An Open-label, Long-term Safety Study of Linaclotide in Patients With Chronic Constipation or Irritable Bowel Syndrome With Constipation

• Sponsor: Ironwood Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00730171
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 1,743
• Locations: 116
• Arm: 1
• Duration (Months): 42
• Patients Per Site: 15
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The objective of this study is to assess the long-term safety of linaclotide administered to patients with chronic constipation (CC) or irritable bowel syndrome with constipation (IBS-C).

Condition or Disease	Intervention/Treatment	Phase
Irritable Bowel Syndrome With Constipation; Chronic Constipation	Drug: Linaclotide	Phase 3

Detailed Description

Participants include randomization-ineligible (RI) patients from the lead-in double-blind trials MCP-103-302 (NCT00938717) or MCP-103-303 (NCT00730015), or rollover (RO) patients from the lead-in double-blind trials MCP-103-302 (NCT00938717), MCP-103-303 (NCT00730015), and from the Phase 2 double-blind studies MCP-103-004 (NCT00306748), MCP-103-005 (NCT00258193), and MCP-103-201 (NCT00402337), or MCP-103-202 (NCT00460811).

Study Design

• Study Type: Interventional
• Actual Enrollment: 1743 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Long-term Safety Study of Oral Linaclotide Administered to Patients With Chronic Constipation or Irritable Bowel Syndrome With Constipation
• Study Start Date: Sep 1, 2008
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Linaclotide Linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.	Drug: Linaclotide; Linaclotide capsules, oral, once daily each morning at least 30 minutes before breakfast for the duration of the study.; Other Names: Linzess

Outcome Measures

Primary Outcome Measures

1. Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) [From first dose of open-label study drug up to 78 weeks]

   For RI and Phase 2 RO participants, an AE that occurred during the study was considered a TEAE if it was not present before the day of the first dose of open-label study drug, or was present before the day of the first dose of open-label study drug but increased in severity on or after that day. For Phase 3 RO participants, an AE that occurred during the study was considered a TEAE if it was not present before the day of the first dose of double-blind study drug in trial MCP-103-302 or MCP-103-303, or was present before the day of the first dose of double-blind study drug in those trials but increased in severity on or after that day. Deaths and serious AEs (SAEs) are those that occurred on or after the date of the first dose of open-label study drug, and within 30 days of the date of last dose of open-label study drug.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have

• entered study MCP-103-303 or MCP-103-302 and at minimum completed the pre-treatment period or

• completed one of the following studies: MCP-103-004, MCP-103-005, MCP-103-201, MCP-103-202

• Sexually active patients of childbearing potential agree to use birth control

• Females of childbearing potential must have a negative urine pregnancy test prior to dosing

• Lactating females must agree not to breastfeed

• Patient must meet protocol criteria for CC or IBS-C

Exclusion Criteria:

• Patient must not use protocol-defined prohibited medicine

• Patient is planning to receive an investigational drug at any time during the study

• Patient has an unresolved adverse events or a clinically significant finding on a physical examination, 12-lead electrocardiogram, or clinical laboratory test

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ironwood Investigational Site	Birmingham	Alabama	United States	35209
2	Ironwood Investigational Site	Huntsville	Alabama	United States	35801
3	Ironwood Investigational Site	Chandler	Arizona	United States	85224
4	Ironwood Investigational Site	Phoenix	Arizona	United States	85020
5	Ironwood Investigational Site	Tucson	Arizona	United States	85710
6	Ironwood Investigational Site	Tucson	Arizona	United States	85715
7	Ironwood Investigational Site	Tucson	Arizona	United States	85741
8	Ironwood Investigational Site	Sherwood	Arkansas	United States	72120
9	Ironwood Investigational Site	Anaheim	California	United States	92801
10	Ironwood Investigational Site	Chula Vista	California	United States	91910
11	Ironwood Investigational Site	Encinitas	California	United States	92024
12	Ironwood Investigational Site	Garden Grove	California	United States	92840
13	Ironwood Investigational Site	Laguna Hills	California	United States	92653
14	Ironwood Investigational Site	Los Angeles	California	United States	90045
15	Ironwood Investigational Site	Orange	California	United States	92868
16	Ironwood Investigational Site	Sacramento	California	United States	95830
17	Ironwood Investigational Site	San Carlos	California	United States	94070
18	Ironwood Investigational Site	San Diego	California	United States	92103
19	Ironwood Investigational Site	San Diego	California	United States	92108
20	Ironwood Investigational Site	San Diego	California	United States	92123
21	Ironwood Investigational Site	Colorado Springs	Colorado	United States	80904
22	Ironwood Investigational Site	Bristol	Connecticut	United States	06010
23	Ironwood Investigational Site	Boynton Beach	Florida	United States	33426
24	Ironwood Investigational Site	Hollywood	Florida	United States	33021
25	Ironwood Investigational Site	Inverness	Florida	United States	34452
26	Ironwood Investigational Site	Jacksonville	Florida	United States	32205
27	Ironwood Investigational Site	Jacksonville	Florida	United States	32256
28	Ironwood Investigational Site	Lauderdale Lakes	Florida	United States	33319
29	Ironwood Investigational Site	Miami	Florida	United States	33156
30	Ironwood Investigational Site	Pinellas Park	Florida	United States	33782
31	Ironwood Investigational Site	Port Orange	Florida	United States	32129
32	Ironwood Investigational Site	Tampa	Florida	United States	33607
33	Ironwood Investigational Site	Newnan	Georgia	United States	30263
34	Ironwood Investigational Site	Peoria	Illinois	United States	61602
35	Ironwood Investigational Site	Anderson	Indiana	United States	46011
36	Ironwood Investigational Site	Clive	Iowa	United States	50325
37	Ironwood Investigational Site	Davenport	Iowa	United States	52807
38	Ironwood Investigational Site	Mission	Kansas	United States	66202
39	Ironwood Investigational Site	Overland Park	Kansas	United States	66215
40	Ironwood Investigational Site	Topeka	Kansas	United States	66606
41	Ironwood Investigational Site	Baton Rouge	Louisiana	United States	70809
42	Ironwood Investigational Site	Metairie	Louisiana	United States	70006
43	Ironwood Investigational Site	Monroe	Louisiana	United States	71201
44	Ironwood Investigational Site	Shreveport	Louisiana	United States	71103
45	Ironwood Investigational Site	Annapolis	Maryland	United States	21401
46	Ironwood Investigational Site	Baltimore	Maryland	United States	21215
47	Ironwood Investigational Site	Hollywood	Maryland	United States	20636
48	Ironwood Investigational Site	Laurel	Maryland	United States	20707
49	Ironwood Investigational Site	Chesterfield	Michigan	United States	48047
50	Ironwood Investigational Site	Traverse City	Michigan	United States	49684
51	Ironwood Investigational Site	Troy	Michigan	United States	48098
52	Ironwood Investigational Site	Plymouth	Minnesota	United States	55446
53	Ironwood Investigational Site	Jackson	Mississippi	United States	39202
54	Ironwood Investigational Site	Tupelo	Mississippi	United States	38801
55	Ironwood Investigational Site	Jefferson City	Missouri	United States	65109
56	Ironwood Investigational Site	Henderson	Nevada	United States	89104
57	Ironwood Investigational Site	Las Vegas	Nevada	United States	89128
58	Ironwood Investigational Site	Cedar Knolls	New Jersey	United States	07927
59	Ironwood Investigational Site	Marlton	New Jersey	United States	08053
60	Ironwood Investigational Site	Ocean City	New Jersey	United States	07712
61	Ironwood Investigational Site	Albuquerque	New Mexico	United States	87108
62	Ironwood Investigational Site	Mineola	New York	United States	11501
63	Ironwood Investigational Site	Pittsford	New York	United States	14534
64	Ironwood Investigational Site	Asheboro	North Carolina	United States	27203
65	Ironwood Investigational Site	Asheville	North Carolina	United States	28801
66	Ironwood Investigational Site	Chapel Hill	North Carolina	United States	27599
67	Ironwood Investigational Site	Charlotte	North Carolina	United States	28211
68	Ironwood Investigational Site	Greensboro	North Carolina	United States	27408
69	Ironwood Investigational Site	Harrisburg	North Carolina	United States	28075
70	Ironwood Investigational Site	Hickory	North Carolina	United States	28602
71	Ironwood Investigational Site	Huntersville	North Carolina	United States	28078
72	Ironwood Investigational Site	Jacksonville	North Carolina	United States	28546
73	Ironwood Investigational Site	New Bern	North Carolina	United States	28562
74	Ironwood Investigational Site	Statesville	North Carolina	United States	28625
75	Ironwood Investigational Site	Summerville	North Carolina	United States	29485
76	Ironwood Investigational Site	Wilmington	North Carolina	United States	28401
77	Ironwood Investigational Site	Winston-Salem	North Carolina	United States	27103
78	Ironwood Investigational Site	Beachwood	Ohio	United States	44122
79	Ironwood Investigational Site	Cincinnati	Ohio	United States	45224
80	Ironwood Investigational Site	Cincinnati	Ohio	United States	45242
81	Ironwood Investigational Site	Dayton	Ohio	United States	45440
82	Ironwood Investigational Site	Mentor	Ohio	United States	44060
83	Ironwood Investigational Site	Sylvania	Ohio	United States	43560
84	Ironwood Investigational Site	Wadsworth	Ohio	United States	44281
85	Ironwood Investigational Site	Zanesville	Ohio	United States	43701
86	Ironwood Investigational Site	Oklahoma City	Oklahoma	United States	73116
87	Ironwood Investigational Site	Yukon	Oklahoma	United States	73099
88	Ironwood Investigational Site	Lancaster	Pennsylvania	United States	17604
89	Ironwood Investigational Site	Lancaster	Pennsylvania	United States	19606
90	Ironwood Investigational Site	Levittown	Pennsylvania	United States	19056
91	Ironwood Investigational Site	Pittsburgh	Pennsylvania	United States	15213
92	Ironwood Investigational Site	Sellersville	Pennsylvania	United States	18960
93	Ironwood Investigational Site	Anderson	South Carolina	United States	29621
94	Ironwood Investigational Site	Charleston	South Carolina	United States	29414
95	Ironwood Investigational Site	Simpsonville	South Carolina	United States	29681
96	Ironwood Investigational Site	Bristol	Tennessee	United States	37620
97	Ironwood Investigational Site	Chattanooga	Tennessee	United States	37421
98	Ironwood Investigational Site	Germantown	Tennessee	United States	38138
99	Ironwood Investigational Site	Kingsport	Tennessee	United States	37660
100	Ironwood Investigational Site	Nashville	Tennessee	United States	37203
101	Ironwood Investigational Site	Beaumont	Texas	United States	77701
102	Ironwood Investigational Site	El Paso	Texas	United States	79905
103	Ironwood Investigational Site	Fort Worth	Texas	United States	76104
104	Ironwood Investigational Site	Houston	Texas	United States	77024
105	Ironwood Investigational Site	Irving	Texas	United States	75061
106	Ironwood Investigational Site	Longview	Texas	United States	75605
107	Ironwood Investigational Site	San Antonio	Texas	United States	78229
108	Ironwood Investigational Site	Sugar Land	Texas	United States	77479
109	Ironwood Investigational Site	Ogden	Utah	United States	84405
110	Ironwood Investigational Site	Salt Lake City	Utah	United States	84107
111	Ironwood Investigational Site	Chesapeake	Virginia	United States	23320
112	Ironwood Investigational Site	Lynchburg	Virginia	United States	24502
113	Ironwood Investigational Site	Spokane	Washington	United States	99208
114	Ironwood Investigational Site	Vancouver	Washington	United States	98664
115	Ironwood Investigational Site	La Crosse	Wisconsin	United States	54601
116	Ironwood Investigational Site	Milwaukee	Wisconsin	United States	53215

Sponsors and Collaborators

• Ironwood Pharmaceuticals, Inc.
• Forest Laboratories

Investigators

• Study Chair: Jeffrey M. Johnston, MD, FACP, Ironwood Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ironwood Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT00730171
• Other Study ID Numbers: MCP-103-305
• First Posted: Aug 8, 2008
• Last Update Posted: Feb 19, 2018
• Last Verified: Jan 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Additional relevant MeSH terms: Irritable Bowel Syndrome; Syndrome; Constipation; Linaclotide

Study Results

Participant Flow

Recruitment Details	Participants were categorized as either randomization-ineligible (RI) from the lead-in double-blind trials MCP-103-302 or MCP-103-303, or rollover (RO) from lead-in double-blind trials MCP-103-302, MCP-103-303, and from Phase 2 double-blind studies MCP-103-004, MCP-103-005, and MCP-103-201, or MCP-103-202 (See Detailed Description for NCT numbers).
Pre-assignment Detail	A total of 1743 participants were enrolled in the study; 1725 received ≥1 dose of open-label linaclotide (included in the Overall Safety Population). One participant enrolled twice in the study under 2 ID numbers and is included as an RI participant in the CC Safety Population, and as an RO participant in the IBS-C and Overall Safety Populations.

Arm/Group Title	Overal Safey Population: Total
Arm/Group Description	All RI and RO participants who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator if a participant experienced AEs intolerable enough to prompt consideration of study withdrawal. After a temporary suspension of dosing, participants may have received either 145 μg/day or 290 μg/day of linaclotide, at the discretion of the Investigator. Subsequent dose adjustments (increases or decreases between 290 μg/day and 145 μg/day) were permitted also at the Investigator's discretion.
Period Title: Overall Study
STARTED	1725
CC Safety Population	607
IBS-C Safety Population	1119
COMPLETED	954
NOT COMPLETED	771

Baseline Characteristics

Arm/Group Title	Overall Safety Population
Arm/Group Description	All RI and RO participants who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator if a participant experienced AEs intolerable enough to prompt consideration of study withdrawal. After a temporary suspension of dosing, participants may have received either 145 μg/day or 290 μg/day of linaclotide, at the discretion of the Investigator. Subsequent dose adjustments (increases or decreases between 290 μg/day and 145 μg/day) were permitted also at the Investigator's discretion.
Overall Participants	1725
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.1 (13.5)
Sex: Female, Male (Count of Participants)
Female	1532 88.8%
Male	193 11.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With at Least One Treatment-Emergent Adverse Event (TEAE)
Description	For RI and Phase 2 RO participants, an AE that occurred during the study was considered a TEAE if it was not present before the day of the first dose of open-label study drug, or was present before the day of the first dose of open-label study drug but increased in severity on or after that day. For Phase 3 RO participants, an AE that occurred during the study was considered a TEAE if it was not present before the day of the first dose of double-blind study drug in trial MCP-103-302 or MCP-103-303, or was present before the day of the first dose of double-blind study drug in those trials but increased in severity on or after that day. Deaths and serious AEs (SAEs) are those that occurred on or after the date of the first dose of open-label study drug, and within 30 days of the date of last dose of open-label study drug.
Time Frame	From first dose of open-label study drug up to 78 weeks

Outcome Measure Data

Analysis Population Description

Enrolled participants who received at least 1 dose of open-label study drug. It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.

Arm/Group Title	CC Safety Population: Total	IBS-C Safety Population: Total	Overall Safety Population: Total
Arm/Group Description	RI and RO participants who met the Rome II criteria for CC and who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.	RI and RO participants who met the Rome II criteria for IBS-C and who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.	All RI and RO participants who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.
Measure Participants	607	1119	1725
Count of Participants [Participants]	65 3.8%	389 NaN	454 NaN

Adverse Events

Time Frame	From first dose of open-label study drug up to 78 weeks for adverse events (AEs) and within 30 days of last dose of study drug (up to 82 weeks) for serious AEs.
Adverse Event Reporting Description	It was identified that 1 participant enrolled twice in the study under 2 ID numbers; this participant is included as an RI participant in the CC Safety Population, and as an RO participant in both the IBS-C and Overall Safety Populations.
Arm/Group Title	CC Safety Population: Total		IBS-C Safety Population: Total		Overall Safety Population: Total
Arm/Group Description	RI and RO participants who met the modified Rome II criteria for CC and who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.		RI and RO participants who met the modified Rome II criteria for IBS-C and who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.		All RI and RO participants who received linaclotide 290 μg/day capsules, administered orally once daily for up to 78 weeks. Dose reduction to 145 μg/day was permitted at the discretion of the Investigator.
All Cause Mortality
	CC Safety Population: Total		IBS-C Safety Population: Total		Overall Safety Population: Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/607 (0.3%)		2/1119 (0.2%)		4/1725 (0.2%)
Serious Adverse Events
	CC Safety Population: Total		IBS-C Safety Population: Total		Overall Safety Population: Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/607 (6.8%)		56/1119 (5%)		97/1725 (5.6%)
Blood and lymphatic system disorders
Aplastic anaemia	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Cardiac disorders
Acute myocardial infarction	2/607 (0.3%)		1/1119 (0.1%)		3/1725 (0.2%)
Bradycardia	2/607 (0.3%)		0/1119 (0%)		2/1725 (0.1%)
Coronary artery disease	1/607 (0.2%)		2/1119 (0.2%)		3/1725 (0.2%)
Angina pectoris	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Atrial fibrillation	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Congenital, familial and genetic disorders
Micrognathia	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Endocrine disorders
Thyrotoxic crisis	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Gastrointestinal disorders
Diverticular perforation	2/607 (0.3%)		0/1119 (0%)		2/1725 (0.1%)
Gastrooesophageal reflux disease	2/607 (0.3%)		0/1119 (0%)		2/1725 (0.1%)
Diverticulitis	1/607 (0.2%)		1/1119 (0.1%)		2/1725 (0.1%)
Duodenal ulcer	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Gastric ulcer perforation	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Haemorrhoids	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Malocclusion	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Peritonitis	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Colitis ischaemic	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Ileus	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Pancreatitis	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Small intestinal obstruction	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
General disorders
Chest pain	1/607 (0.2%)		1/1119 (0.1%)		2/1725 (0.1%)
Non-cardiac chest pain	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Hypothermia	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Oedema peripheral	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Hepatobiliary disorders
Cholecystitis chronic	1/607 (0.2%)		1/1119 (0.1%)		2/1725 (0.1%)
Cholelithiasis	0/607 (0%)		3/1119 (0.3%)		3/1725 (0.2%)
Biliary dyskinesia	0/607 (0%)		2/1119 (0.2%)		2/1725 (0.1%)
Bile duct stone	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Cholecystitis	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Infections and infestations
Escherichia urinary tract infection	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Pneumonia	1/607 (0.2%)		2/1119 (0.2%)		3/1725 (0.2%)
Sepsis	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Subcutaneous abscess	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Bronchitis	0/607 (0%)		2/1119 (0.2%)		2/1725 (0.1%)
Gastroenteritis	0/607 (0%)		2/1119 (0.2%)		2/1725 (0.1%)
Cellulitis	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Clostridial infection	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Clostridium difficile colitis	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Gastroenteritis salmonella	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Intertrigo candida	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Meningitis viral	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Sinusitis	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Injury, poisoning and procedural complications
Fall	1/607 (0.2%)		2/1119 (0.2%)		3/1725 (0.2%)
Multiple injuries	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Pelvic fracture	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Ankle fracture	0/607 (0%)		2/1119 (0.2%)		2/1725 (0.1%)
Drug toxicity	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Gun shot wound	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Investigations
Electrocardiogram QT prolonged	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Metabolism and nutrition disorders
Dehydration	2/607 (0.3%)		0/1119 (0%)		2/1725 (0.1%)
Hypokalaemia	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	3/607 (0.5%)		3/1119 (0.3%)		6/1725 (0.3%)
Back pain	1/607 (0.2%)		1/1119 (0.1%)		2/1725 (0.1%)
Intervertebral disc degeneration	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Intervertebral disc protrusion	1/607 (0.2%)		1/1119 (0.1%)		2/1725 (0.1%)
Osteonecrosis	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Prognathism	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Rotator cuff syndrome	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Lumbar spinal stenosis	0/607 (0%)		2/1119 (0.2%)		2/1725 (0.1%)
Arthralgia	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Kyphosis	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Pain in extremity	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Pseudarthrosis	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Spinal osteoarthritis	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Spondylolisthesis	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/607 (0.2%)		3/1119 (0.3%)		4/1725 (0.2%)
Malignant melanoma	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Oesophageal squamous cell carcinoma stage IV	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Renal cell carcinoma	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Acute myeloid leukaemia	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Breast cancer in situ	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Breast cancer stage I	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Transitional cell carcinoma	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Nervous system disorders
Convulsion	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Syncope	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Cervicobrachial syndrome	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Headache	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Lumbar radiculopathy	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Psychiatric disorders
Bipolar I disorder	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Depression	1/607 (0.2%)		2/1119 (0.2%)		3/1725 (0.2%)
Suicide attempt	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Anorexia nervosa	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Suicidal ideation	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Renal and urinary disorders
Stress urinary incontinence	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Reproductive system and breast disorders
Cystocele	2/607 (0.3%)		0/1119 (0%)		2/1725 (0.1%)
Adenomyosis	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Dysmenorrhoea	1/607 (0.2%)		1/1119 (0.1%)		2/1725 (0.1%)
Endometrial hypertrophy	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Rectocele	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Uterine prolapse	1/607 (0.2%)		1/1119 (0.1%)		2/1725 (0.1%)
Menometrorrhagia	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax traumatic	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Skin and subcutaneous tissue disorders
Lipodystrophy acquired	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Vascular disorders
Hypertension	1/607 (0.2%)		0/1119 (0%)		1/1725 (0.1%)
Orthostatic hypotension	0/607 (0%)		1/1119 (0.1%)		1/1725 (0.1%)
Other (Not Including Serious) Adverse Events
	CC Safety Population: Total		IBS-C Safety Population: Total		Overall Safety Population: Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	283/607 (46.6%)		572/1119 (51.1%)		855/1725 (49.6%)
Gastrointestinal disorders
Diarrhoea	179/607 (29.5%)		358/1119 (32%)		537/1725 (31.1%)
Abdominal pain	23/607 (3.8%)		74/1119 (6.6%)		97/1725 (5.6%)
Nausea	36/607 (5.9%)		59/1119 (5.3%)		95/1725 (5.5%)
Constipation	16/607 (2.6%)		65/1119 (5.8%)		81/1725 (4.7%)
Flatulence	34/607 (5.6%)		36/1119 (3.2%)		70/1725 (4.1%)
Infections and infestations
Urinary tract infection	44/607 (7.2%)		85/1119 (7.6%)		129/1725 (7.5%)
Sinusitis	40/607 (6.6%)		83/1119 (7.4%)		123/1725 (7.1%)
Upper respiratory tract infection	27/607 (4.4%)		61/1119 (5.5%)		88/1725 (5.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

PI may publish or disclose the results of the study 24 months after final data lock provided that sponsor can review the publication prior to public release, sponsor can request removal of confidential information of sponsor (not including results of trial), and sponsor can request a publication delay in order to protect potentially patentable information. Furthermore, if a publication committee is developing an initial publication, PI is to delay disclosure until that publication is published