Lubiprostone in Children With Functional Constipation

• ClinicalTrials.gov Identifier: NCT02042183
• Recruitment Status: Completed
• First Posted: January 22, 2014
• Results First Posted: July 21, 2020
• Last Update Posted: July 21, 2020
• Sponsor: Sucampo Pharma Americas, LLC
• Collaborator: Sucampo AG
• Information provided by (Responsible Party): Mallinckrodt ( Sucampo Pharma Americas, LLC )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Constipation - Functional
• Interventions: Drug: Lubiprostone; Drug: Placebo
• Enrollment: 606

Participant Flow

Recruitment Details
Pre-assignment Details	The two weeks between screening and treatment were used as a washout period for disallowed medications.

Arm/Group Title	Lubiprostone	Placebo
Arm/Group Description	Participants receive lubiprostone twice daily (BID)	Participants receive placebo BID up to 12 weeks
Period Title: Overall Study
Started	404	202
Safety Population [1]	400	195
Modified Intent-to-treat (mITT) [2]	399	195
Completed	339	166
Not Completed	65	36
Reason Not Completed
Physician Decision	7	2
Lack of Efficacy	4	3
Non-compliance with Study Drug	2	3
Adverse Event	17	6
Other	3	3
Withdrawal by Subject	21	16
Site Terminated by Sponsor	2	1
Lost to Follow-up	9	2
[1] All participants who took at least one dose of double-blinded study medication.; [2] All participants in safety population who have at least one efficacy assessment.

Baseline Characteristics

Arm/Group Title		Lubiprostone	Placebo	Total
Arm/Group Description		Participants receive lubiprostone BID up to 12 weeks	Participants receive placebo BID up to 12 weeks	Total of all reporting groups
Overall Number of Baseline Participants		404	202	606
Baseline Analysis Population Description		All enrolled participants
Age, Customized [1]; Measure Type: Count of Participants; Unit of measure: Participants
6-9 years	Number Analyzed	399 participants	195 participants	594 participants
		142 35.6%	66 33.8%	208 35.0%
10-13 years	Number Analyzed	399 participants	195 participants	594 participants
		153 38.3%	78 40.0%	231 38.9%
14-17 years	Number Analyzed	399 participants	195 participants	594 participants
		104 26.1%	51 26.2%	155 26.1%
		[1] Measure Analysis Population Description: The modified intention-to-treat (mITT) population was used for reporting this baseline measure. The mITT population excluded participants from two sites that were terminated by the sponsor.
Sex: Female, Male [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	399 participants	195 participants	594 participants
	Female	216 54.1%	106 54.4%	322 54.2%
	Male	183 45.9%	89 45.6%	272 45.8%
		[1] Measure Analysis Population Description: The modified intention-to-treat (mITT) population was used for reporting this baseline measure. The mITT population excluded participants from two sites that were terminated by the sponsor.
Ethnicity (NIH/OMB) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	399 participants	195 participants	594 participants
	Hispanic or Latino	76 19.0%	44 22.6%	120 20.2%
	Not Hispanic or Latino	323 81.0%	151 77.4%	474 79.8%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
		[1] Measure Analysis Population Description: The modified intention-to-treat (mITT) population was used for reporting this baseline measure. The mITT population excluded participants from two sites that were terminated by the sponsor.
Race (NIH/OMB) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	399 participants	195 participants	594 participants
	American Indian or Alaska Native	0 0.0%	3 1.5%	3 0.5%
	Asian	3 0.8%	3 1.5%	6 1.0%
	Native Hawaiian or Other Pacific Islander	1 0.3%	1 0.5%	2 0.3%
	Black or African American	67 16.8%	39 20.0%	106 17.8%
	White	308 77.2%	138 70.8%	446 75.1%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	20 5.0%	11 5.6%	31 5.2%
		[1] Measure Analysis Population Description: The modified intention-to-treat (mITT) population was used for reporting this baseline measure. The mITT population excluded participants from two sites that were terminated by the sponsor.
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
Canada	Number Analyzed	404 participants	202 participants	606 participants
		5	7	12
Netherlands	Number Analyzed	404 participants	202 participants	606 participants
		14	32	46
Belgium	Number Analyzed	404 participants	202 participants	606 participants
		1	3	4
United States	Number Analyzed	404 participants	202 participants	606 participants
		174	348	522
Poland	Number Analyzed	404 participants	202 participants	606 participants
		3	8	11
United Kingdom	Number Analyzed	404 participants	202 participants	606 participants
		4	6	10
France	Number Analyzed	404 participants	202 participants	606 participants
		1	0	1

Outcome Measures

1. Primary Outcome

Title	Number of Participants Classified as Overall Responders at Week 12
Description	An overall responder is defined as a participant who qualified as a weekly responder for 9 of the 12 treatment weeks, with durability demonstrated by at least 3 of the responder weeks occurring during the last 4 weeks of the treatment period. A weekly responder is defined as a participant who has at least 3 spontaneous bowel movements during the week, and at least one more than at baseline.
Time Frame	at Week 12

Outcome Measure Data

Analysis Population Description

mITT population

Arm/Group Title	Lubiprostone	Placebo
Arm/Group Description:	Participants receive lubiprostone BID for up to 12 weeks	Participants receive placebo BID for up to 12 weeks.
Overall Number of Participants Analyzed	399	195
Measure Type: Count of Participants; Unit of Measure: Participants
	76 19.0%	28 14.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lubiprostone, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1609
	Comments	Cochran-Mantel-Haenszel (CMH) test stratified by baseline spontaneous bowel movement (SBM) frequency (<1.5 or ≥1.5)
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

2. Secondary Outcome

Title	Mean Number of SBMs Observed Each Week for 12 Weeks
Description	Data provided is based on observed cases. Baseline is the average of the 2 weeks before being randomized. Participants are summarized by actual dose received after week 1.
Time Frame	within 12 Weeks

Outcome Measure Data

Analysis Population Description

mITT

Arm/Group Title		Lubiprostone	Placebo
Arm/Group Description:		Participants receive lubiprostone BID up to 12 weeks	Participants receive placebo BID up to 12 weeks
Overall Number of Participants Analyzed		399	195
Mean (Standard Deviation); Unit of Measure: Spontaneous bowel movements
at Baseline	Number Analyzed	399 participants	195 participants
		1.40 (0.836)	1.42 (0.855)
at Week 1	Number Analyzed	387 participants	186 participants
		2.65 (2.137)	2.50 (2.117)
at Week 2	Number Analyzed	380 participants	189 participants
		2.68 (2.422)	2.69 (2.328)
at Week 3	Number Analyzed	371 participants	184 participants
		2.85 (2.446)	2.59 (2.435)
at Week 4	Number Analyzed	370 participants	183 participants
		2.94 (2.531)	2.69 (2.499)
at Week 5	Number Analyzed	356 participants	175 participants
		2.91 (2.498)	2.68 (2.495)
at Week 6	Number Analyzed	360 participants	172 participants
		2.91 (2.454)	2.65 (2.163)
at Week 7	Number Analyzed	342 participants	172 participants
		2.81 (2.483)	2.75 (2.704)
at Week 8	Number Analyzed	337 participants	172 participants
		2.94 (2.501)	2.64 (2.444)
at Week 9	Number Analyzed	336 participants	165 participants
		2.83 (2.286)	2.37 (1.875)
at Week 10	Number Analyzed	330 participants	163 participants
		2.68 (2.326)	2.40 (2.103)
at Week 11	Number Analyzed	328 participants	163 participants
		2.78 (2.251)	2.60 (2.362)
at Week 12	Number Analyzed	312 participants	154 participants
		2.90 (2.497)	2.75 (2.530)

Adverse Events

Time Frame	Treatment emergent adverse events (TEAEs) in the safety population are reported for 14 weeks
Adverse Event Reporting Description	Treatment-emergent adverse events are defined as any event with an onset date that is on or after the first dose of study medication and with an onset date no more than 7 days after the last dose of study medication.; Participants are summarized in the dosing group assigned at randomization. The total number of participants in the 5% non-serious adverse event population was not provided, so the number affected is a total number of adverse events experienced by the 5% population.
Arm/Group Title	Lubiprostone	Placebo
Arm/Group Description	Participants receive lubiprostone BID for up to 12 weeks	Participants received placebo BID for up to 12 weeks
All-Cause Mortality
	Lubiprostone	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/400 (0.00%)	0/195 (0.00%)
Serious Adverse Events
	Lubiprostone	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	11/400 (2.75%)	7/195 (3.59%)
Gastrointestinal disorders
Faecaloma † 1	4/400 (1.00%)	2/195 (1.03%)
Constipation † 1	0/400 (0.00%)	2/195 (1.03%)
General disorders
Chest pain † 1	1/400 (0.25%)	0/195 (0.00%)
Immune system disorders
Anaphylactoid reaction † 1	1/400 (0.25%)	0/195 (0.00%)
Infections and infestations
Cellulitis † 1	1/400 (0.25%)	0/195 (0.00%)
Injury, poisoning and procedural complications
Ligament sprain † 1	0/400 (0.00%)	1/195 (0.51%)
Nervous system disorders
Epilepsy † 1	0/400 (0.00%)	1/195 (0.51%)
Psychiatric disorders
Suicidal ideation † 1	1/400 (0.25%)	1/195 (0.51%)
Major depression † 1	1/400 (0.25%)	0/195 (0.00%)
Hand-foot-and-mouth disease † 1	1/400 (0.25%)	0/195 (0.00%)
Skin and subcutaneous tissue disorders
Rash † 1	1/400 (0.25%)	0/195 (0.00%)
Surgical and medical procedures
Meniscus operation † 1	0/400 (0.00%)	1/195 (0.51%)
1 Term from vocabulary, MedDRA (17.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Lubiprostone	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	234/400 (58.50%)	82/195 (42.05%)
Gastrointestinal disorders
Nausea † 1	57/400 (14.25%)	14/195 (7.18%)
Vomiting † 1	45/400 (11.25%)	12/195 (6.15%)
Abdominal pain † 1	42/400 (10.50%)	23/195 (11.79%)
Diarrhoea † 1	28/400 (7.00%)	6/195 (3.08%)
Abdominal pain upper † 1	20/400 (5.00%)	6/195 (3.08%)
Infections and infestations
Pharyngitis streptococcal † 1	8/400 (2.00%)	11/195 (5.64%)
Nervous system disorders
Headache † 1	34/400 (8.50%)	10/195 (5.13%)
1 Term from vocabulary, MedDRA (17.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

Outcome measures were not identified as such in the protocol, and some tables were recalculated at the request of the Food and Drug Administration, so revised data necessary to calculate the primary endpoint were posted.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

 

Results Point of Contact

• Name/Title: Clinical Team Leader
• Organization: Mallinckrodt Pharmaceuticals
• Phone: 800-844-2830 ext 5
• EMail: clinicaltrials@mnk.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Benninga MA, Hussain SZ, Sood MR, Nurko S, Hyman P, Clifford RA, O'Gorman M, Losch-Beridon T, Mareya S, Lichtlen P, Di Lorenzo C. Lubiprostone for Pediatric Functional Constipation: Randomized, Controlled, Double-Blind Study With Long-term Extension. Clin Gastroenterol Hepatol. 2022 Mar;20(3):602-610.e5. doi: 10.1016/j.cgh.2021.04.005. Epub 2021 Apr 7.

• Responsible Party: Mallinckrodt ( Sucampo Pharma Americas, LLC )
• ClinicalTrials.gov Identifier: NCT02042183
• Other Study ID Numbers: SAG/0211PFC-1131; 2013-004384-31 ( EudraCT Number ); EMEA-000245-PIP01-08 ( Other Identifier: EMEA Paediatric Investigational Plan )
• First Submitted: January 17, 2014
• First Posted: January 22, 2014
• Results First Submitted: May 4, 2020
• Results First Posted: July 21, 2020
• Last Update Posted: July 21, 2020