Μg Od Research Articles

Feasibility, safety and effectiveness of prednisolone and vitamin B1, B6, and B12 in patients with post-COVID-19-syndrome (PreVitaCOV) – protocol of a randomised, double-blind, placebo-controlled multicentre trial in primary care (phase IIIb)

BackgroundAfter infection with SARS-CoV-2 a relevant proportion of patients complains about persisting symptoms, a condition termed Post-COVID-19-syndrome (PC19S). So far, possible treatments are under investigation. Among others, neurotropic vitamins and anti-inflammatory substances are potential options. Thus, the PreVitaCOV trial aims to assess feasibility, safety, and effectiveness of treating patients in primary care with prednisolone and/or vitamin B1, B6 and B12.MethodsThe phase IIIb, multi-centre randomised, double-blind, and placebo-controlled PreVitaCOV trial has a factorial design and is planned as a two-phase approach. The pilot phase assessed feasibility and safety and was transformed into a confirmatory phase to evaluate effectiveness since feasibility was proven. Adult patients with PC19S after a documented SARS-CoV-2 infection at least 12 weeks ago are randomly assigned to 4 parallel treatments: prednisolone 20 mg for five days followed by 5 mg for 23 days (trial drug 1), B vitamins (B1 (100 mg OD), B6 (50 mg OD), and B12 (500 µg OD)) for 28 days (trial drug 2), trial drugs 1 and 2, or placebo. The primary outcome of the pilot phase was defined as the retention rate of the first 100 patients. Values of ≥ 85% were considered as confirmation of feasibility, this criterion was even surpassed by a retention rate of 98%. After transformation, the confirmatory phase proceeds by enrolling 240 additional patients. The primary outcome for the study is the change of symptom severity from baseline to day 28 as assessed by a tailored Patient Reported Outcomes Measurement Information System (PROMIS) total score referring to five symptom domains known to be typical for PC19S (fatigue, dyspnoea, cognition, anxiety, depression). The confirmatory trial is considered positive if superiority of any treatment is demonstrated over placebo operationalised by an improvement of at least 3 points on the PROMIS total score (t-score).DiscussionThe PreVitaCOV trial may contribute to the understanding of therapeutic approaches in PC19S in a primary care context.Trial registrationEudraCT: 2022-001041-20. DRKS: DRKS00029617. ClinicalTrials.gov: F001AM02222_1 (registered: 05 Dec 2022).

Efficacy, Safety, and Systemic Exposure of Once-Daily Indacaterol Acetate in Pediatric Asthma: A Randomized, Double-Blind, Controlled Dose-Finding Study.

Indacaterol acetate (IND), a long-acting β2-agonist in combination with mometasone furoate (MF), an inhaled corticosteroid (ICS), is being explored as a once-daily (od) treatment for asthma in children. This study examined the efficacy, safety, and systemic exposure of IND 75 µg and IND 150 µg in children with persistent asthma. In this Phase IIb, multicenter, randomized, double-blind, parallel-group study, pediatric patients (aged ≥6 to <12 years) with persistent asthma were randomized (1:1) to receive either IND 75 µg od or IND 150 µg od via Breezhaler® in combination with ICS background therapy. The primary endpoint was change from baseline in pre-dose trough forced expiratory volume in one second (FEV1) after two weeks of treatment. In total, 80 patients received IND 75 µg (n = 39) or IND 150 µg (n = 41). The study met its primary endpoint; both doses demonstrated improvements in pre-dose trough FEV1 from baseline to Day 14 (mean change [Δ]: 212 mL, IND 75 µg; 171 mL, IND 150 µg). The secondary spirometry parameters (post-dose FEV1 after 1-h, post-dose forced vital capacity; morning and evening peak expiratory flow) also improved. Overall, 36.1% in IND 75 μg group and 25% patients in IND 150 μg group achieved a decrease from baseline in Pediatric Interviewer-administered Asthma Control Questionnaire score of ≥0.5 units. A dose-dependent increase in plasma IND concentration was noted between the two groups. Both IND doses demonstrated an acceptable safety profile. Once-daily IND 75 μg and IND 150 μg via Breezhaler® in combination with background ICS therapy provided substantial bronchodilation in children with asthma and were well tolerated. Taken together, these clinical and systemic exposure findings support IND 75 μg as the most appropriate dose for evaluation in Phase III trials in combination with MF in pediatric asthma. ClinicalTrials.gov (NCT02892019; 08-Sep-2016).

Pharmacology Versus Convenience: A Benefit/Risk Analysis of Regular Maintenance Versus Infrequent or As-Needed Inhaled Corticosteroid Use in Mild Asthma.

IntroductionThis study compared the bronchoprotective and benefit/risk profiles of various inhaled corticosteroid (ICS) dosing regimens in mild asthma.MethodsA pharmacokinetic/pharmacodynamic model was developed and validated describing the relationship between ICS dose and time-course for airway bronchoprotection, [provocative concentration of adenosine monophosphate (AMP) causing ≥ 20% decline in forced expiratory volume in 1 s (FEV1) (AMP PC20)], for fluticasone furoate (FF), fluticasone propionate (FP) and budesonide (BUD). For regular ICS maintenance therapy (100% and 50% adherence) and infrequent or as-needed use (dosing 3–4 times per week), treatment effectiveness was expressed as percent time during 28 days when bronchoprotection exceeded either the threshold for a treatment-related bronchoprotective effect (AMP PC20 ≥ 0.25 doubling dose) or the threshold for a clinically significant bronchoprotective effect (AMP PC20 ≥ 1.0 doubling dose). This value was divided by the total ICS dose administered expressed in prednisolone equivalents to give a therapeutic index (TI).ResultsThe model-predicted time course of ICS-induced bronchoprotection with regular daily maintenance dosing and 100% adherence showed that all ICS at the highest recommended doses for mild asthma exceeded the threshold for clinically significant bronchoprotective effect for all or most of the 28-day dosing period, mean (90% CI); 100% (96.1–100), 99.9% (8.0–100) and 100% (58.2–100) with TI values of 16.9, 6.6 and 5.4 for FF 100 µg OD, FP 200 µg BID and BUD 200 µg BID, respectively. For simulated poor adherence (50%) to regular daily maintenance therapy, corresponding mean (90% CI) values were; 75.7% (39.4–89.1), 52.3% (0.7–69.2) and 51.3% (28.6–58.3) with TI values of 25.7, 6.9 and 5.6. For simulated infrequent/as needed use the corresponding values were; 77.0% (37.6–87.0), 25.5% (0.0–38.0) and 26.2% (14.3–31.5) with TI values of 26.1, 6.7 and 5.7. For all regimen/scenarios, FF had the most sustained efficacy and favourable TI followed by FP and BUD.ConclusionsAt doses recommended for mild asthma, all ICS regimens provide sustained bronchoprotective efficacy when dosed regularly with high adherence. With poor adherence or use 3–4 times per week (infrequent/as needed), longer-acting ICS molecules will more likely provide sustained protection and a better TI versus shorter duration of action molecules (FF > FP ≥ BUD). These data highlight the benefits of using ICS as regular daily maintenance dosing in mild asthma and the potential risks of under-treatment with ICS (which may occur with ICS/formoterol as-needed approach in mild persistent asthma) associated with reduced levels of bronchoprotection.

Hypothyroidism During Immune Checkpoint Inhibitor Therapy That Is Not Responsive to Thyroxin Substitution. A Peripheral T4-T3 Conversion Block?

Hypothyroidism is a frequently occurring side effect in patients under treatment with immune checkpoint inhibitors. Recently, we were confronted with three patients who were treated with a checkpoint inhibitor expressing clinically overt hypothyroidism that could not be corrected with progressive Thyroxin substitution. The first case, a 90 -year-old man with a solid low differentiated invasive urothelial carcinoma with multiple regional lymph node metastases (cT2N2M0) started with Pembrolizumab. Afterwards, TSH levels increased significantly (TSH 112 mU/l, n < 4.7 mU/l) with reduction in free T4 (1,6 pmol/l, n > 11.5 pmol/l)). L-thyroxine (T4) was started (50 μg OD). After a few weeks, he deteriorated with significantly elevated brain natriuretic peptide (BNP), heart failure (NYHA III). His therapeutic compliance was optimal. No absorption hindrance (diarrhoea or vomiting). His TSH levels remained elevated (103 mU/l). Subsequently, the T4 dose was increased to 100 μg once a day. Due to T4 ineffectiveness and, in parallel, life-threatening heart failure, Cytomel®️ (Liothyronine; T3) was started (12,5 μg twice a day). After two weeks, TSH normalized and in parallel BNP decreased. The second case, an 82-year-old man diagnosed with a non-small cell lung carcinoma (stage: type IIIb; T1bN3M0). Nivolumab was started and hypothyroidism developed (TSH 27 mU/l and fT4 11.3 pmol/l). T4 (50 µg once a day) was promptly started. Despite T4 substitution, TSH rose progressively (towards 51 mU/L), with a further decline in free T4 (8,7 pmol/l). T4 dose was increased to 75 µg OD. However, no beneficial effect was seen on TSH and fT4 levels. Due to our prior experience, Cytomel®️ (Liothyronine) 25 μg three times per day was added to T4 75 µg with a subsequent improvement in thyroid profile. The third case, a 76-year-old woman with low differentiated urothelial carcinoma with diffuse metastasis to liver, lung and bone marrow. After the initiation of pembrolizumab the patient developed hypothyroidism: TSH 52 mU/l and fT4 7.6 pmol/l. Therefore, T4 was started (50 µg daily). At the check-up, 2 months later, TSH rose further to 73.1 mU/l. In this patient, T3 was not started, due to no availability and entering palliative care. We described 3 cases with overt hypothyroidism after the start with immune checkpoint inhibitors unresponsive to thyroxin substitution. In literature, we did not find similar cases. Interestingly, after adding T3, a good clinical and biochemical response was obtained suggesting a peripheral T4-T3 conversion block. The mechanism behind is unknown, but we hypothesize an inhibiting effect of checkpoint inhibitors on expression/activity of tissue deiodinases, intrinsically being affected by a not yet elucidated mutation (heterozygous carriers). Our observation could give rise to novel clinical considerations for those patients successfully treated with immune checkpoint inhibitors.

Comparison of clinical outcomes of inhaled formoterol or fluticasone versus formoterol or mometasone in the patients of bronchial asthma

Background: This study was undertaken because of paucity of literature regarding outcomes of inhaled formeterol/fluticasone versus formoterol/mometasone in asthmatic patients.Methods: Fifty newly (male/female) recruited cases of bronchial asthma were diagnosed on the basis of spirometry. The patients were allocated to two groups viz group A and B. Group-A received mometasone furoate/formoterol (200/10 μg OD) and Group-B received fluticasone/formoterol (200/10 μg OD) respectively. The drugs were administered through metered-dose inhaler (MDI).Results: The mean FEV1/FVC ratio recorded (64.40±9.01) before starting the treatment has significantly changed to (68.92±8.58) after starting the treatment. Mean forced expiratory volume (47.56±14.73%) noted before the use of bronchodilator also changed to mean FEV1 63.98±15.17. Mean forced expiratory volume recorded before treatment (55.02±5.01) in a group who were treated with formoterol/mometasone combination changed to (72.06±5.86) after treatment. However, the mean forced expiratory volume recorded before treatment 54.92±4.47 in a group who were treated with formoterol/fluticasone combination changed to 75.48±5.03 after the treatment. While comparing the two treatment regimens, it is evident from the results that there is no significant difference in FEV1 between the groups. However, the post bronchodilator FEV1 was significantly (p&lt;0.001) higher among the patient group which were treated with fluticasone/formoterol combination than the group who were treated with mometasone/formoterol combination. No significant adverse effect of either of two regimens was observed thus showing that both the combinations are comparatively safe for use.Conclusions: This study reveals that both the treatment regimens showed a significant improvement in lung functions without any significant adverse event.

Study of efficacy and adverse effect of fluticasone and formoterol combination in bronchial asthma

Background: Bronchial asthma is a chronic inflammatory disorder of the airways associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing particularly at night or in the early morning.Methods: This study has recruited 25 newly (male/female) cases of Bronchial Asthma diagnosed on the basis of spirometry in the Department of Pulmonary Medicine, Era’s Lucknow Medical College &amp; Hospital (ELMC&amp;H). Patients were received Fluticasone/Formoterol (200/10 μg OD). The drugs were administered through metered-dose inhaler (MDI).Results: The mean forced expiratory volume recorded before treatment 54.92±4.47 in a group who were treated with formoterol/fluticasone combination changed to 75.48±5.03 after the treatment. No significant adverse effect of this regimens was observed.Conclusions: The results of this study revealed this regimen showed a significant improvement in lung functions without any significant adverse event.

Real-life effectiveness of indacaterol-glycopyrronium after switching from tiotropium or salmeterol/fluticasone therapy in patients with symptomatic COPD: the POWER study.

PurposeIn contrast to randomized controlled trials (RCTs), changes in maintenance pharmacotherapy in clinical practice occur without a washout period. The Prospective cohort study for the real-life effectiveness evaluation of glycOpyrronium With indacatERol combination in the management of COPD in Canada (POWER) study evaluated the real-life effectiveness of indacaterol/glycopyrronium (IND/GLY) following a direct switch from a long-acting muscarinic antagonist (LAMA, tiotropium) or long-acting β2-agonist (LABA)/inhaled corticosteroid (ICS) maintenance treatment (salmeterol/fluticasone [SFC]).MethodsPOWER was a single-cohort, prospective, multicenter, interventional study in which patients with moderate-to-severe COPD, who remained symptomatic on their current treatment of once-daily (od) tiotropium 18 µg or twice-daily (bid) SFC (any dose), were switched to treatment with open-label IND/GLY 110/50 µg od for 16 weeks. Effectiveness end points were change from baseline in trough FEV1, transition dyspnea index (TDI) total scores, and COPD assessment test (CAT) scores at 16 weeks.ResultsTrough FEV1 improved by 175 mL at Week 16 in patients who switched to IND/GLY. The change was 176 mL (95% CI: 135–217) when switched from tiotropium and 172 mL (95% CI: 85–258) when switched from SFC fixed-dose combination (FDC). At Week 16, significant improvements were observed in the mean TDI total scores (Δ=2.5) and CAT scores (Δ=−6.5) after the switch to IND/GLY treatment (both P<0.0001). Additionally, IND/GLY was well tolerated in patients with moderate-to-severe COPD, and no safety signal was observed.ConclusionIn clinical practice settings, a direct switch from previous treatment with either tiotropium or SFC to IND/GLY was safe and provided superior clinically significant improvements in lung function and patient-related outcomes in patients with moderate-to-severe COPD.Clinical trial registrationNCT02202616.

Comparative efficacy of long-acting β2-agonists as monotherapy for chronic obstructive pulmonary disease: a network meta-analysis.

PurposeLong-acting β2-agonists (LABAs) have demonstrated efficacy in patients with COPD in clinical trials. The purpose of this study was to assess the comparative efficacy of all available dosages of all LABA monotherapies using a network meta-analysis.MethodsA systematic literature review identified 33 randomized controlled trials of LABA monotherapies (salmeterol 50 μg twice daily [BID]; formoterol 12 μg BID; indacaterol 75, 150, and 300 μg once daily [OD]; olodaterol 5 and 10 μg OD, and vilanterol 25 μg OD). Clinical efficacy was evaluated at 12 and 24 weeks in terms of trough forced expiratory volume in 1 second (FEV1), transition dyspnea index focal score, St George’s Respiratory Questionnaire total score, and rate of COPD exacerbations. The relative effectiveness of all LABA monotherapies was estimated by Bayesian network meta-analysis.ResultsAt 12 and 24 weeks, indacaterol 300 and 150 μg OD were associated with statistically significant improvement in trough FEV1 compared to all other LABA monotherapies; vilanterol 25 μg OD was superior to formoterol 12 μg BID. At 12 weeks, indacaterol 75 μg OD was associated with significant improvement in trough FEV1 compared to formoterol 12 μg BID and olodaterol (5 and 10 μg OD); salmeterol 50 μg BID was superior to formoterol 12 μg BID and olodaterol 5 μg OD. Indacaterol 300 μg OD was also associated with significant improvement in transition dyspnea index focal score compared to all other LABAs at 12 or 24 weeks. Indacaterol 150 μg OD had significantly better results in exacerbation rates than olodaterol 5 μg and olodaterol 10 μg OD.ConclusionIndacaterol 300 μg, followed by 150 and 75 μg, were the most effective LABA monotherapies for moderate to severe COPD.

Efficacy and safety of once-daily glycopyrronium in predominantly Chinese patients with moderate-to-severe chronic obstructive pulmonary disease: the GLOW7 study [Corrigendum

BACKGROUND Glycopyrronium is a once-daily (od) long-acting muscarinic antagonist for the maintenance treatment of chronic obstructive pulmonary disease (COPD). The GLOW7 study evaluated the efficacy and safety of od glycopyrronium 50 μg in predominantly Chinese patients with moderate-to-severe COPD. METHODS In this 26-week, multi-center, double-blind, placebo-controlled, parallel-group study, men and women ≥40 years with moderate-to-severe COPD were randomized to glycopyrronium 50 μg od or placebo (2:1). The primary objective was to confirm the significant improvement of trough forced expiratory volume in 1 second (FEV1) following 12 weeks of treatment with glycopyrronium compared with placebo. Secondary objectives included the effect of glycopyrronium on health status (St George's Respiratory Questionnaire), breathlessness (Transition Dyspnea Index), other lung function parameters, rescue medication use, and COPD exacerbations. Safety and tolerability were also evaluated. RESULTS Of the 460 patients randomized, 459 were included in the full analysis set (glycopyrronium, n=306; placebo, n=154; mean age 64.7 years; mean post-bronchodilator FEV1: 50.8% predicted); 425 (92.4%) completed the study. At Week 12, glycopyrronium signifcantly improved trough FEV1 with a least square means treatment difference of 141 mL (95% confidence interval 111 mL, 171 mL; P<0.001) compared with placebo. The mean treatment effect of glycopyrronium was greater than the minimum clinically important difference versus placebo in both St George's Respiratory Questionnaire total score (-4.92; P<0.001) and Transition Dyspnea Index focal score (1.0; P<0.001) at week 26. Glycopyrronium reduced the risk of exacerbations in terms of time to first moderate or severe exacerbation by 28% (P=0.153) and rate of moderate or severe COPD exacerbation by 29% (P=0.119) compared with placebo. Incidence of death was 1.3% with glycopyrronium and 0% in placebo during the treatment period. Overall incidence of adverse events (glycopyrronium 43.6%; placebo 47.4%) and serious adverse events (glycopyrronium 5.6%; placebo 9.1%) were similar. CONCLUSION In predominantly Chinese patients with moderate-to-severe COPD, od glycopyrronium 50 μg significantly improved lung function, dyspnea, and health status compared with placebo. The safety and tolerability profile of glycopyrronium was comparable to placebo.

Efficacy and safety of once-daily glycopyrronium in predominantly Chinese patients with moderate-to-severe chronic obstructive pulmonary disease: the GLOW7 study.

BackgroundGlycopyrronium is a once-daily (od) long-acting muscarinic antagonist for the maintenance treatment of chronic obstructive pulmonary disease (COPD). The GLOW7 study evaluated the efficacy and safety of od glycopyrronium 50 μg in predominantly Chinese patients with moderate-to-severe COPD.MethodsIn this 26-week, multi-center, double-blind, placebo-controlled, parallel-group study, men and women ≥40 years with moderate-to-severe COPD were randomized to glycopyrronium 50 μg od or placebo (2:1). The primary objective was to confirm the significant improvement of trough forced expiratory volume in 1 second (FEV1) following 12 weeks of treatment with glycopyrronium compared with placebo. Secondary objectives included the effect of glycopyrronium on health status (St George’s Respiratory Questionnaire), breathlessness (Transition Dyspnea Index), other lung function parameters, rescue medication use, and COPD exacerbations. Safety and tolerability were also evaluated.ResultsOf the 460 patients randomized, 459 were included in the full analysis set (glycopyrronium, n=306; placebo, n=154; mean age 64.7 years; mean post-bronchodilator FEV1: 50.8% predicted); 425 (92.4%) completed the study. At Week 12, glycopyrronium signifcantly improved trough FEV1 with a least square means treatment difference of 141 mL (95% confidence interval 111 mL, 171 mL; P<0.001) compared with placebo. The mean treatment effect of glycopyrronium was greater than the minimum clinically important difference versus placebo in both St George’s Respiratory Questionnaire total score (−4.92; P<0.001) and Transition Dyspnea Index focal score (1.0; P<0.001) at week 26. Glycopyrronium reduced the risk of exacerbations in terms of time to first moderate or severe exacerbation by 28% (P=0.153) and rate of moderate or severe COPD exacerbation by 29% (P=0.119) compared with placebo. Incidence of death was 1.3% with glycopyrronium and 0% in placebo during the treatment period. Overall incidence of adverse events (glycopyrronium 43.6%; placebo 47.4%) and serious adverse events (glycopyrronium 5.6%; placebo 9.1%) were similar.ConclusionIn predominantly Chinese patients with moderate-to-severe COPD, od glycopyrronium 50 μg significantly improved lung function, dyspnea, and health status compared with placebo. The safety and tolerability profile of glycopyrronium was comparable to placebo.

Real‑life cost and cost‑effectiveness for tiotropium 18 μg od monotherapy in moderate and severe COPD patients: a 48‑month survey

BACKGROUND: Tiotropium monotherapy enables a significant minimization of morbidity in COPD. OBJECTIVE: to evaluate and compare cost and cost‑effectiveness of tiotropium monotherapy administrated for 24 months (18 μg od) in mild‑to‑moderate and severe chronic obstructive pulmonary disease (COPD). METHODS: Clinical outcomes (days in hospital; visits in general ward; cycles of systemic steroids; cycles of antibiotics and maintenance therapy drugs) were evaluated in two groups of patients corresponding to predicted FEV1 baseline values ≤ 50% (A) and &gt; 50% (B) from the Italian NHS perspective. In order to perform cost‑effectiveness analysis, FEV1 value, available for each patient, was converted in SGRQ score using a published multivariate linear model. Utilities were then obtained through the Ståhl equation. RESULTS: The comparison between 24 months of standard therapy and subsequent 24‑month period of tiotropium monotherapy showed that hospitalization cost, which represents the driving treatment cost, drops from 77% to 69% (A) and from 67% to 33% (B) of the total cost. Differently, maintenance therapy cost increased but the amount was more than offset by the savings accruing from the shortening of hospitalization. Furthermore, cost‑effectiveness results revealed a mean savings of about 216 € (A) and 961 € (B) other than a mean gain of 0.07 QALY (A) and 0.02 QALY (B). Dominance of tiotropium (calculated only within patients completing treatment course) revealed that in almost 29% (A) and 36% (B) of subjects tiotropium strategy is dominant while only in 2% (A) and 7% (B) of cases is associated to costs increment and worsening on quality of life. The dominance was systematic in severe COPD. Statistical analyses confirm such trend. CONCLUSIONS: Results of the present study suggest that tiotropium used as unique treatment in COPD systematically consents significant costs savings together with positive effects on evaluated quality. These effects prove proportional to COPD severity.

Economic evaluation of aclidinium bromide in the management of moderate to severe COPD: an analysis over 5 years.

PurposeAclidinium bromide is a long-acting muscarinic antagonistic used in maintenance treatment of chronic obstructive pulmonary disease (COPD). A model-based health economic study evaluated the cost-effectiveness of aclidinium 400 μg bid as an alternative to tiotropium 18 μg od for this indication in the US.Patients and methodsPatient characteristics in this model reflect those in the aclidinium clinical studies: age >40 years, stable moderate-to-severe COPD, current or ex-smokers (>10 pack-years), post-salbutamol forced expiratory volume in 1 second (FEV1) ≥30% and <80% of predicted normal value, and FEV1/forced vital capacity <70%. The model consists of five main health states indicating severity of COPD and the level of utility, resource use, and costs. Treatment efficacy over 5 years was modeled using FEV1% predicted; a network meta-analysis comparing aclidinium and tiotropium was used to estimate disease progression during the first 24 weeks, and results from the UPLIFT trial were used for time points after 24 weeks. Quality of life was assessed using utility scores in US patients from the UPLIFT trial. Cost-effectiveness was assessed as the incremental cost per quality-adjusted life year (QALY) gained.ResultsOver 5 years, QALYs were 3.50 for aclidinium versus 3.49 for tiotropium; life years accumulated were 4.52 for both. In this economic model, aclidinium versus tiotropium showed marginally fewer exacerbations (3.364 versus 3.390, respectively) and mean total health care costs (US$126,274 versus US$128,591, respectively). In all scenario analyses performed (discount factors of 0% and 6% for benefits and costs; time horizon of 1 year; mapping St George’s Respiratory Questionnaire to European Quality of Life–5 Dimensions; excluding pharmacy costs, COPD-related cost only; cost of exacerbations; including ACCORD II trial in the network meta-analysis), aclidinium was associated with lower costs and marginally greater QALYs versus tiotropium.ConclusionAclidinium is potentially cost-effective compared with tiotropium for maintenance treatment of moderate-to-severe COPD.

Efficacy and safety of fluticasone furoate 100 μg once-daily in patients with persistent asthma: A 24-week placebo and active-controlled randomised trial

Inhaled corticosteroids (ICSs) improve asthma disease control; once-daily ICS administration may have advantages for patients. Our objective was to assess the efficacy and safety of the novel ICS fluticasone furoate (FF) over 24 weeks versus placebo. This was a 24-week double-blind, double-dummy, placebo- and active-controlled study (NCT01159912) of 343 asthma patients (≥12 years) not controlled by their current ICS. Patients were randomised (1:1:1) to FF100μg, placebo (both administered once-daily [OD] via ELLIPTA™ dry powder inhaler in the evening) or fluticasone propionate (FP) 250μg (administered twice-daily (BD) via DISKUS™/ACCUHALER™). Primary endpoint was change from baseline in pre-dose evening forced expiratory volume in 1s (FEV1) at Week 24; change from baseline in % rescue-free 24-h periods was a powered secondary endpoint. Adverse events (AEs) were assessed. FF100μg OD and FP250μg BD significantly improved pre-dose evening FEV1 compared with placebo at Week 24 (+146ml [p=0.009] and +145ml [p=0.011], respectively). Percentage of rescue-free 24-h periods was increased with FF100μg OD (+14.8%) and FP250μg BD (+17.9%) compared to placebo (both p<0.001). On-treatment AEs were reported by 53% (FF100μg OD), 42% (FP250μg BD) and 40% (placebo) of patients. On-treatment severe asthma exacerbations were lower with FF100μg OD (3%) and FP250μg BD (2%) than placebo (7%). There was significant suppression of urinary cortisol at week 24 with FF100μg OD (p=0.030) and FP250μg BD (p=0.036) relative to placebo. FF100μg OD, administered in the evening, achieves significant improvements in lung function and rescue inhaler use over 24 weeks, comparable to FP250μg BD with similar safety profile.

PWE-028 Significantly Improved Abdominal Pain (AP) with Linaclotide (LIN) vs Placebo (PBO) in Patients (PTS) with Irritable Bowel Syndrome (IBS) Regardless of Baseline Pain Severity in 2 Phase 3 Trials

IntroductionLIN, a 14-amino-acid, minimally absorbed, guanylate cyclase C agonist (GCCA), significantly improved abdominal and bowel symptoms in 2 Phase 3 IBS with constipation (IBS-C) trials. Previous IBS trials of other...

Indacaterol on dyspnea in chronic obstructive pulmonary disease: a systematic review and meta-analysis of randomized placebo-controlled trials.

BackgroundIndacaterol is a novel, once-daily (od), inhaled, long-acting ß2-agonist bronchodilator for maintenance treatment of airflow limitation in patients with COPD. The aim of this study was to evaluate the efficacy of indacaterol on dyspnea, using available randomized placebo-controlled trials.MethodsA systematic search was made of MEDLINE, EMBASE, the Cochrane trials databases, and a manual search of journals. Randomized placebo-controlled trials of 12 weeks or more comparing indacaterol with placebo were reviewed, and eligible studies were included in a meta-analysis. The odds ratio (OR) for likelihood of achieving TDI score ≥ 1 after 12 weeks of treatment was used as an outcome measure to compare indacaterol to placebo.ResultsSix trials were included in the analysis. Relative to placebo, the overall ORs for response were: indacaterol 75 μg od 1.784 (95% CI 1.282 to 2.482); indacaterol 150 μg od 2.149 (95% CI 1.746 to 2.645); and indacaterol 300 μg od 2.458 (95% CI 2.010 to 3.006). Overall OR for response in TDI tended to increase with higher indacaterol doses.ConclusionsPatients receiving indacaterol had clinically significant improvements in symptoms of dyspnea compared to placebo. Incremental benefits in TDI were observed with increasing doses. Indacaterol may provide patients and physicians with a useful treatment option in symptomatic patients with dyspnea.

Profiling the bronchodilator effects of the novel ultra-long-acting β2-agonist indacaterol against established treatments in chronic obstructive pulmonary disease

Indacaterol is a novel, inhaled, ultra-long-acting β(2)-agonist providing 24-h bronchodilation with once-daily (od) dosing for maintenance use in patients with chronic obstructive pulmonary disease (COPD). This article reviews the bronchodilator properties of indacaterol compared with other treatments used in COPD. Data from five published placebo-controlled studies were reviewed. Two 14-day crossover studies, the first comparing indacaterol 300 µg od with salmeterol 50 µg twice daily (bid), the second comparing indacaterol 150 µg and 300 µg od with tiotropium 18 µg od, assessed forced expiratory volume in 1 s (FEV(1)) at 24 h postdose (trough). Third, a 14-day crossover study evaluated trough FEV(1) following indacaterol 300 µg dosed morning or evening compared with salmeterol 50 µg bid. Fourth, a single-dose study of indacaterol 150 and 300 µg measured FEV(1) at 5 min postdose compared with salmeterol/fluticasone 50/500 µg and salbutamol 200 µg. Finally, data from a 1-year study with indacaterol 300 µg and formoterol 12 µg bid were examined to determine whether bronchodilation was maintained long term. In the first two studies, indacaterol increased trough FEV(1) after 14 days by a statistically significant and clinically relevant margin over placebo; indacaterol had a greater effect than salmeterol and a similar effect to tiotropium. In the third study, indacaterol had the same effect on trough FEV(1) whether dosed in the morning or evening. In the fourth study, the onset of the bronchodilator effect of indacaterol was similar to that of salbutamol. In the fifth study, the bronchodilator effect of indacaterol on trough FEV(1) was maintained at a significant and clinically relevant level over 52 weeks, whereas the bronchodilator effect of formoterol diminished over time. To conclude, indacaterol is a highly effective bronchodilator that is superior to or at least as effective as other available long-acting bronchodilators for COPD.

Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design

Background The drug development process can be streamlined by combining the traditionally separate stages of dose-finding (Phase IIb) and confirmation of efficacy and safety (Phase III) using an adaptive seamless design. This approach was used in a clinical study of indacaterol, a novel once-daily (od) inhaled long-acting β 2-adrenoreceptor agonist bronchodilator for the treatment of COPD (chronic obstructive pulmonary disease). Methods The study comprised a dose-finding stage with dose selection after 14 days of treatment, and a second stage evaluating efficacy and safety during 26 weeks of treatment. The dose-finding stage included seven randomized treatment arms: double-blind indacaterol 75 μg, 150 μg, 300 μg or 600 μg od, the β 2-adrenoceptor agonist formoterol 12 μg twice-daily or placebo, or the anticholinergic tiotropium 18 μg od open-label. An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician. The sponsor, investigators and patients remained blinded to the results. The indacaterol doses were selected using pre-set efficacy criteria for trough (24-h post-dose) and early (1–4 h post-dose) bronchodilator effect after 14 days, and all safety data. To qualify for selection, the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol, whichever was the highest value. Selected doses were continued into the second, 26-week stage. The two other indacaterol doses not selected, and formoterol, were discontinued following dose selection. Results 801 patients with moderate-to-severe COPD were evaluated. Indacaterol 150 μg was the lowest effective dose, exceeding criteria for trough FEV 1 (reference value 140 mL vs placebo) and FEV 1 AUC 1–4h (reference value 220 mL vs placebo). No safety signal was observed with any dose of indacaterol. Thus, indacaterol 150 and 300 μg were selected to continue into the second, 26-week stage. Conclusion The adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial.

Dose-ranging study of fluticasone furoate nasal spray for Japanese patients with perennial allergic rhinitis

ABSTRACTBackground: This study was designed to evaluate the efficacy and safety of fluticasone furoate nasal spray (FFNS), a novel enhanced-affinity intranasal corticosteroid, in Japanese patients with perennial allergic rhinitis (PAR), and to determine the optimal dose.Methods: In this phase II, multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-ranging study, 240 patients (aged ≥ 16 years) received once-daily (od) treatment for 2 weeks with either FFNS 110 μg (n = 80), 220 μg (n = 81) or placebo (n = 79). Patients evaluated 3 nasal symptoms using a 4-point scale. Efficacy was assessed as the mean change from baseline in total nasal symptom score (TNSS).Results: Treatment with FFNS resulted in a significantly greater decrease over the treatment period in the mean 3TNSS (sneezing, rhinorrhea, and nasal congestion; p < 0.001 each dose vs. placebo), compared with placebo. More patients receiving FFNS had a markedly or moderately improved impression of treatment than placebo recipients (48% and 49% for FFNS 110 μg and 220 μg, respectively, vs. 18% for placebo; p < 0.001). Nasal rhinoscopy findings revealed significant improvements in mucosal swelling of the inferior turbinate (110 μg: p = 0.004; 220 μg: p = 0.011) and amount of watery rhinorrhea (110 μg: p = 0.003; 220 μg: p < 0.001), compared with placebo. Both doses of FFNS were well tolerated.Conclusions: Both FFNS 110 µg and 220 µg od were effective in alleviating nasal symptoms in Japanese patients with PAR over the 2-week duration of this study. FFNS 110 µg od was selected as the optimal dose for further evaluation in phase III clinical trials.