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Missing values were imputed using Markov chain Monte Carlo methods. Patients with missing baseline values were not included in the analyses.

After baseline up through week 16, visit summary statistics represent average values obtained by averaging the summary statistics generated from each imputed data set. E, Comparisons with placebo from least squares mean and contrast P values from an analysis of covariance with a factor of treatment group and corresponding baseline pruritus numeric rating scale score as the covariate. No imputations were made for missing data patient numbers fluctuate at each visit.

F, Comparisons with placebo from pairwise Cochran-Mantel-Haenszel tests. Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response. Not all submitted comments are published. Please see our commenting policy for details. JAMA Dermatol. Question Is lebrikizumab, a novel, high-affinity, monoclonal antibody targeting interleukin 13 that selectively inhibits interleukin 13 signaling, efficacious and safe in adults with moderate to severe atopic dermatitis?

Findings Among patients with moderate to severe atopic dermatitis in this phase 2b, placebo-controlled randomized clinical trial, lebrikizumab statistically significantly improved measures of clinical manifestations of atopic dermatitis, pruritus, and quality of life in a dose-dependent manner vs placebo during 16 weeks of treatment.

Meaning Lebrikizumab was efficacious for adults with moderate to severe atopic dermatitis, was generally well tolerated, and had a favorable safety profile consistent with previous lebrikizumab studies; these data support the central role of interleukin 13 in the pathophysiology of atopic dermatitis.

Importance Interleukin 13 IL is a central pathogenic mediator driving multiple features of atopic dermatitis AD pathophysiology. Design, Setting, and Participants A phase 2b, double-blind, placebo-controlled, dose-ranging randomized clinical trial of lebrikizumab injections every 4 weeks or every 2 weeks was conducted from January 23, , to May 23, , at 57 US centers.

Participants were adults 18 years or older with moderate to severe AD. Interventions Patients were randomized to placebo every 2 weeks or to subcutaneous injections of lebrikizumab at the following doses: mg every 4 weeks mg loading dose [LD] , mg every 4 weeks mg LD , or mg every 2 weeks mg LD at baseline and week 2.

Safety assessments included treatment-emergent adverse events. Results A total of patients mean [SD] age, Differences vs placebo-treated patients 2 of 44 [4. Treatment-emergent adverse events were reported in 24 of 52 placebo patients Low rates of injection-site reactions 1 of 52 [1. Conclusions and Relevance During 16 weeks of treatment, lebrikizumab provided rapid, dose-dependent efficacy across a broad range of clinical manifestations in adult patients with moderate to severe AD and demonstrated a favorable safety profile.

These data support the central role of IL in AD pathophysiology. If these findings replicate in phase 3 studies, lebrikizumab may meaningfully advance the standard of care for moderate to severe AD. Trial Registration ClinicalTrials. The pathophysiology of atopic dermatitis AD is multifaceted, involving a complex interplay of several factors, including genetics, environment, and dysregulated immune pathways. Previous studies 3 , 5 - 13 have shown that IL has important roles in inflammation, skin barrier dysfunction, skin thickening, infections, pruritus, and allergic responses that characterize AD.

In a phase 2a proof-of-concept trial in adults with moderate to severe AD, overall results with lebrikizumab in single doses or once monthly in combination with a topical corticosteroid TCS showed a dose-dependent response and generally positive findings on key outcomes. This article reports results of the phase 2b randomized clinical trial assessing the efficacy and safety of lebrikizumab monotherapy every 4 weeks or every 2 weeks in adults with moderate to severe AD.

This randomized clinical trial was conducted at 57 US centers. The trial protocol Supplement 1 and the written informed consent form were approved by local institutional review boards or independent ethics committees.

This phase 2b, double-blind, placebo-controlled, parallel-group, dose-ranging randomized clinical trial of lebrikizumab injections every 4 weeks or every 2 weeks consisted of a week treatment period with a week safety follow-up eFigure 1 in Supplement 2.

After a screening period not exceeding 30 days and after eligibility requirements were confirmed on day 1 baseline , screening numbers were entered into an interactive web response system, and patients were randomized to matching placebo every 2 weeks or to subcutaneous injections of lebrikizumab at the following doses: mg every 4 weeks mg loading dose [LD] , mg every 4 weeks mg LD , or mg every 2 weeks mg LD at baseline and week 2.

Additional study design details are available in the eMethods in Supplement 2. The sponsor Dermira, Inc , investigators, study site personnel, and patients were blinded to treatment assignments, and blind integrity was maintained throughout the study. Blinded, coded kits with study drug in prefilled syringes and boxes masked the treatment assignments. Rescue therapy was allowed to manage patient symptoms and to inform the phase 3 program.

Patients requiring a TCS could remain in the study and were to continue TCS use as briefly as possible; those requiring systemic rescue therapy were discontinued from the study. Detailed inclusion and exclusion criteria are available in the eMethods in Supplement 2.

The prespecified primary end point was percentage change from baseline in the EASI to week Visits occurred every 2 weeks through week 16 and at weeks 20 and 24, with a safety telephone follow-up at week 32 eTable 2 in Supplement 2. Safety assessments included treatment-emergent adverse events TEAEs. The sample size target number, approximately patients was based mainly on prior study results, including TCS use, 21 which defined an estimated sample size of approximately 75 patients for active groups and 50 for the placebo group to adequately power the study.

Statistical analyses were conducted with SAS version 9. No interim analyses were planned or performed. All statistical tests were 2-sided and performed at the. Statistical comparisons were performed at week 16 only and between lebrikizumab groups and placebo only. Efficacy analyses used the modified intent-to-treat population all patients who were randomized and received study drug regardless of rescue medication use. The primary end point was evaluated using an analysis of covariance with a factor of treatment group and corresponding baseline EASI as the covariate.

Missing efficacy data were imputed using Markov chain Monte Carlo MCMC methods, which do not rely on the assumption of data missing at random. The continuous secondary end points of percentage change in pruritus NRS score and change in total BSA involvement were evaluated with an analysis of covariance; no imputations were made for missing pruritus NRS score from baseline or missing total BSA involvement.

A total of patients mean [SD] age, Week 16 completion rates were greater for lebrikizumab-treated patients vs placebo-treated patients The most common reasons for discontinuation were withdrawal by patient 41 of [ Patient demographics and disease characteristics were well matched across groups Table 1. A total of 16 patients 4 placebo and 12 lebrikizumab self-reported prior dupilumab use. Dose-dependent differences in mean percentage change in the EASI between placebo-treated patients and lebrikizumab-treated patients were observed as early as the first visit week 4 , with further improvements to week 16 statistical comparison at week 16 only eFigure 2 in Supplement 2.

Dose-dependent differences between placebo-treated patients and lebrikizumab-treated patients were seen as early as the first visit week 4 , with further improvement to week 16 Figure 2. Lebrikizumab patients showed greater improvement vs placebo patients from baseline at week 16 in mean percentage BSA involvement, with statistically significant differences observed in the group receiving mg every 2 weeks Table 2.

Lebrikizumab groups showed dose-dependent, statistically significant improvement in least squares mean percentage change from baseline in pruritus NRS score at week 16 vs the placebo group Table 2 using either no imputation method or MCMC imputation for missing data eFigure 3A in Supplement 2.

Improvements were observed throughout the trial to week 16 Figure 2 E, with statistical comparison at week 16 only. In addition, a greater proportion of lebrikizumab-treated patients vs placebo - treated patients achieved at least a 4-point improvement in pruritus NRS score from baseline at week 16, with statistically significant differences observed in the group receiving mg every 2 weeks on both imputation methods performed Table 2 [ Differences vs placebo-treated patients 4.

Improvements with lebrikizumab vs placebo were observed through week 16 Figure 2 F, with statistical comparison at week 16 only. Of 16 patients self-reporting prior dupilumab use 4 placebo patients and 12 lebrikizumab patients [4, 3, and 5 in the 3 lebrikizumab groups, respectively] , 9 reported lack of efficacy with dupilumab.

Rescue medication use was approximately 3-fold greater among placebo-treated patients vs lebrikizumab-treated patients eTable 3 in Supplement 2. Across treatment groups, most patients used topical rescue medication only, with the exception of the group receiving lebrikizumab mg every 4 weeks, in which more systemic rescue medication was used.

Placebo-treated patients received topical rescue medication earlier than lebrikizumab-treated patients, and the duration of topical medication use was greater for placebo-treated patients vs lebrikizumab-treated patients. These findings suggest that TCS use would not have confounded our study results. Generally, outcomes of sensitivity analyses were consistent with those of the primary analysis and were similar regardless of rescue medication use eTable 4 in Supplement 2. Low rates in TEAEs of clinical interest injection site reactions, herpesvirus infections, and conjunctivitis were reported.

Infrequently, TEAEs led to discontinuation in 1 of 52 placebo patients [1. No deaths were reported during the study. Serious TEAEs were reported by 2 of 52 placebo patients 3. No serious TEAEs were considered to be related to study drug, and none led to trial discontinuation. Few lebrikizumab-treated patients reported TEAEs of clinical interest, namely, injection site reactions, herpesvirus infections, and conjunctivitis Table 3.

Low rates of conjunctivitis were reported preferred terms by MedDRA, version All of these conjunctivitis adverse events were moderate in severity, and none of these events led to discontinuation of study medication or the study; prior conjunctivitis history was not systematically captured.

A similar rate of herpesvirus infections was reported in placebo patients and in all lebrikizumab-treated patients Table 3. No notable differences were observed between placebo patients and lebrikizumab patients with respect to physical examination results, vital signs, electrocardiogram measurements, and laboratory findings. Small increases in eosinophil counts were observed at week 4 in lebrikizumab patients; these changes were transient, and levels approached baseline values by week 16 eFigure 4 in Supplement 2.

During 16 weeks of treatment, lebrikizumab showed rapid, dose-dependent efficacy across a broad range of key AD clinical manifestations, including skin lesions, pruritus, and quality of life, in adult patients with moderate to severe AD not previously controlled by standard topical therapies.

Pruritus, which has substantial negative consequences for quality of life in AD, 29 is regarded as the most burdensome symptom among patients with AD. A reduction in itch severity was observed by day 2 in the high-dose lebrikizumab-treated patients. These data are consistent with preclinical evidence that IL directly sensitizes sensory neurons to respond to pruritogens. The phase 2b data herein, prior successful investigational treatment of AD with lebrikizumab, 21 and phase 2b data in AD with another monoclonal antibody acting on IL tralokinumab 35 suggest that IL may be the central pathogenic mediator in AD.

This hypothesis is supported by AD transcriptome data showing dominant expression of IL cytokine, with much lower levels of IL-4 cytokine, 36 , 37 as well as by the predominance of IL and IL—producing cells in the circulation of patients with AD. Lebrikizumab was generally well tolerated, which is consistent with the safety profile observed in more than a dozen prior phase 2 and phase 3 lebrikizumab trials across multiple indications, during which more than patients received lebrikizumab.

Few lebrikizumab-treated patients reported TEAEs of clinical interest, including injection site reactions, herpesvirus infections, and conjunctivitis. Notably, rates of conjunctivitis were comparatively lower in our trial with lebrikizumab, no apparent dose-response relationship was observed, and no events resulted in discontinuation of study medication or the study.

Based on these phase 2b results and clinical data to date, lebrikizumab could be an important addition to the AD treatment landscape and a central therapeutic agent in the treatment paradigm. In addition to the rapid onset of lebrikizumab action eg, itch relief by day 2 and the possibility of reduced risk for TEAEs of clinical interest ie, injection site reactions, herpesvirus infections, and conjunctivitis vs other biologic agents and small-molecule inhibitors in development, lebrikizumab may offer the possibility of convenient once-monthly dosing: improvements observed with once-monthly dosing were generally consistent with those of twice-monthly dosing.

Indeed, the complex AD pathophysiology may warrant treatment options that target different cytokines and cytokine receptors to account for specific immunologic AD subtypes and a corresponding personalized treatment approach. There are several limitations to this study. First, AD is a chronic disease, and additional studies are needed to assess efficacy beyond 16 weeks, including the potential for less frequent maintenance dosing and maintenance of response over time.

Second, the primary analysis did not account for TCS use.

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Shaji K. Durie, MD Lee Moffitt Cancer Ctr. Patients with significant comorbidities such as heart disease were excluded from the trial. Treatment consisted of three phases: induction, consolidation and maintenance.

What are the 7 Stages of Dementia?

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. We report a randomized prospective phase 3 study CLL7 , designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab FCR in patients with an early-stage high-risk chronic lymphocytic leukemia CLL. The overall response rate after early FCR was Common adverse events were hematological toxicities and infections After median observation time of

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Blood pressure may be the vital sign we measure the most and understand the least. Nurses and physicians often argue over differences between arterial line and non-invasive blood pressure NIBP cuff readings. Revised guidelines for management of high blood pressure increased thresholds for diagnosing and treating hypertension, causing further debate and controvery [1]. To make the best use of blood pressure monitoring equipment, it is helpful to have an insight into how the equipment works and the likely sources of error that can affect readings.

Gene therapy may reverse Hurler syndrome, a rare and severe illness in kids

Respiratory Research volume 21 , Article number: Cite this article. Metrics details. Patients with severe, uncontrolled asthma have a significant unmet need for new treatments that have broader effects on airway inflammation, and that provide greater improvements in asthma outcomes than currently approved biologics and standard-of-care therapies. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. The study comprises a 5—6-week screening period, a week treatment period and a week post-treatment follow-up period.

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