| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate differences in pharmacodynamic effects of prucalopride and PEG 3350 + electrolytes on the number of colonic HAPC during a 12-hour intraluminal manometry in chronically constipated subjects. |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the association between motility parameters and number and consistency of bowel movements in chronically constipated subjects receiving a single dose of prucalopride and 2 doses of PEG 3350 + electrolytes
• To explore the relationship between plasma concentrations and pharmacodynamic endpoints in chronically constipated subjects.
• To collect pharmacogenomic data in chronically constipated subjects for exploratory purposes.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects meeting all of the criteria listed below will be included in the study:
1. Male or female age 18-75 years inclusive at the time of consent. The date of signing informed consent is defined as the beginning of screening. This inclusion criterion will only be assessed at the first Screening Visit.
2. Willingness to comply with any applicable contraceptive requirements of the protocol and is:
– Non-pregnant, non-lactating female
– Females must be at least 90 days postpartum or nulliparous.
– Females of childbearing potential should have a negative serum pregnancy test at the Screening Visit and should use a medically-acceptable method of birth control for the entire duration of the study and until the first menses after a 30-day period after the last dose of investigational product. They must be on a stable regimen, for at least 1 month, of oral contraceptives, contraceptive implant or depot injection, contraceptive patch, intrauterine device (IUD), condom and spermicidal agent, or diaphragm and spermicidal agent, or agree upon continuous abstinence from heterosexual sexual contact and be willing to continue this contraception.
3. Subject has a history of chronic constipation for at least 6 months before the Screening Visit and reports an average of <3 SCBMs per week and 1 or more of the following:
• Very hard (little balls) and/or hard stools at least a quarter of the stools
• Sensation of incomplete evacuation following at least a quarter of the stools
• Straining at defecation at least a quarter of the time.
The above criteria are only applicable for SBMs, i.e., BMs not preceded within a period of 24 hours by the intake of a laxative agent or by the use of an enema. Subjects who never have SBMs are considered to be constipated and are eligible for the study.
4. An understanding, ability, and willingness to fully comply with study procedures and restrictions.
5. Ability to provide written, personally signed, and dated informed consent to participate in the study, in accordance with ICH GCP Guideline E6 and applicable regulations, before completing any study related procedures.
6. Subject agrees to stop their current laxative treatment and is willing to use rescue medication as specified in the protocol.
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| E.4 | Principal exclusion criteria |
Subjects are excluded from the study if any of the following exclusion criteria are met.
1. Subjects in whom constipation is thought to be drug-induced.
2. Body mass index >37.0kg/m².
3. Subjects suffering from secondary causes of chronic constipation, such as.
– Endocrine disorders, e.g. hypopituitarism, hypothyroidism, hypercalcemia, pseudo hypoparathyroidism, pheochromocytoma or glucagon-producing tumors, unless these are controlled by appropriate medical therapy;
– Metabolic disorders, e.g. porphyria, uremia, hypokaliemia 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, hyper-ganglionosis, autonomic neuropathy or neuropathy due to chemotherapy, spinal cord injury, Chaga’s disease, or major depression;
– Surgery.
Note: if a subject was having chronic constipation prior to the onset of a condition listed above and the constipation has not been worsened by this condition, the subject is eligible for screening; however, if the constipation has started after the onset of 1 of the above conditions and the relation between both cannot be excluded (i.e. it is not certain whether it is secondary to it or not), or when the constipation has worsened after the onset of 1 of the above conditions, the subject is not allowed to be screened for this study.
4. Subjects with insulin-dependent diabetes mellitus, irrespective of whether the constipation started prior to or after the onset of diabetes.
5. Rectal evacuation disorder/outlet obstruction. If data are not available regarding rectal evacuation disorder/outlet obstruction, a clinical evaluation should be performed at screening.
6. Subjects with intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn’s disease, ulcerative colitis, or toxic megacolon/megarectum.
When polyps, cancer, stricture, or other structural or organic disease are found at the endoscopic examination in conjunction with the manometry catheter placement or if it is clinically indicated that a repeat colonoscopy/sigmoidoscopy is needed to rule out or treat such abnormalities, the subject should be a screen failure.
7. Severe renal impairment (calculated creatinine clearance <30mL/min) or requiring dialysis.
8. Subjects with clinically significant abnormalities at the physical examination, or in hematology and biochemistry tests performed at the Screening Visit, as judged by the Investigator.
9. Subjects with a history of alcohol or drug abuse in the previous 6 months, or a positive screen for alcohol or drugs of abuse.
10. Use of another investigational product (or active enrollment in another drug or vaccine clinical study) within 30 days prior to receiving the first dose of investigational product within this study.
11. Substantial changes in eating habits within 30 days prior to receiving the first dose of investigational product, as assessed by the Investigator.
12. An inability to follow a standardized diet and meal schedule, including consumption of clear liquids and a low fat meal, as required during the study.
13. Prior screen failure, randomization, or enrollment in this study.
14. Subjects with clinically significant cardiac, vascular, liver, pulmonary, endocrine, neurological, or psychiatric disorders (as evaluated by the Investigator), or metabolic disturbances.
15. Subjects with any condition that, in the opinion of the Investigator, would complicate or compromise the study or the well-being of the subject or evidence of clinically relevant pathology that could interfere with the study results or put the subject’s safety at risk.
16. Subjects with lactose intolerance for whom it is expected that low doses of lactose can lead to diarrhea or a known allergy to ingredients or excipients of the investigational products.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| • The number of HAPCs during the 12 hours after treatment initiation. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12-hour period following AM dosing. |
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| E.5.2 | Secondary end point(s) |
• The area under the curve of all HAPCs during the 12 hours after treatment initiation
• The mean amplitude of HAPC (mmHg), duration (s), and propagation velocity (cm/s)
• Motility index (number of antro- vs. retro-grade complete propagating waves)
• Number and consistency of bowel movements on Day 1 as assessed by the Bristol Stool Scale
• Time between occurrence of BM and last HAPC preceding that BM
• Time to first HAPC and time to first BM after intake of investigational product on Day 1
• Time to catheter expulsion for those subjects that expel the catheter prematurely.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 12-hour period following AM dosing |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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