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Polyethylene glycol 3350 plus electrolytes for pediatric chronic constipation: An open-label clinical study in Japan.
Gondo, M, Nagata, S, Shinbo, K, Oota, A, Tomomasa, T
Pediatrics international : official journal of the Japan Pediatric Society. 2020;(5):600-608
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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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Polyethylene glycol 3350 plus electrolytes for chronic constipation: a 2-week, randomized, double-blind, placebo-controlled study with a 52-week open-label extension.
Nakajima, A, Shinbo, K, Oota, A, Kinoshita, Y
Journal of gastroenterology. 2019;(9):792-803
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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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[Efficacy, tolerance and safety of polyethylene glycol 3350 plus electrolytes for the treatment of functional constipation in children].
Infante Pina, D, Segarra Cantón, O, Vilalta Casas, R, Carnicer de la Pardina, J, López Liñán, MJ, Molera Busoms, C
Anales de pediatria (Barcelona, Spain : 2003). 2014;(5):278-84
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OBJECTIVE To assess the renal safety of treatment with polyethylene glycol 3350 with electrolytes at 1, 3 and 6 months, its gastrointestinal tolerance and dose effectiveness. PATIENTS AND METHODS Three groups of 30 healthy patient aged 2-10 years (mean 6.2 years) who suffered functional constipation (Rome III criteria) with 1, 3 and 6 months of treatment were evaluated. Efficacy was evaluated by the change in the number of stools per week and stool consistency (Bristol scale). Urine screens, sodium and osmolality, were performed at the beginning and after 1, 3 and 6 months of treatment. Stool sample NIRA (near-infrared reflectance analysis) and hydrogen breath test analysis samples were performed on the one-month treatment group. RESULTS The mean dose was 0.37g/kg/day (range 0.18 to 0.8) titrated according to age, weight and response. The number of stools per week during treatment (2.4±0.64) showed a significant difference (P<.001) vs (6.21±1.5) after treatment. There was also a significant difference in the Bristol scale score (1.9±0.75 vs 4.9±1.1 [P<.001]). The mean sodium intake was 112mg (5mg/kg/day [range 4-12mg/kg/day]). The values of sodium and urine osmolality were normal in all groups with no statistical difference compared to normal control values (90 healthy children without treatment). NIRA values were normal in all patients. The hydrogen breath test was normal with a median of 7ppm. CONCLUSION There were no adverse renal biochemical parameters or gastrointestinal disorders. Tolerance and efficacy was shown to be optimal. Polyethylene glycol 3350 with electrolytes can be safely recommended for the treatment of functional constipation in children in the short and long term.
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Randomised clinical trial: the safety and efficacy of AST-120 in non-constipating irritable bowel syndrome - a double-blind, placebo-controlled study.
Tack, JF, Miner, PB, Fischer, L, Harris, MS
Alimentary pharmacology & therapeutics. 2011;(8):868-77
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BACKGROUND There is a need for safe and effective treatment options for irritable bowel syndrome (IBS). AST-120 (spherical carbon adsorbent) is a non-absorbed, carbon-based adsorbent with extensive adsorbing capability for histamine, serotonin and other substances implicated in IBS pathogenesis. AIM: To evaluate the efficacy and safety of AST-120 in non-constipating forms of IBS. METHODS This randomised, double-blind, placebo-controlled trial conducted in the US and Belgium enrolled 115 male and female patients fulfilling Rome III criteria for IBS; individuals with predominantly constipation symptoms were excluded. Subjects were randomised to AST-120 2 g tds or placebo for an 8-week double-blind treatment period, followed by a 2-week single-blind placebo washout and 8-week single-blind active treatment. The primary efficacy endpoint was the proportion of subjects achieving at least a 50% reduction in the number of days with abdominal pain compared with baseline. RESULTS At Week 4, 26.8% of subjects treated with AST-120 responded on the primary endpoint vs. 10.2% in the placebo arm (P=0.029); at Week 8 response rates were 32.1 and 25.4% respectively (NS). More AST-120 treated subjects experienced improvement in bloating and stool consistency. These benefits abated when AST-120 was replaced by placebo, and resumed once AST-120 was restarted. The frequency of adverse events with AST-120 were less than or equal to placebo. CONCLUSIONS AST-120 is safe and well-tolerated and reduces pain and bloating in non-constipating IBS, although beneficial effects may be limited in duration. AST-120 represents a locally acting, non-absorbed, novel treatment for IBS and warrants further studies.
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A randomized placebo-controlled phase IIb trial of a3309, a bile acid transporter inhibitor, for chronic idiopathic constipation.
Chey, WD, Camilleri, M, Chang, L, Rikner, L, Graffner, H
The American journal of gastroenterology. 2011;(10):1803-12
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OBJECTIVES A3309 is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor. We conducted an 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, phase IIb study, which evaluated A3309 in patients with chronic idiopathic constipation (CIC). METHODS Patients with CIC (modified Rome III criteria and <3 complete (CSBM) spontaneous bowel movements (SBMs)/week during the 2-week baseline) were randomized to 5, 10, or 15 mg A3309 or placebo once daily. The primary end point was change in SBM number during week 1 compared with baseline. Other bowel and abdominal symptoms were assessed as secondary end points. Serum 7αC4 and lipids were evaluated as biomarkers of BA synthesis/loss. RESULTS In all, 190 patients (mean 48 years, 90% female) were randomized. Mean increase (95% confidence interval) in SBM for week 1 were 1.7 (0.7-2.8) for placebo vs. 2.5 (1.5-3.5), 4.0 (2.9-5.0), and 5.4 (4.4-6.4) for 5 mg, 10 mg (P<0.002), and 15 mg (P<0.001) A3309, respectively. Increased stool frequency was maintained over 8 weeks. Time to first SBM and CSBM were significantly reduced in the 10- and 15-mg A3309 groups compared with placebo. Straining and bloating decreased with A3309 compared with placebo (P<0.05). Increased 7αC4 and reduced low-density lipoprotein cholesterol with A3309 suggested increased BA synthesis and BA loss. The most common adverse events (AEs) were abdominal pain and diarrhea, which occurred most commonly in the 15-mg A3309 group. No drug-related serious AEs were observed. CONCLUSIONS A3309 increased stool frequency and improved constipation-related symptoms in CIC; effects were maintained over 8 weeks of treatment.
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Polyethylene glycol 3350 plus electrolytes for chronic constipation in children: a double blind, placebo controlled, crossover study.
Thomson, MA, Jenkins, HR, Bisset, WM, Heuschkel, R, Kalra, DS, Green, MR, Wilson, DC, Geraint, M
Archives of disease in childhood. 2007;(11):996-1000
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OBJECTIVES To assess the efficacy and safety of polyethylene glycol 3350 plus electrolytes (PEG+E) for the treatment of chronic constipation in children. DESIGN Randomised, double blind, placebo controlled crossover trial, with two 2-week treatment periods separated by a 2-week placebo washout. SETTING Six UK paediatric departments. PARTICIPANTS 51 children (29 girls, 22 boys) aged 24 months to 11 years with chronic constipation (lasting > or =3 months), defined as < or =2 complete bowel movements per week and one of the following: pain on defaecation on 25% of days; > or =25% of bowel movements with straining; > or =25% of bowel movements with hard/lumpy stools. 47 children completed the double blind treatment. MAIN OUTCOME MEASURES Number of complete defaecations per week (primary efficacy variable), total number of complete and incomplete defaecations per week, pain on defaecation, straining on defaecation, faecal incontinence, stool consistency, global assessment of treatment, adverse events and physical examination. RESULTS The mean number of complete defaecations per week was significantly higher for children on PEG+E than on placebo (3.12 (SD 2.05) v 1.45 (SD 1.20), respectively; p<0.001). Further significant differences in favour of PEG+E were observed for total number of defaecations per week (p = 0.003), pain on defaecation (p = 0.041), straining on defaecation (p<0.001), stool consistency (p<0.001) and percentage of hard stools (p = 0.001). Treatment related adverse events (all mild or moderate) occurred in similar numbers of children on PEG+E (41%) and placebo during treatment (45%). CONCLUSIONS PEG+E is significantly more effective than placebo, and appears to be safe and well tolerated in the treatment of chronic constipation in children.
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An open-label study of chronic polyethylene glycol laxative use in chronic constipation.
Di Palma, JA, Cleveland, MV, McGowan, J, Herrera, JL
Alimentary pharmacology & therapeutics. 2007;(6):703-8
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BACKGROUND Polyethylene glycol 3350 (MiraLAX, Braintree Laboratories Inc., Braintree, MA, USA) is approved for the short-term treatment of occasional constipation. AIM: To extend the safety data of polyethylene glycol used for chronic treatment of chronic constipation. METHODS Study subjects who met defined criteria for chronic constipation were enrolled in this open-labelled, single-treatment multi-centre study to receive polyethylene glycol laxative as a single daily dose of 17 g for 12 months. Subjects returned to their study centres after 2, 4, 6, 9 and 12 months of treatment where blood and urine samples were collected and adverse events were reviewed. At each visit, subjects were queried for ROME constipation criteria and they rated their overall improvement using a global efficacy scale. RESULTS 311 patients including 117, age 65 and older, were enrolled and received treatment at one of 50 centres. One hundred and eighty-four completed all 12 months of treatment. With respect to the 'Global Efficacy Assessment', depending on the month of observation, 80-88% of enrolled patients, and 84-94% of the elderly, were treated successfully. Similar results were obtained from secondary efficacy measures that assessed individual ROME constipation criteria at each visit. The response to treatment was durable over time. Over the 1-year course of study representing 218 patient-years at the labelled dose, medication-associated adverse effects were gastrointestinal complaints of diarrhoea, loose stool, flatulence and nausea. These effects were generally mild or moderate in severity. There were no clinically significant changes in haematology or blood chemistry, particularly electrolytes, for the study population as a whole or the elderly group. CONCLUSIONS Polyethylene glycol laxative is safe and effective for treating constipation in adult and elderly patients for periods up to 12 months, with no evidence of tachyphylaxis.
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Long term efficacy, safety, and tolerabilitity of low daily doses of isosmotic polyethylene glycol electrolyte balanced solution (PMF-100) in the treatment of functional chronic constipation.
Corazziari, E, Badiali, D, Bazzocchi, G, Bassotti, G, Roselli, P, Mastropaolo, G, Lucà, MG, Galeazzi, R, Peruzzi, E
Gut. 2000;(4):522-6
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AIMS: To assess the long term therapeutic effectiveness, safety, and tolerability of low daily doses of isosmotic PEG electrolyte solutions (PMF-100) administered for a six month period for the treatment of functional constipation, in a double blind, placebo controlled, parallel group study. METHODS After an initial four week run in period with PMF-100 (250 ml twice daily; PEG 14.6 g twice daily), 70 patients suffering from chronic constipation (58 females, aged 42 (15) years) with normalised bowel frequency (>3 bowel movements (bm)/week) were randomly allocated to receive either PMF-100 or placebo, contained in sachets (one sachet in 250 ml of water twice daily) for 20 weeks. Patients were assessed at four week intervals, and reported frequency and modality of evacuation, laxative use, and relevant symptoms on a diary card. At weeks 1, 12, and 24, a physical examination and laboratory tests were performed. RESULTS Complete remission of constipation was reported by a significantly (p<0.01) higher number of patients treated with PMF-100 compared with placebo at each four week visit. At the end of the study, 77% of the PMF-100 group and 20% of the placebo group were asymptomatic. Compared with placebo, patients treated with PMF-100 reported hard/pellety stools and straining at defecation less frequently, a significantly higher bowel frequency (week 12: 7. 4 (3.1) v 4.3 (2.5) bm/week, 95% CI 1.64, 4.42; week 24: 7.4 (3.2) v 5.4 (2.1) bm/week, 95% CI 0.13,3.93), reduced consumption of laxative/four weeks (week 12: 0.7 (2.7) v 2.2 (3.3), 95% CI -2.29, 0. 03; week 24: 0.2 (0.8) v 1.4 (2), 95% CI -2.07, -0.023), reduced mean number of sachets used (week 12: 33 (13) v 43 (12), 95% CI -17. 24, 4.56; week 24: 33 (13) v 44 (12), 95% CI -19.68, -2.24), and reduced number of drop outs for therapy failure (16 v 3; p<0.005). Adverse events, physical findings, laboratory values, palatability, and overall tolerance of the solutions did not differ between groups. CONCLUSIONS Administration of small daily doses of isosmotic PEG electrolyte balanced solutions was effective over a six month period for the treatment of functional constipation. A mean daily dose of approximately 300 ml of PEG solution (PEG 17.52 g) appeared to be safe, well tolerated, and devoid of significant side effects.