Mesalamine 4 g Sachet for the Induction of Remission in Active, Mild to Moderate Ulcerative Colitis (UC)

• Sponsor: Ferring Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02522767
• Collaborator: (none)
• Enrollment: 228
• Locations: 93
• Arms: 2
• Actual Duration (Months): 30.1
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this trial is to investigate the efficacy of mesalamine for the induction of clinical and endoscopic remission in subjects with active, mild to moderate UC. Subject will receive 4 g extended release granules (sachet) once daily.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 228 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 4 g Extended Release Granules (Sachet) for the Induction of Clinical and Endoscopic Remission in Active, Mild to Moderate Ulcerative Colitis
• Actual Study Start Date: Oct 1, 2015
• Actual Primary Completion Date: Feb 6, 2018
• Actual Study Completion Date: Apr 3, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mesalamine 4 g extended release granules (sachet)	Drug: Mesalamine; Other Names: Mesalazine Pentasa
Placebo Comparator: Placebo Matching placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Proportion of Subjects With Remission [At Week 8]

   The proportion of subjects with remission was defined by the Clinical and Endoscopic Response Score: 0 for rectal bleeding; 0 or 1 with at least 1 point decrease from baseline for stool frequency; 0 or 1 for endoscopic score. The Clinical and Endoscopic Response Score ranged between 0-9, higher scores indicating greater disease severity. This score had two components: Clinical Response which assessed subject's symptoms and ranged between 0-6, and Endoscopic Response which assessed objective evidence of inflammation and ranged between 0-3. Further, the Clinical Response component included two subscales: stool frequency and rectal bleeding (each ranged between 0-3 each) obtained from subjects' daily records. The Endoscopic Response component had one subscale: flexible sigmoidoscopy/colonoscopy (ranging between 0-3).

Secondary Outcome Measures

1. Proportion of Subjects With Remission in the Primary Endpoint and the Physician's Global Assessment (PGA) Score of ≤1 (Modified Mayo Score) [At Week 8]

   The Modified Mayo score was calculated as the sum of the Clinical and Endoscopic Response Score (Range: 0-9, and the standard PGA score (range: 0-3; normal [score=0], mild disease [score=1], moderate disease [score=2], severe disease [score=3]). The statistical test was to be conducted only if the primary analysis was significant.

2. Time to Cessation of Rectal Bleeding [Up to Week 8]

   Defined as time in days from randomization to the first day of 3 consecutive days with a rectal bleeding score of 0, based on subject's daily diary. The statistical test was to be conducted only if the primary analysis was significant.

3. The Proportion of Subjects With Endoscopic Improvement [At Week 8]

   Defined as an Endoscopic Response Score of 0 or 1, with at least a 1 point reduction from baseline in the endoscopic score at Week 8.

4. The Proportion of Subjects in Clinical Remission at Weeks 2, 4, and 8 [At Week 2, 4, and 8]

   Defined as a score of 0 for rectal bleeding and 0 or 1 with at least 1 point decrease from baseline for stool frequency in the Clinical Response Score subset.

5. Time to Normal Stool Pattern [Up to Week 8]

   Defined as time in days from randomization to the first day of 3 consecutive days with a stool frequency score of 0, based on subject daily diary.

6. The Change From Baseline in Rectal Bleeding Score at Weeks 2, 4, and 8 [From baseline to Week 2, 4, and 8]

   Defined as change from baseline in rectal bleeding score at Week 2, 4, and 8 based on subject daily diary. Rectal Bleeding Score is graded 0-3, where 0 is best.

7. The Change From Baseline in Serum C-reactive Protein (CRP) Levels at Weeks 2, 4, and 8 [From baseline to Week 2, 4, and 8]

   The adjusted mean changes in serum CRP levels from baseline and their difference between treatment groups are presented for each time point.

8. The Change From Baseline in Fecal Calprotectin Levels at Week 8 [From baseline to Week 8]

   The adjusted mean change from baseline in fecal calprotectin levels at Week 8 are presented.

9. The Change From Baseline in Health Related Quality of Life (QoL) Scores [From baseline to Week 2, 4, and 8]

   The change from baseline to Week 2, 4, and 8 in Inflammatory Bowel Disease Questionnaire (IBDQ) scores. The adjusted changes from baseline and their differences between treatment groups are presented. The IBDQ is an instrument used to assess quality of life in adult patients with UC. Subjects were asked to recall symptoms and QoL from last two weeks and to rate each item on a 7- point Likert score (higher scores equate to higher QoL).

10. Number of Participants Experiencing Adverse Events [Up to Week 16]

    An adverse event (AE) is defined as any untoward medical occurrence in a subject taking part in a clinical trial. A 'treatment-emergent AE (TEAE)' is defined as an AE which occurs in the time interval from initial dosing (investigational medicinal product [IMP] intake) to the end of treatment visit. Proportion of subjects with any TEAE (serious or non-serious) are presented.

11. Severity of Adverse Events [Up to Week 16]

    The proportion of subjects with intensity of AEs (classified as mild, moderate or severe) are presented.

12. Proportion of Subject With Abnormal Laboratory Values (Hematology) [Up to Week 16]

    Proportion of subjects with markedly abnormal changes from baseline in hematology values are presented. >= greater than equal to; <= less than equal to.

13. Proportion of Subjects With Abnormal Laboratory Values (Coagulation) [Up to Week 16]

    Proportion of subjects with markedly abnormal changes from baseline values in coagulation laboratory values are presented. INR= International normalized ratio.

14. Proportion of Subjects With Abnormal Laboratory Values (Serum Chemistry) [Up to Week 16]

    Proportion of subjects with markedly abnormal changes in serum chemistry laboratory values are presented. ALT= Alanine aminotransferase; AST= Aspartate aminotransferase; BUN= Blood urea nitrogen; GGT= Gamma glutamyl transferase.

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

• Mild to moderate UC

Exclusion Criteria:

• Disease limited to proctitis <15 cm

• Short bowel syndrome

• Prior colon resection surgery

• History of severe/fulminant UC

• Evidence of other forms of inflammatory bowel disease

• Infectious disease (including human immunodeficiency virus [HIV], hepatitis B virus [HBV], or hepatitis C virus [HCV])

• 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 or 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	37076
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	Medical Center Excelsior OOD	Sevlievo		Bulgaria
21	Medical Center-1-Sevlievo EOOD	Sevlievo		Bulgaria
22	City Clinic University Multiprofile Hospital for Active Treatment EOOD	Sofia		Bulgaria
23	Medical Center Asklepion - Humane Medicine Research EOOD	Sofia		Bulgaria
24	University Multiprofile Hospital for Active Treatment Sv Ivan Rilski EAD	Sofia		Bulgaria
25	University Multiprofile Hospital for Active Treatment Tsaritsa Yoanna - ISUL EAD	Sofia		Bulgaria
26	Diagnostic Consultative Centre Mladost M OOD	Varna		Bulgaria
27	Topstone Research Institute	Ottawa	Ontario	Canada
28	Toronto Digestive Disease Associates	Vaughan		Canada
29	Magyar Honvédség Egészségügyi Központ	Budapest		Hungary
30	Pannónia Magánorvosi Centrum Kft	Budapest		Hungary
31	Semmelweis Egyetem Institute	Budapest		Hungary
32	Vasútegészségügyi Nonprofit Kiemelten Közhasznú Kft. Debreceni Egészségügyi Központja	Debrecen		Hungary
33	ENDOMEDIX Kft.	Miskolc		Hungary
34	Karolina Korhaz Rendelointezet	Mosonmagyarovar		Hungary
35	Clinfan Kft.	Szekszard		Hungary
36	Polana-D, LTD	Daugavpils		Latvia
37	Digestive Diseases Centre Gastro	Riga		Latvia
38	Latvian Maritime Medicine Centre	Riga		Latvia
39	Pauls Stradins Clinical University Hospital	Riga		Latvia
40	Riga East Clinical University Hospital	Riga		Latvia
41	ICARO Investigaciones en Medicina, S.A de C.V	Chihuahua		Mexico
42	Maria Auxiliadora Hospital	Guadalajara		Mexico
43	Investigación Biomédica para el Desarrollo de Fármacos, S.A. de C.V.	Zapopan		Mexico
44	Osrodek Medycyny Rodzinnej Sp. z o.o.	Sobótka	Dolnoslaskie	Poland
45	Lexmedica	Wroclaw	Dolnoslaskie	Poland
46	Zespół Przychodni Specjalistycznych PRIMA Sp. z o.o.	Warszawa	Mazowieckie	Poland
47	Uniwersytecki Szpital Kliniczny w Bialymstoku	Bialystok	Podlaskie	Poland
48	Centrum Badan Klinicznych PI-House sp. z o.o.	Gdansk	Pomorskie	Poland
49	Niepubliczny Zaklad Opieki Zdrowotnej Intermed	Czestochowa		Poland
50	Economicus - NZOZ ALL-MEDICUS	Katowice		Poland
51	Investigational site	Ksawerow		Poland
52	Niepubliczny Zaklad Opieki Zdrowotnej CENTRUM MEDYCZNE Szpital Swietej Rodziny	Lodz		Poland
53	SPZOZ Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego Uniwersytetu Medycznego w Lodzi	Lodz		Poland
54	Investigational site	Sopot		Poland
55	Centrum Zdrowia Matki, Dziecka i Mlodziezy	Warsaw		Poland
56	Regional Clinical Hospital	Krasnoyarsk		Russian Federation
57	City Clinical Hospital #51	Moscow		Russian Federation
58	Nizhegorodskaya Regional Clinical Hospital n.a. Semashko	Nizhny Novgorod		Russian Federation
59	Novosibirsk State Medical University	Novosibirsk		Russian Federation
60	Research Institute of Physiology of Sibirian Branch the RAMS	Novosibirsk		Russian Federation
61	Omsk State Medical Academy	Omsk		Russian Federation
62	Rostov State Medical University	Rostov-on-Don		Russian Federation
63	State Budget Institution of Ryazan region" Regional Clinical Hospital"	Ryazan		Russian Federation
64	City Hospital #31	Saint Petersburg		Russian Federation
65	Russian Medical Military Academy n.a. S.M. Kirov	Saint Petersburg		Russian Federation
66	Railway Clinical Hospital at Station Samara OAO Rzhd	Samara		Russian Federation
67	City Polyclinic #38	St. Petersburg		Russian Federation
68	Stavropol State Medical Academy	Stavropol		Russian Federation
69	Clinical Hospital Centar Zvezdara	Belgrade		Serbia
70	Health Center Valjevo	Valjevo		Serbia
71	Inselspital Bern	Bern		Switzerland
72	Investigational site	Bern		Switzerland
73	Universitätsspital Zürich	Zürich		Switzerland
74	Kyiv Municipal Clinical Hospital #18	Kyiv	Kyïv	Ukraine
75	Medical Center LLC Ukrainian German Antiulcer Gastroenterology Center BIK Kyiv	Kyiv	Kyïv	Ukraine
76	Regional Municipal Institution Chernivtsi Regional Clinical Hospital	Chernivtsi		Ukraine
77	Municipal Institution Dnipropetrovsk Regional Clinical Hospital n.a. I.I. Mechnykov	Dnipropetrovsk		Ukraine
78	Municipal Healthcare Institution Kharkiv City Clinical Hospital #2	Kharkiv		Ukraine
79	SI National Institute of Therapy n.a. L.T. Mala of National Academy of Medical Sciences of Ukraine	Kharkiv		Ukraine
80	Municipal Intitution "Kherson City Clinical Hospital n.a. A. and O. Tropinykh"	Kherson		Ukraine
81	Private Enterprise Private Manufactire Company "Acinus".	Kirovohrad		Ukraine
82	Kremenchuk city Hospital # n.a O.T.Bohaievskyi	Kremenchuk		Ukraine
83	Kyiv City Clinical Hospital #8	Kyiv		Ukraine
84	Kyiv Municipal Clinical Hospital #18	Kyiv		Ukraine
85	Medical Center Universal Clinic Oberih of LLC Kapytal	Kyiv		Ukraine
86	Municipal City Clinical emergency Hospital	Lviv		Ukraine
87	Municipal Institution Odesa Regional Clinical Hospital	Odesa		Ukraine
88	Medical Clinical Research Center of Medical Center LLC Health Clinic	Vinnytsia		Ukraine
89	Vinnytsia Regional Clinical Hospital Hospital n.a. M.I. Pyrohov	Vinnytsia		Ukraine
90	Small Business Private Enterprise Medical Center "Pulse"	Vinnytsya		Ukraine
91	Municipal Institution 6th City Clinical Hospital of Zaporizhzhia City Council	Zaporizhzhia		Ukraine
92	Municipal Institution Zaporizhzhia Regional Clinical Hospital of Zaporizhzhia Regional Council	Zaporizhzhia		Ukraine
93	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 11, 2017
• Statistical Analysis Plan - Apr 2, 2018

More Information

Publications

None provided.

• Responsible Party: Ferring Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02522767
• Other Study ID Numbers: 000174; 2015-002557-35
• First Posted: Aug 13, 2015
• Last Update Posted: Mar 15, 2021
• Last Verified: Feb 1, 2021

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

Study Results

Participant Flow

Recruitment Details	A total of 71 sites in 10 countries (Bulgaria, Canada, Hungary, Latvia, Mexico, Russia, Serbia, Switzerland, Ukraine, and United States) recruited subjects to this trial between October 2015 to November 2017, the last subject completed last visit in April 2018.
Pre-assignment Detail	A total of 411 subjects were screened, of which 228 subjects were randomized in a 1:1 ratio to either mesalamine or placebo group (114 subjects each), for 8 weeks double-blind treatment. Subjects who completed 8 weeks but failed to meet the defined criteria for remission received open-label treatment with mesalamine for additional 8 weeks.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 4 gram (g) extended release granules (sachet), administered orally once daily (QD)	Placebo 4 g to match mesalamine extended release granules, administered orally QD
Period Title: Double-blind
STARTED	114	114
COMPLETED	103	90
NOT COMPLETED	11	24
Period Title: Double-blind
STARTED	88	82
COMPLETED	83	75
NOT COMPLETED	5	7

Baseline Characteristics

Arm/Group Title	Mesalamine	Placebo	Total
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD	Total of all reporting groups
Overall Participants	114	114	228
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	107 93.9%	105 92.1%	212 93%
>=65 years	7 6.1%	9 7.9%	16 7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.2 (13.09)	43.9 (13.68)	42.5 (13.42)
Sex: Female, Male (Count of Participants)
Female	57 50%	64 56.1%	121 53.1%
Male	57 50%	50 43.9%	107 46.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 7.9%	9 7.9%	18 7.9%
Not Hispanic or Latino	105 92.1%	105 92.1%	210 92.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 2.6%	5 4.4%	8 3.5%
Asian	1 0.9%	2 1.8%	3 1.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 4.4%	4 3.5%	9 3.9%
White	105 92.1%	103 90.4%	208 91.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	24.68 (4.546)	24.63 (4.578)	24.66 (4.552)
Stool Frequency Score (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	1.6 (0.81)	1.8 (0.78)	1.7 (0.80)
Rectal Bleeding Score (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	1.2 (0.54)	1.2 (0.58)	1.2 (0.55)
Endoscopic Response Score (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	2.7 (0.47)	2.6 (0.48)	2.7 (0.47)

Outcome Measures

1. Primary Outcome

Title	Proportion of Subjects With Remission
Description	The proportion of subjects with remission was defined by the Clinical and Endoscopic Response Score: 0 for rectal bleeding; 0 or 1 with at least 1 point decrease from baseline for stool frequency; 0 or 1 for endoscopic score. The Clinical and Endoscopic Response Score ranged between 0-9, higher scores indicating greater disease severity. This score had two components: Clinical Response which assessed subject's symptoms and ranged between 0-6, and Endoscopic Response which assessed objective evidence of inflammation and ranged between 0-3. Further, the Clinical Response component included two subscales: stool frequency and rectal bleeding (each ranged between 0-3 each) obtained from subjects' daily records. The Endoscopic Response component had one subscale: flexible sigmoidoscopy/colonoscopy (ranging between 0-3).
Time Frame	At Week 8

Outcome Measure Data

Analysis Population Description

The ITT analysis set comprised all randomized subjects.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD
Measure Participants	114	114
Count of Participants [Participants]	19 16.7%	13 11.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo
	Comments	Proportions were compared between treatment groups, at a two-sided 0.05 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	The p-value was based on chi-square test without a continuity correction.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.55
	Confidence Interval	(2-Sided) 95%; 0.73 to 3.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Proportion of Subjects With Remission in the Primary Endpoint and the Physician's Global Assessment (PGA) Score of ≤1 (Modified Mayo Score)
Description	The Modified Mayo score was calculated as the sum of the Clinical and Endoscopic Response Score (Range: 0-9, and the standard PGA score (range: 0-3; normal [score=0], mild disease [score=1], moderate disease [score=2], severe disease [score=3]). The statistical test was to be conducted only if the primary analysis was significant.
Time Frame	At Week 8

Outcome Measure Data

Analysis Population Description

The ITT analysis set comprised all randomized subjects.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD
Measure Participants	114	114
Count of Participants [Participants]	19 16.7%	11 9.6%

3. Secondary Outcome

Title	Time to Cessation of Rectal Bleeding
Description	Defined as time in days from randomization to the first day of 3 consecutive days with a rectal bleeding score of 0, based on subject's daily diary. The statistical test was to be conducted only if the primary analysis was significant.
Time Frame	Up to Week 8

Outcome Measure Data

Analysis Population Description

The ITT analysis set comprised all randomized subjects.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD
Measure Participants	114	114
Median (95% Confidence Interval) [days]	18.0	43.0

4. Secondary Outcome

Title	The Proportion of Subjects With Endoscopic Improvement
Description	Defined as an Endoscopic Response Score of 0 or 1, with at least a 1 point reduction from baseline in the endoscopic score at Week 8.
Time Frame	At Week 8

Outcome Measure Data

Analysis Population Description

The ITT analysis set comprised randomized subjects.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD
Measure Participants	114	114
Count of Participants [Participants]	34 29.8%	22 19.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo
	Comments	Proportions were compared between treatment groups at a two-sided 0.05 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	The p-value was based on chi-square test without a continuity correction.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.78
	Confidence Interval	(2-Sided) 95%; 0.96 to 3.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	The Proportion of Subjects in Clinical Remission at Weeks 2, 4, and 8
Description	Defined as a score of 0 for rectal bleeding and 0 or 1 with at least 1 point decrease from baseline for stool frequency in the Clinical Response Score subset.
Time Frame	At Week 2, 4, and 8

Outcome Measure Data

Analysis Population Description

The ITT analysis comprised all randomized subjects.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD
Measure Participants	114	114
Week 2	19 16.7%	17 14.9%
Week 4	29 25.4%	26 22.8%
Week 8	40 35.1%	28 24.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo
	Comments	Proportions were compared between treatment groups over 8 weeks, at a two-sided 0.05 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Generalized estimating equation approach
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.30
	Confidence Interval	(2-Sided) 95%; 0.78 to 2.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Time to Normal Stool Pattern
Description	Defined as time in days from randomization to the first day of 3 consecutive days with a stool frequency score of 0, based on subject daily diary.
Time Frame	Up to Week 8

Outcome Measure Data

Analysis Population Description

The ITT analysis set comprised randomized subjects.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD
Measure Participants	114	114
Median (95% Confidence Interval) [days]	55.0	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo
	Comments	Times to normal stool pattern were compared between treatment groups, at a two-sided 0.05 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	The p-value was based on log-rank test.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; 0.91 to 2.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio and its 95% CI were obtained from Cox proportional hazards model with treatment group as a factor.

7. Secondary Outcome

Title	The Change From Baseline in Rectal Bleeding Score at Weeks 2, 4, and 8
Description	Defined as change from baseline in rectal bleeding score at Week 2, 4, and 8 based on subject daily diary. Rectal Bleeding Score is graded 0-3, where 0 is best.
Time Frame	From baseline to Week 2, 4, and 8

Outcome Measure Data

Analysis Population Description

The ITT analysis set comprised randomized subjects.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD
Measure Participants	114	114
Week 2	-0.39 (0.68)	-0.23 (0.84)
Week 4	-0.56 (0.72)	-0.34 (0.92)
Week 8	-0.64 (0.80)	-0.35 (0.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo
	Comments	Change from baseline scores were compared between treatment groups over 8 weeks, at a two-sided 0.05 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Repeated-measures ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.41 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	A repeated-measures ANCOVA model with an unstructured correlation matrix was used to calculate estimate.

8. Secondary Outcome

Title	The Change From Baseline in Serum C-reactive Protein (CRP) Levels at Weeks 2, 4, and 8
Description	The adjusted mean changes in serum CRP levels from baseline and their difference between treatment groups are presented for each time point.
Time Frame	From baseline to Week 2, 4, and 8

Outcome Measure Data

Analysis Population Description

The ITT analysis set comprise all randomized subjects.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD
Measure Participants	114	114
Week 2	0.60 (13.52)	0.25 (19.67)
Week 4	-0.86 (16.52)	-1.05 (16.27)
Week 8	-2.01 (13.09)	-0.73 (22.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo
	Comments	Change from baseline scores were compared between treatment groups over 8 weeks, at a two-sided 0.05 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Repeated-measures ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-2.39
	Confidence Interval	(2-Sided) 95%; -5.46 to 0.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	A repeated-measures ANCOVA model with an unstructured correlation matrix was used to calculate estimate.

9. Secondary Outcome

Title	The Change From Baseline in Fecal Calprotectin Levels at Week 8
Description	The adjusted mean change from baseline in fecal calprotectin levels at Week 8 are presented.
Time Frame	From baseline to Week 8

Outcome Measure Data

Analysis Population Description

The ITT analysis set comprised all randomized subjects.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD
Measure Participants	114	114
Mean (Standard Deviation) [ug/g]	-144.93 (854.41)	-119.56 (1083.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo
	Comments	Changes from baseline were compared between treatment groups, at a two-sided 0.05 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-289.69
	Confidence Interval	(2-Sided) 95%; -514.96 to -64.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	An ANCOVA model was used to calculate estimates.

10. Secondary Outcome

Title	The Change From Baseline in Health Related Quality of Life (QoL) Scores
Description	The change from baseline to Week 2, 4, and 8 in Inflammatory Bowel Disease Questionnaire (IBDQ) scores. The adjusted changes from baseline and their differences between treatment groups are presented. The IBDQ is an instrument used to assess quality of life in adult patients with UC. Subjects were asked to recall symptoms and QoL from last two weeks and to rate each item on a 7- point Likert score (higher scores equate to higher QoL).
Time Frame	From baseline to Week 2, 4, and 8

Outcome Measure Data

Analysis Population Description

The ITT analysis set comprised randomized subjects.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD
Measure Participants	114	114
Week 2	24.79 (25.92)	18.75 (33.87)
Week 4	33.58 (29.69)	28.13 (33.08)
Week 8	34.41 (37.23)	24.73 (36.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mesalamine, Placebo
	Comments	Change from baseline scores were compared between treatment groups over 8 weeks, at a two-sided 0.05 significance level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Repeated-measures ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	12.80
	Confidence Interval	(2-Sided) 95%; 5.10 to 20.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	A repeated-measures ANCOVA model with an unstructured correlation matrix was used to calculate estimates.

11. Secondary Outcome

Title	Number of Participants Experiencing Adverse Events
Description	An adverse event (AE) is defined as any untoward medical occurrence in a subject taking part in a clinical trial. A 'treatment-emergent AE (TEAE)' is defined as an AE which occurs in the time interval from initial dosing (investigational medicinal product [IMP] intake) to the end of treatment visit. Proportion of subjects with any TEAE (serious or non-serious) are presented.
Time Frame	Up to Week 16

Outcome Measure Data

Analysis Population Description

The safety analysis set comprised all subjects who received at least 1 dose of IMP, and was analyzed according to actual treatment received.

Arm/Group Title	Mesalamine	Placebo	Mesalamine (Open-Label)
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD	Mesalamine 4 g extended release granules (sachet), administered orally QD
Measure Participants	114	114	170
Any TEAE	28 24.6%	37 32.5%	31 13.6%
Serious AE	1 0.9%	0 0%	2 0.9%

12. Secondary Outcome

Title	Severity of Adverse Events
Description	The proportion of subjects with intensity of AEs (classified as mild, moderate or severe) are presented.
Time Frame	Up to Week 16

Outcome Measure Data

Analysis Population Description

The safety analysis set comprised all subjects who received at least 1 dose of IMP, and was analyzed according to actual treatment received.

Arm/Group Title	Mesalamine	Placebo	Mesalamine (Open-Label)
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD	Mesalamine 4 g extended release granules (sachet), administered orally QD
Measure Participants	114	114	170
Mild	23 20.2%	27 23.7%	21 9.2%
Moderate	6 5.3%	15 13.2%	11 4.8%
Severe	5 4.4%	3 2.6%	1 0.4%

13. Secondary Outcome

Title	Proportion of Subject With Abnormal Laboratory Values (Hematology)
Description	Proportion of subjects with markedly abnormal changes from baseline in hematology values are presented. >= greater than equal to; <= less than equal to.
Time Frame	Up to Week 16

Outcome Measure Data

Analysis Population Description

The safety analysis set comprised all subjects who received at least 1 dose of IMP, and was analyzed according to actual treatment received.

Arm/Group Title	Mesalamine	Placebo	Mesalamine (Open-Label)
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD	Mesalamine 4 g extended release granules (sachet), administered orally QD
Measure Participants	114	114	170
Eosinophils/Leukocytes (%), Normal>=10 to Abnormal	0 0%	2 1.8%	4 1.8%
Erythrocytes (10^6/uL), Low<=3.5 to Abnormal	2 1.8%	4 3.5%	4 1.8%
Erythrocytes (10^6/uL), Normal<=3.5 to Abnormal	1 0.9%	0 0%	2 0.9%
Hematocrit (%), Low<=0.32 to Abnormal	4 3.5%	1 0.9%	5 2.2%
Hematocrit (%), Normal<=0.32 to Abnormal	0 0%	3 2.6%	4 1.8%
Hematocrit (%), Normal>=0.56 to Abnormal	0 0%	1 0.9%	0 0%
Hemoglobin (g/dL), Low<=115 to Abnormal	21 18.4%	23 20.2%	37 16.2%
Hemoglobin (g/dL), Normal<=115 to Abnormal	12 10.5%	15 13.2%	29 12.7%
Leukocytes (10^3/uL), Normal <=2.8 to Abnormal	1 0.9%	0 0%	2 0.9%
Leukocytes (10^3/uL), Normal >=16.0 to Abnormal	0 0%	2 1.8%	2 0.9%
Leukocytes (10^3/uL), High >=16.0 to Abnormal	0 0%	1 0.9%	1 0.4%
Lymphocytes/Leukocytes (%), Low<=10 to Abnormal	0 0%	3 2.6%	1 0.4%
Lymphocytes/Leukocytes (%), Normal<=10 to Abnormal	4 3.5%	2 1.8%	6 2.6%
Lymphocytes/Leukocytes (%), High>=80 to Abnormal	1 0.9%	0 0%	1 0.4%
Neutrophils/Leukocyte (%), Normal<=15 to Abnormal	2 1.8%	0 0%	2 0.9%
Neutrophils/Leukocyte (%), Normal>=90 to Abnormal	0 0%	1 0.9%	2 0.9%
Neutrophils/Leukocyte (%), High >=90 to Abnormal	0 0%	1 0.9%	1 0.4%
Platelets (10^3/uL), High>=700 to Abnormal	2 1.8%	0 0%	2 0.9%

14. Secondary Outcome

Title	Proportion of Subjects With Abnormal Laboratory Values (Coagulation)
Description	Proportion of subjects with markedly abnormal changes from baseline values in coagulation laboratory values are presented. INR= International normalized ratio.
Time Frame	Up to Week 16

Outcome Measure Data

Analysis Population Description

The safety analysis set comprised all subjects who received at least 1 dose of IMP, and was analyzed according to actual treatment received.

Arm/Group Title	Mesalamine	Placebo	Mesalamine (Open-Label)
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD	Mesalamine 4 g extended release granules (sachet), administered orally QD
Measure Participants	114	114	170
Prothrombin INR, Normal <0.8 to Abnormal	0 0%	0 0%	1 0.4%
Prothrombin INR, Normal >1.1 to Abnormal	14 12.3%	14 12.3%	28 12.3%
Prothrombin INR, High >1.1 to Abnormal	4 3.5%	10 8.8%	22 9.6%

15. Secondary Outcome

Title	Proportion of Subjects With Abnormal Laboratory Values (Serum Chemistry)
Description	Proportion of subjects with markedly abnormal changes in serum chemistry laboratory values are presented. ALT= Alanine aminotransferase; AST= Aspartate aminotransferase; BUN= Blood urea nitrogen; GGT= Gamma glutamyl transferase.
Time Frame	Up to Week 16

Outcome Measure Data

Analysis Population Description

The safety analysis set comprised all subjects who received at least 1 dose of IMP, and was analyzed according to actual treatment received.

Arm/Group Title	Mesalamine	Placebo	Mesalamine (Open-Label)
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD	Placebo 4 g to match mesalamine extended release granules, administered orally QD	Mesalamine 4 g extended release granules (sachet), administered orally QD
Measure Participants	114	114	170
ALT (U/L), Normal >3xULN to Abnormal	1 0.9%	0 0%	2 0.9%
AST (U/L), Normal >3xULN to Abnormal	1 0.9%	0 0%	2 0.9%
AST (U/L), High >3xULN to Abnormal	0 0%	0 0%	1 0.4%
Bilirubin (mg/dL), Normal >=1.5xULN to Abnormal	1 0.9%	0 0%	1 0.4%
Bilirubin (mg/dL), High >=1.5xULN to Abnormal	2 1.8%	1 0.9%	4 1.8%
BUN (mg/dL), Normal >=10.7 to Abnormal	0 0%	1 0.9%	1 0.4%
Calcium (mg/dL), Normal <=1.8 to Abnormal	1 0.9%	0 0%	1 0.4%
Chloride (mmol/L), Normal >=115 to Abnormal	1 0.9%	0 0%	1 0.4%
Chloride (mmol/L), High >=115 to Abnormal	1 0.9%	0 0%	1 0.4%
GGT (U/L), High >3xULN to Abnormal	2 1.8%	2 1.8%	4 1.8%
Glucose (mg/dL), Normal >=10 to Abnormal	1 0.9%	1 0.9%	1 0.4%
Glucose (mg/dL), High >=10 to Abnormal	0 0%	2 1.8%	1 0.4%
Potassium (mmol/L), Normal <=3.0 to Abnormal	1 0.9%	0 0%	1 0.4%
Potassium (mmol/L), Normal >=5.8 to Abnormal	1 0.9%	0 0%	3 1.3%
Potassium (mmol/L), High >=5.8 to Abnormal	0 0%	0 0%	1 0.4%
Sodium (mmol/L), Low<=130 to Abnormal	0 0%	1 0.9%	0 0%

Adverse Events

Time Frame	TEAE occurred in the time interval from initial dosing (IMP intake) to the end of trial visit, up to 8 weeks for the Mesalamine and Placebo Arms and an additional 8 weeks for the Open-Label extension period.
Adverse Event Reporting Description	TEAEs were defined as AE which occurred in the time interval from initial dosing (IMP intake) to the end of treatment visit.
Arm/Group Title	Mesalamine		Placebo		Mesalamine (Open-Label)
Arm/Group Description	Mesalamine 4 g extended release granules (sachet), administered orally QD		Placebo 4 g to match mesalamine extended release granules, administered orally QD		Mesalamine 4 g extended release granules (sachet), administered orally QD
All Cause Mortality
	Mesalamine		Placebo		Mesalamine (Open-Label)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/114 (0%)		0/114 (0%)		0/170 (0%)
Serious Adverse Events
	Mesalamine		Placebo		Mesalamine (Open-Label)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/114 (0.9%)		0/114 (0%)		2/170 (1.2%)
Infections and infestations
Tracheitis	1/114 (0.9%)	1	0/114 (0%)	0	0/170 (0%)	0
Appendicitis	0/114 (0%)	0	0/114 (0%)	0	1/170 (0.6%)	1
Musculoskeletal and connective tissue disorders
Spondylitis	0/114 (0%)	0	0/114 (0%)	0	1/170 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Mesalamine		Placebo		Mesalamine (Open-Label)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/114 (16.7%)		13/114 (11.4%)		8/170 (4.7%)
Blood and lymphatic system disorders
Anaemia	3/114 (2.6%)	3	2/114 (1.8%)	3	0/170 (0%)	0
Leukocytosis	1/114 (0.9%)	1	3/114 (2.6%)	3	0/170 (0%)	0
Gastrointestinal disorders
Colitis ulcerative	3/114 (2.6%)	3	10/114 (8.8%)	10	4/170 (2.4%)	4
Diarrhoea	1/114 (0.9%)	1	3/114 (2.6%)	3	0/170 (0%)	0
Investigations
C-reactive protein increased	6/114 (5.3%)	6	1/114 (0.9%)	1	0/170 (0%)	0
Faecal calprotectin increased	5/114 (4.4%)	5	2/114 (1.8%)	2	4/170 (2.4%)	4

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.