Lubiprostone for Chronic Idiopathic Constipation Treatment

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02729909
• Collaborator: (none)
• Enrollment: 211
• Locations: 10
• Arms: 2
• Actual Duration (Months): 12.8
• Patients Per Site: 21.1
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of oral administration of 24 ug of lubiprostone twice daily (BID) for 4 weeks in participants with chronic idiopathic constipation (CIC) compared with placebo.

Condition or Disease	Intervention/Treatment	Phase
Constipation	Drug: Lubiprostone; Drug: Placebo	Phase 3

Detailed Description

The drug being tested in this study is called lubiprostone. Lubiprostone is being tested to treat people who have chronic idiopathic constipation. This study will look at the frequency of spontaneous bowel movements (SBMs) in people who take lubiprostone compared to placebo.

The study will enroll approximately 211 participants. Participants will be randomly assigned (by chance, like flipping a coin) equally to one of the two treatment groups, which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

• Lubiprostone 24 μg

• Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient

All participants will be asked to take one capsule with breakfast and one capsule with dinner each day throughout the study. All participants will be asked to record each time they have a SBM and all details of each SBM (including the consistency of the stool and the difficulty they have in passing it) in a diary.

This multi-center trial will be conducted in Mexico. The overall time to participate in this study is 8 weeks. Participants will make multiple visits to the clinic, and will be contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 211 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Lubiprostone for the Treatment of Chronic Idiopathic Constipation
• Actual Study Start Date: May 11, 2016
• Actual Primary Completion Date: Apr 28, 2017
• Actual Study Completion Date: Jun 5, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lubiprostone 24 μg Lubiprostone 24 μg, capsules, orally, twice daily, under fed conditions, for 4 weeks.	Drug: Lubiprostone; Lubiprostone capsules; Other Names: AMITIZA
Placebo Comparator: Placebo Lubiprostone placebo-matching capsules, orally, twice daily, under fed conditions, for 4 weeks.	Drug: Placebo; Lubiprostone placebo-matching capsules

Outcome Measures

Primary Outcome Measures

1. Spontaneous Bowel Movement (SBM) Frequency at Week 1 of Administration [Week 1]

   A SBM is defined as any bowel movement (BM) that does not occur within 24 hours after rescue medication use (laxative, suppository, or enema). Participants were given a diary to complete at home where they have recorded all details of each SBM including the consistency of the stool and the difficulty they have in passing it.

Secondary Outcome Measures

1. SBM Frequency at Weeks 2, 3 and 4 [Weeks 2, 3 and 4]

   A SBM is defined as any BM that does not occur within 24 hours after rescue medication use (laxative, suppository, or enema). Participants were given a diary to complete at home where they have recorded all details of each SBM including the consistency of the stool and the difficulty they have in passing it.

2. Percentage of Participants Who Have a SBM Within 24 Hours After First Dose of Study Medication [Up to 24 hours after the first dose of study medication]

   A SBM is defined as any BM that does not occur within 24 hours after rescue medication use. Percentage of participants who have an SBM within 24 hours after the first dose was assessed and derived from the data on SBMs collected in the participant diary.

3. Mean Degree of Straining Score [Weeks 1, 2, 3 and 4]

   For each participant, the mean degree of straining was averaged for all SBMs in a given week. The degree of straining for each SBM was collected in the participant diary. The degree of straining was scored on a 5-point scale where: 0=No straining, 1=Mild straining, 2=Moderate straining, 3=Strong straining or 4=Very strong straining with higher scores indicating more severe straining.

4. Mean Degree of Stool Consistency [Weeks 1, 2, 3 and 4]

   For each participant, the mean stool consistency score was averaged for all SBMs in a given week. The mean degree of stool consistency for each SBM was collected in the participant diary based on the Bristol Stool Chart. The Bristol Stool Chart is a medical aid designed to classify the form of human feces into seven categories where: 1=Hard and round (difficult-to-pass), 2=Sausage-shaped but hard stool, 3=Sausage-shaped stool with cracks on the surface, 4=Sausage-shaped, soft stool with smooth surface, or coiled stool, 5=Soft, half-solid (and easy-to-pass) stool with clear crease, 6=Unshaped, loose stool with small, irregular-shaped pieces, or mushy stool or 7=Watery stool without solid pieces (entirely liquid).

5. Weekly Abdominal Symptoms Score [Weeks 1, 2, 3 and 4]

   Weekly abdominal symptoms of bloating and discomfort upon waking in the morning was scored weekly on a 5-point scale where: 0=None, 1=Mild, 2=Moderate, 3=Severe or 4=Very severe, with a higher score indicating more severe symptoms. Assessment of weekly abdominal symptoms were recorded in the participant in the diary.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. In the opinion of the investigator, is capable of understanding and complying with protocol requirements.

2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

3. Has a history of constipation defined as having spontaneous bowel movement (SBM) frequency of less than 3 times per week on average for 6 months or longer and for whom the same SBM frequency is observed during the Screening Period.

4. Has had 1 or more of the symptoms associated with SBM (described below) for 6months or longer at the start of Screening:

5. Scybalum stool or hard feces in at least 1 out of every 4 bowel movements.

6. Sensation of incomplete evacuation in at least 1 out of every 4 bowel movements.

7. Straining in at least 1 out of every 4 bowel movements.

8. Rarely has loose stools without the use of laxatives.

9. Is willing and able to keep a diary on his/her own and willing and able to complete a questionnaire.

10. Is male or female and aged 18 years or older, at the time of signing an informed consent.

11. A female participant of childbearing potential who is sexually active agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study and 14 days after the last dose of study drug.

Exclusion Criteria:

1. Has received any investigational compound within 30 days prior to Screening.

2. Has received lubiprostone in a previous clinical study or as a therapeutic agent.

3. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.

4. Has, in the judgment of the investigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening.

5. Has a history or clinical manifestations of significant mechanical obstruction (intestinal obstruction due to tumor, hernia etc).

6. Has a history of hypersensitivity or allergies to lubiprostone or any of its excipients.

7. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to the Screening Visit.

8. Is required to take excluded medications.

9. If female, is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.

10. Participant whose constipation is considered to be due to drugs or to whom a prohibited concomitant medication has been administered.

11. Is having chronic constipation due to a secondary cause (medications, diabetes mellitus, hypothyroidism, depression, etc.)

12. Has sufficient criteria for irritable bowel syndrome (IBS) or functional defecation disorder.

13. SBM frequency is 3 or more per week.

14. SBM frequency has been less than 3 times per week for less than 6 months in duration or whose symptoms associated with SBM have been present for less than 6 months (hard feces, sensation of incomplete evacuation, or straining).

15. Has received treatment with a rescue medication within 24 hours prior to the first dose on the morning of Day1: bisacodyl suppository, which is a standard laxative, glycerin enema, or any other rescue medication.

16. Has megacolon/megarectum or has received a diagnosis of intestinal pseudo-obstruction.

17. Has confirmed or suspected organic disorders of the large intestine (obstruction, stenosis, carcinoma, or inflammatory bowel disease). Organic disorders of the large intestine can be confirmed or ruled out using the results of enema X-ray examination or total colonoscopy performed in the previous 2 years. If the participant has no history or shows no current evidence of weight loss, anemia, or rectal bleeding, organic disorders may be ruled out based on the results of such testing performed in the past 3 years. Any participant in whom total colonoscopy has detected a polyp requiring treatment is excluded from this study .Note: Participant should not be screened unless at least 7 days have passed since an enema X-ray examination, total colonoscopy or sigmoidoscopy have been performed.

18. Has been hospitalized for gastrointestinal or abdominal surgery within 3 months prior to Screening.

19. Has a significant cardiovascular, liver, lung, kidney, neurological, or mental disease (including existing alcohol or drug abuse problem) or a systemic disease.

20. Has significant clinical findings or in whom a significant abnormality has been found in hematology test, serum chemistry, or urinalysis.

21. Participant in whom noncompliance with the study protocol (administration schedule, visit schedule, diary completion or other study procedure) is expected.

22. Has a history of malignant disease (except basal cell carcinoma) within 5 years prior to Screening.

23. Has any screening abnormal laboratory value that suggests a clinically significant underlying disease or condition that may prevent the participant from entering the study; or the participant has: creatinine >1.5 mg/dL, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2 times the upper limit of normal (ULN), or total bilirubin >2.0 mg/dL with AST/ALT elevated above the limits of normal values.

24. Participant who the investigator/subinvestigator has determined ineligible to participate in this study for any reason other than the above.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Mexicali	Baja California Norte	Mexico
2		Mexico	Distrito Federal	Mexico
3		Cuautitlan Izcalli	Estado De Mexico	Mexico
4		Tlalnepantla	Estado De Mexico	Mexico
5		Leon	Guanajuato	Mexico
6		Morelia	Michoacan	Mexico
7		Monterrey	Nuevo Le0n	Mexico
8		Culiacan	Sinaloa	Mexico
9		Chihuahua		Mexico
10		Durango		Mexico

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

• Study Protocol - May 18, 2015
• Statistical Analysis Plan - Jun 29, 2017

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02729909
• Other Study ID Numbers: Lubiprostone-3003; U1111-1168-6358; 153300410A0196
• First Posted: Apr 6, 2016
• Last Update Posted: Apr 1, 2019
• Last Verified: Jan 1, 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug therapy
• Additional relevant MeSH terms: Constipation; Lubiprostone

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 10 investigative sites in Mexico from 11 May 2016 to 05 June 2017.
Pre-assignment Detail	Participants with a diagnosis of chronic idiopathic constipation were enrolled in a 1:1 ratio in one of two treatment groups to receive either lubiprostone 24 µg or placebo.

Arm/Group Title	Lubiprostone 24 μg	Placebo
Arm/Group Description	Lubiprostone 24 μg, capsules, orally, twice daily, under fed conditions, for 4 weeks.	Lubiprostone placebo-matching capsules, orally, twice daily, under fed conditions, for 4 weeks.
Period Title: Overall Study
STARTED	105	106
COMPLETED	104	101
NOT COMPLETED	1	5

Baseline Characteristics

Arm/Group Title	Lubiprostone 24 μg	Placebo	Total
Arm/Group Description	Lubiprostone 24 μg, capsules, orally, twice daily, under fed conditions, for 4 weeks.	Lubiprostone placebo-matching capsules, orally, twice daily, under fed conditions, for 4 weeks.	Total of all reporting groups
Overall Participants	105	106	211
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	43.3	40.8	42.05
Sex: Female, Male (Count of Participants)
Female	82 78.1%	90 84.9%	172 81.5%
Male	23 21.9%	16 15.1%	39 18.5%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	73 69.5%	67 63.2%	140 66.4%
White	27 25.7%	30 28.3%	57 27%
Multiracial	5 4.8%	9 8.5%	14 6.6%
Region of Enrollment (Count of Participants)
Mexico	105 100%	106 100%	211 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	161.9 (8.12)	160.7 (7.42)	161.3 (7.78)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	72.48 (13.916)	70.67 (12.873)	71.57 (13.401)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.638 (4.6950)	27.333 (4.3830)	27.485 (4.5326)
Smokers (Count of Participants)
Participant had never smoked	78 74.3%	88 83%	166 78.7%
Participant was a current smoker	23 21.9%	13 12.3%	36 17.1%
Participant was an ex-smoker	4 3.8%	5 4.7%	9 4.3%

Outcome Measures

1. Primary Outcome

Title	Spontaneous Bowel Movement (SBM) Frequency at Week 1 of Administration
Description	A SBM is defined as any bowel movement (BM) that does not occur within 24 hours after rescue medication use (laxative, suppository, or enema). Participants were given a diary to complete at home where they have recorded all details of each SBM including the consistency of the stool and the difficulty they have in passing it.
Time Frame	Week 1

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all participants randomized to receive study treatment whether or not they received treatment. Missing values were imputed by using last observation carried forward (LOCF).

Arm/Group Title	Lubiprostone 24 μg	Placebo
Arm/Group Description	Lubiprostone 24 μg, capsules, orally, twice daily, under fed conditions, for 4 weeks.	Lubiprostone placebo-matching capsules, orally, twice daily, under fed conditions, for 4 weeks.
Measure Participants	105	106
Mean (Standard Deviation) [number of SBM per week]	6.7 (4.55)	5.2 (2.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments	Spontaneous bowel movement was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of confidence interval (CI)
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.1 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	SBM Frequency at Weeks 2, 3 and 4
Description	A SBM is defined as any BM that does not occur within 24 hours after rescue medication use (laxative, suppository, or enema). Participants were given a diary to complete at home where they have recorded all details of each SBM including the consistency of the stool and the difficulty they have in passing it.
Time Frame	Weeks 2, 3 and 4

Outcome Measure Data

Analysis Population Description

FAS included all participants randomized to receive study treatment whether or not they received treatment. Missing values were imputed by using LOCF.

Arm/Group Title	Lubiprostone 24 μg	Placebo
Arm/Group Description	Lubiprostone 24 μg, capsules, orally, twice daily, under fed conditions, for 4 weeks.	Lubiprostone placebo-matching capsules, orally, twice daily, under fed conditions, for 4 weeks.
Measure Participants	105	106
Week 2	6.9 (4.40)	5.5 (2.75)
Week 3	7.6 (4.50)	6.0 (3.74)
Week 4	7.2 (4.21)	5.8 (3.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.051
	Comments	Spontaneous bowel movement was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.0 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	Spontaneous bowel movement was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; 1.0 to 2.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	Spontaneous bowel movement was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.1 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants Who Have a SBM Within 24 Hours After First Dose of Study Medication
Description	A SBM is defined as any BM that does not occur within 24 hours after rescue medication use. Percentage of participants who have an SBM within 24 hours after the first dose was assessed and derived from the data on SBMs collected in the participant diary.
Time Frame	Up to 24 hours after the first dose of study medication

Outcome Measure Data

Analysis Population Description

FAS included all participants randomized to receive study treatment whether or not they received treatment.

Arm/Group Title	Lubiprostone 24 μg	Placebo
Arm/Group Description	Lubiprostone 24 μg, capsules, orally, twice daily, under fed conditions, for 4 weeks.	Lubiprostone placebo-matching capsules, orally, twice daily, under fed conditions, for 4 weeks.
Measure Participants	105	106
Number [percentage of participants]	60.0 57.1%	41.5 39.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	The proportion of participants with an SBM within 24 hours after first dose in Week 1 is analyzed by a Cochran-Mantel-Haenszel (CMH) test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.08
	Confidence Interval	(2-Sided) 95%; 1.19 to 3.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Mean Degree of Straining Score
Description	For each participant, the mean degree of straining was averaged for all SBMs in a given week. The degree of straining for each SBM was collected in the participant diary. The degree of straining was scored on a 5-point scale where: 0=No straining, 1=Mild straining, 2=Moderate straining, 3=Strong straining or 4=Very strong straining with higher scores indicating more severe straining.
Time Frame	Weeks 1, 2, 3 and 4

Outcome Measure Data

Analysis Population Description

FAS included all participants randomized to receive study treatment whether or not they received treatment. Missing values were imputed by using LOCF.

Arm/Group Title	Lubiprostone 24 μg	Placebo
Arm/Group Description	Lubiprostone 24 μg, capsules, orally, twice daily, under fed conditions, for 4 weeks.	Lubiprostone placebo-matching capsules, orally, twice daily, under fed conditions, for 4 weeks.
Measure Participants	105	106
Week 1	1.6 (0.85)	2.0 (0.88)
Week 2	1.5 (0.89)	1.8 (0.93)
Week 3	1.3 (0.82)	1.6 (0.92)
Week 4	1.2 (0.92)	1.5 (0.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	Average Degree of Straining was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.6 to -0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	Average Degree of Straining was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments	Average Degree of Straining was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.4 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments	Average Degree of Straining was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Mean Degree of Stool Consistency
Description	For each participant, the mean stool consistency score was averaged for all SBMs in a given week. The mean degree of stool consistency for each SBM was collected in the participant diary based on the Bristol Stool Chart. The Bristol Stool Chart is a medical aid designed to classify the form of human feces into seven categories where: 1=Hard and round (difficult-to-pass), 2=Sausage-shaped but hard stool, 3=Sausage-shaped stool with cracks on the surface, 4=Sausage-shaped, soft stool with smooth surface, or coiled stool, 5=Soft, half-solid (and easy-to-pass) stool with clear crease, 6=Unshaped, loose stool with small, irregular-shaped pieces, or mushy stool or 7=Watery stool without solid pieces (entirely liquid).
Time Frame	Weeks 1, 2, 3 and 4

Outcome Measure Data

Analysis Population Description

FAS included all participants randomized to receive study treatment whether or not they received treatment. Missing values were imputed by using LOCF.

Arm/Group Title	Lubiprostone 24 μg	Placebo
Arm/Group Description	Lubiprostone 24 μg, capsules, orally, twice daily, under fed conditions, for 4 weeks.	Lubiprostone placebo-matching capsules, orally, twice daily, under fed conditions, for 4 weeks.
Measure Participants	105	106
Week 1	4.1 (1.30)	3.4 (1.08)
Week 2	4.1 (1.13)	3.5 (1.05)
Week 3	4.1 (1.12)	3.5 (0.93)
Week 4	4.1 (1.19)	3.6 (0.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Mean Degree of Stool Consistency was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; 0.4 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Mean Degree of Stool Consistency was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; 0.4 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Mean Degree of Stool Consistency was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; 0.4 to 0.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Mean Degree of Stool Consistency was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; 0.2 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Weekly Abdominal Symptoms Score
Description	Weekly abdominal symptoms of bloating and discomfort upon waking in the morning was scored weekly on a 5-point scale where: 0=None, 1=Mild, 2=Moderate, 3=Severe or 4=Very severe, with a higher score indicating more severe symptoms. Assessment of weekly abdominal symptoms were recorded in the participant in the diary.
Time Frame	Weeks 1, 2, 3 and 4

Outcome Measure Data

Analysis Population Description

FAS included all participants randomized to receive study treatment whether or not they received treatment. Missing values were imputed by using LOCF.

Arm/Group Title	Lubiprostone 24 μg	Placebo
Arm/Group Description	Lubiprostone 24 μg, capsules, orally, twice daily, under fed conditions, for 4 weeks.	Lubiprostone placebo-matching capsules, orally, twice daily, under fed conditions, for 4 weeks.
Measure Participants	105	106
Week 1	1.4 (1.05)	1.8 (0.96)
Week 2	1.2 (0.93)	1.5 (1.01)
Week 3	1.0 (1.01)	1.4 (0.93)
Week 4	0.9 (0.94)	1.2 (0.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments	Abdominal Bloating was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -0.9 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.072
	Comments	Abdominal Bloating was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 3
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Abdominal Bloating was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -0.9 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone 24 μg, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	Abdominal Bloating was analyzed using Van Elteren Test stratified by center. Centers with less participants were pooled based on geographical proximity.
	Method	Van Elteren Test
	Comments
Method of Estimation	Estimation Parameter	Median Value of CI
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -0.9 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	First dose of study drug up to Week 6
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Lubiprostone 24 μg		Placebo
Arm/Group Description	Lubiprostone 24 μg, capsules, orally, twice daily, under fed conditions, for 4 weeks.		Lubiprostone placebo-matching capsules, orally, twice daily, under fed conditions, for 4 weeks.
All Cause Mortality
	Lubiprostone 24 μg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/105 (0%)		0/106 (0%)
Serious Adverse Events
	Lubiprostone 24 μg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/105 (0%)		0/106 (0%)
Other (Not Including Serious) Adverse Events
	Lubiprostone 24 μg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/105 (21.9%)		19/106 (17.9%)
Blood and lymphatic system disorders
Neutropenia	1/105 (1%)		0/106 (0%)
Endocrine disorders
Hypothyroidism	0/105 (0%)		1/106 (0.9%)
Gastrointestinal disorders
Diarrhoea	10/105 (9.5%)		2/106 (1.9%)
Nausea	2/105 (1.9%)		0/106 (0%)
Abdominal pain	1/105 (1%)		0/106 (0%)
Abdominal pain upper	1/105 (1%)		0/106 (0%)
Dyspepsia	1/105 (1%)		0/106 (0%)
Abdominal discomfort	0/105 (0%)		1/106 (0.9%)
Haemorrhoids	0/105 (0%)		1/106 (0.9%)
General disorders
Peripheral swelling	0/105 (0%)		1/106 (0.9%)
Infections and infestations
Influenza	3/105 (2.9%)		1/106 (0.9%)
Urinary tract infection	3/105 (2.9%)		4/106 (3.8%)
Bronchitis	1/105 (1%)		0/106 (0%)
Oral herpes	1/105 (1%)		0/106 (0%)
Pharyngitis	1/105 (1%)		1/106 (0.9%)
Injury, poisoning and procedural complications
Limb injury	1/105 (1%)		0/106 (0%)
Investigations
Lymphocyte count increased	1/105 (1%)		0/106 (0%)
Blood bilirubin increased	0/105 (0%)		1/106 (0.9%)
Blood creatine phosphokinase increased	0/105 (0%)		2/106 (1.9%)
Blood thyroid stimulating hormone increased	0/105 (0%)		1/106 (0.9%)
Metabolism and nutrition disorders
Dyslipidaemia	1/105 (1%)		0/106 (0%)
Hyperuricaemia	1/105 (1%)		0/106 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/105 (0%)		1/106 (0.9%)
Back pain	0/105 (0%)		1/106 (0.9%)
Nervous system disorders
Headache	2/105 (1.9%)		3/106 (2.8%)
Dizziness	1/105 (1%)		0/106 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	2/105 (1.9%)		0/106 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.