Anti-KIT antibody, barzolvolimab, reduces skin mast cells and disease activity in chronic inducible urticaria.

BACKGROUND: Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)-mediated wheals in response to triggers: cold in cold urticaria (ColdU) and friction in symptomatic dermographism (SD). KIT receptor activation by stem cell factor (SCF) is essential for MC function. Barzolvolimab (CDX-0159) is a humanized antibody that inhibits KIT activation by SCF and was well tolerated in healthy volunteers with dose-dependent plasma tryptase suppression indicative of systemic mast cell ablation. METHODS: This is an open-label, trial in patients with antihistamine refractory ColdU or SD, receiving one IV dose of barzolvolimab (3 mg/kg), with a 12-week follow-up. Primary endpoint was safety/tolerability; pharmacodynamic (PD)/clinical endpoints included serum tryptase, plasma SCF, skin MC histology, provocation tests, urticaria control test (UCT), and dermatology life quality index (DLQI). RESULTS: Analysis populations were safety (n = 21) and pharmacodynamics/clinical activity (n = 20). Barzolvolimab was well tolerated; most adverse events were mild and resolved. Treatment resulted in significant depletion of skin MCs, decreased tryptase (

Streamlining Safety Data Collection in Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Trials: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team.

BACKGROUND: Resistant bacteria are one of the leading causes of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). HABP/VABP trials are complex and difficult to conduct due to the large number of medical procedures, adverse events, and concomitant medications involved. Differences in the legislative frameworks between different regions of the world may also lead to excessive data collection. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development (ABDD) by streamlining clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. METHODS: In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with current data collection processes. Experts defined "data collection" as the act of capturing and reporting certain data on the case report form as opposed to recording of data as part of routine clinical care. The ABDD Project Team developed strategies for streamlining safety data collection in HABP/VABP trials using a Quality by Design approach. RESULTS: Current safety data collection processes in HABP/VABP trials often include extraneous information. More targeted strategies for safety data collection in HABP/VABP trials will rely on optimal protocol design and prespecification of which safety data are essential to satisfy regulatory reporting requirements. CONCLUSIONS: A consensus and a cultural change in clinical trial design and conduct, which involve recognition of the need for more efficient data collection, are urgently needed to advance ABDD and to improve HABP/VABP trials in particular.

Improving Conduct and Feasibility of Clinical Trials to Evaluate Antibacterial Drugs to Treat Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team.

BACKGROUND: The etiology of hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) is often multidrug-resistant infections. The evaluation of new antibacterial drugs for efficacy in this population is important, as many antibacterial drugs have demonstrated limitations when studied in this population. HABP/VABP trials are expensive and challenging to conduct due to protocol complexity and low patient enrollment, among other factors. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development by streamlining HABP/VABP clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. METHODS: In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with HABP/VABP protocol complexity. The Project Team developed potential solutions to streamline HABP/VABP trials using a Quality by Design approach. RESULTS: CTTI recommendations focus on 4 key areas to improve HABP/VABP trials: informed consent processes/practices, protocol design, choice of an institutional review board (IRB), and trial outcomes. Informed consent processes should include legally authorized representatives. Protocol design decisions should focus on eligibility criteria, prestudy antibacterial therapy considerations, use of new diagnostics, and sample size. CTTI recommends that sponsors use a central IRB and discuss trial endpoints with regulators, including defining a clinical failure and evaluating the impact of concomitant antibacterial drugs. CONCLUSIONS: Streamlining HABP/VABP trials by addressing key protocol elements can improve trial startup and patient recruitment/retention, reduce trial complexity and costs, and ensure patient safety while advancing antibacterial drug development.

Good Clinical Practice Training: Identifying Key Elements and Strategies for Increasing Training Efficiency.

Good Clinical Practice (GCP) is an international standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials. The goal of GCP is to ensure the protection of the rights, integrity, and confidentiality of clinical trial participants and to ensure the credibility and accuracy of data and reported results. In the United States, trial sponsors generally require investigators to complete GCP training prior to participating in each clinical trial to foster GCP and as a method to meet regulatory expectations (ie, sponsor's responsibility to select qualified investigators per 21 CFR 312.50 and 312.53(a) for drugs and biologics and 21 CFR 812.40 and 812.43(a) for medical devices). This training requirement is often extended to investigative site staff, as deemed relevant by the sponsor, institution, or investigator. Those who participate in multiple clinical trials are often required by sponsors to complete repeated GCP training, which is unnecessarily burdensome. The Clinical Trials Transformation Initiative convened a multidisciplinary project team involving partners from academia, industry, other researchers and research staff, and government to develop recommendations for streamlining current GCP training practices. Recommendations drafted by the project team, including the minimum key training elements, frequency, format, and evidence of training completion, were presented to a broad group of experts to foster discussion of the current issues and to seek consensus on proposed solutions.

Marijuana Use Among Patients With Glaucoma in a City With Legalized Medical Marijuana Use.

IMPORTANCE: Previous research has shown several limitations associated with the use of marijuana as a treatment for glaucoma. However, little is known regarding patients' perceptions toward using marijuana for glaucoma and their intentions to use this therapeutic alternative. OBJECTIVE: To identify factors among patients with glaucoma that could lead to intentions to use marijuana for treatment. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional survey study of 204 patients with glaucoma or suspected to have glaucoma was conducted at an academic-based glaucoma clinic in Washington, DC, between February 1 and July 31, 2013. Patients completed a self-administered survey assessing demographics, perceived severity of glaucoma, prior knowledge about marijuana use in glaucoma, past marijuana use, perceptions toward marijuana use (legality, systemic adverse effects, safety and effectiveness, and false beliefs), satisfaction with current glaucoma management, relevance of treatment costs, and intentions to use marijuana for glaucoma. Medical records were reviewed for disease severity. Data analysis was conducted from September 1, 2013, to September 30, 2015. MAIN OUTCOMES AND MEASURES: The main outcome was patients' intentions to use marijuana for glaucoma. Multiple linear regression analysis was conducted to identify factors associated with patients' intentions to use marijuana for glaucoma. RESULTS: Of the 334 patients who were invited to participate in the study, 204 (61.1%) completed the survey. About half the participants were women (104 [51.0]%), and 82 (40.2%) were white. Regression analysis of 204 respondents indicated that perceptions of legality of marijuana use (ß, 0.378; 95% CI, 0.205 to 0.444; P < .001), false beliefs regarding marijuana (ß, 0.323; 95% CI, 0.236 to 0.504; P < .001), satisfaction with current glaucoma care (ß, -0.222; 95% CI, -0.362 to -0.128; P < .001), and relevance of marijuana and glaucoma treatment costs (ß, 0.127; 95% CI, 0.008 to 0.210; P = .04) were significantly associated with intentions to use marijuana for glaucoma treatment after controlling for demographic variables, disease severity, and previous marijuana use. CONCLUSIONS AND RELEVANCE: This study's findings suggest a need for more education on this topic for ophthalmologists to be able to protect patients with glaucoma against the increased acceptability among the public of using marijuana based on false perceptions of its therapeutic value in glaucoma therapy. Considering the strong influence of perceptions of the legality of marijuana use on intentions to use this substance as a treatment for glaucoma, patient education might be particularly relevant in states in which marijuana use for glaucoma is legal, as in the case of the current study's setting.

Respiratory Tract Infection Clinical Trials from 2007 to 2012. A Systematic Review of ClinicalTrials.gov.

RATIONALE: Respiratory tract infections are highly prevalent and variable, and confer considerable morbidity and mortality. There is a growing need for new treatments for such infections, particularly in the setting of worsening antibacterial resistance. OBJECTIVES: We analyzed data from ClinicalTrials.gov to summarize activity in respiratory infection trials, identify gaps in research activity, and inform efforts to address disparities between antimicrobial resistance and development of new antibacterial drugs. METHODS: We examined 69,779 interventional trials registered with ClinicalTrials.gov from 2007 to 2012, focusing on study conditions and interventions to identify respiratory infection-related trials. Programmatic identification with manual confirmation yielded 6,253 infectious disease trials, 1,377 respiratory infection trials, and 270 lower respiratory tract infection trials for analysis. MEASUREMENTS AND MAIN RESULTS: The 1,377 respiratory infection trials accounted for 2% of all trials and 22% of infectious diseases trials. Such trials (54.8%) were more likely than either nonrespiratory infectious diseases trials (48.1%) or noninfectious disease trials (42.8%) to receive industry funding. Stratification of respiratory infection trials by registration year demonstrated declining industry funding: 181 (64.9%) in 2007-2008 to 110 (46.0%) in 2011-2012. Respiratory infection trials more frequently evaluated vaccines (52.7 vs. 15.5% of nonrespiratory tract infection trials). Lower respiratory tract infection trials (excluding tuberculosis) focused primarily on bacterial pathogens (78.5%) followed by viral (12.6%), fungal (5.6%), and nontuberculous mycobacterial (3.0%) pathogens. Approximately 40% of 120 lower respiratory tract infection trials that were completed or terminated published results in the literature. On multivariable logistic regression analysis, a treatment focus was associated with decreased odds of publishing results (odds ratio, 0.28; 95% confidence interval, 0.10-0.82; P = 0.02). There were also generally low numbers of studies evaluating novel antimicrobial agents (community-acquired pneumonia, 15.9%; hospital-acquired pneumonia, 16.7%; ventilator-associated pneumonia, 5.3%). CONCLUSIONS: From 2007 to 2012, respiratory infection trials did not occur in numbers commensurate with global impact. The number of trials registered per year did not increase throughout the study period, partly due to declining industry support. There was a concerning reduction in prevention-oriented lower respiratory infection trials and an overall low number of such trials involving novel antimicrobials.

Indirect cyclopexy for treatment of a chronic traumatic cyclodialysis cleft with hypotony.

Cyclodialysis cleft is a rare clinical finding and therefore, reports on surgical repair techniques in the literature are limited. Additionally, hypotony can make repair technically challenging. We share a novel, simple surgical approach to management of a case of chronic traumatic cyclodialysis cleft with a successful outcome.

Structure and clinical significance of central optic disc pits.

OBJECTIVE: To assess the structure of central optic disc pits (ODPs) using enhanced-depth imaging optical coherence tomography (EDI OCT) and to ascertain their clinical significance. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Patients with an ophthalmoscopically visible central ODP in either eye, irrespective of accompanying ocular disease, were enrolled from the neuro-ophthalmology and glaucoma referral practices. Each subject with a central ODP was matched with 2 healthy subjects with normal-appearing optic disc within 5 years of age. METHODS: Each participant received a complete ophthalmologic examination including standard automated perimetry, retinal nerve fiber layer (RNFL) thickness measurement by OCT, and serial horizontal and vertical cross-sectional EDI OCT of the optic nerve head. MAIN OUTCOME MEASURES: Structure of the lamina cribrosa (LC) in relation to the central ODP in EDI OCT images. RESULTS: Eighteen eyes (13 subjects) with a central ODP and 52 healthy eyes (26 controls) were included. Four eyes (2 subjects) with a central ODP were otherwise normal with intact macula, neuroretinal rim, RNFL, and visual field. Fourteen eyes (11 subjects) with a central ODP had glaucoma with glaucomatous neuroretinal rim thinning, RNFL loss, and corresponding visual field defect. No eye had associated maculopathy. On EDI OCT, the central ODP corresponded with a full-thickness defect in the LC center with no serous retinal detachment or herniation of neural tissue through the LC defect. Central ODPs were separated from (type 1) or merged with (type 2) the LC opening for the central retinal vascular trunk. In control eyes, no LC defect was detected. CONCLUSIONS: Central ODPs are full-thickness LC defects unassociated with maculopathy and different from glaucomatous acquired pits of the optic nerve, which represent focal laminar defect adjacent to the disc edge.

Enhanced depth imaging optical coherence tomography of optic nerve head drusen.

OBJECTIVE: To assess the value of enhanced depth imaging optical coherence tomography (EDI OCT) in diagnosing and evaluating optic nerve head drusen (ONHD) compared with conventional diagnostic methods. DESIGN: Prospective, comparative, cross-sectional study. PARTICIPANTS: Thirty-four patients with clinically visible or suspected ONHD in either eye based on dilated optic disc examination or optic disc stereophotography and without ocular comorbidity. METHODS: Spectral-domain OCT of the optic nerve head in both conventional (non-EDI) and EDI modes, ultrasound B-scan, and standard automated perimetry were performed on both eyes of all participants. MAIN OUTCOME MEASURES: Detection and findings of ONHD between EDI OCT and conventional diagnostic methods. RESULTS: Sixty-eight eyes were clinically classified into 3 groups: 32 eyes with definite ONHD, 25 eyes with suspected ONHD, and 11 normal-appearing fellow eyes. In the definite ONHD group, EDI OCT, non-EDI OCT, and ultrasound B-scan were positive for ONHD in all eyes and visual field (VF) was abnormal in 24 eyes. In the suspected ONHD group, EDI OCT, non-EDI OCT, ultrasound B-scan, and VF were positive in 17, 14, 7, and 3 eyes, respectively; 8 eyes had no evidence of ONHD in any of the tests. In normal-appearing fellow eyes, EDI OCT, non-EDI OCT, ultrasound B-scan, and VF were positive in 3, 1, 1, and 0 eyes, respectively; 4 eyes had no evidence of ONHD in any of the tests. Enhanced depth imaging OCT had a significantly higher ONHD detection rate than ultrasound B-scan in all eyes (52/68 eyes vs. 40/68 eyes; P<0.001), in eyes with clinically suspected ONHD or normal-appearing fellow eyes (20/36 eyes vs. 8/36 eyes; P<0.001), and in eyes with clinically suspected ONHD (17/25 eyes vs. 7/25 eyes; P = 0.002). Enhanced depth imaging OCT-detected ONHD appeared as signal-poor regions surrounded by short, hyper-reflective bands or isolated/clustered hyper-reflective bands without a signal-poor core. In non-EDI OCT, posterior surfaces of the ONHD and deep-seated hyper-reflective bands were invisible or less clear than in EDI OCT. CONCLUSIONS: Enhanced depth imaging OCT detects lesions likely representing ONHD more often and better assesses their shape and structure than conventional tests.

Rifaximin treatment in hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS: Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)

Parents of children with periodic limb movement disorder versus sleep-disordered breathing report greater daytime mood and behavior difficulties in their child: the importance of using ICSD-2nd Edition criteria to define a PLMD study group.

Data from 249 children referred to a pediatric sleep clinic were analyzed. The first question of interest examined whether an International Classification of Sleep Disorders-Second Edition (ICSD-2)-based diagnosis of periodic limb movement disorder (PLMD) or sleep-disordered breathing (SDB) would more strongly associate with parental perceptions of daytime attention and behavior problems in their child. The second question was whether the outcome would differ based on PLMD diagnostic criteria-that is, previously used criteria to define PLMD (Periodic Limb Movement Index [PLMI] < 5 per hour vs. PLMI >or= 5 per hour only) versus the ICSD-2 criteria. Parents of children with ICSD-2-defined PLMD perceived more problems with daytime behavior and attention, more symptoms of internalizing and externalizing, longer sleep latency, and more difficulty falling back to sleep than did parents of children with SDB. Most effects were lost when groups were defined by PLMI alone. The PLMI had acceptable sensitivity but low specificity in diagnosing PLMD.

A short-term comparison of fluticasone propionate/salmeterol with ipratropium bromide/albuterol for the treatment of COPD.

BACKGROUND: This is the first comparison of two combination therapies, fluticasone propionate/salmeterol and ipratropium bromide/albuterol (salbutamol), for the treatment of patients with COPD. METHODS: A randomized, double-blind, double-dummy, parallel group, multicenter evaluation of fluticasone propionate/salmeterol 250/50 microg twice daily via DISKUS and ipratropium bromide/albuterol 36/206 microg four times daily via metered-dose inhaler over 8 weeks was conducted at 41 research sites in the US. Morning pre-dose FEV(1), 6-hour serial spirometry, PEF, dyspnea, night-time awakenings, supplemental albuterol use, and patient diary evaluations of symptoms were evaluated. RESULTS: A total of 365 patients with symptomatic COPD were enrolled. The treatment groups were similar in mean age (63.3 and 63.9 years), screening pulmonary function (44.1% and 43.2% of predicted FEV(1)), race (96% and 95% White), and sex distribution (59% and 60% male). Both fluticasone propionate/salmeterol and ipratropium bromide/albuterol improved lung function, symptoms, and supplemental albuterol use compared with baseline. Fluticasone propionate/salmeterol was more effective than ipratropium bromide/albuterol for improvement in morning pre-dose FEV(1), morning PEF, 6-hour FEV(1) area under the curve (AUC(6)), Transition Dyspnea Index (TDI) focal score, daytime symptom score, night-time awakenings, sleep symptoms, and albuterol-free nights (p < or = 0.013). Compared with day 1, at week 8 the FEV(1) AUC(6) significantly increased with fluticasone propionate/salmeterol and significantly decreased with ipratropium bromide/albuterol (p < or = 0.003). The incidence of adverse events was similar between treatment groups, except for a higher incidence of oral candidiasis with fluticasone propionate/salmeterol. CONCLUSIONS: Short-term treatment with the combined inhaled corticosteroid and long-acting beta(2)-adrenoceptor agonist fluticasone propionate/salmeterol resulted in greater control of lung function and symptoms than combined ipratropium bromide/albuterol bronchodilator therapy, in patients with COPD.

Patient perceptions of an inhaled asthma medication administered as an inhalation powder via the Diskus or as an inhalation aerosol via a metered-dose inhaler.

OBJECTIVE: To evaluate patient preference, ease of use, and correctness of use of fluticasone propionate administered as inhalation powder via the Diskus (GlaxoSmithKline, Research Triangle Park, NC) and as inhalation aerosol administered via metered-dose inhaler (MDI). METHODS: In 154 patients 12 years of age and older with asthma and a history of MDI use, the Diskus and the MDI were compared in a randomized, open-label, 7-week crossover study. RESULTS: In patients who had used both devices, more found the Diskus easier to use (59%) and preferred it overall (60%) compared with the MDI (P < or = 0.025). Ninety-eight percent (for the MDI) vs 91% (for the Diskus) of patients were able to correctly perform all the maneuvers necessary to use the devices correctly by either viewing a single demonstration and/or reading the instructions for use. Ninety-four percent of all patients found it easier to tell the number of residual doses with the Diskus (P < 0.001), and 59% of patients indicated that they would most likely request the Diskus from their physician (P = 0.025). Compliance was significantly better with the Diskus; 91.1% of patients used the Diskus as directed compared with 78.6% for the MDI (P = 0.013). CONCLUSIONS: In patients exposed to both devices, the majority preferred the Diskus and found it easier to use compared with the MDI. Ninety-one percent of patients used the Diskus correctly with minimal training, and when given a choice, most indicated they would likely request the Diskus from their physicians. Together, these data indicate a significant level of acceptance of the Diskus device in this patient population.

OxyR: a molecular code for redox-related signaling.

Redox regulation has been perceived as a simple on-off switch in proteins (corresponding to reduced and oxidized states). Using the transcription factor OxyR as a model, we have generated, in vitro, several stable, posttranslational modifications of the single regulatory thiol (SH), including S-NO, S-OH, and S-SG, and shown that each occurs in vivo. These modified forms of OxyR are transcriptionally active but differ in structure, cooperative properties, DNA binding affinity, and promoter activities. OxyR can thus process different redox-related signals into distinct transcriptional responses. More generally, our data suggest a code for redox control through which allosteric proteins can subserve either graded (cooperative) or maximal (noncooperative) responses, and through which differential responsivity to redox-related signals can be achieved.