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Analysis of Nausea in Clinical Studies of Lubiprostone for the Treatment of Constipation Disorders.

ABSTRACT: Lubiprostone is a ClC-2 chloride channel activator approved for the treatment of chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) in adults and irritable bowel syndrome with constipation (IBS-C) in women. Lubiprostone is generally well tolerated, with nausea being the most common adverse event.To characterize nausea with lubiprostone using pooled results from clinical studies in patients with CIC, OIC, or IBS-C.Data from three 3- and 4-week placebo-controlled studies and three long-term open-label studies were pooled for the CIC analysis. The OIC and IBS-C analyses each used pooled data from three 12-week placebo-controlled studies and one 36-week open-label extension study.The populations included the following numbers of patients: CIC, 316 (placebo) and 1113 (lubiprostone 24 mcg twice daily [BID]); OIC, 652 (placebo) and 889 (lubiprostone 24 mcg BID); and IBS-C, 435 (placebo) and 1011 (lubiprostone 8 mcg BID). The incidence of nausea in lubiprostone-treated patients ranged from 11.4 to 31.1%, with the highest incidence in patients with CIC. Among patients with any nausea, most reported only mild or moderate severity (96.5-99.1% across indications) and only one event (83.6-88.7%); most events occurred within the first 5 days of treatment.Nausea was the most common adverse event following the treatment with lubiprostone. Event rates varied by indication and dose, and the majority of nausea adverse events were mild to moderate in severity. Nausea events predominantly occurred early in the treatment period in all of the pooled study populations.

SUBMITTER: Cryer B

PROVIDER: S-EPMC5694526 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Analysis of Nausea in Clinical Studies of Lubiprostone for the Treatment of Constipation Disorders.

Cryer Byron B Drossman Douglas A DA Chey William D WD Webster Lynn L Habibi Sepideh S Wang Martin M

Digestive diseases and sciences 20170828 12

<h4>Background</h4>Lubiprostone is a ClC-2 chloride channel activator approved for the treatment of chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) in adults and irritable bowel syndrome with constipation (IBS-C) in women. Lubiprostone is generally well tolerated, with nausea being the most common adverse event.<h4>Aims</h4>To characterize nausea with lubiprostone using pooled results from clinical studies in patients with CIC, OIC, or IBS-C.<h4>Methods</h4>Data from ...[more]

PMID: 28849329

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Project description:ObjectivesThis multicenter, phase 3 trial evaluated oral lubiprostone for constipation associated with non-methadone opioids in patients with chronic noncancer-related pain.MethodsAdults with opioid-induced constipation (OIC; <3 spontaneous bowel movements [SBMs] per week) were randomized 1:1 to double-blind lubiprostone 24??g or placebo twice daily for 12 weeks. The primary end point was the overall SBM response rate. Responders had at least moderate response (?1 SBM improvement over baseline frequency) in all treatment weeks with available observed data, as well as full response (?3 SBMs per week) for at least 9 of the 12 treatment weeks.ResultsIn total, 431 patients were randomized; 212 each received lubiprostone and placebo, and 7 were not treated. Overall, the SBM response rate was significantly higher for patients treated with lubiprostone vs. placebo (27.1 vs. 18.9%, respectively; P=0.030). Overall mean change from baseline in SBM frequency was significantly greater with lubiprostone vs. placebo (3.2 vs. 2.4, respectively; P=0.001). The median time to first SBM was significantly shorter with lubiprostone vs. placebo (23.5 vs. 37.7?h, respectively; P=0.004). Compared with placebo, the patients treated with lubiprostone exhibited significant improvements in straining (P=0.004), stool consistency (P<0.001), and constipation severity (P=0.010). No significant differences were observed in quality-of-life measures or the use of rescue medication; however, the percentage of patients who used rescue medication was consistently lower in the lubiprostone group than in the placebo group at months 1 (34.9 vs. 37.7%), 2 (23.4 vs. 26.6%), and 3 (20.5 vs. 22.0%). Adverse events (AEs) >5% were diarrhea, nausea, vomiting, and abdominal pain (lubiprostone: 11.3, 9.9, 4.2, and 7.1%, respectively; placebo, 3.8, 4.7, 5.2, and 0%, respectively). None of the serious AEs (lubiprostone, 3.3%; placebo, 2.8%) were related to lubiprostone.ConclusionsLubiprostone significantly improved symptoms of OIC and was well tolerated in patients with chronic noncancer pain.

Project description:IntroductionLubiprostone capsules are approved for managing three different chronic constipation conditions. A "sprinkle" formulation may facilitate use in individuals with difficulty swallowing capsules. Our objective was to evaluate the bioequivalence, pharmacokinetics (PK), and bioavailability of lubiprostone sprinkles vs lubiprostone capsules, compared with placebo.MethodsA 1-week randomized, placebo-controlled, double-blinded, bioequivalence study (study 302) and a single-dose PK and bioavailability crossover study (study 304) were conducted. In study 302, 522 subjects with chronic constipation were randomized to lubiprostone sprinkle 24 μg twice daily (BID), lubiprostone capsule 24 μg BID, or placebo. The primary efficacy endpoint was observed spontaneous bowel movement (SBM) counts (equivalence defined as showing the 90% confidence interval [CI] of the "between-group SBM ratio" to be contained within 0.8-1.25). Study 304 included two cohorts of healthy volunteers randomized to a single 48-μg lubiprostone dose, sprinkle, or capsule (n = 35) or to a single 48-μg sprinkle dose, in fed or fasted state (n = 14).ResultsBoth lubiprostone formulations significantly improved SBM count (sprinkle, 4.82 ± 3.66, P = 0.002; capsule, 5.74 ± 3.79, P < 0.0001) vs placebo (3.68 ± 2.16), but equivalent efficacy was not demonstrated, with a 90% CI for the SBM count ratio of 0.69-0.95. Quantifiable PK data on lubiprostone were limited; however, overall exposure to the M3 metabolite was approximately 44% higher with sprinkles vs capsules under fasted conditions (geometric mean ratio 1.441 [90% CI, 1.166, 1.782]), and exposure with the sprinkle formulation was 11% lower in the fed state vs the fasted state (geometric mean ratio 0.888 [90% CI, 0.675, 1.168]). Both formulations were generally well tolerated.ConclusionDespite the significant improvement in SBM counts vs placebo, the sprinkle formulation did not demonstrate bioequivalence to the capsule formulation in either pharmacodynamic or PK key parameters.Trial registrationStudy 302: ClinicalTrials.gov identifier, NCT03097861; https://www.clinicaltrials.gov/ct2/show/NCT03097861 ; Study 304: ClinicalTrials.gov identifier, NCT03010631; https://www.clinicaltrials.gov/ct2/show/NCT03010631 .

Project description:Background: Functional constipation in children is a common disease that causes a psychological burden on infants and young children across the world. It will greatly affect infant quality of life in early childhood and even affect their psychological and physical health. At present, infant functional constipation is treated with western drugs alone, but this can produce drug dependency. In recent years, Traditional Chinese Medicine (TCM) infant massage has been used as a complementary and alternative therapy, and its effectiveness and safety have been proven, attracting the attention of numerous researchers. Objective: Our study aimed to compare the influence of infant massage intervention on defecation frequency and consistency, determine the effectiveness, and safety of infant massage in the treatment of infant functional constipation, and obtain high-quality clinical evidence. Methods: Based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Statement, inclusion, and exclusion criteria were formulated. Randomized controlled trials (RCTs) on TCM infant massage for the treatment of infant functional constipation were found following a search of four mainstream medical databases. RCTs found to meet the study's requirement were included; data information was then extracted, and the quality was assessed using the Cochrane bias risk assessment tool. Through RevMan software, a meta-analysis was carried out for overall effective rate, stool form, defecation frequency, defecation difficulty, and constipation symptom scoring index. The relative risk (RR) and 95% confidence interval (95% CI) were calculated, heterogeneity was tested and its source was found, and publication bias was assessed through the Egger's and Begg's tests and by means of funnel plots. Results: A total of 23 RCTs and 2,005 patients were included. The results of the meta-analysis showed that compared to drug therapy alone, TCM infant massage had a superior effect on the treatment of infant functional constipation. This difference was statistically significant (p < 0.05) and evaluated according to the overall effective rate (RR = 1.25; 95% CI = 1.17, 1.33), defecation frequency [mean difference (MD) = -0.72; 95% CI = -0.80, -0.65], and constipation symptom score (MD = -0.81; 95% CI = -1.20, -0.43), showing that TCM infant massage is indeed superior to drug therapy alone in the treatment of infant functional constipation. TCM infant massage was found to be equivalent to drug therapy alone in terms of the stool form score [-0.30 (-0.38, -0.22)] and the defecation difficulty score [-0.73 (-0.81, -0.65)], since the difference was not statistically significant (p > 0.05). The source of heterogeneity might be related to the state of patient, manipulation of the massages, efficacy of drugs in the control group, and difference in judgment criteria for efficacy. The Egger's test and Begg's test showed that publication bias did not occur in our study. Conclusion: TCM infant massage can increase defecation frequency and reduce the symptoms of constipation in children suffering from functional constipation; in addition, the clinical trial showed beneficial effects. Since some of the RCTs featured a very small sample size, the reliability and validity of our study's conclusion may have been affected as well; therefore, the explanation should be treated with some caution. In the future, a large number of higher-quality RCTs are still needed to confirm the results of our study.

Project description:To investigate the efficacy of lubiprostone compared to Senna on bowel symptoms and constipation in post-operative orthopedic patients treated with opioids.In this double blind, randomized, active comparator trial, adults who required opioids for analgesia following orthopedic procedures and who were admitted in inpatient rehabilitation were randomized following baseline assessments to lubiprostone (Amitza(®)), orally twice a day or Senna (generic) two capsules administered daily for six days. Subjects were assessed using the patient assessment of constipation (PAC)-symptoms (PAC-SYM) and the PAC-quality of life (PAC-QOL) scales measured at baseline and Day 7; Subjects were assessed daily for secondary measures included the Bristol stool scale bowel consistency, specific bowel symptom score (Nausea, cramping, straining, completeness, abdominal pain, time per lavatory attempt, assistance needed), adverse events and rescue medications required. Function was measured using the functional independence measure (FIM) at admission and discharge; length of stay (LOS) and missed treatments due to gastrointestinal symptoms were also assessed.64 adults were enrolled; 56 participants (28 in each group) had baseline and follow up measures and were included in the intention to treat (ITT) analyses. 43 participants completed the study, 21 in the active lubiprostone and 22 in the active Senna group. The mean age of the participants was 71.5 years (SD = 11.4 years, range: 28-96 years). In the ITT analyses, participants showed significant improvement in bowel symptoms as measured by the PAC-SYM (mean ± SD, -0.28 ± 0.60, range: -1-2.33) and PAC-QOL (mean ± SD, 0.33 ± 0.81, range: -1.5-2.0) over time, but there were no significant differences between the lubiprostone and Senna groups in mean change in the PAC-SYM (-0.20 ± 0.60 vs -0.36 ± 0.61, P = 0.61 respectively) or the PAC-QOL (0.29 ± 0.76 vs 0.37 ± 0.87, P = 0.61 respectively). The mean change in each bowel symptom also did not significantly differ between treatment groups on ITT analyses, except for completeness of bowel movement, with the Senna group showing greater negative mean change in bowel movement completeness (-0.56 ± 1.01 vs -2.00 ± 1.41, P = 0.03) and for reduction of abdominal pain, favoring Senna (-0.14 ± 0.73 vs -0.73 ± 1.08, P = 0.04). Fifteen (75%) participants in the lubiprostone and in the Senna group requested rescue treatments. Participants made significant functional improvement from admission to discharge over a median LOS of 12 d, with a mean FIM change of 29.13 ± 13.58 and no significant between group differences (27.0 ± 9.2 vs 31.5 ± 16.6, P = 0.27).Both lubiprostone and Senna improved constipation-related symptoms and QOL in opioid-induced constipation, with no significant between-group differences.

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Analysis of Nausea in Clinical Studies of Lubiprostone for the Treatment of Constipation Disorders.

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Analysis of Nausea in Clinical Studies of Lubiprostone for the Treatment of Constipation Disorders.

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