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

• Sponsor: Ferring Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02522780
• Collaborator: (none)
• Enrollment: 276
• Locations: 96
• Arms: 2
• Actual Duration (Months): 31.6
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Ulcerative Colitis	Drug: Mesalamine; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 276 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: Sep 19, 2018
• Actual Study Completion Date: Sep 19, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mesalamine Mesalamine 2 g extended release granules (sachet), administered orally once daily (QD) for 6 months.	Drug: Mesalamine; Pharmaceutical form: Granules in sachet; Route of administration: Oral use; Other Names: Mesalazine Pentasa
Placebo Comparator: Placebo Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.	Drug: Placebo; Pharmaceutical form: Granules in sachet; Route of administration: Oral use

Outcome Measures

Primary Outcome Measures

1. Proportion of Subjects With Remission at Month 6 [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.

Secondary Outcome Measures

1. Proportion of Subjects in Clinical Remission at Month 2, 4, and 6 [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.

2. Time to Relapse [Time from randomization to the day of withdrawal due to escalation of therapy (up to 6 months)]

   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.

3. 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 [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.

4. Change From Baseline in Serum C-reactive Protein (CRP) Levels at Month 2, 4, and 6 [Baseline, 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.

5. Change From Baseline in Fecal Calprotectin Levels at Month 2, 4, and 6 [Baseline, 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.

6. Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Scores at Months 2, 4, and 6 [Baseline, Month 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.

7. Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up to Month 6]

   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.

8. Severity of Adverse Events [Up to Month 6]

   The number of subjects with intensity of AEs (classified as mild, moderate or severe) were presented. Data is presented cumulative for all pathways.

9. Proportion of Subjects With Markedly Abnormal Laboratory Values: Hematology [Baseline, Month 6]

   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.

10. Proportion of Subjects With Markedly Abnormal Laboratory Values: Coagulation [Baseline, Month 6]

    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.

11. Proportion of Subjects With Markedly Abnormal Laboratory Values: Serum Chemistry [Baseline, Month 6]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Preferred Research Partners	Little Rock	Arkansas	United States
2	United Research Institute	Murrieta	California	United States
3	Research Associates of South Florida, LLC	Miami	Florida	United States
4	IMIC	Palmetto Bay	Florida	United States
5	Medical Research Center of Florida	Pembroke Pines	Florida	United States
6	Lenus Research and Medical Group	Sweetwater	Florida	United States
7	Clinical Trials of SWLA, LLC	Lake Charles	Louisiana	United States
8	Cumberland Research Associates, LLC	Fayetteville	North Carolina	United States
9	Wilmington Gastroenterology Associates	Wilmington	North Carolina	United States
10	Associates in Gastroenterology, PLC	Hermitage	Tennessee	United States
11	Quality Medical Research, PLLC	Nashville	Tennessee	United States
12	BI Research Center	Houston	Texas	United States
13	Biopharma Informatic Inc.	Houston	Texas	United States
14	Digestive Health Center	Pasadena	Texas	United States
15	DM Clinical Research	Tomball	Texas	United States
16	Advanced Research Institute	Ogden	Utah	United States
17	New River Valley Research Institute	Christiansburg	Virginia	United States
18	Digestive & Liver Disease Specialists	Norfolk	Virginia	United States
19	Multiprofile Hospital For Active Treatment Avis Medica	Pleven		Bulgaria
20	University Multiprofile Hospital for Active Treatment Kaspela	Plovdiv		Bulgaria
21	Medical Center Excelsior OOD	Sevlievo		Bulgaria
22	Medical Center-1-Sevlievo EOOD	Sevlievo		Bulgaria
23	City Clinic University Multiprofile Hospital for Active Treatment EOOD	Sofia		Bulgaria
24	Medical Center Asklepion - Humane Medicine Research EOOD	Sofia		Bulgaria
25	University Multiprofile Hospital for Active Treatment Sv Ivan Rilski EAD	Sofia		Bulgaria
26	University Multiprofile Hospital for Active Treatment Tsaritsa Yoanna - ISUL EAD	Sofia		Bulgaria
27	Diagnostic Consultative Centre Mladost M OOD	Varna		Bulgaria
28	Topstone Research Institute	Ottawa	Ontario	Canada
29	Toronto Digestive Disease Associates Inc	Toronto	Vaughan	Canada
30	Magyar Honvédség Egészségügyi Központ	Budapest		Hungary
31	Pannónia Magánorvosi Centrum Kft	Budapest		Hungary
32	Semmelweis Egyetem Institute	Budapest		Hungary
33	Vasútegészségügyi Nonprofit Kiemelten Közhasznú Kft. Debreceni Egészségügyi Központja	Debrecen		Hungary
34	ENDOMEDIX Kft.	Miskolc		Hungary
35	Karolina Korhaz Rendelointezet	Mosonmagyarovar		Hungary
36	Clinfan Kft.	Szekszard		Hungary
37	Polana-D, LTD	Daugavpils		Latvia
38	Digestive Diseases Centre Gastro	Riga		Latvia
39	Latvian Maritime Medicine Centre	Riga		Latvia
40	Pauls Stradins Clinical University Hospital	Riga		Latvia
41	Riga East Clinical University Hospital	Riga		Latvia
42	ICARO Investigaciones en Medicina, S.A de C.V	Chihuahua		Mexico
43	Maria Auxiliadora Hospital	Guadalajara		Mexico
44	Investigación Biomédica para el Desarrollo de Fármacos, S.A. de C.V.	Zapopan		Mexico
45	Osrodek Medycyny Rodzinnej Sp. z o.o.	Sobótka	Dolnoslaskie	Poland
46	Lexmedica	Wroclaw	Dolnoslaskie	Poland
47	Zespół Przychodni Specjalistycznych PRIMA Sp. z o.o.	Warszawa	Mazowieckie	Poland
48	Uniwersytecki Szpital Kliniczny w Bialymstoku	Bialystok	Podlaskie	Poland
49	Centrum Badan Klinicznych PI-House sp. z o.o.	Gdansk	Pomorskie	Poland
50	Niepubliczny Zaklad Opieki Zdrowotnej Intermed	Czestochowa		Poland
51	Economicus - NZOZ ALL-MEDICUS	Katowice		Poland
52	Investigational site	Ksawerow		Poland
53	Niepubliczny Zaklad Opieki Zdrowotnej CENTRUM MEDYCZNE Szpital Swietej Rodziny	Lodz		Poland
54	SPZOZ Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego Uniwersytetu Medycznego w Lodzi	Lodz		Poland
55	Endoskopia Sp. z o.o.	Sopot		Poland
56	Instytut Pomnik Centrum Zdrowia Dziecka	Warsaw		Poland
57	Regional Clinical Hospital	Krasnoyarsk		Russian Federation
58	City Clinical Hospital # 51	Moscow		Russian Federation
59	Nizhegorodskaya Regional Clinical Hospital n.a. Semashko	Nizhny Novgorod		Russian Federation
60	Novosibirsk State Medical University	Novosibirsk		Russian Federation
61	Research Institute of Physiology of Sibirian Branch the RAMS	Novosibirsk		Russian Federation
62	Omsk State Medical Academy	Omsk		Russian Federation
63	Rostov State Medical University	Rostov-on-Don		Russian Federation
64	Ryazan Regional Clinical Hospital	Ryazan		Russian Federation
65	State Budget Institution of Ryazan region" Regional Clinical Hospital"	Ryazan		Russian Federation
66	City Hospital #31	Saint Petersburg		Russian Federation
67	Russian Medical Military Academy n.a. S.M. Kirov	Saint Petersburg		Russian Federation
68	Medical Company "Hepatolog", LLC	Samara		Russian Federation
69	City Polyclinic #38	St. Petersburg		Russian Federation
70	Stavropol State Medical Academy	Stavropol		Russian Federation
71	Clinical Hospital Centar Zvezdara	Belgrade		Serbia
72	Clinical Hospital Center Bezanijska Kosa	Belgrade		Serbia
73	Health Center Valjevo	Valjevo		Serbia
74	Inselspital Bern	Bern		Switzerland
75	Investigational site	Bern		Switzerland
76	Universitätsspital Zürich	Zürich		Switzerland
77	Kyiv Municipal Clinical Hospital #18	Kyiv	Kyïv	Ukraine
78	Medical Center LLC Ukrainian German Antiulcer Gastroenterology Center BIK Kyiv	Kyiv	Kyïv	Ukraine
79	Regional Municipal Institution Chernivtsi Regional Clinical Hospital	Chernivtsi		Ukraine
80	Municipal Institution Dnipropetrovsk Regional Clinical Hospital n.a. I.I. Mechnykov	Dnipropetrovsk		Ukraine
81	Municipal Healthcare Institution Kharkiv City Clinical Hospital #2	Kharkiv		Ukraine
82	SI National Institute of Therapy n.a. L.T. Mala of National Academy of Medical Sciences of Ukraine	Kharkiv		Ukraine
83	Municipal Intitution "Kherson City Clinical Hospital n.a. A. and O. Tropinykh"	Kherson		Ukraine
84	Private Enterprise Private Manufactire Company "Acinus"	Kirovohrad		Ukraine
85	Kremenchuk city Hospital # n.a O.T.Bohaievskyi	Kremenchuk		Ukraine
86	Kyiv City Clinical Hospital #8	Kyiv		Ukraine
87	Kyiv Municipal Clinical Hospital #18	Kyiv		Ukraine
88	Medical Center Universal Clinic Oberih of LLC Kapytal	Kyiv		Ukraine
89	Municipal City Clinical emergency Hospital	Lviv		Ukraine
90	Municipal Institution Odesa Regional Clinical Hospital	Odesa		Ukraine
91	Medical Clinical Research Center of Medical Center LLC Health Clinic	Vinnytsia		Ukraine
92	Vinnytsia Regional Clinical Hospital Hospital n.a. M.I. Pyrohov	Vinnytsia		Ukraine
93	Small Business Private Enterprise Medical Center "Pulse"	Vinnytsya		Ukraine
94	Municipal Institution 6th City Clinical Hospital of Zaporizhzhia City Council	Zaporizhzhia		Ukraine
95	Municipal Institution Zaporizhzhia Regional Clinical Hospital of Zaporizhzhia Regional Council	Zaporizhzhia		Ukraine
96	Medical Centre of PE First Private Clinic	Zhytomyr		Ukraine

Sponsors and Collaborators

• Ferring Pharmaceuticals

Investigators

• Study Director: Global Clinical Compliance, Ferring Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Jan 17, 2017
• Statistical Analysis Plan - Apr 2, 2018

More Information

Publications

None provided.

• Responsible Party: Ferring Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02522780
• Other Study ID Numbers: 000175; 2015-002558-11
• First Posted: Aug 13, 2015
• Last Update Posted: Nov 8, 2021
• Last Verified: Sep 1, 2019

• Additional relevant MeSH terms: Colitis; Colitis, Ulcerative; Ulcer; Mesalamine

Study Results

Participant Flow

Recruitment Details	A total of 50 sites in 10 countries randomized subjects to this trial between February 2016 to April 2018, the last subject completed last visit in September 2018. Of 403 subjects screened, 276 subjects were randomized in a 1:1 ratio to either mesalamine or placebo group (138 subjects each), for 6 months.
Pre-assignment Detail	Of 276 subjects, (a) 53 were rolled-over from Trial 000174 (NCT02522767) who achieved remission after 8-weeks double-blind treatment with placebo (Pathway 1a; 4 subjects) or mesalamine (Pathway 1b; 10 subjects), or an additional 8-weeks open-label treatment with mesalamine (Pathway 2; 39 subjects), and (b) 223 subjects were de novo (Pathway 3).

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally once daily (QD) for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Period Title: Overall Study
STARTED	138	138
Treated	137	135
Intention-to-treat (ITT) Population	136	136
COMPLETED	121	111
NOT COMPLETED	17	27

Baseline Characteristics

Arm/Group Title	Mesalamine	Placebo	Total
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.	Total of all reporting groups
Overall Participants	136	136	272
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	130 95.6%	126 92.6%	256 94.1%
>=65 years	6 4.4%	10 7.4%	16 5.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.5 (13.50)	45.2 (13.65)	43.4 (13.67)
Sex: Female, Male (Count of Participants)
Female	70 51.5%	77 56.6%	147 54%
Male	66 48.5%	59 43.4%	125 46%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 4.4%	9 6.6%	15 5.5%
Not Hispanic or Latino	130 95.6%	127 93.4%	257 94.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	4 2.9%	4 2.9%	8 2.9%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 1.5%	1 0.7%	3 1.1%
White	130 95.6%	130 95.6%	260 95.6%
More than one race	0 0%	1 0.7%	1 0.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	24.56 (4.812)	24.89 (4.657)	24.73 (4.729)

Outcome Measures

1. Primary Outcome

Title	Proportion of Subjects With Remission at Month 6
Description	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.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized subjects who were assigned to mesalamine 4 g extended release granules in Trial 000174 (NCT02522767) (Pathway 1b) or randomized via Pathways 2 or 3.

Arm/Group Title	Mesalamine	Placebo.
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Measure Participants	136	136
Count of Participants [Participants]	82 60.3%	67 49.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo.
	Comments	Proportions were compared between treatment groups at Month 6.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	The p-value was based on Cochran-Mantel-Haenszel test by controlling pathway of randomization, at a 0.05 significance level.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.57
	Confidence Interval	(2-Sided) 95%; 0.96 to 2.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Proportion of Subjects in Clinical Remission at Month 2, 4, and 6
Description	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.
Time Frame	Month 2, 4, and 6

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized subjects who were assigned to mesalamine 4 g extended release granules in Trial 000174 (NCT02522767) (Pathway 1b) or randomized via Pathways 2 or 3.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Measure Participants	136	136
Month 2	122 89.7%	116 85.3%
Month 4	113 83.1%	113 83.1%
Month 6	96 70.6%	89 65.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo.
	Comments	Proportions were compared between treatment groups over 6 months.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	The p-value was based on Generalized estimating equations (GEE) approach with binary outcomes (clinical remission) and an unstructured working correlation matrix, at a 0.05 significance level.
	Method	Generalised estimating equation approach
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95%; 0.76 to 2.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Time to Relapse
Description	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 Frame	Time from randomization to the day of withdrawal due to escalation of therapy (up to 6 months)

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized subjects who were assigned to mesalamine 4 g extended release granules in Trial 000174 (NCT02522767) (Pathway 1b) or randomized via Pathways 2 or 3.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Measure Participants	136	136
Median (95% Confidence Interval) [days]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo.
	Comments	Times to relapse were compared between treatment groups up to 6 months.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	The p-value was based on log-rank test using pathway of randomization as the stratification factor, at a 0.05 significance level.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; 0.25 to 1.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	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
Description	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.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized subjects who were assigned to mesalamine 4 g extended release granules in Trial 000174 (NCT02522767) (Pathway 1b) or randomized via Pathways 2 or 3.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Measure Participants	136	136
Count of Participants [Participants]	14 10.3%	30 22.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo.
	Comments	Proportions were compared between treatment groups at Month 6.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	The p-value was based on Cochran-Mantel-Haenszel test by controlling pathway of randomization, at a 0.05 significance level.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; 0.19 to 0.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Serum C-reactive Protein (CRP) Levels at Month 2, 4, and 6
Description	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.
Time Frame	Baseline, Month 2, 4, and 6

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized subjects who were assigned to mesalamine 4 g extended release granules in Trial 000174 (NCT02522767) (Pathway 1b) or randomized via Pathways 2 or 3.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Measure Participants	136	136
Month 2	0.8 (4.76)	2.2 (15.63)
Month 4	1.0 (5.69)	0.9 (5.53)
Month 6	0.8 (3.67)	2.5 (16.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo.
	Comments	Adjusted mean treatment difference in CRP levels over 6 months was reported.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	The p-value was based on a repeated-measures analysis of covariance (ANCOVA) model with an unstructured correlation matrix , at a 0.05 significance level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -2.7 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Fecal Calprotectin Levels at Month 2, 4, and 6
Description	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.
Time Frame	Baseline, Month 2, 4, and 6

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized subjects who were assigned to mesalamine 4 g extended release granules in Trial 000174 (NCT02522767) (Pathway 1b) or randomized via Pathways 2 or 3.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Measure Participants	136	136
Month 2	-94.8 (553.00)	12.8 (509.70)
Month 4	-41.7 (533.02)	53.6 (581.64)
Month 6	-43.5 (553.13)	36.4 (559.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo.
	Comments	Adjusted mean treatment difference in fecal calprotectin levels over 6 months was reported.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	The p-value was based on a repeated-measures ANCOVA model with an unstructured correlation matrix, at a 0.05 significance level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-66.92
	Confidence Interval	(2-Sided) 95%; -140.2 to 6.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Scores at Months 2, 4, and 6
Description	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.
Time Frame	Baseline, Month 2, 4, and 6

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized subjects who were assigned to mesalamine 4 g extended release granules in Trial 000174 (NCT02522767) (Pathway 1b) or randomized via Pathways 2 or 3.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Measure Participants	136	136
Month 2	-1.3 (17.78)	-0.4 (20.00)
Month 4	-0.6 (20.40)	-0.3 (18.53)
Month 6	-0.5 (24.80)	-1.2 (23.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo.
	Comments	Adjusted mean treatment difference in IBDQ total scores over 6 months was reported.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	The p-value was based on a repeated-measures ANCOVA model with an unstructured correlation matrix, at a 0.05 significance level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -4.41 to 3.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	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.
Time Frame	Up to Month 6

Outcome Measure Data

Analysis Population Description

The analysis was based on safety analysis set which included all subjects who received at least 1 dose of IMP.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Measure Participants	137	135
Any Treatment-Emergent AEs	42 30.9%	49 36%
Treatment-Emergent SAEs	2 1.5%	3 2.2%

9. Secondary Outcome

Title	Severity of Adverse Events
Description	The number of subjects with intensity of AEs (classified as mild, moderate or severe) were presented. Data is presented cumulative for all pathways.
Time Frame	Up to Month 6

Outcome Measure Data

Analysis Population Description

The analysis was based on safety analysis set.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Measure Participants	137	135
Mild	32 23.5%	32 23.5%
Moderate	18 13.2%	22 16.2%
Severe	2 1.5%	3 2.2%

10. Secondary Outcome

Title	Proportion of Subjects With Markedly Abnormal Laboratory Values: Hematology
Description	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.
Time Frame	Baseline, Month 6

Outcome Measure Data

Analysis Population Description

The analysis was based on safety analysis set. Here, 'Number Analyzed' signifies number of subjects with available data at specified category for each arm, respectively.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Measure Participants	137	135
Basophils/Leukocytes: >=5%	0 0%	1 0.7%
Eosinophils/Leukocytes: >=10%	3 2.2%	7 5.1%
Erythrocytes: <=3.5*10^6/μL	2 1.5%	1 0.7%
Hematocrit: <=0.32%	1 0.7%	0 0%
Hematocrit: >=0.56%	8 5.9%	12 8.8%
Hemoglobin: <=11.5 g/dL	29 21.3%	23 16.9%
Leukocytes: <=2.8*10^3/μL	4 2.9%	4 2.9%
Leukocytes: >=16.0*10^3/μL	2 1.5%	0 0%
Lymphocytes/Leukocytes: <=10%	3 2.2%	4 2.9%
Lymphocytes/Leukocytes: >=80%	0 0%	0 0%
Monocytes/Leukocytes: >=20%	0 0%	1 0.7%
Neutrophils/Leukocytes: <=15%	0 0%	0 0%
Neutrophils/Leukocytes: >=90%	0 0%	0 0%
Platelets: <=75*10^3/μL	0 0%	0 0%
Platelets: >=700*10^3/μL	1 0.7%	0 0%

11. Secondary Outcome

Title	Proportion of Subjects With Markedly Abnormal Laboratory Values: Coagulation
Description	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.
Time Frame	Baseline, Month 6

Outcome Measure Data

Analysis Population Description

The analysis was based on safety analysis set. Here, 'Number Analyzed' signifies number of subjects with available data at specified category for each arm, respectively.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Measure Participants	137	135
aPTT: >70 sec	0 0%	0 0%
Prothrombin INR: <0.8	0 0%	2 1.5%
Prothrombin INR: >1.1	46 33.8%	54 39.7%

12. Secondary Outcome

Title	Proportion of Subjects With Markedly Abnormal Laboratory Values: Serum Chemistry
Description	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.
Time Frame	Baseline, Month 6

Outcome Measure Data

Analysis Population Description

The analysis was based on safety analysis set. Here, 'Number Analyzed' signifies number of subjects with available data at specified category for each arm, respectively.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.	Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
Measure Participants	137	135
ALT: >3*ULN	1 0.7%	1 0.7%
ALP: >3*ULN & 25% inc from BL	0 0%	0 0%
AST: >3*ULN	2 1.5%	2 1.5%
Bilirubin: >=1.5*ULN	8 5.9%	5 3.7%
Blood Urea Nitrogen: >=10.7 mg/dL	8 5.9%	11 8.1%
Calcium: <=1.8 mg/dL	0 0%	0 0%
Calcium: >=3.9 mg/dL	9 6.6%	12 8.8%
Chloride: <=90 mmol/L	0 0%	0 0%
Chloride: >=115 mmol/L	0 0%	0 0%
Creatinine: >=177 mg/dL	0 0%	0 0%
Gamma Glutamyl Transferase: >3*ULN	6 4.4%	4 2.9%
GFR: <30 mL/min	0 0%	0 0%
Glucose: <=2.8 mg/dL	0 0%	0 0%
Glucose: >=10 mg/dL	11 8.1%	14 10.3%
Potassium: <=3.0 mmol/L	0 0%	0 0%
Potassium: >=5.8 mmol/L	0 0%	2 1.5%
Sodium: <=130 mmol/L	0 0%	0 0%
Sodium: >=155 mmol/L	0 0%	0 0%

Adverse Events

Time Frame	Up to Month 6
Adverse Event Reporting Description	Treatment-Emergent AEs were defined as AEs which occurred in the time interval from initial dosing (IMP intake) to the end of treatment visit.
Arm/Group Title	Mesalamine		Placebo
Arm/Group Description	Mesalamine 2 g extended release granules (sachet), administered orally QD for 6 months.		Placebo matched to mesalamine extended release granules (sachet), administered orally QD for 6 months.
All Cause Mortality
	Mesalamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/137 (0%)		0/135 (0%)
Serious Adverse Events
	Mesalamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/137 (1.5%)		3/135 (2.2%)
Cardiac disorders
Acute myocardial infarction	1/137 (0.7%)		0/135 (0%)
Gastrointestinal disorders
Colitis ulcerative	0/137 (0%)		1/135 (0.7%)
Infections and infestations
Ecthyma	0/137 (0%)		1/135 (0.7%)
Pneumonia	0/137 (0%)		1/135 (0.7%)
Sepsis	0/137 (0%)		1/135 (0.7%)
Vascular disorders
Hypertension	1/137 (0.7%)		0/135 (0%)
Other (Not Including Serious) Adverse Events
	Mesalamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/137 (16.8%)		28/135 (20.7%)
Gastrointestinal disorders
Colitis ulcerative	14/137 (10.2%)		20/135 (14.8%)
Infections and infestations
Respiratory tract infection viral	3/137 (2.2%)		1/135 (0.7%)
Investigations
Glomerular filtration rate decreased	1/137 (0.7%)		5/135 (3.7%)
Alanine aminotransferase increased	4/137 (2.9%)		1/135 (0.7%)
Gamma-glutamyltransferase increased	4/137 (2.9%)		1/135 (0.7%)
Faecal calprotectin increased	3/137 (2.2%)		1/135 (0.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review the draft manuscript prior to publication and can request delay of publication where any contents are deemed patentable by the sponsor or confidential to the sponsor. Comments will be given within four weeks from receipt of the draft manuscript. Additional time may be required to allow Ferring to seek patent protection of the invention.