Mesalamine 2 g Sachet for the Maintenance of Clinical and Endoscopic Remission in Ulcerative Colitis (UC)

Study Overview
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Brief Summary
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The purpose of this trial was to investigate the safety and efficacy of mesalamine 2 g extended release granules (sachet) once a day (QD) for maintenance of clinical and endoscopic remission in subjects with UC. The duration of treatment for each subject was 6 months.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Investigating the Efficacy and Safety of Mesalamine 2 g Extended Release Granules (Sachet) for Maintenance of Clinical and Endoscopic Remission in Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Mesalamine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects aged 18 to 75 years, with Ulcerative Colitis in remission Exclusion Criteria: Evidence of other forms of inflammatory bowel disease Infectious disease (including human immunodeficiency virus [HIV], hepatitis B virus [HBV], or hepatitis C virus [HCV]) Disease limited to proctitis <15 cm Short bowel syndrome Prior colon resection surgery History of severe/fulminant UC Intolerant or allergic to aspirin or salicylate derivatives Use of rectal formulations (5-aminosalicylic acid [5-ASA], steroids) within ≤7 days Women who are pregnant or nursing History of known malignancy History of bleeding disorders, active gastric or active duodenal ulcers, autoimmune diseases, or mental/ emotional disorders, that would interfere with their participation in the trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mesalamine<br>Mesalamine 2 g extended release granules (sachet), administered orally once daily (QD) for 6 months. | Drug: Mesalamine<br>* Pharmaceutical form: Granules in sachet; Route of administration: Oral use<br>* Other names: Pentasa;|
| Placebo Comparator: Placebo<br>Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months. | Drug: Placebo<br>* Pharmaceutical form: Granules in sachet; Route of administration: Oral use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects With Remission at Month 6 | The proportion of subjects with remission was defined by Clinical and Endoscopic Response Score: 0 for rectal bleeding; 0 or 1 for stool frequency; 0 or 1 for endoscopic score. The Clinical and Endoscopic Response Score ranged between 0 (normal) to 9 (severe disease), higher scores indicating greater disease severity. The score included clinical response component to assess subject's symptoms and endoscopic response component to assess objective evidence of inflammation. Clinical response component had two subscales: stool frequency ranging from 0 (normal number of stools) to 3 (>=5 stools more than normal) and rectal bleeding ranging from 0 (no blood seen) to 3 (blood alone passes). The Endoscopic response component had one subscale: flexible sigmoidoscopy/colonoscopy ranging from 0 (normal) to 3 (severe disease). Data is presented cumulative for all pathways. | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects in Clinical Remission at Month 2, 4, and 6 | The proportion of subjects in clinical remission was defined as a score of 0 for rectal bleeding and 0 or 1 for stool frequency based on clinical response score component of the Clinical and Endoscopic Response Score. Clinical response score component had two subscales to assess subject's symptoms: rectal bleeding ranging from 0 (no blood seen) to 3 (blood alone passes) and stool frequency ranging from 0 (normal number of stools) to 3 (>=5 stools more than normal). The scores of clinical response component ranged from 0 (normal) to 6 (severe disease), higher scores indicating greater disease severity. Data is presented cumulative for all pathways. | Month 2, 4, and 6 | 
| Time to Relapse | Time to relapse was defined as the number of days from randomization to the day of withdrawal due to escalation of therapy. Data is presented cumulative for all pathways. | Time from randomization to the day of withdrawal due to escalation of therapy (up to 6 months) | 
| Proportion of Subjects With an Increase From Baseline in the Clinical and Endoscopic Response Score by 2 or More Points in at Least 1 Component or by 1 or More Points in at Least 2 Components at Month 6 | The proportion of subjects with an increase from baseline in the Clinical and Endoscopic Response Score by 2 or more points in at least 1 component, or by 1 or more points in at least 2 components were reported. The Clinical and Endoscopic Response Score ranged between 0 (normal) to 9 (severe disease), higher scores indicating greater disease severity. The score included clinical response component to assess subject's symptoms and endoscopic response component to assess objective evidence of inflammation. Clinical Response component had two subscales: stool frequency ranging from 0 (normal number of stools) to 3 (>=5 stools more than normal) and rectal bleeding ranging from 0 (no blood seen) to 3 (blood alone passes). The Endoscopic Response component had one subscale: flexible sigmoidoscopy/colonoscopy ranging from 0 (normal) to 3 (severe disease). Data is presented cumulative for all pathways. | Month 6 | 
| Change From Baseline in Serum C-reactive Protein (CRP) Levels at Month 2, 4, and 6 | The adjusted mean change from baseline in serum CRP levels at Month 2, 4, and 6 were reported. Data is presented cumulative for all pathways. | Baseline, Month 2, 4, and 6 | 
| Change From Baseline in Fecal Calprotectin Levels at Month 2, 4, and 6 | The adjusted mean change from baseline in fecal calprotectin levels at Month 2, 4, and 6 were reported. Data is presented cumulative for all pathways. | Baseline, Month 2, 4, and 6 | 
| Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Scores at Months 2, 4, and 6 | The IBDQ is an instrument used to assess quality of life in adult subjects with ulcerative colitis. It includes 32 questions on 4 domains of Health-Related Quality-of-Life (HRQOL): Bowel Systems (10 items), Emotional Function (12 items), Social Function (5 items), and Systemic Function (5 items). Subjects were asked to recall symptoms and quality of life from the last 2 weeks and rate each item on a 7-point Likert scale (1=worst to 7=best). The total IBDQ was computed as the sum of the responses to the individual IBDQ questions. The total score can range between 32 to 224 with higher scores indicating a better HRQOL. The adjusted mean change from baseline at Month 2, 4, and 6 for the IBDQ total scores were reported. Data is presented cumulative for all pathways. | Baseline, Month 2, 4, and 6 | 
| Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is defined as any untoward medical occurrence in a subject participating in a clinical trial. Any AEs includes serious as well as non-serious AEs. An SAE is defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital anomaly/birth defect, or was an important medical event. Any AE which occurred in the time interval from initial dosing (investigational medicinal product [IMP] intake) to the end of treatment visit (Month 6) was considered treatment-emergent. Data is presented cumulative for all pathways. | Up to Month 6 | 
| Severity of Adverse Events | The number of subjects with intensity of AEs (classified as mild, moderate or severe) were presented. Data is presented cumulative for all pathways. | Up to Month 6 | 
| Proportion of Subjects With Markedly Abnormal Laboratory Values: Hematology | Proportion of subjects with markedly abnormal changes from baseline in hematology values are presented. Criteria for markedly abnormal laboratory (Hematology): Basophils/Leukocytes: >=5%, Eosinophils/Leukocytes: >=10%, Erythrocytes: <=3.5*10^6/μL, Hematocrit: <=0.32%; >=0.56%, Hemoglobin: <=11.5 g/dL, Leukocytes: <=2.8*10^3/μL; >=16.0*10^3/μL, Lymphocytes/Leukocytes: <=10%; >=80%, Monocytes/Leukocytes: >=20%, Neutrophils/Leukocytes: <=15%; >=90%, Platelets: <=75*10^3/μL; >=700*10^3/μL. Data is presented cumulative for all pathways. | Baseline, Month 6 | 
| Proportion of Subjects With Markedly Abnormal Laboratory Values: Coagulation | Proportion of subjects with markedly abnormal changes from baseline in coagulation values are presented. Criteria for markedly abnormal laboratory (coagulation): Activated Partial Thromboplastin Time (aPTT): >70 seconds (sec), Prothrombin International Normalized Ratio (INR): <0.8; >1.1. Data is presented cumulative for all pathways. | Baseline, Month 6 | 
| Proportion of Subjects With Markedly Abnormal Laboratory Values: Serum Chemistry | Proportion of subjects with markedly abnormal changes from baseline in serum chemistry values are presented. Criteria for markedly abnormal laboratory (serum chemistry): Alanine Aminotransferase (ALT): >3*upper limit of normal (ULN), Alkaline Phosphatase (ALP): >3*ULN and 25% increase (inc) from baseline (BL), Aspartate Aminotransferase (AST): >3* ULN, Bilirubin: >=1.5* ULN, Blood Urea Nitrogen: >=10.7 mg/dL, Calcium: <=1.8 mg/dL; >=3.9 mg/dL, Chloride: <=90 mmol/L; >=115 mmol/L, Creatinine: >=177 mg/dL, Gamma Glutamyl Transferase: >3*ULN, Glomerular Filtration Rate (GFR): <30 mL/min, Glucose: <=2.8 mg/dL; >=10 mg/dL, Potassium: <=3.0 mmol/L; >=5.8 mmol/L, Sodium: <=130 mmol/L; >=155 mmol/L. Data is presented cumulative for all pathways. | Baseline, Month 6 |