Study to Investigate Prucalopride vs. Polyethylene Glycol 3350 on Colon Activity

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01707667
• Collaborator: (none)
• Enrollment: 13
• Locations: 3
• Arms: 2
• Actual Duration (Months): 9
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

To evaluate the different effects of prucalopride and PEG 3350 + electrolytes on colon motor activity in subjects that are chronically constipated.

Condition or Disease	Intervention/Treatment	Phase
Chronic Constipation	Drug: prucalopride; Drug: PEG 3350	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Randomized, Crossover, Reader-blinded Study to Investigate the Effect of Prucalopride and Polyethylene Glycol 3350 on Colon Motility With Intramural Manometry in Subjects With Chronic Constipation
• Actual Study Start Date: Feb 27, 2013
• Actual Primary Completion Date: Nov 27, 2013
• Actual Study Completion Date: Nov 27, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prucalopride	Drug: prucalopride; One 2 mg tablet orally administered on Day 1; Other Names: Resolor (Marketed name in Europe)
Active Comparator: PEG 3350	Drug: PEG 3350; 13.8g polyethylene glycol (PEG) 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water. Administered twice orally on Day 1(once in the morning and once prior to lunch).; Other Names: Movicol

Outcome Measures

Primary Outcome Measures

1. The Number of High-Amplitude Propagating Contractions (HAPC) [over 12 hours post-dose]

   Manometry recordings were read by an experienced gastroenterologist who was blinded to the treatment each subject received. The tracings were analyzed using computer-based validated software. HAPC and manometry data were available for every sensor as well as average values for each HAPC and manometry time point. The primary outcome analysis of HAPC data used the following threshold: Mean amplitude ≥100mmHg and extension ≥20cm (9 sensors).

Secondary Outcome Measures

1. Area Under the Concentration Curve (AUC) of All HAPCs [over 12 hours post-dose]

   The AUC of all HAPCs during the first 12 hours after treatment was calculated as the sum of the AUC at all sensors of each HAPC at the ≥100mmHg and ≥20cm threshold.

2. The Mean Amplitude of HAPC [over 12 hours post-dose]

   The mean amplitude of all HAPCs was calculated as the sum of the mean amplitude for each HAPC divided by the number of HAPCs.

3. Time to First HAPC [over 12 hours post-dose]

   The median (95% CI) time to first HAPC after administration of investigational product with amplitude ≥100mmHg and extension ≥20cm.

4. Propagation Velocity of HAPC [over 12 hours post-dose]

   Propagation velocity was calculated as the extension divided by the duration for each HAPC. Mean propagation velocity is the sum of the propagation velocities divided by the number of HAPCs.

5. Duration of HAPC [over 12 hours post-dose]

   The mean duration of all HAPCs was calculated as the sum of the duration of each HAPC divided by the number of HAPCs.

6. Motility Index [over 12 hours post-dose]

   Motility index (mmHg) was summarized for the following 3 time points: pre-dose, 0-5 hours post-dose, and 5-12 hours post-dose. The motility index is defined as the natural logarithm of all peak amplitudes of every contraction +1.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Chronic constipation

• Male or female ages 18-75 years

• Non-pregnant, non-lactating female

Exclusion Criteria:

• Drug-induced constipation

• Subjects suffering from secondary causes of chronic constipation, such as:

• Endocrine disorders, e.g. hypopituitarism, hypothyroidism, hypercalcemia, pseudohypoparathyroidism, pheochromocytoma or glucagon-producing tumors, unless these are controlled by appropriate medical therapy.

• Metabolic disorders, e.g. porphyria, uremia, hypokalemia or amyloid neuropathy, unless these are controlled by appropriate medical therapy

• Neurological disorders, e.g. Parkinson's disease, cerebral tumors, cerebrovascular accidents, multiple sclerosis, meningocele, aganglionosis, hypoganglionosis, hyperganglionosis, autonomic neuropathy or neuropathy due to chemotherapy, spinal cord injury, Chaga's disease, or major depression

• Surgery.

• Subjects with insulin-dependent diabetes mellitus

• Rectal evacuation disorder/outlet obstruction

• Subjects with intestinal perforation or obstruction

• Severe renal impairment

• Subjects with a history of alcohol or drug abuse

• Subjects with lactose intolerance

• Subjects with clinically significant cardiac, vascular, liver, pulmonary, endocrine, neurological or psychiatric disorders

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oklahoma Foundation for Digestive Research	Oklahoma City	Oklahoma	United States	73104
2	UNIVERSITY OF LEUVEN, UNVERSITY HOSPITAL, Gasthuisberg	Leuven		Belgium	3000
3	Barts Health NHS Trust	Whitechapel	London	United Kingdom	E1 1BB

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT01707667
• Other Study ID Numbers: SPD555-403; 2012-002495-13
• First Posted: Oct 16, 2012
• Last Update Posted: Jul 2, 2021
• Last Verified: Jun 1, 2021

• Additional relevant MeSH terms: Constipation; Prucalopride; Polyethylene glycol 3350

Study Results

Participant Flow

Arm/Group Title	PRU-PEG	PEG-PRU
Arm/Group Description	A single dose of prucalopride 2mg in the first period followed by 2 doses of polyethylene glycol (PEG) 3350 (13.8g) plus electrolytes in the second period.	Two doses of PEG 3350 (13.8g) plus electrolytes in the first period followed by a single dose of prucalopride 2mg in the second period.
Period Title: Period 1
STARTED	7	6
COMPLETED	6	6
NOT COMPLETED	1	0
Period Title: Period 1
STARTED	6	6
COMPLETED	6	6
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	PRU-PEG	PEG-PRU	Total
Arm/Group Description	A single dose of prucalopride 2mg in the first period followed by 2 doses of polyethylene glycol (PEG) 3350 (13.8g) plus electrolytes in the second period.	Two doses of PEG 3350 (13.8g) plus electrolytes in the first period followed by a single dose of prucalopride 2mg in the second period.	Total of all reporting groups
Overall Participants	7	6	13
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	40.3 (11.04)	35.2 (13.18)	37.9 (11.85)
Age, Customized (Count of Participants)
18 - 64	7 100%	6 100%	13 100%
Sex: Female, Male (Count of Participants)
Female	7 100%	6 100%	13 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
UNITED STATES	7 100%	6 100%	13 100%

Outcome Measures

1. Primary Outcome

Title	The Number of High-Amplitude Propagating Contractions (HAPC)
Description	Manometry recordings were read by an experienced gastroenterologist who was blinded to the treatment each subject received. The tracings were analyzed using computer-based validated software. HAPC and manometry data were available for every sensor as well as average values for each HAPC and manometry time point. The primary outcome analysis of HAPC data used the following threshold: Mean amplitude ≥100mmHg and extension ≥20cm (9 sensors).
Time Frame	over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

The Pharmacodynamic Analysis Set consisted of all randomized subjects who had taken at least 1 dose of investigational product and who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.

Arm/Group Title	Prucalopride	PEG 3350
Arm/Group Description	A single dose of 2mg prucalopride, administered orally as tablets with 125mL of water on Day 1.	13.8g polyethylene glycol (PEG) 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water. Administered twice orally on Day 1 (once in the morning and once prior to lunch).
Measure Participants	12	12
Least Squares Mean (Standard Error) [Number of HAPC with amplitude ≥100mmHg]	8.7 (2.06)	2.9 (2.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prucalopride, PEG 3350
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Linear Mixed-Effect Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.8
	Confidence Interval	(2-Sided) 95%; 1.6 to 9.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Area Under the Concentration Curve (AUC) of All HAPCs
Description	The AUC of all HAPCs during the first 12 hours after treatment was calculated as the sum of the AUC at all sensors of each HAPC at the ≥100mmHg and ≥20cm threshold.
Time Frame	over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

The Pharmacodynamic Analysis Set consisted of all randomized subjects who had taken at least 1 dose of investigational product and who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.

Arm/Group Title	Prucalopride	PEG 3350
Arm/Group Description	A single dose of 2mg prucalopride, administered orally as tablets with 125mL of water on Day 1.	13.8g polyethylene glycol (PEG) 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water. Administered twice orally on Day 1 (once in the morning and once prior to lunch).
Measure Participants	9	6
Least Squares Mean (Standard Error) [mmHg.sec]	110204.1 (28279.91)	41152.7 (34432.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prucalopride, PEG 3350
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.079
	Comments
	Method	Linear Mixed-Effect Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	69051.4
	Confidence Interval	(2-Sided) 95%; -12004.5 to 150107.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	The Mean Amplitude of HAPC
Description	The mean amplitude of all HAPCs was calculated as the sum of the mean amplitude for each HAPC divided by the number of HAPCs.
Time Frame	over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

The Pharmacodynamic Analysis Set consisted of all randomized subjects who had taken at least 1 dose of investigational product and who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.

Arm/Group Title	Prucalopride	PEG 3350
Arm/Group Description	A single dose of 2mg prucalopride, administered orally as tablets with 125mL of water on Day 1.	13.8g polyethylene glycol (PEG) 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water. Administered twice orally on Day 1 (once in the morning and once prior to lunch).
Measure Participants	9	6
Least Squares Mean (Standard Error) [mmHg]	199.0 (15.15)	189.8 (19.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prucalopride, PEG 3350
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.717
	Comments
	Method	Linear Mixed-Effect Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.2
	Confidence Interval	(2-Sided) 95%; -45.3 to 63.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Time to First HAPC
Description	The median (95% CI) time to first HAPC after administration of investigational product with amplitude ≥100mmHg and extension ≥20cm.
Time Frame	over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

The Pharmacodynamic Analysis Set included all subjects in the Safety Analysis Set who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.

Arm/Group Title	Prucalopride	PEG 3350
Arm/Group Description	A single dose of 2mg prucalopride, administered orally as tablets with 125mL of water on Day 1.	13.8g polyethylene glycol (PEG) 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water. Administered twice orally on Day 1 (once in the morning and once prior to lunch).
Measure Participants	9	6
Median (95% Confidence Interval) [hours]	4.5	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prucalopride, PEG 3350
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.295
	Comments
	Method	Log Rank
	Comments

5. Secondary Outcome

Title	Propagation Velocity of HAPC
Description	Propagation velocity was calculated as the extension divided by the duration for each HAPC. Mean propagation velocity is the sum of the propagation velocities divided by the number of HAPCs.
Time Frame	over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

The Pharmacodynamic Analysis Set consisted of all randomized subjects who had taken at least 1 dose of investigational product and who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.

Arm/Group Title	Prucalopride	PEG 3350
Arm/Group Description	A single dose of 2mg prucalopride, administered orally as tablets with 125mL of water on Day 1.	13.8g polyethylene glycol (PEG) 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water. Administered twice orally on Day 1 (once in the morning and once prior to lunch).
Measure Participants	9	6
Least Squares Mean (Standard Error) [cm/sec]	0.467 (0.0803)	0.646 (0.1074)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prucalopride, PEG 3350
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.180
	Comments
	Method	Linear Mixed-Effect Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.179
	Confidence Interval	(2-Sided) 95%; -0.465 to 0.107
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Duration of HAPC
Description	The mean duration of all HAPCs was calculated as the sum of the duration of each HAPC divided by the number of HAPCs.
Time Frame	over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

The Pharmacodynamic Analysis Set consisted of all randomized subjects who had taken at least 1 dose of investigational product and who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.

Arm/Group Title	Prucalopride	PEG 3350
Arm/Group Description	A single dose of 2mg prucalopride, administered orally as tablets with 125mL of water on Day 1.	13.8g polyethylene glycol (PEG) 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water. Administered twice orally on Day 1 (once in the morning and once prior to lunch).
Measure Participants	9	6
Least Squares Mean (Standard Error) [sec]	84.9 (8.05)	69.1 (10.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prucalopride, PEG 3350
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.225
	Comments
	Method	Linear Mixed-Effect Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	15.8
	Confidence Interval	(2-Sided) 95%; -12.6 to 44.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Motility Index
Description	Motility index (mmHg) was summarized for the following 3 time points: pre-dose, 0-5 hours post-dose, and 5-12 hours post-dose. The motility index is defined as the natural logarithm of all peak amplitudes of every contraction +1.
Time Frame	over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

The Pharmacodynamic Analysis Set consisted of all randomized subjects who had taken at least 1 dose of investigational product and who had 1 evaluable manometry assessment (minimum of 4 hours of manometry recordings from the intake of investigational product) for each treatment period.

Arm/Group Title	Prucalopride	PEG 3350
Arm/Group Description	A single dose of 2mg prucalopride, administered orally as tablets with 125mL of water on Day 1.	13.8g polyethylene glycol (PEG) 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water. Administered twice orally on Day 1 (once in the morning and once prior to lunch).
Measure Participants	9	11
Pre-Dose	9.467 (0.4668)	8.312 (0.4403)
0-5 hours post-dose	13.661 (0.3221)	13.349 (0.3520)
5-12 hours post-dose	14.208 (0.2976)	14.390 (0.2489)

Adverse Events

Arm/Group Title	Prucalopride		Polyethylene Glycol
Arm/Group Description	A single dose of 2mg prucalopride, administered orally as tablets with 125mL of water on Day 1.		13.8g polyethylene glycol (PEG) 3350 with sodium bicarbonate, sodium chloride, and potassium chloride as a solution in water. Administered twice orally on Day 1 (once in the morning and once prior to lunch).
All Cause Mortality
	Prucalopride		Polyethylene Glycol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Prucalopride		Polyethylene Glycol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Prucalopride		Polyethylene Glycol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/13 (23.1%)		0/12 (0%)
Gastrointestinal disorders
ABDOMINAL PAIN	2/13 (15.4%)	2	0/12 (0%)	0
DIARRHOEA	1/13 (7.7%)	1	0/12 (0%)	0
NAUSEA	1/13 (7.7%)	1	0/12 (0%)	0
RECTAL HAEMORRHAGE	1/13 (7.7%)	1	0/12 (0%)	0
Nervous system disorders
HEADACHE	1/13 (7.7%)	1	0/12 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.