Effect of Triple Therapy on Cardiovascular and Severe Cardiopulmonary Events in COPD: A Post-hoc Analysis of a Randomized, Double-Blind, Phase 3 Clinical Trial (ETHOS).

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with increased risk of cardiovascular and cardiopulmonary events. In the Phase III, 52-week ETHOS trial (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) reduced rates of moderate/severe exacerbations and all-cause mortality versus dual therapy with glycopyrrolate/formoterol fumarate (GFF) or budesonide/formoterol fumarate (BFF). However, the effect of BGF on cardiovascular events versus GFF remains unevaluated. Further, the effect of BGF on time to first severe exacerbation has not been reported. Objective: Assess the effects of BGF 320/18/9.6 µg (BGF 320) and other ICS-containing arms on cardiovascular and severe cardiopulmonary endpoints versus GFF in patients with COPD from ETHOS. Methods: Patients with moderate-to-very severe COPD and a history of exacerbations were randomized to twice-daily BGF 320, BGF 160/18/9.6 µg, BFF 320/9.6 µg, or GFF 18/9.6 µg (GFF). Time to first severe COPD exacerbation was a pre-specified endpoint; post-hoc cardiovascular and severe cardiopulmonary endpoints included time to first major adverse cardiac event (MACE), time to first cardiovascular adverse event (AE) of special interest (CVAESI), time to first cardiac AE, and time to the composite endpoint of first severe cardiopulmonary event. Measurements and Main Results: BGF 320 reduced the rate of first occurrence (hazard ratio [95% confidence interval]) of cardiovascular and severe cardiopulmonary events versus GFF, including for CVAESI (0.63 [0.48, 0.82]), cardiac AE (0.60 [0.48, 0.76]), and severe cardiopulmonary event (0.80 [0.67, 0.95]). Conclusions: BGF had a benefit on cardiovascular endpoints and severe cardiopulmonary events versus GFF in patients with moderate-to-very severe COPD.

Assessing health program performance in low- and middle-income countries: building a feasible, credible, and comprehensive framework.

BACKGROUND: Many health service delivery models are adapting health services to meet rising demand and evolving health burdens in low- and middle-income countries. While innovative private sector models provide potential benefits to health care delivery, the evidence base on the characteristics and impact of such approaches is limited. We have developed a performance measurement framework that provides credible (relevant aspects of performance), feasible (available data), and comparable (across different organizations) metrics that can be obtained for private health services organizations that operate in resource-constrained settings. METHODS: We synthesized existing frameworks to define credible measures. We then examined a purposive sample of 80 health organizations from the Center for Health Market Innovations (CHMI) database (healthmarketinnovations.org) to identify what the organizations reported about their programs (to determine feasibility of measurement) and what elements could be compared across the sample. RESULTS: The resulting measurement framework includes fourteen subgroups within three categories of health status, health access, and operations/delivery. CONCLUSIONS: The emphasis on credible, feasible, and comparable measures in the framework can assist funders, program managers, and researchers to support, manage, and evaluate the most promising strategies to improve access to effective health services. Although some of the criteria that the literature views as important - particularly population coverage, pro-poor targeting, and health outcomes - are less frequently reported, the overall comparison provides useful insights.

Positioning As-needed Budesonide-Formoterol for Mild Asthma: Effect of Prestudy Treatment in Pooled Analysis of SYGMA 1 and 2.

Rationale: The SYGMA (Symbicort Given as Needed in Mild Asthma) studies evaluated the efficacy and safety of as-needed budesonide (BUD)-formoterol (FORM) in patients whose asthma was uncontrolled on as-needed inhaled short-acting bronchodilators (subgroup 1) or controlled on inhaled corticosteroids (ICS) or leukotriene receptor antagonists (subgroup 2). Objectives: To assess the influence of prestudy treatment in a post hoc analysis of the SYGMA studies. Methods: In the SYGMA 1 (NCT022149199) and SYGMA 2 (NCT02224157) 52-week, double-blind, randomized, parallel-group studies, 6,735 patients with mild asthma were randomized to as-needed BUD-FORM, low-dose BUD + as-needed terbutaline (BUD maintenance), or as-needed terbutaline (SYGMA 1 only). Exacerbation rates and changes in symptom control and lung function were compared among treatments for both subgroups. Results: In a pooled analysis of SYGMA 1 and 2, the annual severe exacerbation rate in subgroup 1 was significantly lower with as-needed BUD-FORM (0.08 [95% confidence interval (CI), 0.06-0.10]) than with BUD maintenance (0.10 [95% CI, 0.09-0.13]) (rate ratio [RR], 0.74 [95% CI, 0.56-0.98]; P = 0.03), and similar results were shown in subgroup 2 with BUD-FORM (0.12 [95% CI, 0.10-0.14]) and BUD maintenance (0.10 [95% CI, 0.09-0.13]) (RR, 1.10 [95% CI, 0.86-1.41]; P = 0.44). In SYGMA 1, the annual severe exacerbation rate in both subgroups was significantly lower with as-needed BUD-FORM than with as-needed terbutaline (subgroup 1: RR, 0.34 [95% CI, 0.20-0.58]; P < 0.001; subgroup 2: RR, 0.37 [95% CI, 0.25-0.54]; P < 0.001). The number needed to treat to prevent one severe exacerbation with as-needed BUD-FORM and BUD maintenance versus as-needed terbutaline were 20 and 34 in subgroup 1 and 13 and 12 in subgroup 2, respectively. Conclusions: These findings suggest that, for patients with mild asthma currently receiving short-acting ß2-agonists alone, as-needed low-dose ICS-FORM should be preferred over maintenance ICS as initial controller treatment. For patients whose asthma is controlled on maintenance low-dose ICS, as-needed BUD-FORM is an alternative to maintenance ICS without the need for daily treatment, and both of these options are safer than switching to short-acting ß2-agonist-only treatment.

Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

BACKGROUND: The role of interleukin 13 in airway inflammation and remodelling in asthma is unclear. Tralokinumab is a human monoclonal antibody that neutralises interleukin 13. We aimed to evaluate whether tralokinumab would have an effect on airway eosinophilic infiltration, blood and sputum eosinophil concentrations, eosinophil activation, and airway remodelling. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 15 centres across the UK, Denmark, and Canada. We enrolled participants of either sex aged 18-75 years with inadequately controlled moderate-to-severe asthma for 12 months or more, requiring treatment with inhaled corticosteroids at a stable dose. We randomly assigned participants (1:1) to receive tralokinumab (300 mg) or placebo by an interactive web-based system or voice response system. Participants and study personnel were masked to treatment allocation. Both tralokinumab and placebo were administered subcutaneously every 2 weeks. The primary outcome measure was change from baseline to week 12 in bronchial biopsy eosinophil count. Secondary outcome measures included change in blood and sputum eosinophil counts. Exploratory outcomes included fractional exhaled nitric oxide (FENO) and blood IgE concentrations. Safety analyses were carried out in all participants who received study drug. This trial is registered with ClinicalTrials.gov, number NCT02449473, and with the European Clinical Trials Database, EudraCT 2015-000857-19. FINDINGS: Between Sept 25, 2015, and June 21, 2017, 224 participants were enrolled and screened. Of these participants, 79 were randomly assigned to receive tralokinumab (n=39) or placebo (n=40). Tralokinumab did not significantly affect bronchial eosinophil count compared with placebo at week 12 (treatment effect ratio 1·43, 95% CI 0·63-3·27; p=0·39). Compared with placebo, tralokinumab did not significantly affect blood eosinophil count (treatment effect ratio 1·21, 95% CI 1·00-1·48; p=0·055) or sputum eosinophil count (0·57, 0·06-6·00; p=0·63), but FENO concentration (0·78, 0·63-0·96; p=0·023) and total blood IgE concentration (0·86, 0·77-0·97; p=0·014) were significantly reduced. 33 (85%) of 39 patients receiving tralokinumab and 32 (80%) of 40 receiving placebo reported at least one adverse event during the treatment period. No deaths in either treatment group were observed. Treatment-related adverse events occurred more frequently in the tralokinumab group than in the placebo group (11 [28%] of 39 vs seven [18%] of 40). INTERPRETATION: Tralokinumab did not significantly affect eosinophilic inflammation in bronchial submucosa, blood, or sputum compared with placebo, but did reduce FENO and IgE concentrations. These results suggest interleukin 13 is not crucial for eosinophilic airway inflammation control in moderate-to-severe asthma. FUNDING: AstraZeneca.

Trans-national scale-up of services in global health.

BACKGROUND: Scaling up innovative healthcare programs offers a means to improve access, quality, and health equity across multiple health areas. Despite large numbers of promising projects, little is known about successful efforts to scale up. This study examines trans-national scale, whereby a program operates in two or more countries. Trans-national scale is a distinct measure that reflects opportunities to replicate healthcare programs in multiple countries, thereby providing services to broader populations. METHODS: Based on the Center for Health Market Innovations (CHMI) database of nearly 1200 health programs, the study contrasts 116 programs that have achieved trans-national scale with 1,068 single-country programs. Data was collected on the programs' health focus, service activity, legal status, and funding sources, as well as the programs' locations (rural v. urban emphasis), and founding year; differences are reported with statistical significance. FINDINGS: This analysis examines 116 programs that have achieved trans-national scale (TNS) across multiple disease areas and activity types. Compared to 1,068 single-country programs, we find that trans-nationally scaled programs are more donor-reliant; more likely to focus on targeted health needs such as HIV/AIDS, TB, malaria, or family planning rather than provide more comprehensive general care; and more likely to engage in activities that support healthcare services rather than provide direct clinical care. CONCLUSION: This work, based on a large data set of health programs, reports on trans-national scale with comparison to single-country programs. The work is a step towards understanding when programs are able to replicate their services as they attempt to expand health services for the poor across countries and health areas. A subset of these programs should be the subject of case studies to understand factors that affect the scaling process, particularly seeking to identify mechanisms that lead to improved health outcomes.

Early relief of osteoarthritis symptoms with a natural mineral supplement and a herbomineral combination: a randomized controlled trial [ISRCTN38432711].

BACKGROUND: This study was designed to determine if a natural mineral supplement, sierrasil, alone and in combination with a cat's claw extract (Uncaria guianensis), vincaria, has therapeutic potential in mild to moderate osteoarthritis of the knee. METHODS: Patients (n = 107) with mild to moderate osteoarthritis of the knee were randomly assigned to one of 4 groups; high dose sierrasil (3 g/day), low dose sierrasil (2 g/day), low dose sierrasil (2 g/day) + cat's claw extract (100 mg/day) or placebo, administered for 8 weeks. Treatment was double blinded. Primary efficacy variables were WOMAC scores (A, B, C and total). Visual analog score (VAS) for pain, consumption of rescue medication (paracetamol), and tolerability were secondary variables. Safety measures included vital signs and laboratory-based assays. RESULTS: Ninety-one of the 107 patients successfully completed the protocol. All four groups showed improvement in WOMAC and VAS scores after 8 weeks (p < 0.001), in all 3 groups receiving sierrasil the magnitude of benefits were greater vs. placebo (WOMAC Total 38-43% vs. 27%) but this was not statistically significant. In reference to baseline values sierrasil treated groups had a considerably faster onset of benefits. Placebo-treated individuals failed to show significant benefits at 4 weeks (11% reduction in total WOMAC). In contrast, after 1 or 2 weeks of therapy all the sierrasil groups displayed significant reductions in WOMAC scores (p < 0.05) and at week 4 displayed a 38-43% improvement. VAS was significantly improved at 4 weeks in all groups (p < 0.001) but was significantly greater in all sierrasil groups compared to placebo (p < 0.05). Rescue medication use was 28-23% lower in the herbomineral combination and high dose sierrasil groups although not statistically different from placebo (P = 0.101 and P = 0.193, respectively). Tolerability was good for all groups, no serious adverse events were noted and safety parameters remained unchanged. CONCLUSION: The natural mineral supplement, sierrasil alone and in combination with a cat's claw extract, improved joint health and function within 1-2 weeks of treatment but significant benefits over placebo were not sustained, possibly due to rescue medication masking. Sierrasil may offer an alternative therapy in subjects with joint pain and dysfunction.