Search

IntroductionAtopic dermatitis (AD) is a chronic inflammatory skin disorder with limited treatment options for adolescents with moderate-to-severe disease. Lebrikizumab, a monoclonal antibody targeting interleukin (IL)-13, demonstrated clinical benefit in previous Phase 3 trials: ADvocate1 (NCT04146363), ADvocate2 (NCT04178967), and ADhere (NCT04250337). We report 52-week safety and efficacy outcomes from ADore (NCT04250350), a Phase 3, open-label study of lebrikizumab in adolescent patients with moderate-to-severe AD. The primary endpoint was to describe the proportion of patients who discontinued from study treatment because of adverse events (AEs) through the last treatment visit.MethodsAdolescent patients (N = 206) (≥ 12 to

IntroductionPeople who inject drugs (PWID) experience high HIV incidence and face significant barriers to engagement in HIV care and substance use treatment. Strategies for HIV treatment as prevention and substance use treatment present unique challenges in PWID that may vary regionally. Understanding differences in the risk structure for HIV transmission and disease progression among PWID is essential in developing and effectively targeting intervention strategies of HIV treatment as prevention.MethodsWe present a baseline analysis of HIV Prevention Trials Network (HPTN) 074, a two-arm, randomized controlled trial among PWID in Indonesia (n = 258), Ukraine (n = 457) and Vietnam (n = 439). HPTN 074 was designed to determine the feasibility, barriers and uptake of an integrated intervention combining health systems navigation and psychosocial counselling for the early engagement of antiretroviral therapy (ART) and substance use treatment for PWID living with HIV. Discordant PWID networks were enrolled, consisting of an HIV-positive index and their HIV-negative network injection partner(s). Among the enrolled cohort of 1154 participants (502 index participants and 652 network partners), we examine regional differences in the baseline risk structure, including sociodemographics, HIV and substance use treatment history, and injection and sexual risk behaviours.ResultsThe majority of participants were male (87%), with 82% of the enrolled females coming from Ukraine. The overall mean age was 34 (IQR: 30, 38). Most commonly injected substances included illegally manufactured methadone in Ukraine (84.2%), and heroin in Indonesia (81.8%) and Vietnam (99.5%). Injection network sizes varied by region: median number of people with whom participants self-reported injecting drugs was 3 (IQR: 2, 5) in Indonesia, 5 (IQR: 3, 10) in Ukraine and 3 (IQR: 2, 4) in Vietnam. Hazardous alcohol use, assessed using the Alcohol Use Disorders Identification Test - Alcohol Consumption Questions (AUDIT-C), was prominent in Ukraine (54.7%) and Vietnam (26.4%). Reported sexual risk behaviours in the past month, including having two or more sex partners and giving/receiving money or drugs in exchange for sex, were uncommon among all participants and regions.ConclusionsWhile regional differences in risk structure exist, PWID particularly in Ukraine need immediate attention for risk reduction strategies. Substantial regional differences in risk structure will require flexible, tailored treatment as prevention interventions for distinct PWID populations.

BackgroundPeople who inject drugs (PWID) have a high incidence of HIV, little access to antiretroviral therapy (ART) and medication-assisted treatment (MAT), and high mortality. We aimed to assess the feasibility of a future controlled trial based on the incidence of HIV, enrolment, retention, and uptake of the intervention, and the efficacy of an integrated and flexible intervention on ART use, viral suppression, and MAT use.MethodsThis randomised, controlled vanguard study was run in Kyiv, Ukraine (one community site), Thai Nguyen, Vietnam (two district health centre sites), and Jakarta, Indonesia (one hospital site). PWID who were HIV infected (index participants) and non-infected injection partners were recruited as PWID network units and were eligible for screening if they were aged 18-45 years (updated to 18-60 years 8 months into study), and active injection drug users. Further eligibility criteria for index participants included a viral load of 1000 copies per mL or higher, willingness and ability to recruit at least one injection partner who would be willing to participate. Index participants were randomly assigned via a computer generated sequence accessed through a secure web portal (3:1) to standard of care or intervention, stratified by site. Masking of assignment was not possible due to the nature of intervention. The intervention comprised systems navigation, psychosocial counselling, and ART at any CD4 count. Local ART and MAT services were used. Participants were followed up for 12-24 months. The primary objective was to assess the feasibility of a future randomised controlled trial. To achieve this aim we looked at the following endpoints: HIV incidence among injection partners in the standard of care group, and enrolment and retention of HIV-infected PWID and their injection partners and the uptake of the integrated intervention. The study was also designed to assess the feasibility, barriers, and uptake of the integrated intervention. Endpoints were assessed in a modified intention-to-treat popualtion after exclusion of ineligible participants. This trial is registered on ClinicalTrials.gov, NCT02935296, and is active but not recruiting new participants.FindingsBetween Feb 5, 2015, and June 3, 2016, 3343 potential index participants were screened, of whom 502 (15%) were eligible and enrolled. 1171 injection partners were referred, and 806 (69%) were eligible and enrolled. Index participants were randomly assigned to intervention (126 [25%]) and standard of care (376 [75%]) groups. At week 52, most living index participants (389 [86%] of 451) and partners (567 [80%] of 710) were retained, and self-reported ART use was higher among index participants in the intervention group than those in the standard of care group (probability ratio [PR] 1·7, 95% CI 1·4-1·9). Viral suppression was also higher in the intervention group than in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Index participants in the intervention group reported more MAT use at 52 weeks than those in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Seven incident HIV infections occurred, and all in injection partners in the standard of care group (intervention incidence 0·0 per 100 person-years, 95% CI 0·0-1·7; standard of care incidence 1·0 per 100 person-years, 95% CI 0·4-2·1; incidence rate difference -1·0 per 100 person-years, 95% CI -2·1 to 1·1). No severe adverse events due to the intervention were recorded.InterpretationThis vanguard study provides evidence that a flexible, scalable intervention increases ART and MAT use and reduces mortality among PWID. The low incidence of HIV in both groups impedes a future randomised, controlled trial, but given the strength of the effect of the intervention, its implementation among HIV-infected PWID should be considered.FundingUS National Institutes of Health.

Missing data occur in clinical trials and have the potential to lead to biased results. Subsequently, the analytical methods for handling the missing data are important to evaluate. In atopic dermatitis (AD) trials, missing data are not handled consistently across studies. Lebrikizumab is a monoclonal antibody that binds with high affinity and slow off-rate to interleukin (IL)-13, thereby blocking the downstream effects of IL-13 with high potency. In ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967), two randomized, double-blinded, placebo-controlled Phase 3 trials evaluating the efficacy and safety of lebrikizumab monotherapy in adolescent and adult patients with moderate-to-severe AD, a combined nonresponder/multiple imputation (NRI/MI) approach, was applied on the primary and key secondary endpoints. This study aims to illustrate the NRI/MI method using individual patient examples and to present Week 16 study results from ADvocate1 and ADvocate2 with NRI/MI and single imputation methods, NRI and last-observation carried forward (LOCF). In the combined NRI/MI method, data from patients after initiating rescue medication or discontinuing treatment due to lack of efficacy were imputed with NRI, and missing data for other reasons were imputed with MI, which uses a statistical model based on all available patient data to impute missing values. The MI method considers each patient's trajectory and leverages information from other patients within the same treatment arm to impute the missing data. With NRI alone, the cause leading to the missing data is not considered and missing data for any reason are imputed as nonresponse. With LOCF, missing data are replaced with the last available measurement; LOCF assumes that the patient response would be stable over time and does not consider the reason for missing data. We determined the amount of missing data in ADvocate1 and ADvocate2, and we assessed patient-level imputed IGA scores to illustrate NRI/MI, NRI and LOCF. With these missing data handling methods, we evaluated the percentage of patients achieving the co-primary endpoints of ADvocate1 and ADvocate2: an Investigator's Global Assessment score of 0 or 1 [IGA (0,1); clear or almost clear] with ≥2-point improvement from baseline or 75% improvement in Eczema Area and Severity Index (EASI 75) at Week 16. With the NRI/MI method, most missing data at Week 16 were imputed with NRI (ADvocate1: 73%, ADvocate2: 82%) compared with MI (ADvocate1: 27%, ADvocate2: 18%). Example imputed IGA scores based on patient-level data will be presented to demonstrate the missing data handling methods. For NRI/MI, NRI and LOCF, respectively, the percentage of patients achieving IGA 0,1 were 12.7%, 11.3% and 12.8% for placebo in ADvocate1 and 10.8%, 9.6% and 11.0% for placebo in ADvocate2; 43.1%, 41.0% and 42.4% for lebrikizumab in ADvocate1 and 33.2%, 31.3% and 33.5% for lebrikizumab in ADvocate2. The percentage of patients achieving EASI 75 were 16.2%, 14.2% and 16.3% for placebo in ADvocate1 and 18.1%, 17.1% and 19.2% for placebo in ADvocate2; 58.8%, 56.5% and 60.1% for lebrikizumab in ADvocate1 and 52.1%, 50.2% and 55.5% for lebrikizumab in ADvocate2. When using the NRI/MI method, we determined most missing data in ADvocate1 and ADvocate2 were handled with NRI. This analysis suggests that the NRI/MI method may provide a realistic estimation of response rate in ADvocate1 and ADvocate2. [ABSTRACT FROM AUTHOR]

Etiologic heterogeneity occurs when distinct sets of events or exposures give rise to different subtypes of disease. Inference about subtype-specific exposure effects from two-phase outcome-dependent sampling data requires adjustment for both confounding and the sampling design. Common approaches to inference for these effects do not necessarily appropriately adjust for these sources of bias, or allow for formal comparisons of effects across different subtypes. Herein, using inverse probability weighting (IPW) to fit a multinomial model is shown to yield valid inference with this sampling design for subtype-specific exposure effects and contrasts thereof. The IPW approach is compared to common regression-based methods for assessing exposure effect heterogeneity using simulations. The methods are applied to estimate subtype-specific effects of various exposures on breast cancer risk in the Carolina Breast Cancer Study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)