm/Group Description:
Subjects received 4.8g/day given QD for 8 weeks in the Acute Phase and were classified as having complete remission at the end of the Acute Phase. Complete (clinical and endoscopic) remission was defined as a modified UC-DAI <=1 with a score of 0 for rectal bleeding and stool frequency and at least a 1-point reduction in endoscopy score from baseline. These subjects then received 2.4g/day given QD for 12 months in the Maintenance Phase.
Subjects received 4.8g/day given QD for 8 weeks in the Acute Phase and were classified as having partial remission at the end of the Acute Phase. Partial remission was defined as a modified UC-DAI <=3 with a combined stool frequency and rectal bleeding score of <=1 and not in complete remission. These subjects then received 2.4g/day given QD for 12 months in the Maintenance Phase.
Overall Number of Participants Analyzed 182 277
Measure Type: Number
Unit of Measure: percentage of subjects
58.8 40.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MMX Mesalamine/ Mesalazine (Complete Remission Acute Phase), MMX Mesalamine/ Mesalazine (Partial Remission Acute Phase)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.10
Confidence Interval (2-Sided) 95%
1.44 to 3.07
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Relapse in Ulcerative Colitis at Month 12 of Maintenance Phase
Hide Description Relapse was defined in the Maintenance Phase as the need for alternative treatment for UC (including surgery); subjects were classified as having a relapse if they had withdrawn from the study due to a lack of efficacy.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Maintenance Phase Efficacy Population included all subjects who, during the Maintenance Phase, took at least 1 dose of investigational product and had at least 1 post-dose efficacy assessment.
Arm/Group Title MMX Mesalamine/ Mesalazine (Complete Remission Acute Phase) MMX Mesalamine/ Mesalazine (Partial Remission Acute Phase)
Hide Arm/Group Description:
Subjects received 4.8g/day given QD for 8 weeks in the Acute Phase and were classified as having complete remission at the end of the Acute Phase. Complete (clinical and endoscopic) remission was defined as a modified UC-DAI <=1 with a score of 0 for rectal bleeding and stool frequency and at least a 1-point reduction in endoscopy score from baseline. These subjects then received 2.4g/day given QD for 12 months in the Maintenance Phase.
Subjects received 4.8g/day given QD for 8 weeks in the Acute Phase and were classified as having partial remission at the end of the Acute Phase. Partial remission was defined as a modified UC-DAI <=3 with a combined stool frequency and rectal bleeding score of <=1 and not in complete remission. These subjects then received 2.4g/day given QD for 12 months in the Maintenance Phase.
Overall Number of Participants Analyzed 182 277
Measure Type: Number
Unit of Measure: percentage of subjects
6.0 10.5
4.Secondary Outcome
Title Percentage of Subjects With Mucosal Healing at 12 Months of Maintenance Phase
Hide Description

Subjects with mucosal healing were defined as subjects who had an endoscopy score <=1.

Endoscopy score (mucosal appearance) ranges from 0-3 (0 = normal, 1 = mild , 2 = moderate, 3 = severe).

Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Maintenance Phase Efficacy Population included all subjects who, during the Maintenance Phase, took at least 1 dose of investigational product and had at least 1 post-dose efficacy assessment.
Arm/Group Title MMX Mesalamine/ Mesalazine (Complete Remission Acute Phase) MMX Mesalamine/ Mesalazine (Partial Remission Acute Phase)
Hide Arm/Group Description:
Subjects received 4.8g/day given QD for 8 weeks in the Acute Phase and were classified as having complete remission at the end of the Acute Phase. Complete (clinical and endoscopic) remission was defined as a modified UC-DAI <=1 with a score of 0 for rectal bleeding and stool frequency and at least a 1-point reduction in endoscopy score from baseline. These subjects then received 2.4g/day given QD for 12 months in the Maintenance Phase.
Subjects received 4.8g/day given QD for 8 weeks in the Acute Phase and were classified as having partial remission at the end of the Acute Phase. Partial remission was defined as a modified UC-DAI <=3 with a combined stool frequency and rectal bleeding score of <=1 and not in complete remission. These subjects then received 2.4g/day given QD for 12 months in the Maintenance Phase.
Overall Number of Participants Analyzed 182 277
Measure Type: Number
Unit of Measure: percentage of subjects
76.4 63.5
5.Secondary Outcome
Title Improvement in Rectal Bleeding Score During the Acute Phase
Hide Description

Improvement was defined as at least a 1-point reduction in the rectal bleeding score from baseline at each assessment point.

Rectal bleeding is assessed on a scale from 0-3 (0 = no rectal bleeding, 1 = streaks of blood, 2 = obvious blood, 3 = mostly blood).

Time Frame 3 and 8 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Acute Phase Safety Population included all subjects who, during the Acute Phase, took at least 1 dose of investigational product.
Arm/Group Title MMX Mesalamine/ Mesalazine
Hide Arm/Group Description:
4.8g/day given QD for 8 weeks in the Acute Phase
Overall Number of Participants Analyzed 717
Measure Type: Number
Unit of Measure: percentage of subjects
Week 3 42.4
Week 8 59.8
6.Secondary Outcome
Title Improvement in Stool Frequency Symptoms During the Acute Phase
Hide Description

Improvement was defined as at least a 1-point reduction in the stool frequency score from baseline at each assessment point.

Stool frequency is assessed on a scale of 0-2 (0 = 0-1 more than normal per day, 1 = 2-3 more than normal per day, 2 = 4 or more than normal per day).

Time Frame 3 and 8 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Acute Phase Safety Population included all subjects who, during the Acute Phase, took at least 1 dose of investigational product.
Arm/Group Title MMX Mesalamine/ Mesalazine
Hide Arm/Group Description:
4.8g/day given QD for 8 weeks in the Acute Phase
Overall Number of Participants Analyzed 717
Measure Type: Number
Unit of Measure: percentage of subjects
3 Weeks 38.5
8 Weeks 58.9
7.Secondary Outcome
Title Percentage of Subjects in Complete Remission at Week 8 of Acute Phase
Hide Description

Complete (clinical and endoscopic) remission was defined as a modified UC-DAI <=1 with a score of 0 for rectal bleeding and stool frequency and at least a 1-point reduction in endoscopy score from baseline.

The modified UC-DAI score is the sum of the scores of 4 parameters (stool frequency, rectal bleeding, endoscopy score, and physician global assessment), each scoring between 0 and 3, making 12 the worst score.

Endoscopy score (mucosal appearance) ranges from 0-3 (0 = normal, 1 = mild , 2 = moderate, 3 = severe).

Rectal bleeding is assessed on a scale from 0-3 (0 = no rectal bleeding, 1 = streaks of blood, 2 = obvious blood, 3 = mostly blood).

Stool frequency is assessed on a scale of 0-2 (0 = 0-1 more than normal per day, 1 = 2-3 more than normal per day, 2 = 4 or more than normal per day).

Time Frame 8 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Acute Phase Safety Population included all subjects who, during the Acute Phase, took at least 1 dose of investigational product.
Arm/Group Title MMX Mesalamine/ Mesalazine
Hide Arm/Group Description:
4.8g/day given QD for 8 weeks in the Acute Phase
Overall Number of Participants Analyzed 717
Measure Type: Number
Unit of Measure: percentage of subjects
25.9
8.Secondary Outcome
Title Percentage of Subjects in Partial Remission at Week 8 of Acute Phase
Hide Description

Partial remission was defined as a modified UC-DAI <=3 with a combined stool frequency and rectal bleeding score of <=1 and not in complete remission.

The modified UC-DAI score is the sum of the scores of 4 parameters (stool frequency, rectal bleeding, endoscopy score, and physician global assessment), each scoring between 0 and 3, making 12 the worst score.

Endoscopy score (mucosal appearance) ranges from 0-3 (0 = normal, 1 = mild , 2 = moderate, 3 = severe).

Rectal bleeding is assessed on a scale from 0-3 (0 = no rectal bleeding, 1 = streaks of blood, 2 = obvious blood, 3 = mostly blood).

Stool frequency is assessed on a scale of 0-2 (0 = 0-1 more than normal per day, 1 = 2-3 more than normal per day, 2 = 4 or more than normal per day).

Time Frame 8 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Acute Phase Safety Population included all subjects who, during the Acute Phase, took at least 1 dose of investigational product.
Arm/Group Title MMX Mesalamine/ Mesalazine
Hide Arm/Group Description:
4.8g/day given QD for 8 weeks in the Acute Phase
Overall Number of Participants Analyzed 717
Measure Type: Number
Unit of Measure: percentage of subjects
39.3
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title MMX Mesalamine/ Mesalazine (Acute Phase) MMX Mesalamine/ Mesalazine (Maintenance Phase)
Hide Arm/Group Description 4.8g/day given QD for 8 weeks in the Acute Phase 2.4 g/day given QD for 12 months in the Maintenance Phase
All-Cause Mortality
MMX Mesalamine/ Mesalazine (Acute Phase) MMX Mesalamine/ Mesalazine (Maintenance Phase)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
MMX Mesalamine/ Mesalazine (Acute Phase) MMX Mesalamine/ Mesalazine (Maintenance Phase)
Affected / at Risk (%) Affected / at Risk (%)
Total   13/717 (1.81%)   14/461 (3.04%) 
Blood and lymphatic system disorders     
Anemia  0/717 (0.00%)  2/461 (0.43%) 
Cardiac disorders     
Myocardial infarction  1/717 (0.14%)  0/461 (0.00%) 
Atrial fibrillation  0/717 (0.00%)  1/461 (0.22%) 
Bundle branch block left  0/717 (0.00%)  1/461 (0.22%) 
Gastrointestinal disorders     
Colitis ulcerative  2/717 (0.28%)  1/461 (0.22%) 
Pancreatitis acute  1/717 (0.14%)  0/461 (0.00%) 
Abdominal pain  0/717 (0.00%)  2/461 (0.43%) 
Diarrhea  0/717 (0.00%)  3/461 (0.65%) 
General disorders     
Pyrexia  0/717 (0.00%)  1/461 (0.22%) 
Infections and infestations     
Arthritis bacterial  1/717 (0.14%)  0/461 (0.00%) 
Lung infection  1/717 (0.14%)  0/461 (0.00%) 
Pneumonia staphylococcal  1/717 (0.14%)  0/461 (0.00%) 
Pyelonephritis acute  1/717 (0.14%)  0/461 (0.00%) 
Appendicitis  0/717 (0.00%)  1/461 (0.22%) 
Gastroenteritis  0/717 (0.00%)  1/461 (0.22%) 
Hepatitis B  0/717 (0.00%)  1/461 (0.22%) 
Injury, poisoning and procedural complications     
Femoral neck fracture  1/717 (0.14%)  0/461 (0.00%) 
Forearm fracture  0/717 (0.00%)  1/461 (0.22%) 
Road traffic accident  0/717 (0.00%)  2/461 (0.43%) 
Investigations     
HIV test positive  1/717 (0.14%)  0/461 (0.00%) 
C-reactive protein increased  0/717 (0.00%)  1/461 (0.22%) 
Metabolism and nutrition disorders     
Dehydration  1/717 (0.14%)  1/461 (0.22%) 
Musculoskeletal and connective tissue disorders     
Arthritis reactive  1/717 (0.14%)  0/461 (0.00%) 
Back pain  0/717 (0.00%)  1/461 (0.22%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Brain neoplasm  0/717 (0.00%)  1/461 (0.22%) 
Nervous system disorders     
Cerebrovascular accident  0/717 (0.00%)  1/461 (0.22%) 
Hemorrhagic stroke  0/717 (0.00%)  1/461 (0.22%) 
Radiculopathy  0/717 (0.00%)  1/461 (0.22%) 
Pregnancy, puerperium and perinatal conditions     
Pregnancy  1/717 (0.14%)  0/461 (0.00%) 
Renal and urinary disorders     
Nephrolithiasis  1/717 (0.14%)  0/461 (0.00%) 
Reproductive system and breast disorders     
Metrorrhagia  0/717 (0.00%)  1/461 (0.22%) 
Vascular disorders     
Venous thrombosis limb  0/717 (0.00%)  1/461 (0.22%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
MMX Mesalamine/ Mesalazine (Acute Phase) MMX Mesalamine/ Mesalazine (Maintenance Phase)
Affected / at Risk (%) Affected / at Risk (%)
Total   60/717 (8.37%)   65/461 (14.10%) 
Gastrointestinal disorders     
Colitis ulcerative  10/717 (1.39%)  43/461 (9.33%) 
General disorders     
Drug ineffective  50/717 (6.97%)  22/461 (4.77%) 
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
Results Point of Contact
Name/Title: Study Physician
Organization: Shire Development LLC
Phone: +1 866 842 5335
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT01124149     History of Changes
Other Study ID Numbers: SPD476-409
2009-017044-13 ( EudraCT Number )
First Submitted: May 13, 2010
First Posted: May 14, 2010
Results First Submitted: September 30, 2013
Results First Posted: December 2, 2013
Last Update Posted: June 12, 2014