Results from the single-use autoinjector for self-administration of subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis (MOSAIC) study

Background: Patients with multiple sclerosis (MS) often receive long-term injectable therapy, and difficulties associated with self-injection can affect treatment adherence and efficacy.

Objective: The objective of this study was to evaluate an investigational, ready-to-use, single-use autoinjector for self-injection of subcutaneous (sc) interferon beta-1a (IFNβ-1a).

Methods: In this multicenter, open-label, single-arm study, patients with relapsing MS who were receiving IFNβ-1a sc 44 μg three times weekly for ≥ 12 weeks continued therapy using a single-use autoinjector and completed a user trial questionnaire at baseline and weeks 6 and 12. The primary endpoint was the proportion of patients rating the autoinjector as easy or very easy to use at week 12.

Results: At 12 weeks, 86% of 109 patients included in the intent-to-treat population rated the autoinjector easy or very easy to use (95% confidence interval, 80% ? 93%), and the most important perceived benefit was its overall convenience. The majority (74%) of patients reported the device as somewhat or extremely convenient to use, and most (83%) agreed or strongly agreed that the device made injections simple.

Conclusion: The single-use autoinjector was well received and supported by favorable ratings for simplified injections and convenience. The results suggest that the device may improve overall injection experience in patients with relapsing MS.     

Single-use autoinjector for peginterferon-β1a treatment of relapsing-remitting multiple sclerosis: safety,tolerability and patient evaluation data from the Phase IIIb ATTAIN study

Objectives: A sub-study to evaluate safety, tolerability, ease-of-use and patient satisfaction with a single-use autoinjector administering subcutaneous peginterferon-β_1a (a pegylated interferon-β_1a in clinical development) in a subset of relapsing-remitting multiple sclerosis (MS) patients participating in ATTAIN, a long-term dose-frequency blinded extension of the Phase III randomized ADVANCE study.

Methods: Over 8 weeks, patients self-administered peginterferon-β_1a 125 µg or placebo every 2 weeks (two injections via manual pre-filled syringe [PFS]; two injections via single-use autoinjector). Primary end points were incidence of adverse events (AEs), patient assessment of injection pain score (10-point Visual Analog Scale), and clinician assessment of injection site reactions (ISRs). Secondary objectives included patient assessment of ease-of-use and satisfaction with the autoinjector and evaluation of autoinjector training materials.

Results: In 39 patients, the safety profile of peginterferon-β_1a was similar when delivered via autoinjector or PFS; AEs were mostly mild or moderate in severity. Clinicians and patients reported a similar tolerability profile using both PFS and autoinjector, and pain scores were low (< 1), with no reports of clinician-assessed ISRs after administration with the autoinjector. Patients perceived the single-use autoinjector to be easy to use and convenient; overall patient satisfaction with the autoinjector and accompanying training materials was high.

Conclusion: The safety and tolerability profile of peginterferon-β_1a delivered via autoinjector was similar to delivery via PFS. Patients found the autoinjector easy to use and convenient; this device may simplify the injection process for MS patients who require long-term therapy, thereby potentially improving patient’s quality of life and adherence.     

Comparative usability study for a certolizumab pegol autoinjection device in patients with rheumatoid arthritis

Objectives: To compare the usability of a new certolizumab pegol (CZP) autoinjector with the adalimumab, etanercept, and golimumab devices in patients with rheumatoid arthritis.

Methods: Two identical studies were performed in 2013 and 2016; patients performed a simulated self-injection with the CZP autoinjector and the most up-to-date device versions at the time in a randomized, consecutive sequence. The primary end point was the ranking of the four autoinjectors in order of preference. Device usability and intuitiveness were assessed across a range of secondary and exploratory end points.

Results: The 2013 and 2016 study populations included 76 patients each; a significant majority (2013: 67%; 2016: 59%) ranked the CZP autoinjector as their most preferred device (p < 0.001). Most patients agreed that the CZP autoinjector was easier to use, start, and manipulate, and were more willing to use it than the comparator devices (p < 0.001 for all pairwise comparisons with CZP). Likert score differences also favored the CZP autoinjector regarding how easy it was to determine injection completion. The CZP autoinjector was associated with a low rate of use error.

Conclusions: In both studies, the CZP autoinjector was the preferred choice compared to the alternative devices and was associated with a high level of patient satisfaction.     

Multiple sclerosis patients treated with intramuscular IFN-β-1a autoinjector in a real-world setting: prospective evaluation of treatment persistence,adherence, quality of life and satisfaction

Objectives: The 12-month observational PERSIST study (NCT01405872) evaluated adherence associated with the intramuscular IFNβ-1a (i.m. IFN-β-1a) autoinjector pen in multiple sclerosis (MS) patients.

Methods: MS patients initiating i.m. IFN-β-1a autoinjector treatment were prospectively assessed for physician-reported persistence (percentage of patients remaining on therapy) and patient-reported outcomes, including adherence (percentage of unmissed injections), compliance (percentage of patients missing no injections), tolerability (injection-site reactions [ISRs] and pain) and satisfaction.

Results: The intent-to-treat population included 232 patients; of the 188 physician-reported 12-month completers, 182 patients remained on treatment (96.8% persistence). Monthly compliance rates were 87.5 – 96.2%. Mean monthly pain scores were 1.5 – 1.8 (scale: 0 = ‘no pain’; 10 = ‘extremely painful’). At 12 months, 73.5% of respondents reported no ISRs, 94.9% were satisfied/very satisfied with the autoinjector and 88.2% found using the device easy/very easy. Injection fear, injection anxiety and need for injection assistance by caregivers decreased from the initial visit to 12 months. No new safety signals were observed.

Conclusions: The autoinjector pen is associated with high levels of persistence, compliance, adherence, and satisfaction, little-to-no pain and low need for caregiver assistance. Although these data are limited by reliance on patient questionnaires and the absence of a direct comparator group, this treatment may reduce barriers to injection therapy, while supporting long-term MS management.     

Adherence to,and effectiveness of,subcutaneous interferon β-1a administered by RebiSmart® in patients with relapsing multiple sclerosis: results of the 1-year,observational SMART study

Background: Patients with multiple sclerosis who have poor adherence to treatment have a higher risk of relapse than adherent patients. This study assessed adherence to, and effectiveness and convenience of, treatment with subcutaneous (sc) interferon (IFN) β-1a (Rebif®, Merck Serono SA) 44 or 22 μg three times weekly in patients with relapsing multiple sclerosis (RMS) using the RebiSmart® electronic, multidose, autoinjector for 1 year.

Study design: European, multicentre, observational study among neurologists: inclusion criteria included RMS, Expanded Disability Status Scale score ≤ 6, sc IFN β-1a administered by RebiSmart for ≤ 6 weeks. The primary endpoint was cumulative adherence recorded by RebiSmart.

Results: The safety population included 912 patients, 77.4% (n = 823) of whom completed the Month-12 visit. Mean (± standard deviation) cumulative adherence was 97.1 ± 7.3% (n = 791). The most common reason for missed injection was ‘forgot to inject’ (37.0%). At Month 12/ED, 79.5% of patients were relapse-free. Of 353 patients who rated the convenience of the device, 68.3% found injecting ‘very easy’. No unknown safety issues were detected.

Conclusions: Patients with RMS self-injecting sc IFN β-1a with RebiSmart had excellent adherence at Month 12/ED, which was associated with good clinical outcomes and no unexpected safety issues. Patients rated RebiSmart as convenient and easy to use.     

High prevalence of constipation and reduced quality of life in opioid-dependent patients treated with opioid substitution treatments

Objectives To evaluate prevalence and severity of constipation and quality of life (QoL) in a cohort of opioid-addicted patients treated with opioid substitution treatments (OST).

Methods: A total of 1057 heroin-dependent patients treated with methadone or buprenorphine were enrolled in a multicenter observational study. Constipation was assessed by Wexner Constipation Scoring System (Wexner CSS), QoL by General Health Questionnaire (GHQ-12).

Results: 38.5% patients reported mild constipation, 33.3% reported moderate constipation, 14.8% severe constipation and 5.1% very severe constipation. Mean Wexner CSS score was 6.6 ± 4.8. 44.9% patients showed a GHQ-12 score ≥14; of these 18.3% patients showed a GHQ-12 score ≥20. Mean GHQ score was 13.8 ± 6.5. Mean Wexner CSS score was significantly higher in methadone patients (p = 0.004), in those taking psychoactive drugs (p = 0.0001) and in female (p < 0.0001) with respect to counterparts. Similarly, GHQ-12 mean scores were higher methadone group (p = 0.003), in those taking psychoactive drugs (p < 0.0001), and in female (p = 0.039) with respect to counterparts. ANOVA and ANCOVA showed a significant influence of methadone and female gender on Wexner CSS score while psychoactive drugs significantly influenced both tests.

Conclusions: The present study shows that patients affected by opioid-dependence in OST with methadone and buprenorphine have a high prevalence of constipation and reduced QoL.     

Evaluation of rotigotine transdermal patch for the treatment of depressive symptoms in patients with Parkinson’s disease

Objective: To evaluate the dopamine receptor agonist, rotigotine, for improving depressive symptoms in patients with Parkinson’s disease (PD).

Methods: Patients were randomized 1:1 to rotigotine or placebo, titrated for ≤7 weeks, and maintained at optimal/maximum dose for 8-weeks. Primary efficacy variable: 17- item Hamilton Depression Rating Scale (HAM-D 17) total score change from baseline to end-of-maintenance. Secondary variables: changes in Beck Depression Inventory-II, Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living [ADL]) and III (motor) subscores, UPDRS II+III total, patient-rated Apathy Scale (AS), and Snaith-Hamilton Pleasure Scale.

Results: Of 380 patients randomized, 149/184 (81.0%) rotigotine-treated and 164/196 (83.7%) placebo-treated patients completed the study. Patients: mean (±SD) age 65.2 (±8.5) years; time since PD-diagnosis 2.74 (±3.08) years; 42.6% male. The treatment difference (LS mean [95% CI]) in change from baseline HAM-D 17 was ?1.12 (?2.56, 0.33; p = 0.1286). UPDRS II, III, II+III and AS scores improved numerically with rotigotine versus placebo. Common adverse events with higher incidence with rotigotine: nausea, application/instillation site reactions, vomiting, and pruritus. Forty-one (10.8%) patients discontinued owing to adverse events (25 rotigotine/16 placebo).

Conclusions: No statistically significant improvement in depressive symptoms were observed with rotigotine versus placebo. ADL, motor function, and patient-rated apathy improved numerically.

ClinicalTrials.gov: NCT01523301     

Memantine in Japanese patients with moderate to severe Alzheimer’s disease: meta-analysis of multiple-index responder analyses

Background: Responder analyses assessing clinical worsening have attempted to clarify clinically meaningful drug efficacy enhancements in patients with Alzheimer’s disease (AD).

Research design and methods: This was a meta-analysis of two multicenter, randomized, double-blind, parallel-group, 24-week studies of 633 Japanese patients with moderate to severe AD receiving memantine 20 mg/day (n = 318) or placebo (n = 315). The clinical trial registration number is UMIN000026013.

Results: Overall odds ratios (OR) for a reduced likelihood of clinical worsening (memantine versus placebo) were statistically significant on the following individual and combined rating scales: Severe Impairment Battery-Japanese version (SIB-J, OR 0.52; 95% CI: 0.37, 0.73; p = 0.0001); Behavioral Pathology in AD Rating Scale (BEHAVE-AD, OR 0.53; 95% CI: 0.37, 0.75; p = 0.0003); and SIB-J + Clinician’s Interview-Based Impression of Change-plus-Japanese version (SIB-J + CIBIC-plus-J; OR 0.53; 95% CI: 0.37, 0.77; p = 0.0009). A significantly reduced risk of triple worsening was evident in the memantine versus placebo group on the combined SIB-J + CIBIC-plus-J + BEHAVE-AD rating scales (OR 0.38; 95% CI: 0.22, 0.65; p = 0.0003).

Conclusions: Memantine is a viable treatment option for patients with AD presenting not only with cognitive impairment, but also with a broader range of symptoms, including the behavioral and psychological symptoms of dementia.     

Safety and effectiveness of empagliflozin in Japanese patients with type 2 diabetes: interim analysis from a post-marketing surveillance study

ABSTRACT

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective treatments for type 2 diabetes mellitus (T2DM). We present the interim findings of an ongoing post-marketing surveillance (PMS) study in Japanese patients with T2DM receiving empagliflozin.

Research design and methods: This 3-year, prospective, observational, multicenter PMS evaluated the safety and effectiveness of empagliflozin in Japanese clinical practice. Patients with T2DM who had not been treated with empagliflozin before enrollment were eligible. Assessments, including the primary endpoint of incidence of adverse drug reactions (ADRs), were based on electronic case report forms (eCRF).

Results: Of 8,180 registered patients from 1,103 sites, 7,618 patients had an eCRF including a follow-up visit and were treated (mean age, 58.8 years; 10.5% aged ≥75 years; 63.2% male; mean HbA1c, 8.01%; 41.8% with HbA1c ≥8.0%; 24.8% and 61.8% with at least mild hepatic and renal impairment, respectively). Mean treatment duration was 98.4 weeks; 644 (8.5%) patients had ≥1 ADR, including 8.5% of patients aged ≥75 years. Hypoglycemia, urinary tract infection, genital infections, volume depletion, diabetic ketoacidosis, and lower limb amputation occurred in 0.28%, 0.62%, 0.53%, 0.33%, 0%, and 0.03% of patients, respectively.

Conclusions: The reported ADRs were consistent with the known safety profile of empagliflozin.

Trial registration: ClinicalTrials.gov identifier: NCT02489942.     

Efficacy and safety of saxagliptin in combination with insulin in Japanese patients with type 2 diabetes mellitus: a 16-week double-blind randomized controlled trial with a 36-week open-label extension

Background: We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus.

Research design and methods: We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint.

Results: At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference ?0.92% [95% confidence interval ?1.07%, ?0.76%; p < 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups.

Conclusions: Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes.     

A randomized,double-blind trial on the use of 1% hydrocortisone cream for the prevention of acute radiation dermatitis

Background: To determine whether the application of 1% hydrocortisone cream during radiation therapy can prevent the occurrence of moist desquamation.

Methods: Fifty adult female breast carcinoma patients were randomized after modified radical mastectomy and chemotherapy to receive prophylactic placebo cream (n = 27) or 1% hydrocortisone cream (n = 23) during radiation therapy. The patients, caregiver and assessor were all blinded to the treatment received. Occurrence of moist desquamation, severity of acute radiation dermatitis (ARD) and hyperpigmentation were evaluated weekly until the end of radiotherapy.

Results & conclusion: Five patients in each group developed moist desquamation; however, its extent and severity were milder in the steroid group. Mean ARD scores were also lower in the steroid group (0.713 vs. 0.874, p = 0.024). A lower incidence of Grades 1 and 2 radiation dermatitis was also noted in the steroid group at weeks 2 and 4, respectively, indicating prophylactic use of steroids delayed the onset of radiodermatitis.     

Comparison between insulin degludec/liraglutide treatment and insulin glargine/lixisenatide treatment in type 2 diabetes: a systematic review and meta-analysis

Aim: To evaluate the efficacy and adverse effects of IDegLira and IGlarLixi treatment and to perform a comparison between two strategies.

Methods: The registration number is CRD42017053952. Randomized controlled trials of IGlarLixi treatment or IDegLira treatment compared with placebo or active hypoglycemic agents in type 2 diabetes were included.

Results: Eight trials were included. The absolute HbA1c change relative to baseline after IGlarLixi treatment was ?1.50% with significance (95% CI, ?1.89% to ?1.12%, p < 0.01); the absolute HbA1c change after IDegLira treatment was ?1.89% with significance (95% CI, ?2.04% to ?1.73%, p < 0.01). Comparisons between IGlarLixi treatment and IDegLira treatment indicated no significant differences between groups. The absolute weight change after IGlarLixi treatment significantly decreased (weighted mean difference (WMD), ?0.62 kg; 95% CI, ?0.93 to ?0.31 kg, p = < 0.01), but the absolute weight change after IDegLira treatment was not significantly changed (WMD, ?0.81 kg; 95% CI, ?3.26 to 1.65 kg, p = 0.52). There were no significant differences between groups.

Conclusion: Glucose control of IGlarLixi treatment or IDegLira treatment was significantly lower than that at baseline. Comparisons between the two treatment groups indicated no significant differences between groups in absolute HbA1c changes or body weight changes relative to baseline.     

Renal impairment in patients with chronic hepatitis C treated with first generation protease inhibitors

Background: The incidence, course and risk factors associated with renal impairment (RI) in patients treated with triple therapy (TT) with pegylated interferon, ribavirin and telaprevir/boceprevir (PR/TVR/BOC) vs. dual therapy (DT) with PR were analyzed in this study. The association between RI and the decline of hemoglobin (Hb) was also examined.

Methods: Retrospective analysis included 110 patients with genotype 1b chronic HCV infection, aged 18 – 80 years, who underwent TT (48TVR/14BOC) or DT (48 patients). The estimated glomerular filtration rate (eGFR), serum creatinine concentration (SCr) and Hb were measured at baseline, at weeks 4, 12, 24, 48 of treatment, and post-treatment week 24.

Results: RI occurred in 9/62 (14.5%) patients who underwent TT, eight of whom were treated with TVR, one with BOC, and none treated with DT. The risk factors associated with RI were the following: TT (p = 0.0078), usage of nephrotoxic drugs (p = 0.0288), and older age (p < 0.0001). RI was reversible. A drop of Hb was associated with RI, older age and TT.

Conclusions: RI is not a rare but a reversible complication of TT. It is necessary to monitor SCr and eGFR, especially in patients with a potential risk factor of RI occurrence. The Hb drop is more severe in patients with RI than in those without it.     

Effect of 24-week treatment with ipragliflozin on proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes

Background: Chronic hyperglycemia has an adverse influence on beta-cell function, which is known as ‘glucotoxicity’. Sodium-glucose cotransporter-2 (SGLT2) inhibitors lower the blood glucose concentration by enhancing urinary glucose excretion. This study was performed to clarify the influence of the SGLT2 inhibitor ipragliflozin on beta-cell function assessed from the plasma intact proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes.

Research design and methods: This was a 24-week, prospective, single-center, open-label, single-arm study. The subjects were 19 Japanese patients with type 2 diabetes. After a 4- to 8-week period of lifestyle modification, ipragliflozin (50 mg/d) was added to their existing treatment. At baseline and at 12 and 24 weeks after starting ipragliflozin treatment, a meal test was performed to evaluate the fasting and 2-hour proinsulin/C-peptide ratio.

Results: After 24 weeks, the body mass index, fasting plasma glucose, and hemoglobin A1c were all decreased significantly. Both the fasting and 2-hour proinsulin/C-peptide ratio decreased significantly from 25.0 ± 18.9 × 10^–3 to 14.3 ± 9.0 × 10^–3 and from 23.2 ± 14.9 × 10^–3 to 13.7 ± 5.4 × 10^–3, respectively (both p < 0.01 vs. baseline).

Conclusions: These findings indicate that ipragliflozin might have a beneficial effect on beta-cells.     

Pharmacological treatments for functional nausea and functional dyspepsia in children: a systematic review

ABSTRACT

Introduction: Chronic idiopathic nausea (CIN) and functional dyspepsia (FD) cause considerable strain on many children’s lives and their families.

Areas covered: This study aims to systematically assess the evidence on efficacy and safety of pharmacological treatments for CIN or FD in children. CENTRAL, EMBASE, and Medline were searched for Randomized Controlled Trials (RCTs) investigating pharmacological treatments of CIN and FD in children (4–18 years). Cochrane risk of bias tool was used to assess methodological quality of the included articles.

Expert commentary: Three RCTs (256 children with FD, 2–16 years) were included. No studies were found for CIN. All studies showed considerable risk of bias, therefore results should be interpreted with caution. Compared with baseline, successful relief of dyspeptic symptoms was found for omeprazole (53.8%), famotidine (44.4%), ranitidine (43.2%) and cimetidine (21.6%) (p = 0.024). Compared with placebo, famotidine showed benefit in global symptom improvement (OR 11.0; 95% CI 1.6–75.5; p = 0.02). Compared with baseline, mosapride versus pantoprazole reduced global symptoms (p = 0.011; p = 0.009). One study reported no occurrence of adverse events. This systematic review found no evidence to support the use of pharmacological drugs to treat CIN or FD in children. More high-quality clinical trials are needed.

Abbreviations: AP-FGID: Abdominal Pain Related Functional Gastrointestinal Disorders; BART: Biofeedback-Assisted Relaxation Training; CIN: Chronic Idiopathic Nausea; COS: Core Outcomes Sets; EPS: Epigastric Pain Syndrome; ESPGHAN: European Society for Pediatric Gastroenterology Hepatology and Nutrition; FAP: Functional Abdominal Pain; FD: Functional Dyspepsia; GERD: Gastroesophageal Reflux Disease; GES: Gastric Electrical Stimulation; H₂RAs: H2 Receptor Antagonists; IBS: irritable bowel syndrome; NASPGHAN: North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; PDS: Postprandial Distress Syndrome; PPIs: Proton Pump Inhibitor; PROMs: Patient Reported Outcome Measures; RCTs: Randomized Controlled Trials; SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic antidepressants     

Efficacy and tolerability of intramuscular interferon beta-1a compared with subcutaneous interferon beta-1a in relapsing MS: results from PROOF

ABSTRACT

Objective: Benefits from interferon beta (IFNβ) treatment in patients with multiple sclerosis are affected by many factors, including sustained clinical efficacy, acceptable tolerability, adherence to therapy, and the development of neutralizing antibodies (NAbs). The Prospective and Retrospective Long-Term Observational Study of Avonex and Rebif (PROOF) was designed to compare the relative efficacy and tolerability of the two IFNβ-1a products for up to 5 years.

Methods: PROOF compared the relative efficacy and tolerability of intramuscular (IM) IFNβ-1a (Avonex) 30?µg once weekly (n= 69) and subcutaneous (SC) IFNβ-1a (Rebif) 44?µg three times per week (n= 67). The duration of the retrospective portion of the study was 12–24 months. Due to slow enrollment, PROOF ended earlier than planned and the final duration of the prospective portion of the study was 6 months. Therefore, between 18 and 30?months of efficacy and tolerability data were available for analysis.

Results: After controlling for baseline disability level, Expanded Disability Status Scale (EDSS) scores revealed no statistically significant differences between the treatment groups during the prospective portion of the study, with sustained disability progression similar in both groups (25.8% IM IFNβ-1a 30?µg once weekly vs. 26.7% SC IFNβ-1a 44?µg three times per week). Relapse rates were similar in the groups, as were MRI endpoints of brain parenchymal fraction, T1 lesion volume, T2 lesion volume, number of new/enlarging T2 lesions, and gadolinium-enhancing (Gd+) lesion volume and count. Treatment groups differed in frequency of NAbs, with 19% of patients treated with SC IFNβ-1a 44?µg three times per week NAb+ compared with none treated with IM IFNβ-1a 30?µg once weekly. More NAb+ patients compared with NAb– patients had disability progression (40.0% vs. 27.8%, p= NS), new or enlarging T2 lesions at the end of treatment (63.6% vs. 40.7%, p= 0.003), and Gd+ lesions after 12–24 months of treatment (36.4% vs. 15%, p= 0.001). The IFNβ-1a products had comparable tolerability. However, fewer patients treated with IM IFNβ-1a 30?µg once weekly had injection-site reactions (2.9% vs. 6.0%). Limitations of this study include its design and sample size, both of which hinder detection of differences in efficacy between IFNβ-1a treatments.

Conclusions: The results of the present study show that the two IFNβ-1a products have comparable efficacy and differing immunogenicity.     

Baseline characteristics and interim (3-month) efficacy and safety data from STELLA-LONG TERM,a long-term post-marketing surveillance study of ipragliflozin in Japanese patients with type 2 diabetes in real-world clinical practice

Objective: To evaluate the efficacy and safety of ipragliflozin in real-world clinical practice in Japanese patients with type 2 diabetes.

Research design and methods: We conducted interim analyses at 3 months of a 3-year prospective study of patients who were first prescribed ipragliflozin between 17 July 2014 and 16 October 2015, and whose data were locked by 16 January 2016.

Main outcome measures: Changes in glycemic control, blood pressure, and laboratory variables from baseline, and incidence of adverse drug reactions (ADRs).

Results: Of 11,412 patients initially registered, efficacy and safety data were available for 3481 (30.5%) and 4360 (38.2%) patients, respectively. Hemoglobin A1c and fasting plasma glucose decreased by 0.67% and 28.8 mg/dL, respectively, at 3 months/last assessment (both P < .001) from baseline (8.00% and 166.4 mg/dL, respectively). Blood pressure and lipid levels also improved significantly. There were 258 ADRs in 194 patients. The ADRs included ‘renal and urinary disorders’ (system organ class) in 110 patients (2.5%).

Conclusions: These 3-month interim results indicate that ipragliflozin improved glycemic control, lipids, and blood pressure with low rates of ADRs in Japanese patients with type 2 diabetes in real-world clinical practice. The results were consistent with those of placebo-controlled, randomized clinical trials.

Clinicaltrials.gov identifier: NCT02479399     

Efficacy of fulvestrant 500 mg in Japanese postmenopausal advanced/recurrent breast cancer patients and factors associated with prolonged time-to-treatment failure

Objective: We aimed to confirm the efficacy of fulvestrant in Japanese postmenopausal advanced/recurrent breast cancer (ABC) patients, and investigate factors contributing to time-to-treatment failure (TTF) prolongation.

Research design and methods: This retrospective study included 194 ABC patients who received fulvestrant (500 mg) from January 2012 to December 2014.

Main outcome measures: TTF (efficacy measure), overall survival (OS), factors prolonging TTF and adverse events were evaluated.

Results: The median age was 65 (42 – 90) years. Overall, TTF was 5.48 months. In patients without prior chemotherapy (n = 59), OS was significantly longer (p = 0.0131) than in patients with prior chemotherapy (n = 135). There was no strong correlation between TTF with fulvestrant and other endocrine therapies, total duration of endocrine therapy and maximum duration of endocrine therapy. TTF was significantly longer in patients with less than two prior chemotherapy regimens (p = 0.0093), de novo metastatic disease (p = 0.0124) and without liver metastasis (p = 0.0024). We observed one case each of pulmonary infarction and psychiatric disorder.

Conclusions: Fulvestrant is effective for ABC patients and may show greater efficacy in patients with few prior chemotherapy regimens, de novo metastatic disease and absence of liver metastasis. Prior endocrine therapy duration might not be a predictive factor for fulvestrant TTF in heavily treated ABC patients.     

The efficacy and safety of teneligliptin added to ongoing metformin monotherapy in patients with type 2 diabetes: a randomized study with open label extension

Objective: The study investigated the efficacy and tolerability of teneligliptin co-administered to patients with type 2 diabetes mellitus (T2DM) who were inadequately controlled by stable metformin monotherapy ≥ 1000 mg/day.

Methods: A total of 447 patients from 55 European centers who completed a 14-day screening and 14-day run-in phase, received randomized double-blind treatment with 5, 10, 20 or 40 mg teneligliptin or placebo once daily, for 24 weeks. 364 patients continued treatment in a 28-week open label extension during which they received teneligliptin 20 mg once daily.

Results: Co-administration of teneligliptin (5 to 40 mg) with metformin demonstrated dose-related and statistically significant reductions in HbA_1c after 24 weeks (-0.30 to -0.63% placebo adjusted) of double-blind treatment. The greatest reduction in HbA_1c was seen with teneligliptin at 40 mg (-0.63%) at Week 24. There was also a dose-dependent increase in proportion of responders achieving HbA_1c < 7.0% at this endpoint. Responses were maintained throughout 28 weeks open label treatment with 20 mg teneligliptin. Treatment was well tolerated to Week 52 and the overall incidence of hypoglycemia during 52 weeks was 2.3%.

Conclusions: Teneligliptin co-administered with metformin produced significant reductions in HbA_1c in patients with T2DM without increasing the risk of hypoglycemia.     

Collaborative approach of individual participant data of prospective studies of de-escalation in non-immunosuppressed critically ill patients with sepsis

Background: There is a concern to conduct de-escalation in very sick patients.

Aims: To determine if de-escalation is feasible in ICU settings.

Methods: We performed a metaanalysis of published studies conducted comparing de-escalation (defined by withdrawal of at least one antimicrobial empirically prescribed, switch to a new antimicrobial with narrower spectrum and withdrawal of at least one antimicrobial plus change of another drug to a new one with narrower spectrum) in non-immunocompromised patients with sepsis admitted to ICU.

Results: Eight hundred and seventeen patients with severe sepsis or septic shock were evaluated. De-escalation was applied in 274 patients (33.5%). We found no differences in hospital long of stay between de-escalation group compared to those who did not receive it. We also found significant lower hospital mortality in de-escalation group as compared with no modification group in front of the others (25.9 vs. 43.1%; p < 0.001). Taking into account the etiology of infection, in both gram negative and gram positives microorganisms, de-escalation strategy was assessed as a good prognosis factor for mortality in the adjusted multivariate analysis (OR 0.41; 95% CI 0.22–0.74 and OR 0.33; 95% CI 0.15–0.70 respectively) whereas SOFA score along with age were found as a factors independently associated with a worse clinical outcome (OR 1.23; 95% CI 1.12–1.35 and OR 1.02; 95% CI 1.01–1.04 respectively).

Conclusions: In our study there was an independent association of de-escalation and decrease mortality rate.