OPAL: Opioid-induced Bowel Dysfunction: Pivotal Assessment of Lubiprostone

• Sponsor: Sucampo Pharma Americas, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00595946
• Collaborator: Sucampo Pharmaceuticals, Inc. (Industry)
• Enrollment: 439
• Locations: 95
• Arms: 2
• Duration (Months): 19
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary purpose of this study is to evaluate the efficacy and safety of lubiprostone administration in patients with Opioid-induced Bowel Dysfunction.

Condition or Disease	Intervention/Treatment	Phase
Opioid-Induced Bowel Dysfunction	Drug: Lubiprostone; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 439 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Randomized, Double-Blinded Study of the Efficacy and Safety of Lubiprostone in Patients With Opioid-induced Bowel Dysfunction (OBD)
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Mar 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo 0 mcg capsules twice daily (BID)	Drug: Placebo; 0 mcg capsules twice daily (BID); Other Names: No other names
Experimental: Lubiprostone 24 mcg capsules twice daily (BID)	Drug: Lubiprostone; 24 mcg capsules twice daily (BID); Other Names: Amitiza®

Outcome Measures

Primary Outcome Measures

1. Mean Weekly Spontaneous Bowel Movements at Week 8 [at Week 8]

   Spontaneous bowel movements (SBMs) are defined as bowel movements without the aid of drugs.

Secondary Outcome Measures

1. Mean Number of Spontaneous Bowel Movements (SBM) Per Week Within 12 Weeks [within 12 weeks]

   Average weekly SBM frequency was calculated from data collected from Week 1 through Week 12

2. Number of Participants With the First Post-dose Spontaneous Bowel Movement Within 48 Hours Post-dose [within 48 hours post-dose]

   The number of participants who experienced their first post-dose Spontaneous Bowel Movement within 24 and 48 hours after dosing started.

3. Number of Participants Classified as Responders [within 12 weeks]

   Number of participants who remained on treatment for at least 8 weeks, and reported at least 3 SBMs for at least half the weeks on study.

4. Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity [within 12 weeks]

   Measures collected over 12-week treatment period were averaged, and the score at baseline was subtracted from the score at week 12 to determine the change from baseline. Straining scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Stool consistency scale: 0 = very loose, 1 = loose, 2 = normal, 3 = hard, 4 = very hard (little balls) - middle scores are best; Constipation severity scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Abdominal bloating scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Abdominal discomfort scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Bowel habit regularity scale: 7-point scale, where 1 = very regular and 7 = very irregular - higher scores are worse

5. Participant Reported Outcome of Treatment Effectiveness [within 12 weeks]

   Participants rated treatment effectiveness at the end of each treatment week during the study on a 5-point scale, where 0 = not at all effective, 1 = a little bit effective, 2 = moderately effective, 3 = quite a bit effective, 4 = extremely effective. The 12 weekly scores were averaged. Higher scores mean the drug was more effective.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Consistent treatment for chronic, non-cancer-related pain with any full agonist opioid for at least 30 days prior to screening.

• Diagnosis of opioid-induced bowel dysfunction (OBD) as confirmed during the screening period.

• If patient has a history of chronic constipation, condition must have been exacerbated by initiation of opioid treatment.

• Use of prescribed or Over-the-Counter (OTC) medication that affects gastrointestinal motility (other than opioid therapy) must be discontinued during the study.

• If treated for clinical depression with Selective serotonin reuptake inhibitor (SSRIs), Serotonin-norepinephrine reuptake inhibitor (SNRIs), or Monoamine oxidase inhibitor (MAO) inhibitors, treatment must have been at a stable dose for at least 30 days prior to screening.

• Use of laxative and stool softeners (with the exception of approved rescue medications) must be discontinued while on study.

Exclusion Criteria:

• Treatment with opioid therapy for cancer-related pain, abdominal pain, scleroderma, and/or for the management of drug addiction.

• Patient has been treated for cancer in the past 5 years (with the exception of localized basal cell, squamous cell skin cancer, or in situ cancer that has been resected).

• Opioid dose adjustment (+/- 30%), and/or change in opioid agent or route of administration within 30 days of screening.

• Gastrointestinal or abdominal surgical procedures within 90 days prior to screening.

• Non-ambulatory patients, or those who are unable to eat/drink, take oral medications, or to hold down oral medications due to vomiting.

• Female patients of childbearing potential who are unable/unwilling to use protocol-specified method(s) of birth control and/or are pregnant, nursing, or plan to become pregnant or nurse during the study.

• Prior use of Amitiza, lubiprostone, SPI-0211, or RU-0211.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Birmingham Pain Center	Birmingham	Alabama	United States	35242
2	Simon Williamson Clinic, PC	Hueytown	Alabama	United States	35023
3	Alabama Orthopedic Clinic	Mobile	Alabama	United States	36608
4	Clinical Research Advantage, Inc./ Mesa Family Medical Center	Mesa	Arizona	United States	85203
5	Clinical Research Advantage, Inc.	Tempe	Arizona	United States	85282
6	Harmony Clinical Research, Inc.	Tucson	Arizona	United States	85705
7	Verona Clinical Research, Inc.	Tucson	Arizona	United States	85710-3539
8	Quality of Life Medical & Research Center, LLC	Tucson	Arizona	United States	85712
9	Genova Clinical Research, Inc.	Tucson	Arizona	United States	85741
10	Pusch Ridge Family Medicine / WC Clinical Research	Tucson	Arizona	United States	85741
11	Advanced Clinical Research Institute	Anaheim	California	United States	92801
12	Orange County Clinical Trials, Inc.	Anaheim	California	United States	92801
13	Gregory J. Wiener, MD PC	Chula Vista	California	United States	91910
14	Digestive and Liver Disease Specialists	Garden Grove	California	United States	92840
15	RX Clinical Research, Inc	Garden Grove	California	United States	92843
16	Physicians Clinical Research Corporation	Laguna Hills	California	United States	92653
17	Loma Linda University Physicians Medical Group	Loma Linda	California	United States	92354
18	HealthCare Partners Medical Group	Long Beach	California	United States	90807
19	Impact Clinical Trials	Los Angeles	California	United States	90036
20	The Regents of the University of California, Los Angeles	Los Angeles	California	United States	90095
21	Pasadena Rehabilitation Institute	Pasadena	California	United States	91105
22	Northern California Research Corporation	Sacramento	California	United States	95831
23	SB Family Medicine	Solana Beach	California	United States	92075
24	Lynn Institute of the Rockies	Colorado Springs	Colorado	United States	80909
25	Lynn Institute of Pueblo	Pueblo	Colorado	United States	81001
26	Advanced Diagnostic Pain Treatment Center	New Haven	Connecticut	United States	06511
27	International Research Clinicians of Conneticut	Ridgefield	Connecticut	United States	06877
28	New England Research Associates, LLC	Trumbull	Connecticut	United States	06611
29	Meridien Research	Brooksville	Florida	United States	34613
30	South Lake Pain Institute	Clermont	Florida	United States	34711
31	Century Clinical Research	Daytona Beach	Florida	United States	32117
32	International Medical Research	Daytona Beach	Florida	United States	32117
33	Clinical Physiology Associates/Clinical Study Center	Fort Myers	Florida	United States	33916
34	Southeaster Integrated Medical, PL d/b/a Florida Medical Research Institute	Gainesville	Florida	United States	32607
35	Palm Beach Research Center	West Palm Beach	Florida	United States	33409
36	North Georgia Premier Research	Dawsonville	Georgia	United States	30534
37	Best Clinical Research	Decatur	Georgia	United States	30034
38	Drug Studies America	Marietta	Georgia	United States	30060
39	Pinnacle Trials Inc.	Stockbridge	Georgia	United States	30281
40	Rosemark Women Care Specialists	Idaho Falls	Idaho	United States	83404
41	Saltzer Medical Group	Nampa	Idaho	United States	83686
42	Millenium Pain Center	Bloomington	Illinois	United States	61701
43	University of Illinois Medical Center	Chicago	Illinois	United States	60612
44	Redhead Research Inc., dba Research Associates of Central Illinois	Peoria	Illinois	United States	61614
45	Integrated Clinical Trial Services, Inc.	West Des Moines	Iowa	United States	50265
46	The Pain Treatment Center of the Bluegrass and Ballard Wright, MD PSC	Lexington	Kentucky	United States	40503
47	Gulf Coast Research, LLC	Baton Rouge	Louisiana	United States	70808
48	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
49	The Willis-Knighton Pain Management Center	Shreveport	Louisiana	United States	71103
50	Pain and Rehabilitation Medicine	Bethesda	Maryland	United States	20814
51	The Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
52	Professional Clinical Research, Benzonia	Benzonia	Michigan	United States	49616
53	Center for Clinical Studies	Dearborn	Michigan	United States	48124
54	Apex Medical Research, AMR, Inc.	Flint	Michigan	United States	48504
55	Digestive Health Specialists, PA	Tupelo	Mississippi	United States	38801
56	Impact Clinical Trials, Las Vegas	Las Vegas	Nevada	United States	89106
57	Office of Stephen H. Miller, MD	Las Vegas	Nevada	United States	89106
58	University of Nevada	Reno	Nevada	United States	89557
59	Cooper Health System	Camden	New Jersey	United States	08103
60	UMDNJ	Stratford	New Jersey	United States	08084
61	Partners in Primary Care	Voorhees	New Jersey	United States	08043
62	Abraham D. Morganoff, MD PA	Watchung	New Jersey	United States	07069
63	Northway Medical Associates	Fulton	New York	United States	13069
64	Long Island Clinical Research Associates, LLP	Great Neck	New York	United States	11021
65	Long Island Gastrointestinal Research Group	Great Neck	New York	United States	11023
66	University of Rochester	Rochester	New York	United States	14642
67	Diversified Research	Durham	North Carolina	United States	27704
68	Medoff Medical/ Vital re:Search	Greensboro	North Carolina	United States	27408
69	Carolina Pharmaceutical Research	Statesville	North Carolina	United States	28625
70	Center for Clinical Research, LLC	Winston-Salem	North Carolina	United States	27103
71	St. Alexius Medical Center	Bismarck	North Dakota	United States	58501
72	Cleveland Clinic	Cleveland	Ohio	United States	44195
73	COR Clinical Research, LLC	Oklahoma City	Oklahoma	United States	73103
74	Pain Research of Oregon, LLC	Eugene	Oregon	United States	97401
75	Affinity Research	Portland	Oregon	United States	97219
76	Private Practice of Dr. Hasan	Allentown	Pennsylvania	United States	18104
77	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
78	Preferred Primary Care Physicians	Uniontown	Pennsylvania	United States	15401
79	Partners in Clinical Research	Cumberland	Rhode Island	United States	02864
80	University Gastroenterology	Providence	Rhode Island	United States	02905
81	Trident Institute of Medical Research, LLC	North Charleston	South Carolina	United States	29406
82	Southeastern Clinical Research	Chattanooga	Tennessee	United States	37403
83	Comprehensive Pain Specialists, PLLC	Hendersonville	Tennessee	United States	37075
84	Vanderbilt University - Interventional Pain Center	Nashville	Tennessee	United States	37232
85	Integrity Clinical Research, LLC	Savannah	Tennessee	United States	38372
86	Dallas VA Research Corporation, Inc.	Dallas	Texas	United States	75216
87	Bexar Clinical Trials, LLC	Dallas	Texas	United States	75234
88	Permian Research Foundation	Odessa	Texas	United States	79761
89	Bexar Clinical Trials, LLC	Richardson	Texas	United States	75082
90	Salt Lake Research, PLLC	Salt Lake City	Utah	United States	84107
91	Digestive and Liver Disease Specialists	Norfolk	Virginia	United States	23502
92	General Clinical Research Center, Virginia Commonwealth University, North Hospital	Richmond	Virginia	United States	23298
93	Metro Physicians a Division of Wheaton Franciscan Medical Group	Milwaukee	Wisconsin	United States	53221
94	Clement J. Zablocki VA Medical Center	Milwaukee	Wisconsin	United States	53295
95	Health Sciences Center	Hamilton	Ontario	Canada	L8N 3Z5

Sponsors and Collaborators

• Sucampo Pharma Americas, LLC
• Sucampo Pharmaceuticals, Inc.

Investigators

• Study Director: Clinical Team Leader, Mallinckrodt

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sucampo Pharma Americas, LLC
• ClinicalTrials.gov Identifier: NCT00595946
• Other Study ID Numbers: OBD0631
• First Posted: Jan 16, 2008
• Last Update Posted: Dec 16, 2019
• Last Verified: Dec 1, 2015

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Intestinal Diseases; Gastrointestinal Diseases; Opioid-Induced Constipation; Lubiprostone

Study Results

Participant Flow

Recruitment Details	Recruitment period: 03 August 2007 to 06 March 2009 Recruitment sites: 77 U.S. investigative sites and 3 Canadian investigative sites
Pre-assignment Detail	Safety evaluable population, defined as all participants who were randomized and dosed, according to the product actually received.

Arm/Group Title	Placebo	Lubiprostone
Arm/Group Description	Placebo : 0 mcg capsules twice daily (BID) for up to 12 weeks	Lubiprostone : 24 mcg capsules twice daily (BID) for up to 12 weeks
Period Title: Overall Study
STARTED	218	221
COMPLETED	154	152
NOT COMPLETED	64	69

Baseline Characteristics

Arm/Group Title	Placebo	Lubiprostone	Total
Arm/Group Description	Placebo : 0 mcg capsules twice daily (BID)	Lubiprostone : 24 mcg capsules twice daily (BID)	Total of all reporting groups
Overall Participants	217	221	438
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.9 (11.94)	50.1 (9.89)	50.0 (10.94)
Sex: Female, Male (Count of Participants)
Female	144 66.4%	136 61.5%	280 63.9%
Male	73 33.6%	85 38.5%	158 36.1%
Region of Enrollment (participants) [Number]
United States	216 99.5%	218 98.6%	434 99.1%
Canada	1 0.5%	3 1.4%	4 0.9%

Outcome Measures

1. Primary Outcome

Title	Mean Weekly Spontaneous Bowel Movements at Week 8
Description	Spontaneous bowel movements (SBMs) are defined as bowel movements without the aid of drugs.
Time Frame	at Week 8

Outcome Measure Data

Analysis Population Description

Per protocol population at Week 8 without dose reduction

Arm/Group Title	Placebo	Lubiprostone
Arm/Group Description	Placebo : 0 mcg capsules twice daily (BID)	Lubiprostone : 24 mcg capsules twice daily (BID)
Measure Participants	169	164
Mean (Standard Deviation) [SBMs/Week]	2.4 (3.25)	3.2 (3.35)

2. Secondary Outcome

Title	Mean Number of Spontaneous Bowel Movements (SBM) Per Week Within 12 Weeks
Description	Average weekly SBM frequency was calculated from data collected from Week 1 through Week 12
Time Frame	within 12 weeks

Outcome Measure Data

Analysis Population Description

Intention to treat with scores at all 12 weeks

Arm/Group Title	Placebo	Lubiprostone
Arm/Group Description	Placebo : 0 mcg capsules twice daily (BID)	Lubiprostone : 24 mcg capsules twice daily (BID)
Measure Participants	216	218
at Week 12	2.2 (3.26)	2.8 (3.60)
within 12 weeks	2.1 (2.35)	2.7 (2.59)

3. Secondary Outcome

Title	Number of Participants With the First Post-dose Spontaneous Bowel Movement Within 48 Hours Post-dose
Description	The number of participants who experienced their first post-dose Spontaneous Bowel Movement within 24 and 48 hours after dosing started.
Time Frame	within 48 hours post-dose

Outcome Measure Data

Analysis Population Description

Intention to treat

Arm/Group Title	Placebo	Lubiprostone
Arm/Group Description	Placebo : 0 mcg capsules twice daily (BID)	Lubiprostone : 24 mcg capsules twice daily (BID)
Measure Participants	217	221
within 24 hours	65 30%	89 40.3%
within 48 hours	116 53.5%	138 62.4%

4. Secondary Outcome

Title	Number of Participants Classified as Responders
Description	Number of participants who remained on treatment for at least 8 weeks, and reported at least 3 SBMs for at least half the weeks on study.
Time Frame	within 12 weeks

Outcome Measure Data

Analysis Population Description

Intention to Treat

Arm/Group Title	Placebo	Lubiprostone
Arm/Group Description	Placebo : 0 mcg capsules twice daily (BID)	Lubiprostone : 24 mcg capsules twice daily (BID)
Measure Participants	217	221
Count of Participants [Participants]	87 40.1%	103 46.6%

5. Secondary Outcome

Title	Mean Change From Baseline in Straining, Stool Consistency, Constipation Severity, Abdominal Bloating, Abdominal Discomfort, and Bowel Habit Regularity
Description	Measures collected over 12-week treatment period were averaged, and the score at baseline was subtracted from the score at week 12 to determine the change from baseline. Straining scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Stool consistency scale: 0 = very loose, 1 = loose, 2 = normal, 3 = hard, 4 = very hard (little balls) - middle scores are best; Constipation severity scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Abdominal bloating scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Abdominal discomfort scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe - higher scores are worse; Bowel habit regularity scale: 7-point scale, where 1 = very regular and 7 = very irregular - higher scores are worse
Time Frame	within 12 weeks

Outcome Measure Data

Analysis Population Description

Intention to Treat

Arm/Group Title	Placebo	Lubiprostone
Arm/Group Description	Placebo : 0 mcg capsules twice daily (BID)	Lubiprostone : 24 mcg capsules twice daily (BID)
Measure Participants	217	221
Straining	-0.6 (0.88)	-1.0 (1.00)
Stool consistency	-0.5 (0.77)	-0.8 (0.91)
Constipation severity	-0.4 (0.71)	-0.6 (0.74)
Abdominal bloating	-0.4 (0.63)	-0.4 (0.63)
Abdominal discomfort	-0.3 (0.63)	-0.5 (0.62)
Bowel habit regularity	-0.5 (1.63)	-0.6 (1.45)

6. Secondary Outcome

Title	Participant Reported Outcome of Treatment Effectiveness
Description	Participants rated treatment effectiveness at the end of each treatment week during the study on a 5-point scale, where 0 = not at all effective, 1 = a little bit effective, 2 = moderately effective, 3 = quite a bit effective, 4 = extremely effective. The 12 weekly scores were averaged. Higher scores mean the drug was more effective.
Time Frame	within 12 weeks

Outcome Measure Data

Analysis Population Description

Intention to Treat with all required scores

Arm/Group Title	Placebo	Lubiprostone
Arm/Group Description	Placebo : 0 mcg capsules twice daily (BID)	Lubiprostone : 24 mcg capsules twice daily (BID)
Measure Participants	214	211
Mean (Standard Deviation) [score on a scale]	1.3 (0.99)	1.6 (1.04)

Adverse Events

Time Frame	from time of first dose to 7 days after the final treatment (within 13 weeks)
Adverse Event Reporting Description	Treatment-emergent adverse events (TEAEs) are collected from participants based on the treatment actually received. TEAEs are defined as adverse events that began or got worse after the start of study drug. The safety evaluable population is based on the treatment actually received.
Arm/Group Title	Placebo		Lubiprostone
Arm/Group Description	Placebo : 0 mcg capsules twice daily (BID)		Lubiprostone : 24 mcg capsules twice daily (BID)
All Cause Mortality
	Placebo		Lubiprostone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/218 (0%)		0/221 (0%)
Serious Adverse Events
	Placebo		Lubiprostone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/218 (3.7%)		12/221 (5.4%)
Cardiac disorders
Myocardial infarction	1/218 (0.5%)		0/221 (0%)
Coronary artery disease	0/218 (0%)		1/221 (0.5%)
Angina unstable	0/218 (0%)		1/221 (0.5%)
Gastrointestinal disorders
Small intestinal obstruction	0/218 (0%)		1/221 (0.5%)
Duodenal ulcer perforation	0/218 (0%)		1/221 (0.5%)
Infections and infestations
Gastroenteritis	1/218 (0.5%)		1/221 (0.5%)
Pneumonia	1/218 (0.5%)		0/221 (0%)
Cellulitis	0/218 (0%)		1/221 (0.5%)
Bronchitis	1/218 (0.5%)		0/221 (0%)
Appendicitis	1/218 (0.5%)		0/221 (0%)
Injury, poisoning and procedural complications
Pelvic fracture	0/218 (0%)		1/221 (0.5%)
Ileum fracture	0/218 (0%)		1/221 (0.5%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	1/218 (0.5%)		0/221 (0%)
Bursitis	1/218 (0.5%)		0/221 (0%)
Back pain	0/218 (0%)		1/221 (0.5%)
Nervous system disorders
Toxic encephalopathy	0/218 (0%)		1/221 (0.5%)
Psychiatric disorders
Suicide Attempt	0/218 (0%)		1/221 (0.5%)
Postpartum depression	0/218 (0%)		1/221 (0.5%)
Bipolar disorder	0/218 (0%)		1/221 (0.5%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/218 (0.5%)		0/221 (0%)
Vascular disorders
Hypertension	0/218 (0%)		1/221 (0.5%)
Other (Not Including Serious) Adverse Events
	Placebo		Lubiprostone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/218 (10.1%)		59/221 (26.7%)
Gastrointestinal disorders
Nausea	13/218 (6%)		35/221 (15.8%)
Diarrhoea	7/218 (3.2%)		21/221 (9.5%)
Abdominal distension	5/218 (2.3%)		17/221 (7.7%)

Limitations/Caveats

Three participants were randomized to the wrong product, so only the safety evaluable set includes all participants according to the product actually received.

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 results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.