Salbutamol Easyhaler provides non-inferior relief of methacholine induced bronchoconstriction in comparison to Ventoline Evohaler with spacer: A randomized trial.

BACKGROUND: Salbutamol is a cornerstone for relieving acute asthma symptoms, typically administered through a pressurized metered-dose inhaler (pMDI). Dry powder inhalers (DPIs) offer an alternative, but concerns exist whether DPIs provide an effective relief during an obstructive event. OBJECTIVE: We aimed to show non-inferiority of Salbutamol Easyhaler DPI compared to pMDI with spacer in treating methacholine-induced bronchoconstriction. Applicability of Budesonide-formoterol Easyhaler DPI as a reliever was also assessed. METHODS: This was a randomized, parallel-group trial in subjects sent to methacholine challenge (MC) test for asthma diagnostics. Participants with at least 20 % decrease in forced expiratory volume in 1 s (FEV1) were randomized to receive Salbutamol Easyhaler (2 × 200 µg), Ventoline Evohaler with spacer (4 × 100 µg) or Budesonide-formoterol Easyhaler (2 × 160/4.5 µg) as a reliever. The treatment was repeated if FEV1 did not recover to at least -10 % of baseline. RESULTS: 180 participants (69 % females, mean age 46 yrs [range 18-80], FEV1%pred 89.5 [62-142] %) completed the trial. Salbutamol Easyhaler was non-inferior to pMDI with spacer in acute relief of bronchoconstriction showing a -0.083 (95 % LCL -0.146) L FEV1 difference after the first dose and -0.032 (-0.071) L after the last dose. The differences in FEV1 between Budesonide-formoterol Easyhaler and Salbutamol pMDI with spacer were -0.163 (-0.225) L after the first and -0.092 (-0.131) L after the last dose. CONCLUSION: The study confirms non-inferiority of Salbutamol Easyhaler to Ventoline Evohaler with spacer in relieving acute bronchoconstriction, making Easyhaler a sustainable and safe reliever for MC test and supports its use during asthma attacks.

A non-interventional switch study in adult patients with asthma or COPD on clinical effectiveness of salmeterol/fluticasone Easyhaler® in routine clinical practice.

BACKGROUND: Selection of the most appropriate device for a switch from one inhaler to an equivalent product is known to have a major impact on clinical outcomes in patients with asthma or chronic obstructive pulmonary disease (COPD). Salmeterol/fluticasone propionate (S/F) Easyhaler® has been demonstrated to be therapeutically equivalent with a reference product. However, no data on real-life effectiveness are currently available for patients switching to S/F Easyhaler from another S/F inhaler. METHODS: The aim of this prospective, open, multicenter, non-interventional study was to assess clinical effectiveness of propionate S/F Easyhaler in adult asthma and COPD patients switched from another inhaler. The primary endpoints were Asthma Control Test (ACT) and COPD Assessment Test (CAT). Secondary endpoints included assessments of patient satisfaction and preference and physician/nurse perception on S/F Easyhaler use. The study included three visits during a 12-week follow-up. RESULTS: A total of 211 patients (160 with asthma; 51 with COPD) were included in the analyses. In patients with asthma, there was a statistically significant increase in the mean ACT score at week 12 (20.2 ± 3.9) compared with the baseline (18.6 ± 4.1), with a mean increase of 1.6 (±3.5) points (p < 0.0001). In patients with COPD, CAT score persisted from baseline (19.9 ± 8.6) to week 12 (19.6 ± 7.0). Patients were significantly more satisfied with Easyhaler and most patients preferred Easyhaler over their previous inhaler. The physicians/nurses reported that it was 'very easy' to teach the use of Easyhaler and the training took less than 5 minutes in most cases. CONCLUSION: The results from this prospective real-life clinical study indicate better or at least similar treatment control of asthma and COPD after switching to S/F Easyhaler from another S/F inhaler. This study also shows that S/F Easyhaler was favored by the patients and that it is easy to teach, learn and use in a real-life setting.The reviews of this paper are available via the supplemental material section.

Equivalent bronchodilation with budesonide/formoterol combination via Easyhaler and Turbuhaler in patients with asthma.

BACKGROUND: Therapeutic equivalence of Budesonide/formoterol Easyhaler compared to Symbicort Turbuhaler has been previously demonstrated with in vitro and pharmacokinetic studies. This study was performed to confirm equivalent bronchodilator efficacy of the products in asthmatic patients. METHODS: A randomised, single-dose, 4-period crossover study was carried out in a double-blind, double-dummy manner in 11 study sites. The studied doses were 320/9 µg and 1280/36 µg of budesonide/formoterol delivered by Easyhaler and Turbuhaler. Spirometry was performed before and 10 min, 20 min and 1, 2, 3, 4, 6, 8, 10 and 12 h after administration of the study treatments. The primary efficacy endpoint was average 12-h forced expiratory volume in 1 s (FEV1). The secondary efficacy endpoints were maximum FEV1 and FEV1 at 12 h post-dose. RESULTS: 72 asthma patients with reversible airway obstruction were randomised to receive study treatments. 53 patients completed all study periods according to the protocol and had sufficient data available to calculate the primary endpoint. They were included in the per-protocol analyses. The assay sensitivity of the study was shown as the common slope of average 12-h FEV1 between doses was 0.063 (95% CI 0.032-0.093) and showed statistical significance (p < 0.001). In equivalence testing, the difference in average 12-h FEV1 between the treatments (Easyhaler-Turbuhaler) was 0.013 l at the lower dose and -0.028 l at the higher dose, and their 95% confidence intervals (CIs) (-0.047 to 0.073 and -0.087 to 0.032, respectively) fell within the range of a clinically non-relevant difference. The results of the secondary efficacy endpoints were in line with the results of the primary endpoint. All treatments were well tolerated. CONCLUSIONS: The results confirm equivalent bronchodilator efficacy of Budesonide/formoterol Easyhaler compared to Symbicort Turbuhaler. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov, Identifier: NCT02308098.

Equivalent Lung Dose and Systemic Exposure of Budesonide/Formoterol Combination via Easyhaler and Turbuhaler.

BACKGROUND: Easyhaler(®) device-metered dry powder inhaler containing budesonide and formoterol fumarate dihydrate (hereafter formoterol) for the treatment of asthma and chronic obstructive pulmonary disease has been developed. The current approvals of the product in Europe were based on several pharmacokinetic (PK) bioequivalence (BE) studies, and in vitro-in vivo correlation (IVIVC) modeling. METHODS: Four PK studies were performed to compare the lung deposition and total systemic exposure of budesonide and formoterol after administration of budesonide/formoterol Easyhaler and the reference product, Symbicort Turbuhaler. The products were administered concomitantly with oral charcoal (lung deposition) and in two of the studies also without charcoal (total systemic exposure). Demonstration of BE for lung deposition (surrogate marker for efficacy) and non-inferiority for systemic exposure (surrogate marker for safety) were considered a proof of therapeutic equivalence. In addition, IVIVC models were constructed to predict study outcomes with different reference product fine particle doses (FPDs). RESULTS: In the first pivotal study, the exposure and lung dose via Easyhaler were higher compared to the reference product (mean comparison estimates between 1.07 and 1.28) as the FPDs of the reference product batch were low. In the following studies, reference product batches with higher FPDs were utilized. In the second pivotal study, non-inferiority of Easyhaler compared to Turbuhaler was shown in safety and BE in efficacy for all other parameters except the formoterol AUCt. In the fourth study where two reference batches were compared to each other and Easyhaler, budesonide/formoterol Easyhaler was bioequivalent with one reference batch but not with the other having the highest FPDs amongst the 28 reference batches studied. In the IVIVC based study outcome predictions, the test product was bioequivalent with great proportion of the reference batches. For the test product and the median FPD reference product BE was predicted. CONCLUSIONS: Equivalence regarding both safety and efficacy between budesonide/formoterol Easyhaler and Symbicort Turbuhaler was shown based on totality of evidence from the PK studies and IVIVC analyses, and therefore, therapeutic equivalence between the products can be concluded. The results of the PK studies are likely dependent on the variability of FPDs of the reference product batches.

Colonic methane production modifies gastrointestinal toxicity associated with adjuvant 5-fluorouracil chemotherapy for colorectal cancer.

GOALS: To investigate the association of colonic methane, formed by methanogenic achaea, and pH with gastrointestinal symptoms during colorectal cancer chemotherapy. BACKGROUND: Adjuvant 5-fluorouracil chemotherapy reduces recurrences in colorectal cancer, but causes severe gastrointestinal toxicity, partly related to disturbed intestinal microbiota. STUDY: Resected colorectal cancer patients (n=143) were analyzed for colonic methanogenesis and pH before and during the 24 weeks of 5-fluorouracil chemotherapy and for gastrointestinal symptoms during chemotherapy. This study was performed within the setting of an intervention study on the effects of Lactobacillus on chemotherapy-related gastrointestinal toxicity. The site of resected cancer, resection type, stoma, chemotherapy regimen, hypolactasia, and Lactobacillus intervention were considered as possible confounding factors, and multivariate models were constructed. RESULTS: Baseline methane producers had less frequent diarrhea (more than or equal to moderate) during chemotherapy than nonproducers [odds ratio (OR), 0.42; 95% confidence interval (CI), 0.20 to 0.88; P=0.022] and more frequent constipation (OR, 4.56; 95% CI, 2.01 to 10.32; P<0.001). Baseline fecal pH was also associated with symptoms during chemotherapy; higher the pH, the lower the risk of diarrhea (OR, 0.56; 95% CI, 0.31 to 1.02; P=0.058) and higher the risk of constipation (OR, 2.23; 95% CI, 1.35 to 3.68; P=0.002). In multivariate stepwise models, methanogenesis was a significant explaining factor with inverse association with diarrhea and positive association with constipation. Fecal pH, which was significantly associated with methane production, was no longer a significant explaining factor when methanogensis was included in the model. CONCLUSIONS: Methane producer status has a role in determining whether patient experiences diarrhea or constipation during 5-fluorouracil therapy. This underscores the importance of intestinal microbiota in the development of intestinal toxicity during 5-fluorouracil therapy.

Colonic methanogenesis in vivo and in vitro and fecal pH after resection of colorectal cancer and in healthy intact colon.

PURPOSE: We compared colonic methanogenesis in vivo and in vitro as well as fecal pH in healthy subjects and in patients with resected colorectal cancer thus without the possible confounding effects of the tumor. METHODS: A total of 144 subjects, 96 with resected colorectal cancer (of whom, 48 were with metastatic disease), 48 healthy subjects with intact colon, were analyzed for breath methane, fecal methanogenesis in vitro and fecal pH. In addition, the association between methanogenesis and pH with cancer site, operation technique and abdominal discomfort was investigated. RESULTS: In vivo and in vitro methane measurements were in agreement. The percentage of breath methane excretors and fecal pH did not significantly differ in participants resected for colorectal cancer, either with (46%, 6.76) or without (46%, 6.77) metastatic disease, from healthy participants (40%, 6.80). Breath methane excretors had higher fecal pH than nonexcretors (7.05 versus 6.57, P< 0.001) and less abdominal discomfort (30% versus 54%, P = 0.016). Among patients with resected right-sided cancer (n = 15), there were less breath methane excretors (20%) than among those with resected left-sided cancer (51%, n = 81, P = 0.029) as well as lower fecal pH than among those with resected left-sided cancer (6.27 versus 6.86, P = 0.002) and among healthy subjects (6.80, P = 0.010). CONCLUSIONS: Patients with resected colorectal cancer were as frequently methane producers as healthy subjects with intact colon, and there was no difference in their fecal pH. Low methanogenesis was found in patients with abdominal discomfort and is a possible characteristic, along with low fecal pH, to right-sided colorectal cancer.

Comparison of polyethylene glycol with and without electrolytes in the treatment of constipation in elderly institutionalized patients: a randomized, double-blind, parallel-group study.

BACKGROUND: Polyethylene glycol (PEG) is a commonly used osmotic laxative. PEG with electrolytes is mixed with water, but PEG without electrolytes can also be mixed with, for example, juice, coffee or tea, making it more palatable. Laxatives, including PEG, are commonly used by the elderly, particularly those living in institutions. Few clinical studies, however, have investigated the use of PEG in this population. OBJECTIVE: To test whether PEG 4000 without electrolytes (hypotonic PEG) is at least as effective and safe as PEG 4000 with electrolytes (isotonic PEG) in elderly institutionalized constipated patients. The acceptability of the treatments was also compared. METHODS: This randomized, double-blind, parallel-group study was conducted at ten private assisted-living facilities or communal nursing homes in Finland. Eligible patients were required to have used isotonic PEG at a stable dose without any other treatment for constipation (except for Plantago ovata seeds) for at least 2 weeks prior to a run-in period. After the 1-week run-in, 62 patients (mean age 86 years; range 66-99 years) were randomly either switched to receive hypotonic PEG or continued to receive isotonic PEG, both dissolved in water, 12 g once or twice daily or once every other day, for 4 weeks. Stool frequency, stool consistency, stool straining and gastrointestinal symptoms were recorded. Safety laboratory tests were conducted before and after the treatment period. Acceptability was assessed at the end of the study. RESULTS: At week 4, mean (SD) weekly stool frequencies in the hypotonic and isotonic PEG groups were 8.5 (4.5) and 8.4 (3.6), respectively. The mean stool frequency ratio (95% CI) was 0.90 (0.74, 1.10); thus, the PEG products were considered equally effective. At week 4, the proportion of patients with soft or normal stool consistency was higher in the hypotonic PEG group than in the isotonic PEG group (70% vs 52%), but this difference was not statistically significant. There were no differences between the groups in stool straining or gastrointestinal symptoms. In the safety laboratory tests, no clinically significant differences between the groups were detected, although plasma sodium level was statistically significantly lower in the hypotonic PEG group at the end of the study (137.7 vs 138.9 mmol/L, respectively; p = 0.012). Most patients were willing to continue their study treatment (85% in the hypotonic PEG and 63% in the isotonic PEG group; p = 0.070). Compared with only 12% of the patients receiving hypotonic PEG, however, 31% of the patients in the isotonic PEG group rated the taste of the study treatment as bad or very bad (p = 0.101). CONCLUSION: Hypotonic PEG solution is as effective as isotonic PEG in the treatment of constipation in elderly institutionalized patients. Both treatments appear safe, well tolerated and, when dissolved in water, well accepted by the majority of the patients. When desired, switching from isotonic to hypotonic PEG can safely take place in elderly individuals without compromising efficacy.

The effect of probiotic fermented milk and inulin on the functions and microecology of the intestine.

We investigated the effects of a probiotic fermented milk and inulin on gastrointestinal function and microecology. The study was double-blinded and comprised 66 healthy adults (22 male, 44 female), mean age 40 years (range, 22-60 years). After a 12-d baseline period the subjects were randomized to consume, for 3 weeks, 3x200 ml daily of either (1) a fermented milk with probiotics (Bifidobacterium longum BB536, Bifidobacterium spp. 420 and Lactobacillus acidophilus 145), (2) a fermented milk with the same probiotics plus 4 g inulin, or (3) a control fermented milk. During the last 7 d of the baseline and the intervention periods, the subjects kept a record of their defaecation frequency and gastrointestinal symptoms, and collected all their faeces. Intestinal transit time, stool weight and faecal enzyme activities were measured. Thirty-nine subjects were randomized to give faecal samples for analysis of pH and microbes, including lactobacilli, bifidobacteria, coliforms, Escherichia coli, Bacteroides and Clostridium perfringens. Consumption of fermented milk with probiotics or with probiotics and inulin increased the faecal number of lactobacilli (P=0.009, P=0.003) and bifidobacteria (P=0.046, P=0.038) compared with the baseline. Compared with the control fermented milk, both active products increased lactobacilli (P=0.005, ANCOVA). Subjects consuming fermented milk with probiotics and inulin suffered from gastrointestinal symptoms, especially flatulence, more than the others (P<0.001). In conclusion, the probiotic fermented milk product had a positive effect by increasing the number of lactobacilli and bifidobacteria in the colon. Inulin did not alter this effect but it increased gastrointestinal symptoms.

Correct use of three powder inhalers: comparison between Diskus, Turbuhaler, and Easyhaler.

A Phase IV, 4-week, open, randomized multicenter parallel group trial compared correct use and acceptability of Diskus, Turbuhaler, and Easyhaler powder inhalers among 326 inhaler naive asthmatics/symptomatics. The subjects were asked to read the instruction leaflet before taking one dose at the first visit. The correct use was evaluated when the subject took the dose. After that, the subjects were instructed in correct use. The use of the devices was also videotaped at every visit, and independent referees judged correct use. Acceptability was evaluated by a questionnaire. At the first visit, the proportions of subjects who used the devices correctly were as follows: Easyhaler, 45%; Diskus, 43%; and Turbuhaler, 51%. The corresponding figures at the last visit were 84%, 89%, and 81%. The differences at any visit were not statistically significant. Acceptability was greater for Easyhaler and Diskus for three of eight items throughout the study, all pertaining to receiving the powder from the device and control of the inhalation of the powder. Patient education in the use of devices is important, because only half of the subjects used the devices correctly, and still after 4 weeks 10-20% could not use the devices satisfactorily, regardless of which device.