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Background and Aim: Elobixibat is a triple mode of action laxative that increases water secretion into the colon, promotes colonic motility, and reestablishes the defecation desire. This study aims to evaluate the effectivity and safety of elobixibat in chronic constipation (CC) patients refractory to conventional laxatives. Methods: A single-center retrospective observational study was conducted in refractory CC patients diagnosed according to the Rome IV criteria and received elobixibat between April 2018 and June 2022 at Osaka Saiseikai Nakatsu Hospital. Data were collected for spontaneous bowel movement (SBM), Bristol stool form scale (BSFS) scores, abdominal symptoms, and adverse events. Results: Eligible 311 patients were selected for the analysis. Two-week Elobixibat treatment significantly increased SBM (times/week) from 2.9 ± 1.9 to 4.3 ± 1.9 (P < 0.0001). The BSFS score improved significantly from 3.2 ± 1.7 to 4.4 ± 1.4 (P < 0.0001). The percentages of patients with hard stool were decrease and that with normal stools were increase. Improvements in abdominal symptoms (sensation of incomplete bowel evacuation, straining, abdominal pain and distention, and difficulty defecating) were also significant (P < 0.05). These constipation symptoms were improved irrespective of patient characteristics or previous laxatives. The 43.9% of previous laxatives were discontinued at the start of or after starting elobixibat treatment. A few adverse events were observed, elobixibat was well tolerated. Conclusion: Elobixibat was effective in patients who were refractory to other laxatives, irrespective of previous therapy or patient characteristics. Elobixibat may contribute to resolving polypharmacy with single mode of action laxatives.
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Background: Multiple pharmacological interventions and modalities are available for managing chronic idiopathic constipation (CIC), with variable efficacy. Vibrating capsule (VC) is a device that has shown variable results in alleviating constipation by tactile stimulation of the colonic wall and inducing peristalsis. This meta-analysis is to investigate the efficacy and safety of this modality. Methods: Comprehensive literature search was performed through June 14th, 2023, on databases including Embase, PubMed/MEDLINE, Cochrane Central, Web of Science, Global Index Medicus, and Google Scholar. Core concepts of VC, constipation, and bowel movement were searched. The DerSimonian-Laird method and random effects model were utilized. We calculated odds ratio (OR) and mean difference (MD) for proportional and continuous variables, respectively, with 95% confidence interval (CI) and a P value of <0.05 considered statistically significant. Results: The search strategy yielded 117 articles. Four studies with 705 total patients were finalized comparing VC to placebo/sham treatment. The pooled complete spontaneous bowel movement (CSBM), defined as bowel movement without use of laxatives within the last 48 hours with sense of complete evacuation did not achieve statistical improvement with VC (MD =0.153; 95% CI: -0.218 to 0.523; P=0.422). However, spontaneous bowel movement (SBM), defined as bowel movement without use of laxatives within the last 48 hours, showed statistical improvement with VC (MD =0.159; 95% CI: 0.095 to 0.223; P<0.001). VC didn't show an increase in pooled adverse events (OR =1.431; 95% CI: 0.702 to 2.916; P=0.324). Conclusions: The systematic review and meta-analysis suggest that VC is safe and efficacious in some outcomes, however, larger randomized controlled trials (RCTs) and real-world data are needed to establish this.
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Background and aims: The treatment of chronic constipation is still a great challenge in clinical practice. This study aimed to determine the efficacy and sustained effects of transcutaneous electrical acustimulation (TEA) at acupoint ST36 on the treatment of chronic constipation and explore possible underlying mechanisms. Methods: Forty-four patients with chronic constipation were recruited and randomly assigned to a TEA group or sham-TEA group. A bowel diary was recorded by the patients. The Patient Assessment of Constipation Symptom (PAC-SYM) and the Patient Assessment of Constipation Quality of Life (PAC-QoL) questionnaires were administered during each visit. Anal and rectal functions were evaluated with anorectal manometry. Autonomic functions were assessed by the special analysis of heart rate variability derived from the ECG recording. Results: Compared with sham-TEA, 2-week TEA treatment significantly increased the number of spontaneous bowel movements (SBMs) (5.64 ± 0.54 vs. 2.82 ± 0.36, P < 0.001) and lowered the total scores of PAC-SYM (0.90 ± 0.14 vs. 1.35 ± 0.13, P < 0.001) and PAC-QoL (0.89 ± 0.13 vs. 1.32 ± 0.14, P < 0.05). TEA improved symptoms, as reflected by a reduction in the straining (P < 0.001), the incomplete defecation (P < 0.05), the frequency of emergency drug use (P < 0.05), the days of abdominal distension (P < 0.01) and an increase in intestinal satisfaction (P < 0.01). Interestingly, the effects of TEA on the improvement of weekly SBMs sustained four weeks after the cessation of treatment (P < 0.001). Anorectal manometry indicated that 2-week treatment of TEA lowered the threshold of first sensation (P < 0.05), desire of defecation (P < 0.01) and maximum tolerable volume (P < 0.001) compared with sham-TEA group. TEA also significantly enhanced vagal activity, reflected by high-frequency band of heart rate variability, compared with sham-TEA (57.86 ± 1.83 vs. 48.51 ± 2.04, P < 0.01). Conclusion: TEA ameliorates constipation with sustained effects, which may be mediated via improvement of rectal sensitivity and enhancement of vagal activity. Clinical trial registration: [https://clinicaltrials.gov/], identifier [ChiCTR210004267].
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OBJECTIVE: To estimate the minimal clinically important difference (MCID) of the frequency of bowel movement for the patients with chronic severe functional constipation treated with acupuncture so as to provide the evidence for the clinical decision. METHODS: In this study, 813 patients with chronic severe functional constipation treated with acupuncture in two previous randomized controlled trials were included. Through the anchor-based method (anchored by the item 28 "satisfaction with previous treatment" of the patient assessment of constipation-quality of life [PAC-QOL]) and the distribution-based method, the MCID of the weekly frequency of complete spontaneous bowel movement (CSBM) and spontaneous bowel movement (SBM) was analyzed statistically in the patients. RESULTS: The MCID of the mean weekly frequency of CSBM and SBM was 1.3 times and 1.6 times in patients with chronic severe functional constipation treated with acupuncture, respectively. CONCLUSION: The mean increase of the weekly CSMB is ≥ 1.3 times and that of SBM is ≥ 1.6 times after treatment when compared with the baseline respectively, suggesting the clinical significance.
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Terapia por Acupuntura , Calidad de Vida , Humanos , Diferencia Mínima Clínicamente Importante , Resultado del Tratamiento , Estreñimiento/terapiaRESUMEN
Background: Functional constipation (FC) is an intractable disease that carries large financial burden as well as emotional and physical stress. We aimed to assess the efficacy and safety of the newly developed smartphone-controlled vibrating capsule (VC) in patients with FC. Methods: From December 2018 to February 2020, we did a multicenter, blinded, placebo-controlled randomised trial in six top general hospitals in China focusing on patients aged 18 to 80 with FC. Patients were randomly assigned in a 1:1 ratio to receive VCs or placebo treatment for six weeks (two capsules per week) after a two-week baseline period. The primary outcome was the responder rate, defined as the proportion of patients with an increase of at least one complete spontaneous bowel movement (CSBM) per week during treatment compared to baseline in the full analysis set. This trial is registered with ClinicalTrials.gov, number NCT04671264, and is completed. Findings: 107 patients aged from 18 to 74 were randomly assigned to receive VC (n = 53) or placebo treatment (n = 54). The responder rate in the VC group was significantly higher than that in the placebo group (64·2% vs. 35·8%; difference, 27·7% [95% CI, 10·4-45·1]; P = 0·005). More patients in the VC group reported weekly CSBMs ≥ 1 for at least four weeks during treatment (difference, 22·7% [95% CI, 8-46]; P = 0·022) and follow-up period (difference, 17.3% [95% CI, 0-35]; P = 0·048). The mean Patient Assessment of Constipation-Symptoms score and Patient Assessment of Constipation-Quality of Life score differed significantly from the baseline in both groups (all P < 0·0001). The most common adverse event associated with VC was abdominal discomfort (3·7%). Interpretation: VCs can promote defecation, as well as ameliorating symptoms and improving the quality of life in patients with FC with sustained efficacy. VC appears to be a potential alternative physical treatment for FC with the exact mechanism and parameters warranting further investigation. Funding: The study was supported by "One hundred leading scientists for 21st century" of Health Department of Shanghai Municipal Government (to ZL, No.2017BR005).
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Opioid-induced constipation (OIC) may occur in patients receiving opioid treatment, decreasing their quality of life (QOL). We compared the effectiveness of magnesium oxide (MgO) with that of naldemedine (NAL) in preventing OIC. This proof-of-concept, randomized controlled trial (registration number UMIN000031891) involved 120 patients with cancer scheduled to receive opioid therapy. The patients were randomly assigned and stratified by age and sex to receive MgO (500 mg, thrice daily) or NAL (0.2 mg, once daily) for 12 weeks. The change in the average Japanese version of Patient Assessment of Constipation QOL (JPAC-QOL) from baseline to 2 weeks was assessed as the primary endpoint. The other endpoints were spontaneous bowel movements (SBMs) and complete SBMs (CSBMs). Deterioration in the mean JPAC-QOL was significantly lower in the NAL group than in the MgO group after 2 weeks. There were fewer adverse events in the NAL group than in the MgO group. Neither significant differences in the change in SBMs between the groups nor serious adverse events/deaths were observed. The CSBM rate was higher in the NAL group than in the MgO group at 2 and 12 weeks. In conclusion, NAL significantly prevented deterioration in constipation-specific QOL and CSBM rate compared with MgO.
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The spore-forming Bacillus coagulans has attracted attention for their therapeutic action in the colon. However, the mechanism of this action remains unclear. In this study, healthy subjects with mild intermittent constipation were supplemented with B. coagulans SNZ 1969 (BC) or the placebo for 8 weeks (n = 80). Then, we assessed colonic transit time (CTT), weekly complete spontaneous bowel movement (CSBM) scores, bowel discomfort symptom (BDS) scores, and 16S rRNA fecal microbiome profiles. The association between the critically altered gut microbiome and clinical outcomes was analyzed using redundancy analysis (RDA) and validated by receiver operating characteristic (ROC) curves. BC supplementation significantly improved CTT (p = 0.031), CSBM at weeks 2 (p = 0.045) and 9 (p = 0.038), and BDS at weeks 3 (p = 0.019) and 6 (p = 0.029) compared with the placebo, while altering the community composition of the gut microbiota. We also confirmed that BC was effectively delivered to the gut. Finally, the multivariate redundancy analysis concluded that BC-induced enrichment of Lactobacillales and diminishment of Synergistales were related to CTT improvements. This study provides important new data on how spore-forming B. coagulans SNZ 1969 contributes to improving gut motility and presents evidence supporting the use of B. coagulans SNZ 1969 in adults with mild intermittent constipation and habitual low intake of fruit and vegetables.
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Bacillus coagulans , Adulto , Estreñimiento , Motilidad Gastrointestinal , Humanos , Percepción , ARN Ribosómico 16S , Esporas BacterianasRESUMEN
Objective:Based on the previous animal experiments, to preliminarily explore the safety and efficacy of self-developed new smartphone-controlled vibrating capsule (VC) in the treatment of patients with functional constipation (FC).Methods:At the Outpatient Department of Gastroenterology, Changhai Hospital, Naval Medical University, 24 patients with FC were prospectively enrolled. The trial process included basic period for ≥two weeks, treatment period for six weeks, and follow-up visits ≥six (once every two weeks). During treatment period, the patients were assigned into sham capsule group, VC at low frequency mode group and VC at high frequency mode group and the patients swallowed 12 corresponding capsules. The safety of VC treatment was evaluated based on the observation the occurrence of adverse events (AE) in patients of three groups, which included abdominal pain, abdominal distention, capsule retention and abnormal laboratory indicators. The efficacy of VC treatment was assessed by comparison of the patients of three groups in mean complete spontaneous bowel movements (CSBM) per week, mean spontaneous bowel movements (SBM) per week, capsule discharge time, patient assessment of constipation quatity of life questionnaire (PAC-QOL), patient assessment of constipation symptom questionnaire (PAC-SYM). Chi-square test, least significant difference- t test, Kruskal-Wallis test, Wilcoxon rank sum test and Fisher exact test were used for statistical analysis. Results:Two patients were lost in follow up. In the end, seven, eight and seven patients were enrolled in sham capsule group, VC at low frequency mode group and VC at high frequency mode group. AE occurred in three patients. At the sixth week of treatment, the difference between average CSBM in one week and baseline of sham capsule group, VC at low frequency mode group and VC at high frequency mode group was 0.0 (0.0, 2.0), 2.0 (1.0, 2.8) and 1.0 (0.0, 5.0), respectively; and the difference between average SBM in one week and baseline of sham capsule group, VC at low frequency mode group and VC at high frequency mode group was -1.0 (2.0, 2.0), 1.0 (-0.8, 2.0) and 1.0 (0.0, 4.0), respectively. During the six weeks of treatment period, the difference between mean CSBM per week and baseline of three, seven and five patients of sham capsule group, VC at low frequency mode group and VC at high frequency mode group was more than one, and the difference between SBM per week and baseline of two, five and five patients was more than one. At the sixth week of treatment, capsule discharge time of VC at low frequency mode group and VC at high frequency mode group was shorter than that of sham capsule group ((65.7±9.3) and (59.1±3.4) h vs. (96.7±10.0) h), and during the whole treatment period capsule discharge time of VC at low frequency mode group and VC at high frequency mode group was shorter than that of sham capsule group ((63.6±8.6) and (59.8±6.6) h vs. (100.5±13.1) h), and the differences were statistically significant ( t=3.119, 3.584, 2.832 and 3.036, all P<0.05). The PAC-SYM score of patients of sham capsule group, VC at low frequency mode group and VC at high frequency mode group during the period of treatment was 14.3±2.0, 9.9±2.3 and 7.0±2.0, respectively, there were no statistically significant differences among the three groups ( P>0.05). The PAC-QOL score of patients of sham capsule group, VC at low frequency mode group and VC at high frequency mode group during the period of treatment was 31.3±4.4, 24.0±3.8 and 13.9±4.1, respectively, and the PAC-QOL score of VC at high frequency mode group was lower than that of sham capsule group, and the difference was statistically significant ( t=2.808, P=0.012), however, there was no statistically significant difference in the PAC-QOL score between VC at low frequency mode group and sham capsule group, and between VC at high frequency mode group and VC at low frequency mode group (both P>0.05). Conclusions:VC can be safely used in patients with FC, which can promote defecation and relieve the symptoms of constipation. However, there is no significant difference in the therapeutic effect of capsules with different vibration frequencies.
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BACKGROUND: Despite the abundance of study evidence for its efficacy and tolerability for the treatment of constipation in other countries, polyethylene glycol 3350 plus electrolytes (PEG3350+E) was not available in Japan until recently. The purpose of this study was to establish the efficacy and safety of PEG3350+E for the treatment of functional constipation in children in Japan. METHODS: Japanese children aged 2-14 years with a mean spontaneous bowel movement (SBM) frequency of 2 times/week or less for at least 2 months prior to informed consent were enrolled into the study. After a 2-week screening period, treatment with PEG3350+E was initiated on the day of enrollment and continued for 12 weeks. Change in SBM frequency from screening period week 2 (baseline) to treatment period week 2 was set as the primary endpoint. Secondary endpoints and adverse events were also examined. RESULTS: Thirty-nine patients were enrolled and completed the 12-week study period. The SBM frequency (mean ± SD) at baseline and treatment period week 2 was 1.00 ± 0.89 and 6.54 ± 4.38, respectively. The change in SBM frequency was 5.54 ± 4.55 (one-sample t test, P < 0.0001) and remained stable through week 12. Stool consistency was also improved over the entire treatment period. Three mild adverse drug reactions were reported: decreased appetite, abdominal pain, and diarrhea (each in 1 of 39 [2.6%] patients). CONCLUSION: PEG3350+E can be considered as a new treatment option for chronic constipation in children in Japan. CLINICAL TRIAL REGISTRATION NUMBER: Japic CTI-163167.
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Estreñimiento/tratamiento farmacológico , Electrólitos/uso terapéutico , Laxativos/uso terapéutico , Polietilenglicoles/uso terapéutico , Dolor Abdominal/etiología , Administración Oral , Adolescente , Niño , Preescolar , Enfermedad Crónica , Diarrea/etiología , Electrólitos/efectos adversos , Femenino , Humanos , Japón , Laxativos/efectos adversos , Masculino , Polietilenglicoles/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVE: This post hoc, pooled, subgroup analysis of two randomised studies evaluated baseline characteristics that may influence the efficacy and safety of naldemedine in patients with opioid-induced constipation (OIC) and cancer. METHODS: Data for patients who received 0.2 mg naldemedine or placebo were pooled from randomised, placebo-controlled, phase IIb and phase III studies. Proportions of spontaneous bowel movement (SBM) responders and patients with diarrhoea were assessed for each treatment group. For the patient subgroups with or without possible blood-brain barrier (BBB) disruptions, changes in Numerical Rating Scale (NRS) and Clinical Opioid Withdrawal Scale (COWS) scores were assessed. RESULTS: A total of 307 patients were included in this analysis (naldemedine: n=155; placebo: n=152). The pooled proportion of SBM responders was 73.5% with naldemedine versus 35.5% with placebo. There was a significant increase in the proportion of SBM responders with naldemedine versus placebo (38.0% (95% CI 27.6% to 48.4%); p<0.0001). Greater proportions of SBM responders and patients who experienced diarrhoea were observed with naldemedine versus placebo in all subgroups. Changes from baseline in NRS and COWS scores were similar with naldemedine or placebo in patients with or without brain metastases. CONCLUSIONS: Although not powered to detect statistically significant differences in treatment effect among subgroups, this study demonstrated that naldemedine appeared to benefit patients with OIC and cancer, irrespective of baseline characteristics, and did not seem to affect analgesia or withdrawal-even in patients with potential BBB disruptions. Baseline characteristics did not appear to affect the incidence of diarrhoea in patients who received naldemedine. TRIAL REGISTRATION NUMBERS: JapicCTI-111510 and JapicCTI-132340.
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Functional gastrointestinal disorders including constipation affect up to 14 % of the world's population. Treatment is difficult and challenging resulting in a need for alternative safe and effective therapies. The present study investigated whether daily consumption of three gold-fleshed kiwifruit could alleviate constipation and improve gastrointestinal discomfort in mildly constipated individuals with and without pain. A total of thirty-two participants were enrolled in a 16-week randomised, single-blind, crossover study. Participants received either three 'Zesy002' kiwifruit or 14·75 g Metamucil® (5 g dietary fibre/d (a positive control)) for 4 weeks each with a 4-week washout between treatments. A 2-week washout period was included at the beginning and end of the study. Daily bowel habit diaries were kept throughout the study. The primary outcome measure was differences in the number of complete spontaneous bowel movements (CSBM). Secondary outcome measures were bowel movement frequency and stool form as well as digestive symptoms and comfort. The number of CSBM per week was significantly greater during daily consumption of three kiwifruit compared with the baseline (6·3 v. 3·3; P < 0·05) and the Metamucil® treatment (6·3 v. 4·5; P < 0·05). Stool consistency was also improved, with kiwifruit producing softer stools and less straining (P < 0·05). Gastrointestinal discomfort was also improved compared with baseline for abdominal pain, constipation and indigestion (P < 0·05) during the kiwifruit intervention and constipation during the Metamucil® intervention (P < 0·05). This randomised controlled trial demonstrates that daily consumption of three gold-fleshed kiwifruit is associated with a significant increase of two CSBM per week and reduction in gastrointestinal discomfort in mildly constipated adults.
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Actinidia/química , Estreñimiento/tratamiento farmacológico , Frutas/química , Tracto Gastrointestinal/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Psyllium/uso terapéutico , Dolor Abdominal/complicaciones , Adolescente , Adulto , Anciano , Estudios Cruzados , Defecación , Método Doble Ciego , Heces , Femenino , Tránsito Gastrointestinal/efectos de los fármacos , Humanos , Intestinos/efectos de los fármacos , Síndrome del Colon Irritable/complicaciones , Síndrome del Colon Irritable/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Nueva Zelanda , Método Simple Ciego , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Although polyethylene glycol 3350 plus electrolytes (PEG3350 + E) is the most widely used osmotic laxative in Europe, prospective data on its long-term (over 6 months) safety and efficacy are not available to date. METHODS: Japanese patients with chronic constipation were randomized to receive PEG3350 + E or placebo for 2 weeks orally. Following this, the patients received PEG3350 + E in the 52-week extension study. The starting dose was 13.7 g/day dissolved in 125 mL of water, and dose titration was allowed (upper limit 41.1 g/day) according to the patient's bowel condition. The primary efficacy endpoint was the change from baseline in frequency of spontaneous bowel movements (SBMs) at week 2 in the double-blind study. Secondary endpoints and adverse events were assessed. Safety and efficacy were also assessed in the extension study. RESULTS: Among 204 patients who provided informed consent, 156 were randomized and included in the full analysis. The frequency of SBMs was significantly higher with PEG3350 + E [least squares mean (LSM) 4.3, 95% confidence interval (CI) 3.6-4.9] compared with placebo (LSM 1.6, 95% CI 1.2-2.1; P < 0.0001). A total of 153 patients entered the extension study; PEG3350 + E led to a sustained improvement in bowel function. The common adverse drug reactions during the entire study period were mild gastrointestinal disorders (abdominal pain 4.5%, diarrhea 3.8%, nausea 3.2%, abdominal distension 2.6%). CONCLUSIONS: Treatment with PEG3350 + E resolved constipation in the short term, was well tolerated, and led to sustained improvement in bowel function in the long-term treatment of Japanese patients with chronic constipation. CLINICAL TRIAL REGISTRATION NUMBER: Japic CTI-163167.
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Estreñimiento/tratamiento farmacológico , Electrólitos/administración & dosificación , Laxativos/administración & dosificación , Polietilenglicoles/administración & dosificación , Adulto , Anciano , Enfermedad Crónica , Método Doble Ciego , Electrólitos/efectos adversos , Femenino , Humanos , Japón , Laxativos/efectos adversos , Masculino , Persona de Mediana Edad , Polietilenglicoles/efectos adversos , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: In two phase 3 trials, elobixibat, a locally acting ileal bile acid transporter inhibitor, resolved constipation and was well tolerated in Japanese patients with chronic constipation. We analyzed the efficacy, safety, and impact on quality of life (QOL) of elobixibat in patients with symptomatically more severe constipation in the two phase 3 trials. METHODS: This post hoc analysis of elobixibat treatment outcomes included data from a 2-week, randomized, placebo-controlled, phase 3 trial (10 mg/d), and a 52-week, open-label trial (5-15 mg/d) in subgroups with severe constipation defined as ≤2 spontaneous bowel movements (SBMs) and ≤3 Bristol Stool Form Scale score during the second week of the 2-week run-in period. We also analyzed the rates of abdominal pain, diarrhea, and QOL in subgroups according to sex, presence of constipation-predominant irritable bowel syndrome (IBS-C) and side effects. KEY RESULTS: In patients with severe constipation, there was significant improvement in the 10 mg elobixibat group compared to the placebo group in change in SBMs from baseline at week 1 (primary endpoint) of the 2-week trial. The differences between groups were reduced in patients with more severe constipation. Increasing the dose to 15 mg was effective for more severe constipation in improving the number of SBMs per week in the 52-week trial. Overall, elobixibat was well tolerated and improved QOL scores, irrespective of gender, presence of IBS-C or side effects. CONCLUSIONS & INFERENCES: Elobixibat is effective for symptomatically severe constipation, is well tolerated and improves QOL, irrespective of potentially confounding patient characteristics.
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Estreñimiento/tratamiento farmacológico , Dipéptidos/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Calidad de Vida , Tiazepinas/uso terapéutico , Adulto , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Japón , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios RetrospectivosRESUMEN
BACKGROUND & AIMS: Several secretagogues have been approved for the treatment of irritable bowel syndrome with constipation (IBS-C). However, their relative efficacy is unclear because there have been no head-to-head randomized controlled trials. We conducted a network meta-analysis to compare their efficacies in patients with IBS-C. METHODS: We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane Central Register of Controlled Trials through June 2018 to identify randomized controlled trials assessing the efficacy of secretagogues in adults with IBS-C. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random-effects model. Efficacy and safety of secretagogues were reported as a pooled relative risk with 95% confidence interval to summarize the effect of each comparison tested, and treatments were ranked according to their P score. RESULTS: We identified 15 eligible randomized controlled trials of secretagogues that included 8462 patients. Linaclotide, lubiprostone, plecanatide, and tenapanor were superior to placebo for the treatment of IBS-C. Linaclotide (290 µg once daily) was ranked first in efficacy based on the end point recommended by the Food and Drug Administration for trials in IBS-C, the primary end point used in each trial, abdominal pain, and complete spontaneous bowel movements. Tenapanor (50 mg twice daily) was ranked first for decreasing bloating. Total numbers of adverse events were significantly larger with linaclotide (290 and 500 µg once daily) and plecanatide (3 mg once daily) compared with placebo. However, plecanatide 6 mg once daily ranked first for safety. Diarrhea was significantly more common with all drugs, except lubiprostone (8 µg twice daily). Nausea was significantly more common in patients who received lubiprostone. CONCLUSIONS: In a network analysis of randomized controlled trials of secretagogues for IBS-C, we found all drugs to be superior to placebo. Efficacy was similar among individual drugs and dosages for most end points. However, data were extracted at the 12-week time point, so the long-term relative efficacy of these drugs is unknown.
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Estreñimiento/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Síndrome del Colon Irritable/tratamiento farmacológico , Secretagogos/uso terapéutico , Adulto , Estreñimiento/etiología , Femenino , Humanos , Síndrome del Colon Irritable/complicaciones , Isoquinolinas/uso terapéutico , Lubiprostona/uso terapéutico , Masculino , Persona de Mediana Edad , Péptidos Natriuréticos/uso terapéutico , Metaanálisis en Red , Péptidos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Sulfonamidas/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Elobixibat is an oral treatment candidate for chronic constipation with a novel mechanism of action via inhibition of the ileal bile acid transporter. We performed this randomized, double-blind, placebo-controlled, dose-finding phase IIb study in Japanese patients with chronic constipation to determine the optimal clinical dose of elobixibat. METHODS: Japanese patients with chronic constipation were randomized to receive elobixibat (5, 10, or 15 mg) or placebo once daily for 2 weeks. The primary efficacy endpoint was the change from baseline in frequency of spontaneous bowel movements at Week 1 of treatment. Secondary endpoints and adverse events were also examined. RESULTS: Among 226 patients who provided informed consent, 163 patients were randomized and included in the full analysis set. In the 10- and 15-mg groups, frequency of spontaneous bowel movements (±standard deviation) were significantly higher than baseline (5.7 ± 4.2 and 5.6 ± 3.5 times per week, respectively, compared with 2.6 ± 2.9 times per week in the placebo group [P = 0.0005, P = 0.0001, respectively]). Subgroup analysis indicated that elobixibat was equally effective in patients with or without constipation-predominant irritable bowel syndrome. Common adverse events included mild abdominal pain and diarrhea in the elobixibat groups; no serious or severe adverse events occurred. Elobixibat was well tolerated at once-daily oral doses up to 15 mg for 2 weeks. CONCLUSIONS: Our study results suggest that 10 mg of elobixibat is a clinically optimal dose for Japanese patients with chronic constipation. CLINICAL TRIAL REGISTRATION NUMBER: JapicCTI-142608.
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Estreñimiento/tratamiento farmacológico , Dipéptidos/administración & dosificación , Fármacos Gastrointestinales/administración & dosificación , Tiazepinas/administración & dosificación , Administración Oral , Adulto , Anciano , Proteínas Portadoras/antagonistas & inhibidores , Enfermedad Crónica , Estreñimiento/fisiopatología , Defecación/efectos de los fármacos , Dipéptidos/efectos adversos , Dipéptidos/farmacología , Dipéptidos/uso terapéutico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/farmacología , Fármacos Gastrointestinales/uso terapéutico , Humanos , Síndrome del Colon Irritable/tratamiento farmacológico , Síndrome del Colon Irritable/fisiopatología , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Persona de Mediana Edad , Tiazepinas/efectos adversos , Tiazepinas/farmacología , Tiazepinas/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: Plecanatide, with the exception of a single amino acid replacement, is identical to human uroguanylin and is approved in the United States for adults with chronic idiopathic constipation (CIC). This double-blind, placebo-controlled, phase III study evaluated the efficacy and safety of plecanatide versus placebo in CIC. METHODS: Adults meeting modified Rome III CIC criteria were randomized to plecanatide 3 mg (n = 443), 6 mg (n = 449), or placebo (n = 445). Patients recorded bowel movement (BM) characteristics [including spontaneous BMs (SBMs) and complete SBMs (CSBMs)] and rated CIC symptoms in daily electronic diaries. The primary endpoint was the percentage of durable overall CSBM responders (weekly responders for ⩾9 of 12 treatment weeks, including ⩾3 of the last 4 weeks). Weekly responders had ⩾3 CSBMs/week and an increase of ⩾1 CSBM from baseline for the same week. RESULTS: A significantly greater percentage of durable overall CSBM responders resulted with each plecanatide dose compared with placebo (3 mg = 20.1%; 6 mg = 20.0%; placebo = 12.8%; p = 0.004 each dose). Over the 12 weeks, plecanatide significantly improved stool consistency and stool frequency. Significant increases in mean weekly SBMs and CSBMs began in week 1 and were maintained through week 12 in plecanatide-treated patients. Adverse events were mostly mild/moderate, with diarrhea being the most common (3 mg = 3.2%; 6 mg = 4.5%; placebo = 1.3%). CONCLUSIONS: Plecanatide resulted in a significantly greater percentage of durable overall CSBM responders and improved stool frequency and secondary endpoints. Plecanatide was well tolerated; the most common AE, diarrhea, occurred in a small number of patients.[ClinicalTrials.gov identifier: NCT02122471].
RESUMEN
BACKGROUND: US Food and Drug Administration (FDA) set a rigorous standard for defining patient responders in irritable bowel syndrome-C (IBS-C; i.e., FDA's Responder Endpoint) for regulatory approval. However, this endpoint's utility for health-care practitioners to assess clinical response has not been determined. We analyzed pooled IBS-C linaclotide trial data to evaluate clinically significant responses in linaclotide-treated patients who did not meet the FDA responder definition. METHODS: Percentages of FDA non-responders reporting improvement in abdominal pain, bowel function and/or global relief measures were determined using pooled data from two linaclotide Phase 3 IBS-C trials. KEY RESULTS: 1602 IBS-C patients enrolled; 34% of linaclotide-treated and 17% of placebo-treated patients met the FDA Responder Endpoint (p < 0.0001). Among FDA non-responders at week 12, 63% of linaclotide-treated patients reported their abdominal pain was at least somewhat relieved, compared with 48% of placebo-treated patients. For stool frequency, 62% of linaclotide-treated patients reported that they were at least somewhat improved at week 12, compared with 46% of placebo-treated patients. For global IBS symptoms, 65% of linaclotide-treated patients reported at least some IBS-symptom relief, 43% reported adequate relief of IBS symptoms, and 57% reported being satisfied with linaclotide treatment, vs placebo rates of 48%, 34%, and 41% respectively. CONCLUSIONS & INFERENCES: Most linaclotide-treated IBS-C patients who were FDA non-responders reported some improvement in abdominal pain and stool frequency, and global relief/satisfaction. In addition to the FDA Responder Endpoint, differing response thresholds and symptom-specific change from baseline should be considered by clinicians for a complete understanding of clinical response to linaclotide and other IBS-C therapies.
Asunto(s)
Síndrome del Colon Irritable/tratamiento farmacológico , Péptidos/uso terapéutico , Dolor Abdominal/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND & AIMS: Linaclotide is a minimally absorbed, 14-amino acid peptide used to treat patients with irritable bowel syndrome with constipation (IBS-C) or chronic constipation (CC). We performed a meta-analysis to determine the efficacy of linaclotide, compared with placebo, for patients with IBS-C or CC. METHODS: MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched for randomized, placebo-controlled trials examining the effect of linaclotide in adults with IBS-C or CC. Dichotomous results were pooled to yield a relative risk (RR), 95% confidence intervals (CIs), and number needed to treat (NNT). RESULTS: The search identified 7 trials of linaclotide in patients with IBS-C or CC; 6 were included in the analysis. Two of 3 trials of IBS-C used the end point recommended by the U.S. Food and Drug Administration: an increase from baseline of 1 or more complete spontaneous bowel movement (CSBM)/week and a 30% or more reduction from baseline in the weekly average of daily worst abdominal pain scores for 50% of the treatment weeks. On the basis of this end point, the RR for response to treatment with 290 µg linaclotide, compared with placebo, was 1.95 (95% CI, 1.3-2.9), and the NNT was 7 (95% CI, 5-11). For CC, on the basis of data from 3 trials of patients with CC, the RR for the primary end point (more than 3 CSBMs/week and an increase in 1 or more CSBM/week, for 75% of weeks) was 4.26 for 290 µg linaclotide vs placebo (95% CI, 2.80-6.47), and the NNT was 7 (95% CI, 5-8). Linaclotide also improved stool form and reduced abdominal pain, bloating, and overall symptom severity in patients with IBS-C or CC. CONCLUSIONS: On the basis of a meta-analysis, linaclotide improves bowel function and reduces abdominal pain and overall severity of IBS-C or CC, compared with placebo.