The Gray Zone Feldman, Gregory
2019, 2019-01-08
eBook
Based on rare, in-depth fieldwork among an undercover police investigative team working in a southern EU maritime state, Gregory Feldman examines how taking action against human smuggling rings ...requires the team to enter the gray zone , a space where legal and policy prescriptions do not hold. Feldman asks how this seven-member team makes ethical judgments when they secretly investigate smugglers, traffickers, migrants, lawyers, shopkeepers, and many others. He asks readers to consider that gray zones create opportunities both to degrade subjects of investigations and to take unnecessary risks for them. Moving in either direction largely depends upon bureaucratic conditions and team members' willingness to see situations from a variety of perspectives. Feldman explores their personal experiences and daily work in order to crack open wider issues about sovereignty, action, ethics, and, ultimately, being human. Situated at the intersection of the EU migration apparatus and the global, clandestine networks it identifies as security threats, this book allows Feldman to outline an ethnographically-based theory of sovereign action.
Background Long-acting muscarinic antagonist (LAMA)/long-acting β2 -agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a ...LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate GP/formoterol FF 18/9.6-μg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD. Methods These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 μg, FF MDI 9.6 μg, or placebo MDI (all twice daily), or tiotropium 18 μg dry powder inhaler (once daily in PINNACLE-1 only open-label active comparator). Efficacy and safety were assessed. Results At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms). Conclusions We conclude that GFF MDI 18/9.6 μg demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD. Trial Registry ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658 ; URL: www.clinicaltrials.gov.
Introduction
We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β
2
-agonist (LAMA/LABA) combinations ...umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD.
Methods
This was a randomized, two-period crossover open-label study in symptomatic patients with COPD age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV
1
) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV
1
at week 8 with a noninferiority margin of − 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed.
Results
In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV
1
at week 8 FEV
1
change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28–77 mL);
p
< 0.001. Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV
1
at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34–3.14). Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group.
Conclusion
In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV
1
at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD. Both treatments had similar safety profiles. These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class.
Trial Registration
ClinicalTrials.gov identifier NCT02799784.
Funding
GlaxoSmithKline.
Olodaterol is a long-acting β2-agonist with a 24-hour bronchodilator profile. Two replicate, randomized, double-blind, placebo-controlled, parallel-group, Phase III trials were performed as part of a ...comprehensive clinical program to investigate the long-term safety and efficacy of olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) receiving usual-care background therapy.
Patients received olodaterol 5 μg or 10 μg or placebo once daily for 48 weeks. Coprimary end points were forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours (AUC0-3) response (change from baseline), and trough FEV1 response at 12 weeks. Secondary end points included additional lung function assessments, use of rescue medications, FEV1 AUC response from 0 to 12 hours, and Patient Global Rating over 48 weeks.
Overall, 624 and 642 patients were evaluated in studies 1222.11 and 1222.12, respectively. In both studies, olodaterol 5 μg and 10 μg significantly improved the FEV1 AUC0-3 response (P<0.0001) and trough FEV1 (study 1222.11, P<0.0001; study 1222.12, P<0.05, post hoc) at week 12, with an incidence of adverse events comparable with that of placebo. Secondary end points supported the efficacy of olodaterol.
These studies demonstrate the long-term efficacy and safety of once-daily olodaterol 5 μg and 10 μg in patients with moderate to very severe COPD continuing with usual-care maintenance therapy.
Toward an Anthropology of Public Policy Wedel, Janine R.; Shore, Cris; Feldman, Gregory ...
The Annals of the American Academy of Political and Social Science,
07/2005, Letnik:
600, Številka:
1
Journal Article
Recenzirano
As the rational choice model of "policy" proliferates in "policy studies," the social sciences, modern governments, organizations, and everyday life, a number of anthropologists are beginning to ...develop a body of work in the anthropology of public policy that critiques the assumptions of "policy" as a legal-rational way of getting things done. While de-masking the framing of public policy questions, an anthropological approach attempts to uncover the constellations of actors, activities, and influences that shape policy decisions, their implementation, and their results. In a rapidly changing world, anthropologists' empirical and ethnographic methods can show how policies actively create new categories of individuals to be governed. They also suggest that the long-established frameworks of "state" and "private," "local" or "national" and "global," "macro" and "macro," "top down" and "bottom up," and "centralized" and "decentralized" not only fail to capture current dynamics in the world but actually obfuscate the understanding of many policy processes.
The Phase III PINNACLE studies assessed the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), a dual long-acting bronchodilator for chronic obstructive ...pulmonary disease (COPD). Here we present a pre-specified pooled analysis of PINNACLE-1, PINNACLE-2, and PINNACLE-4.
PINNACLE-1, -2, and -4 were multicenter, double-blind, randomized controlled trials that enrolled patients with moderate-to-very severe COPD, with no requirement for exacerbation history or a high symptom burden. Patients received GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI, twice-daily for 24 weeks. The primary endpoint of the pooled analysis was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV
) at week 24. Secondary endpoints included COPD exacerbations and clinically important deterioration (CID). Adverse events were also assessed.
The pooled intent-to-treat population included 4983 patients; of these, 61.9% had a COPD assessment test (CAT) score ≥15, and 25.0% had experienced ≥1 moderate/severe exacerbation in the past year. At week 24, GFF MDI improved morning pre-dose trough FEV
versus GP MDI (least squares mean LSM difference 95% confidence interval (CI): 59 mL 43, 75), FF MDI (65 mL 48, 81), and placebo MDI (146 mL 125, 166); all p < 0.0001. GFF MDI reduced the risk of a moderate/severe exacerbation by 18% (p = 0.0168), 15% (p = 0.0628), and 28% (p = 0.0012) compared with GP MDI, FF MDI, and placebo MDI, respectively. In general, exacerbation risk reduction with GFF MDI versus comparators was greater in subgroups of symptomatic patients (CAT ≥15) and those who had an exacerbation history, than in the pooled intent-to-treat population. The risk of CID was also lower with GFF MDI versus GP MDI (23% decrease), FF MDI (17%), and placebo MDI (49%); all p < 0.0001. All treatments were well tolerated, with no unexpected safety signals.
This pooled analysis of the PINNACLE studies demonstrated that GFF MDI improved lung function and reduced the risk of exacerbations compared with monocomponents and placebo in patients with COPD. Exacerbation reductions with GFF MDI versus comparators were generally greater in patients with higher symptom burden and those with exacerbation history.
ClinicalTrials.gov NCT01854645, NCT01854658, and NCT02343458. Registered 13 May 2013 (NCT01854645, NCT01854658) and 6 January 2015 (NCT02343458).
Introduction
Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, is the only approved fixed-dose combination long-acting muscarinic ...antagonist/long-acting β
2
-agonist (LAMA/LABA) delivered via MDI. Direct comparisons of GFF MDI versus other LAMA/LABAs have not previously been performed. We assessed the efficacy and safety of GFF MDI relative to umeclidinium/vilanterol dry powder inhaler (UV DPI) in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD).
Methods
In this phase IIIb randomized, double-blind, double-dummy, multicenter, 24-week study, patients received GFF MDI 18/9.6 μg (equivalent to glycopyrronium/formoterol fumarate dihydrate 14.4/10 μg; two inhalations per dose, twice-daily;
n
= 559) or UV DPI 62.5/25 μg (one inhalation, once-daily;
n
= 560). Primary endpoints were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV
1
) and peak change from baseline in FEV
1
within 2 h post-dose, both over 24 weeks. Additional lung function, symptom and safety endpoints were also assessed.
Results
For the primary endpoints, GFF MDI was non-inferior to UV DPI (using a margin of − 50 mL) for peak FEV
1
(least squares mean LSM difference − 3.4 mL, 97.5% confidence interval CI − 32.8, 25.9) but not for trough FEV
1
(LSM difference − 87.2 mL; − 117.0, − 57.4). GFF MDI was nominally superior to UV DPI for onset of action (
p
< 0.0001) and was nominally non-inferior to UV DPI for all symptom endpoints (Transition Dyspnea Index focal score, Early Morning/Night-Time Symptoms COPD instrument scores, and COPD Assessment Test score). Exacerbation and safety findings were similar between groups.
Conclusions
Over 24 weeks of treatment, GFF MDI was non-inferior to UV DPI for peak FEV
1
, but not for morning pre-dose trough FEV
1
. GFF MDI had a faster onset of action versus UV DPI. There were no clinically meaningful differences between treatments in symptom endpoints. Both treatments were well tolerated with similar safety profiles.
Trial registration
NCT03162055 (Clinicaltrials.gov)
Funding
AstraZeneca
Chronic obstructive pulmonary disease (COPD) is a common disease in the general population and it places a considerable burden on patients, with the disease negatively affecting quality of life. In ...practice, patients with COPD generally seek medical attention because of symptoms, particularly breathlessness, and the resulting physical limitations, which affect the health-related quality of life (HR-QOL) in patients. The defining feature of COPD is airflow limitation that causes air trapping and increased hyperinflation as the ventilation rate increases during physical effort. Hyperinflation causes or worsens breathlessness as breathing becomes inefficient, with the end result being an avoidance of physical exertion and a cycle of increasing dyspnea caused by inactivity and deconditioning, with deleterious effects on HR-QOL. Current published guidelines for COPD state that the goals of pharmacologic therapy should be to control symptoms, improve health status and exercise tolerance, and reduce the frequency of COPD exacerbations. Effective and sustained bronchodilation has emerged as a key strategy for improving dyspnea and ability to exercise. As there is no cure for COPD, a major goal of treatment and of research into new therapies is to improve HR-QOL in COPD patients.
More recently, indacaterol, an inhaled ultra-long-acting β(2)-agonist (24-hour action), has been approved in many countries at different doses (between 75 and 300 μg once daily) for treatment of patients with stable but symptomatic COPD. The aim of this review was to explore once-daily indacaterol clinical data as related to improvement in HR-QOL in COPD. Indacaterol studies have shown significant improvements in lung function of COPD patients, and these improvements have also translated into clinically meaningful improvements in patient symptoms and HR-QOL.
Symptoms of chronic obstructive pulmonary disease may vary throughout the day and it is important that therapeutic approaches provide 24-h symptom control. We report the results of two phase IIIb ...crossover studies, PT003011 and PT003012, investigating the 24-h lung function profile of GFF MDI (glycopyrrolate/formoterol fumarate 18/9.6 μg delivered using innovative co-suspension delivery technology) administered twice daily.
Patients with moderate-to-very severe chronic obstructive pulmonary disease received 4 weeks' treatment with each of GFF MDI, placebo MDI, and open-label tiotropium (PT003011 only). Lung function was assessed over 24 h on day 29 of each treatment period. The primary outcome was forced expiratory volume in 1 second area under the curve from 0 to 24 h (FEV
AUC
). Other outcomes included change from baseline in average daily rescue medication use over the treatment period. In addition, we conducted a post-hoc analysis of data pooled from both studies to further characterize the effect of GFF MDI on inspiratory capacity.
GFF MDI treatment significantly increased FEV
AUC
versus placebo in studies PT003011 (n = 75) and PT003012 (n = 35) on day 29 (both studies p < 0.0001), with similar improvements in FEV
AUC versus placebo for hours 0-12 and 12-24. In PT003011, improvements with GFF MDI versus tiotropium in FEV
AUC were greater during hours 12-24 compared to 0-12 h. GFF MDI treatment also resulted in a significant reduction in rescue medication use versus placebo (-0.84 p<0.0001 and -1.11 p=0.0054 puffs/day in PT003011 and PT003012, respectively), and versus tiotropium in PT003011 (-0.44 p=0.017 puffs/day). A post-hoc pooled analysis showed patients treated with GFF MDI were more likely to achieve a >15% increase from baseline in inspiratory capacity than patients treated with placebo or tiotropium (72.1%, 19.0% and 47.0% of patients, respectively after the evening dose on day 29). There were no significant safety/tolerability findings.
GFF MDI significantly improved 24-h lung function versus placebo in patients with moderate-to-very severe chronic obstructive pulmonary disease, with similar benefits in the second 12-h period compared to the first, supporting twice-daily dosing of GFF MDI.
Pearl Therapeutics, Inc.; www.clinicaltrials.gov ; NCT02347072 and NCT02347085 . Registered 21 January 2015.
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