Long-term safety of glycopyrrolate: A randomized study in patients with moderate-to-severe COPD (GEM3)

AbstractBackgroundChronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the United States. Long-acting muscarinic antagonists (LAMAs) are a class of medications used as maintenance therapy for COPD. The GEM3 (Glycopyrrolate Effect on syMptoms and lung function) study assessed the long-term safety and efficacy of a LAMA, glycopyrrolate (GLY) 15.6 μg twice daily (b.i.d.), compared with an approved long-acting β2-agonist (LABA), indacaterol (IND) 75 μg once daily (q.d.) in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation.MethodsThis 52-week, multicenter, double-blind, parallel-group study randomized patients (1:1) of the United States to receive GLY 15.6 μg b.i.d. or IND 75 μg q.d. both delivered via the Neohaler® device. The primary objective was to assess the safety and tolerability in terms of adverse event (AE) reporting rates over 52 weeks. Safety was also determined by evaluating multiple secondary endpoints, including vital signs, electrocardiograms (ECGs), and time to first moderate or severe exacerbation. Efficacy-related secondary endpoints included pre-dose forced expiratory volume in one second (FEV1) and forced vital capacity (FVC).ResultsOf the 511 randomized patients (GLY, n = 254; IND, n = 257), 81.6% completed the study. The overall incidences of AEs (GLY, 77.3%; IND, 77.0%) and serious AEs (GLY, 13.1%; IND, 13.3%) were comparable between the groups. The incidence of major adverse cardiovascular events was low and comparable between the groups. No clinically relevant differences for vital signs or ECG parameters were observed between the treatment groups. The three sudden deaths reported within 30 days of the treatment (GLY, n = 2; IND, n = 1) were adjudicated as unrelated to the study medication. In terms of efficacy, GLY 15.6 μg b.i.d. showed improvements in pre-dose FEV1 and FVC from baseline, which was comparable to those with IND 75 μg q.d., with no statistically significant differences. No significant differences were observed between the treatment groups in the time to first moderate or severe COPD exacerbation.ConclusionGLY 15.6 μg b.i.d. showed a long-term safety profile comparable to that of IND 75 μg q.d. and provided rapid and sustained bronchodilation over 52 weeks in patients with COPD with moderate-to-severe airflow limitation.Clinical trial registration numberNCT01697696

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Cambodian Monk with Malaise

A 26 year-old Cambodian monk presents with complaintsof a three week history of fatigue and malaise. The patientreports that four days prior to presentation he developedfevers to 103F, chills and a severe headache. The patientreports that he had returned from Cambodia one weekprior to initiation of symptoms. He denies any sickcontacts and denies any neck stiffness, photophobia,visual changes or abdominal pain. The patient does reportdiarrhea for one week with approximately 8-10 bowelmovements per day. The patient denies any risk factorsfor HIV. The patient had been seen in the EmergencyDepartment one day prior to admission. His temperaturewas 102F, pulse was 110 beats per minute, respirationswere 20 breaths per minute and blood pressure was110/80mm Hg. A lumbar puncture was performed,blood cultures and stool cultures were sent. The patientwas discharged with a prescription for Percocet

An exploration of clinical, behavioral, and community factors associated with sleep duration and efficiency among middle-aged Black/African American smokers

Study objectives: We examined the most important correlates to sleep duration and efficiency from a comprehensive array of multilevel factors. Methods: Baseline data from a cohort of 216 Black/African American smokers aged 40-65 years were examined. The binary outcomes of healthy sleep duration (6-8 h/night) and efficiency (≥85%) were ascertained from 14 consecutive days of actigraphy. Seventy-three independent variables from socio-demographic, individual behavioral, individual physiological, interpersonal, and community domains were assessed. Random survival forest decision trees were generated for each outcome, and variable importance metrics used to rank the predictive abilities of exposure variables. The 5 most predictive exposure variables for each outcome were entered into a regression model of the respective outcome (with age and sex). Results: Study participants (N = 216) had a mean age of 54.57 years (SD = 6.17) and 57% were male. Healthy sleep duration was achieved by 56.5% and healthy sleep efficiency by 13.6% of the sample. Regression models showed every additional minute of light physical activity was associated with 1% increased odds, while every unit decrease in the inflammation marker of interleukin-8 was associated with 12% increased odds, of achieving a healthy sleep duration. Every unit increase in total social support was associated with a 34% increased odds, while every unit increase in the hazardous drinking score corresponded with 30% decreased odds, of achieving healthy sleep efficiency. Conclusions: Light physical activity, social support, and alcohol consumption may be key modifiable intervention targets to improving sleep duration and sleep efficiency in this population.National Institute on Drug Abuse12 month embargo; first published online 16 March 2021This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Concordance in caregiver and child sleep health metrics among families experiencing socioeconomic disadvantage: A pilot study

Purpose: Child and caregiver sleep occurs in a family system, with socioeconomically disadvantaged families experiencing disproportionately worse sleep health than more advantaged families. The extent to which objectively measured sleep health metrics (i.e., sleep duration, midpoint, regularity, efficiency) are concordant within disadvantaged family systems, including caregiver-child dyads, is not clear. To address this gap, this study aimed to: (1) characterize sleep health metrics and (2) identify levels of sleep health concordance among caregiver-child dyads living in families experiencing socioeconomic disadvantage. Design and methods: We enrolled 20 caregivers and 26 children in this micro-longitudinal study. Eligible primary caregivers slept in the same house as the child ≥4 nights/week and had no sleep disorders. Eligible children were aged 6-14 years and reported no medical problems. Dyads wore an actigraphy device continuously for 14 consecutive days. Sleep duration, bedtime, midpoint, and efficiency were estimated, and concordance evaluated using linear mixed modeling (R v.3.5.2). Results: Most caregivers were female (85%), Non-Hispanic Black (80%), and aged 40.45 years (SD=11.82). On average, caregivers were not meeting national recommendations for sleep duration and efficiency. Similarly, sleep duration recommendations were not met by child participants. Bivariate results showed that bedtime =0.19, p\u3c.001), sleep efficiency (=0.24, p\u3c.001), and sleep midpoint (=0.39, p\u3c.001), were concordant between child and caregiver. Multivariable models showed that caregiver bedtime was predictive of child sleep midpoint (b=0.16, p\u3c.05), and caregiver sleep midpoint was predictive of child bedtime (b=0.29, p\u3c.01) and child sleep midpoint (b=0.31, p\u3c.001). Conclusion: Objectively estimated caregiver sleep may be connected to the sleep timing of their children. Improving child sleep may require addressing caregiver sleep habits too. Practice Implications: Results highlight the importance of providers considering caregiver sleep health when assessing child sleep health during well child visits

The Long-Term Oxygen Treatment Trial for Chronic Obstructive Pulmonary Disease: Rationale, Design, and Lessons Learned

The Long-Term Oxygen Treatment Trial demonstrated that long-term supplemental oxygen did not reduce time to hospital admission or death for patients who have stable chronic obstructive pulmonary disease and resting and/or exercise-induced moderate oxyhemoglobin desaturation, nor did it provide benefit for any other outcome measured in the trial. Nine months after initiation of patient screening, after randomization of 34 patients to treatment, a trial design amendment broadened the eligible population, expanded the primary outcome, and reduced the goal sample size. Within a few years, the protocol underwent minor modifications, and a second trial design amendment lowered the required sample size because of lower than expected treatment group crossover rates. After 5.5 years of recruitment, the trial met its amended sample size goal, and 1 year later, it achieved its follow-up goal. The process of publishing the trial results brought renewed scrutiny of the study design and the amendments. This article expands on the previously published design and methods information, provides the rationale for the amendments, and gives insight into the investigators' decisions about trial conduct. The story of the Long-Term Oxygen Treatment Trial may assist investigators in future trials, especially those that seek to assess the efficacy and safety of long-term oxygen therapy. Clinical trial registered with clinicaltrials.gov (NCT00692198)