The future of clinical trials-is it virtual?

INTRODUCTION: Participant recruitment to clinical trials is often sub-optimal. Decentralized clinical trials have the potential to address challenges in traditional site-based clinical trial recruitment. SOURCES OF DATA: This review is based on recently published literature and the experience of running a large industry-sponsored interventional trial using both traditional and decentralized methods. AREAS OF AGREEMENT: Efficient delivery of clinical trials is essential to continue to provide therapeutic improvements in a timely and cost-efficient way. Clinical trial designs are constantly evolving to achieve effective trial delivery, manage the complexity of new therapeutic algorithms and conform to cultural developments. AREAS OF CONTROVERSY: Digitally innovative decentralized clinical trials may be a solution to improve recruitment and retention. Although many trials incorporate digital innovations to reduce patient burden, decentralized clinical trials allow remote access to clinical research, potentially enhancing geographical diversity as well as reducing participant burden. GROWING POINTS: Areas for development currently being discussed are developing a 'recruitment platform' that exploits the reach of digital connectivity, automated identification of eligible participants from volunteers, employing technology for remote interaction and exploring the logistic process of delivering the interventions. AREAS TIMELY FOR RELEVANT RESEARCH: The focus of development must ensure that the overall impact will widen participation and reduce inequalities in healthcare.

Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: A randomized controlled trial.

AIM: The aim was to determine whether specialist-led habit training using Habit Training with Biofeedback (HTBF) is more effective than specialist-led habit training alone (HT) for chronic constipation and whether outcomes of interventions are improved by stratification to HTBF or HT based on diagnosis (functional defaecation disorder vs. no functional defaecation disorder) by radio-physiological investigations (INVEST). METHOD: This was a parallel three-arm randomized single-blinded controlled trial, permitting two randomized comparisons: HTBF versus HT alone; INVEST- versus no-INVEST-guided intervention. The inclusion criteria were age 18-70 years; attending specialist hospitals in England; self-reported constipation for >6 months; refractory to basic treatment. The main exclusions were secondary constipation and previous experience of the trial interventions. The primary outcome was the mean change in Patient Assessment of Constipation Quality of Life score at 6 months on intention to treat. The secondary outcomes were validated disease-specific and psychological questionnaires and cost-effectiveness (based on EQ-5D-5L). RESULTS: In all, 182 patients were randomized 3:3:2 (target 384): HT n = 68; HTBF n = 68; INVEST-guided treatment n = 46. All interventions had similar reductions (improvement) in the primary outcome at 6 months (approximately -0.8 points of a 4-point scale) with no statistically significant difference between HT and HTBF (-0.03 points; 95% CI -0.33 to 0.27; P = 0.85) or INVEST versus no-INVEST (0.22; -0.11 to 0.55; P = 0.19). Secondary outcomes showed a benefit for all interventions with no evidence of greater cost-effectiveness of HTBF or INVEST compared with HT. CONCLUSION: The results of the study at 6 months were inconclusive. However, with the caveat of under-recruitment and further attrition at 6 months, a simple, cheaper approach to intervention may be as clinically effective and more cost-effective than more complex and invasive approaches.

Double-blinded randomised placebo controlled trial of enterosgel (polymethylsiloxane polyhydrate) for the treatment of IBS with diarrhoea (IBS-D).

OBJECTIVE: Irritable bowel syndrome with diarrhoea (IBS-D) is a common and challenging condition that significantly reduces quality of life. Enterosgel (polymethylsiloxane polyhydrate) is an intestinal adsorbent which sequesters harmful molecules and is safe and effective in acute infective diarrhoea. This randomised controlled multicentre trial aimed to investigate its safety and efficacy in patients with IBS-D. DESIGN: After a 2-week screening phase, participants were randomised into an 8-week double-blind phase, followed by an 8-week open-label and follow-up phase. Participants recorded stool consistency, pain and global symptoms in e-diaries and questionnaires. The primary outcome was the percentage of responders on a composite abdominal pain (≥30% decrease in the weekly score) and stool consistency (50% reduction in days per week with at least one stool of BSFS type 6 or 7) score during at least 4 weeks of the treatment period. RESULTS: 440 patients with IBS-D were randomised to the double-blind phase with 393 continuing to the open-label phase. The Primary outcome responder rate by intention-to-treat for enterosgel versus placebo was 37.4% vs 24.3% (OR 1.95, NNT 8, p=0.002). Enterosgel also improved stool consistency (48.5% vs 32.5%, p<0.0001) abdominal pain (53.3% vs 40.2%, p=0.003), stool frequency (treatment effect -0.32 (-0.62 to -0.02)) and urgency (treatment effect -0.59 (-0.85 to -0.33)). 60% of patients reported adequate relief of symptoms after open-label treatment. Adverse event frequency was similar in both groups, with no serious events attributable to enterosgel. CONCLUSION: Enterosgel is safe and effective in IBS-D, providing an alternative to the limited current treatment options. TRIAL REGISTRATION NUMBER: ISRCTN17149988.

Natural History and Disease Impact of Rome IV Vs Rome III Irritable Bowel Syndrome: A Longitudinal Follow-Up Study.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a chronic functional bowel disorder diagnosed using the Rome criteria, which have evolved since their original description 30 years ago. Little is known about the effects on the natural history of IBS of moving to the latest iteration, Rome IV, from the previous Rome III criteria. We conducted a 12-month longitudinal follow-up study to examine this. METHODS: We collected complete demographic, symptom, mood, and psychological health data at baseline from 1097 adults who self-identified as having IBS and met either Rome IV or Rome III criteria. At 12 months, we collected data regarding IBS symptom severity and impact, consultation behavior, treatments commenced, and psychological health. We examined whether subsequent disease behavior in Rome IV- or Rome III-defined IBS differed. RESULTS: At 12 months, 638 (58.2%) of the 1097 participants were followed up successfully. Of these, 452 met Rome IV criteria and 186 met Rome III criteria at baseline. During the 12-month study period, individuals with Rome IV IBS were significantly more likely to have seen a primary care physician (44.7% vs 28.5%; P < .001) or a gastroenterologist (26.3% vs 12.4%; P < .001) for their IBS symptoms, were significantly more likely to have commenced a new treatment (73.0% vs 60.2%; P = .001), and cycled through significantly more treatments (P = .007), for their IBS compared with those with Rome III IBS. At follow-up evaluation, individuals with Rome IV IBS had more severe symptoms, which had a significantly greater impact on activities of daily living, were more likely to report continuous abdominal pain, and a higher proportion showed poor psychological health, compared with those with Rome III IBS (P < .001 for all analyses). CONCLUSIONS: The natural history of IBS defined according to Rome IV criteria is more severe than that of Rome III-defined IBS. This has important implications for future treatment trials in IBS.

Overlap of Rome IV Irritable Bowel Syndrome and Functional Dyspepsia and Effect on Natural History: A Longitudinal Follow-Up Study.

OBJECTIVES: Disorders of gut-brain interaction, such as irritable bowel syndrome (IBS) and functional dyspepsia (FD), frequently overlap, but the impact of this on the natural history is unknown. We examined this issue in a longitudinal follow-up study conducted in a large cohort of individuals. METHODS: We collected complete demographic, symptom, mood, and psychological health data from 1374 adults who self-identified as having IBS. We applied the Rome IV criteria to examine what proportion met criteria for IBS and FD, as well as the degree of overlap between them. At 12 months, we collected data regarding IBS symptom severity and impact, consultation behavior, treatments commenced, and psychological health according to degree of overlap between IBS and FD. RESULTS: Overall, 807 individuals met the Rome IV criteria for IBS at baseline and provided complete data. At study entry, overlap of FD occurred in 446 (55.3%) people who met Rome IV criteria for IBS. At 12 months, 451 (55.9%) individuals were successfully followed up. The proportion of individuals consulting their primary care physician (P = .001) or a gastroenterologist (P < .001) because of their IBS was significantly higher in those with overlap of IBS and FD, and the number of new IBS treatments commenced was significantly higher (P = .007). Those with overlap of IBS and FD reported significantly more severe IBS symptoms (P < .001), continuous abdominal pain, and that their IBS symptoms limited normal daily activities ≥50% of the time. Finally, those with overlap were more likely to report abnormal anxiety and depression scores at 12 months compared with those with IBS alone, and to have higher levels of somatization (P < .001 for all analyses). CONCLUSIONS: The natural history of people with IBS with overlap FD defined according to Rome IV criteria is more severe than those with IBS alone. This has important implications for future treatment trials in IBS.

British Society of Gastroenterology guidelines on the management of irritable bowel syndrome.

Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the last British Society of Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients. One of the strengths of this guideline is that the recommendations for treatment are based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of trial-based and network meta-analyses assessing the efficacy of dietary, pharmacological and psychological therapies in treating IBS. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research.

Symptom Stability in Rome IV vs Rome III Irritable Bowel Syndrome.

INTRODUCTION: Irritable bowel syndrome (IBS) is a chronic functional bowel disorder, which follows a relapsing and remitting course. Little is known about how evolving definitions of IBS or treatment for the condition affect symptom stability. We conducted a 12-month longitudinal follow-up study of individuals who self-identified as having IBS to examine these issues. METHODS: We collected demographic, gastrointestinal symptom, mood, and psychological health data at baseline, and gastrointestinal symptom data at 12 months, from adults who self-identified as having IBS, registered with 3 organizations providing services to people with IBS. We applied the Rome III and Rome IV criteria simultaneously at baseline and 12 months and subtyped participants according to predominant stool form or frequency. We examined stability of a diagnosis of IBS, and stability of IBS subtype, for the Rome IV and III criteria separately and examined the effect of commencing new therapy on fluctuation of symptoms. RESULTS: Of 1,375 individuals recruited at baseline, 784 (57.0%) provided data at 12 months. Of these, 452 met the Rome IV criteria for IBS at baseline, of whom 133 (29.4%) fluctuated to another functional bowel disorder at 12 months. In the remaining 319 (70.6%) who still met the Rome IV criteria for IBS, IBS subtype changed in 101 (31.7%) subjects, with IBS with mixed bowel habit (IBS-M) the least stable. Commencing a new treatment for IBS did not affect symptom stability. Among 631 who met the Rome III criteria at baseline responding at 12 months, 104 (16.5%) fluctuated to another functional bowel disorder. In the 527 (83.5%) who still met the Rome III criteria for IBS, IBS subtype fluctuated in 129 (24.5%), with IBS-M the most stable subtype. Again, commencing a new treatment for IBS did not affect symptom stability. DISCUSSION: Fluctuation between functional bowel disorders and predominant stool subtype is common in people with IBS and does not appear to be influenced solely by treatment. Rome IV IBS appears less stable than Rome III IBS.

A Novel Method to Classify and Subgroup Patients With IBS Based on Gastrointestinal Symptoms and Psychological Profiles.

INTRODUCTION: Conventionally, patients with irritable bowel syndrome (IBS) are subgrouped based on their predominant bowel habit. Given the relevance of psychological comorbidity to IBS symptoms, our aim was to explore an alternative approach to subgrouping by incorporating factors beyond stool form and frequency. METHODS: We collected demographic, symptom, and psychological health data from 1,375 adult subjects in the community who self-identified as having IBS, identifying 2 cohorts meeting either Rome III or Rome IV criteria. In each cohort, we performed latent class analysis, a method of model-based clustering, to identify specific subgroups (clusters). For each cluster, we drew a radar plot and compared these by visual inspection, describing cluster characteristics. RESULTS: In total, 1,080 individuals met the Rome III criteria for IBS, and 811 met the Rome IV criteria. In both cohorts, a 7-cluster model was the optimum solution, and the characteristics of the clusters were almost identical between Rome III and IV. Four clusters were defined by the pattern of gastrointestinal symptoms (loose stools and urgency or hard stools and bloating), further differentiated by the presence of abdominal pain not relieved by defecation, and by the extent of psychological comorbidity. Two clusters had below-average gastrointestinal symptoms, differentiated by the extent of psychological comorbidity. The final cluster had well-above-average gastrointestinal symptoms and high levels of psychological comorbidity. The proportion of subjects with severe IBS symptom scores, high levels of perceived stress, and high levels of gastrointestinal symptom-specific anxiety was significantly higher in clusters with high psychological comorbidity (P < 0.001). DISCUSSION: Latent class analysis identified 7 distinct IBS subgroups characterized by varying degrees of gastrointestinal symptoms, extraintestinal symptoms, and psychological comorbidity. Further research is needed to assess whether they might be used to direct treatment.

Constipation Predominant Irritable Bowel Syndrome and Functional Constipation Are Not Discrete Disorders: A Machine Learning Approach.

INTRODUCTION: Chronic constipation is classified into 2 main syndromes, irritable bowel syndrome with constipation (IBS-C) and functional constipation (FC), on the assumption that they differ along multiple clinical characteristics and are plausibly of distinct pathophysiology. Our aim was to test this assumption by applying machine learning to a large prospective cohort of comprehensively phenotyped patients with constipation. METHODS: Demographics, validated symptom and quality of life questionnaires, clinical examination findings, stool transit, and diagnosis were collected in 768 patients with chronic constipation from a tertiary center. We used machine learning to compare the accuracy of diagnostic models for IBS-C and FC based on single differentiating features such as abdominal pain (a "unisymptomatic" model) vs multiple features encompassing a range of symptoms, examination findings and investigations (a "syndromic" model) to assess the grounds for the syndromic segregation of IBS-C and FC in a statistically formalized way. RESULTS: Unisymptomatic models of abdominal pain distinguished between IBS-C and FC cohorts near perfectly (area under the curve 0.97). Syndromic models did not significantly increase diagnostic accuracy (P > 0.15). Furthermore, syndromic models from which abdominal pain was omitted performed at chance-level (area under the curve 0.56). Statistical clustering of clinical characteristics showed no structure relatable to diagnosis, but a syndromic segregation of 18 features differentiating patients by impact of constipation on daily life. DISCUSSION: IBS-C and FC differ only about the presence of abdominal pain, arguably a self-fulfilling difference given that abdominal pain inherently distinguishes the 2 in current diagnostic criteria. This suggests that they are not distinct syndromes but a single syndrome varying along one clinical dimension. An alternative syndromic segregation is identified, which needs evaluation in community-based cohorts. These results have implications for patient recruitment into clinical trials, future disease classifications, and management guidelines.

Impact of Psychological Comorbidity on the Prognosis of Irritable Bowel Syndrome.

INTRODUCTION: Psychological comorbidities are associated with irritable bowel syndrome (IBS), but little is known about their cumulative effect on its prognosis. We examined this issue in a longitudinal 12-month follow-up study. METHODS: We collected complete demographic, symptom, and psychological comorbidity data (anxiety, depression, somatic symptom disorder, perceived stress, and gastrointestinal symptom-specific anxiety) at baseline from 807 adults who met Rome IV criteria for IBS. At 12 months, we collected data regarding IBS symptom severity and impact, consultation behavior, and treatments commenced from 452 individuals successfully followed up. We examined the cumulative effects of psychological comorbidities at baseline on subsequent IBS disease behavior. RESULTS: At baseline, among the 807 participants, 177 (21.9%) had 1, 139 (17.2%) 2, 103 (12.8%) 3, 89 (11.0%) 4, and 54 (6.7%) 5 psychological comorbidities. IBS symptom severity at baseline increased significantly with the number of psychological comorbidities (72.2% of those with 5 psychological comorbidities reported severe symptoms, vs 29.1% of those with none, P < 0.001). Among 452 (56.0%) participants followed up at 12 months, those with a higher number of psychological comorbidities at baseline were significantly more likely to have seen a gastroenterologist (33.3% of those with 5 psychological comorbidities, vs 21.4% of those with none, P = 0.001), cycle through more treatments (P < 0.0001), to report more severe IBS symptoms (66.7% with 5, vs 24.4% with none, P < 0.001) and continuous abdominal pain (22.1% with none, vs 61.9% with 5, P < 0.001), and to report that symptoms impacted on daily activities ≥50% of the time (90.5% with 5, vs 41.2% with none, P < 0.001). DISCUSSION: The prognosis of individuals with Rome IV-defined IBS worsens according to incremental increases in psychological comorbidity. This has important clinical and research implications.

The connected patient project: moving towards a population-based primary health care research registry.

BACKGROUND: The NHS pledges to give all patients access to clinical research. In England, 32% of General Practices are research active and only 14% of patients engage in research. This project aimed to evaluate consent-for-contact and communication in primary care patients. METHODS: An explanatory mixed methods study of patients and staff within a single general practice. The study included all patients over the age of 18 years, and excluded those on the palliative care register and those unable to give informed consent. The questionnaire asked recipients to indicate their preferred contact method and data-sharing permissions with three organisations: NHS, Universities and Commercial Companies. Survey recipients and staff were invited to take part in a semi-structured interview. Interviews explored project acceptability, feasibility and reasoning behind choices made. Statistical data were triangulated with interview data. RESULTS: The target patient population was 4678, 24% (n = 1148) responded. Seven hundred and three gave permission for at least one of the organisations to contact them. Older people were more likely to respond than young people, (p < 0.001). There was a trend for more women than men to give permissions however, in the 70 years plus age group this was reversed. Short message service was the preferred method of communication (48% n = 330), but those aged 70 years and over, preferred letter (p = 0.001). Interviews suggested patients felt the project was primarily about improving communication and secondly access to research. Patients trusted the NHS and university researchers. Staff interviewees found the project was less onerous than expected. Barriers to wider rollout included workload and the fragmented nature of NHS digital systems. CONCLUSIONS: A registry of patients was established; however, the response rate of 24% needs increasing before wider adoption. Health promotion and chronic disease-based research may recruit better when based in primary health care. Older demographics would be more likely to volunteer for research. NHS and academic researchers are trusted, commercial organisations less so. The move to digitalise communication methods has the potential to marginalise older women. Findings were used to drive forward two novel developments: a consent registry (Research+Me) and a federation-wide participant identification process.

Epidemiological, Clinical, and Psychological Characteristics of Individuals with Self-reported Irritable Bowel Syndrome Based on the Rome IV vs Rome III Criteria.

OBJECTIVES: Few studies have examined the effects of applying the Rome IV criteria for irritable bowel syndrome (IBS) vs the previous standard, the Rome III criteria. We conducted a cross-sectional survey of individuals who self-identify as having IBS to examine this issue. METHODS: We collected complete demographic, symptom, mood, and psychological health data from 1375 adults who self-identified as having IBS, but were not recruited from a referral population. We applied the Rome III and the Rome IV criteria simultaneously to examine what proportion met each of these diagnostic criteria for IBS. We measured the level of agreement between the Rome III and Rome IV criteria, and assessed for presence of an alternative functional bowel disorder in individuals who no longer met diagnostic criteria for IBS with the more restrictive Rome IV criteria. Finally, we compared characteristics of individuals who met only Rome III criteria with those who met Rome IV criteria. RESULTS: In total, 1080 of 1368 individuals (78.9%) with IBS met the Rome III criteria. In contrast, 811 of 1373 individuals (59.1%) with IBS met the Rome IV criteria. Agreement between the criteria was only moderate (Kappa = 0.50). Among those who no longer had IBS according to the Rome IV criteria, 33 (11.5%) met Rome IV criteria for functional constipation, 118 (41.3%) for functional diarrhea, 68 (23.8%) for functional abdominal bloating or distension, and 67 (23.4%) for an unspecified functional bowel disorder. Individuals with Rome IV-defined IBS had more severe symptoms, and a higher proportion had a mood disorder and evidence of poor psychological health, compared with individuals who only met the Rome III criteria for IBS (P < .001). CONCLUSIONS: The characteristics of people who believe they have IBS differ between those who meet criteria as defined by Rome IV vs Rome III, including the spectrum of disease severity. Studies are needed to determine how these changes will affect outcomes of clinical trials.

Economic burden of moderate to severe irritable bowel syndrome with constipation in six European countries.

BACKGROUND: Irritable bowel syndrome with predominant constipation (IBS-C) is a complex disorder with gastrointestinal and nervous system components. The study aim was to assess the economic burden of moderate to severe IBS-C in six European countries (France, Germany, Italy, Spain, Sweden and the UK). METHODS: An observational, one year retrospective-prospective (6 months each) study of patients diagnosed in the last five years with IBS-C (Rome III criteria) and moderate to severe disease at inclusion (IBS Symptom Severity Scale score ≥ 175). The primary objective was to assess the direct cost to European healthcare systems. RESULTS: Five hundred twenty-five patients were included, 60% (range: 43.1-78.8%) suffered from severe IBS-C. During follow-up 11.1-24.0% of patients had a hospitalisation/emergency room (ER) visit, median stay range: 1.5-12.0 days and 41.1-90.4% took prescription drugs for IBS-C. 21.4-50.8% of employed patients took sick leave (mean: 11.6-64.1 days). The mean annual direct cost to the healthcare systems was €937.1- €2108.0. The total direct cost (combined costs to healthcare systems and patient) for IBS-C was €1421.7-€2487.1. CONCLUSIONS: IBS-C is not a life-threatening condition; however, it has large impact on healthcare systems and society. Direct and indirect costs for moderate to severe IBS-C were high with the largest direct cost driver being hospitalisations/ER visits.

Professional identity and the Clinical Research Nurse: A qualitative study exploring issues having an impact on participant recruitment in research.

AIMS: The aim of this study was to explore the experiences of Clinical Research Nurses, with an emphasis on factors that may have an impact on successful study delivery. BACKGROUND: The Clinical Research Nurse workforce is pivotal to improving health outcomes through supporting research-active health economies. Investment in research infrastructure has led to nurses and midwives increasingly undertaking extended roles to deliver clinical research. Despite such opportunities, the recruitment of sufficient participants into research studies remains problematic. A growing body of literature is exploring barriers to successful study delivery, indicating the emergence of a caring-recruiting dichotomy in clinical research staff. DESIGN: This qualitative study investigates the experiences of Clinical Research Nurses delivering research in the United Kingdom National Health Service. METHODS: Four Focus groups (total 19 participants) were conducted in a large North East National Health Service Foundation Trust from November 2015 - February 2016. FINDINGS: Thematic analysis identified perceptions of the role in the wider context of professional identity. Role transition, altered relationships and workload complexity, affected participants' practice, leading to inconsistency between core clinical values and perceived identities as research delivery staff. A duty of care as patient advocates contrasted elements of the work reflecting that of salespeople. The emotional labour of approaching patients and unease regarding peer perceptions of the Clinical Research Nurse role, affected the positive aspects of research delivery. CONCLUSION: Professional-identity and self-concept appear to have an impact on practice in a research delivery role. Further research should explore these issues further, to enlighten the basis on which such feelings are positioned and to work towards practical solutions.

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

OBJECTIVES: 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. METHODS: In this large, observational cohort study, we assessed the clinical, molecular, and radiological characteristics of patients with genetically determined m.3243A>G-related mitochondrial disease, who presented with severe symptoms suggestive of bowel obstruction in the absence of an occluding lesion. RESULTS: Between January 2009 and June 2015, 226 patients harbouring the m.3243A>G mutation were recruited to the Medical Research Council Centre Mitochondrial Disease Patient Cohort, Newcastle. Thirty patients (13%) presented acutely with IPO. Thirteen of these patients had a preceding history of stroke-like episodes, whereas 1 presented 27 years previously with their first stroke-like episode. Eight patients developed IPO concomitantly during an acute stroke-like episode. Regression analysis suggested stroke was the strongest predictor for development of IPO, in addition to cardiomyopathy, low body mass index and high urinary mutation load. Poor clinical outcome was observed in 6 patients who underwent surgical procedures. INTERPRETATION: Our findings suggest, in this common mitochondrial disease, that IPO is an under-recognized, often misdiagnosed clinical entity. Poor clinical outcome associated with stroke and acute surgical intervention highlights the importance of the neurologist having a high index of suspicion, particularly in the acute setting, to instigate timely coordination of appropriate care and management with other specialists. Ann Neurol 2016;80:686-692.

Efficacy and Safety of Prucalopride in Chronic Constipation: An Integrated Analysis of Six Randomized, Controlled Clinical Trials.

BACKGROUND: Prucalopride, a selective, high-affinity 5-hydroxytryptamine 4 receptor agonist, stimulates gastrointestinal and colonic motility and alleviates common symptoms of chronic constipation (CC) in adults. The relative efficacy by gender has not been evaluated. AIM: To evaluate the global efficacy and safety of prucalopride 2 mg daily in men and women with CC using data from six large, randomized, controlled clinical trials. METHODS: Data were combined from six phase 3 and 4, double-blind, randomized, placebo-controlled, parallel-group trials. The primary efficacy endpoint was the percentage of patients with a mean of ≥3 spontaneous complete bowel movements (SCBMs) per week over 12 weeks of treatment. Safety was assessed throughout all the trials. RESULTS: Overall, 2484 patients (597 men; 1887 women; prucalopride, 1237; placebo, 1247) were included in the integrated efficacy analysis and 2552 patients were included in the integrated safety analysis. Significantly more patients achieved a mean of ≥3 SCBMs/week over the 12 weeks of treatment in the prucalopride group (27.8 %) than in the placebo group [13.2 %, OR 2.68 (95 % CI 2.16, 3.33), p < 0.001]. Prucalopride had a favorable safety and tolerability profile. Efficacy and safety outcomes were not significantly different between men and women. CONCLUSION: The integrated analysis demonstrates the efficacy and safety of prucalopride in the treatment of CC in men and women.

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.

Trans-anal irrigation therapy to treat adult chronic functional constipation: systematic review and meta-analysis.

BACKGROUND: Trans-anal irrigation (TAI) is used widely to treat bowel dysfunction, although evidence for its use in adult chronic functional constipation remains unclear. Long-term outcome data are lacking, and the effectiveness of therapy in this patient group is not definitively known. METHODS: Evidence for effectiveness and safety was reviewed and the quality of studies was assessed. Primary research articles of patients with chronic functional constipation, treated with TAI as outpatients and published in English in indexed journals were eligible. Searching included major bibliographical databases and search terms: bowel dysfunction, defecation, constipation and irrigation. Fixed- and random-effect meta-analyses were performed. RESULTS: Seven eligible uncontrolled studies, including 254 patients, of retrospective or prospective design were identified. The definition of treatment response varied and was investigator-determined. The fixed-effect pooled response rate (the proportion of patients with a positive outcome based on investigator-reported response for each study) was 50.4 % (95 % CI: 44.3-56.5 %) but featured substantial heterogeneity (I(2) = 67.1 %). A random-effects estimate was similar: 50.9 % (95 % CI: 39.4-62.3 %). Adverse events were inconsistently reported but were commonplace and minor. CONCLUSIONS: The reported success rate of irrigation for functional constipation is about 50 %, comparable to or better than the response seen in trials of pharmacological therapies. TAI is a safe treatment benefitting some patients with functional constipation, which is a chronic refractory condition. However findings for TAI vary, possibly due to varying methodology and context. Well-designed prospective trials are required to improve the current weak evidence base.

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.

Longitudinal follow-up of a novel classification system for irritable bowel syndrome: natural history and prognostic value.

BACKGROUND: Conventionally, irritable bowel syndrome (IBS) is subgrouped using predominant stool form, yet it is a complex disorder, with multiple biopsychosocial contributors. We previously derived and validated a latent class model subgrouping people with IBS into seven clusters based on gastrointestinal and extraintestinal symptoms and psychological profile. AIMS: To conduct longitudinal follow-up examining the natural history and prognostic value of these clusters. METHODS: Participants completed a 12-month follow-up questionnaire. We applied our model to these data, comparing cluster membership between the two time points in those still meeting Rome IV criteria at follow-up, including stratifying the analysis by predominant stool pattern, and level of psychological burden, at baseline. We examined whether baseline cluster predicted the course of IBS, and whether starting new treatment was associated with changing cluster. RESULTS: Eight hundred and eleven participants met Rome IV criteria for IBS at baseline, of whom 452 (55.7%) responded, and 319 (70.6%) still met Rome IV criteria for IBS at follow-up. Of these, 172 (53.9%) remained in the same IBS cluster as at baseline and 147 changed cluster. Cluster membership stratified according to psychological comorbidity was more stable; 84% of those in a cluster with high psychological burden at baseline remained in such a cluster at follow-up. People in clusters with high psychological burden at baseline had more severe symptoms (P < 0.001), received a higher mean number of subsequent treatments (P < 0.001), and were more likely to consult a doctor than people in clusters with low psychological burden (P < 0.001). There was no significant association between starting a new treatment and changing cluster at follow-up. CONCLUSIONS: Longitudinal follow-up demonstrated little transition between clusters with respect to psychological burden, and these appeared to predict disease course. Directing treatment according to cluster, including earlier use of psychological therapies, and exploring how this approach influences outcomes in IBS, should be examined.