Statistical Plan Research Articles

Response-adapted therapy (tx) with nivolumab plus brentuximab vedotin (nivo + BV) without autologous hematopoietic cell transplantation (auto-HCT) in children, adolescents, and young adults (CAYA) with low-risk relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL): CheckMate 744.

7515 Background: Outcomes are poor for patients (pts) with cHL who develop R/R disease after first-line (1L) chemotherapy ± radiotherapy (RT). Salvage tx that attain high event-free survival (EFS) rates and minimize late toxicity by omitting high-dose chemotherapy (HDCT)/auto-HCT are needed. CheckMate 744 (NCT02927769) is the first multicenter phase 2 study evaluating a risk-stratified, response-adapted salvage tx with nivo + BV in CAYA with R/R cHL. In the standard-risk cohort, complete molecular response (CMR) rate before consolidation with HDCT/auto-HCT was 94% (Harker-Murray et al. Blood 2022). With highly active salvage tx, pts in low-risk cohort could achieve high EFS without HDCT/auto-HCT; we report data from this cohort. Methods: Pts were aged 5–30 y and had ≤ 3 cycles (C) of 1L anthracycline-based systemic tx. Risk stratification was described in Harker-Murray et al. Pts received 4C of nivo + BV induction. Pts with CMR received additional 2C nivo + BV before involved-site radiation therapy (ISRT) consolidation (dose, 30–30.6 Gy). Pts with suboptimal response received 2C BV + bendamustine intensification; pts with CMR proceeded to ISRT consolidation. Primary endpoints: CMR rate (Lugano 2014) any time before ISRT and 3-y EFS rate, both per blinded independent central review (BICR). For CMR and overall response rate (ORR), a 90% confidence interval (CI) was used per statistical plan. Results: Among 28 pts treated with nivo + BV, median (range) age was 17 (6–27) y; 64% of pts were aged < 18 y. Most (64%) pts had stage II disease at relapse; 82% had relapse ≥ 12 mo after 1L tx, 2 pts had prior RT. Median (range) follow-up was 31.9 (2.2–55.3) mo. CMR, ORR, 3-y EFS and PFS rates are shown in Table. Median duration of response was not reached; 87% of pts had sustained response at 36 mo’ follow-up. Efficacy outcomes were comparable in the pediatric population (CMR per BICR before ISRT, 88.9%; 3-y EFS rate, 78.3%). During induction, 22 (78.6%) pts had treatment-related adverse events (TRAEs; grade 3/4, 25.0% pts; hematologic, < 10% pts; immune-mediated, 21.4%). Serious AEs leading to discontinuation included rash, pyrexia, and acute kidney injury (1 pt each). Conclusions: The findings demonstrate that most CAYA with low-risk R/R cHL can be salvaged with chemoimmunotherapy with a favorable toxicity profile, and do not require HDCT/auto-HCT. Clinical trial information: NCT02927769 . [Table: see text]

Participation in phase I oncology trials by minorities: Survival and compliance data.

e18628 Background: Since 1993, the National Institutes of Health requires all clinical trials to include women and minority participation in clinical research. Despite this initiative, Minority (M) participation in Phase I Oncology clinical trials is subpar; historical data indicate a participation of 79% Caucasian (C) versus 21% (M) in Phase I clinical trials. The purpose of this study is to compare demographics, survival, and compliance data between (C) versus (M) patients participating in Phase I Oncology clinical trials in our Cancer Institute. Methods: We performed a retrospective analysis in all patients enrolled in phase I clinical trials in our institution from April 2019 until October 2022. This information was obtained via OnCore. Data was abstracted manually and entered in a spreadsheet (Excel). Data variables include race, gender, withdrawal of consent, and lost follow-up. Statistical plan was determined by our statistical team with data analysis to be performed with statistical software to generate Kaplan Meyer (KM) Survival Curve. Results: A total of 99 patients were identified. 61.5% were (C) and 38.4 % were (M). (M) consisted of Hispanic (81%), African American (18%) and Asian (1%). Female Gender on (C) were 57.4% and 55.3% on (M). Lost follow-up was 2.8% on (C) and 5.9% on (M). Withdrawal of consent was 5.6% on (C) and 0% on M. The (KM) curve revealed non statistically significant difference in survival p = 0.7316. Conclusions: In our analysis, we found statistically similar (KM) survival curves for (C) and (M) participating in Phase I clinical trials (p = 0.7316). We found a significant higher participation of (M) patients in our institute than historical data. There was no significant difference in withdrawal of consent between (C) and (M) and no difference on lost follow-up. We plan to identify patterns of success in enrolling minorities in our site and validate a questionnaire to screen patients for Phase I clinical trials with the goal to minimize perception bias and barriers for enrollment of (M) in Phase I studies.

Choosing the Best Design in Surgical Research.

Choosing the Best Design in Surgical Research.

Pro-Con Debate: Interdisciplinary Perspectives on Industry-Sponsored Research.

Pro: Nearly all new devices and drugs come from industry that provides two-thirds of the funding for medical research, and a much higher fraction of clinical research. Realistically, without corporate-funded studies, perioperative research would stagnate with little innovation and few new products. Opinions are ubiquitous and normal, but do not constitute epidemiologic bias. Competent clinical research includes many protections against selection and measurement bias, and the publication process provides at least moderate protection against misinterpretation of results. Trial registries largely prevent selective data presentation. Sponsored trials are particularly protected against inappropriate corporate influence because they are usually codesigned with the US Food and Drug Administration, and analyses are based on formal predefined statistical plans, as well as being conducted with rigorous external monitoring. Novel products, which are essential for advances in clinical care, largely come from industry, and industry appropriately funds much of the required research. We should celebrate industry's contribution to improvements in clinical care. Con: While industry funding contributes to research and discovery, examples of industry-funded research demonstrate bias. In the setting of financial pressures and potential conflict of interest, bias can influence the type of study design, hypotheses being tested, rigor and transparency in data analysis, interpretation, as well as reporting of the results. Unlike public granting agencies, industry does not necessarily provide funding based on unbiased peer review following an open call for proposals. The focus on success can influence the choice of a comparator, which might not be ideal among the possible alternatives, the language used in the publication, and even the ability to publish. Unpublished negative trials can result in selected information being withheld from the scientific community and the public. Appropriate safeguards are needed to ensure that research addresses the most important and relevant questions, that results are available even when they do not support the use of a product produced by the funding company, that populations studied reflect the relevant patients, that the most rigorous approaches are applied, that studies have the appropriate power to address the question posed, and that conclusions are presented in an unbiased manner.

Pro-Con Debate: Interdisciplinary Perspectives on Industry-Sponsored Research

ProNearly all new devices and drugs come from industry that provides two-thirds of the funding for medical research, and a much higher fraction of clinical research. Realistically, without corporate-funded studies, perioperative research would stagnate with little innovation and few new products. Opinions are ubiquitous and normal but do not constitute epidemiologic bias. Competent clinical research includes many protections against selection and measurement bias, and the publication process provides at least moderate protection against misinterpretation of results. Trial registries largely prevent selective data presentation. Sponsored trials are particularly protected against inappropriate corporate influence because they are usually codesigned with the US Food and Drug Administration, and analyses are based on formal predefined statistical plans, as well as being conducted with rigorous external monitoring. Novel products, which are essential for advances in clinical care, largely come from industry, and industry appropriately funds much of the required research. We should celebrate industry’s contribution to improvements in clinical care. ConWhile industry funding contributes to research and discovery, examples of industry-funded research demonstrate bias. In the setting of financial pressures and potential conflict of interest, bias can influence the type of study design, hypotheses being tested, rigor and transparency in data analysis, interpretation, as well as reporting of the results. Unlike public granting agencies, industry does not necessarily provide funding based on unbiased peer review following an open call for proposals. The focus on success can influence the choice of a comparator, which might not be ideal among the possible alternatives, the language used in the publication, and even the ability to publish. Unpublished negative trials can result in selected information being withheld from the scientific community and the public. Appropriate safeguards are needed to ensure that research addresses the most important and relevant questions, that results are available even when they do not support the use of a product produced by the funding company, that populations studied reflect the relevant patients, that the most rigorous approaches are applied, that studies have the appropriate power to address the question posed, and that conclusions are presented in an unbiased manner.

Design and statistics of pharmacokinetic drug-drug, herb-drug, and food-drug interaction studies in oncology patients

Polypharmacy is becoming increasingly prevalent in society. Patients with polypharmacy are at greater risk for drug-drug interactions, which can influence the efficacy of treatment. Especially, in oncology this is a concern since neoplasms are increasing prevalent with age, as well as polypharmacy is. Besides drug-drug interactions, also herb-drug and food-drug interactions could be present. Knowledge of these interactions is of great importance for safe and effective anti-cancer treatment, because the therapeutic window of most of these oncologic drugs are small. To study pharmacokinetic interaction effects, a cross-over pharmacokinetic study is a widely used, efficient and scientifically robust design. Yet, several aspects need to be considered when carrying out an interaction study. This includes the knowledge of the advantages and disadvantages of a cross-over design. Furthermore, determination of the end point and research question of interest, calculation of the required sample size, analysis of the generated data with a robust statistical plan and consideration of the logtransformation for some pharmacokinetic parameters are important aspects to consider. Even though some guidelines exist regarding these key issues, no clear overview exists. In this article an overview of these aspects is provided and their effect is discussed.

An Evaluation of Screening Pathways Using a Combination of Magnetic Resonance Imaging and Prostate-specific Antigen: Results from the IP1-PROSTAGRAM Study

BackgroundThe use of prostate-specific antigen (PSA) testing to screen for prostate cancer has been fraught with under- and overdiagnosis. Short, noncontrast magnetic resonance imaging (MRI) might detect more grade group ≥2 cancers with similar rates of biopsy. ObjectiveTo evaluate strategies that combined PSA and MRI to select men based in the community for a prostate biopsy. Design, setting, and participantsIP1-PROSTAGRAM was a prospective, population-based, paired cohort study of 408 men aged 50–69 yr conducted at seven UK primary care practice and two imaging centres (from October 10, 2018 to May 15, 2019). InterventionAll participants underwent screening with a PSA test, MRI (T2-weighted and diffusion), and transrectal ultrasound (b-mode and elastography). If any test was screen positive, a systematic 12-core biopsy was performed. Additional image-fusion targeted biopsies were taken if the MRI or ultrasound was positive. Outcome measurements and statistical analysisWe conducted an analysis, set out in the statistical plan a priori, comparing 13 different pathways including PSA-alone, MRI-alone, and a range of PSA thresholds and MRI scores. The performance of each pathway was evaluated focusing on the trade-offs between biopsy referral rates and detection of grade group ≥2 cancers. A targeted biopsy was performed only where the PROSTAGRAM MRI showed a lesion score of 3, 4, or 5. Results and limitationsThe standard PSA pathway (PSA ≥3 ng/ml + systematic biopsy) would lead to 10% of men being referred for a biopsy and a 1.0% detection rate of grade group ≥2 cancers. Pathways that relied on MRI alone set at a threshold score of 3 for a biopsy led to higher biopsy rates, but with benefit of high cancer detection rates. The pathway that combined an initial low PSA threshold (≥1.0 ng/ml) and MRI score ≥4 accurately identified a high rate of grade group ≥2 cancers (2.5%, 95% confidence interval 1.3–4.6) while recommending fewer patients for a biopsy (7.1%, 95% confidence interval 4.9–10.2). The results are pertinent to only one screening round, the impact of repeat screening rounds is not evaluated, and the required MRI capacity is currently lacking. ConclusionsOur results highlight the trade-off that exists between reducing excessive numbers of biopsies and maintaining grade group ≥2 cancer detection rates. A pathway that combines PSA ≥1 ng/ml and MRI score ≥4 maintains the detection of grade group ≥2 cancers while recommending fewer men for biopsies and would be the preferred strategy to evaluate in future studies at the first screening round. Patient summaryThe IP1-PROSTAGRAM study shows that PROSTAGRAM magnetic resonance imaging in men with a prostate-specific antigen level of ≥1.0 ng/ml could be a promising pathway to evaluate in future screening trials.

Guidance for Treating the Older Adults with Colorectal Cancer.

The need for evidence-based data in the rapidly growing group of older patients is vast and more elderly-specific studies are desperately needed, for which there is clear demand from both patients and providers. Notably, many of the studies discussed in this review included unplanned subset analyses based on age and/or were not originally stratified by age; therefore, these data, particularly overall survival data, need to be interpreted with some caution as they may not be statistically valid based on the initial trial design and statistical plan. As we await data from ongoing elderly-specific trials, our recommendation for managing older patients with CRC should include geriatric screening tools (e.g., CSGA, VES-13, G8, CARG, CRASH) to help guide treatment adjustments for improved tolerability without sacrificing efficacy. For patients with a positive screen for significant geriatric concerns, a full geriatric assessment is recommended to guide treatment approach and supportive care. Prior data support the use of all approved medications for CRC in older adults who are fit; however, treatment breaks and dose attenuation with potential escalation are reasonable options for these patients. Ultimately, management decisions in the care of older adults with mCRC must be made through shared decision-making with the patient with consideration for the patient's functional status, comorbidities, goals of care, social support, as well as potential toxicities and possible effect on QoL.

Delivery of an at-home transcranial direct current stimulation intervention to mitigate pain in patients with end-stage kidney disease receiving hemodialysis (ESKD/HD).

Poorly controlled pain remains a problem for many patients with end-stage kidney disease requiring hemodialysis (ESKD/HD) and customary approaches to pain management (e.g., opioids, non-steroidals) confer substantial risk. Accordingly, non-pharmacologic therapies are needed for use in this population. Non-invasive transcranial Direct Current Simulation (tDCS) constitutes a promising nonpharmacologic method for pain management in affected individuals. This study seeks to: 1) determine the effects of an 8-week course of at-home tDCS vs. sham tDCS on pain intensity, pain interference, medication usage, quality of life, and mood; 2) determine if tDCS effects vary by race/ethnicity; and 3) ascertain patient satisfaction with device use. This double-blind, randomized, sham-controlled clinical trial will enroll 100 ESKD/HD patients with moderate-to-severe (≥4 on 0-10 scale) chronic pain. The active study intervention consists of 20 min of tDCS delivered over the primary motor cortex 5 days/week for 8 weeks. The comparator is a sham procedure that provides no effective stimulation. The primary outcome analysis will evaluate efficacy of tDCS for pain reduction after two months of stimulation. We will also assess the effects of treatment on analgesic consumption, pain interference, depressed mood, and quality of life. The statistical plan will include fixed classification factors for treatment (vs. sham), clinic sites, and assessment time, and the interaction of these factors adjusting for covariates (e.g., race/ethnicity, pain level). At-home tDCS constitutes a promising nonpharmacologic treatment for pain mitigation in persons with ESKD/HD. This unique RCT could transform the way pain is managed in this vulnerable population. NCT05311956.

Rigour and reproducibility in perinatal and paediatric epidemiologic research using big data.

Rigour and reproducibility in perinatal and paediatric epidemiologic research using big data.

Abstract OT3-20-04: SerMa – Seroma formations of the Mammary gland in breast cancer patients after mastectomy and implant-based reconstruction (EUBREAST 5)

Abstract Background Postoperative seroma formations are one of the most common and serious complications after implant-based breast reconstruction and can lead to implant and thus breast loss. The cause hasn`t yet been clarified. Hypothesis generating and thus as a basis for this multicenter study is the suspicion of a connection between immunological-inflammatory processes that promote the development of a seroma. First promising results of the pilot phase (SerMa pilot) have been published and gave the first impulse for this study. Trial design The SerMa (EUBREAST 5) study is a prospective, multicenter, interventional, international study including patients with primary breast cancer and a skin-/nipple-sparing mastectomy combined with an implant-based reconstruction method. Control groups were chosen to work out common group-specific differences. Intra- or directly preoperatively collected blood as well as intraoperatively collected local smear using swabs are preserved specimens. Follow-up includes visits after 2 and 6 weeks as well as after 6 months. In case of a seroma formation fluid aspirations are preserved for laboratory analyses. Eligibility criteria: The study population contains patients with primary diagnosis of breast cancer scheduled for skin-/nipple-sparing mastectomy and implant-based breast reconstruction. The three control groups are: one with simple mastectomy without breast reconstruction as well as healthy persons with implant insert but without breast cancer after bilateral risk reducing mastectomy or last in case of purely cosmetic implant placement. Specific aims: The main objective of the study is to identify a patient subgroup with an increased risk of seroma development for future precision elucidation regarding the prevention of postoperative complications such as implant and thus breast loss. FACS-/Bioplex and microbiome analyses will be applied for the detection of certain immune markers, microbiobes and microbiome diversity using preoperative blood samples, intraoperative local smear collection and in case of later seroma formations also postoperative seroma aspirations. Secondary endpoints include the comparison of these factors and elaborate differences between study and control groups. Furthermore clinico-pathological factors as well as different surgical methods are compared. Statistical methods: A statistical plan for this analysis was specifically developed (Power analyses with Wilcoxon-Mann-Whitney test) and leads to a number of 300 participants per group. Target accrual: Planned start: Q1/2023 Contact: EUBREAST e.V. Citation Format: Nina Ditsch, Nicole Pochert, Udo Jeschke, Mariella Schneider, Melitta Koepke, Maggie Banys-Paluchowski, Claudia Traidl-Hoffmann, Christian Dannecker, Thorsten Kühn. SerMa – Seroma formations of the Mammary gland in breast cancer patients after mastectomy and implant-based reconstruction (EUBREAST 5) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-20-04.

Targeted intra-arterial gemcitabine vs. continuation of IV gemcitabine plus nab-paclitaxel following induction with sequential IV gemcitabine plus nab-paclitaxel and radiotherapy for unresectable locally advanced pancreatic cancer (TIGeR-PaC): A randomized phase 3 multicenter study.

TPS773 Background: Prognosis for locally advanced pancreatic cancer (LAPC) remains dismal even with advances in cancer therapy. Beyond systemic therapies, local disease control is important in these patients. Local double balloon mediated delivery of intra-arterial gemcitabine (IAG) was demonstrated to be safe in this patient population in a prior study1. TIGeR-PaC is an ongoing Phase-3 clinical trial comparing the efficacy of this approach compared to standard of care IV gemcitabine/nab-paclitaxel (GN) for patients with LAPC. Methods: The trial is designed with an induction phase of upfront systemic therapy prior to IAG. Patients with LAPC diagnosed within 6 weeks and ECOG 0-1, receive 3 cycles of GN and 1 cycle of radiation. The form of radiation was either IMRT, 50 Gy in 25 fractions, with concomitant capecitabine or SBRT, 33 Gy in 5 fractions (per site preference). Following induction, patients with non-progressive disease were randomized to receive IAG (8 treatments every two weeks for 16 weeks) or continuing therapy with 4 cycles of GN. After the 16 weeks of randomized therapy, the patients with non-progressive disease went on to continue systemic therapy (GN or capecitabine, per investigator’s preference) until disease progression and then followed for survival only. The primary endpoint is overall survival, and the study has an 80% power to detect a hazard ratio of 0.6 between the two arms. As of September 1st, 2022, 189 patients have been enrolled in the trial. In its initial design the trial expected a 35% drop out rate during the induction phase; however, two years into the trial the actual observed dropout rate was 53%. Beyond progression (22%), the key element of dropout rate was AE/SAE during radiation with IMRT/capecitabine (17%) vs. only 6% with SBRT. To increase accrual of randomized patients, the protocol and the statistical plan were modified to restrict the mode of radiation during induction to SBRT only starting December 2021. Since the modification of the protocol, the dropout rate during induction has decreased to 38%. As of this abstract, 43 patients have been randomized following induction with GN and SBRT. The rate of SAE during active treatment is not different between the 2 arms (20% in each arm), and the most common SAE is GI side effects in both arms. The protocol has a pre-planned interim analysis after 26 events, with 23 events at this writing we expect our first interim analysis later this year. 1. Rosemurgy AS, e al: J Pancreat Cancer. 2017;3(1):58-65. doi:10.1089/pancan.2017.0011. Clinical trial information: NCT03257033 .

Design, power, and alpha levels in randomized phase II oncology trials

The statistical plan of a phase II trial should balance minimizing the premature termination of potentially beneficial therapies (i.e. false negatives) and the further, costly testing of ineffective drugs (i.e. false positives). We sought to examine the methodology, reporting, and bias in the interpretation of outcomes of phase II oncology trials in recent years. In a retrospective cross-sectional analysis, we reviewed all full-length articles published on PubMed from 1 January 2021 to 20 June 2022. We searched for data regarding the sample size calculation (number, α value, power, and expected effect size), the primary and secondary outcomes and results, and the authors' conclusion of the study. About 5.4% of studies (n= 10) used a statistical power that was inferior to 80%, and 16.7% (n= 34) did not indicate the level of power for the sample size calculation. Approximately 16.7% (n= 31) of studies used a one-sided α level of ≤0.025; 17.7% (n= 33) of studies used a predefined threshold (no comparator effect size or difference between groups) to determine the sample size for efficacy. The percentage of studies with a positive authors' conclusion but not meeting the primary endpoint, or the endpoint was equivocal, was 27.4% (n= 51). Many randomized phase II studies in oncology failed to report essential data for determining sample size calculations, many did not actually use a comparator to determine efficacy even though the studies were randomized, and many had positive conclusions even though the results were indeterminate or the primary endpoint was not met.

Effect of Diamond Burnishing on the Properties of FSW Joints of EN AW-2024 Aluminum Alloys

The article presents the results of an analysis of the surface roughness parameters, microhardness, and the stresses of the surface layer ofFSW butt joints subjected to the burnishing process with a diamond tip. This can be useful in selecting the optimal parameters of the burnishing process, ensuring the best properties of the surface layer of the FSW joint. Burnishing force and feed rate influence were analyzed according to the two-factor three-level full factorial statistical completed plan PS/DC 32. The tested material was 2024-T3 aluminum alloy sheets with a thickness of 2 mm. The results show that burnishing significantly reduced the surface roughness from Sa = 6.46 μm to Sa in the range of 0.33 μm–1.7 μm. This treatment provides high compressive residual stresses σx from −86 to −130 MPa and σy from −158 to −242 MPa. Microhardness increased from 84.19% to 174.53% compared to butt joints. Based on the obtained results, multi-criteria optimization was carried out. This optimization allows us to obtain a compromise solution ensuring compressive stresses in the surface layer (σx=−123 MPa and σy=−202 MPa) and microhardness HV=362.56 mm/mm2 with the roughness of the weld surface Sa = 0.28 µm, Sku = 3.93 and Spc = 35.88 1/mm.

문화재 활용정책의 평가

The purpose of this study is to evaluate the performance of the Local cultural heritage utilization project and to seek future improvement plans. this study applied Vedung (2010)'s policy evaluation system model to empirically evaluate the local cultural heritage utilization project, which is a representative project of cultural heritage utilization policy. First of all, the evaluation model was set up in the steps of input-implementation-result. The results were more specified as outputs and impacts. The evaluation was based on project statistical data, related reports, work plans or performance reports of the Cultural Heritage Administration. Finally, through the evaluation results, this study suggested improvement directions in terms of business continuity, institutional arrangements, and program planning and capacity building.

Predicting the quality and evaluating the use of administrative data for the 2021 Canadian Census of Population

This paper presents the statistical contingency plan for the 2021 Canadian Census of Population, developed in response to the COVID-19 pandemic, wherein administrative data was to impute non-responding households in areas with a low response rate and where the administrative data were of sufficient quality. We describe the modeling approach for predicting the quality of data available for administrative households, including important extensions to existing approaches. As well, we provide a framework for evaluating direct imputation using administrative data, relative to traditional donor imputation, in the absence of a simulation study. We conclude by discussing the evaluation using preliminary data and subsequent implementation for the 2021 Canadian Census of Population.

ALLG AMLM26 Phase 1B/2 Study Investigating Novel Therapies to Target Early Relapse and Clonal Evolution As Pre-Emptive Therapy in AML (INTERCEPT): A Multi-Arm, Precision-Based, Recursive, Platform Trial

Background Clinical trials investigating novel therapies in relapsed/refractory acute myeloid leukemia (AML) are challenged by rapid disease progression, severe cytopenias and a high frequency of infectious complications, limiting the capacity of such trials to determine efficacy and hematologic tolerance for new drugs and combinations. Guidelines for monitoring measurable residual disease (MRD) and defining MRD relapse have been established (Heuser, Blood 2021), with MRD relapse known to precede clinical relapse by 3-4 months (Ivey, NEJM 2016). A prospective pilot study utilizing low-dose cytarabine (LDAC) plus venetoclax (VEN) for patients with MRD relapse or oligoblastic relapse (5-15% marrow blasts) demonstrated a high response rate and durable outcomes (Tiong, ASH 2021). To extend this concept to include a broader range of targeted drug combinations directed against MRD relapse, we developed the Australasian Leukaemia and Lymphoma Group (ALLG) AMLM26 INTERCEPT study, a multi-domain, multi-arm, platform trial enabling proof-of-concept (POC) efficacy and tolerability to be obtained for multiple therapies in parallel in the setting of MRD relapse. Study Design and Methods Figure 1 summarizes the trial schema. The INTERCEPT trial (ANZCTR: ACTRN12621000439842), due activation in August 2022, is sponsored by the ALLG and conducted in partnership with the ALLG sites and the MD Anderson Cancer Center, U.S. The trial incorporates 2 phases, an MRD Monitoring Phase, and a Treatment Phase. Patients in first or second remission consent to a Master Protocol linked to a coordinated MRD monitoring framework to track FLT3-ITD, RUNX1::RUNX1T1, CBFB::MYH11, NPM1, KMT2A::X and aberrant myeloid immunophenotype. In patients in whom pre-leukemic clonal hematopoiesis is excluded by reduction of variant frequency in remission to <2.5%, IDH1 and IDH2 are also tracked. For molecular markers, MRD relapse is defined according to ELN recommendations (a log10 increase in serial MRD confirmed by repeat testing on concordant tissue). Flow cytometric detected disease for the INTERCEPT study is defined as an aberrant MRD phenotype ≥0.1% confirmed on repeat testing. MRD relapse is confirmed by a central laboratory and eligibility adjudicated by a blinded MRD reference committee. For the Treatment Phase, a clinical Trial Management Committee (TMC) will apply a pre-determined set of clinical decision rules to direct allocation of patients to the most applicable treatment "domain", based on review of prior therapy, baseline molecular profile and MRD relapse characteristics. For example, a patient with rising FLT3-ITD MRD meeting relapse criteria may be allocated to treatment with gilteritinib + VEN, rising IDH1 mutation to ivosidenib + VEN, rising KMT2A::X to SNDX-5613, rising NPM1 to LDAC + VEN or alternatively, to SNDX-5613. Where no specific targeted treatment is available, patients will be randomly allocated to non-targeted therapies, if more than one applicable arm exists, to arms including sabatolimab, sabatolimab + azacitidine, ASTX727 + VEN or LDAC + VEN. Future treatment options can be seamlessly incorporated in the INTERCEPT framework by amendment of the Master Protocol and addition of new Therapy-Specific Protocol Appendices (TSPAs). Each TSPA outlines specific eligibility criteria, dose schedules, study conduct and the statistical plan for each treatment arm. Patients may also be allocated to a morphologic relapse stratum, if MRD relapse was not captured by MRD surveillance. This will enable comparison of treatment tolerance and response at MRD vs morphologic relapse. If progression occurs with one treatment arm (including MRD relapse), the protocol allows the same patient to be transitioned to an alternative treatment arm if eligibility criteria are met. The primary objective is to determine if novel treatment options can produce an MRD response rate of ≥40% as determined by a Bayesian Proof of Concept design in each domain. The primary endpoint is MRD response (≥1 log10 reduction in molecular MRD or flow MRD<0.1%) within 100 days of the first dose of study drug. MRD responses will be determined centrally. Key secondary endpoints will be nadir MRD response, MRD clearance rate, median time to and duration of MRD response, relapse-free survival, overall survival and quality of life measures. Exploratory objectives will include analysis of drug resistance mechanisms and correlates of response. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Bayesian Inference for Optimization of Interim Analysis in Clinical Trials By Incorporation of Historical Data: Reanalysis of the HOVON AML 132 Clinical Trial

Background Prospective randomized trials remain pivotal to evaluate the benefit of new therapies. Primary endpoints typically focus on long-term endpoints after study completion, whereas interim analyses are monitoring safety and toxicity. Although the traditional or frequentist approach is widely used to analyze endpoints and anticipate the number of events needed upon trial completion, it is limited by the need for prior assumptions of the expected treatment effect, long-term follow-up, and conservative stopping rules. Bayesian inference might overcome these limitations, for which prior knowledge is combined with new data to compute the posterior distribution, enhancing the strength of the ongoing trial. This study aims to evaluate whether a Bayesian approach using historical data as prior knowledge might support decision-making at interim time points of the HO132 phase 3 clinical trial for patients with acute myeloid leukemia (AML), that was recently reported (Löwenberg et al, 2021). Methods In the HO132 trial, 927 patients aged 18 to 65 years with newly diagnosed AML were randomized between intensive induction ± lenalidomide. The primary endpoint EFS was not different between experimental and control treatment (HR 0.99, p=0.96). After excluding 64 patients for lenalidomide dose selection, three interim analyses were retrospectively introduced after inclusion of 150, 300 and 600 patients to assess whether the lack of efficacy emerged early during conduct of the trial. The control treatment arm was reinforced using 445 historical control treatment patients from the preceding AML trial (HO102). Patients of both control arms were matched 1:1 using propensity scores based on age and leukemia risk. At each interim analysis, posterior distributions were calculated for endpoints including complete remission (CR) after induction, minimal residual disease (MRD) in CR, early death within 2 months, and EFS. The posterior distributions were summarized to provide point estimates and 95% credible intervals (CI) on the treatment difference and hazard ratio (HR) between both arms. For binary outcomes, the probability of success (range 0-100%) of the control versus the experimental treatment was computed. For EFS, the probability of the HR being below 0.76 was calculated, which was the assumed effect size in the HO132 statistical plan. A probability of <10% was considered as the futility threshold. Results We compared HO132 experimental treatment with control treatment reinforced with matched historical patients for the previously mentioned endpoints. The proportion of patients obtaining CR was lower with experimental compared with control treatment at interim analysis 1 (Fig 1A, treatment difference: -9.0% [95% CI -19.9 to 1.4]) and the probability for demonstrating a superior CR rate with experimental treatment was 4%. At interim analysis 2 and 3 the treatment difference was -8.1% [95% CI -16.3 to 0.001] and -9.8% [95% CI -18.6 to -4.1] with a probability of success of 3% and 0%, respectively. Patients in CR and assigned to the experimental treatment arm were less often MRDneg compared with control at every interim analysis (treatment difference: -10.3% [95% CI -28.7 to 8.0]; -8.1% [95% CI -21.5 to 5.6]; -5.6% [95% CI -14.5 to 3.4], respectively), with a respective probability not meeting the futility stopping rule of 13%, 12% and 11%. Early deaths were more frequently observed with experimental treatment versus control (treatment difference: 5.5% [95% CI -0.7 to 12.8]), with 4% probability of fewer early deaths with experimental treatment than control at interim analysis 1. The treatment differences for early death at interim analyses 2 and 3 were 3.5% (95% CI -1.7 to 9.2) and 2.0% (95% CI -1.9 to -6.0) with a probability of 10% and 15%, respectively. EFS was similar between both arms at interim analysis 2 and 3 (HR 1.00, and HR 1.04, respectively, Fig 1B), with a median follow-up time of 10 and 16 months, respectively. At interim analysis 2, this resulted in a probability of 4% reaching the anticipated HR of 0.76, which probability was 0% at interim analysis 3. Conclusion Reanalyzing the prospective conduct of the HO132 study using Bayesian inference identified a low probability of success of the experimental treatment at three successive putative interim analyses based on important efficacy markers. Consequently, a low probability of efficacy during trial conduct might support early termination of the trial. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Exploring Industry-Level Fairness of Auto Insurance Premiums by Statistical Modeling of Automobile Rate and Classification Data

The study of actuarial fairness in auto insurance has been an important issue in the decision making of rate regulation. Risk classification and estimating risk relativities through statistical modeling become essential to help achieve fairness in premium rates. However, because of minor adjustments to risk relativities allowed by regulation rules, the rates charged eventually may not align with the empirical risk relativities calculated from insurance loss data. Therefore, investigating the relationship between the premium rates and loss costs at different risk factor levels becomes important for studying insurance fairness, particularly from rate regulation perspectives. This work applies statistical models to rate and classification data from the automobile statistical plan to investigate the disparities between insurance premiums and loss costs. The focus is on major risk factors used in the rate regulation, as our goal is to address fairness at the industry level. Various statistical models have been constructed to validate the suitableness of the proposed methods that determine a fixed effect. The fixed effect caused by the disparity of loss cost and premium rates is estimated by those statistical models. Using Canadian data, we found that there are no significant excessive premiums charged at the industry level, but the disparity between loss cost and premiums is high for urban drivers at the industry level. This study will help better understand the extent of auto insurance fairness at the industry level across different insured groups characterized by risk factor levels. The proposed fixed-effect models can also reveal the overall average loss ratio, which can tell us the fairness at the industry level when compared to loss ratios by the regulation rules.

Impact of atrial fibrillation on in-hospital outcomes of coronary artery bypass graft surgery: an analysis by propensity score matching

Abstract Background/Introduction Many patients referred for coronary artery bypass graft (CABG) surgery have persistent or permanent atrial fibrillation (AF). Despite the significant occurrence, the impact of this arrythmia on surgical outcomes remains uncertain. Purpose To assess the impact of persistent or permanent AF on post-CABG in-hospital outcomes. Methods A cohort of 3,124 patients undergoing to isolated CABG between 2010 and 2020 was evaluated. A propensity score pairing was applied, considering persistent or permanent AF as a dependent variable and another 19 baseline characteristics as independent variables in the regression model used to build the propensity score. Pairing was performed at a ratio of 3:1 – Group 1: 324 patients without persistent or permanent AF; Group 2: 108 patients with the documented diagnosis of persistent or permanent AF. The statistical plan also included normality analyses, descriptive and univariate analyses, binary logistic regression, ROC curves and DeLong test to compare de curves. The significance level adopted was 5%. The analyses were performed by the programming language Python. Results None of the baseline characteristics evaluated showed a significant difference between the groups, including the EuroScore II (Group 1: 1.54±1.45 vs Group 2: 1.49±1.59; p=0.990). Likewise, none of the analysed surgical characteristics showed a significant difference, indicating a very approximate pattern of complexity of the surgeries. The absence of differences demonstrated a high degree of homogeneity between the groups. The use of pairing by propensity score aimed to form two extremely similar study groups, which differed only in relation to the diagnosis of the arrhythmia under study. Among the outcomes evaluated, AMI (1.5 vs 6.5; p=0.013), MACCE (7.1% vs 14.8%; p=0.015) and death (1.5% vs 6.5%; p=0.013) had significantly higher incidences in Group 2, formed by patients with persistent or permanent AF. From the multivariate analysis, it can be identified that permanent AF was an independent risk predictor for the occurrence of in-hospital death (OR: 5.009; 95% CI 1.433–17.507; p=0.012). Finally, it was also possible to verify that the association of EuroScore II with persistent or permanent AF showed higher predictive accuracy than EuroScore II alone (ESII+FA = AUC 0.852 vs ESII alone = AUC 0.775, p&amp;lt;0,05). Conclusion(s) Patients with persistent or permanent AF had significantly higher incidences of AMI, MACCE and in-hospital death. Persistent or permanent AF was characterized as an independent predictor for the occurrence of death and the association with the EuroScore II resulted in a 9.9% increase in the predictive accuracy of the surgical risk score. Funding Acknowledgement Type of funding sources: None.