Chronic Constipation
Conditions
Brief summary
To evaluate the different effects of prucalopride and PEG 3350 + electrolytes on colon motor activity in subjects that are chronically constipated.
Interventions
DRUGprucalopride
One 2 mg tablet orally administered on Day 1
DRUGPEG 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).
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Belgium, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PRU-PEG 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. | 7 |
| PEG-PRU 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. | 6 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | expulsion of colonic sensor catheter | 1 | 0 |
Baseline characteristics
| Characteristic | PRU-PEG | PEG-PRU | Total |
|---|---|---|---|
| Age, Continuous | 40.3 Years STANDARD_DEVIATION 11.04 | 35.2 Years STANDARD_DEVIATION 13.18 | 37.9 Years STANDARD_DEVIATION 11.85 |
| Age, Customized 18 - 64 | 7 Participants | 6 Participants | 13 Participants |
| Region of Enrollment UNITED STATES | 7 Participants | 6 Participants | 13 Participants |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 13 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 13 | 0 / 12 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 |
Outcome results
Primary
The Number of High-Amplitude Propagating Contractions (HAPC)
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Prucalopride | The Number of High-Amplitude Propagating Contractions (HAPC) | 8.7 Number of HAPC with amplitude ≥100mmHg | Standard Error 2.06 |
| PEG 3350 | The Number of High-Amplitude Propagating Contractions (HAPC) | 2.9 Number of HAPC with amplitude ≥100mmHg | Standard Error 2.06 |
p-value: 0.01295% CI: [1.6, 9.9]Linear Mixed-Effect Models Analysis
Secondary
Area Under the Concentration Curve (AUC) of All HAPCs
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Prucalopride | Area Under the Concentration Curve (AUC) of All HAPCs | 110204.1 mmHg.sec | Standard Error 28279.91 |
| PEG 3350 | Area Under the Concentration Curve (AUC) of All HAPCs | 41152.7 mmHg.sec | Standard Error 34432.61 |
p-value: 0.07995% CI: [-12004.5, 150107.3]Linear Mixed-Effect Models Analysis
Secondary
Duration of HAPC
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Prucalopride | Duration of HAPC | 84.9 sec | Standard Error 8.05 |
| PEG 3350 | Duration of HAPC | 69.1 sec | Standard Error 10.75 |
p-value: 0.22595% CI: [-12.6, 44.3]Linear Mixed-Effect Models Analysis
Secondary
Motility Index
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Prucalopride | Motility Index | Pre-Dose | 9.467 mmHg | Standard Error 0.4668 |
| Prucalopride | Motility Index | 0-5 hours post-dose | 13.661 mmHg | Standard Error 0.3221 |
| Prucalopride | Motility Index | 5-12 hours post-dose | 14.208 mmHg | Standard Error 0.2976 |
| PEG 3350 | Motility Index | Pre-Dose | 8.312 mmHg | Standard Error 0.4403 |
| PEG 3350 | Motility Index | 0-5 hours post-dose | 13.349 mmHg | Standard Error 0.352 |
| PEG 3350 | Motility Index | 5-12 hours post-dose | 14.390 mmHg | Standard Error 0.2489 |
Secondary
Propagation Velocity of HAPC
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Prucalopride | Propagation Velocity of HAPC | 0.467 cm/sec | Standard Error 0.0803 |
| PEG 3350 | Propagation Velocity of HAPC | 0.646 cm/sec | Standard Error 0.1074 |
p-value: 0.1895% CI: [-0.465, 0.107]Linear Mixed-Effect Models Analysis
Secondary
The Mean Amplitude of HAPC
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Prucalopride | The Mean Amplitude of HAPC | 199.0 mmHg | Standard Error 15.15 |
| PEG 3350 | The Mean Amplitude of HAPC | 189.8 mmHg | Standard Error 19.56 |
p-value: 0.71795% CI: [-45.3, 63.7]Linear Mixed-Effect Models Analysis
Secondary
Time to First HAPC
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Prucalopride | Time to First HAPC | 4.5 hours |
| PEG 3350 | Time to First HAPC | NA hours |
p-value: 0.295Log Rank