857358 research-article20192019 TAG0010.1177/1756284819857358Therapeutic Advances in GastroenterologyB Serrano-Falcón, S Delgado-Aros Therapeutic Advances in Gastroenterology Original Research Clinical response to linaclotide at week 4 Ther Adv Gastroenterol 2019, Vol. 12: 1–14 predicts sustained response in irritable DOI: 10.1177/ https://doi.org/10.1177/1756284819857358 https://doi.org/10.1177/1756284819857358 1756284819857358 bowel syndrome with constipation © The Author(s), 2019. Article reuse guidelines: sagepub.com/journals- and improvements in digestive and permissions extra-digestive symptoms Blanca Serrano-Falcón, Sílvia Delgado-Aros, Fermín Mearin, Constanza Ciriza de los Ríos, Jordi Serra, Miguel Mínguez, Miguel Montoro Huguet, Antonia Perelló, Cecilio Santander, Ángeles Pérez Aisa, Inmaculada Bañón-Rodríguez and Enrique Rey Abstract Background: Linaclotide is approved for the treatment of moderate-to-severe irritable Correspondence to: bowel syndrome (IBS) with constipation (IBS-C) in adults. This study aimed to assess factors Enrique Rey Servicio de Aparato predictive of a clinical response and improvements in non-IBS symptoms with linaclotide Digestivo, Hospital treatment in a Spanish patient population. Clínico San Carlos, Universidad Complutense, Methods: In this open-label phase IIIb study, patients with moderate-to-severe IBS-C received Instituto de Investigación linaclotide 290 μg once daily for 12 weeks. The primary endpoint was clinical response at Sanitaria San Carlos (IdISSC), 28040 Madrid, week 12, defined as >30% reduction in IBS symptom severity score (IBS-SSS) or IBS-SSS <75 Spain enrique.rey@salud. plus self-reported response of feeling ‘better’ or ‘much better’ versus the baseline. Digestive madrid.org nonintestinal and extra-digestive symptom scores were assessed. Baseline characteristics Blanca Serrano-Falcón Hospital Clínico San and week 4 clinical response were assessed as predictors of week 12 clinical response. Carlos, Instituto de Results: A total of 96 patients were eligible; 91 were female and the mean age was 47.4 Investigación Sanitaria San Carlos (IdISSC), years. Mean (SD) baseline IBS-SSS was 371 (72.5). In the intention-to-treat and per-protocol Madrid, Spain populations, 22.9% and 31.7% were clinical responders at week 4, respectively, and 25.0% Sílvia Delgado-Aros Hospital del Mar, and 36.7% were clinical responders at week 12. Digestive nonintestinal and extra-digestive Barcelona, Spain symptom scores were significantly improved at weeks 4 and 12. Baseline characteristic was Fermín Mearin Centro Médico Teknon, not associated with week 12 clinical response; however, clinical response at week 4 was Barcelona, Spain predictive of response at week 12 (OR: 6.5; 95%IC: 2.1–19.8). The most common adverse event Constanza Ciriza was diarrhea inclusive of loose or watery stools (35.4%). de los Ríos Hospital 12 de Octubre, Conclusions: Linaclotide improves IBS-C symptoms, including digestive nonintestinal and Madrid, Spain extra-digestive symptoms. A clinical response at week 4 may predict response at week 12. Jordi Serra University Hospital German Trias i Pujol, Centro de Investigación Keywords: abdominal pain, constipation, functional gastrointestinal diseases, irritable bowel Biomédica en Red de Enfermedades syndrome Hepáticas y Digestivas (CIBEREHD), Badalona, Spain Received: 8 November 2018; revised manuscript accepted: 24 April 2019. Miguel Mínguez Hospital Clínico de València, Universitat de València, València, Introduction stool patterns including IBS with constipation Spain Miguel Montoro Huguet Irritable bowel syndrome (IBS) is a common and (IBS-C), IBS with diarrhea, IBS with a mixed Hospital San Jorge, chronic gastrointestinal (GI) disorder character- stool pattern, and unclassified IBS.1,3 Huesca, Spain ized by recurrent abdominal pain and altered Antonia Perelló Hospital de Viladecans, bowel movements.1 IBS is a disorder of gut–brain IBS affects approximately 11% of the global pop- Barcelona, Spain interaction2 and is subtyped by its predominant ulation and 11.5% in Europe, including an journals.sagepub.com/home/tag 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Gastroenterology 12 Cecilio Santander Hospital Universitario de estimated 10% of people in Spain.4,5 IBS-C is periodically thereafter, depending on the individ- La Princesa, Instituto de estimated to account for approximately one-third ual patient’s needs.18,19 Investigación Sanitaria Princesa (IIS-IP), of all IBS cases, and is one of the most common Universidad Autónoma reasons for patient visits to both primary care The aim of this study was to identify factors that de Madrid, Centro de Investigación Biomédica physicians and gastroenterologists.6 Mean overall may help predict a short- and long-term clinical en Red de Enfermedades costs for IBS-C in a United States (US) commu- response to linaclotide and to assess the impact of Hepáticas y Digestivas (CIBEREHD), Madrid, Spain nity center analysis were US$11,406 over a 2-year linaclotide on IBS-C symptoms, including GI, Ángeles Pérez Aisa period, and in Europe, the mean annual overall digestive nonintestinal, and extra-digestive symp- Agencia Sanitaria Costa costs to the healthcare system for moderate-to- toms after 12 weeks. del Sol, Marbella, Spain severe IBS-C were €4639.7,8 Inmaculada Bañón-Rodríguez Allergan plc, Madrid, Spain While some patients with IBS-C may experience Methods mild or intermittent symptoms, for some, these symptoms are severe and debilitating. IBS is also Study design associated with a significant GI and non-GI This was an open-label, uncontrolled, single-arm comorbidity burden,9 which contributes to the phase IIIb clinical trial conducted at 12 hospital significant impact of IBS-C on patients’ health- centers across Spain from November 2014 to related quality of life. As a result, IBS-C is associ- February 2016. Physicians at the hospital centers ated with a high economic and humanistic burden invited patients who met all inclusion and no due to greater use of healthcare resources and exclusion criteria to participate. Written informed work productivity loss, including presenteeism consent was obtained from all patients or their and activity impairment.10,11 legal representatives before any procedure or par- ticipation in the trial commenced. Following con- IBS-C management options include nonpharma- sent, patient information was entered into an cological measures such as dietary modifications, electronic case report system. Linaclotide 290 µg increasing physical activity, and psychological capsules were administered once daily for therapy.12 Pharmacological therapy of IBS-C 12 weeks, in accordance with its approved indica- includes antispasmodics, over-the-counter medi- tion, and taken at least 30 minutes before meals.18 cations (e.g. laxatives), as well as approved pre- scription medications such as lubiprostone and Patients completed a 4-week screening period linaclotide.12–14 In two phase III trials, linaclotide (weeks −4 to 0) and a baseline visit at week 0, fol- significantly improved pain, constipation, and lowed by study visits for assessment of efficacy abdominal bloating in patients with IBS-C and is and safety at weeks 4, 8, and 12 (Table S1). After therefore approved by the European Medicines completion of the 12-week treatment period, an Agency for moderate-to-severe IBS-C in adults.15,16 additional safety visit was scheduled at week 16. Treatment adherence was evaluated through cap- IBS-C is a chronic condition requiring long-term sule counting. All laxatives, enemas, and supposi- management, and patient dissatisfaction with tories were stopped during the screening period available treatment options or lack of response to and allowed as rescue medication for a maximum treatment can result in negative outcomes such as of 12 days during the treatment period. repeated physician consultations, use of multiple Medications that were not permitted included treatments (over-the-counter or prescription medi- opiates, spasmolytic drugs, and herbal therapies, cations), medication switching, use of unproven which included probiotics. Physicians also medications, or unnecessary surgery.13,17 There­ stopped medications such as antihistamines, pro- fore, it is important to understand the effectiveness ton pump inhibitors, antacids, selective serotonin of any treatment over time. The ability to identify reuptake inhibitors, and calcium channel blockers patients who will or will not respond to a treat- during screening or immediately before study ment, both in the short and long term, would be of entry. However, these medications could be substantial clinical value and will be important in restarted, if clinically indicated. establishing reasonable patient, prescriber, and payer expectations of the effectiveness of a treat- The study protocol was conducted in accordance ment. Current treatment recommendations for with the Helsinki Declaration, approved by the linaclotide suggest a first follow-up visit 4 weeks World Medical Association (version revised at the after initiation, with a second visit at 12 weeks and 59th World Medical Association General Assembly, 2 journals.sagepub.com/home/tag B Serrano-Falcón, S Delgado-Aros et al. Seoul, Republic of Korea, October 2008), Oviedo higher scores indicate greater pain/bloating sever- Convention (1977), Good Clinical Practices (GCP ity and lower satisfaction with bowel habit. of ICH, 1996), and current regulatory require- ments. The study protocol was approved by the Global improvement was evaluated through the ethics committees of all study centers and by the question: ‘Overall, how do you feel about your Spanish Agency of Medicines and Health Products. IBS symptoms compared with how you felt before The trial protocol was registered with EudraCT beginning treatment?’, using a five-point Likert (EudraCT Number: 2013-001248-67). scale with five response options ranging from ‘much worse’ to ‘much better’. Study population Digestive nonintestinal symptom score was meas- Eligible patients were aged ⩾18 years and had a ured using a validated Spanish version of the Rome diagnosis of moderate-to-severe IBS-C based on III questionnaire.20,23 It consists of six questions Rome III criteria20 and a baseline IBS symptom regarding symptom frequency (heartburn and acid severity score (IBS-SSS) of >175. Additionally, reflux, postprandial fullness, early satiety, epigastric patients must have shown blood analysis without pain, nausea, and vomiting) in the last 4 weeks, anemia in the previous 6 months and, if aged scored from 0 (never) to 3 (most of the time, >50 years, must have had a normal colonoscopy ⩾3 days weekly). The total score for digestive non- in the previous 5 years. intestinal symptoms was the sum of these responses. Exclusion criteria included diagnosis of any chronic Extra-digestive symptom score was measured digestive disease other than IBS, any abdominal using the patient health questionnaire 12 somatic surgery (except hysterectomy, cholecystectomy, symptom scale,24 which consists of questions on and appendectomy), a diagnosis of cancer or extra-digestive symptoms such as back pain, head- chronic inflammatory disease, or a diagnosis of ache, chest pain, dizziness, fainting spells, short- other disorders that could affect IBS (cardiologic, ness of breath, joint pain, feeling tired, pain or neurologic, pneumologic, endocrinologic, or renal problems during sex, menstrual cramps, and trou- disorders). Patients taking opioids, anticholiner- ble sleeping. Bothersomeness of each symptom is gics, or calcium antagonists were also excluded. scored on a three-point scale, where 0 is ‘not both- ered at all’ and 2 is ‘bothered a lot’, and summed to provide a total score on a scale of 0–24.24 Study assessments IBS severity was measured using the IBS-SSS, a Constipation-related quality of life was measured validated measure consisting of five domains using the validated quality of life in constipa- [abdominal pain frequency, abdominal pain tion-20 questionnaire.25 It consists of four severity, abdominal distention (bloating) severity, domains (emotional, general physical, rectal satisfaction with bowel habit, and impact of IBS physical, and social) and includes 20 items scored on daily activities], scored from 0 to 100 on a on a five-point Likert scale with responses rang- visual analog scale (VAS), producing an overall ing from ‘always’ to ‘never’. reported score on a scale of 0–500, with higher scores representing more severe symptoms. Pain/constipation index was obtained by calculat- Disease severity was stratified by IBS-SSS score ing the ratio of the pain severity score and bowel as follows: normal: <75; mild: 75 to <175; mod- habit satisfaction score components of the IBS- erate: 175 to <300; severe: ⩾300.21 A reduction SSS. An index score >1 was defined as pain pre- in IBS-SSS score of ⩾50 points is considered to dominance, while an index score <1 was defined represent a clinically meaningful improvement.21 as constipation predominance. Anxiety and A validated Spanish version of the IBS-SSS is depression were measured using the hospital anx- available which, in addition to the VAS, features iety and depression scale.26 a numerical scoring system for each domain on a scale of 0–12, with higher scores indicating more The safety of linaclotide was assessed via the severe symptoms.22 The IBS-SSS VAS (0–100) observation and recording of adverse events was used to evaluate individual symptom scores (AEs) throughout the trial duration. AEs were for abdominal pain severity, abdominal bloating collected by the investigators according to their severity, and satisfaction with bowel habit, where clinical judgment. A definition of diarrhea was journals.sagepub.com/home/tag 3 Therapeutic Advances in Gastroenterology 12 not prespecified in the protocol; those AEs < 0.05 in the univariate analysis and the following described as ‘loose/watery stools’, ‘increased baseline variables were included in the model as number of bowel movements’, or ‘diarrhea’ were potential predictive factors in a backward stepwise coded using the Medical Dictionary for Regulatory selection: age, time since IBS diagnosis, IBS-SSS Activities version 17.1. score, abdominal pain severity score, digestive non- intestinal symptom score, extra-digestive symptom score, anxiety/depression score, fear/concern score, Efficacy endpoints drug confidence score, and pain/constipation index. The primary endpoint was clinical response at Relative risks were reported with 95% CI and week 12, assessed using the IBS-SSS and global model classification power was assessed with area improvement scores. A clinical response was under the curve analysis at 95% CI. In order to defined as meeting both of the following criteria: assess whether a response at week 4 is predictive of firstly, either a decrease in IBS-SSS score >30% a response at week 12, a logistic regression model versus baseline or an IBS-SSS score <75; and sec- was generated using predictive factors identified in ondly, a self-reported response on the five-point the binary model above, with the additional varia- Likert scale of feeling ‘better’ or ‘much better’ ver- ble of clinical response at week 4. The area under sus baseline. Patients had to meet both criteria at the curve of both models were compared to assess week 4 and week 12 to be considered a responder. improvement in predictive capacity from the addi- tion of week 4 response. Statistical analyses Exploratory Pearson’s correlation analyses were The intention-to-treat (ITT) population was conducted to assess the relationship between defined as all patients who completed the screen- anxiety/depression score and digestive non­ ing phase and received at least one dose of study intestinal and extra-digestive symptom scores at medication. The population that completed the screening (week −4) and during the treatment protocol, or protocol completers,27 was defined as phase (ITT population), and to evaluate the all patients who completed the treatment period association between change in IBS-SSS score of 12 weeks. Statistical analyses were performed and change in digestive nonintestinal and extra- for both the ITT and CP (protocol completer) digestive symptom scores during the treatment populations. Sample size was determined by phase (ITT population). logistic regression analyses where the dependent variable was clinical response and potentially associated factors were included. A 5% signifi- Results cance level was used for all tests. Patient disposition, demographics, and baseline For descriptive analyses, quantitative variables characteristics were reported as mean and standard deviation A total of 121 patients were screened; 109 patients (SD) with 95% confidence interval (CI). For uni- completed the screening phase and 96 entered variate analyses, the study-dependent variable the treatment phase (ITT population). During was clinical response at week 12. Association the study, 36 patients discontinued linaclotide between qualitative independent variables and treatment. The reasons for discontinuation were clinical response was evaluated through Pearson’s AEs (n = 12, 12.5%), withdrawal of consent Chi-squared test or Fisher’s exact test. Relative (n = 3, 3.1%), protocol deviation (n = 9, 9.4%), risks were reported with 95% CI. For quantitative and lack of efficacy (n = 12, 12.5%). A total of 60 independent variables, a comparison of means patients completed the treatment phase (CP pop- through a Student’s t test was performed and a ulation; Figure 1). nonparametric test of the median was performed for quantitative variables that were not adjusted In the ITT population, the mean (SD) age was to a normal distribution. Mean differences were 47.4 (14.7) years (range 18–80) and 94.8% of reported with 95% CI. patients were female. Patients had been previously diagnosed with IBS-C for a mean (SD) duration To identify predictive factors independently related of 7.5 (10) years. At the screening visit, the IBS- to clinical response at week 12, a binary regression SSS total mean (SD) score was 371.0 (72.5), and model was generated. Variables with significance p the IBS-SSS domain mean (SD) scores were 68.4 4 journals.sagepub.com/home/tag B Serrano-Falcón, S Delgado-Aros et al. Figure 1. Study design and patient disposition. aAdverse event was diarrhea in all 12 patients. CP, protocol completer; ITT, intention-to-treat. (19.5) for abdominal pain severity, 76.3 (20.2) for based on meeting both the IBS-SSS and global abdominal bloating severity, and 65.9 (21.7) for improvement from the responder definition, was satisfaction with bowel habit (Table 1). achieved in 25.0% and 36.7% of patients, respec- tively, at week 12 [Figure 2(a)]. In terms of the IBS-SSS component alone, 32.3% and 46.7% of Efficacy patients showed a response at week 12 in the ITT Primary endpoint: clinical response at week 12. A and CP populations, respectively [Figure 2(b)]. clinical response in the ITT and CP populations, From global improvement alone, 55.2% and journals.sagepub.com/home/tag 5 Therapeutic Advances in Gastroenterology 12 Table 1. Patient demographics and characteristics at screening. ITT population CP population (n = 96) (n = 60) Age, years, mean (SD) 47.4 (14.7) 43.0 (14.7) Female, n (%) 91 (94.8) 58 (96.7) BMI, kg/m2, mean (SD) 24.2 (4.8) − Years since last colonoscopy for patients aged ⩾50 years, mean (SD) 0.8 (1.2) 0.8 (1.3) Years since IBS-C diagnosis, mean (SD) 7.5 (10.0) 8.0 (9.3) IBS-SSS overall scorea mean (SD) 371.0 (72.5) 376.7 (68.5) Abdominal pain severity scoreb mean (SD) 68.4 (19.5) 67.4 (18.1) Abdominal bloating severity scoreb mean (SD) 76.3 (20.2) 79.0 (17.8) Bowel habit satisfaction scoreb mean (SD) 65.9 (21.7) 66.4 (21.3) Pain/constipation index, mean (SD) 1.2 (0.8) 1.2 (0.7) Digestive nonintestinal scorec mean (SD) 8.9 (3.9) 9.1 (3.9) Extra-digestive scored mean (SD) 10.7 (4.2) 10.5 (4.5) aScaleof 0–500. bAssessedwith IBS-SSS VAS of 0–100, where higher scores indicate more severe symptoms/lower satisfaction with bowel habits. cBased on Rome III questionnaire. dAssessed with PHQ-12, scale of 0–24, where higher scores indicate greater bothersomeness of symptoms. BMI, body mass index; CP, protocol completer; IBS-C, irritable bowel syndrome with constipation; IBS-SSS, irritable bowel syndrome symptom severity score; ITT, intention-to-treat; PHQ-12, patient health questionnaire 12 somatic symptom scale; SD, standard deviation; VAS, visual analog scale. 70.0% were responders at week 12 in the ITT 79.1 to 72.0 (p < 0.001) [Figure 4(b)], and the and CP populations, respectively [Figure 2(c)]. mean bowel habit satisfaction score improved At week 12, 61.5% and 80.0% of patients met from 64.1 to 45.5 (p < 0.001) [Figure 4(c)]. either of the individual criteria in the ITT and CP populations, respectively (Figure 2). Digestive nonintestinal and extra-digestive symp- toms. Digestive nonintestinal symptom scores Change in IBS-SSS total score and symptom were significantly lower at all subsequent visits scores. Between baseline (week 0) and week 12, compared with the baseline (Figure 5). In the ITT approximately half (47.9%) of patients in the population, the mean digestive nonintestinal symp- ITT population had a decrease in IBS-SSS of tom score remained stable during the screening ⩾50 points and one-third (33.3%) had a decrease phase from week −4 (8.89) to baseline (8.65) of ⩾100 points (Figure 3). Similarly, in the CP (p > 0.05) and decreased from baseline to 6.81 at population, 56.7% of patients had a decrease in week 12 [21.2% improvement; p < 0.001; Figure IBS-SSS of ⩾50 points and 45.0% had a decrease 5(a)]. Extra-digestive symptom scores slightly of ⩾100 points (Figure 3). worsened from week −4 (11.71) to baseline (12.65) (p < 0.05), and significantly decreased at weeks 4, At weeks 4, 8, and 12, individual symptom scores 8, and 12. In the ITT population, the mean extra- were all significantly lower compared with base- digestive symptom score decreased from baseline to line in both the ITT and CP populations (Figure 4). 7.39 at week 12 [41.5% improvement; p < 0.001; In the ITT population at week 12, the mean Figure 5(b)]. abdominal pain severity score decreased from 66.6 to 49.2 (p < 0.001) [Figure 4(a)], the mean An exploratory analysis revealed that at week −4 abdominal bloating severity score decreased from (screening), anxiety/depression score correlated 6 journals.sagepub.com/home/tag B Serrano-Falcón, S Delgado-Aros et al. Figure 2. Proportions of patients displaying a clinical response (a); response based on the IBS-SSS component only (b); and response based on global improvement only (c): ITT and CP populations. A clinical response was defined as meeting both of the following criteria: firstly, either a decrease in IBS-SSS score >30% versus baseline or an IBS-SSS score <75; and secondly, a self-reported response on a five-point Likert scale of feeling ‘better’ or ‘much better’ versus baseline. CP, protocol completer; IBS-SSS, irritable bowel syndrome symptom severity score; ITT, intention-to-treat. with digestive nonintestinal symptom score population reported use of laxatives, enemas, or (r = 0.39; p < 0.001) and extra-digestive symp- suppositories; use of rescue medication was tom score (r = 0.49; p < 0.001). However, in the reported in 12.5% of ITT patients between base- ITT population, change in anxiety score during line and week 4, and there was a further decrease to the treatment phase did not show a correlation 11.5% between weeks 4 and 12 (Table S2). with change in digestive nonintestinal symptom score (r = 0.11; p = 0.365) or extra-digestive Quality of life. Linaclotide treatment was associated symptom score (r = −0.06; p = 0.713). Change in with an improvement in the mean (SD) global IBS-SSS score during the treatment phase in the quality of life in constipation-20 questionnaire ITT population was moderately correlated with score, from 32.3 (13.8) at baseline to 37.2 (14.2) at change in digestive nonintestinal symptom score week 12 (p = 0.005) in the ITT population [Figure (r = 0.44; p ⩽ 0.001) but not with change in extra- S1(a)], and from 33.1 (13.6) at baseline to 38.0 digestive symptom score (r = −0.14; p = 0.309). (13.9) at week 12 (p = 0.001) in the CP population [Figure S1(b)]. Significant improvements at week Use of concomitant medications for constipation. 12 were observed in the physical (p < 0.001, ITT At baseline, 42.7% of patients in the ITT and CP populations), emotional (p < 0.005, ITT journals.sagepub.com/home/tag 7 Therapeutic Advances in Gastroenterology 12 Figure 3. Change from baseline in IBS-SSS overall score at week 12: ITT and CP populations. A reduction in IBS-SSS score of ⩾50 points is considered to represent a clinically meaningful improvement.21 CP, protocol completer; IBS-SSS, irritable bowel syndrome symptom severity score; ITT, intention-to-treat. population; p = 0.007, CP population), and rectal Discussion physical role (p ⩽ 0.001, ITT and CP populations) This single-country, multicenter, open-label study subscales; however, there was no significant change provides real-world evidence of the efficacy and in the social role subscale (Figure S1). safety of linaclotide in a Spanish population of adults with moderate-to-severe IBS-C, supporting the findings of the phase III linaclotide clinical Prediction of clinical response at week 12 trial program. Improvements in both digestive and None of the evaluated baseline demographics extra-digestive symptoms were observed with lina- or clinical characteristics were independently clotide treatment, and linear regression analysis associated with a clinical response at week 12 demonstrated that clinical response at week 4, (Table S3). However, clinical response at based on simultaneous improvement in symptom week 4 was independently associated with a severity and global improvement, was predictive clinical response at week 12, with an odds of sustained clinical response at week 12. ratio of 6.5 [95% CI: 2.1, 19.8; Figure S2 and Table S3]. In this study, approximately one-third of patients achieved a clinical response at week 12, based on the restrictive definition of both an improve- Safety ment in IBS-SSS and a patient-reported global In the ITT population, 67.7% of patients improvement. However, this finding does not experienced at least one AE, with diarrhea necessarily indicate that only one-third of patients being the most common, occurring in 34 obtained a benefit from linaclotide. A clinically (35.4%) patients (Table 2) and leading to meaningful reduction (⩾50-point decrease) in treatment discontinuation in 12 (12.5%) IBS-SSS score was achieved at week 12 in almost patients. In total, 42 incidences of diarrhea 50% and 60% of patients in the ITT and CP were reported, 41 of which were deemed treat- populations, respectively. In addition, approxi- ment-related; of these cases, 43.9% were rated mately two-thirds of patients reported that they mild, 51.2% were moderate, and 4.9% were felt ‘better’ or ‘much better’ at week 12 versus severe. Nearly half (48.8%) of the AEs of diar- baseline. Treatment with linaclotide also led to rhea related to study medication occurred in improvements in individual symptom scores for week 1. The median duration of diarrhea abdominal pain, abdominal bloating, and bowel related to study drug was 9 days, with 36.6% habit satisfaction. Use of rescue medication was of episodes lasting ⩽7 days. No serious AEs or minimal during the treatment phase, reflecting deaths occurred. the efficacy of linaclotide. Further, bowel habit 8 journals.sagepub.com/home/tag B Serrano-Falcón, S Delgado-Aros et al. Figure 4. IBS-SSS scores from baseline (week 0) through week 12: abdominal pain severity (a); abdominal bloating severity (b); and bowel habit satisfaction (c): ITT and CP populations. IBS-SSS scores for abdominal pain severity, abdominal bloating severity and bowel habit satisfaction were assessed using a VAS of 0–100, where higher scores indicate greater symptom severity/lower satisfaction with bowel habit. *p < 0.05; **p < 0.001; ITT population. †p < 0.05; ††p < 0.001; CP population. CP, protocol completers; IBS-SSS, irritable bowel syndrome symptom severity score; ITT, intention-to-treat; SD, standard deviation; VAS, visual analog scale. satisfaction score improved with sustained lina- CP population: 36.7%) supports the previously clotide treatment. reported findings of two large phase III trials of linaclotide.16,28 These trials utilized the US Food The proportion of week 12 clinical responders and Drug Administration-mandated responder in the present study (ITT population: 25.0%; criteria of ⩾30% reduction in average daily worst journals.sagepub.com/home/tag 9 Therapeutic Advances in Gastroenterology 12 Figure 5. Digestive nonintestinal (a) and extra-digestive (b) symptoms from screening start (week −4) to end of treatment (week 12): ITT and CP populations. *p < 0.05; **p < 0.001 versus baseline (week 0); ITT population. †p < 0.05; ††p < 0.001 versus baseline (week 0); CP population. CP, protocol completers; ITT, intention-to-treat; SD, standard deviation. abdominal pain score and an increase by ⩾1 The overall safety profile of linaclotide in this trial complete spontaneous bowel movement from was consistent with that previously reported, with baseline in the same week for at least 50% of diarrhea being the most frequent AE. Diarrhea was weeks, and reported responder proportions of reported in 35.4% of patients and led to discon- 33.7% and 33.6%, respectively, after 12 weeks of tinuation in 12.5%, regardless of relatedness to linaclotide treatment.16,28 study medication; only 96 patients were included 10 journals.sagepub.com/home/tag B Serrano-Falcón, S Delgado-Aros et al. Table 2. Summary of safety and AEs occurring during and extra-digestive symptoms. These symptoms are the treatment period, regardless of relatedness to known to contribute to the overall impact of IBS on study drug. quality of life,10,11 and this finding may be important ITT population in the clinical setting, since IBS is often comorbid (n = 96) with GI and non-GI disorders (e.g. functional heartburn, dyspepsia, fibromyalgia). The results Patients with AEs, n (%)a 65 (67.7) presented in this study support the hypothesis that an improvement in digestive nonintestinal and AEs occurring in >2% of patients, n (%) extra-digestive symptoms leads to an improvement Diarrhea 34 (35.4) in other symptoms related to non-GI disorders. Headache 10 (10.4) Improvement of digestive nonintestinal symptoms Nausea/vomiting 8 (8.3) with a pharmacological treatment has not been reported previously, and no medication for IBS has Abdominal pain 8 (8.3) previously been investigated in this regard. In an exploratory analysis, improvement in IBS symptoms Abdominal distension 8 (8.3) was correlated with improvement in digestive nonin- Constipation 6 (6.3) testinal symptoms (possibly from the actions of improved bowel function on enteroenteric reflexes), Respiratory tract infection 6 (6.3) but not with improvement in extra-digestive symp- Lower back pain 4 (4.2) toms. Neither improvement in digestive nonintesti- nal symptoms nor extra-digestive symptoms were Cough 3 (3.1) correlated with a decrease in anxiety. As linaclotide is known to be locally active with minimal bioavail- Muscle contraction 3 (3.1) ability,29,30 these effects of linaclotide treatment are Gastroesophageal reflux 2 (2.1) unlikely to be attributable to central effects. Further research on how linaclotide may mediate the Dyspepsia 2 (2.1) observed improvements in digestive nonintestinal Otitis 2 (2.1) and extra-digestive symptoms is warranted. Changes in the gut microbiota have been shown to modulate Dizziness 2 (2.1) brain activity in healthy individuals,31 so exploring the potential impact of linaclotide on the gut micro- Anxiety 2 (2.1) biota in IBS-C may be of interest. Contusion 2 (2.1) aAEs Patients with IBS experience increased mucosal recorded using the Medical Dictionary for Regulatory Activities version 17.1. immune activation, predominantly characterized AE, adverse event; ITT, intention-to-treat. by the infiltration of mast cells and T lymphocytes that produce serine proteases, histamine, and pros- taglandins.32,33 This immune activation in low- in this analysis, which should be taken into consid- grade inflammation may be the consequence of a eration when interpreting these data. The majority perturbation in gut microbiota, and may promote (95%) of AEs of reported diarrhea were mild or changes in intestinal sensory motor function, sensi- moderate and typically not prolonged, with a tizing both the intrinsic primary efferent and extrin- median duration of 9 days. In the previous two sic primary afferent neurons. IBS-C could therefore phase III studies, treatment-­emergent AEs of diar- lead to neural and muscle dysfunction (e.g. altered rhea with linaclotide treatment were reported in intestinal motility and visceral sensitivity), resulting 19.7% and 19.5% of patients, respectively, and in symptom development.34 The role of linaclotide AEs of diarrhea with linaclotide treatment led to in modulating these mechanisms and its influence discontinuation in 4.5% and 5.7% of patients, on the intestinal mucosal barrier remains to be elu- respectively.16,28 No new safety signals were cidated in the clinical setting. observed in the present study. This study aimed to identify whether easily rec- Interestingly, linaclotide treatment was also associ- ognized clinical features may predict a response ated with an improvement in digestive nonintestinal to linaclotide; however, none of the baseline journals.sagepub.com/home/tag 11 Therapeutic Advances in Gastroenterology 12 patient characteristics evaluated in a logistic Conclusion regression model could predict a clinical This trial demonstrated that linaclotide is an effec- response to linaclotide at week 12. In line with tive treatment for IBS-C that improves GI, digestive linaclotide’s mechanism of action, a higher pain/ nonintestinal, and extra-digestive symptoms related constipation index, indicating pain predomi- to the disorder. In line with previous findings, lina- nance, was hypothesized to be associated with clotide is effective in patients with IBS-C, regardless treatment response; however, the response to of factors such as baseline disease severity and the linaclotide was independent of pain or constipa- presence of anxiety or depression. Furthermore, a tion predominance. In addition, these data indi- clinical response to linaclotide after 4 weeks of treat- cated that a response to linaclotide is ment, based on simultaneous improvement in independent of factors such as the presence of symptom severity and global improvement, may psychological comorbidities (anxiety and predict a response with continued use; results from depression) and symptom severity. These results this study suggest that improvements may be support the findings of earlier phase III studies observed by week 12. Taken together, these find- in which the efficacy of linaclotide was similar, ings may allow for better clinical decision-making, irrespective of baseline disease severity.35 as they validate the comparable efficacy of linaclo- However, the key finding of this study (i.e. that tide in patients with severe IBS symptoms and pro- a clinical response to linaclotide treatment at vide a basis for evaluation of response to linaclotide week 4 was predictive of a response at week 12) over time in clinical practice. may facilitate the identification of patients in clinical practice who will have a long-term Acknowledgements response. This finding also supports the current This study was sponsored by Allergan plc, Dublin, recommendation that a follow-up visit be con- Ireland. Writing and editorial assistance was pro- ducted 4 weeks after initiation of linaclotide vided to the authors by Beatrice Vetter-Ceriotti, treatment.36 However, not all patients respond- Helen Woodroof, and Madeeha Aqil, PhD of ing at week 12 were predicted to respond based Complete HealthVizion, Inc., Chicago, IL, USA on their results at week 4, suggesting that in and funded by Allergan plc, Dublin, Ireland. All some cases, the maximum efficacy of linaclotide authors met the ICMJE authorship criteria. Neither may only be observed after >1 month of treat- honoraria nor payments were made for authorship. ment. This is supported by the phase III clinical trial data, which showed that the time to maxi- Some of the data presented in this work have previ- mum treatment effect varied by symptom, with ously been submitted as an abstract and presented as mean change from baseline in worst abdominal a poster (Asociación Española de Gastroenterología pain scores reaching a plateau after 8–12 weeks 2017, Madrid, Spain, 8–10 March 2017) and oral of linaclotide treatment.16,28 presentation (Digestive Disease Week® 2017, Chicago, Illinois, USA, 6–9 May 2017). With the majority of patients in the ITT and CP populations (>90% in both) being female, this Author contributions study is limited by a potential selection bias. BSF, SDA, FM, CCR, JS, MM, MMH, AP, CS, However, given a higher prevalence of IBS in and APA served as investigators, performed the women,4 the study was likely to enroll more female research, and collected and analyzed the data. patients with IBS. Other study limitations include IBR designed the research study and analyzed the the relatively small number of patients entering the data. ER served as the coordinating investigator, treatment phase and the lack of a placebo compara- designed the research study, performed the tor. In addition, this was an open-label study pri- research, and collected and analyzed the data. All marily conducted in hospital centers in a single authors met ICMJE criteria and approved the country and therefore may not be representative of final version of the manuscript. the wider IBS patient population in a real-world setting. However, the prospective, multicenter Author note nature of the study lends validity to its findings, Some of these data have previously been submit- which represent a broad geographic distribution of ted as an abstract and presented as a poster IBS patients in Spain. The results should therefore (Asociación Española de Gastroenterología 2017, be viewed in light of these limitations. Madrid, Spain, March 8–10, 2017) and oral 12 journals.sagepub.com/home/tag B Serrano-Falcón, S Delgado-Aros et al. presentation (Digestive Disease Week® 2017, 4. Canavan C, West J and Card T. The Chicago, Illinois, USA, May 6–9, 2017). epidemiology of irritable bowel syndrome. Clin Epidemiol 2014; 6: 71–80. Funding 5. Hungin APS, Whorwell PJ, Tack J, et al. The The authors disclosed receipt of the following prevalence, patterns and impact of irritable bowel financial support for the research, authorship, syndrome: an international survey of 40,000 and/or publication of this article: This study was subjects. Aliment Pharmacol Ther 2003; 17: 643–650. sponsored by Allergan plc and Almirall S.A. It 6. Cash BD and Chey WD. Irritable bowel received no specific grant from any funding syndrome - an evidence-based approach to agency in the public, commercial, or not-­ for- diagnosis. Aliment Pharmacol Ther 2004; 19: profit sectors. 1235–1245. 7. Herrick LM, Spalding WM, Saito YA, et al. Conflict of interest statement A case-control comparison of direct healthcare- S. Delgado-Aros has acted as a consultant for provider medical costs of chronic idiopathic Allergan plc, Almirall, and Shire Pharmaceuticals constipation and irritable bowel syndrome with Iberia and has received compensation from Abbot constipation in a community-based cohort. J Med Laboratories. F. Mearin has received grant sup- Econ 2017; 20: 273–279. port from Alfa Wassermann, Allergan, and 8. Coffin B, Follet M, Mackinnon J, et al. The burden of Menarini. C. Ciriza de los Ríos has acted as a moderate-to-severe irritable bowel syndrome with consultant for Allergan and Bayer. J. Serra has constipation (Ibs-C) in France: a comparison with acted as a consultant and has participated in advi- the European results from the Ibis-C observational sory boards or in invited conferences for Allergan, study. Value Health 2015; 18: A632. Almirall, Norgine, Reckitt Benckiser, Bayer, and Zespri. M. Mínguez has acted as a consultant for 9. Enck P, Aziz Q, Barbara G, et al. Irritable bowel syndrome. Nat Rev Dis Primers 2016; 2: 16014. Allergan plc, Farmasierra SL, and Bayer. M. Montoro Huguet has served as advisor for MSD, 10. Doshi JA, Cai Q, Buono JL, et al. Economic Almirall, and Vifor Pharma. A. Pérez Aisa has burden of irritable bowel syndrome with acted as a consultant for Allergan and Shionogi constipation: a retrospective analysis of health and has received compensation from Mylan, care costs in a commercially insured population. Norgine, and Cassen for formative actions. I. J Manag Care Pharm 2014; 20: 382–390. Bañón-Rodríguez is a former employee of 11. 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