Overall safety of relamorelin in adults with diabetic gastroparesis: Analysis of phase 2a and 2b trial data.

BACKGROUND: Relamorelin, a pentapeptide ghrelin receptor agonist, accelerated gastric emptying significantly and improved symptoms in adults with diabetic gastroparesis in phase 2 trials. AIM: To assess the safety and tolerability of relamorelin across phase 2 trials. METHODS: Safety assessments in patients aged 18-75 years (weight, adverse events [AEs] and laboratory tests) from two randomised, double-blind phase 2 trials (NCT01571297, NCT02357420; results published previously) were reviewed descriptively. Analysis of covariance assessed treatment effect on glycated haemoglobin (HbA1c) and blood glucose post hoc. Phase 2a and 2b trial durations were, respectively, 4 weeks (relamorelin 10 µg once or twice daily [b.d.] or placebo b.d.) and 12 weeks (relamorelin 10, 30 or 100 µg or placebo b.d.) with 1- and 2-week, single-blind placebo run-ins. RESULTS: Among 204 phase 2a and 393 phase 2b patients, respectively, 67% and 62% were female, and 88% and 89% had type 2 diabetes. Proportions of patients reporting serious AEs were similar across treatment groups, as were those with ≥1 treatment-emergent AE (TEAE). TEAE-related discontinuations were proportionally higher in relamorelin groups than placebo. Of 12 serious TEAEs in phase 2a, none occurred in >1 patient. In phase 2b, five serious TEAEs were reported in >1 patient, and one (100 µg) died (urosepsis), all unrelated to relamorelin. In phase 2b, increased HbA1c and fasting blood glucose levels were dose-related (P < 0.0001 and P = 0.0043, respectively). CONCLUSIONS: Relamorelin showed acceptable safety and tolerability in phase 2 trials. Relamorelin may elevate blood glucose: this should be managed proactively in relamorelin-treated patients.

Evaluation of functional health and well-being in patients receiving levomilnacipran ER for the treatment of major depressive disorder.

INTRODUCTION: Levomilnacipran extended-release (ER) is an FDA-approved serotonin norepinephrine reuptake inhibitor (SNRI) for treating major depressive disorder (MDD). SF-36v2 Health Survey outcomes from a Phase III, randomized, double-blind, placebo-controlled study (NCT00969709) were evaluated. METHODS: Prospective and post hoc analyses of SF-36 Mental and Physical Component Summaries (MCS, PCS), and individual domains compared pooled levomilnacipran ER doses (40, 80, 120 mg/day) with placebo. Patients (18-65 years) had MDD, depressive episode ≥ 8 weeks, and Montgomery-Åsberg Depression Rating Scale total score ≥ 30. SF-36 score changes from baseline to Week 8 were analyzed using ANCOVA and the observed cases approach (Intent-to-Treat [ITT] Population). Minimally important differences (MID) evaluated clinical relevance. RESULTS: Baseline MCS scores reflected marked mental deficits in the ITT Population (levomilnacipran ER = 529; placebo = 175). MCS change at Week 8 was significantly greater for levomilnacipran ER than placebo (LSMD [SE] = 4.8 [1.5]; P = 0.0011); MID exceeded the 3-point threshold. Baseline PCS scores suggested minimal physical deficits; no between-group difference at Week 8 was noted. LSMD was nominally statistically significant (P < 0.05) for levomilnacipran ER versus placebo in 5 domains (General Health [2.44; P = 0.0010], Vitality [2.48; P = 0.0307], Social Functioning [3.25; P = 0.0097], Role-Emotional [3.38; P = 0.0078], Mental Health [4.34; P = 0.0005]); changes in Vitality, Social Functioning, and Mental Health exceeded MID. LIMITATIONS: The trial was limited by short duration; analyses were post hoc and adjustments were not made for multiplicity. CONCLUSION: Statistically significant and clinically meaningful improvement on the MCS and several individual domains suggest overall and dimensional improvement in health-related functioning for patients with MDD treated with levomilnacipran ER versus placebo.

Psychometric validation of patient-reported outcome measures assessing chronic constipation.

BACKGROUND: Measures assessing treatment outcomes in previous CC clinical trials have not met the requirements described in the US Food and Drug Administration's guidance on patient-reported outcomes. AIM: Psychometric analyses using data from one Phase IIb study and two Phase III trials of linaclotide for the treatment of chronic constipation (CC) were conducted to document the measurement properties of patient-reported CC Symptom Severity Measures. STUDY METHODS: Each study had a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, comparing placebo to four doses of oral linaclotide taken once daily for 4 weeks in the Phase IIb dose-ranging study (n=307) and to two doses of linaclotide taken once daily for 12 weeks in the Phase III trials (n=1,272). The CC Symptom Severity Measures addressing bowel function (Bowel Movement Frequency, Stool Consistency, Straining) and abdominal symptoms (Bloating, Abdominal Discomfort, Abdominal Pain) were administered daily using interactive voice-response system technology. Intraclass correlations, Pearson correlations, factor analyses, F-tests, and effect sizes were computed. RESULTS: The CC Symptom Severity Measures demonstrated satisfactory test-retest reliability and construct validity. Factor analyses indicated one factor for abdominal symptoms and another for bowel symptoms. Known-groups F-tests substantiated the discriminating ability of the CC Symptom Severity Measures. Responsiveness statistics were moderate to strong, indicating that these measures are capable of detecting change. CONCLUSION: In large studies of CC patients, linaclotide significantly improved abdominal and bowel symptoms. These psychometric analyses support the reliability, validity, discriminating ability, and responsiveness of the CC Symptom Severity Measures for evaluating treatment outcomes in the linaclotide clinical studies.

Impact of linaclotide treatment on work productivity and activity impairment in adults with irritable bowel syndrome with constipation: results from 2 randomized, double-blind, placebo-controlled phase 3 trials.

BACKGROUND: Irritable bowel syndrome with constipation (IBS-C), a chronic functional gastrointestinal disorder, has been shown to negatively affect work productivity and impair daily activity, resulting in a substantial burden for patients and employers. Linaclotide is a first-in-class guanylate cyclase-C agonist approved for the treatment of adults with IBS-C and chronic idiopathic constipation in the United States. OBJECTIVE: To analyze the impact of treatment with linaclotide on work productivity and daily activity impairment in adults with IBS-C and estimate the indirect costs associated with this condition. METHODS: This was a post-hoc analysis of data on IBS-C-related work time missed and work and activity impairment from 2 phase 3 clinical trials that assessed the efficacy and safety of linaclotide therapy in adults with IBS-C. The Work Productivity and Activity Impairment Questionnaire for IBS-C (WPAI:IBS-C) was self-administered at baseline and at weeks 4, 8, and 12 during the 12-week treatment periods in Trials 1 and 2 and at weeks 16, 20, and 26 during the extended treatment period in Trial 2. An analysis of covariance was conducted to assess changes from baseline to all study weeks for each WPAI:IBS-C measure. Indirect costs were calculated by converting overall work productivity losses into monetary values using the human capital cost approach. RESULTS: Of the 1602 patients with IBS-C who were randomized in the 2 clinical trials, 1555 (97.1%) completed a baseline and at least 1 postbaseline WPAI:IBS-C assessment and were included in the analysis cohort; 1148 (71.7%) of these patients were employed. Once-daily treatment with linaclotide significantly reduced overall work productivity loss and daily activity impairment among patients with IBS-C at all study weeks. From baseline to week 12, compared with placebo, linaclotide significantly reduced presenteeism by 5.2%, overall work productivity loss by 6.1%, and daily activity impairment by 4.7% (all P <.01) and led to a numerically greater decrease in absenteeism. From baseline to week 26, compared with placebo, reductions with linaclotide were 5.9% for presenteeism, 7.5% for overall work productivity loss, and 6.7% for daily activity impairment (all P <.05). Reductions in overall work productivity loss from baseline to week 26 translate to 103 hours to 156 hours annually and correspond to an avoided overall work loss of $3209 to $4861 annually for an employee with IBS-C. CONCLUSION: The results of this analysis indicate that appropriate treatment of IBS-C with medications such as linaclotide can reduce work-related impairment associated with IBS-C. In addition, IBS-C therapies that effectively manage this chronic condition and improve employees' quality of life and work productivity may represent significant cost-savings for employers in the form of avoided work productivity losses.

Roflumilast and dyspnea in patients with moderate to very severe chronic obstructive pulmonary disease: a pooled analysis of four clinical trials.

PURPOSE: Breathlessness is a predominant symptom of chronic obstructive pulmonary disease (COPD), making it a valuable outcome in addition to lung function to assess treatment benefit. The phosphodiesterase-4 inhibitor roflumilast has been shown to provide small but significant improvements in dyspnea, as measured by the transition dyspnea index (TDI), in two 1-year studies in patients with severe to very severe COPD. PATIENTS AND METHODS: To provide a more comprehensive assessment of the impact of roflumilast on dyspnea, post hoc analyses of four 1-year roflumilast studies (M2-111, M2-112, M2-124, and M2-125) in patients with moderate to very severe COPD were conducted. RESULTS: In this pooled analysis (N=5,595), roflumilast significantly improved TDI focal scores versus placebo at week 52 (treatment difference, 0.327; P<0.0001). Roflumilast was associated with significantly greater TDI responders and significantly fewer TDI deteriorators (≥1-unit increase or decrease from baseline, respectively) versus placebo at week 52 (P<0.01, both); these significant differences were apparent by week 8 and maintained until study end (P<0.05, all). At study end, the postbronchodilator forced expiratory volume in 1 second improvement in TDI responders was significantly greater with roflumilast versus placebo (P<0.05). Similar to the overall population, improvements in TDI focal scores at week 52 were small but consistently significant over placebo in patients with chronic bronchitis, regardless of exacerbation history, concomitant treatment with short-acting muscarinic antagonists or long-acting ß2-agonists, or pretreatment with inhaled corticosteroids. CONCLUSION: This analysis shows that patients treated with roflumilast to reduce exacerbation risk may also experience small but significant improvements in dyspnea, with accompanying improvements in lung function.

Economic impact of switching from metoprolol to nebivolol for hypertension treatment: a retrospective database analysis.

OBJECTIVE: To estimate the real-world economic impact of switching hypertensive patients from metoprolol, a commonly prescribed, generic, non-vasodilatory ß1-blocker, to nebivolol, a branded-protected vasodilatory ß1-blocker. METHODS: Retrospective analysis with a pre-post study design was conducted using the MarketScan database (2007-2011). Hypertensive patients continuously treated with metoprolol for ≥6 months (pre-period) and then switched to nebivolol for ≥6 months (post-period) were identified. The index date for switching was defined as the first nebivolol dispensing date. Data were collected for the two 6-month periods pre- and post-switching. Monthly healthcare resource utilization and healthcare costs pre- and post-switching were calculated and compared using Wilcoxon test and paired t-test. Medical costs at different years were inflated to the 2011 dollar. RESULTS: In total, 2259 patients (mean age: 60 years; male: 52%; cardiovascular [CV] disease: 37%) met the selection criteria. Switching to nebivolol was associated with statistically significant reductions in the number of all-cause hospitalization (-33%; p < 0.01), CV-related hospitalizations (-60%; p < 0.01), and outpatient visits (-7%; p < 0.01). Monthly inpatient costs were reduced by $111 (p < 0.01), while monthly drug costs increased by $52 (p < 0.01). No statistically significant differences were found in overall costs and costs of outpatient or ER visits. Sensitivity analyses, conducted using various lengths of medication exposure, controlling for spill-over effect or excluding patients with compelling indications for metoprolol, all found some level of reduction in resource utilization and no significant difference in overall healthcare costs. CONCLUSIONS: This real-world study suggests that switching from metoprolol to nebivolol is associated with an increase in medication costs and significant reductions in hospitalizations and outpatient visits upon switching, resulting in an overall neutral effect on healthcare costs. These results may be interpreted with caution due to lack of a comparator group and confounding control caused by design and limitations inherent in insurance claims data.

Memantine discontinuation and the health status of nursing home residents with Alzheimer's disease.

OBJECTIVE: To estimate the effect of memantine discontinuation for a nonmedical reason (eg, formulary restriction or family decision) on the health status of nursing home (NH) residents with Alzheimer's disease (AD). DESIGN: Retrospective chart review. SETTING: NHs (n = 113) in the United States. PARTICIPANTS: Residents (minimum stay of 90 days) with AD, continuously treated with memantine (MC: n = 273) or discontinued for 60 days or longer (MD: n = 248). The subset of patients who discontinued for a nonmedical reason (MD-N: n = 163) was also analyzed, as was the subset of patients in groups MC and MD-N whose doses of concomitant medications remained stable (MC(s): n = 185; MD-N(s): n = 70). MEASUREMENTS: Thirty-one common geriatric and AD symptoms from NH charts were scored based on their emergence or resolution (+1 or -1 points, respectively), worsening or improvement (+0.5 or -0.5 points, respectively), or absence of change (0 points), compared with the baseline period (the first 30 days analyzed in the charts, during which all residents received memantine treatment). Patients' weight change was also captured. RESULTS: Compared with continuous treatment, memantine discontinuation was associated with a significant increase in the Total AD Symptom Change Score (ie, worsening) in all comparison pairs (MC versus MD, MC versus MD-N, and MC(s) versus MD-N(s): P < .001 for all). The symptoms showing greatest worsening aggregated into two factors: cognition and mood. CONCLUSION: Memantine discontinuation in NH residents with AD may be associated with declining health status, and should be considered with care. A randomized, placebo-controlled trial of treatment discontinuation is merited.

Escitalopram in the treatment of adolescent depression: a randomized placebo-controlled multisite trial.

OBJECTIVE: This article presents the results from a prospective, randomized, double-blind, placebo-controlled trial of escitalopram in adolescent patients with major depressive disorder. METHOD: Male and female adolescents (aged 12-17 years) with DSM-IV-defined major depressive disorder were randomly assigned to 8 weeks of double-blind treatment with escitalopram 10 to 20 mg/day (n = 155) or placebo (n = 157). The primary efficacy parameter was change from baseline to week 8 in Children's Depression Rating Scale-Revised (CDRS-R) score using the last observation carried forward approach. RESULTS: A total of 83% patients (259/312) completed 8 weeks of double-blind treatment. Mean CDRS-R score at baseline was 57.6 for escitalopram and 56.0 for placebo. Significant improvement was seen in the escitalopram group relative to the placebo group at endpoint in CDRS-R score (-22.1 versus -18.8, p =.022; last observation carried forward). Adverse events occurring in at least 10% of escitalopram patients were headache, menstrual cramps, insomnia, and nausea; only influenza-like symptoms occurred in at least 5% of escitalopram patients and at least twice the incidence of placebo (7.1% versus 3.2%). Discontinuation rates due to adverse events were 2.6% for escitalopram and 0.6% for placebo. Serious adverse events were reported by 2.6% and 1.3% of escitalopram and placebo patients, respectively, and incidence of suicidality was similar for both groups. CONCLUSIONS: In this study, escitalopram was effective and well tolerated in the treatment of depressed adolescents.

A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania.

OBJECTIVE: The authors compared the efficacy and safety of aripiprazole, a novel antipsychotic, to placebo for treatment of patients in an acute manic or mixed episode of bipolar disorder. METHOD: This 3-week, multicenter, double-blind study randomly assigned 262 bipolar disorder patients in an acute manic or mixed episode to aripiprazole, 30 mg/day (reduced to 15 mg/day if needed for tolerability), or placebo. Patients remained hospitalized for at least 2 of the weeks. The primary efficacy measure was mean change from baseline in total score on the Young Mania Rating Scale; response was defined as a decrease in score of > or =50%. RESULTS: Aripiprazole produced statistically significant mean improvements in total score on the Young Mania Rating Scale compared with placebo (-8.2 versus -3.4, respectively) and produced a significantly higher response rate (40% versus 19%). For key efficacy variables (response per Young Mania Rating Scale; Clinical Global Impression-Bipolar Version scores for severity of illness [mania] and change from preceding phase [mania]), aripiprazole separated from placebo by day 4. The completion rate was significantly higher with aripiprazole than with placebo (42% versus 21%). Discontinuations due to adverse events did not differ significantly between the aripiprazole and placebo groups. There were no significant changes in body weight versus placebo, and aripiprazole was not associated with elevated serum prolactin or QTc prolongation. CONCLUSIONS: Aripiprazole had significantly greater efficacy than placebo for the treatment of bipolar disorder patients in acute manic or mixed episodes and was safe and well tolerated in this randomized controlled trial.