Leveraging external or historical data to improve the efficiency of randomized clinical trials without introducing bias or inflating the Type I error rate remains challenging. Recent work on externally trained prognostic scores, such as PROCOVA for continuous endpoint, has demonstrated a risk-free approach via covariate adjustment. However, extending this paradigm to time-to-event endpoints is nontrivial due to the non-collapsibility of the marginal hazard ratio (HR). In this paper, we address this challenge by proposing a unified framework for incorporating complex, high-dimensional prognostic information learned from external data into the primary analysis of RCTs with time- to-event endpoints, while targeting the marginal hazard ratio. The proposed procedure proceeds in two steps. First, a prognostic score is estimated from external or historical data by regressing martingale residuals on baseline covariates using flexible supervised learning methods. Second, the fitted score is included as an additional covariate in the nonparametric covariate-adjusted log-rank test and the associated marginal HR estimator of Ye et al. [2024]. The proposed method controls Type I error and provides asymptotic unbiased estimation of the marginal HR, irrespective of prognostic model misspecification, or population heterogeneity between external/historical and trial data. We show that the variance reduction, and corresponding event count savings, are approximately equal to the squared correlation between the prognostic score and the martingale pseudo-outcome in the trial. Extensions to stratified randomization are straightforward. Simulation studies demonstrate satisfactory finite-sample performance and meaningful efficiency gains when historical prognostic information is informative.

PURPOSE Innovate a novel Bayesian nonparametric approach for clinical trial analysis devised to infer intrinsic survival benefit mechanisms of action (SBMoA) in confirmatory randomized controlled trials (RCTs) with survival end point by comparing 12 intrinsic state transitions between stable disease, early response, progression/recurrence, and death. METHODS The method characterizes patient trajectories through states of stable disease, response, progression, and death using multiplicative transition intensities. Bayesian inference compares observed transition rate differences with benchmark distributions for five SBMoAs (Null, Survival Null, Mediation, Direct, Mixed), yielding posterior predictive probabilities. Performance was evaluated via simulations of phase III trials implemented to compare the accuracy of 12-month interim analyses with final survival analysis results, as well as to compare these results with those obtained using Bayesian mediation modeling, 2-in-1 seamless designs, and group sequential designs for survival analysis. RESULTS The accuracy of interim decision making in forecasting a trial's final outcome was highest for the SBMoA method (0.82), which outperformed conditional power (0.65), Pocock (0.60), Chen 2-in-1 (0.55), and O'Brien-Fleming (0.53). The method achieved positive predictive value (PPV) of 0.80 and negative predictive value (NPV) of 0.82, nearest to the ideal truth oracle (PPV 0.96, NPV 0.84) that assumes perfect knowledge of the true scenario. Comparators performed worse: conditional power (PPV 0.63, NPV 0.68), Pocock (PPV 0.72, NPV 0.58), Chen 2-in-1 (PPV 0.52, NPV 0.60), and O'Brien-Fleming (PPV 0.81, NPV 0.53). CONCLUSION Inferring SBMoA using the Bayesian approach provides reliable interim forecasts of survival benefit in the absence of mature survival data. The innovation provides avenues for accelerating interim decision making with enhanced accuracy in confirmatory trials.

Comparing emerging treatment options is often challenging because of the sparseness of direct comparisons from head-to-head trials and inconsistencies in outcome measures among published placebo-controlled trials for each treatment. One potential solution is to aggregate the different outcome measures into a single ordinal response variable for consistent evaluation. The ordinal response variable will inevitably contain unknown response categories because they cannot be directly derived from published data in the literature. In this paper, we propose a statistical methodology to overcome such a common but unresolved issue in the context of network meta-regression for aggregate ordinal outcomes. Specifically, we introduce unobserved latent counts and model these counts within a Bayesian framework. The proposed approach includes several existing models as special cases and also allows us to conduct a proper statistical analysis in the presence of trials with certain missing categories. We then develop an efficient Markov chain Monte Carlo sampling algorithm to carry out Bayesian computation. Variations of the deviance information criterion and widely applicable information criterion are used for the assessment of goodness-of-fit under different distributions of the latent counts. A case study demonstrating the usefulness of the proposed methodology is conducted using aggregate ordinal outcome data from 18 clinical trials in treating Crohn's Disease.

In clinical trials, it is often valuable to borrow information from external data sources. Unfortunately, when the external data are fully or partially incompatible with the current trial data, type I error rates can be highly inflated under traditional blanket discounting schemes such as power priors, commensurate priors, and meta-analytic predictive priors. However, such inflation of the probability of a false positive can be necessary, as the alternative is to have an underpowered study. For clinical trials with time-to-event (TTE) outcomes, this problem is exacerbated since many observations are censored. In this paper, we develop the latent exchangeability prior for TTE data. We also present a novel framework to borrow information about the treatment effect between groups as well as incorporate information from external controls. Simulation results suggest that, although efficiency gains can be achieved by borrowing information among external controls, operating characteristics in general can be quite poor under a lack of exchangeability. We apply our approach to a real clinical trial in second-line metastatic colorectal cancer.

With the availability of unprecedented human genomic biomarker data, incorporating such biomarker data has received a lot of attention in phase 3 clinical trials. One particular enrichment design proposed recently in the literature is to recruit more biomarker positive patients in an all-comer study if the treatment effect in the biomarker negative group is less promising than expected. The intuition is to improve the chance of success of the trial since the success rate in the all-comer population may be low. We propose an enrichment design that unifies the existing biomarker adaptive designs for phase 3 clinical trials. In addition, we propose a new test accounting for the correlations among the test statistics based on different groups of patients, including all-comers, biomarker positive patients only, and biomarker negative patients only. We investigate the theoretical properties of the design and demonstrate the new test accurately controls the type I error rate and gains power over existing methods through extensive simulations. A computer program is developed for power calculations given a set of design parameters, including the proportion of biomarker positive patients, the distribution of the failure time in each treatment and biomarker group, and the number of patients in the first stage and the second stage (i.e. the enrichment stage), among others.

It is becoming increasingly popular to elicit informative priors on the basis of historical data. Popular existing priors, including the power prior, commensurate prior, and robust meta-analytic prior provide blanket discounting. Thus, if only a subset of participants in the historical data are exchangeable with the current data, these priors may not be appropriate. In order to combat this issue, propensity score (PS) approaches have been proposed. However, PS approaches are only concerned with the covariate distribution, whereas exchangeability is typically assessed with parameters pertaining to the outcome. In this paper, we introduce the latent exchangeability prior (LEAP), where observations in the historical data are classified into exchangeable and non-exchangeable groups. The LEAP discounts the historical data by identifying the most relevant subjects from the historical data. We compare our proposed approach against alternative approaches in simulations and present a case study using our proposed prior to augment a control arm in a phase 3 clinical trial in plaque psoriasis with an unbalanced randomization scheme.

In immuno-oncology, developing combination therapies to overcome resistance to single agent or induce synergistic effects has become a new focus. To accelerate the screening process to identify promising combinations based on objective response rates, we propose a Bayesian adaptive Umbrella Trial design to simultaneously evaluate combinations of an investigational compound with different backbones, where information borrowing across combinations is allowed to increase trial efficiency. A robust borrowing approach is developed to strike a balance between borrowing and not borrowing by accounting for different configurations of homogeneity of treatment effects using Bayesian model averaging. Unlike existing methods that use the response rates to measure the degree of homogeneity by assuming all arms share a common control rate, an advantage of our approach is that it uses relative treatment effects to determine the degree of homogeneity by adjusting for different control effects across combinations. In the proposed design, Bayesian adaptive interim analyses are implemented to drop futile combinations and graduate early efficacious combinations. Simulation studies demonstrate that the proposed design with robust information borrowing outperforms some existing approaches. It improves power when treatment effects are homogeneous and maintains reasonable arm-wise Type I error rates when heterogeneity is present across combinations. for this article are available online.

The discussions of our paper provide insights into the practical considerations of the latent exchangeability prior while also highlighting further extensions. In this rejoinder, we briefly summarize the discussions and provide comments.

SLE is a complex autoimmune disease with considerable unmet need. Numerous clinical trials designed to investigate novel therapies are actively enrolling patients straining limited resources and creating inefficiencies that increase enrolment challenges. This has motivated investigators developing novel drugs and treatment strategies to consider innovative trial designs that aim to improve the efficiency of generating evidence; these strategies propose conducting fewer trials, involving smaller numbers of patients, while maintaining scientific rigour in safety and efficacy data collection and analysis. In this review we present the design of two innovative phase IIb studies investigating efavaleukin alfa and rozibafusp alfa for the treatment of SLE which use an adaptive study design. This design was selected as a case study, investigating efavaleukin alfa, in the Food and Drug Administration's Complex Innovative Trial Design Pilot Program. The adaptive design approach includes prospectively planned modifications at predefined interim timepoints. Interim assessments of futility allow for a trial to end early when the investigational therapy is unlikely to provide meaningful treatment benefits to patients, which can release eligible patients to participate in other-potentially more promising-trials, or seek alternative treatments. Response-adaptive randomisation allows randomisation ratios to change based on accumulating data, in favour of the more efficacious dose arm(s), while the study is ongoing. Throughout the trial the placebo arm allocation ratio is maintained constant. These design elements can improve the statistical power in the estimation of treatment effect and increase the amount of safety and efficacy data collected for the optimal dose(s). Furthermore, these trials can provide the required evidence to potentially serve as one of two confirmatory trials needed for regulatory approval. This can reduce the need for multiple phase III trials, the total patient requirements, person-exposure risk, and ultimately the time and cost of investigational drug development programmes.

Background Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. The efficacy, safety and oral corticosteroid-sparing potential of tezepelumab are being investigated in two ongoing, phase 3, randomized, double-blind, placebo-controlled studies (NAVIGATOR [NCT03347279] and SOURCE [NCT03406078]). DESTINATION (NCT03706079) is a long-term extension (LTE) of these studies. Methods DESTINATION is a randomized, double-blind, placebo-controlled LTE study in adults (18–80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids. The study population will comprise patients who complete the 52- and 48-week NAVIGATOR and SOURCE studies, respectively. Patients who were randomized to receive tezepelumab 210 mg every 4 weeks (Q4W) in either predecessor study will continue to receive this regimen for 1 year; those who were previously randomized to receive placebo will be re-randomized (1:1) to receive either tezepelumab 210 mg Q4W or placebo for 1 year. Patients will receive their prescribed controller medications throughout DESTINATION and study physicians will have the opportunity to down- or up-titrate dosage of these medications, if appropriate. The primary objective is to evaluate the long-term safety and tolerability of tezepelumab over 104 weeks (inclusive of the treatment period of either predecessor study). The secondary objective is to assess the long-term effect of tezepelumab on asthma exacerbations. Patients recruited from SOURCE will be followed up post-treatment for 12 weeks. Patients recruited from NAVIGATOR who complete 100 weeks of tezepelumab treatment will be eligible for either 12 weeks of follow-up or a 36-week extended follow-up during which the clinical benefit of tezepelumab after treatment cessation will be investigated. Discussion DESTINATION will evaluate the long-term safety, tolerability and efficacy of tezepelumab versus placebo with continued dosing for up to 2 years. DESTINATION will also evaluate the clinical effect of tezepelumab after treatment cessation. This LTE study aims to elucidate the long-term safety implications of receiving tezepelumab and to assess its potential long-term treatment benefits in patients with severe, uncontrolled asthma. Trial registration NCT03706079 (ClinicalTrials.gov). Registered 15 October 2018.

Background Many patients with severe asthma continue to experience asthma symptoms and exacerbations despite standard-of-care treatment. A substantial proportion of these patients require long-term treatment with oral corticosteroids (OCS), often at high doses, which are associated with considerable multiorgan adverse effects, including metabolic disorders, osteoporosis and adrenal insufficiency. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma. Several ongoing phase 3 trials (SOURCE, NCT03406078; NAVIGATOR, NCT03347279; DESTINATION, NCT03706079) are assessing the efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma. Here, we describe the design and objectives of SOURCE, a phase 3 OCS-sparing study. Methods SOURCE is an ongoing phase 3, multicentre, randomized, double-blind, placebo-controlled study to evaluate the effect of tezepelumab 210 mg administered subcutaneously every 4 weeks on OCS dose reduction in adults with OCS-dependent asthma. The study comprises a 2-week screening and enrolment period, followed by an OCS optimization phase of up to 8 weeks and a 48-week treatment period, which consists of a 4-week induction phase, followed by a 36-week OCS reduction phase and an 8-week maintenance phase. The primary objective is to assess the effect of tezepelumab compared with placebo in reducing the prescribed OCS maintenance dose. The key secondary objective is to assess the effect of tezepelumab on asthma exacerbation rates. Other secondary objectives include the proportion of patients with a reduction in OCS dose (100% or 50% reduction or those receiving < 5 mg) and the effect of tezepelumab on lung function and patient-reported outcomes. Conclusions SOURCE is evaluating the OCS-sparing potential of tezepelumab in patients with OCS-dependent asthma. SOURCE also aims to demonstrate that treatment with tezepelumab in patients with severe asthma is associated with reductions in exacerbation rates and improvements in lung function, asthma control and health-related quality of life, while reducing OCS dose. Trial registration NCT03406078 ( ClinicalTrials.gov ). Registered 23 January 2018. https://clinicaltrials.gov/ct2/show/NCT03406078

Background Secondary hyperparathyroidism (sHPT), a complication of chronic kidney disease (CKD) characterized by persistently elevated parathyroid hormone (PTH), alterations in calcium-phosphorus homeostasis, and vitamin D metabolism, affects 50% of children receiving dialysis. A significant proportion of these children develop CKD-mineral and bone disorder (CKD-MBD), associated with an increased risk of fractures and vascular calcification. The standard of care for sHPT in children includes vitamin D sterols, calcium supplementation, and phosphate binders. Several agents are approved for sHPT treatment in adults undergoing dialysis, including vitamin D analogs and calcimimetics, with limited information on their safety and efficacy in children. The calcimimetic cinacalcet is approved for use in adults with sHPT on dialysis, but is not approved for pediatric use outside Europe. Methods This review provides dosing, safety, and efficacy information from Amgen-sponsored cinacalcet pediatric trials and data from non-Amgen sponsored clinical studies. Results The Amgen cinacalcet pediatric clinical development program consisted of two Phase 3 randomized studies, one Phase 3 single arm extension study, one open-label Phase 2 study, and two open-label Phase 1 studies. Effects of cinacalcet on PTH varied across studies. Overall, 7.4 to 57.1% of subjects who received cinacalcet in an Amgen clinical trial attained PTH levels within recommended target ranges and 22.2 to 70.6% observed a ≥ 30% reduction in PTH. In addition, significant reductions in PTH were demonstrated in all non-Amgen-supported studies. Conclusions To help inform the pediatric nephrology community, this manuscript contains the most comprehensive review of cinacalcet usage in pediatric CKD patients to date.

Crohn's disease (CD) is a life-long condition associated with recurrent relapses characterized by abdominal pain, weight loss, anemia, and persistent diarrhea. In the US, there are approximately 780 000 CD patients and 33 000 new cases added each year. In this article, we propose a new network meta-regression approach for modeling ordinal outcomes in order to assess the efficacy of treatments for CD. Specifically, we develop regression models based on aggregate covariates for the underlying cut points of the ordinal outcomes as well as for the variances of the random effects to capture heterogeneity across trials. Our proposed models are particularly useful for indirect comparisons of multiple treatments that have not been compared head-to-head within the network meta-analysis framework. Moreover, we introduce Pearson residuals and construct an invariant test statistic to evaluate goodness-of-fit in the setting of ordinal outcome data. A detailed case study demonstrating the usefulness of the proposed methodology is carried out using aggregate ordinal outcome data from 16 clinical trials for treating CD.

In most drug development settings, the regulatory approval process is accompanied by extensive studies performed to understand the drug's pharmacokinetic (PK) and pharmacodynamic (PD) properties. In this article, we attempt to utilize the rich PK/PD data to inform the borrowing of information from adults during pediatric drug development. In pediatric settings, it is especially crucial that we are parsimonious with the patients recruited for experimentation. We illustrate our approaches in the context of clinical trials of cinacalcet for treating secondary hyperparathyroidism in pediatric and adult patients with chronic kidney disease, where we model both parathyroid hormone (efficacy endpoint) and corrected calcium levels (safety endpoint). We use population PK/PD modeling of the cinacalcet data to quantitatively assess the similarity between adults and children, and use this information in various hierarchical Bayesian adult borrowing rules whose statistical properties can then be evaluated. In particular, we simulate the bias and mean square error performance of our approaches in settings where borrowing is and is not warranted to inform guidelines for the future use of our methods.

Many treatments and drugs are intended to reduce the occurrence of negative events of interest, control the severity of the events, accelerate recovery from the events, or a combination of these effects. While assessing the clinical effect is typically the primary objective of a trial, testing the treatment effect on the health status of patients based on patient reported outcome (PRO) can be a useful component in determining the value of a treatment. Analysis of PROs in this setting, however, face the following challenges: the PRO value immediately after the event occurrence is often not captured, and the effect of the event on health status measured by the PRO is transient as subjects recover over time. Therefore, traditional statistical methods used to assess treatment effects suffer from low power for PROs. In this manuscript, we apply a kernel smoothing technique to estimate before‐ and after‐event PRO values. We also propose new test outcomes based on observed and estimated PRO values and evaluate tests that focus on the tail distributions. We demonstrate that the tail distribution tests using the new outcomes can achieve high power under certain conditions.

Background: Tezepelumab (AMG 157/MEDI9929), a first-in-class monoclonal antibody, targets thymic stromal lymphopoietin, a cytokine that is implicated in the pathogenesis of atopic dermatitis (AD). Objective: We sought to evaluate the efficacy and safety of tezepelumab in adults with moderate to severe AD. Methods: In this phase 2a study (NCT02525094), 113 patients were randomized 1: 1 to subcutaneous tezepelumab 280 mg or placebo every 2 weeks, plus class 3 topical corticosteroids (TCS). The primary endpoint was the week 12 response rate for a >= 50% reduction in the Eczema Area and Severity Index (EASI50). Secondary endpoints including EASI75, Investigator's Global Assessment, SCORAD 50, SCORAD 75, pruritus numeric rating and 5-D itch scales, and exploratory endpoints (including EASI90) were assessed at weeks 12, and 16 (post hoc). Results: A numerically greater percentage of tezepelumab plus TCS-treated patients achieved EASI50 (64.7%) versus placebo plus TCS (48.2%; P = .091). Numerical improvements over placebo were demonstrated for week 12 secondary and exploratory endpoints, with further improvements at week 16. Treatment-emergent adverse events were similar between treatment groups. Limitations: Greater than expected response rates in placebo-treated patients were possibly attributable to TCS. Conclusion: Although not statistically significant, numerical improvements over placebo for all week 12 endpoints were demonstrated, with greater week 16 responses.

To evaluate the effect of tezepelumab, a human anti-thymic stromal lymphopoietin mAb, on asthma control in patients with severe, uncontrolled asthma. This 52-week, randomized, double-blind, placebo-controlled study (NCT02054130) included patients with severe, uncontrolled asthma (Asthma Control Questionnaire-6 [ACQ-6] ≥1.5). A total of 584 eligible adults were randomly assigned to subcutaneous tezepelumab 70mg Q4W (low), 210mg Q4W (medium), 280mg Q2W (high), or placebo Q2W. Mean change from baseline to Week 52 in ACQ-6; proportion of patients classified as responders (improvement ≥0.5); proportion of patients who were well-controlled (ACQ-6 ≤0.75), partially controlled (>0.75 ACQ-6 ≤1.5), and uncontrolled (ACQ-6 >1.5); and time-to-first asthma control (partial or well) were compared between treatment groups as secondary endpoints, without multiplicity adjustment. At Week 52, mean improvements from baseline in ACQ-6 were: placebo (–0.89); tezepelumab low (–1.13), medium (–1.16), high (–1.22) (P <0.05 for medium and high doses). A greater proportion of patients in the tezepelumab groups (75.6% overall) achieved clinically meaningful improvements ≥0.5 from baseline compared with placebo (61.7%) at Week 52 (P <0.05, LOCF). A greater proportion of patients in the tezepelumab groups were either well-controlled (27.2% in tezepelumab overall; 14.9% in placebo) or partially-controlled (22.0% in tezepelumab overall; 19.1% in placebo) at Week 52 (P <0.05, LOCF). The median time-to-first partially- or well-controlled asthma was reduced by half in the tezepelumab groups compared with placebo (70 days in tezepelumab overall; 140 days in placebo; P <0.05) through Week 52. Tezepelumab improves asthma control in patients with severe, uncontrolled asthma.

long-term evaluation of efficacy and safety of ozanimod 1 mg.TOUCHSTONE was a randomized, double-blind, placebo-controlled phase 2 trial designed to assess the efficacy and safety of ozanimod 0.5 mg and 1 mg versus placebo during induction and maintenance in patients with moderate to severe UC [1], and established that ozanimod induced and maintained clinical response, clinical remission (CR), endoscopic mucosal healing, and HR through weeks 8 and 32.Methods: A total of 197 patients were randomized (1:1:1) and treated with daily ozanimod at 0.5 mg, 1 mg, or placebo in TOUCHSTONE.Of the initial 197 patients randomized, 170 (86%) entered OLE and received daily ozanimod 1 mg, and 131 (77%) and 105 (62%) completed assessments at weeks 44 and 80.In this analysis, HR was defined as a Geboes score < 2 and CR was defined as rectal bleeding score = 0 and stool frequency score ≤ 1. Results: Of the patients who entered OLE, 27% showed histologic remission at the time of OLE entry and 34% were in CR.Clinical remission increased to 62% at OLE week 32, with 62%, and 55% in CR at OLE weeks 44 and 80.At OLE weeks 44 and 80, CR was seen in 83% and 80% of those in HR at OLE entry compared to 55% and 46% of those not in HR at OLE entry.The proportion of patients in CR increased throughout OLE while receiving 1 mg of ozanimod, regardless of prior treatment in the TOUCHSTONE study or HR status at OLE entry.The highest rates of CR were seen in patients in HR at OLE entry who had received ozanimod for 32 weeks prior to OLE entry, with CR rates at OLE weeks 4 and 8, with over 90% in CR.The lowest CR rates were seen in patients naïve to ozanimod and not in HR at OLE entry, with CR increasing from 13% at entry to 50% at OLE week 8, reaching a peak of 56% at OLE week 32.Overall, treatment with ozanimod for 32 to 36 weeks resulted in CR in 80% of patients.Most common adverse events seen in OLE were UC flare, back pain, URTI, anemia, and nasopharyngitis.Transient asymptomatic elevations in ALT or AST >3x ULN were seen in 3% of patients.Conclusion: Histological remission is predictive of CR in patients with UC receiving ozanimod 1 mg in OLE.All patients, whether naïve to or having received ozanimod in TOUCHSTONE, showed additional improvements in CR upon continued treatment with ozanimod 1 mg in OLE.Patients naïve to ozanimod had a rapid improvement in CR over the first 8 weeks of treatment with ozanimod 1 mg in OLE.[1]

BACKGROUND:In some patients with moderate-to-severe asthma, particularly those with noneosinophilic inflammation, the disease remains uncontrolled. This trial evaluated the efficacy and safety of tezepelumab (AMG 157/MEDI9929), a human monoclonal antibody specific for the epithelial-cell-derived cytokine thymic stromal lymphopoietin (TSLP), in patients whose asthma remained uncontrolled despite treatment with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids.METHODS:In this phase 2, randomized, double-blind, placebo-controlled trial, we compared subcutaneous tezepelumab at three dose levels with placebo over a 52-week treatment period. The primary end point was the annualized rate of asthma exacerbations (events per patient-year) at week 52.RESULTS:The use of tezepelumab at a dose of 70 mg every 4 weeks (low dose; 145 patients), 210 mg every 4 weeks (medium dose; 145 patients), or 280 mg every 2 weeks (high dose; 146 patients) resulted in annualized asthma exacerbation rates at week 52 of 0.26, 0.19, and 0.22, respectively, as compared with 0.67 in the placebo group (148 patients). Thus, exacerbation rates in the respective tezepelumab groups were lower by 61%, 71%, and 66% than the rate in the placebo group (P<0.001 for all comparisons). Similar results were observed in patients regardless of blood eosinophil counts at enrollment. The prebronchodilator forced expiratory volume in 1 second at week 52 was higher in all tezepelumab groups than in the placebo group (difference, 0.12 liters with the low dose [P=0.01], 0.11 liters with the medium dose [P=0.02], and 0.15 liters with the high dose [P=0.002]). A total of 2 patients in the medium-dose group, 3 in the high-dose group, and 1 in the placebo group discontinued the trial regimen because of adverse events.CONCLUSIONS:Among patients treated with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids, those who received tezepelumab had lower rates of clinically significant asthma exacerbations than those who received placebo, independent of baseline blood eosinophil counts. (Funded by MedImmune [a member of the AstraZeneca Group] and Amgen; PATHWAY ClinicalTrials.gov number, NCT02054130 .).

Background: Thymic stromal lymphopoietin (TSLP) is an epithelial cytokine and key regulator of inflammatory pathways including type 2 responses. Tezepelumab is a human anti-TSLP monoclonal antibody that reduces the early and late phase asthmatic responses to inhaled allergen. Objectives: To evaluate efficacy and safety of tezepelumab in patients with inadequately controlled, severe asthma. Methods: This was a 52-week randomized, double-blind, placebo-controlled study (NCT02054130). A total of 584 eligible adults with severe asthma and recurrent exacerbations were randomly assigned (1:1:1:1) to subcutaneous tezepelumab 70mg every 4 weeks (Q4W), 210mg Q4W, 280mg every 2 weeks (Q2W) or placebo Q2W. Randomization was stratified by region, blood eosinophils, and ICS dose. The primary endpoint was the annualized asthma exacerbation rate (AER) at Week 52. Results: Compared with placebo, AER reductions of 61%, 72%, and 66% were seen in 70, 210, and 280mg groups, respectively (p<0.001 for all comparisons; figure). Improvement in prebronchodilator FEV1, ACQ-6, and AQLQ (s) was seen in all tezepelumab dose groups. The incidence of adverse events (~60%) was similar across all treatment groups. Conclusion: Tezepelumab was well-tolerated and effective in reducing AER and improving FEV1 and asthma control in a broad population of patients with inadequately controlled, severe asthma. Study supported by MedImmune and Amgen.