Predicted number of peanut-allergic patients needed to treat with epicutaneous immunotherapy (EPIT) to prevent one allergic reaction: A novel approach to assessing relevance.
Ontology highlight
ABSTRACT:
SUBMITTER: Remington BC
PROVIDER: S-EPMC9291584 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
Publications
Predicted number of peanut-allergic patients needed to treat with epicutaneous immunotherapy (EPIT) to prevent one allergic reaction: A novel approach to assessing relevance.
Remington Benjamin C BC Koppelman Stef J SJ Green Todd D TD Lack Gideon G Roberts Graham G Campbell Dianne E DE
Allergy 20210619 10
Similar Datasets
Project description:BackgroundWe propose a new measure of treatment effect based on the expected reduction in the number of patients to treat (RNT) which is defined as the difference of the reciprocals of clinical measures of interest between two arms. Compared with the conventional number needed to treat (NNT), RNT shows superiority with both binary and time-to-event endpoints in randomized controlled trials (RCTs).MethodsFive real RCTs, two with binary endpoints and three with survival endpoints, are used to illustrate the concept of RNT and compare the performances between RNT and NNT. For survival endpoints, we propose two versions of RNT: one is based on the survival rate and the other is based on the restricted mean survival time (RMST). Hypothetical scenarios are also constructed to explore the advantages and disadvantages of RNT and NNT.ResultsBecause there is no baseline for computation of NNT, it fails to differentiate treatment effect in the absolute scale. In contrast, RNT conveys more information than NNT due to its reversed order of differencing and inverting. For survival endpoints, two versions of RNT calculated as the difference of the reciprocals of survival rates and RMSTs are complementary to each other. The RMST-based RNT can capture the entire follow-up profile and thus is clinically more intuitive and meaningful, as it inherits the time-to-event characteristics for survival endpoints instead of using truncated binary endpoints at a specific time point.ConclusionsThe RNT can serve as an alternative measure for quantifying treatment effect in RCTs, which complements NNT to help patients and clinicians better understand the magnitude of treatment benefit.
| S-EPMC7945324 | biostudies-literature
Project description:BackgroundLegume consumption has increased during the two past decades. In France, legumes are responsible for 14.6% of food-related anaphylaxis in children, with peanut as the main allergen (77.5%). Few studies have demonstrated cross-reactivities between peanut and other legumes. The aim of this study was to determine prevalence and relevance of sensitization to legumes in peanut-allergic children.MethodsAll children, aged of 1-17 years, admitted to the Pediatric Allergy Department of the University Hospital of Nancy between January 1, 2017 and February 29, 2020 with a confirmed peanut allergy (PA) and a documented consumption or sensitization to at least one other legume were included. Data were retrospectively collected regarding history of consumption, skin prick tests, specific immunoglobulin E (IgE), prior allergic reactions, and oral food challenges for each legume.ResultsAmong the 195 included children with PA, 122 were sensitized to at least one other legume (63.9%). Main sensitizations were for fenugreek (N = 61, 66.3%), lentil (N = 38, 42.2%), soy (N = 61, 39.9%), and lupine (N = 63, 34.2%). Among the 122 sensitized children, allergy to at least one legume was confirmed for 34 children (27.9%), including six children who had multiple legume allergies (4.9%). Lentil, lupine, and pea were the main responsible allergens. Half of allergic reactions to legumes other than peanut were severe.ConclusionThe high prevalence of legume sensitization and the frequent severe reactions reported in children with PA highlight that tolerated legume consumption should be explored for each legume in the case of PA, and sensitization should be investigated if not.
| S-EPMC9544501 | biostudies-literature
Project description:Clinicians are expected to select a therapy based on their appraisal of evidence on benefit-to-risk profiles of therapies. In the management of relapsing-remitting multiple sclerosis (RRMS), evidence is typically expressed in terms of risk (proportion) of event, risk reduction, relative and hazard rate reduction, or relative reduction in the mean number of magnetic resonance imaging lesions. Interpreting treatment effect using these measures from a RRMS clinical trial is fairly reliable; however, this might not be the case when treatment effect is expressed in terms of the number needed to treat (NNT). The objective of this review is to discuss the utility of NNT in RRMS trials. This article presents an overview of the methodological definition and characteristics of NNT as well as the relative merit of NNT use in RRMS controlled clinical trials, where endpoints are typically time-to-event and frequency of recurrent events. The authors caution against using NNT in multiple sclerosis, a clinically heterogeneous disease that can change course and severity unpredictably. The authors also caution against the use of NNT to interpret results in comparative trials where the absolute risk difference is not statistically significant, computing NNT using the time-to-event endpoint at intermediate time points, computing NNT using the annualized relapse rate, and comparing NNT across trials.
| S-EPMC5447556 | biostudies-literature
Project description:ImportanceThere are currently no approved treatments for peanut allergy.ObjectiveTo assess the efficacy and adverse events of epicutaneous immunotherapy with a peanut patch among peanut-allergic children.Design, setting, and participantsPhase 3, randomized, double-blind, placebo-controlled trial conducted at 31 sites in 5 countries between January 8, 2016, and August 18, 2017. Participants included peanut-allergic children (aged 4-11 years [n = 356] without a history of a severe anaphylactic reaction) developing objective symptoms during a double-blind, placebo-controlled food challenge at an eliciting dose of 300 mg or less of peanut protein.InterventionsDaily treatment with peanut patch containing either 250 μg of peanut protein (n = 238) or placebo (n = 118) for 12 months.Main outcomes and measuresThe primary outcome was the percentage difference in responders between the peanut patch and placebo patch based on eliciting dose (highest dose at which objective signs/symptoms of an immediate hypersensitivity reaction developed) determined by food challenges at baseline and month 12. Participants with baseline eliciting dose of 10 mg or less were responders if the posttreatment eliciting dose was 300 mg or more; participants with baseline eliciting dose greater than 10 to 300 mg were responders if the posttreatment eliciting dose was 1000 mg or more. A threshold of 15% or more on the lower bound of a 95% CI around responder rate difference was prespecified to determine a positive trial result. Adverse event evaluation included collection of treatment-emergent adverse events (TEAEs).ResultsAmong 356 participants randomized (median age, 7 years; 61.2% male), 89.9% completed the trial; the mean treatment adherence was 98.5%. The responder rate was 35.3% with peanut-patch treatment vs 13.6% with placebo (difference, 21.7% [95% CI, 12.4%-29.8%; P < .001]). The prespecified lower bound of the CI threshold was not met. TEAEs, primarily patch application site reactions, occurred in 95.4% and 89% of active and placebo groups, respectively. The all-causes rate of discontinuation was 10.5% in the peanut-patch group vs 9.3% in the placebo group.Conclusions and relevanceAmong peanut-allergic children aged 4 to 11 years, the percentage difference in responders at 12 months with the 250-μg peanut-patch therapy vs placebo was 21.7% and was statistically significant, but did not meet the prespecified lower bound of the confidence interval criterion for a positive trial result. The clinical relevance of not meeting this lower bound of the confidence interval with respect to the treatment of peanut-allergic children with epicutaneous immunotherapy remains to be determined.Trial registrationClinicalTrials.gov Identifier: NCT02636699.
| S-EPMC6439674 | biostudies-literature
Project description:ObjectiveSchizophrenia clinical trials commonly measure observed changes in Positive and Negative Syndrome Scale (PANSS) total score. However, it is more intuitive to think of response vs nonresponse, a binary outcome. Assessing binary outcomes enables calculation of number needed to treat (NNT) for therapeutic outcomes, number needed to harm (NNH) for adverse outcomes, and likelihood to be helped or harmed (LHH) to demonstrate benefit/risk tradeoffs. Here, NNT, NNH, and LHH were used to evaluate the clinical usefulness of aripiprazole lauroxil in patients with an acute schizophrenia exacerbation.MethodsCategorical efficacy and tolerability data were taken from the pivotal Phase 3 trial evaluating aripiprazole lauroxil for treatment of an acute exacerbation of schizophrenia. NNT and NNH values, with 95% CIs, were calculated in this post hoc analysis.ResultsUsing the intent-to-treat population for the pooled doses of aripiprazole lauroxil (441 mg [n=196] and 882 mg [n=204] q4w), responder rates (≥30% improvement from baseline PANSS total score) were 35.3% for aripiprazole lauroxil arms vs 18.4% for placebo (n=196), yielding a NNT of 6 (95% CI: 5-11). Discontinuation rates due to adverse events (AEs) were higher among patients randomized to placebo than to either aripiprazole lauroxil dose. Akathisia was the only AE with an incidence ≥5% in each aripiprazole lauroxil group and at least twice that of placebo (11.6%, 11.5%, and 4.3% of the patients receiving aripiprazole lauroxil 441 mg, 882 mg, and placebo, respectively), producing a NNH of 14 (95% CI: 9-33) for pooled aripiprazole lauroxil doses vs placebo. Calculating LHH for therapeutic response vs akathisia, aripiprazole lauroxil was 2.3 times more likely to result in a therapeutic response than an incident of akathisia.ConclusionUsing metrics of NNT, NNH, and LHH, aripiprazole lauroxil was an efficacious and well-tolerated intervention in a pivotal study in patients with an acute schizophrenia exacerbation.
| S-EPMC6751763 | biostudies-literature
Project description:ImportanceEpicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed only in preclinical and early human trials.ObjectiveTo determine the optimal dose, adverse events (AEs), and efficacy of a peanut patch for peanut allergy treatment.Design, setting, and participantsPhase 2b double-blind, placebo-controlled, dose-ranging trial of a peanut patch in peanut-allergic patients (6-55 years) from 22 centers, with a 2-year, open-label extension (July 31, 2012-July 31, 2014; extension completed September 29, 2016). Patients (n = 221) had peanut sensitivity and positive double-blind, placebo-controlled food challenges to an eliciting dose of 300 mg or less of peanut protein.InterventionsRandomly assigned patients (1:1:1:1) received an epicutaneous peanut patch containing 50 μg (n = 53), 100 μg (n = 56), or 250 μg (n = 56) of peanut protein or a placebo patch (n = 56). Following daily patch application for 12 months, patients underwent a double-blind, placebo-controlled food challenge to establish changes in eliciting dose.Main outcomes and measuresThe primary efficacy end point was percentage of treatment responders (eliciting dose: ≥10-times increase and/or reaching ≥1000 mg of peanut protein) in each group vs placebo patch after 12 months. Secondary end points included percentage of responders by age strata and treatment-emergent adverse events (TEAEs).ResultsOf 221 patients randomized (median age, 11 years [quartile 1, quartile 3: 8, 16]; 37.6% female), 93.7% completed the trial. A significant absolute difference in response rates was observed at month 12 between the 250-μg (n = 28; 50.0%) and placebo (n = 14; 25.0%) patches (difference, 25.0%; 95% CI, 7.7%-42.3%; P = .01). No significant difference was seen between the placebo patch vs the 100-μg patch. Because of statistical testing hierarchical rules, the 50-μg patch was not compared with placebo. Interaction by age group was only significant for the 250-μg patch (P = .04). In the 6- to 11-year stratum, the response rate difference between the 250-μg (n = 15; 53.6%) and placebo (n = 6; 19.4%) patches was 34.2% (95% CI, 11.1%-57.3%; P = .008); adolescents/adults showed no difference between the 250-μg (n = 13; 46.4%) and placebo (n = 8; 32.0%) patches: 14.4% (95% CI, -11.6% to 40.4%; P = .40). No dose-related serious AEs were observed. The percentage of patients with 1 or more TEAEs (largely local skin reactions) was similar across all groups in year 1: 50-μg patch = 100%, 100-μg patch = 98.2%, 250-μg patch = 100%, and placebo patch = 92.9%. The overall median adherence was 97.6% after 1 year; the dropout rate for treatment-related AEs was 0.9%.Conclusions and relevanceIn this dose-ranging trial of peanut-allergic patients, the 250-μg peanut patch resulted in significant treatment response vs placebo patch following 12 months of therapy. These findings warrant a phase 3 trial.Trial registrationclinicaltrials.gov Identifier: NCT01675882.
| S-EPMC5820709 | biostudies-literature
Project description:BackgroundReliable prognostic markers for predicting severity of allergic reactions during oral food challenges (OFCs) have not been established.ObjectiveTo develop a predictive algorithm of a food challenge severity score (CSS) to identify those at higher risk for severe reactions to a standardized peanut OFC.MethodsMedical history and allergy test results were obtained for 120 peanut allergic participants who underwent double-blind, placebo-controlled food challenges. Reactions were assigned a CSS between 1 and 6 based on cumulative tolerated dose and a severity clinical indicator. Demographic characteristics, clinical features, peanut component IgE values, and a basophil activation marker were considered in a multistep analysis to derive a flexible decision rule to understand risk during peanut of OFC.ResultsA total of 18.3% participants had a severe reaction (CSS >4). The decision rule identified the following 3 variables (in order of importance) as predictors of reaction severity: ratio of percentage of CD63hi stimulation with peanut to percentage of CD63hi anti-IgE (CD63 ratio), history of exercise-induced asthma, and ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio. The CD63 ratio alone was a strong predictor of CSS (P < .001).ConclusionThe CSS is a novel tool that combines dose thresholds and allergic reactions to understand risks associated with peanut OFCs. Laboratory values (CD63 ratio), along with clinical variables (exercise-induced asthma and FEV1/FVC ratio) contribute to the predictive ability of the severity of reaction to peanut OFCs. Further testing of this decision rule is needed in a larger external data source before it can be considered outside research settings.Trial registrationClinicalTrials.gov identifier: NCT02103270.
| S-EPMC6026554 | biostudies-literature
Project description:BackgroundUnexpected allergic reactions to peanut are the most common cause of fatal food-related anaphylaxis. Mechanisms underlying the variable severity of peanut-allergic reactions remain unclear.ObjectivesWe sought to expand mechanistic understanding of reaction severity in peanut allergy.MethodsWe performed an integrated transcriptomic and epigenomic study of peanut-allergic children as they reacted in vivo during double-blind, placebo-controlled peanut challenges. We integrated whole-blood transcriptome and CD4+ T-cell epigenome profiles to identify molecular signatures of reaction severity (ie, how severely a peanut-allergic child reacts when exposed to peanut). A threshold-weighted reaction severity score was calculated for each subject based on symptoms experienced during peanut challenge and the eliciting dose. Through linear mixed effects modeling, network construction, and causal mediation analysis, we identified genes, CpGs, and their interactions that mediate reaction severity. Findings were replicated in an independent cohort.ResultsWe identified 318 genes with changes in expression during the course of reaction associated with reaction severity, and 203 CpG sites with differential DNA methylation associated with reaction severity. After replicating these findings in an independent cohort, we constructed interaction networks with the identified peanut severity genes and CpGs. These analyses and leukocyte deconvolution highlighted neutrophil-mediated immunity. We identified NFKBIA and ARG1 as hubs in the networks and 3 groups of interacting key node CpGs and peanut severity genes encompassing immune response, chemotaxis, and regulation of macroautophagy. In addition, we found that gene expression of PHACTR1 and ZNF121 causally mediates the association between methylation at corresponding CpGs and reaction severity, suggesting that methylation may serve as an anchor upon which gene expression modulates reaction severity.ConclusionsOur findings enhance current mechanistic understanding of the genetic and epigenetic architecture of reaction severity in peanut allergy.
| S-EPMC7192362 | biostudies-literature
Project description:To investigate the issues of the NNT based on the absolute risk reduction (ARR), namely NNTARR; and to propose an alternative definition and an estimation procedure based on the restricted mean survival time (RMST), namely NNTRMST, for RCTs. Three recent clinical trials with survival endpoints, representing different scenarios, were selected to compare the performance of the NNTARR and NNTRMST. For each trial, both versions of NNT were estimated using the reconstructed individual-level data, and the average life gain (ALG) was derived to show the differences between the NNTARR and NNTRMST. Four hypothetical scenarios were constructed to further explore the advantages and disadvantages of each definition of the NNT for survival endpoints. For the illustrative trial examples, the NNTARR failed to capture the profile of the treatment effect over time as it is calculated at a specific time point. Sometimes it may even result in misinterpretations of the treatment benefit. In particular, when either the observed event rates are low, the two survival curves cross, or a mixture of survival patterns exist. In contrast, the NNTRMST based on the average survival (or event-free) time can quantify the treatment effect more accurately and its interpretation is more intuitive and clinically meaningful. The NNTRMST can be used as an alternative measure for quantifying treatment effect in RCTs, especially so in the case of the ALG, which helps practitioners to better understand the magnitude of the benefit conferred by treatment.
| S-EPMC6799908 | biostudies-literature
Project description:The number needed to treat (NNT) is considered an intuitive as well as popular effect measure. The aims of this review were to 1) explain why we cannot compare trial-specific NNT estimates for the competing treatments evaluated in different randomized controlled trials (RCTs) and 2) outline the principles of how relative treatment effects of different trials can be compared and results can be presented as NNT, without violating the principles of valid between-trial comparisons. Our premise is that ratio measures for relative treatment effects of response outcomes are less prone to effect modification than absolute difference measures of response outcomes. Accordingly, any between-trial comparisons of the efficacy of competing interventions using the study-specific ORs are less likely to be invalid or biased than comparisons based on the study-specific NNT estimates. However, treatment-specific ORs obtained from a meta-analysis or taken directly from an individual study can be transformed into consistent treatment-specific NNT estimates that allow for credible comparisons of treatments when these ratio measures are applied to the same reference response estimate. The theoretical discussion is illustrated with a relevant indirect comparison of biologics for the treatment of ulcerative colitis. Between-trial comparisons directly based on the NNT of individual trials may result in erroneous conclusions and should be avoided. Treatment-specific NNT estimates need to be based on the same probability of response with the common reference treatment against which the interventions are compared.
| S-EPMC6298880 | biostudies-literature