Predicted number of peanut-allergic patients needed to treat with epicutaneous immunotherapy (EPIT) to prevent one allergic reaction: A novel approach to assessing relevance.
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SUBMITTER: Remington BC
PROVIDER: S-EPMC9291584 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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:BackgroundPeanut allergy is common, life-threatening, and without therapeutic options. We evaluated peanut epicutaneous immunotherapy (EPIT) by using Viaskin Peanut for peanut allergy treatment.ObjectiveWe sought to evaluate the clinical, safety, and immunologic effects of EPIT for the treatment of peanut allergy.MethodsIn this multicenter, double-blind, randomized, placebo-controlled study, 74 participants with peanut allergy (ages 4-25 years) were treated with placebo (n = 25), Viaskin Peanut 100 μg (VP100; n = 24) or Viaskin Peanut 250 μg (VP250; n = 25; DBV Technologies, Montrouge, France). The primary outcome was treatment success after 52 weeks, which was defined as passing a 5044-mg protein oral food challenge or achieving a 10-fold or greater increase in successfully consumed dose from baseline to week 52. Adverse reactions and mechanistic changes were assessed.ResultsAt week 52, treatment success was achieved in 3 (12%) placebo-treated participants, 11 (46%) VP100 participants, and 12 (48%) VP250 participants (P = .005 and P = .003, respectively, compared with placebo; VP100 vs VP250, P = .48). Median change in successfully consumed doses were 0, 43, and 130 mg of protein in the placebo, VP100, and VP250 groups, respectively (placebo vs VP100, P = .014; placebo vs VP250, P = .003). Treatment success was higher among younger children (P = .03; age, 4-11 vs >11 years). Overall, 14.4% of placebo doses and 79.8% of VP100 and VP250 doses resulted in reactions, predominantly local patch-site and mild reactions (P = .003). Increases in peanut-specific IgG4 levels and IgG4/IgE ratios were observed in peanut EPIT-treated participants, along with trends toward reduced basophil activation and peanut-specific TH2 cytokines.ConclusionsPeanut EPIT administration was safe and associated with a modest treatment response after 52 weeks, with the highest responses among younger children. This, when coupled with a high adherence and retention rate and significant changes in immune pathways, supports further investigation of this novel therapy.
| S-EPMC8609774 | 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:BackgroundConsortium for Food Allergy Research investigators previously reported 52-week outcomes from a randomized controlled trial of peanut epicutaneous immunotherapy, observing modest and statistically significant induction of desensitization, highest in children ages 4 to 11 years.ObjectiveWe sought to evaluate changes in efficacy, safety, and mechanistic parameters following extended open-label peanut epicutaneous immunotherapy.MethodsPeanut-allergic participants (4-25 years) received 52 weeks of placebo (PLB), Viaskin Peanut 100 μg (VP100) or 250 μg (VP250), and then crossed over to VP250 for PLB (PLB-VP250) and VP100 (VP100-VP250) participants and continued treatment for VP250 participants (total = 130 weeks of active epicutaneous immunotherapy). Efficacy was assessed by double-blind, placebo-controlled food challenge (5044 mg peanut protein), and adherence, safety, and mechanistic parameters were evaluated.ResultsAt week 130, desensitization success was achieved in 1 of 20 (5%) PLB-VP250, 5 of 24 (20.8%) VP100-VP250, and 9 of 25 (36%) VP250 participants, with median successfully consumed dose change from baseline of 11.5 mg, 141.5 mg, and 400 mg, respectively. Median age (years) for week 130 desensitization success was 6.2 years (interquartile range, 5.2-9.1) versus 9.4 years (interquartile range, 7.6-12.8) for failures (P < .001). Adherence was 96%. Adverse reactions were predominantly local patch-site reactions. Significant increases in peanut- and Ara h2-specific IgG4 observed at week 52 persisted to week 130. By a post hoc analysis, there were no statistically significant increases from week 52 to week 130 in either desensitization success or successfully consumed dose.ConclusionsExtended treatment with VP250 was well tolerated, and desensitization observed at week 52 persisted between weeks 52 and 130. Treatment success was observed predominantly in younger participants, with younger age at initiation of active therapy an important predictor of success.
| S-EPMC8612061 | 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:In Westernized countries, over 1% of the population is allergic to peanuts or tree nuts, which carries a risk of severe allergic reactions. Several studies support the efficacy of peanut oral immunotherapy (OIT) for reducing the clinical sensitivity of affected individuals; however, the mechanisms of this effect are still being characterized. One mechanism that may contribute is the suppression of effector cells, such as basophils. Basophil anergy has been characterized in vitro as a pathway-specific hyporesponsiveness; however, this has not been demonstrated to occur in vivo.To evaluate the hypothesis that basophil anergy occurs in vivo due to chronic allergen exposure in the setting of a clinical oral immunotherapy trial.Samples of peripheral blood were obtained from subjects during a placebo-controlled clinical trial of peanut OIT. Basophil reactivity to in vitro stimulation with peanut allergen and controls was assessed by the upregulation of activation markers, CD63 and CD203c, measured by flow cytometry.The upregulation of CD63 following stimulation of the IgE receptor, either specifically with peanut allergen or non-specifically with anti-IgE antibody, was strongly suppressed by active OIT. However, OIT did not significantly suppress this response in basophils stimulated by the distinct fMLP receptor pathway. In the subset of subjects with egg sensitization, active peanut OIT also suppressed CD63 upregulation in response to stimulation with egg allergen. Allergen OIT also suppressed the upregulation of CD203c including in response to stimulation with IL-3 alone.Peanut OIT induces a hyporesponsive state in basophils that is consistent with pathway-specific anergy previously described in vitro. This suggests the hypothesis that effector cell anergy could contribute to clinical desensitization.
| S-EPMC3779434 | biostudies-literature
Project description:Objective:Schizophrenia 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. Methods:Categorical 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. Results:Using 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. Conclusion:Using 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: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
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