Yan Yiannakou

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Evaluate the Efficacy, Safety, and Tolerability of Prucalopride in Men With Chronic Constipation

OBJECTIVES:Prucalopride is effective at alleviating symptoms of chronic constipation in women. The aim of this study was to assess the efficacy of 12 weeks of prucalopride treatment compared with placebo in men with chronic constipation.METHODS:This was a multicenter, stratified, randomized, parallel-group, double-blind, placebo-controlled, phase 3 study (ClinicalTrials.gov identifier: NCT01147926). The primary end point was the proportion of patients with a mean of three or more spontaneous complete bowel movements (SCBMs) per week across the treatment period. Efficacy end points were assessed using daily electronic diaries, global assessment of the severity of constipation and efficacy of treatment, and Patient Assessment of Constipation—Symptoms (PAC-SYM) and Patient Assessment of Constipation—Quality of Life (PAC-QOL) questionnaires.RESULTS:In total, 374 patients were enrolled in the study. Significantly more patients achieved a mean of three or more SCBMs per week in the prucalopride group (37.9%) than in the placebo group (17.7%, P<0.0001). The proportion of patients rating their constipation treatment as “quite a bit” to “extremely” effective at the final on-treatment visit was 46.7 and 30.4% in the prucalopride and placebo groups, respectively. The difference between treatment groups was statistically significant (P<0.0001). The proportion of patients with an improvement of at least 1 point in PAC-QOL satisfaction subscale score was 52.7 and 38.8% in the prucalopride and placebo groups, respectively (P=0.0035). Prucalopride had a good safety profile and was well tolerated.CONCLUSIONS:Prucalopride is effective, has a good safety profile, and is well tolerated for the treatment of men with chronic constipation.

Blinded comparison of faecal loading on plain radiography versus radio-opaque marker transit studies in the assessment of constipation

AIM To compare faecal loading on plain radiography versus radio-opaque marker transit studies in the assessment of constipation. METHODS The study group was a convenience sample of patients attending the Durham Constipation Clinic. All patients underwent transit studies according to an established protocol, and severity of constipation was assessed contemporaneously using a validated questionnaire (PAC-SYM). Transit studies were performed using radio-opaque markers that were ingested over 3 consecutive days, with a radiograph taken on the fourth day. Digital images of the radiograph were digitally altered to remove all traces of the transit markers without affecting the underlying pattern of faecal loading. Four observers assessed faecal loading independently; two clinicians (C1 and C2) and two radiologists (R1 and R2). C1 and R1 used a previously described formal scoring method of assessing faecal loading, whereas C2 and R2 assessed the images as if they were in a clinic or reporting session, grading the faecal loading as mild, moderate, or severe. RESULTS One hundred patients were recruited out of 186 presenting in a 2-year period. All patients completed assessments. The correlation between observers was only fair to moderate (r ranging from 0.34-0.51). There were some surprisingly marked disagreements in 10-18% of assessments. The correlation between faecal loading and transit was weak for all observers (r ranging from 0.261-0.311). Symptom severity did not correlate with faecal loading. CONCLUSION These results suggest that there is considerable inter-observer variation in the radiological assessment of faecal loading, irrespective of the training or method used by the observer, and that there is very poor correlation with colonic transit. The diagnosis of constipation, and the assessment of severity, is best performed clinically.

Factors affecting satisfaction with treatment in European women with chronic constipation: An internet survey

Background Data on factors affecting treatment satisfaction in European women with chronic constipation are limited. Objective To assess factors associated with treatment satisfaction among European women with chronic constipation. Methods A 2011–2012 internet survey was conducted in men and women from 12 European countries. Respondents analysed were female with self-reported chronic constipation (≥1 symptoms for ≥6 months of lumpy/hard stools, feeling of incomplete evacuation, and pain during defecation, as well as <3 bowel movements/week). For laxative users, satisfaction with treatment, factors affecting satisfaction, and interactions with healthcare professionals were collected. Results and conclusions In total, 4805/50,319 participants fulfilled the inclusion criteria (female with chronic constipation). Of the laxative users (1575/4805), 57% (n = 896) were satisfied with their treatment, while 26% were neutral, and 17% dissatisfied. Dissatisfied respondents visited their GP less frequently in the past 12 months, were more likely to obtain over-the-counter laxatives, and took a dose higher than recommended more frequently than those satisfied. Respondents were most satisfied with ease of use of treatment and least satisfied with relief from bloating. Newer treatments aimed at alleviating symptoms, particularly bloating, are required for respondents neutral or dissatisfied with their current treatment.

Functional defecation disorder as a clinical subgroup of chronic constipation : Analysis of symptoms and physiological parameters

Objective. Patients with functional constipation can be classified according to symptoms and physiological parameters as either having a disorder of defecation or having normal defecation. It is hypothesized that the disordered defecation, where it exists, is a causative factor of the constipation. However, the utility of this classification has yet to be proven in terms of predicting response to therapy. The definitions are non-specific and based on tests that are done in an artificial setting and with derived normal ranges. It is therefore possible that the symptoms and physiological parameters of a defecatory disorder may occur as a continuous spectrum in these patients, rather than defining a discrete entity or subtype. The aim of this study was to use cluster analysis and factor analysis of defecatory symptoms and physiological parameters to look for evidence of subgroups in patients with functional constipation. Material and methods. Consecutive patients presenting to a specialist constipation clinic and satisfying the inclusion criteria were assessed to determine the severity of defecatory symptoms, and underwent isotope defecating proctography and the Sitzmark transit study. Assessments were made contemporaneously and results of any test not performed within 6 weeks of the initial assessment were excluded. Principle components analysis and cluster analysis were performed to look for evidence of subgroups. Relationships between evacuatory symptoms, index parameters, and test results were explored. The detailed and unselected nature of the analyses produced hundreds of test results, and statistically significant results were critically evaluated in this context. Results. A total of 116 patients were studied (age range 18–73 years, mean 40.5 years). Based on the results of the transit study and proctography, 38% of patients showed evidence of slow transit constipation, 20% FDD (functional defecation disorder), 29% both, and 12% neither. Principle components analysis did not demonstrate an obvious dimension reduction for the variables tested. Cluster analysis (over 150 solutions tested) failed to show evidence of clustering. There were no useful predictive relationships between evacuatory symptoms, index parameters and test results. Conclusions. We used multiple statistical analyses to look for clustering and predictive relationships between clinical and physiological parameters in consecutive patients with functional constipation and found no evidence of the existence of a subgroup of patients with a defecatory disorder. This may be due to weaknesses in the study design, poor validity of the assessments performed, or that defecatory features do not identify a distinct pathophysiological entity, but rather are manifested variably as a continuous spectrum.

A prospective trial of temporary sacral nerve stimulation for constipation associated with neurological disease.

This study assessed the effectiveness of temporary sacral nerve stimulation (SNS) in patients with constipation associated with neurological disease using an off–on–off design, and evaluated the long‐term response in patients undergoing permanent SNS.

Pseudo-obstruction, stroke, and mitochondrial dysfunction: A lethal combination

The m.3243A>G MTTL1 mutation is the most common cause of mitochondrial disease; yet there is limited awareness of intestinal pseudo‐obstruction (IPO) in this disorder. We aimed to determine the prevalence, severity, and clinical outcome of patients with m.3243A>G‐related mitochondrial disease manifesting with IPO.

Challenging the Biopsychosocial Model in a Chronic Constipation Clinic

In this article we discuss the results of an ethnographic study of professionals’ and patients’ experiences within a specialist constipation clinic in England. Chronic constipation tends to be poorly understood and inadequately treated. Eleven patients were followed through their illness trajectory during a 5-month fieldwork period, involving 21 home interviews, clinic-based interviews, participant observation, and a focus group. Professionals were likewise observed and interviewed. The clinic could be broadly described as biopsychosocial in its approach. However, professionals expressed uncertainty about how best to provide biopsychosocial care and suggested that some patients were not “open” to psychosocial therapies or to discussing psychosocial aspects of their disease. Patients’ concerns were with being taken seriously, receiving treatment, and narrating intersections of life events, emotional well-being, and the bowels. We situate these findings within the discourse of “functional” disorders and discuss why implementing a biopsychosocial approach is problematic in this case.

OC-066 Economic and quality-of-life burden of moderate-to-severe irritable bowel syndrome with constipation (ibs-c) in the uk: the ibis-c study

Introduction This is the first study to assess the burden of IBS-C in 6 European countries (France, Germany, Italy, Spain, Sweden, UK). Here we present the results for the UK. Method Observational, retrospective-prospective (6 months each) study in patients (pts) diagnosed with IBS-C in the last five years (Rome-III criteria) and moderate-to-severe symptoms at baseline: IBS-Symptom Severity Score (IBS-SSS) ≥175. Health resource utilisation was retrospectively and prospectively assessed. Symptom evolution was assessed in the prospective period, and quality-of-life (QoL) was assessed at baseline with EuroQoL-5D (EQ-5D) and IBS-QoL. Work productivity was prospectively assessed using the Work Productivity and Activity Impairment (WPAI): IBS-C questionnaire. Results 104 pts were included (79% severe, mean age [± SD] 45.5 ± 14.6 yrs, 93% female). At baseline, symptom severity (IBS-SSS; severe >300) was 373.1 ± 82.5; presenteeism (WPAI:IBS-C; mean ± SD): 47.9% ± 28.7%; absenteeism: 8.4% ± 24.2%; work productivity loss: 51.5% ± 27.2%; daily activity impairment: 56.8% ± 29.6%. Mean IBS-QoL was 57.2 ± 24.2, (scale: 0–100 [best-to-worst]) and mean EQ-5D was 54.0 ± 23.3 (scale: 0–100 [worst-to-best]. 87.5% and 64.4% of pts reported moderate-to-severe problems in pain/discomfort, anxiety/depression respectively. Most prevalent symptoms were abdominal pain (92%) and bloating (91%). 70% pts consulted a GP, and 100% a gastroenterologist; mean: 6.2 and 2.7 visits, respectively. 24% pts required emergency department visits or hospitalisation (mean stay [95% CI]: 12 [2.5–21.1] days). 52% had a diagnostic test (mean [95% CI]: 3.6 [2.9–4.4]). 90% pts took prescription drugs for IBS-C. Mean (95% CI) annual direct cost for the NHS: £ 1753 (1251–2308); the mean pt cost: £ 315 (184–482). 51% of pts took sick leave (mean: 5.2 times; mean duration: 26 days) and 82% had productivity losses (mean: 162 h). Mean indirect costs were £ 3407 (2078–4977). Total costs amounted to £ 5443 (3970–7252)/year. Conclusion Moderate-to-severe IBS-C has a major impact on patient QoL, productivity, and healthcare resource utilisation. Disclosure of interest Y. Yiannakou Conflict with: Grants: Shire; Medtronic. Speaker fees: Almirall; Shire; Sucampo, M. Eugenicos Conflict with: Consultant/Advisory Board Member: Almirall; Astellas; Dr Falk Pharma; NAPP; and Shire, D. Sanders Consultant for: Almirall, A. Emmanuel Conflict with: Advisory Board and Educational Talk honoraria: Almirall., P. Whorwell Conflict with: Consultant/research grant support: Almirall; Chr. Hansen; Danone Research; Ironwood; Salix; Shire; Sucampo, F. Butt: None Declared, S. Bridger: None Declared, N. Arebi: None Declared, A. Millar Conflict with: The hospital received payment from Almirall for the conduct of the study, V. Kaushik Conflict with: Advisory Board and Educational Talk honoraria: Almirall. Meeting support: Cooks; Tillotts; AbbVie., M. Rance Employee of: Almirall, J. Mackinnon Employee of: TFS Develop S. L., contracted by Almirall S. A to conduct the study, J. Bertsch Employee of: TFS Develop S. L, contracted by Almirall S. A. to conduct the study, J. Fortea Employee of: Almirall, J. Tack Conflict with: Grants/research support: Abbott; Novartis; Shire. Honoraria/consultancy fees: Almirall; AstraZeneca; Danone; GI Dyamics; GlaxoSmithKline; Ironwood; Janssen; Menarini; Novartis; Rhythm; Shire; Takeda; Theravance; Tsumura; Will Pharma; Zeria. Speaker fees: Abbott; Almirall; AstraZeneca; Janssen; Menarini; Novartis; Shire; Takeda; Zeria.

The PAC‐SYM questionnaire for chronic constipation: defining the minimal important difference

The Patient Assessment of Constipation‐Symptoms (PAC‐SYM) questionnaire is frequently used in clinical trials of constipation. However, the threshold for reduction in total PAC‐SYM score used to define a clinical response on this 0‐4 point scale has not undergone formal appraisal, and its relationship with clinical benefit as perceived by patients has not been defined.

929g Efficacy and safety of prucalopride in men with chronic constipation: a phase 3, randomized, double-blind, placebo-controlled trial

Introduction Prucalopride (PRU) is a high-affinity serotonin receptor (5-HT 4 ) agonist approved in Europe for the symptomatic treatment of chronic constipation (CC) in women. The aim of this study was to evaluate the efficacy and safety of PRU in men with CC. Method This was a phase 3, multicentre, parallel-group, double-blind trial (NCT01147926). Men aged ≥ 18 years with CC who had ≤ 2 spontaneous complete bowel movements (SCBMs)/week were randomised to receive placebo (PLA) or PRU 2 mg (starting dose of 1 mg for patients aged ≥ 65 years) once daily for 12 weeks. The primary endpoint was the proportion of men achieving a mean of ≥ 3 SCBMs/week over 12 weeks. Secondary endpoints included Patient Assessment of Constipation-Symptoms (PAC-SYM) and Patient Assessment of Constipation-Quality of Life (PAC-QOL) questionnaire scores. Safety was assessed throughout the study. Results Overall, 374 patients were randomised. More men in the PRU group than in the PLA group (37.9% vs. 17.7%, respectively; p p = 0 .0743) and ≥ 1 SBM/week (65.5% vs. 43.1%; p p = 0 .3152) or abdominal (39.1% vs. 35.1%; p = 0 .4874) or rectal (34.9% vs. 29.2%; p = 0 .2759) subscale scores. However, there was a significant difference in stool symptoms score (53.3% vs. 36.3%; p = 0 .0005). The proportion of men with an improvement of ≥ 1 in total PAC-QOL score was higher with PRU (40.2%) than PLA (32.7%; p = 0 .0755). PRU had a good safety profile and was well tolerated, consistent with previous studies. The incidences of serious adverse events and ischaemic cardiovascular adverse events were low and similar in both treatment groups. Conclusion Results from this study demonstrate that PRU is effective, has a good safety profile and is well tolerated in men with CC, similar to the findings for women with CC. Disclosure of interest Y. Yiannakou Grant/ Research Support from: Shire, Consultant for: Shire, M. Bouchoucha: None Declared, I. Schiefke: None Declared, H. Piessevaux Conflict with: Shire, R. Filip: None Declared, L. Gabalec: None Declared, D. Stephenson Employee of: Shire, R. Kerstens Employee of: Shire, K. Etherson Conflict with: Shire, A. Levine Employee of: Shire.