This prospective, multi-center, non-interventional post-marketing surveillance of prucalopride was conducted from October 2012 to October 2018 (Protocol no. PRUCOP4004). Institutional ethics approval was obtained from the institutional review board of each of the 28 participating hospitals.

All patients included in the study were adults who received prucalopride for the symptomatic treatment of chronic constipation, and laxatives failed to provide adequate relief. All patients provided written informed consent. The exclusion criteria were as follows: patients i) who had diseases, such as ischemic colitis, Crohn’s disease, or ulcerative colitis; ii) with renal impairment requiring dialysis; iii) those who violated the dosage regimen, according to patient age; iv) those with missing safety or efficacy data; and v) those who received prucalopride before enrollment in the study. Patients were administered 2 mg of prucalopride once daily. In the geriatric population (older 65 years), 1 mg of prucalopride was administered once daily.

The baseline characteristics included gender, age, duration of chronic constipation, comorbidities, daily dose of prucalopride at first administration, and the number of spontaneous complete bowel movements (SCBM). Information on concomitant laxatives, non-pharmacological therapies for chronic constipation, and concomitant medications were collected for the 6 months before study initiation and throughout the study period.

AEs were recorded and observed throughout the study. The investigator classified the causality between prucalopride and each AE into six grades: ‘certain,’ ‘probable/likely,’ ‘possible,’ ‘unlikely,’ ‘conditional/unclassified,’ and ‘unassessable/unclassifiable’. Adverse drug reactions (ADRs), which were defined as AEs caused by prucalopride, were also evaluated. The AE was classified as an ADR if the causality between prucalopride and AE was considered ‘certain,’ ‘probable/likely,’ ‘possible,’ ‘conditional/unclassified,’ or ‘unassessable/unclassifiable’. Serious adverse events (SAEs) based on the International Conference on Harmonization and European Union guidelines on pharmacovigilance for medicinal products for human use are defined as any untoward medical occurrence at any dose that is life-threatening, results in persistent or significant disability/incapacity, results in hospitalization or prolonged hospitalization, may have caused a congenital anomaly/birth defect, may have been caused by the suspected transmission of any infectious agent via a medical product, is medically important, and results in death.

The number of SCBM per week was an inappropriate efficacy parameter because concomitant laxatives were permitted in the present study. Thus, the Clinical Global Impression-Improvement (CGI-I) scale was used to evaluate the improvements in the relief of constipation symptoms.^7,11 The CGI-I is a seven-point scale (very much improved, much improved, minimally improved, no change, minimally worse, much worse, and very much worse) based on the investigators’ assessment of the extent of improvement of the patient’s condition since the initiation of prucalopride compared to the baseline.

All data were collected and managed using electronic case report forms on the cubeCDMS^® system (CRScube Inc., Seoul, Korea). Medical coding was performed for concomitant laxatives, concomitant medications, comorbidities, and AEs. The drugs were classified using the Anatomical Therapeutic Chemical Classification System 2018, with level 4 indicating concomitant laxatives and level 1 indicating concomitant medications. The comorbidities were classified into five categories, ‘cardiovascular disorders,’ ‘hepatic disorder,’ ‘renal disorder,’ ‘allergies,’ and ‘others,’ as judged by the investigators and then classified according to the System Organ Class of Medical Dictionary for Regulatory Activities version 21.0. All collected AEs were classified based on System Organ Class and preferred terms using Medical Dictionary for Regulatory Activities 21.0.

The dataset for analysis was obtained from the case report form collected from patients and classified as an evaluable set. The evaluable set was comprised of patients treated with at least one dose of prucalopride for chronic constipation and assessed at least once using the CGI-I scale.

The demographic and baseline characteristics were summarized in terms of descriptive statistics. For continuous variables, the data are presented as means with standard deviations and medians with ranges (minimum and maximum). For categorical variables, the data are presented as frequencies and their respective percentages. For safety assessment, the incidence rate of AEs and the number of patients are summarized descriptively.

For efficacy assessment, the number of patients and the percentage of CGI-I responses at each visit (weeks 4, 8, and 12) were determined. For the factors associated with efficacy, “very much improved,” “much improved,” and “minimally improved” were considered “effective” and the other responses were considered “ineffective.” A Chi-square test, Cochran Armitage trend test, or logistic regression was used to analyze whether the baseline characteristics were effective or ineffective at the last visit for each patient.

All statistical analyses were performed using SAS ver. 9.2 (SAS Institute, Cary, NC, USA), and a p-value <0.05 was considered significant. For ORs, 95% CIs for the ratios were calculated.

Seven hundred and thirty-one patients were enrolled in this study. Of these, 130 patients, including 109 patients who violated the dosage regimen, eight patients who received prucalopride before enrollment in the study, eight patients with contraindications, such as ischemic colitis, Crohn’s disease, ulcerative colitis, and renal impairment requiring dialysis, and five patients with missing safety or efficacy data were excluded.

Table 1 lists the baseline demographics and clinical characteristics of the evaluable set. Of 601 patients in the evaluable set, the majority were females (67.7%), and the mean age was 62.3 years. Among the enrolled patients, one-third of patients had chronic constipation for more than 5 years. At least one comorbidity was observed in 89.0% of patients. The most common comorbidity was cardiovascular disorders in 248 patients (345 events), including hypertension and angina pectoris. Hepatic disorder (3.5%), renal disorder (2.5%), and allergies (1.0%) were rarely observed. There was no case of dose modification due to comorbidities. Four hundred and sixty patients (76.5%) were treated with concomitant laxatives. One-hundred and five patients (17.5%) received non-pharmacological treatments for constipation, and lifestyle intervention was the most common non-pharmacological treatment (60.0%, 63/105). One patient received an enema. No patients received biofeedback therapy during the study period. Four hundred and fifty-seven patients (76.0%) used concomitant medications. The frequently used concomitant medication classes were alimentary tract and metabolism (n=383, 963 cases), nervous system (n=275, 690 cases), and cardiovascular system (n=203, 433 cases) drugs. Of the concomitant medications, opioids were used by 157 patients (26.1%, 238 cases), antidepressants by 66 patients (11.0%, 82 cases), calcium channel blockers by 56 patients (9.3%, 57 cases), and antineoplastic agents by 10 patients (1.7%, 14 cases). The daily dose of prucalopride at the initial administration was 1 mg daily in 49.9% of patients (n=300) and 2 mg daily in 50.1% of patients (n=301). These results indicate compliance with the daily doses assigned according to the age group (over 65 years or below). More than 70% of patients reported SCBM less than 2 times per week.

Table 2 summarizes the AEs with more than 1.0% incidence. Overall, 144 AEs were reported in 107 patients (17.7%) from the evaluable set (n=601). The frequently reported AEs were headache in 3.2% of patients (19/601 patients, 19 cases), followed by diarrhea in 2.8% (17/601 patients, 17 cases), abdominal pain in 2.3% (14/601 patients, 14 cases), nausea in 1.5% (9/601 patients, nine cases), nasopharyngitis in 1.2% (7/601 patients, seven cases), and dyspepsia in 1.0% (6/601 patients, six cases). In total, 60 ADRs were reported in 46 patients.

Seven SAEs were reported in five patients (0.8%), including vertebral foraminal stenosis, diabetic neuropathy, inadequate control of diabetes mellitus, thermal burn, dyspepsia, chest discomfort, and ventricular extrasystoles. The SAEs in all five patients were resolved without complications, and there were no cases of death. All SAEs were assessed as ‘unlikely’ causality with prucalopride. In all except for one patient, prucalopride administration was maintained despite the SAE. Among the SAEs, vertebral foraminal stenosis, diabetic neuropathy, inadequate control of diabetes mellitus, and dyspepsia were assessed as severe, whereas chest discomfort and ventricular extrasystoles were assessed as mild.

Two cardiac AEs, palpitation and ventricular extrasystoles, were reported infrequently (0.2%). Mild palpitation was assessed as an ADR, resulting in the discontinuation of prucalopride in that patient, but it was resolved according to the investigator’s judgment. This patient had a medical history of angina pectoris, arrhythmias, hypertension, and hyperlipidemia. The patient in whom ventricular extrasystoles were reported had a previous history of hypertension, angina pectoris, hyperlipidemia, and chest discomfort.

Fifteen patients had an impaired renal function, but only one AE occurred; a moderate headache was reported in one patient with severe chronic kidney disease who had received 1 mg of prucalopride.

Table 3 lists the CGI-I responses. In the evaluation set with 601 patients, the proportion of patients with efficacious improvement was 72.7% (437/601), 69.7% (288/413), and 68.5% (230/336) at weeks four, eight, and 12, respectively. There were no patients with the response ‘very much worse’ and few patients reported ‘minimally worse’ and ‘much worse’ responses throughout the study.

Univariate and multivariate logistic regression analyses were performed to observe any clinical factors that may have resulted in a negative CGI-I response to the prucalopride treatment at the last visit of each patient. Univariate analysis showed that a longer duration of chronic constipation, use of non-pharmacological therapies for chronic constipation, and use of concomitant medications had a significant negative effect on the CGI-I response (p=0.0002, p=0.0404, and p=0.0388, respectively) (Table 4). Multivariate logistic regression analysis showed that the CGI-I response deteriorated in those with a longer duration of chronic constipation (OR 0.463; 95% CI 0.303, 0.708; p=0.0011) and use of concomitant medications (OR 0.576; 95% CI 0.369, 0.899; p=0.0151) (Table 5).