Lifitegrast for the treatment of dry eye disease in adults

Introduction: Dry eye disease (DED) is a common ocular disorder that can have a substantial burden on quality of life and daily activities. Lifitegrast ophthalmic solution 5.0% is the first medication approved in the US for the treatment of the signs and symptoms of DED. The aim of this article is to summarize the preclinical and clinical data on lifitegrast and discuss how lifitegrast may fit into the current treatment landscape for DED.

Areas covered: A literature search of published preclinical and clinical data was conducted to review the chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy/safety of lifitegrast. The impact that lifitegrast may have on DED treatment practices is also discussed.

Expert opinion: The introduction of lifitegrast provides a potentially important additional option for eye care professionals treating DED. In clinical trials conducted in adults with DED, lifitegrast ophthalmic solution 5.0% improved both signs and symptoms of DED. Of note, in 2 phase 3 trials, symptom improvements were observed as early as 2 weeks, which may be explained by lifitegrast’s unique mechanism of action of blocking a specific signaling pathway in inflammation. Future research should include evaluation of whether lifitegrast can be used in combination with other DED treatments.     

Comparison of the effect of a hyaluronate–trehalose solution to hyaluronate alone on Ocular Surface Disease Index in patients with moderate to severe dry eye disease

Objective: To describe a post hoc analysis comparing the effect of a hyaluronic acid (HA)–trehalose solution to an established eyedrop solution containing HA alone using Ocular Surface Disease Index (OSDI) score <19 as a threshold for moderate to severe dry eye disease (DED).

Methods: A phase III, randomized, controlled, single-blind, multicenter study was conducted in France and Tunisia to evaluate the efficacy and safety of HA–trehalose (N?=?52) and HA (N?=?53) administered for 84 days. Eligible patients had moderate to severe DED with OSDI ≥18. Here the results of a post hoc analysis of the percentage of patients with OSDI <19 on Day 35 and Day 84 are reported.

Results: Significantly more patients had OSDI <19 at Day 84 in the HA–trehalose group than in the HA group (78.8% versus 58.5%; p?=?.025). At Day 35, more patients had OSDI <19 in the HA–trehalose group than in the HA group, but this difference was not statistically significant. Furthermore, approximately twice as many patients in the HA group (41.5%) still had OSDI 19–100 at Day 84 compared to the HA–trehalose group (21.2%).

Conclusions: This data supports the addition of trehalose to HA-containing eyedrop solutions to provide better symptomatic relief from moderate to severe DED, based on an OSDI score of <19 after 84 days of treatment.     

Tapentadol prolonged-release for moderate-to-severe chronic osteoarthritis knee pain: a double-blind,randomized, placebo- and oxycodone controlled release-controlled study

Objective: To assess efficacy and safety of tapentadol prolonged release (PR) for moderate-to-severe chronic osteoarthritis knee pain.

Methods: Patients (n?=?990) were randomized (1:1:1) to tapentadol PR, oxycodone controlled release (CR; reference compound for assay sensitivity), or placebo for a double-blind 3-week titration and 12-week maintenance period. Primary efficacy end-points were change from baseline in average pain intensity at week 12 of maintenance (US end-point) and over the entire maintenance period (non-US end-point) with “last observation carried forward” as imputation method for missing scores.

Results: Both primary end-points were not significantly different for tapentadol PR nor for oxycodone CR vs placebo at week 12 (least squares [LS] mean difference?=?–0.3 [95% CI?=?–0.61–0.09]; p?=?0.152 and 0.2 [95% CI?=?–0.16–0.54]; p?=?0.279, respectively) and over the maintenance period (LS mean difference?=?–0.2 [95% CI?=?–0.55–0.07]; p?=?0.135 and 0.1 [95% CI?=?–0.18–0.44]; p?=?0.421, respectively). Considerably more patients receiving tapentadol PR than oxycodone CR completed the trial (58.3% vs 36.6%). This is consistent with better results with tapentadol PR on the overall health status (PGIC) compared to oxycodone CR. Indeed, respectively, 56% and 42.5% rated at least “much improved” at the end of treatment. Incidences of gastrointestinal adverse events were higher for both active treatments compared to placebo. Tapentadol PR was associated with a better gastrointestinal tolerability profile with incidences of constipation (17.9% vs 35%) and of the composite of nausea and/or vomiting (23.8% vs 46.8%) significantly lower vs oxycodone CR (p?Conclusions: The study did not demonstrate assay sensitivity. The finding that both primary end-points for tapentadol PR were not met can, thus, not be interpreted. Tapentadol PR was better tolerated than oxycodone CR, largely due to fewer gastrointestinal side-effects.     

Efficacy and safety analysis of new P2Y12 inhibitors versus clopidogrel in patients with percutaneous coronary intervention: a meta-analysis

Objective:

New P2Y₁₂ inhibitors, classified as oral (prasugrel and ticagrelor) and intravenous (cangrelor and elinogrel) drugs, have shown improved antithrombotic effects compared with clopidogrel in patients with acute coronary syndrome (ACS) or patients undergoing percutaneous coronary intervention (PCI) in landmark trials. The purpose of this study was to perform a meta-analysis of randomized trials that compared new P2Y₁₂ inhibitors with clopidogrel to determine their efficacy and safety in patients undergoing PCI.

Methods:

Randomized controlled trials of at least 4 weeks, comparing new P2Y₁₂ inhibitors with clopidogrel in PCI, were identified using the electronic databases Cochrane Central Register of Controlled Trials, Medline, PubMed, Web of Science, and Google Scholar from January 1, 1980, to July 31, 2014.

Main outcome measures:

The primary efficacy endpoints were all-cause death and major adverse cardiovascular events (MACEs). The primary safety endpoint was thrombolysis in myocardial infarction (TIMI) major bleeding.

Results:

Twelve studies including 71,097 patients met the inclusion criteria. New P2Y₁₂ inhibitors significantly reduced all-cause death (odds ratio [OR]: 0.81; 95% confidence interval [CI] 0.73–0.90, p?p?p?p?=?0.03) and cardiovascular death (OR 0.82; 95% CI 0.73–0.92, p?=?0.001) compared with clopidogrel. There were no significant differences between stroke (OR 0.87; 95% CI 0.72–1.05, p?=?0.14) and major bleeding events (OR 1.22; 95% CI 0.99–1.52, p?=?0.06) between the new P2Y₁₂ inhibitor and clopidogrel groups.

Conclusion:

New P2Y₁₂ inhibitors decreased death in patients undergoing PCI compared with clopidogrel with a considerable safety and tolerability profile; however, the risk/benefit ratio of ischemic and bleeding events should be further investigated.     

Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus: meta-analysis of randomised controlled trials

ABSTRACT

Objective: To assess the impact of lipid lowering treatment with fibrates on cardiovascular endpoints in patients with type 2 diabetes mellitus.

Methods: MEDLINE (from inception to November 2005) and the Cochrane Controlled Trials Register (including Issue 3, 2005) were searched for randomised controlled trials comparing therapy with fibrates to placebo in patients with type 2 diabetes mellitus. Electronic searches were supplemented by manual searching of reference lists, reviews, conference abstracts and specialist journals. Incidence rate ratios (IRRs) were estimated using a fixed effects model. The primary endpoint was the IRR for coronary heart disease (CHD) events (a combination of non fatal myocardial infarction and death due to CHD). Secondary endpoints included: (1) death due to CHD; (2) fatal and non fatal myocardial infarction; and (3) fatal and non fatal stroke.

Results: Eight trials and 12?249 patients with type 2 diabetes were included in the analyses. A total of 924 CHD events (418 and 506 in the treatment and placebo groups, respectively) occurred during a follow up of 60?395 person-years (30?106 and 30?289 in treatment and placebo groups). The combined IRR for CHD events was 0.84 (95% confidence interval [CI] 0.74–0.96, p = 0.008). The numbers needed to treat (NNTs) to prevent one CHD event over 10 years were nine and 26 for patients with and without pre-existing CHD, respectively. IRRs for death due to CHD, myocardial infarction and stroke were 0.96 (95% CI 0.77–1.20, p = 0.73), 0.88 (95% CI 0.69–1.12, p = 0.30) and 0.87 (95% CI 0.73–1.05, p = 0.14), respectively. Larger benefits were found when restricting the analysis to trials that were not confounded by unequal provision of additional lipid-lowering therapy.

Conclusions: Fibrates are associated with a substantial reduction of CHD events, but their exact role in lipid lowering treatment of patients with type 2 diabetes mellitus remains to be defined.     

A randomized clinical trial evaluating the efficacy and safety of the once-weekly dipeptidyl peptidase-4 inhibitor omarigliptin in patients with type 2 diabetes inadequately controlled on metformin monotherapy

Objective: To examine the efficacy and safety of the once-weekly (q.w.) dipeptidyl peptidase-4 inhibitor, omarigliptin, in patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy.

Methods: In a randomized, double-blind trial, patients with T2DM on a stable dose of metformin monotherapy (≥1500?mg/day) with glycated hemoglobin (HbA1c) of 7.0–10.5% were randomized to omarigliptin 25?mg q.w. or matching placebo (n?=?201 in both) for 24 weeks (primary timepoint) followed by an additional 80-week treatment period.

Results: At week 24, from a mean baseline HbA1c of 8.0–8.1%, the least squares (LS) mean (95% CI) change from baseline in HbA1c (primary end-point) was –0.54% (–0.69%, –0.40%) in the omarigliptin group and 0.00% (–0.14%, 0.15%) in the placebo group, for a between-group difference of –0.55% (–0.75%, –0.34%); p?p?=?.011) and –0.5 mmol/L (–0.9, –0.1) (p?=?.010), respectively. At week 24, the incidences of symptomatic hypoglycemia and subjects with one or more adverse event (AE), serious AEs, and discontinuations due to an AE were similar in the omarigliptin and placebo groups. Over 104 weeks, omarigliptin treatment provided a clinically meaningful reduction in HbA1c.

Conclusions: In patients with T2DM, adding omarigliptin 25?mg q.w. to metformin monotherapy improved glycemic control over 104 weeks and was generally welltolerated with a low risk of hypoglycemia.     

Effects of rotigotine on daytime symptoms in patients with primary restless legs syndrome: a randomized,placebo-controlled study

Objective:

This 12 week double-blind, placebo-controlled study (ClinicalTrials.gov: NCT01569464) was conducted to evaluate the effects of rotigotine transdermal patch on daytime symptoms in patients with idiopathic restless legs syndrome (RLS).

Methods:

Adult patients with moderate-to-severe RLS were randomized to rotigotine (optimal dose: 1–3?mg/24?h) or placebo. A modified four-assessment version (4:00?pm, 6:00?pm, 8:00?pm, and 10:00?pm) of the Multiple Suggested Immobilization Test (m-SIT) was performed at baseline and end of 4 week maintenance (EoM). Primary study outcomes were change from baseline to EoM in International Restless Legs Syndrome Rating Scale (IRLS) and in average of means for the m-SIT Discomfort Scale (m-SIT-DS) (combined average of mean values from each of the individual assessments). Secondary outcomes included average of means of Periodic Limb Movement during Wakefulness Index (PLMWI; PLM/hour) for the combination of m-SIT.

Results:

A total of 150 patients were randomized and 137 (rotigotine: 92/101 [91.1%]; placebo: 45/49 [91.8%]) completed maintenance. All 150 randomized patients were assessed for efficacy. At EoM, mean change in IRLS was ?14.9?±?9.3 with rotigotine vs. ?12.7?±?7.6 with placebo (ANCOVA, LS mean treatment difference [95% CI]: ?0.27 [?2.96, 2.42]; p?=?0.8451). Changes in average of means of m-SIT-DS values of each individual SIT were comparable with rotigotine (?2.68?±?2.31) vs. placebo (?2.62?±?2.61) (ANCOVA, LS mean treatment difference [95% CI]: 0.07 [?0.61, 0.75]; p?=?0.8336) and comparable reductions in PLMWI were observed in both treatment groups (8.34 [?8.50, 25.17]; p?=?0.3290). Rotigotine was generally well tolerated. Application site reactions (rotigotine: 20 patients [19.8%]; placebo: 4 [8.2%]) and nausea (16 [15.8%]; 3 [6.1%]) were the most common AEs.

Conclusions:

Rotigotine was beneficial in improving overall RLS symptom severity (assessed by IRLS) and RLS symptom severity at various times of the day (m-SIT-DS); however, superiority to placebo was not established.     

Systematic review of trials of the effect of continued use of oral non-selective NSAIDs on blood pressure and hypertension

ABSTRACT

Objective: To investigate the effects of continued use of non-selective NSAIDs (nsNSAIDs) on blood pressure and hypertension.

Research design and methods: This was a systematic review of randomized clinical trials of oral nsNSAIDs used for at least a 4-week duration. Searches were conducted of PubMed and the Cochrane Database of Systematic Reviews, using key terms for nsNSAIDs and blood pressure or hypertension, to identify articles published in the English language peer-reviewed literature through March 2007.

Main outcome measures: Change from baseline to end of study in systolic blood pressure (SBP) and diastolic blood pressure (DBP), and the incidence of hypertension. Pooled statistics were computed using fixed and random-effects analyses.

Results: Thirty-two articles were included. The mean change (95% confidence interval [CI]) in blood pressure (in mmHg) from baseline to end of study for five trials of ibuprofen was 3.54 (2.70, 4.39) for SBP and 1.16 (0.68, 1.64) for DBP (?p < 0.001 for both changes). Results of four trials of indomethacin were similar to those for ibuprofen: 2.90 (–0.28, 6.08) for SBP (?p = 0.07) and 1.58 (0.29, 2.87) for DBP (?p = 0.02). Mean changes from baseline for two trials of diclofenac were –0.46 (–1.48, 0.56) for SBP (?p = 0.38) and –0.56 (–1.19, 0.07) for DBP (?p = 0.08) and were similar to those for placebo. Changes from baseline in SBP were positive but not statistically significant for naproxen, sulindac, and nabumetone. Compared with placebo, the risk ratio (95% CI) for hypertension was 2.85 (1.44, 5.65; p = 0.003) in two ibuprofen trials.

Conclusions: Continued use of ibuprofen increases blood pressure and raises the incidence of hypertension. There appears to be heterogeneity in such effects with continued use of other nsNSAIDs but, due to limitations in the data, results for naproxen, sulindac, and nabumetone are inconclusive.     

Health care resource use analysis of paliperidone palmitate 3 month injection from two phase 3 clinical trials

Objective: The objective of this study was to compare occupational status and health care resource use between treatment groups in clinical trials 3012 (PP3M versus placebo) and 3011 (PP3M versus PP1M).

Methods: Occupational status was assessed at each study visit. Logistic regressions modeled the probability of hospitalization during the double-blind phase.

Results: At the start of each study, a low percentage of patients were full-time employed or gainfully self-employed (approximately 10% in trial 3012 and 11%–13% in trial 3011). Improvement from baseline in occupational status was slightly higher in the PP3M group than in placebo or PP1M groups. The odds of a hospitalization for psychiatric and social reasons during 1 year was 7.74 (95% CI, 2.39–25.05; p?Conclusions: In both trials, most patients were unemployed and not seeking work or were retired at open-label baseline, and only a small number of patients changed their occupational status during the trials. In trial 3012, subjects who received placebo had significantly higher odds of hospitalization for either psychiatric and social reasons or for psychiatric reasons alone compared with subjects who received PP3M. In contrast, in trial 3011, the odds of hospitalizations were not significantly different between PP3M and PP1M.     

Pioglitazone as monotherapy or in combination with sulfonylurea or metformin enhances insulin sensitivity (HOMA-S or QUICKI) in patients with type 2 diabetes

Background: Miyazaki etal, demonstrated using the hyperinsulinemic, euglycemic clamp that pioglitazone (PIO) enhanced insulin sensitivity in patients (n?=?23) with type 2 diabetes (T2D). Although considered the reference method for measuring insulin sensitivity, the clamp is seldom used in large clinical trials because of its complexity. The Homeostasis Model Assessment-Insulin Sensitivity (HOMA-S) and Quantitative Insulin Sensitivity Check Index (QUICKI) are two alternative insulin sensitivity surrogates that correlate with the clamp method and are suitable for use with large study populations.

Study aim: To evaluate the effect of PIO monotherapy and in combination therapy with sulfonylurea (SU) or metformin (MET) on insulin sensitivity as assessed by HOMA-S and QUICKI in a large group of patients (～1000).

Research design and methods: Patient data from three randomized, double blind, multicenter, parallel group, placebo-controlled registration trials (Studies-001 PIO monotherapy and 010 and 027 combination therapy with SU or MET, respectively) were analyzed for this study. We

evaluated insulin sensitivity for all three studies using HOMA-S and QUICKI.

Results: PIO 15, 30 and 45?mg enhanced HOMA-S compared with baseline (56.9-63.6%, p?=?0.0298); (53.7-64.7%, p?=?0.0008); (59.0-75.9%, p?<?0.0001), respectively. Only the 45?mg dose showed a difference from placebo (p?=?0.0025). Similarly, PIO enhanced QUICKI versus baseline (0.290-0.296, p?=?0.0026); (0.287-0.299, p?=?0.0001); (0.290-0.306, p?=?0.0001), respectively. Both the 30 and 45mg doses were different from placebo for QUICKI (p?=?0.0005, p?<?0.0001). PIO 15 and 30mg plus SU enhanced HOMA-S compared with baseline (58.4–.7%, p?=?0.0007; 53.2–68.4%, p?<?0.0001) and placebo plus SU (p?=?0.0129, p?<?0.0001, respectively). Likewise, PIO 15 and 30?mg plus SU enhanced QUICKI versus baseline (0.289-0.300, p?=?0.0001; 0.287-0.305, p?=?0.0001, respectively). Both doses had different effects from placebo plus SU (p?=?0.0001) for QUICKI. PIO 30mg combined with MET enhanced HOMA-S versus baseline (66.2–82.2%, p?<?0.0001) and placebo plus MET (p?=?0.0002).     

Work productivity loss in patients with dry eye disease: an online survey

Abstract

Objective:

To assess the impact of dry eye disease (DED) on productivity.     

Emerging drugs for the treatment of dry eye disease

Introduction: Dry eye disease (DED) is a common, age-related ocular condition that in its mildest forms causes bothersome symptoms of ocular discomfort, fatigue, and visual disturbance that interfere with quality of life and in its more severe forms causes chronic pain and fluctuating vision. Though it is highly prevalent and costs billions of dollars to manage, current treatments have largely been inadequate, making it a frustrating condition, both for physicians and patients alike.

Areas covered: This article will cover the recently discovered pathophysiology of DED that has prompted investigators to explore new molecules that target the core mechanisms that drive DED. These include anti-inflammatory/immune-modulatory drugs, secretagogues, lubricant, hormones, and autologous serum. Their potential mechanism of action and data from recent trials on efficacy/safety will be reviewed.

Expert opinion: The emerging drugs have a vast range of putative mechanisms of action that may not only provide symptomatic relief but may potentially break the vicious cycle of DED and provide long-lasting cure. Current and future research may change our perspective on DED and redefine its treatment algorithms.     

Impact of postoperative nausea and vomiting prophylaxis with dexamethasone on the risk of recurrence of endometrial cancer

Objective:

To assess whether antiemetic doses of dexamethasone are associated with an increased risk of cancer recurrence in women who underwent surgery for endometrial cancer.

Research design and methods:

This is a retrospective study at an academic university medical center. Women who underwent surgery for endometrial cancer from 2003 to 2007 were identified from a prospectively collected endometrial cancer database. Perioperative records were reviewed to determine administration of dexamethasone. Patients were divided into two groups: those who received dexamethasone 4–10?mg for postoperative nausea and vomiting prophylaxis and those who did not receive dexamethasone. We collected information on patient demographics, cancer stage, cancer grade, histology, year of surgery, chemotherapy, radiation therapy, duration of surgery, perioperative blood transfusion, receipt of epidural analgesia, dose of dexamethasone given, follow-up time, and co-morbidities.

Main outcome measures:

Primary endpoint was recurrence-free survival. Secondary endpoints included progression-free survival and overall survival.

Results:

Three hundred and nine patients were included in the analysis. There were no significant differences between dexamethasone exposed (n?=?107) and non-exposed patients in recurrence-free survival ([5 year estimate (95% CI)]?=?71 (62–82) % vs. 71 (64–78) %, p?=?1.0), progression-free survival (57 [47–68] % vs. 60 [53–68] %, p?=?0.9), or overall survival (68 [59–79] % vs. 71 [64–79] %, p?=?1.0). In univariate analysis, significant predictors of recurrence-free survival were tumor stage (p?=?0.02), tumor grade (0.003) and receipt of adjuvant chemotherapy (p?<?0.001). In the multivariable model, higher tumor grade (hazard ratio [HR] [95% CI]?=?2.3 [1.4–3.9], p?=?0.002) and receipt of adjuvant chemotherapy (3.2 [1.8–5.8], p?<?0.001), but not dexamethasone (0.9 [0.5–1.5], p?=?0.7), were significant predictors of recurrence-free survival.

Conclusions:

Dexamethasone administration was not associated with an increased risk of recurrence in women having surgery for endometrial cancer. Limitations of the study include its retrospective single center design and the fact that administration of dexamethasone was not randomized.     

Ocular surface changes following oral anticholinergic use for overactive bladder

Objective: To investigate the effect of oral solifenacin succinate on Schirmer I test results, tear break-up time (TBUT) and Ocular Surface Disease Index (OSDI) scores in overactive bladder (OAB) patients and to compare these results with those of healthy control subjects.

Materials and methods: The female OAB patients who were prescribed oral solifenacin succinate 5?mg/day (Group I, N?=?80) and age-matched healthy female subjects (Group II, N?=?40) were recruited for the study and underwent ophthalmological examination prior to oral treatment and after 4 weeks. They completed the OSDI questionnaire and underwent ocular surface tests including Schirmer I test and TBUT.

Results: The statistical analysis of the Schirmer I test and TBUT revealed no significant difference between the baseline and 4th week values in both groups (Group I, p?=?0.506 and p?=?0.070 consecutively) (Group II, p?=?0.810 and p?=?0.823 consecutively). OSDI scores were found to be significantly increased in group I (21.8?±?4.2 vs 23.1?±?4.6, p?=?0.020) and remained unchanged in group II (20.5?±?7.0 vs 20.7?±?7.0, p?=?0.805).

Conclusions: Short-term solifenacin succinate treatment has no effect on the Schirmer I test results and TBUT, but ocular surface symptoms appeared to be exacerbated in respect with increased OSDI scores. However, the clinical significance needs to be further evaluated with larger studies.     

Exenatide effects on diabetes,obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years

ABSTRACT

Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A_1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of?≥?3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.

Methods: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5?µg exenatide, or 10?µg exenatide for 30 weeks, followed by 5?µg exenatide BID for 4 weeks, then 10?µg exenatide BID for ≥3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.

Results: 217 patients (64% male, age 58?±?10 years, weight 99?±?18?kg, BMI 34?±?5?kg/m², A1C 8.2?±?1.0% [mean?±?SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (?1.1?±?0.1% [mean?±?SEM]) were sustained to 3 years (?1.0?±?0.1%; p?<?0.0001), with 46% achieving A1C?≤?7%. Exenatide progressively reduced body weight from baseline (?5.3?±?0.4?kg at 3 years; p?<?0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n?=?116) had reduced ALT (?10.4?±?1.5?IU/L; p?<?0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (?6.1?±?0.6?kg vs. ?4.4?±?0.5?kg; p?=?0.03), however weight change was minimally correlated with baseline ALT (r?=??0.01) or ALT change (r?=?0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n?=?151). Triglycerides decreased 12% (p?=?0.0003), total cholesterol decreased 5% (p?=?0.0007), LDL-C decreased 6% (p?<?0.0001), and HDL-C increased 24% (p <?0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison.

Conclusion: Adjunctive exenatide treatment for ≥3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.     

A randomized,double-blind,placebo-controlled study of escitalopram in patients with social anxiety disorder in Japan

Objective This randomized, double-blind placebo-controlled study compared the efficacy and tolerability of escitalopram (10 and 20?mg/day) in Japanese patients with social anxiety disorder (SAD).

Research design and methods Patients aged 18–64 years with a primary diagnosis of DSM-IV-TR defined SAD, a Liebowitz Social Anxiety Scale Japanese version (LSAS-J) total score ≥60 and a Clinical Global Impression–Severity (CGI-S) score ≥4 at baseline were randomly assigned (1:1:1) to placebo, escitalopram 10?mg or escitalopram 20?mg. The primary endpoint was change from baseline to Week 12 in the LSAS-J total score for both escitalopram 10?mg and 20?mg versus placebo (ANCOVA, FAS, LOCF), using a hierarchical testing procedure. Pre-specified secondary endpoints included LSAS-J sensitivity analyses.

Clinical trial registration This study has the www.japic.or.jp identifier: JapicCTI-121842.

Results For the primary efficacy endpoint, the difference from placebo in the LSAS-J was ?3.9 (p?=?0.089) for escitalopram 10?mg. Since the superiority of escitalopram 10?mg over placebo was not confirmed, an analysis without multiplicity adjustment was made, which showed a difference for escitalopram 20?mg versus placebo of ?9.8 (p?<?0.001). In pre-specified sensitivity analyses, the difference versus placebo was ?4.9 (p?=?0.035) (ANCOVA, FAS, OC) and ?5.0 (p?=?0.028) (MMRM, FAS) (escitalopram 10?mg) and ?10.1 (p?<?0.001) (ANCOVA, FAS, OC) and ?10.6 (p?<?0.001) (MMRM, FAS) (escitalopram 20?mg). Common adverse events (incidence ≥5% and significantly different from placebo) were somnolence, nausea and ejaculation disorder.

Conclusion Escitalopram was efficacious, safe and well tolerated by patients with SAD in Japan. Study limitations are discussed including patient characteristics.     

Prognostic and predictive biomarkers of abdominal aortic aneurysm growth rate

Objectives:

To test the utility of clinical and circulating biomarkers to predict abdominal aortic aneurysm (AAA) growth rate and response to doxycycline therapy.

Methods:

Plasma samples were obtained in the Pharmaceutical Aneurysm Stabilization Trial that tested the effect of doxycycline (n?=?44) vs. placebo (n?=?49) in patients with a 35–50?mm AAA. Approximately 200 biomarkers were evaluated in a candidate approach that included markers of matrix turnover and cathepsin S activity and a broad-based approach of predominantly inflammation-related and clinical biomarkers.

Results:

In a recursive partitioning based analysis, total cholesterol, baseline AAA size, and apolipoprotein B were prognostic of AAA growth in the placebo group whereas elastin and biglycan degradation products were predictive of AAA growth with doxycycline treatment. Univariate analysis of these biomarkers showed that baseline total cholesterol (r?=?0.38, unadjusted P?=?0.011), apolipoprotein B (r?=?0.41, unadjusted P?=?0.005), and baseline AAA size (r?=?0.35, unadjusted P?=?0.013) correlated with AAA growth in the placebo but not the doxycycline group. Elastin fragments were associated with 18 month AAA growth (r?=?0.33, unadjusted P?=?0.031) in the doxycycline group.

Limitations:

Limitations of this study include small sample size, a retrospective growth analysis, and translatability of the method used to measure the analytes.

Conclusions:

This study implies that total cholesterol, baseline AAA size, and apolipoprotein B are predictors of AAA growth. Levels of elastin and biglycan fragments are predictive of doxycycline effects on AAA growth and provide a clue towards this unexpected negative effect.     

Warfarin therapy in Chinese patients with atrial fibrillation treated with percutaneous coronary intervention: a 5 year follow-up retrospective cohort study

Objective: To evaluate warfarin use in Chinese patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) by investigating the stroke and major adverse cardiac and cerebral events (MACCEs) and bleeding events.

Methods: Retrospective cohort study of the 5?year follow-up of 1134 patients with AF who underwent PCI. The patients were grouped according to whether they received warfarin or not. Baseline characteristics and the occurrence of MACCEs and bleeding events were compared between the two groups using the CHA2DS2-VASc and HAS-BLED scoring. Cox regression analysis was used to identify factors related to the occurrence of MACCEs and bleeding.

Results: Overall MACCE (p?=?.008) and mortality (p?=?.004) rates were significantly lower in the warfarin group compared with the non-warfarin group. Major bleeding, minor bleeding and overall bleeding were comparable in the two groups. Recurrent myocardial infarction (HR?=?10.129, 95% CI?=?4.737–21.655; p?<?.001) and a baseline CHA2DS2-VASc score >4 (HR?=?2.035, 95% CI?=?1.121–3.692; p?=?.019) were independent predictors of MACCEs in the warfarin group. A baseline HAS-BLED score ≥3 (HR?=?5.498, 95% CI?=?3.773–8.013; p?<?.001) and previous bleeding (HR?=?3.058, 95% CI?=?1.319–7.088; p?=?.009) were independent predictors of bleeding.

Conclusions: Warfarin reduces the incidence of MACCEs but does not increase bleeding events in Chinese patients with AF who underwent PCI. For patients taking warfarin, recurrent myocardial infarction and a baseline CHA2DS2-VASc score >4 were related to MACCE occurrence.     

The association between blood eosinophil count and benralizumab efficacy for patients with severe,uncontrolled asthma: subanalyses of the Phase III SIROCCO and CALIMA studies

Objective: Benralizumab, an anti-eosinophilic monoclonal antibody, in combination with high-dosage inhaled corticosteroids and long-acting β₂-agonists (ICS/LABA), significantly reduced asthma exacerbations, improved lung function, and reduced symptoms for patients with severe, uncontrolled asthma with blood eosinophil counts ≥300 cells/μL in the Phase III SIROCCO and CALIMA studies. To understand the efficacy and safety of benralizumab for patients with eosinophil-driven disease with blood eosinophil counts lower than 300 cells/μL, we evaluated the effect of applying an eosinophil cutoff of ≥150 cells/μL.

Methods: Adult patients with uncontrolled asthma despite high-dosage ICS/LABA?±?additional asthma controller(s) received subcutaneous benralizumab 30?mg every 8 weeks (Q8W; first three doses every 4 weeks) or placebo for 48 (SIROCCO) or 56 (CALIMA) weeks. Efficacy measures including annual exacerbation rate, prebronchodilator FEV₁, and total asthma symptom score were analyzed by baseline blood eosinophil counts ≥150 vs. <150 cells/μL.

Results: Benralizumab reduced asthma exacerbation rates by 42% in SIROCCO (rate ratio?=?0.58; 95% CI?=?0.46–0.74; p?n?=?325) and 36% in CALIMA (rate ratio?=?0.64; 95% CI?=?0.50–0.81; p?n?=?300) vs. placebo (n?=?306 for SIROCCO, n?=?315 for CALIMA) for patients with blood eosinophil counts ≥150 cells/μL. Benralizumab increased prebronchodilator FEV₁ (both studies, p?≤?0.002) and improved total asthma symptom score in SIROCCO (p?=?0.009) at end of treatment vs. placebo for patients with blood eosinophil counts ≥150 cells/μL. The overall adverse events frequency was similar between treatment groups and eosinophil count cohorts.

Conclusion: These results support the efficacy and safety of benralizumab for patients with severe asthma and blood eosinophil counts ≥150 cells/μL.     

VITALITY: impact of adalimumab on health and disability outcomes in patients with Crohn’s disease,rheumatoid arthritis,or psoriasis treated in clinical practice in New Zealand

Objective: VITALITY, a 6-month, multicenter, prospective, observational study, assessed the effects of originator adalimumab (HUMIRA) on health and disability outcomes in patients with Crohn’s disease (CD), rheumatoid arthritis (RA), or psoriasis treated in routine clinical practice in New Zealand (NZ).

Methods: Biologic-naïve adults initiating adalimumab in accordance with NZ funding requirements were recruited. The primary endpoint was 6-month change from baseline in World Health Organization Disability Assessment Schedule (WHODAS) 2.0 score in all participants completing the study (full analysis set). Secondary endpoints included 6-month change in other patient-reported outcomes (PROs) of work activity and wellbeing (Work Productivity and Activity Impairment Questionnaire: General Health, Kessler Psychological Distress Scale, Flourishing Scale, and Subject Vitality Scale) and in disease-specific PRO measures.

Results: In total, 164 participants with severe disease initiating adalimumab completed the WHODAS 2.0 at baseline, of whom 114 (69.5%) completed the study at 6?months. Mean WHODAS 2.0 score halved from 15.2 points (SD =?±9.1) at baseline to 7.3 points (SD =?±7.2) after 6 months’ adalimumab treatment (mean difference = 7.9 points; 95% CI = 6.4–9.4; p?<?.001), with statistically significant improvements seen as early as 2?months after adalimumab initiation (p?<?.001). The proportion of participants with a WHODAS 2.0 score ≥ 10 more than halved, from 68.3% to 28.9%, between baseline and 6?months. Other PROs also improved significantly at 6?months, as did disease-specific measures. No new adalimumab safety signals were observed.

Conclusions: Health and disability outcomes improved significantly after 6?months of adalimumab use in NZ patients with severe CD, RA, or psoriasis.

Clinicaltrials.gov: NCT02451839.