The Effectiveness of Mindfulness in the Treatment of Methamphetamine Addiction Symptoms: Does Neuroplasticity Play a Role?

INTRODUCTION: Methamphetamine is a highly stimulating psychoactive drug that causes life-threatening addictions and affects millions of people around the world. Its effects on the brain are complex and include disturbances in the neurotransmitter systems and neurotoxicity. There are several known treatment methods, but their effectiveness is moderate. It must be emphasised that no drugs have been approved for treatment. For this reason, there is an urgent need to develop new, effective, and safe treatments for methamphetamine. One of the potential treatments is mindfulness meditation. In recent years, this technique has been researched extensively in the context of many neurological and psychiatric disorders. METHODS: This review explores the use of mindfulness in the treatment of methamphetamine addiction. Searches were conducted in the PubMed/Medline, Research Gate, and Cochrane databases. RESULTS: Ten studies were identified that used mindfulness-based interventions in the treatment of methamphetamine addiction. The results show that mindfulness is an effective form of reducing hunger, risk of relapses, stress indicators, depression, and aggression, alone or in combination with transcranial direct current stimulation (tDCS). Mindfulness also improved the cognitive function in addicts. The included studies used only behavioural measures. The potential mechanisms of mindfulness in addiction were explained, and it was proposed that it can induce neuroplasticity, alleviating the symptoms of addiction. CONCLUSIONS: Evidence from the studies suggest that mindfulness may be an effective treatment option for methamphetamine addiction, used alone or in combination with tDCS. However, further high-quality research is required to establish the role of this treatment option in this field. The use of neuroimaging and neurophysiological measures is fundamental to understand the mechanisms of mindfulness.

Effect of Transcranial Direct Current Stimulation (tDCS) on Depression in Parkinson's Disease-A Narrative Review.

INTRODUCTION: Depression is the most prevalent comorbid neuropsychiatric condition in individuals with Parkinson's disease (PD), and its underlying mechanisms are not yet fully understood. Current treatment methods are characterised by moderate effectiveness and possible side effects, prompting the search for new non-invasive and safe treatment methods. METHODS: This narrative review explores the use of transcranial direct current stimulation (tDCS) in the treatment of depression in PD, based on neuropsychological measures. Searches were conducted in the PubMed/Medline, Research Gate, and Cochrane databases. RESULTS: Nine relevant studies were identified, where depression scores served as either primary or secondary outcomes. Stimulation protocols displayed heterogeneity, especially concerning choice of stimulation site. Patient samples were also heterogeneous. The majority of the studies incorporated anodal stimulation targeting the left dorsolateral prefrontal cortex (DLPFC). The results revealed a reduction in depression scores among PD patients following tDCS. Potential mechanisms through which tDCS may alleviate depression in PD were discussed and recommendations for future research were made. CONCLUSIONS: Preliminary evidence suggests that tDCS applied anodally to the left DLPFC reduces depression scores in people with PD; however, due to the heterogeneity of the studies analysed, the use of tDCS in this field should be approached with caution and warrants further validation and confirmation.

EEG in Down Syndrome-A Review and Insights into Potential Neural Mechanisms.

Introduction: Down syndrome (DS) stands out as one of the most prevalent genetic disorders, imposing a significant burden on both society and the healthcare system. Scientists are making efforts to understand the neural mechanisms behind the pathophysiology of this disorder. Among the valuable methods for studying these mechanisms is electroencephalography (EEG), a non-invasive technique that measures the brain's electrical activity, characterised by its excellent temporal resolution. This review aims to consolidate studies examining EEG usage in individuals with DS. The objective was to identify shared elements of disrupted EEG activity and, crucially, to elucidate the neural mechanisms underpinning these deviations. Searches were conducted on Pubmed/Medline, Research Gate, and Cochrane databases. Results: The literature search yielded 17 relevant articles. Despite the significant time span, small sample size, and overall heterogeneity of the included studies, three common features of aberrant EEG activity in people with DS were found. Potential mechanisms for this altered activity were delineated. Conclusions: The studies included in this review show altered EEG activity in people with DS compared to the control group. To bolster these current findings, future investigations with larger sample sizes are imperative.

Nasal airway inflammatory responses and pathogen detection in infants with cystic fibrosis.

BACKGROUND: Detecting airway inflammation non-invasively in infants with cystic fibrosis (CF) is difficult. We hypothesized that markers of inflammation in CF [IL-1ß, IL-6, IL-8, IL-10, IL-17A, neutrophil elastase (NE) and tumor necrosis factor (TNF-α)] could be measured in infants with CF from nasal fluid and would be elevated during viral infections or clinician-defined pulmonary exacerbations (PEx). METHODS: We collected nasal fluid, nasal swabs, and hair samples from 34 infants with CF during monthly clinic visits, sick visits, and hospitalizations. Nasal fluid was isolated and analyzed for cytokines. Respiratory viral detection on nasal swabs was performed using the Luminex NxTAG® Respiratory Pathogen Panel. Hair samples were analyzed for nicotine concentration by reverse-phase high-performance liquid chromatography. We compared nasal cytokine concentrations between the presence and absence of detected respiratory viruses, PEx, and smoke exposure. RESULTS: A total of 246 samples were analyzed. Compared to measurements in the absence of respiratory viruses, mean concentrations of IL-6, IL-8, TNF-α, and NE were significantly increased while IL-17A was significantly decreased in infants positive for respiratory viruses. IL-17A was significantly decreased and NE increased in those with a PEx. IL-8 and NE were significantly increased in infants with enteric pathogen positivity on airway cultures, but not P. aeruginosa or S. aureus. Compared to those with no smoke exposure, there were significantly higher levels of IL-6, IL-10, and NE in infants with detectable levels of nicotine. CONCLUSIONS: Noninvasive collection of nasal fluid may identify inflammation in infants with CF during changing clinical or environmental exposures.

The Effect of Transcranial Direct Current Stimulation (tDCS) on Anorexia Nervosa: A Narrative Review.

(1) Introduction: Anorexia nervosa (AN) is a severe, debilitating disease with high incidence and high mortality. The methods of treatment used so far are moderately effective. Evidence from neuroimaging studies helps to design modern methods of therapy. One of them is transcranial direct current stimulation (tDCS), a non-invasive brain neuromodulation technique. (2) Methods: The purpose of this narrative review is to bring together all studies investigating the use of tDCS in the treatment of AN and to evaluate its effect and efficiency. Searches were conducted in the Pubmed/Medline, Research Gate, and Cochrane databases. (3) Results: The literature search resulted in five articles. These studies provide preliminary evidence that tDCS has the potential to alter eating behaviour, body weight, and food intake. Additionally, tDCS reduced symptoms of depression. Throughout all trials, stimulation targeted the left dorsolateral prefrontal cortex (DLPFC). Although the number of studies included is limited, attempts were made to elucidate the potential mechanisms underlying tDCS action in individuals with AN. Recommendations for future tDCS research in AN were issued. (4) Conclusions: The included studies have shown that tDCS stimulation of the left DLPFC has a positive effect on AN clinical symptoms and may improve them, as measured by various assessment measures. It is important to conduct more in-depth research on the potential benefits of using tDCS for treating AN. This should entail well-designed studies incorporating advanced neuroimaging techniques, such as fMRI. The aim is to gain a better understanding of how tDCS works in AN.

The Effect of Transcranial Direct Current Stimulation (tDCS) on Cocaine Addiction: A Narrative Review.

Cocaine addiction is a significant problem worldwide. The development of addiction involves a reward system, which consists of certain brain regions like the ventral tegmental area, nucleus accumbens, and prefrontal cortex. Currently, there are no approved medications for treating cocaine dependence, so researchers are actively searching for effective treatments that can impact the brain. One potential treatment under investigation is transcranial direct current stimulation (tDCS), a non-invasive method of stimulating the brain to modulate its activity. In this review, we explore the use of tDCS in treating cocaine addiction. We found nine relevant articles via a literature search, and the results indicate that applying tDCS to the right dorsolateral prefrontal cortex (DLPFC) holds promise for reducing drug cravings in individuals with cocaine addiction. The review also discusses the possible mechanisms by which tDCS works and provides recommendations for future research in this field.

Human Mesenchymal Stem Cell (hMSC) Donor Potency Selection for the "First in Cystic Fibrosis" Phase I Clinical Trial (CEASE-CF).

Human Mesenchymal Stem Cell (hMSC) immunotherapy has been shown to provide both anti-inflammatory and anti-microbial effectiveness in a variety of diseases. The clinical potency of hMSCs is based upon an initial direct hMSC effect on the pro-inflammatory and anti-microbial pathophysiology as well as sustained potency through orchestrating the host immunity to optimize the resolution of infection and tissue damage. Cystic fibrosis (CF) patients suffer from a lung disease characterized by excessive inflammation and chronic infection as well as a variety of other systemic anomalies associated with the consequences of abnormal cystic fibrosis transmembrane conductance regulator (CFTR) function. The application of hMSC immunotherapy to the CF clinical armamentarium is important even in the era of modulators when patients with an established disease still need anti-inflammatory and anti-microbial therapies. Additionally, people with CF mutations not addressed by current modulator resources need anti-inflammation and anti-infection management. Furthermore, hMSCs possess dynamic therapeutic properties, but the potency of their products is highly variable with respect to their anti-inflammatory and anti-microbial effects. Due to the variability of hMSC products, we utilized standardized in vitro and in vivo models to select hMSC donor preparations with the greatest potential for clinical efficacy. The models that were used recapitulate many of the pathophysiologic outcomes associated with CF. We applied this strategy in pursuit of identifying the optimal donor to utilize for the "First in CF" Phase I clinical trial of hMSCs as an immunotherapy and anti-microbial therapy for people with cystic fibrosis. The hMSCs screened in this study demonstrated significant diversity in antimicrobial and anti-inflammatory function using models which mimic some aspects of CF infection and inflammation. However, the variability in activity between in vitro potency and in vivo effectiveness continues to be refined. Future studies require and in-depth pursuit of hMSC molecular signatures that ultimately predict the capacity of hMSCs to function in the clinical setting.

Immunoreactive Trypsinogen in Infants Born to Women with Cystic Fibrosis Taking Elexacaftor-Tezacaftor-Ivacaftor.

Most people with cystic fibrosis (CF) are diagnosed following abnormal newborn screening (NBS), which begins with measurement of immunoreactive trypsinogen (IRT) values. A case report found low concentrations of IRT in an infant with CF exposed to the CF transmembrane conductance regulator (CFTR) modulator, elexacaftor-tezacaftor-ivacaftor (ETI), in utero. However, IRT values in infants born to mothers taking ETI have not been systematically assessed. We hypothesized that ETI-exposed infants have lower IRT values than newborns with CF, CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID), or CF carriers. IRT values were collected from infants born in Indiana between 1 January 2020, and 2 June 2022, with ≥1 CFTR mutation. IRT values were compared to infants born to mothers with CF taking ETI followed at our institution. Compared to infants identified with CF (n = 51), CRMS/CFSPID (n = 21), and CF carriers (n = 489), ETI-exposed infants (n = 19) had lower IRT values (p < 0.001). Infants with normal NBS results for CF had similar median (interquartile range) IRT values, 22.5 (16.8, 30.6) ng/mL, as ETI-exposed infants, 18.9 (15.2, 26.5). IRT values from ETI-exposed infants were lower than for infants with abnormal NBS for CF. We recommend that NBS programs consider performing CFTR variant analysis for all ETI-exposed infants.

A phase I study assessing the safety and tolerability of allogeneic mesenchymal stem cell infusion in adults with cystic fibrosis.

BACKGROUND: Mesenchymal stem cells are of particular interest in cystic fibrosis (CF) as a potential therapeutic. Data from pre-clinical studies suggest that allogeneic bone marrow-derived human mesenchymal stem cells (hMSCs) may provide a new therapeutic treatment for CF lung disease by attenuating pulmonary inflammation while decreasing bacterial growth and enhancing antibiotic efficacy. METHODS: Fifteen adults with CF were enrolled in a phase 1 dose-escalation trial of a single intravenous infusion of hMSCs derived from bone marrow aspirates obtained from a single pre-clinically validated healthy volunteer donor. The study employed a 3+3 dose escalation design with subjects receiving a single, intravenous dose of either 1×106, 3×106, or 5×106 hMSCs/kg. Subjects were monitored inpatient for 24 hours and by outpatient visits and telephone calls for 12 months after the infusion. Safety and tolerability were evaluated by monitoring symptoms, patient reported outcome questionnaires, adverse events (AEs), physical exam findings, spirometry, and analyses of safety laboratories. Preliminary evidence for potential efficacy using inflammatory markers in the blood and sputum were also evaluated. RESULTS: No dose-limiting toxicities, deaths or life-threatening adverse events were observed. Most AEs and serious adverse events (SAEs) were consistent with underlying CF. Vital signs, physical exam findings, spirometry and safety laboratory results showed no significant change from baseline. No trends over time were seen in serum or sputum inflammatory markers nor with clinical spirometry. CONCLUSION: Allogeneic hMSC intravenous infusions were safe and well-tolerated in this phase 1 study and warrant additional clinical testing as a potential therapeutic for CF lung disease.

Testing the effects of combining azithromycin with inhaled tobramycin for P. aeruginosa in cystic fibrosis: a randomised, controlled clinical trial.

RATIONALE: Inhaled tobramycin and oral azithromycin are common chronic therapies in people with cystic fibrosis and Pseudomonas aeruginosa airway infection. Some studies have shown that azithromycin can reduce the ability of tobramycin to kill P. aeruginosa. This trial was done to test the effects of combining azithromycin with inhaled tobramycin on clinical and microbiological outcomes in people already using inhaled tobramycin. We theorised that those randomised to placebo (no azithromycin) would have greater improvement in forced expiratory volume in one second (FEV1) and greater reduction in P. aeruginosa sputum in response to tobramycin. METHODS: A 6-week prospective, randomised, placebo-controlled, double-blind trial testing oral azithromycin versus placebo combined with clinically prescribed inhaled tobramycin in individuals with cystic fibrosis and P. aeruginosa airway infection. RESULTS: Over a 6-week period, including 4 weeks of inhaled tobramycin, the relative change in FEV1 did not statistically significantly differ between groups (azithromycin (n=56) minus placebo (n=52) difference: 3.44%; 95% CI: -0.48 to 7.35; p=0.085). Differences in secondary clinical outcomes, including patient-reported symptom scores, weight and need for additional antibiotics, did not significantly differ. Among the 29 azithromycin and 35 placebo participants providing paired sputum samples, the 6-week change in P. aeruginosa density differed in favour of the placebo group (difference: 0.75 log10 CFU/mL; 95% CI: 0.03 to 1.47; p=0.043). CONCLUSIONS: Despite having greater reduction in P. aeruginosa density in participants able to provide sputum samples, participants randomised to placebo with inhaled tobramycin did not experience significantly greater improvements in lung function or other clinical outcomes compared with those randomised to azithromycin with tobramycin.

Somatic cell hemoglobin modulates nitrogen oxide metabolism in the human airway epithelium.

Endothelial hemoglobin (Hb)α regulates endothelial nitric oxide synthase (eNOS) biochemistry. We hypothesized that Hb could also be expressed and biochemically active in the ciliated human airway epithelium. Primary human airway epithelial cells, cultured at air-liquid interface (ALI), were obtained by clinical airway brushings or from explanted lungs. Human airway Hb mRNA data were from publically available databases; or from RT-PCR. Hb proteins were identified by immunoprecipitation, immunoblot, immunohistochemistry, immunofluorescence and liquid chromatography- mass spectrometry. Viral vectors were used to alter Hbß expression. Heme and nitrogen oxides were measured colorimetrically. Hb mRNA was expressed in human ciliated epithelial cells. Heme proteins (Hbα, ß, and δ) were detected in ALI cultures by several methods. Higher levels of airway epithelial Hbß gene expression were associated with lower FEV1 in asthma. Both Hbß knockdown and overexpression affected cell morphology. Hbß and eNOS were apically colocalized. Binding heme with CO decreased extracellular accumulation of nitrogen oxides. Human airway epithelial cells express Hb. Higher levels of Hbß gene expression were associated with airflow obstruction. Hbß and eNOS were colocalized in ciliated cells, and heme affected oxidation of the NOS product. Epithelial Hb expression may be relevant to human airways diseases.

Early-Life Height Attainment in Cystic Fibrosis Is Associated with Pulmonary Function at Age 6 Years.

Rationale: In contrast to the well-described association between early-life weight for age, body mass index (BMI), and later lung disease in people with cystic fibrosis (CF), the relationship between height-for-age (HFA) percentiles and respiratory morbidity is not as well-studied. We hypothesized that changes in HFA in children with CF in the first 6 years of life would be associated with pulmonary function at the age of 6-7 years. Objectives: To determine if an association exists between changes in HFA in early life and pulmonary function in school-aged children with CF. Methods: We performed a retrospective longitudinal cohort study of children with CF followed in the CF Foundation Patient Registry who were born between 2003 and 2010, had CF diagnosed before the age of 2 years, and were followed through at least the age of 7 years. Changes in annualized HFA were classified into mutually exclusive categories. Multivariable analysis of covariance models were used to test for an association between the percent-predicted forced expiratory volume in 1 second (FEV1) at the age of 6-7 years and height-trajectory categories. Results: There were 5,388 eligible children in the CF Foundation Patient Registry. The median (interquartile range) HFA at the age of 6-7 years was in the 39.5th (17.2th-64.9th) percentile. The mean (95% confidence interval) FEV1% predicted at the age of 6-7 years was 95.6% (95.1-96.1%). In a multivariable regression model, the mean (95% confidence interval) FEV1% predicted was higher for children with HFA that was always above the 50th percentile (97.8% [96.3-99.4%]) than for children whose height had been below the 50th percentile for at least 1 year and increased by ≥10 percentile points (95.1% [93.7-96.6%]), was stable (94.3% [92.8-95.7%]), or decreased by ≥10 percentile points (95.7% [94.2-97.3%]). The association between HFA categories and FEV1% predicted was not affected by adding the mean annualized BMI percentile at the age of 6-7 years to the regression model. Among those with HFA that decreased by ≥10 percentile points, there was a correlation between the nadir annualized HFA percentile and the FEV1% predicted at the age of 6-7 years. Conclusions: Children with CF with HFA that is always above the 50th percentile have the highest pulmonary function at the age of 6-7 years. Maintaining a BMI above the 50th percentile remains an important achievable goal for children with CF but is not the sole marker that should be examined in evaluating nutrition.

Drug development for cystic fibrosis.

The first regulatory approval for a drug developed specifically for cystic fibrosis (CF) occurred in 1993, and since then, several other drugs have been approved. Median predicted survival in people with CF in the United States has increased from approximately 30 years to 44.4 years over that same period. Highly effective modulators of the cystic fibrosis transmembrane conductance regulator became available to approximately 90% of people with CF ages 12 years and older in the United States in 2019 and in Europe in 2020. These transformative therapies will surely reduce morbidity and further extend longevity. The drug development pipeline is filled with therapies that address most aspects of CF disease. As survival and CF therapies advance, and the complexity of CF care increases, the process of drug development has become more sophisticated. In addition, detecting meaningful changes in outcome measures has become more difficult as the health status of people with CF improves. Innovative approaches are required to continue to advance drug development in CF. This review provides a general overview of drug development from the preclinical phase through Phase IV. Special considerations with respect to CF are integrated into the discussion of each phase of drug development. As CF care evolves, drug development must continue to evolve as well, until a one-time cure is available to all people with CF.

Safety and efficacy of lenabasum in a phase 2 randomized, placebo-controlled trial in adults with cystic fibrosis.

BACKGROUND: Few therapies specifically address the chronic airway inflammation in cystic fibrosis (CF) that contributes to progressive destruction of lung tissue and loss of lung function. Lenabasum is a cannabinoid type 2 receptor (CB2) agonist that resolves inflammation in a number of in vitro and in vivo models. METHODS: A Phase 2 double-blind, randomized, placebo-controlled study assessed the safety and tolerability of lenabasum in adults with CF. Subjects with FEV1% (ppFEV1) ≥40% predicted were randomized to lenabasum 1 or 5 mg or placebo once daily (QD) (Weeks 1-4), then 20 mg QD, 20 mg twice daily (BID) or placebo (Weeks 5-12), with follow-up at Week 16. Pulmonary exacerbations (PEx) were recorded and biomarkers of blood and lung inflammation were measured. RESULTS: Of 89 subjects randomized, 51 lenabasum and 23 placebo-only subjects completed the study. No deaths or serious or severe adverse events (AE) were considered related to lenabasum. Most AEs were mild/moderate, and the most common were PEx, hemoptysis, dry mouth, and upper respiratory infection. Three lenabasum and one placebo-only subjects discontinued the study for a treatment related AE. New PEx were treated with intravenous antibiotics in 4.0% of lenabasum-treated vs. 11.4% of placebo-treated subjects, during Weeks 1-4 and 5.2% compared to 13.0% during Weeks 5-12 (p<0.2). No significant differences in ppFEV1 were observed between treatment groups. Sputum neutrophils, eosinophils, and neutrophil elastase were numerically reduced, and significant (p<0.05) reductions in IL-8 and immunoglobulin G levels occurred with lenabasum. CONCLUSIONS: The safety findings of lenabasum, coupled with biomarker data, support further testing in a larger study with a longer duration.

Preventing asthma in high risk kids (PARK) with omalizumab: Design, rationale, methods, lessons learned and adaptation.

Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma - viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2-3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma.

Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma.

BACKGROUND: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. METHODS: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. RESULTS: When quintupling the dose of fluticasone (to 250 µg twice a day) was compared with adding salmeterol (50 µg twice a day) and doubling the fluticasone (to 100 µg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age. CONCLUSIONS: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).

A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis.

BACKGROUND: Tezacaftor/ivacaftor is a new treatment option in many regions for patients aged ≥12 years who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function (F/RF) mutation. This Phase 3, 2-part, open-label study evaluated the pharmacokinetics (PK), safety, tolerability, and efficacy of tezacaftor/ivacaftor in children aged 6 through 11 years with these mutations. METHODS: Part A informed weight-based tezacaftor/ivacaftor dosages for part B. The primary objective of part B was to evaluate the safety and tolerability of tezacaftor/ivacaftor through 24 weeks; the secondary objective was to evaluate efficacy based on changes from baseline in percentage predicted forced expiratory volume in 1 s (ppFEV1), growth parameters, sweat chloride, and the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. RESULTS: After PK analysis in part A, 70 children received ≥1 dose of tezacaftor/ivacaftor in part B; 67 children completed treatment. Exposures in children aged 6 through 11 years were within the target range for those observed in patients aged ≥12 years. The safety profile of tezacaftor/ivacaftor was generally similar to prior studies in patients aged ≥12 years. One child discontinued treatment for a serious adverse event of constipation. Tezacaftor/ivacaftor treatment improved sweat chloride levels and CFQ-R respiratory domain scores, mean ppFEV1 remained stable in the normal range, and growth parameters remained stable over 24 weeks. CONCLUSIONS: Tezacaftor/ivacaftor was generally safe and well tolerated, and improved CFTR function in children aged 6 through 11 years with CF with F/F and F/RF genotypes, supporting tezacaftor/ivacaftor use in this age group. NCT02953314.

Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level.

BACKGROUND: In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS: In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (<2% or ≥2%). The primary outcome was the response to mometasone as compared with placebo and to tiotropium as compared with placebo among patients with a low sputum eosinophil level who had a prespecified differential response to one of the trial agents. The response was determined according to a hierarchical composite outcome that incorporated treatment failure, asthma control days, and the forced expiratory volume in 1 second; a two-sided P value of less than 0.025 denoted statistical significance. A secondary outcome was a comparison of results in patients with a high sputum eosinophil level and those with a low level. RESULTS: A total of 73% of the patients had a low eosinophil level; of these patients, 59% had a differential response to a trial agent. However, there was no significant difference in the response to mometasone or tiotropium, as compared with placebo. Among the patients with a low eosinophil level who had a differential treatment response, 57% (95% confidence interval [CI], 48 to 66) had a better response to mometasone, and 43% (95% CI, 34 to 52) had a better response to placebo (P = 0.14). In contrast 60% (95% CI, 51 to 68) had a better response to tiotropium, whereas 40% (95% CI, 32 to 49) had a better response to placebo (P = 0.029). Among patients with a high eosinophil level, the response to mometasone was significantly better than the response to placebo (74% vs. 26%) but the response to tiotropium was not (57% vs. 43%). CONCLUSIONS: The majority of patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo. These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level. (Funded by the National Heart, Lung, and Blood Institute; SIENA ClinicalTrials.gov number, NCT02066298.).