Summary of ceftaroline fosamil clinical trial studies and clinical safety

In October 2010, the new cephalosporin, ceftaroline fosamil, was approved by the US Food and Drug Administration for therapy of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSIs). The active metabolite, ceftaroline, demonstrates in vitro activity against typical bacterial pathogens most often associated with CABP or ABSSSIs, including resistant Gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. The efficacy and safety of ceftaroline fosamil was assessed in 2 large phase 3 programs of randomized, double-blind, clinical trials for CABP and ABSSSIs. For both indications, therapy with ceftaroline fosamil was observed to be noninferior to the comparator agents (ceftriaxone for CABP and vancomycin plus aztreonam for ABSSSIs) at both a standard test of cure assessment time (8-15 days after discontinuation of study drug) and an early assessment time point (day 3 or 4 of study). In the integrated analysis of the trials for CABP (FOCUS 1 and 2), clinical cure rates for the ceftaroline group were numerically higher than those for the ceftriaxone group (for the clinically evaluable population 84.3% vs 77.7%; difference: 6.6%; 95% confidence interval, 1.6%-11.8%). Among patients with CABP caused by S. pneumoniae, clinical cure rates were markedly higher in the ceftaroline treatment group than in the ceftriaxone treatment group (59 of 69 [85.5%] vs 48 of 70 [68.6%], respectively). For the ABSSSI studies (CANVAS 1 and 2), microbiologically evaluable (ME) success rates were similar between the treatment groups. Notably, the clinical cure rates in ME patients with methicillin-resistant S. aureus ABSSSIs were 142 of 152 (93.4%) and 115 of 122 (94.3%), for ceftaroline and vancomycin plus aztreonam, respectively, and did not differ from those achieved in infections due to methicillin-susceptible S. aureus (93.0%-94.5%). Ceftaroline fosamil was well tolerated, with a safety profile similar to the comparator agents used in these phase 3 trials.     

Pooled analysis of the efficacy and safety of self-expanding metal stenting in malignant colorectal obstruction

BACKGROUND: Self-expanding metal stents have been used in the management of colorectal obstruction as an alternative to emergency surgery. Our aim was to systematically review the efficacy and safety of these stents in the setting of malignant colorectal obstruction. METHODS: Both English and foreign language reports were identified from Medline, Embase, Cancerlit, Science Citation Index, Cochrane Library, and proceedings of relevant meetings. Data were collected on technical success, clinical success, and safety parameters. RESULTS: Fifty-four studies reported the use of stents in a total of 1,198 patients. The median technical and clinical success rates were 94% (i.q.r. 90-100) and 91% (i.q.r. 84-94), respectively. The clinical success when used as a bridge to surgery was 71.7%. Major complications related to stent placement included perforation (3.76%), stent migration (11.81%), and reobstruction (7.34%). Factors related to an increased complication risk were identified. Stent-related mortality was 0.58%. Limited available data suggest that this approach may be cost effective in the preoperative setting. CONCLUSION: Placement of self-expanding metal stents is an effective and safe definitive procedure in the palliation of malignant colorectal obstruction. In operable patients, it provides a useful option to avoid colostomy, by facilitating safer single-stage surgery.     

Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial

Background and objective: Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions. We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4‐year COPD trial. Methods: Subgroup analysis from a randomized, double‐blinded, placebo‐controlled trial of tiotropium 18 µg daily in COPD. Primary end‐point was rate of decline in FEV₁. Secondary end‐points included spirometry at individual time points, health‐related quality of life (St George's Respiratory Questionnaire), exacerbations and mortality. Results: Of 5992 patients, 362 were from Asian centres (100 from Japan). Mean age 66 years, 95% men, 13% current smokers, BMI: 21 kg/m²; post‐bronchodilator FEV₁: 44% predicted; St George's Respiratory Questionnaire total score: 44 units. No treatment effect was observed for rate of decline in FEV₁ although annual decline was less in Asian patients. Morning pre‐bronchodilator FEV₁ and forced vital capacity improved in Asian patients (P < 0.05). Tiotropium reduced number of exacerbations (rate ratio (95% confidence interval (CI)): 0.73 (0.57–0.94)). Hazard ratios (95%CI) for exacerbations and hospitalized exacerbations (tiotropium/control) were 0.81 (0.62–1.05) and 0.85 (0.61–1.19), respectively. St George's Respiratory Questionnaire total score improved by 1.5–6.1 units (P < 0.05 for months 18, 24, 30 and 36) with tiotropium. Fatal events occurred in 34 tiotropium (18.5%) and 42 control (23.6%) patients. Conclusions: In COPD patients from Asia, tiotropium improves lung function, improves health‐related quality of life and reduces exacerbations over 4 years of treatment.     

Cardiovascular safety of mirabegron: analysis of an integrated clinical trial database of patients with overactive bladder syndrome

Mirabegron is a β₃-adrenoreceptor agonist used for the treatment of overactive bladder syndrome. We evaluated the cardiovascular (CV) safety of mirabegron using pooled data from 13 studies. The analysis included 13,396 patients who received ≥1 dose of mirabegron (25 mg/50 mg) or comparator antimuscarinics (solifenacin 2.5 mg/5 mg/10 mg or tolterodine extended release 4 mg) as monotherapies, or placebo. We focused on changes in blood pressure and CV adverse events. Baseline CV risk factors had an imbalanced effect on subsequent CV adverse events. The frequency of these adverse events was comparable for overactive bladder treatments (0.4%–1.5%) and placebo (0.9%). Changes from baseline in blood pressure were similar for the overactive bladder treatments and placebo, and did not confer increased risk of CV adverse events. Multivariate analyses demonstrated that baseline CV risk factors (history of arrhythmia, history of coronary artery disease, and history of stroke/transient ischemic attack) were significantly associated with subsequent CV adverse events in the trials, whereas overactive bladder therapies were not. In conclusion, using an analytical approach to carefully control for CV characteristics of patients in these trials demonstrated no evidence of increased CV risk for mirabegron or antimuscarinics over placebo in the treatment of overactive bladder syndrome.     

噻托溴铵粉雾剂治疗慢性阻塞性肺病的有效性及安全性

目的观察噻托溴铵粉雾剂治疗慢性阻塞性肺病（COPD）的有效性及安全性。方法采用随机、双盲、双模拟阳性药平行对照、多中心临床研究的方法。对223例COPD稳定期Ⅰ、Ⅱ和Ⅲ级患者,分别吸入噻托溴铵粉雾剂（试验组）和异丙托溴铵定量气雾剂（对照组）,治疗28 d,测定患者用药前后不同时间的肺功能。结果 1.治疗28 d,对照组和试验组的临床改善率分别为47.71%（P〈0.05）和59.46%（P〈0.05）。2.各组给药后30、60、120 m in、28 d,FEV1与基线相比,差别均有统计学意义（P〈0.05）。治疗后28 d,试验组FEV1、FVC与对照组相比,差别有统计学意义（P〈0.01）。结论规律吸入噻托溴铵粉雾剂可显著改善COPD患者的临床症状,无严重药物不良反应。     

Pooled analysis of Helicobacter pylori eradication regimes in Asia

BACKGROUND AND AIMS: Differences in Helicobacter pylori strains and their resistance to antimicrobials between Asian and Western countries may affect the success in eradicating this bacterium. Our objective was to systematically review the regimens that have been tested in Asia. METHODS: Data on anti-H. pylori therapies reported from Asia in a large number of publications identified up to December 1998 were pooled into a few groups based on the combination of drugs used. A comparison of different groups was made by calculating the pooled eradication rates. RESULTS: Seventy-three studies with 134 treatment arms were reviewed. Pooled eradication rates of dual, triple and quadruple therapies were 61.0, 86.5 and 93.4%, respectively. Proton pump inhibitor (PPI)-based combinations were more widely used and effective, with overall eradication rates of 90.7% in triple therapy and 93.4% in quadruple therapy. Bismuth combined with tetracycline and metronidazole also showed a high eradication rate of 92.0%. CONCLUSIONS: Proton pump inhibitor-based triple therapy with either clarithromycin, amoxycillin or metronidazole was one of the most commonly used and effective anti-H. pylori triple therapy regimens in Asia. The classical triple therapy with a bismuth, tetracycline and metronidazole combination has a similar efficacy. The results of anti-H. pylori treatment in Asia are not different from those in Western countries.     

Dermatophagoides pteronyssinus cluster immunotherapy. A controlled trial of safety and clinical efficacy.

We designed a cluster schedule of immunotherapy for patients allergic to Dermatophagoides pteronyssinus to reach the maximal recommended dose in 7 weeks. We compared its safety and clinical efficacy with those of a conventional schedule in a controlled trial. Sixty-three patients were randomized as follows: 29 were treated with the cluster schedule, 15 with a conventional schedule and 19 without immunotherapy. A standardized extract was used. Clinical efficacy was measured by visual analog scale, clinical severity score, symptom/medication diary cards and control of peak expiratory flow (PEF) in asthmatic patients, before immunotherapy (T0), on reaching the maintenance phase (T1), and after 6 (T2), 12 (T3) and 18 months of maintenance (T4). The safety of immunotherapy was found to be good. Visual analog scale improved significantly at T4 in the cluster and conventional schedules, and clinical severity score also improved from T1 in these schedules. Diary cards improved from T1 in the cluster schedule and from T2 in the conventional schedule in asthmatic patients. Significant improvements in diary cards in rhinitis patients and PEF were found only in the cluster schedule. There were no changes in the group without immunotherapy. In conclusion, our cluster schedule showed as good tolerance and clinical efficacy as the conventional schedule in patients allergic to D. pteronyssinus. These clinical improvements did not appear in the group without immunotherapy.     

Meta-analysis of efficacy and safety of intravenous ferric carboxymaltose (Ferinject) from clinical trial reports and published trial data

Background

Recommendations given for intravenous iron treatment are typically not supported by a high level of evidence. This meta-analysis addressed this by summarising the available date from clinical trials of ferric carboxymaltose using clinical trial reports and published reports.

Methods

Clinical trial reports were supplemented by electronic literature searches comparing ferric carboxymaltose with active comparators or placebo. Various outcomes were sought for efficacy (attainment of normal haemoglobin (Hb), increase of Hb by a defined amount, for example), together with measures of harm, including serious adverse events and deaths.

Results

Fourteen studies were identified with 2,348 randomised patients exposed to ferric carboxymaltose, 832 to oral iron, 762 to placebo, and 384 to intravenous iron sucrose. Additional data were available from cohort studies. Intravenous ferric carboxymaltose was given up to the calculated iron deficit (up to 1,000 mg in one week) for iron deficiency anaemia secondary to chronic kidney disease, blood loss in obstetric and gynaecological conditions, gastrointestinal disease, and other conditions like heart failure. The most common comparator was oral iron, and trials lasted 1 to 24 weeks. Intravenous ferric carboxymaltose improved mean Hb, serum ferritin, and transferrin saturation levels; the mean end-of-trial increase over oral iron was, for Hb 4.8 (95% confidence interval 3.3 to 6.3) g/L, for ferritin 163 (153 to 173) μg/L, and for transferrin saturation 5.3% (3.7 to 6.8%). Ferric carboxymaltose was significantly better than comparator in achievement of target Hb increase (number needed to treat (NNT) 6.8; 5.3 to 9.7) and target Hb NNT (5.9; 4.7 to 8.1). Serious adverse events and deaths were similar in incidence in ferric carboxymaltose and comparators; rates of constipation, diarrhoea, and nausea or vomiting were lower than with oral iron.

Conclusions

This review examined the available trials of intravenous ferric carboxymaltose using details from published papers and unpublished clinical trial reports. It increases the evidence available to support recommendations given for intravenous iron treatment, but there are limited trial data comparing different intravenous iron preparations.     

Efficacy and safety of indacaterol and tiotropium in COPD patients according to dyspnoea severity

BackgroundGuidelines for chronic obstructive pulmonary disease (COPD) recommend that treatment choices be based partly on symptoms.MethodsA post-hoc analysis of pooled data from clinical studies compared the efficacy and safety of once-daily inhaled bronchodilators indacaterol (150 and 300 μg) and open-label tiotropium (18 μg) according to baseline dyspnoea severity on the modified Medical Research Council (mMRC) scale in patients with COPD (mMRC scores <2 = ‘less dyspnoea’; scores ≥2 = ‘more dyspnoea’). Outcomes were assessed after 26 weeks.ResultsThe analysis included 3177 patients. In patients with less dyspnoea: indacaterol (both doses) improved 24-h post-dose (‘trough’) forced expiratory volume in 1 s (FEV₁), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores at week 26 and reduced the risk of COPD exacerbations vs placebo; and open-label tiotropium improved trough FEV₁ and TDI total score vs placebo at week 26. In patients with more dyspnoea: indacaterol (both doses) improved trough FEV₁, TDI and SGRQ total scores at week 26; indacaterol 300 μg was the only treatment to improve the TDI total score by more than the minimum clinically important difference (≥1 point) vs placebo; and open-label tiotropium improved trough FEV₁, TDI total score at week 26 and decreased the risk of COPD exacerbations vs placebo. In both subgroups, all treatments were well tolerated.ConclusionsIn patients with less dyspnoea, all treatments had similar effects. Indacaterol 300 μg may be a useful treatment option for patients with COPD who experience more severe breathlessness.     

Pooled analysis of amino acid changes in the HBV polymerase in patients from four major adefovir dipivoxil clinical trials

BACKGROUND/AIMS: The rtA181V and rtN236T mutations have been associated with resistance to adefovir dipivoxil (ADV). Recent reports have proposed other ADV resistance (ADV-R) mutations. The aims of this study were to confirm the role of rtA181V and rtN236T in clinical resistance to ADV and to screen for other potential ADV-R mutations. METHODS: Patients from ADV studies (n=998) were screened for viral breakthrough and/or insufficient HBV DNA suppression after at least 48 weeks of ADV therapy [virologic failure, VF]. McNemar's exact test was used to test for differences in the proportion of patients with switches from consensus amino acid (AA) at baseline to non-consensus AA at VF and vice versa. RESULTS: Data obtained from 172 paired HBV polymerase sequences demonstrated that only positions rt181 and rt236 had significantly more changes among patients with VF after adjusting for multiple comparisons (p<0.0005). When tested separately, the mutations rtA181V and rtN236T were statistically significant (p<0.0005); no other AA position was associated with VF. Patients who had HBV DNA breakthrough were more likely to develop ADV-R mutations than patients with insufficient HBV DNA suppression (36% vs. 5%). CONCLUSIONS: rtA181V and rtN236T were the only HBV polymerase mutations significantly associated with virologic failure to adefovir dipivoxil.     

Pooled analysis on metabolic gene polymorphisms and lung cancer

This article reports an update of pooled analysis on metabolic gene polymorphisms and cancer (the Genetic Susceptibility to Environmental Carcinogens [GSEC] study). The study started in 1997, and has collected data from over 52,000 subjects (half cases, half controls). The distribution of cases shows that the most represented cancer is lung cancer (6465 cases), followed by bladder cancer (3289 cases). The analyses conducted on lung cancer and metabolic gene polymorphisms are summarized and discussed. Pooled analysis allows one to study rare subgroups of subjects, such as lung cancer at young ages, or in nonsmokers, and is a useful approach for generating new working hypothesis and for fostering collaboration.