Formal Statistical Tests Research Articles

Spesolimab for Hidradenitis Suppurativa: A Proof-of-Concept Study

Introduction: Hidradenitis suppurativa (HS) is a chronic, inflammatory disorder characterized by painful inflammatory nodules (N), abscesses (A) and draining tunnels (dT), primarily affecting intertriginous areas. Interleukin-36 (IL-36) signaling has been notably expressed within HS inflammatory lesions. To address the need for targeted therapies, this Phase IIa proof-of-clinical-concept (PoCC) study (NCT04762277) explored the effect of spesolimab, an anti-IL-36 receptor monoclonal antibody, in patients with moderate-to-severe HS.
 Methods: Eligible patients (N=52) were randomized (2:1) to receive spesolimab or placebo (1200 mg intravenous dosing once weekly for three weeks [loading dose], followed by 1200 mg subcutaneous dosing every 2 weeks for 12 weeks). No formal statistical tests were performed, as this was an exploratory study. Of patients who completed the study, 45 were enrolled in an ongoing open-label extension (OLE) study (NCT04876391) with spesolimab. For each study, endpoints included change from baseline at Weeks 12 and 24 in total A, N and dT (ANdT) counts, and adverse events (AEs).
 Results: Mean changes from baseline at Week 12 in dT, A and total ANdT counts were -1.30, -0.53 and -4.87 in the spesolimab arm, and 1.07, 3.07 and -0.86 in the placebo arm, respectively. Mean changes in N count were numerically similar between the spesolimab (-3.00) and placebo (-5.00) arms. Of patients with ≥1 dT at baseline, a numerically greater proportion had a decrease in dT count at Week 12 in the spesolimab (16/24, 66.7%) versus the placebo (5/13, 38.5%) arm. Least squares mean changes from baseline in total AN count at Week 12 were -38.8% and -34.7% in the spesolimab and placebo arms, respectively, which may have been affected by higher baseline AN and N counts in the spesolimab versus placebo arm. In the OLE, patients originally randomized to spesolimab (n=30) achieved sustained reductions in dT count and in International Hidradenitis Suppurativa Severity Score (IHS4) at Week 24. The safety profile of spesolimab was similar to that reported in other trials; among the 52 patients enrolled in the PoCC study, 77.8% (spesolimab) and 87.5% (placebo) of patients reported ≥1 AE. No patients receiving spesolimab reported serious AEs, and no new safety concerns were identified by Week 24. No deaths were reported.
 Conclusion: Our findings show that spesolimab was well tolerated and decreased all HS lesions. These results support the development of spesolimab in HS.
 This study was supported and funded by Boehringer Ingelheim.

Modifiable risk factors for multiple sclerosis have consistent directions of effect across diverse ethnic backgrounds: a nested case–control study in an English population-based cohort

BackgroundMultiple sclerosis is a leading cause of non-traumatic neurological disability among young adults worldwide. Prior studies have identified modifiable risk factors for multiple sclerosis in cohorts of White ethnicity, such as infectious mononucleosis, smoking, and obesity during adolescence/early adulthood. It is unknown whether modifiable exposures for multiple sclerosis have a consistent impact on risk across ethnic groups.AimTo determine whether modifiable risk factors for multiple sclerosis have similar effects across diverse ethnic backgrounds.MethodsWe conducted a nested case–control study using data from the UK Clinical Practice Research Datalink. Multiple sclerosis cases diagnosed from 2001 until 2022 were identified from electronic healthcare records and matched to unaffected controls based on year of birth. We used stratified logistic regression models and formal statistical interaction tests to determine whether the effect of modifiable risk factors for multiple sclerosis differed by ethnicity.ResultsWe included 9662 multiple sclerosis cases and 118,914 age-matched controls. The cohort was ethnically diverse (MS: 277 South Asian [2.9%], 251 Black [2.6%]; Controls: 5043 South Asian [5.7%], 4019 Black [4.5%]). The age at MS diagnosis was earlier in the Black (40.5 [SD 10.9]) and Asian (37.2 [SD 10.0]) groups compared with White cohort (46.1 [SD 12.2]). There was a female predominance in all ethnic groups; however, the relative proportion of males was higher in the South Asian population (proportion of women 60.3% vs 71% [White] and 75.7% [Black]). Established modifiable risk factors for multiple sclerosis—smoking, obesity, infectious mononucleosis, low vitamin D, and head injury—were consistently associated with multiple sclerosis in the Black and South Asian cohorts. The magnitude and direction of these effects were broadly similar across all ethnic groups examined. There was no evidence of statistical interaction between ethnicity and any tested exposure, and no evidence to suggest that differences in area-level deprivation modifies these risk factor-disease associations. These findings were robust to a range of sensitivity analyses.Conclusions and relevanceEstablished modifiable risk factors for multiple sclerosis are applicable across diverse ethnic backgrounds. Efforts to reduce the population incidence of multiple sclerosis by tackling these risk factors need to be inclusive of people from diverse ethnicities.

The effect of piling behavior on the production and mortality of free-range laying hens

Piling, a dense cluster of hens, is a behavior of major concern to the cage-free egg industry. It can cause large numbers of mortalities at which point it is considered smothering. The aim of this study was to quantify whether piling can also have consequences on production and non-smothering mortalities, which have not previously been described. Additionally, we aimed to describe characteristics of piling behavior relevant to for management. Video footage from 12 flocks of laying hens was analyzed for piling behavior across 3 wks. Production and mortality data were accessed using an integrated online management system. Bayesian linear mixed-effect models were used for formal statistical testing of the relationships between piling and production. Accounting for some missing data, a total of 252 d amounting to approximately 15,624 h were analyzed for the presence or absence of piling behavior, which we believe constitutes the largest analysis of piling behavior in the scientific literature to date. All flocks observed exhibited piling behavior even if they had no history of smothering. On average, flocks piled more than 4 times per day for around 44 min per event and the peak piling time occurred between 1300 and 1359. We found that the number of piling events was associated with a reduction in the number of eggs produced the next day; based on the average of 4 piles per day this amounted to 7.35 fewer eggs per 1,000 birds per day. Contrary to our hypothesis, we found total piling duration per day was positively associated with fewer Grade B eggs, with a decrease of 0.74 Grade B eggs for every hour of piling per day. No relationship was observed between piling and mortality not attributed to smothering. We discuss possible causes and explanations for these results including birds' response to stress, crowd dynamics, and daily rhythms. Here we show the potential for piling behavior to have sublethal consequences on production even in the absence of smothering-related deaths.

Does the timing of treatment affect the clinical and psychological outcomes of Twin-block therapy?

This study is a multicenter, two-arm parallel randomized control trial carried out across 3 hospital orthodontic units. A total of 75 patients participated in the study, with 41 randomly allocated in an Immediate Treatment Group (ITG) and 34 randomly allocated into an 18-month delayed Later Treatment Group (LTG). The patients were aware as to which group they were being allocated, as were the clinicians. Both patient groups received the same twin block appliance for use during the study. The appliance was to be worn full time, including eating, but to be removed while participating in contact sports or swimming. Achieving an overjet reduction between 2-4 mm was defined as being the clinical endpoint. After this, the appliance was only worn at night up until the next data collection point, allowing an 18-month window to finish treatment. Blinded clinicians measured skeletal changes using lateral cephalograms and overjet change via study models. Psychological impact was measured using two questionnaires: Oral Aesthetic Subjective Impact Scale (OASIS) and the Oral Health Quality of Life (OHQL). Data was collected from when the patient first registered in the study (DC1), 18 months after registration (DC2) and 3 years after registration (DC3). In total, 41 boys and 34 girls were included in the study. Ages for the boys ranged from within 1 month of their 12th birthday to 13.5 years old. For the girls, the range was from within 1 month of their 11th birthday to 12.5 years old. Further inclusion criteria included a class II skeletal pattern and having an overjet of 7 mm+. Exclusion criteria included patients of non-white Caucasian origin, girls aged 12.5 years+ and boys aged 13.5 years+. Furthermore, patients with a history of cleft lip or palate, mandibular asymmetry, muscular dystrophy, general health precluding compliance with treatment, a medically diagnosed growth excess or deficiency, not dentally fit or having previously received orthodontic treatment were not included in the study. SPSS Version 25 software was used to undertake the data analysis. No formal statistical testing was undertaken. To analyze and compare the scores between the two groups, independent t-tests were used. All analysis was carried out at 0.05 level of significance. The reliability of the examining clinicians was assessed using Bland-Altman limits of agreement. As only the ITG were in treatment over the periods of DC1-DC2 a comparison of the clinical outcomes cannot be made. With regards to the psychological outcome, no statically significant impact was noted for the ITG when compared with the LTG, who had not started treatment (OASIS P = 0.53, OHQL P = 0.92). When comparing the treatment effects of twin block therapy for the ITG (DC1-DC2) and the LTG (DC2-DC3), study model overjet and cephalometric changes were not statistically significant with the exception of % lower facial height (which was deemed not to be clinically significant) and mandibular unit length. There was no statistical significance with regards to the psychological outcomes post treatment when comparing the groups (OASIS P = 0.30, OHQL P = 0.85) CONCLUSIONS: The findings of this study suggest that adolescents (with a mean age of 12 years 8 months for boys and 11 years 8 months for girls) will not be disadvantaged, either clinically or psychologically, by waiting 18 months for twin block therapy.

P-767 Urogenital defects in live births to women dispensed clomiphene citrate: A study within a whole of population birth cohort

Abstract Study question Is the risk of urogenital defects increased in live births where clomiphene citrate is known to have been dispensed by a pharmacist to the individual? Summary answer The risk of urogenital defects is elevated in singletons, and approximately doubled in male babies among women dispensed clomiphene citrate, as compared to unexposed women. What is known already Clomiphene citrate (CC) has been used for ovulation induction since 1967 & is both inexpensive and largely effective. However, CC is a selective estrogen receptor modulator (SERM), which is a class of drugs with the potential for endocrine disruption during fetal development. The link between urogenital defects and CC has previously been reported by ourselves and others. Whether the link continues to exist where individual level pharmaceutical prescribing and dispensing patterns are clearly ascertained has not been determined. Secondly, the interaction of prescribed clomiphene citrate functioning as an endocrine disruptor by fetal sex has not undergone formal statistical testing. Study design, size, duration A population-based cohort study of South Australia was assembled by linking all records from the state-wide perinatal registry for births between July 2003 and December 2011, including defects coded to ICD9 and BPA, with Commonwealth government data on pharmaceutical dispensing in the national Pharmaceutical Benefits Scheme (PBS), which includes individual level prescribing and dispensing of drugs for ovulation induction, including clomiphene citrate. Participants/materials, setting, methods We analysed de-identified pregnancy outcome data for all births in South Australia, linked to individual level national prescription data, to examine the prevalence of urogenital birth defects (>20 weeks gestation) for births occurring between July 2003 and December 2011following clomiphene citrate dispensing, with 5-years follow-up for defect notifications. Multivariate analysis in STATA within a Secure Unified Research Environment (SURE) was used to calculate odds ratios, adjusted for maternal confounders and socioeconomic circumstance. Main results and the role of chance We examined 2,264 singleton live births where women were dispensed clomiphene citrate for infertility. Births among women dispensed clomiphene citrate, compared to those without this exposure, had increased urogenital defects (odds ratio (OR) = 1.73, CI = 1.34 - 2.24). This association was slightly reduced after adjustment for maternal characteristics that were potential confounders: age, socio-economic status (based on postcode of residence), Aboriginal ethnicity, born outside Australia in low or middle income country, parity, smoking, pre-existing diabetes or hypertension, pregnancy-induced hypertension and pre-eclampsia (OR = 1.66, CI = 1.28 -, 2.15). There was evidence of an interaction with fetal sex, such that males were at particular risk. Sex-by-clomiphene interaction Male 1.92 (1.47, 2.52) Female 0.88 (0.37, 2.14) Test for interaction χ2(1) = 2.72; p = 0.09 The observed main effects are unlikely to be due to chance, and the sex-specific effect is biologically plausible, but limited in power. Further, there were 280 babies from multiple pregnancies to women exposed to clomiphene citrate that were excluded due to statistical limitations. Limitations, reasons for caution Our data report pharmacy dispensing, but not observed consumption, although infertile women are highly motivated to take this drug and over 5% of pregnancies were multiples, consistent with extensive use. The analysis for interactions and for multiples is currently restricted by power, which may resolve as the cohort number increases. Wider implications of the findings Clomiphene citrate (CC) may be a potent endocrine disruptor inducing urogenital defects, particularly in males. This is important as CC continues to be a WHO essential drug and a first line treatment globally, but with largely unmonitored use and without any industry initiated prospective safety study. Trial registration number Not applicable

Apalutamide for metastatic castration-sensitive prostate cancer: final analysis of the Asian subpopulation in the TITAN trial.

The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan-Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg (n = 111) or placebo (n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.42-1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21-0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13-0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44-1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.

Association of cannabis use with real-world time to treatment discontinuation (rwTTD) in patients with advanced cancer initiating immune checkpoint inhibition (ICI).

e18846 Background: Studies suggest that the immunomodulatory effect of cannabis may impair responsiveness to ICI in cancer patients. These studies were limited by small sample size in a heterogeneous group. Determining the impact of cannabis on cancer control in patients receiving ICI is critical to informing patients and clinicians. We assessed the relationship of cannabis with cancer treatment outcomes using a large national healthcare claims database linked to retail cannabis purchase data. Methods: Using the Forian Inc database from 2017-2022, we identified adults (age > 18 years) with advanced cancer who had ≥ 90 days of continuous health plan enrollment and received ≥ 1 ICI treatment. Point-of-sale purchase records from 18 state cannabis programs defined cannabis consumers (CC; any purchase prior to first ICI to last known follow-up) and cannabis non-consumers (CNC; no known cannabis purchases). We abstracted data on patient demographics, cancer history, cannabis utilization (dates of purchases, routes, strains), and all cancer-directed therapy claims. rwTTD was calculated from time of first ICI to a defining discontinuation event (change in therapy, gap of > 120 days, or end of enrollment in health plan). Results: From a database of nearly 68 million patients, 20,675 patients met the inclusion criteria (374 CC and 20,301 CNC). Baseline characteristics were similar between the two groups (e.g., age, diagnosis type, time to first ICI) (Table 1). Lung, melanoma and renal cancers account for nearly half of all identified diagnoses. By day 30 after ICI initiation, 45% of CC had made at least one cannabis purchase. Median time from advanced cancer diagnosis to first ICI and median follow up time were also similar (Table 1). The difference in median rwTTD between CC and CNC groups was small relative to the overall variation of this outcome (Table 1) and remained similar (88 days) when restricting analysis to CC with first purchase within 30 days of ICI. Conclusions: Cannabis use does not appear to be associated with rwTTD in advanced cancer patients initiating ICI. Formal statistical testing using inverse probability treatment propensity weighting and adjustment for confounding factors (opioids/glucocorticoids) to assess rwTTD and real-world overall survival is ongoing. Well designed, prospective cohort studies of CC and CNC are needed to minimize selection bias in studies of cannabis use. [Table: see text]

Effects of microcurrent therapy in promoting function and pain management of knee osteoarthritis: a systematic review and meta-analysis protocol

IntroductionMicrocurrent therapy (MCT) is a rising conservative treatment for patients with knee osteoarthritis (OA). Considering its potential benefits and convenience, MCT’s application in those individuals with knee OA is capacious....

The Baikal subtype of tick-borne encephalitis virus is evident of recombination between Siberian and Far-Eastern subtypes.

Tick-borne encephalitis virus (TBEV) is a flavivirus which causes an acute or sometimes chronic infection that frequently has severe neurological consequences, and is a major public health threat in Eurasia. TBEV is genetically classified into three distinct subtypes; however, at least one group of isolates, the Baikal subtype, also referred to as "886-84-like", challenges this classification. Baikal TBEV is a persistent group which has been repeatedly isolated from ticks and small mammals in the Buryat Republic, Irkutsk and Trans-Baikal regions of Russia for several decades. One case of meningoencephalitis with a lethal outcome caused by this subtype has been described in Mongolia in 2010. While recombination is frequent in Flaviviridae, its role in the evolution of TBEV has not been established. Here, we isolate and sequence four novel Baikal TBEV samples obtained in Eastern Siberia. Using a set of methods for inference of recombination events, including a newly developed phylogenetic method allowing for formal statistical testing for such events in the past, we find robust support for a difference in phylogenetic histories between genomic regions, indicating recombination at origin of the Baikal TBEV. This finding extends our understanding of the role of recombination in the evolution of this human pathogen.

A randomized clinical study to assess the performance of a marketed denture adhesive in a model of food infiltration in healthy, edentulous adults.

An optimized food infiltration methodology was utilized to assess the objective and subjective efficacy of a marketed denture adhesive regarding denture dislodgment and infiltration and perception of food particles under maxillary and mandibular dentures. A pilot study helped optimize methodologies before the efficacy study. Participants were healthy adults (n =48 for both studies) with fair- to well-fitting and well-made full maxillary and mandibular dentures. In the pilot, groups were a denture adhesive applied in a conventional dabbed-on pattern, a denture adhesive applied in continuous strips, or no adhesive. In the efficacy study, groups were the Test denture adhesive (continuous strips pattern application) or no adhesive, employed in a crossover design. Food infiltration was investigated through measurement of peanut particle mass retrieved from under each denture (30-32 g chewed). No formal statistical testing was performed in the pilot. Statistical analysis in the efficacy study was performed using analysis of variance. Primary efficacy evaluation was combined peanut particle mass from both dentures. Secondary efficacy evaluations included peanut particle mass under separate dentures, participant-reported denture dislodgements, and awareness/rates of how bothersome peanut particles under dentures were. In the pilot, the median peanut particle mass was lower with either pattern application compared with no adhesive. In the efficacy study, peanut particle mass under combined dentures was lower with than without adhesive (geometric mean [product of values]: 5.56vs. 29.13 mg) with a between-group geometric mean ratio (adhesive over no adhesive) of 0.19 (95% confidence interval: 0.12, 0.30) favoring the Test adhesive (p < .0001). Similar Test adhesive beneficial outcomes in both studies included significantly fewer denture dislodgements and awareness and how bothersome peanut particles under dentures were. Treatments were generally well-tolerated. These findings, including reduced peanut particle infiltration, fewer denture dislodgments, and lower ratings of bothersomeness, corroborate those studies investigating the benefits of denture adhesive in preventing food infiltration.

A Phase II, Single-Arm Study of De-Escalation and Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with Nilotinib in First-Line Therapy Followed By a Second Attempt after Nilotinib and Asciminib Combination: Dante Study

Introduction: Treatment-free remission (TFR) is considered one of the main goals of therapy in patients with chronic myeloid leukemia (CML). Several studies have shown that treatment discontinuation can be successfully achieved in roughly 50% of patients with a sustained deep molecular response (sDMR). However, the remaining 50% require reintroduction of tyrosine kinase inhibitor (TKI) therapy. Although about 90% of patients who experience molecular relapse regain a major molecular response (MMR) after restarting TKI therapy, due to poorly understood mechanism(s), the probability for those patients of failing a second attempt to discontinue TKI (TFR2) is higher compared to the first attempt. The above-mentioned data implies that, to aim to a second TFR, a different therapeutic strategy might be needed. Asciminib (ASC), unlike all approved TKIs that bind to the ATP site of the BCR-ABL1 oncoprotein, is an allosteric, first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action that has shown efficacy in heavily pre-treated patients after two or more TKIs (Rea et al. 2021). An ongoing phase I dose-finding study (NCT02081378) has shown that ASC combined with TKI is both effective and well tolerated in heavily pretreated CML patients, suggesting that combination treatment between an allosteric and an ATP-competitive TKI may deepen clinical responses without serious safety concerns (Mauro et al. 2019). The changes introduced in the DANTE study (NCT03874858) by the amendment 4 aim to assess whether ASC in combination with nilotinib (NIL) can lead to higher and more durable TFR2 rates than those reported in other studies. Methods: After providing written informed consent, the TFR2 phase will enroll - from 29 Italian centers, approximately 60-70 adult CML patients in chronic phase, who have been (i) treated for at least 3 calendar years with NIL, (ii) failed a first TFR attempt, (iii) restarted NIL for at least 1 year and (iv) fulfill all inclusion/exclusion criteria. The study consists of 4 phases: screening, re-induction (week 0-96), TFR2 (week 96-144) and follow up phase. In the re-induction phase, patients will be treated with ASC 40 mg BID and NIL 300 mg BID for 96 weeks and will have scheduled biweekly/monthly visits until week 12, and then every 12 weeks. NIL dose may be less than 300 mg BID if appropriate by clinical judgement but must be at least 300 mg daily. During re-induction, sDMR is defined as no loss of MR4.0 (BCR-ABL level ≤ 0.01% IS) in any BCR-ABL RQ-PCR assessment. Patients with sDMR at the end of re-induction will enter in TFR2 and ASC plus NIL will be discontinued. If two or more consecutive quarterly BCR-ABL RQ-PCR assessments are not performed during re-induction or results are not available, the patient will not be eligible for TFR2 and will be treated with NIL 300 mg BID until the end of the TFR2 stage (week 144). Patients not eligible for TFR2 but with a response more than an MMR will continue treatment with ASC and NIL until the end of re-induction (week 96) and then continue NIL monotherapy at 300 mg BID until the end of the TFR2 stage (week 144). Patients with loss of MMR at any time during re-induction or during NIL monotherapy will be discontinued from the study. If MMR loss occurs during TFR2, NIL 300 mg BID will be restarted and administered until end of study (Fig1). Endpoints: The primary endpoint is the percentage of patients in TFR 48 weeks after stopping NIL and ASC combination. Key secondary endpoints are: (i) percentage of patients eligible for TFR2, (ii) the number of patients with loss of MMR in TFR2 and regain MMR/DMR by the end of the TFR2 stage (iii) BCR-ABL kinetics in the different study phases (iv), OS, TFS and PFS and (v) the safety of the combination. The TFR2 stage is descriptive and no formal statistical testing is necessary or applicable. Conclusions: The expected results from this phase II interventional study, will potentially represent a milestone in treatment strategy for those patients who aim to discontinue NIL for the second time by providing them with several benefits including an improved quality of life.

33553 Real-world treatment patterns and outcomes up to 1 year among children aged

Background: We describe real-world treatment patterns in patients aged <12 years with moderate-to-severe AD, focusing on systemic treatments. Methods: PEDISTAD (NCT03687359) is an ongoing, international, noninterventional registry in patients aged <12 years with moderate-to-severe AD inadequately controlled with topical therapies. Treatment was per investigator discretion. In this interim analysis (data cutoff 30 July 2020), we report baseline data for all patients, and changes in the following outcomes (from therapy start [TS] to last observation [LO]) for patients receiving systemic treatments of interest (dupilumab, cyclosporine, or methotrexate): Eczema Area and Severity Index (EASI), AD-affected body surface area (BSA), Patient-Oriented Eczema Measure (POEM), Children’s Dermatology Life Quality Index (CDLQI; 4–<12 years), and current-day peak pruritus numerical rating scale (PP-NRS). No formal statistical testing was performed. Results: At baseline, 77.2% (565/732) of patients were receiving nonsystemic AD therapies (topical corticosteroids: 69.9%); 23.1% were receiving systemic therapies, including: dupilumab: 2.6% [n = 19]; cyclosporine: 8.1% [n = 59]; and methotrexate: 9.0% [n = 66]. The median duration of patient follow-up was 8.7 months. Physician-reported outcomes (change in mean ± SD) improved from TS to LO: EASI (dupilumab [n = 31], cyclosporine [n = 80], methotrexate [n = 69]: -13.8 ± 15.4, -4.6 ± 12.2, -6.2 ± 12.8) and % BSA (-18.4 ± 25.0, -13.6 ± 22.3, -14.6 ± 18.8). Change in patient/caregiver-reported outcomes were: POEM (-7.6 ± 8.5, -2.1 ± 11.1, -4.3 ± 11.2), CDLQI (-7.2 ± 7.8, 0.3 ± 5.5, -2.9 ± 6.8) and PP-NRS (-2.6 ± 2.3, 0.7 ± 3.0, 0.6 ± 2.5). Time-to-discontinuation (mean ± SD, months) was: dupilumab (8.6 ± 6.4); cyclosporine (5.2 ± 4.1); methotrexate (7.0 ± 4.7). Conclusions: The most common treatment at baseline for children aged <12 years with moderate-to-severe AD was topical corticosteroids. Dupilumab was associated with greater improvements in clinical assessments/patient-reported outcomes vs other systemic therapies.

Effects of Government Debt on Monetary Policy Strategy in Tanzania

This paper examines the fiscal dominance hypothesis in Tanzania by exploring the relationship between the monetary base and the government debt using monthly data from 2003:1 to 2019:12. Results from formal statistical tests indicate no evidence of a long-run relationship between the variables. Structural vector autoregressive model is thus estimated to analyse the short-run dynamics. The findings point to a positive and statistically significant impact of government debt on monetary base. The findings identifies political phenomenon that before the fourth phase government (2003-2005), monetary policy witnessed relatively intensive fiscal dominance as compared to the fourth phase (2005-2015) and fifth phase government (2015-2019). However, in comparison with the fourth phase government, findings suggest that during the first four years of the fifth phase government, monetary policy encountered a relatively high fiscal influence, partly attributed to implementation of huge development projects and reduction in foreign financing in the government budget. The identified fiscal dominance for the sample period, implies a subordinated monetary policy, compromising on Bank of Tanzania’s primary objective of price stability.

A Systematic Review on Mediation Studies of Self-Compassion and Physical Health Outcomes in Non-Clinical Adult Populations

ObjectivesGrowing research indicates that self-compassion is associated with key physical health outcomes in non-clinical adult populations. This systematic review was designed to characterize the mediators linking self-compassion to physical health outcomes, evaluate study quality and theoretical evidence, compare findings to the mental health literature, and provide directions for future research.MethodsWe searched Embase, Medline, APA PsycInfo, Scopus, AMED, and Web of Science for relevant articles (including the inclusion of formal statistical mediation tests) from 2003 to February 2022. Study quality was assessed with Downs and Black Checklist for Measuring Quality and Mediation Quality Checklist tools.ResultsWe screened 6439 articles for title and abstracts, assessed 101 full texts for eligibility, and included 20 relevant articles. A range of mediators were categorized as testing psychological or behavioral factors. Perceived stress (n = 5), emotion regulation (n = 5), negative affect (n = 3), and coping strategies (n = 3) were the most frequently assessed mediators. In general, self-compassion had a significant indirect effect on physical health via negative affect and perceived stress (in the absence of overlapping affective mediators). Findings for emotion regulation and coping strategies were mixed.ConclusionsThe mediational evidence linking self-compassion to physical health via psychological and behavioral factors remains underdeveloped and focused on the measures of affect and emotion regulation. Future studies need to broaden the scope of mediators to include other self-regulatory factors indicated by theory (e.g., motivational and physiological indices) and implement designs other than cross-sectional/correlational.Protocol RegistrationPROSPERO CRD42021241915.

PB2112: MINDWAY: A PHASE IB/II DOSE OPTIMIZATION STUDY TO ASSESS SAFETY AND PHARMACOKINETICS OF TAFASITAMAB + LENALIDOMIDE IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA

Background: Tafasitamab is an Fc-enhanced, humanized, anti-CD19 monoclonal antibody which, in combination with the immunomodulatory drug lenalidomide, has been granted accelerated FDA approval and EU conditional marketing authorization based on results from L-MIND (NCT02399085) for the treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in adult patients ineligible for autologous stem cell transplant. Treatment schedule optimization aims to reduce the frequency of hospital visits and decrease treatment burden and healthcare utilization while maintaining clinical benefits. Aims: MINDway (NCT05222555) will investigate if administration of tafasitamab at levels higher than the approved 12 mg/kg dose at a reduced dosing frequency can maintain the benefit-risk relationship of tafasitamab + lenalidomide treatment for patients with R/R DLBCL. Methods: MINDway is an open-label, multicenter, Phase Ib/II study in patients aged 18‒80 years with histologically confirmed DLBCL and R/R status after at least one, but no more than three, prior systemic regimens, including CD20-targeted therapy. Patients previously treated with CD19-targeted therapy or with immunomodulatory imide drugs such as lenalidomide are excluded. The modified tafasitamab dosing regimen will be investigated in a stepwise design with two sequential dose-finding cohorts (planned n=6 each) followed by an expansion cohort (planned n=39; Figure). Lenalidomide 25 mg will be administered in all cohorts on Day (D) 1‒21 of each 28-D cycle for up to 12 cycles. After Cycle 12, patients will continue tafasitamab monotherapy at the assigned dosing regimen until progression. Following a review of the safety and pharmacokinetic data from Cohorts 1 and 2, patients will be enrolled in an expansion cohort to receive tafasitamab + lenalidomide at the tafasitamab dose of 24 mg/kg or 30 mg/kg for further evaluation. No intra-patient dose escalation from 24 mg/kg to 30 mg/kg is permitted. The primary endpoint is the incidence and severity of treatment-emergent adverse events; key secondary endpoints include tafasitamab serum concentrations after 3 and 12 treatment cycles and best objective response rate, duration of response, and progression-free survival by investigator assessment. All endpoints will be analyzed using descriptive statistics; no formal statistical tests will be performed. MINDway is currently enrolling, with a planned sample size of 51 patients. Results: Results for this study are not yet available: outcome data as described above will be presented in due course. Image:Summary/Conclusion: MINDway will optimize the tafasitamab dosing regimen to reduce the frequency of hospital/clinic visits for tafasitamab treated R/R DLBCL patients. Reducing the overall frequency of clinic visits by half is expected to reduce the patient burden and support long-term treatment compliance. Furthermore, given the severity of the disease, reduced hospital visits may result in less exposure to hospital infections in this already susceptible population.

Abstract CT241: ENVOY-001: A phase 1, multicenter, open-label study of SQZ-AAC-HPV as monotherapy and in combination with immune checkpoint inhibitors in HLA-A*02+ patients with HPV16+ recurrent, locally advanced, or metastatic solid tumors

Abstract Background: AAC-HPV consists of autologous RBCs engineered using Cell Squeeze® technology to deliver synthetic long peptides (SLP) of HPV16 E6, E7 and the adjuvant, poly I:C. After intravenous (IV) administration, the AACs are designed to be phagocytosed by endogenous antigen presenting cells (APCs) and the E6 and E7 antigens presented on the APC’s major histocompatibility complexes (MHCs). The concurrent delivery of antigen and adjuvant to the APCs is designed to elicit a potent antitumor T cell response to drive HPV16+ tumor killing. Preclinical experiments demonstrated that post IV administration of mouse AAC-HPV in a HPV16 E7-expressing TC-1 mouse model, E7 specific CD8+ T cells are recruited to the tumor, inhibiting tumor growth, prolonging survival, and forming immunological memory. Murine AAC-HPV treatment was also shown to be synergistic with cisplatin combinations. In vitro studies with human volunteer derived SQZ-AAC-HPV demonstrated to be endocytosed by dendritic cells and drive IFN-gamma production by T cell clones specific to human E7. The Phase 1/2 study’s biomarker program investigates whether pharmacodynamic effects observed in nonclinical studies correlate with potential clinical benefit. Immunogenic and pharmacodynamic endpoints include quantification and characterization of TILs and tumor microenvironment, changes in numbers and functions of circulating blood cells. In addition, cytokine responses and cell-free HPV16 DNA will be measured. Methods: ENVOY-001 (NCT04892043) is open for enrollment to HLA A*02+ patients with HPV16+ recurrent, locally advanced, or metastatic solid tumors and includes escalation cohorts for monotherapy and in combination with anti-PD-1 and anti-CTLA-4 checkpoint inhibitors. The study is divided in two parts, the first will assess the safety in monotherapy dose-escalation following a Bayesian Optimal Interval approach. The second part of the study will assess the safety of SQZ-AAC-HPV when combined with nivolumab 360 mg q3w and/or ipilimumab 3 mg/kg q3w x4 or 1 mg/kg q6w when combined with nivolumab. The cycle length is 3 weeks, and patients will receive SQZ-AAC-HPV for up to 1 year or until available autologous drug product is exhausted. Eligible patients including but not limited to anal, cervical and head and neck tumors will undergo a 200 mL whole blood collection at the study site. The manufacturing process takes less than 24 hours to produce multiple cryopreserve patient doses and this therapy does not necessitate pre-conditioning. The vein-to-vein time for the 1st administration is approximately one week. Patients must have a lesion that can be biopsied with acceptable clinical risk and agree to have a fresh biopsy at Screening and on study. A Data Monitoring Committee is in place. No formal statistical hypothesis testing will be performed. Results: N/A Conclusions: N/A Citation Format: Victoria Villaflor, Rajwanth Veluswamy, Elena Garralda, Richard Maziarz, Emese Zsiros, Anthony Shields, Mariano Ponz-Sarvise, Martijn Lolkema, Mehdi Brahmi, Julia Jennings, Nathan Miselis, Lindsay Moore, Katarina Blagovic, Rui-Ru Ji, Scott Loughhead, Ricardo Zwirtes, Sandip Patel. ENVOY-001: A phase 1, multicenter, open-label study of SQZ-AAC-HPV as monotherapy and in combination with immune checkpoint inhibitors in HLA-A*02+ patients with HPV16+ recurrent, locally advanced, or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT241.

STRO-002-GM2: A phase 1, open-label, safety, pharmacokinetic, and preliminary efficacy study of STRO-002, an anti-folate receptor alpha (FolRα) antibody-drug conjugate (ADC), in combination with bevacizumab in patients with advanced epithelial ovarian cancer (EOC, including fallopian tube or primary peritoneal cancers).

TPS5622 Background: STRO-002 is a novel FolRα targeting ADC, generated using cell-free antibody production and site-specific conjugation technology. STRO-002 demonstrates potent in vitro cytotoxicity in EOC cell lines and anti-tumor activity in xenograft models, including induction of immunogenic cell death. STRO-002 is currently being studied as a single agent in ovarian and endometrial cancer (Phase 1 Study STRO-002-GM1; NCT03748186). Preliminary efficacy data in relapsed/progressive platinum resistant EOC compared favorably to standard chemotherapy (Naumann W., et al, ASCO 2021). Pre-clinical models tested with STRO-002/bevacizumab combinations demonstrated additive anti-tumor activity compared to monotherapy. This study is a first in human study of STRO-002 plus bevacizumab in patients with advanced ovarian cancer that have progressed on standard therapy. Methods: STRO-002-GM2 is a Phase 1, open-label, multicenter, dose escalation study with a standard 3+3 design with a 21-day dose-limiting toxicity (DLT) assessment period followed by dose expansion. The study will assess safety, establish recommended phase 2 dose (RP2D), and preliminary efficacy of STRO-002/bevacizumab combination in patients with recurrent high-grade EOC. Bevacizumab will be administered at the labeled dose of 15 mg/kg given with STRO-002 starting at 3.5 mg/kg, both administered IV q 3 weeks. Planned dose escalation doses of STRO-002 include 3.5, 4.3, and 5.2 mg/kg and will continue until MTD/MAD is reached. Additional intermediate dose level cohorts may be added for RP2D optimization. Once a cohort is cleared per dose escalation rules, up to 10 additional subjects may be enrolled and treated at that cleared dose level in order to obtain additional safety and efficacy data for RP2D determination and ungating of the expansion stage. Dose expansion will enroll approximately 40 patients treated at the RP2D. The patient population is relapsed high-grade EOC with up to 4 prior regimens. Subjects with primary platinum refractory disease will be enrolled in dose escalation only. Key inclusion criteria include: measurable disease, adequate bone marrow and renal function. Key exclusion criteria include: contraindication to receive bevacizumab and prior treatment with a FolRα ADC or ADC containing a tubulin inhibitor. Efficacy evaluation is per RECIST v1.1. Tumor tissue (archival or fresh biopsy) is required. Study oversight includes a Safety Evaluation Team. Samples will be collected to assess the PK and immunogenicity. No formal statistical hypothesis testing will be conducted in this study. This study is currently open for enrollment in the U.S. Clinical trial information: NCT05200364.

Health-related quality of life at 3months following head and neck cancer treatment is a key predictor of longer-term outcome and of benefit from using the patient concerns inventory.

IntroductionDuring clinical follow‐up it can be difficult to identify those head and neck cancer (HNC) patients who are coping poorly and could benefit from additional support. Health‐related quality of life (HRQOL) questionnaires and prompt lists provide a means by which patients can express their perceived outcomes and raise concerns. The first aim of this secondary analysis following a randomized trial was to explore which patient characteristics, at around 3 months following treatment completion (baseline), best predict HRQOL 12 months later. The second aim was to attempt to ascertain which patients were most likely to benefit from using prompt list.MethodsCluster‐controlled pragmatic trial data were analyzed. HRQOL was measured by the University of Washington Quality of life questionnaire (UW‐QOLv4). The prompt list was the Patient Concerns Inventory (PCI‐HN).ResultsThe trial involved 15 eligible consultants and a median (inter‐quartile range) of 16 (13–26) primary HNC patients per consultant, with 140 PCI patients and 148 controls. Baseline HRQOL was the dominant predictor of 12‐month HRQOL with other predictors related to social, financial, and lifestyle characteristics as well as clinical stage and treatment. Although formal statistical tests for interaction were non‐significant the trend in analyses over a range of outcomes suggested that patients with worse baseline HRQOL could benefit more from the PCI‐HN.DiscussionHRQOL early post‐treatment is a key predictor of longer‐term outcome. Measuring and using HRQOL and the PCI‐HN are not only surrogates for predicting HRQOL at 15 months post‐treatment, but also tools to help guide interventions.

Model-Based ROC Curve: Examining the Effect of Case Mix and Model Calibration on the ROC Plot.

BackgroundThe performance of risk prediction models is often characterized in terms of discrimination and calibration. The receiver-operating characteristic (ROC) curve is widely used for evaluating model discrimination. However, when comparing ROC curves across different samples, the effect of case mix makes the interpretation of discrepancies difficult. Further, compared with model discrimination, evaluating model calibration has not received the same level of attention. Current methods for examining model calibration require specification of smoothing or grouping factors.MethodsWe introduce the “model-based” ROC curve (mROC) to assess model calibration and the effect of case mix during external validation. The mROC curve is the ROC curve that should be observed if the prediction model is calibrated in the external population. We show that calibration-in-the-large and the equivalence of mROC and ROC curves are together sufficient conditions for the model to be calibrated. Based on this, we propose a novel statistical test for calibration that, unlike current methods, does not require any subjective specification of smoothing or grouping factors.ResultsThrough a stylized example, we demonstrate how mROC separates the effect of case mix and model miscalibration when externally validating a risk prediction model. We present the results of simulation studies that confirm the properties of the new calibration test. A case study on predicting the risk of acute exacerbations of chronic obstructive pulmonary disease puts the developments in a practical context. R code for the implementation of this method is provided.ConclusionmROC can easily be constructed and used to interpret the effect of case mix and calibration on the ROC plot. Given the popularity of ROC curves among applied investigators, this framework can further promote assessment of model calibration.HighlightsCompared with examining model discrimination, examining model calibration has not received the same level of attention among investigators who develop or examine risk prediction models.This article introduces the model-based ROC (mROC) curve as the basis for graphical and statistical examination of model calibration on the ROC plot.This article introduces a formal statistical test based on mROC for examining model calibration that does not require arbitrary smoothing or grouping factors.Investigators who develop or validate risk prediction models can now also use the popular ROC plot for examining model calibration, as a critical but often neglected component in predictive analytics.

Long-term safety and efficacy of olokizumab in patients with rheumatoid arthritis and inadequate response to tumor necrosis factor inhibitor therapy in phase II studies.

This study aimed to evaluate the long-term safety and efficacy of olokizumab (OKZ), an anti-interleukin (IL)-6 monoclonal antibody, in patients with rheumatoid arthritis (RA) and inadequate response to tumor necrosis factor-alpha inhibitors. Eligible patients completed study RA0056, which tested several doses of OKZ, placebo (PBO), and tocilizumab (TCZ) plus methotrexate (MTX) in Western countries, and RA0083 included several doses of OKZ and PBO plus MTX in Asian countries. Both studies were followed by open-label extension (OLE) studies with OKZ 120 mg every 2 weeks, RA0057 and RA0089, respectively. Safety assessments were reported up to 124 weeks in RA0057 and 92 weeks in RA0089. Efficacy assessments were reported up to week 60 in RA0057 and week 52 in RA0089. No formal statistical hypothesis testing was performed, and missing data were not imputed. A total of 190 patients in RA0057 and 103 patients in RA0089 received OKZ with median treatment duration of 14.1 and 10.1 months, respectively. Serious adverse events (SAEs) were reported in 44 patients (23.2%, 32.7 events per 100 patient-years [PY]) in RA0057 and in 13 patients (12.6%, 23.6 events per 100 PY) in RA0089. Among treatment-emergent adverse events (TEAEs), including SAEs, infections were the most common events. TEAEs leading to withdrawal were reported in 33 (17.4%) patients in RA0057 and in 7 (6.8%) patients in RA0089. Disease activity score 28-joint count on the basis of C-reactive protein level, clinical disease activity index, and simplified disease activity index, as well as the American College of Rheumatology 20%, 50%, and 70% response rates were maintained during the OLE studies, including in those who switched from PBO or TCZ. Improvements in patient-reported outcomes were maintained in OLEs as well. In the 2 long-term studies, OKZ treatment demonstrated a safety profile expected for IL-6 blocking agents without new safety signals and led to sustained improvements in RA symptoms, physical function, and quality of life.