A phase 2 trial of CD24Fc for prevention of graft-versus-host disease.

ABSTRACT: Patients who undergo human leukocyte antigen-matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor-based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD-free survival at day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P = .03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD-free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as #NCT02663622.

The Efficacy and Safety of Gefapixant in a Phase 3b Trial of Patients with Recent-Onset Chronic Cough.

PURPOSE: We evaluated gefapixant, a P2X3 receptor antagonist, in participants with recent-onset (≤ 12 months) refractory chronic cough (RCC) or unexplained chronic cough (UCC). METHODS: Participants (≥ 18 years of age; ≥ 40 mm on a 100-mm cough severity visual analog scale [VAS] at screening and randomization) with chronic cough for < 12 months were enrolled in this phase 3b, double-blind, placebo-controlled, parallel group, multicenter study (NCT04193202). Participants were randomized 1:1 to gefapixant 45 mg BID or placebo for 12 weeks with a 2-week follow-up. The primary efficacy endpoint was change from baseline at Week 12 in Leicester Cough Questionnaire (LCQ) total score. Adverse events were monitored and evaluated. RESULTS: There were 415 participants randomized and treated (mean age 52.5 years; median [range] duration 7.5 [1-12] months): 209 received placebo and 206 received gefapixant 45 mg BID. A statistically significant treatment difference of 0.75 (95% CI: 0.06, 1.44; p = 0.034) for gefapixant vs. placebo was observed for change from baseline in LCQ total score at Week 12. The most common AE was dysgeusia (32% gefapixant vs. 3% placebo participants); serious AEs were rare (1.5% gefapixant vs. 1.9% placebo participants). CONCLUSION: Gefapixant 45 mg BID demonstrated significantly greater improvement in cough-specific health status from baseline compared to placebo, in participants with recent-onset chronic cough. The most common AEs were related to taste and serious AEs were rare.

Chemiresistive Sensor Array with Nanostructured Interfaces for Detection of Human Breaths with Simulated Lung Cancer Breath VOCs.

Timely screening of lung cancer represents a challenging task for early diagnosis and treatment, which calls for reliable, low-cost, and noninvasive detection tools. One type of promising tools for early-stage cancer detection is breath analyzers or sensors that detect breath volatile organic compounds (VOCs) as biomarkers in exhaled breaths. However, a major challenge is the lack of effective integration of the different sensor system components toward the desired portability, sensitivity, selectivity, and durability for many of the current breath sensors. In this report, we demonstrate herein a portable and wireless breath sensor testing system integrated with sensor electronics, breath sampling, data processing, and sensor arrays derived from nanoparticle-structured chemiresistive sensing interfaces for detection of VOCs relevant to lung cancer biomarkers in human breaths. In addition to showing the sensor viability for the targeted application by theoretical simulations of chemiresistive sensor array responses to the simulated VOCs in human breaths, the sensor system was tested experimentally with different combinations of VOCs and human breath samples spiked with lung cancer-specific VOCs. The sensor array exhibits high sensitivity to lung cancer VOC biomarkers and mixtures, with a limit of detection as low as 6 ppb. The results from testing the sensor array system in detecting breath samples with simulated lung cancer VOC constituents have demonstrated an excellent recognition rate in discriminating healthy human breath samples and those with lung cancer VOCs. The recognition statistics were analyzed, showing the potential viability and optimization toward achieving the desired sensitivity, selectivity, and accuracy in the breath screening of lung cancer.

Treatment with the P2X3-Receptor Antagonist Gefapixant for Acute Cough in Induced Viral Upper Respiratory Tract Infection: A Phase 2a, Randomized, Placebo-Controlled Trial.

INTRODUCTION: Available therapies for acute cough, a condition frequently caused by a viral upper respiratory tract infection (URTI), have shown limited evidence of efficacy. Gefapixant, a P2X3-receptor antagonist, has demonstrated efficacy and safety in studies of the treatment of refractory or unexplained chronic cough, but its efficacy for treating acute cough has not been previously studied. METHODS: This was a phase 2a, randomized, double-blind, placebo-controlled, parallel-group, pilot study. Healthy volunteers were randomized 1:1 to receive twice-daily gefapixant 45 mg or placebo and inoculated with human rhinovirus 16 to induce URTI and cough. Participants were observed while quarantined for 7 days after the start of treatment. The primary endpoint was awake cough frequency on day 3, which was objectively measured with a cough-recording device. Secondary endpoints included change from baseline to day 3 in subjective cough severity measures (cough severity visual analog scale, Cough Severity Diary) and cough-specific quality of life (Leicester Cough Questionnaire-acute). RESULTS: Of the 46 participants who met inclusion criteria [mean (standard deviation, SD) age, 24.6 (6.5) years; females, n = 8], 40 completed the study (gefapixant, n = 21; placebo, n = 19). There was no significant difference in awake cough frequency on day 3 between the gefapixant and placebo groups [least squares means, 2.4 versus 2.7 coughs per hour, respectively; mean difference (95% confidence interval, CI), -0.3 (-2.3, 1.7); P = 0.75]. There were no significant between-group differences for any of the secondary endpoints. Peak cough frequency was low and occurred later in the study than expected (days 4-5). The safety profile was consistent with that of previous studies of gefapixant. CONCLUSION: Compared with placebo, gefapixant did not reduce the frequency or severity of acute cough secondary to induced URTI. Induced viral URTI produced mild symptoms, including lower cough frequency than observed in previous studies of patients selected for acute cough associated with naturally occurring URTI. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03569033; EudraCT, 2017-000472-28; protocol number, MK-7264-013.

Are firms with 'deep pockets' more responsive to tort liability? Evidence from nursing homes.

We provide time series evidence of tort reform's impact on inputs and quality in the nursing home industry. Between 2000 and 2010, 11 state reforms capped noneconomic damages for health care services. Small chain and unaffiliated nursing homes enjoyed "judgment proof standing" and were less apt to be sued, prior to reform. We find that the managers of such homes were relatively unresponsive to the implementation of state caps on noneconomic damages. Large "deep-pocketed" chain-affiliated homes lacked judgment proof standing and implemented greater reductions in their nursing inputs in the aftermath of tort relief. However, we find little evidence of service quality erosion across four measured dimensions of care outcomes. Our findings are consistent with a "defensive care" model in which large chain homes employ unproductive inputs in an effort to meet a negligence standard of care.

A Low-Current and Multi-Channel Chemiresistor Array Sensor Device.

This paper describes the design of a low-current, multichannel, handheld electronic device integrated with nanostructured chemiresistor sensor arrays. A key design feature of the electronic circuit board is its low excitation current for achieving optimal performance with the arrays. The electronics can rapidly acquire the resistances for different sensors, not only spanning several orders of magnitude, but also as high as several hundreds of megaohms. The device tested is designed using a chemiresistor array with nanostructured sensing films prepared by molecularly-mediated assemblies of gold nanoparticles for detection. The low-current, wide-range, and auto-locking capabilities, along with the effective coupling with the nanostructured chemiresistor arrays, meet the desired performances of a low excitation current and low power consumption, and also address the potential instability of the sensors in a complex sensing environment. The results are promising for potential applications of the device as a portable sensor for the point-of-need monitoring of air quality and as a biosensor for point-of-care human breath screening for disease biomarkers.

Nano-Filamented Textile Sensor Platform with High Structure Sensitivity.

A key challenge to the creation of chemically responsive electro-functionality of nonconductive, hydrophobic, and free-contacted textile or fibrous network materials is how to impart the 3D structure with functional filaments to enable responsive structure sensitivity, which is critical in establishing the fibrous platform technology for sensor applications. We demonstrate this capability using an electrospun polymeric fibrous substrate embedded with nano-filaments defined by size-tunable gold nanoparticles and structurally sensitive dendrons as crosslinkers. The resulting interparticle properties strongly depend on the assembly of the nano-filaments, enabling an interface with high structure sensitivity to molecular interactions. This is demonstrated with chemiresistive responses to vaporous alcohol molecules with different chain lengths and isomers, which is critical in breath and sweat sensing involving a high-moisture or -humidity background. The sensitivity scales with the chain length and varies with their isomers. This approach harnesses the multifunctional tunability of the nano-filaments in a sensor array format, showing high structure sensitivity to the alcohol molecules with different chain lengths and isomers. The high structure sensitivity and its implications for a paradigm shift in the design of textile sensor arrays for multiplexing human performance monitoring via breath or sweat sensing and environmental monitoring of air quality are also discussed.

Efficacy and Safety of Ragweed SLIT-Tablet in Children with Allergic Rhinoconjunctivitis in a Randomized, Placebo-Controlled Trial.

BACKGROUND: Ragweed sublingual immunotherapy (SLIT) tablet reduces symptoms and symptom-relieving medication use in adults with allergic rhinitis with or without conjunctivitis (AR/C) but has not been evaluated in children. OBJECTIVE: This international, multicenter, double-blind, placebo-controlled trial evaluated the efficacy and safety of ragweed SLIT-tablet in children with AR/C. METHODS: Children (N = 1025; 77.7% polysensitized) aged 5 to 17 years with ragweed pollen-induced AR/C with or without asthma (FEV1 ≥80% predicted) were randomized 1:1 to daily ragweed SLIT-tablet (12 Amb a 1-Unit) or placebo for up to 28 weeks (NCT02478398). The primary end point was the average total combined score (TCS; sum of rhinoconjunctivitis daily symptom score [DSS] and daily medication score [DMS]) during peak ragweed pollen season (RPS). Key secondary end points were TCS during the entire RPS, and DSS and DMS during the peak RPS. RESULTS: Relative TCS (95% CI) improvements with ragweed SLIT-tablet versus placebo were -38.3% (-46.0% to -29.7%; least square [LS] mean difference, -2.73; P < .001) during peak RPS and -32.4% (-40.7% to -23.3%; LS mean difference, -1.86; P < .001) during the entire RPS. DSS and DMS during peak RPS improved with SLIT-tablet versus placebo by -35.4% (-43.2% to -26.1%; LS mean difference, -1.40; P < .001) and -47.7% (-59.8% to -32.5%; LS mean difference, -1.84; P < .001), respectively. Asthma DSS, short-acting ß-agonist use, and nocturnal awakenings during peak RPS improved with SLIT-tablet versus placebo by -30.7%, -68.1%, and -75.1%, respectively (all nominal P ≤ .02). No events of anaphylaxis, airway compromise, or severe treatment-related systemic allergic reactions were reported. CONCLUSIONS: Ragweed SLIT-tablet significantly improved symptoms and decreased symptom-relieving medication use in children with ragweed pollen-induced AR/C and was well tolerated.

Body Mass Index and 30-Day Adverse Outcomes Among Newly Admitted Residents to Skilled Nursing Facilities.

OBJECTIVE: To examine the association between body mass index (BMI) and outcomes, including discharge to home, hospitalization, death, or continued residence in the skilled nursing facilities (SNFs), among residents newly admitted to SNFs. DESIGN: Retrospective observational design using the national Minimum Data Set 2.0 from 2006 to 2010. SETTING: SNFs in the United States. PARTICIPANTS: Newly admitted SNF residents. MEASUREMENTS: Four discharge outcomes were assessed at 30 days subsequent to the initial admission to SNF, including discharge to home, hospitalization, death, or continued residence in the SNFs, and examined using a competing hazards model. SNF residents were categorized as underweight (BMI < 18.5), normal to overweight (18.5 ≤ BMI < 30), mildly obese (30 ≤ BMI < 35), and moderately to severely obese (BMI ≥ 35). RESULTS: The study sample was composed of 3,812,333 newly admitted SNF residents. As compared with normal to overweight SNF residents, underweight individuals were less likely [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.82-0.83] to be discharged home and more likely to be hospitalized (HR 1.06, 95% CI 1.05-1.07), or to die (HR 1.59, 95% CI 1.56-1.62), rather than continue to reside in the facility. Residents with mild obesity were more likely (HR 1.12, 95% CI 1.11-1.13) to be discharged home and less likely to be hospitalized (HR 0.96, 95% CI 0.95-0.97) or to die (HR 0.74, 95% CI 0.73-0.76). Moderately to severely obese individuals were also more likely to be discharged home (HR 1.11, 95% CI 1.10-1.11) and less likely to be hospitalized (HR 0.94, 95% CI 0.93-0.95) or die (HR 0.66, 95% CI 0.64-0.68). CONCLUSIONS/IMPLICATIONS: SNF residents with obesity experience more favorable short-term outcomes compared with underweight or normal to overweight residents. Underweight residents are at the greatest risk for adverse outcomes, emphasizing the need for special surveillance and preventive efforts targeting these individuals.

Evaluation of Natural Language Processing (NLP) systems to annotate drug product labeling with MedDRA terminology.

INTRODUCTION: The FDA Adverse Event Reporting System (FAERS) is a primary data source for identifying unlabeled adverse events (AEs) in a drug or biologic drug product's postmarketing phase. Many AE reports must be reviewed by drug safety experts to identify unlabeled AEs, even if the reported AEs are previously identified, labeled AEs. Integrating the labeling status of drug product AEs into FAERS could increase report triage and review efficiency. Medical Dictionary for Regulatory Activities (MedDRA) is the standard for coding AE terms in FAERS cases. However, drug manufacturers are not required to use MedDRA to describe AEs in product labels. We hypothesized that natural language processing (NLP) tools could assist in automating the extraction and MedDRA mapping of AE terms in drug product labels. MATERIALS AND METHODS: We evaluated the performance of three NLP systems, (ETHER, I2E, MetaMap) for their ability to extract AE terms from drug labels and translate the terms to MedDRA Preferred Terms (PTs). Pharmacovigilance-based annotation guidelines for extracting AE terms from drug labels were developed for this study. We compared each system's output to MedDRA PT AE lists, manually mapped by FDA pharmacovigilance experts using the guidelines, for ten drug product labels known as the "gold standard AE list" (GSL) dataset. Strict time and configuration conditions were imposed in order to test each system's capabilities under conditions of no human intervention and minimal system configuration. Each NLP system's output was evaluated for precision, recall and F measure in comparison to the GSL. A qualitative error analysis (QEA) was conducted to categorize a random sample of each NLP system's false positive and false negative errors. RESULTS: A total of 417, 278, and 250 false positive errors occurred in the ETHER, I2E, and MetaMap outputs, respectively. A total of 100, 80, and 187 false negative errors occurred in ETHER, I2E, and MetaMap outputs, respectively. Precision ranged from 64% to 77%, recall from 64% to 83% and F measure from 67% to 79%. I2E had the highest precision (77%), recall (83%) and F measure (79%). ETHER had the lowest precision (64%). MetaMap had the lowest recall (64%). The QEA found that the most prevalent false positive errors were context errors such as "Context error/General term", "Context error/Instructions or monitoring parameters", "Context error/Medical history preexisting condition underlying condition risk factor or contraindication", and "Context error/AE manifestations or secondary complication". The most prevalent false negative errors were in the "Incomplete or missed extraction" error category. Missing AE terms were typically due to long terms, or terms containing non-contiguous words which do not correspond exactly to MedDRA synonyms. MedDRA mapping errors were a minority of errors for ETHER and I2E but were the most prevalent false positive errors for MetaMap. CONCLUSIONS: The results demonstrate that it may be feasible to use NLP tools to extract and map AE terms to MedDRA PTs. However, the NLP tools we tested would need to be modified or reconfigured to lower the error rates to support their use in a regulatory setting. Tools specific for extracting AE terms from drug labels and mapping the terms to MedDRA PTs may need to be developed to support pharmacovigilance. Conducting research using additional NLP systems on a larger, diverse GSL would also be informative.

SQ house dust mite sublingual immunotherapy tablet subgroup efficacy and local application site reaction duration.

BACKGROUND: Allergic rhinitis with or without conjunctivitis (AR/C) is common, necessitating evaluation of SQ house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet efficacy in various subgroups. OBJECTIVE: To evaluate 12 SQ-HDM efficacy and safety across subgroups, and the onset, duration, and recurrence of local application site reactions. METHODS: Subgroup (age, sex, race, asthma status, and allergen sensitization) efficacy was assessed using pooled data from 2 previously described trials of daily 12 SQ-HDM vs placebo for AR/C (n = 2,138). Efficacy was measured by average total combined rhinitis score (TCRS; rhinitis daily symptom plus medication score) during the last 8 weeks of treatment. Safety in subgroups and local application site reaction onset, duration, and recurrence were evaluated using pooled data from 5 previously described trials of SQ HDM SLIT-tablet (n = 2,923). RESULTS: Significant (based on 95% confidence intervals [CIs]) reduction in TCRS was seen with 12 SQ-HDM relative to placebo across all subgroups, with TCRS improvements ranging from 15% to 25%. The AE profile was generally similar within subgroups. Approximately 95% of local application site reactions were mild to moderate in severity. Median duration on day 1 of treatment for the most common local application site reactions (throat irritation, oral pruritus, ear pruritus, and lip swelling) ranged from 30 to 60 minutes; median first day of onset ranged from days 1 to 4 of treatment; median days that reactions recurred ranged from 3 to 12 days. CONCLUSION: Treatment with 12 SQ-HDM consistently improved symptoms and was well tolerated in relevant subgroups of subjects with HDM AR/C. Local application site reactions to 12 SQ-HDM were typically mild to moderate and transient.

Body Mass Index, Falls, and Hip Fractures Among Nursing Home Residents.

Background: To examine the association between body mass index (BMI) and the risk for falls and hip fractures among nursing home (NH) residents. Methods: A cohort study of newly admitted NH residents, excluding those with a prior history of hip fracture. Using the Minimum Data Set 2.0 (2006-2010), we determined the occurrence of new falls and hip fractures among NH residents during their first 3 months of stay. Residents were categorized as underweight (BMI < 18.5), normal-to-overweight (18.5 ≤ BMI < 30), mildly obese (30 ≤ BMI < 35), and moderately-to-severely obese (BMI ≥ 35). Results: Among newly admitted NH residents over the first 3 months, 51.1% of underweight residents, 53.1% of normal-to-overweight residents, 49.1% of residents with mild obesity, and 43.1% of residents with moderate-to-severe obesity experienced a fall; 3.1% of underweight residents, 2.5% of normal-to-overweight residents, 1.5% of residents with mild obesity, and 1.1% of residents with moderate-to-severe obesity experienced a hip fracture. In comparison with normal-to-overweight residents, after adjustment for resident-level and facility-level characteristics, mildly obese residents (odds ratio [OR] = 0.94, 95% confidence interval [CI] = [0.91-0.93]), and moderately-to-severely obese residents (OR = 0.84 [95% CI = 0.83-0.85]) were less likely to experience a fall; Mildly obese residents (OR = 0.65 [95% CI = 0.63-0.68]), and moderately-to-severely obese residents (OR = 0.84 [95% CI = 0.83-0.85]) were less likely, and underweight residents were more likely (OR = 1.22 [95% CI = 1.18-1.26]) to experience a hip fracture. Conclusion: Obesity is associated with reduced risks for falls and hip fractures among newly admitted NH residents. Future studies are needed to explore possible explanations for these associations.

Impact of Adverse Event Solicitation on the Safety Profile of SQ House Dust Mite Sublingual Immunotherapy Tablet.

BACKGROUND: It has been recommended that sublingual immunotherapy (SLIT) safety be assessed using solicited adverse event (AE) collection methods. OBJECTIVES: The objectives of this study were to describe the impact on the safety profile of SQ house dust mite (HDM) SLIT-tablet (12 SQ-HDM dose) when prespecified local application site reactions were solicited versus unsolicited, and discuss ramifications of AE solicitation. METHODS: Subjects were randomized to daily 12 SQ-HDM or placebo for up to 52 weeks in 4 double-blinded, multicenter trials. In one trial (NCT01700192; N = 1272), subjects documented daily the presence or absence of 15 World Allergy Organization-defined local application site reactions using a structured questionnaire of closed-ended questions (solicited AEs). Subjects in the other trials were not asked about specific AEs (unsolicited AEs), and AE data were pooled (N = 1287). Analysis was limited to adults aged 18 to 65 years. RESULTS: Whether AEs were solicited or unsolicited, the most common AEs leading to study discontinuation with 12 SQ-HDM were throat irritation and oral pruritus. Approximately 95% of treatment-related AEs were mild to moderate. Placebo-subtracted frequencies of local application site reactions associated with 12 SQ-HDM were higher when solicited versus unsolicited (ie, throat irritation, 46% vs 13%, respectively; oral pruritus, 47% vs 17%; ear pruritus, 40% vs 4%; mouth swelling, 8% vs 2%; tongue ulceration, 10% vs 0%; mouth ulceration, 7% vs <1%). CONCLUSIONS: Qualitatively, the safety profile of 12 SQ-HDM was similar when AEs were solicited versus unsolicited; hence, solicitation did not alter the safety profile. Higher observed frequencies of local application site reactions with AE solicitation may be partly due to suggestive reporting bias, as observed in placebo-treated subjects.

Acute Myocardial Infarction in Patients with Paraplegia: Characteristics, Management, and Outcomes.

BACKGROUND: Cardiovascular disease has become a leading cause of death for patients with paraplegia. Acute myocardial infarction in patients with paraplegia has not been described in the literature. This study investigates clinical features, management strategies, and outcomes of these patients. METHODS: Acute myocardial infarction in patients with or without paraplegia was identified in the New York State Inpatient Database between 2007 and 2013. Clinical comorbidities, management strategies and their associated outcomes were compared using propensity score-matching analysis. RESULTS: Among 402,569 patients with acute myocardial infarction, 1400 had a concomitant diagnosis of paraplegia. Compared with those without, patients with paraplegia were younger, more likely to be black, and had a higher prevalence of hypertension, anemia, congestive heart failure, coagulopathy, and depression, but a lower prevalence of diabetes, hyperlipidemia, obesity, chronic lung disease, and renal failure. Patients with paraplegia were more likely to receive medical therapy without a diagnostic cardiac catheterization than those without (83.7% vs 64.5%, P < .001). Nine percent of patients with paraplegia received revascularization, which was significantly lower than that without paraplegia. In terms of the clinical outcome, patients with paraplegia had higher in-hospital mortality than those without (22.4% vs 16.8%, P < .001). Among the patients with paraplegia, the subcohort that received revascularization had lower in-hospital mortality (9.5% vs 22.0%, P < .01), had shorter length of stay (13.0 vs 16.9 days, P =.08), and higher hospital charges ($130,079 vs $92,125, P < .001) than those without revascularization. Furthermore, the paraplegic subcohort underwent coronary artery bypass grafting that was associated with higher in-hospital mortality (21.7% vs 1.7%, P < .001), longer length of stay (24.8 vs 14.2 days, P < .001), and higher hospital charges ($231,323 vs $144,449, P < .01) than subcohort that received percutaneous coronary intervention. CONCLUSIONS: Acute myocardial infarction patients with concomitant paraplegia had distinct clinical characteristics and comorbidity profiles; were less likely to receive revascularization therapy; and had higher in-hospital mortality. Acute myocardial infarction patient with paraplegia who underwent revascularization were associated with better clinical outcomes, in particular, those who were treated with percutaneous coronary intervention had significantly lower in-hospital mortality than those treated with coronary artery bypass grafting.

Sublingual immunotherapy tablets as a disease-modifying add-on treatment option to pharmacotherapy for allergic rhinitis and asthma.

Allergic rhinitis (AR) with or without conjunctivitis (AR/C) is associated with a significant health and economic burden, and is often accompanied by asthma. Pharmacotherapies are the mainstay treatment options for AR and asthma, but guidelines also recommend allergy immunotherapy (AIT). Unlike pharmacotherapies, AIT has the ability to modify the underlying immunologic mechanisms of AR and asthma with the potential for long-term benefits after treatment is discontinued. Immunotherapy may also prevent progression of AR/C to asthma. Sublingual immunotherapy (SLIT)-tablets are a self-administered alternative to subcutaneous immunotherapy that provide the benefits of AIT without the cost and inconvenience of frequent office visits or the discomfort of injections. SLIT-tablets are also an option that can be utilized by primary care clinicians. Pharmacotherapies are generally effective in mild disease although a number of patients remain uncontrolled. SLIT-tablets have proven efficacy for AR in adults, children, and poly-sensitized allergic patients. Indirect comparisons indicate that SLIT-tablets have superior or comparable efficacy compared with traditional pharmacotherapies for seasonal AR, and superior efficacy for perennial AR. House dust mite (HDM) SLIT-tablets have also demonstrated clinically relevant benefits for asthma, with significant observed reductions in daily inhaled corticosteroid use, risk of asthma exacerbations, and asthma symptoms. SLIT-tablets are well tolerated, with minimal risk of systemic allergic reactions. The most common treatment-related adverse events are oral site reactions such as oral pruritus and throat irritation. Based on the favorable efficacy and safety profile, as well as the convenience of at-home oral administration and disease-modifying effects, SLIT-tablets should be considered as an alternative or add-on treatment to pharmacotherapy for AR/C, and as an add-on treatment for HDM allergic asthma.

Epinephrine Use in Clinical Trials of Sublingual Immunotherapy Tablets.

BACKGROUND: Allergy immunotherapy can result in systemic allergic reactions and even life-threatening anaphylaxis requiring epinephrine administration. OBJECTIVE: The objective of this study was to describe epinephrine use in the clinical trial development programs of 3 rapidly dissolving sublingual immunotherapy tablets (SLIT-tablets; Merck & Co., Inc., Kenilworth, NJ/ALK, Hørsholm, Denmark/Torii Pharmaceutical Co., Ltd., Tokyo, Japan). METHODS: Data on epinephrine use were collected from 13 timothy grass SLIT-tablet trials (MK-7243; ≤2800 bioequivalent allergen units/75,000 SQ-T dose, n = 2497; placebo, n = 2139), 5 short ragweed SLIT-tablet trials (MK-3641; ≤12 Amb a 1-U, n = 1725; placebo, n = 770), and 11 house dust mite (HDM) SLIT-tablet trials (MK-8237; ≤12 SQ-HDM; n = 3930; placebo, n = 2246). RESULTS: In grass SLIT-tablet trials, epinephrine was used 13 times (grass SLIT-tablet, n = 10; placebo, n = 3). Eight administrations were for grass SLIT-tablet-related adverse events (AEs): 4 for systemic allergic reactions and 4 for local mouth and/or throat swelling. In ragweed SLIT-tablet trials, epinephrine was used 9 times in 8 subjects (ragweed SLIT-tablet, n = 7; placebo, n = 1 [2 administrations for protracted anaphylaxis]). Four administrations were for ragweed SLIT-tablet-related AEs: 1 for systemic allergic reaction and 3 for local mouth and/or pharynx/throat swelling. In HDM SLIT-tablet trials, epinephrine was administered 13 times (HDM SLIT-tablet, n = 8; placebo, n = 5). Four administrations were for HDM SLIT-tablet-related AEs: 1 for systemic allergic reaction and 3 for local events. Of the 16 epinephrine administrations for events related to SLIT-tablet treatment, 11 occurred within the first week of treatment (7 administrations on day 1) and 5 were subject self-administered. CONCLUSIONS: Epinephrine administrations in response to SLIT-tablet-related reactions in clinical trials are uncommon, typically occur within the first week of treatment, and are rarely self-administered. All SLIT-tablet-related events treated with epinephrine were nonserious.

Efficacy of house dust mite sublingual immunotherapy tablet in North American adolescents and adults in a randomized, placebo-controlled trial.

BACKGROUND: The house dust mite (HDM) sublingual immunotherapy (SLIT) tablet (MK-8237; Merck & Co, Kenilworth, NJ/ALK-Abelló, Hørsholm, Denmark) has demonstrated beneficial effects on allergic rhinoconjunctivitis and asthma outcomes in European trials. OBJECTIVE: This is the first trial to assess the efficacy/safety of HDM SLIT-tablets in North American subjects with HDM-induced allergic rhinitis with or without conjunctivitis (AR/C). METHODS: In this double-blind, multicenter trial (NCT01700192) 1482 subjects (aged ≥12 years) with HDM-induced AR/C with or without asthma were randomized to a daily SQ HDM SLIT-tablet (12 SQ-HDM dose) or placebo for up to approximately 52 weeks. A rhinitis daily symptom score (DSS; 4 nasal symptoms, maximum score = 12) of 6 or greater, or 5 or greater with 1 symptom being severe, on 5 of 7 consecutive days before randomization was required. The primary end point was the average total combined rhinitis score, which was defined as the rhinitis DSS plus rhinitis daily medication score (DMS), during the last 8 treatment weeks. RESULTS: Treatment with 12 SQ-HDM improved the total combined rhinitis score by 17% (95% CI, 10% to 25%) versus placebo. Improvements versus placebo in the secondary end points of average rhinitis DSS, rhinitis DMS, total combined rhinoconjunctivitis score, and visual analog scale-assessed AR/C symptoms were 16%, 18%, 17%, and 16%, respectively. All nominal P values were less than .001 versus placebo, except rhinitis DMS (P = 0.15). No treatment-related adverse events meeting the International Council on Harmonization definition of a serious adverse event were reported; 1 nonserious treatment-related systemic allergic reaction occurred (assessed as moderate intensity) at first administration under medical supervision and was treated with epinephrine. CONCLUSIONS: In the first North American trial of use of a SLIT-tablet for HDM allergy, 12 SQ-HDM was well tolerated and improved HDM-induced rhinitis symptoms in adults and adolescents.