Covariate-adaptive Randomization Research Articles

FINDINGS AND FUTURE DIRECTIONS FROM A SMOKING CESSATION TRIAL UTILIZING A CLINICAL DECISION SUPPORT TOOL.

Tobacco smoking is the leading cause of disease, death, and disability in the United States. Dental practitioners are advised to provide evidence-based smoking cessation interventions to their patients, yet dental practitioners frequently fail to deliver brief smoking cessation advice. To test whether giving dental practitioners a clinical decisions support (CDS) system embedded in their electronic dental record would increase the rate at which patients who smoke (1) report receiving a brief intervention or referral to treatment during a recent dental visit, (2) taking action related to smoking cessation within 7 days of visit, and (3) stop smoking for 1 day or more or reduce the amount smoked by 50% within 6 months. Two-group, parallel arm, cluster-randomized trial. From March through December 2019, 15 nonacademic primary care dental clinics were randomized via covariate adaptive randomization to either a usual care arm or the CDS arm. Adult smokers completed an initial telephone survey within 7 days of their visit and another survey after 6 months. Forty-three patients from 5 CDS and 13 patients from 2 usual care clinics completed the 7-day survey. While the proportion of patients who reported receipt of a brief intervention or referral to treatment was significantly greater in the CDS arm than the usual care arm (84.3% vs 58.6%; P = .005), the differences in percentage of patients who took any action related to smoking cessation within 7 days (44.4% vs 22.3%; P = .077), or stopped smoking for one day or more and/or reduced amount smoked by 50% within 6 months (63.1% vs 46.2%; P = .405) were large but not statistically significant. Despite interruption by COVID-19, these results demonstrate a promising approach to assist dental practitioners in providing their patients with smoking cessation screening, brief intervention and referral to treatment.

Estimation of hurst exponent for sequential monitoring of clinical trials with covariate adaptive randomization

BackgroundClassical Brownian motion (BM) has been commonly used in monitoring clinical trials including those with covariate adaptive randomization (CAR). Independent increment property is commonly assumed in the sequential monitoring process of the clinical trials with CAR designs. However, in reality, correlation may exist in the error terms of the underlying model, resulting in dependent increment in the sequential monitoring process. MethodsWe conducted simulations for estimating the Hurst exponent to evaluate the stochastic property in the covariate adaptive randomized clinical trials under two scenarios: 1. CAR designs with independent and identically distributed error terms. 2. CAR designs with correlated error terms. The theoretical properties of covariate adaptive randomized clinical trials with correlated error structure were investigated. A test statistic including the covariance pattern of the error terms was proposed. ConclusionIn our study, the sequential test statistics under CAR procedure is shown to be asymptotically Brownian motion when the error structure is correctly specified. Further, Brownian motion is a special case of fractional Brownian motion when Hurst exponent equals to 0.5. Our simulations are consistent with the theoretical asymptotic results.

Effects of a Gamified, Behavior Change Technique-Based Mobile App on Increasing Physical Activity and Reducing Anxiety in Adults With Autism Spectrum Disorder: Feasibility Randomized Controlled Trial.

BackgroundPhysical activity (PA) has an impact on physical and mental health in neurotypical populations, and addressing these variables may improve the prevalent burden of anxiety in adults with autism spectrum disorder (ASD). Gamified mobile apps using behavior change techniques present a promising way of increasing PA and reducing sedentary time, thus reducing anxiety in adults with ASD.ObjectiveThis study aimed to compare the effectiveness of a gamified and behavior change technique–based mobile app, PuzzleWalk, versus a commercially available app, Google Fit, on increasing PA and reducing sedentary time as an adjunct anxiety treatment for this population.MethodsA total of 24 adults with ASD were assigned to either the PuzzleWalk or Google Fit group for 5 weeks using a covariate-adaptive randomization design. PA and anxiety were assessed over 7 days at 3 different data collection periods (ie, baseline, intervention start, and intervention end) using triaxial accelerometers and the Beck Anxiety Inventory. Group differences in outcome variables were assessed using repeated-measures analysis of covariance, adjusting for age, sex, and BMI.ResultsThe findings indicated that the PuzzleWalk group spent a significantly longer amount of time on app use compared with the Google Fit group (F2,38=5.07; P=.01; partial η2=0.21), whereas anxiety was unfavorably associated with increases in light PA and decreases in sedentary time after intervention (all P<.05).ConclusionsFurther research is needed to clarify the determinants of physical and mental health and their interrelationship in adults with ASD to identify the factors that facilitate the use and adoption of mobile health technologies in these individuals. Despite these mixed results, the small changes in PA or anxiety may be clinically significant for adults with ASD.Trial RegistrationClinicalTrials.gov NCT05466617; https://clinicaltrials.gov/show/NCT05466617

Multi-arm covariate-adaptive randomization.

Simultaneously investigating multiple treatments in a single study achieves considerable efficiency in contrast to the traditional two-arm trials. Balancing treatment allocation for influential covariates has become increasingly important in today’s clinical trials. The multi-arm covariate-adaptive randomized clinical trial is one of the most powerful tools to incorporate covariate information and multiple treatments in a single study. Pocock and Simon’s procedure has been extended to the multi-arm case. However, the theoretical properties of multi-arm covariate-adaptive randomization have remained largely elusive for decades. In this paper, we propose a general framework for multi-arm covariate-adaptive designs which also includes the two-arm case, and establish the corresponding theory under widely satisfied conditions. The theoretical results provide new insights about balance properties of covariate-adaptive randomization procedures and make foundations for most existing statistical inferences under two-arm covariate-adaptive randomization. Furthermore, these open a door to study the theoretical properties of statistical inferences for clinical trials based on multi-arm covariate-adaptive randomization procedures.

Lasso-adjusted treatment effect estimation under covariate-adaptive randomization

Summary We consider the problem of estimating and inferring treatment effects in randomized experiments. In practice, stratified randomization, or more generally, covariate-adaptive randomization, is routinely used in the design stage to balance treatment allocations with respect to a few variables that are most relevant to the outcomes. Then, regression is performed in the analysis stage to adjust the remaining imbalances to yield more efficient treatment effect estimators. Building upon and unifying recent results obtained for ordinary-least-squares adjusted estimators under covariate-adaptive randomization, this paper presents a general theory of regression adjustment that allows for model mis-specification and the presence of a large number of baseline covariates. We exemplify the theory on two lasso-adjusted treatment effect estimators, both of which are optimal in their respective classes. In addition, nonparametric consistent variance estimators are proposed to facilitate valid inferences, which work irrespective of the specific randomization methods used. The robustness and improved efficiency of the proposed estimators are demonstrated through numerical studies.

MP23-10 LONGITUDINAL ASSESSMENT OF 1-YR HEALTH RELATED QUALITY OF LIFE OUTCOMES: HEAD TO HEAD COMPARISON BETWEEN OPEN AND ROBOT-ASSISTED RADICAL CYSTECTOMY WITH TOTALLY INTRACORPOREAL URINARY DIVERSION FROM A SINGLE CENTER RANDOMISED CONTROLLED TRIAL

You have accessJournal of UrologyCME1 May 2022MP23-10 LONGITUDINAL ASSESSMENT OF 1-YR HEALTH RELATED QUALITY OF LIFE OUTCOMES: HEAD TO HEAD COMPARISON BETWEEN OPEN AND ROBOT-ASSISTED RADICAL CYSTECTOMY WITH TOTALLY INTRACORPOREAL URINARY DIVERSION FROM A SINGLE CENTER RANDOMISED CONTROLLED TRIAL Riccardo Mastroianni, Gabriele Tuderti, Umberto Anceschi, Alfredo Maria Bove, Aldo Brassetti, Mariaconsiglia Ferriero, Leonardo Misuraca, Salvatore Guaglianone, Michele Gallucci, and Giuseppe Simone Riccardo MastroianniRiccardo Mastroianni More articles by this author , Gabriele TudertiGabriele Tuderti More articles by this author , Umberto AnceschiUmberto Anceschi More articles by this author , Alfredo Maria BoveAlfredo Maria Bove More articles by this author , Aldo BrassettiAldo Brassetti More articles by this author , Mariaconsiglia FerrieroMariaconsiglia Ferriero More articles by this author , Leonardo MisuracaLeonardo Misuraca More articles by this author , Salvatore GuaglianoneSalvatore Guaglianone More articles by this author , Michele GallucciMichele Gallucci More articles by this author , and Giuseppe SimoneGiuseppe Simone More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002562.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Radical Cystectomy (RC) with urinary diversion (UD) is still considered a complex surgery associated with significant morbidity and impact on HRQoL. In this study, we performed analysis of 1yr HRQoL outcomes from an ongoing RCT comparing ORC and RARC with totally intracorporeal UD (NCT03434132). METHODS: Patients were eligible for randomization if they had a diagnostic TURBt cT2-4cN0cM0, or recurrent HG NMIBC and no anesthesiologic contraindications to robotic surgery. Between Jan 2018 and Sept 2020, patients were enrolled with a covariate adaptive randomization process based on: BMI, ASA, preoperative Hgb, UD (padua ileal bladder or conduit), neoadjuvant chemo and cTstage. Data from questionnaires EORTCgeneric QLQ-C30; QLQ-BLM30 were collected. Normally distributed HRQoL continuous variables were compared with paired t test. A generalized linear mixed effect regression (GLMER) model including a random effect at patients’ level was implemented to test variation of HRQoL items along time and between the two surgical approaches. RESULTS: Out of 116 patients enrolled, 101 with a 1yr minimum follow-up length were included. 13 patients died within 1yr after surgery (RARC: 7 vs ORC: 6), 2 patients were lost to follow-up. Baseline HRQoL outcomes were reported (Tab.1). At 1yr HRQoL evaluation, both cohorts reported significant worsening in terms of physical, and sexual functioning, and a significant impairment of dyspnea, constipation and body image (all p <0.05, Tab. 2). Patients receiving ORC were more likely to report 1yr impairment of role functioning, diarrhea, financial difficulties, and abdominal bloating and flatulence (all p <0.013). Otherwise, patients receiving RARC reported a significant 1yr impairment in terms of fatigue and a significant improvement in future perspectives (all p <0.036). At GLMER analysis, ORC cohort displayed a significant impairment in terms of abdominal bloating and flatulence and body image (p <0.043) compared with RARC arm. CONCLUSIONS: At 1yr HRQoL analysis, patients who underwent RARC-iUD reported significant benefits in terms of body image and abdominal bloating and flatulence compared to patients who underwent ORC. Source of Funding: no © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e384 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Riccardo Mastroianni More articles by this author Gabriele Tuderti More articles by this author Umberto Anceschi More articles by this author Alfredo Maria Bove More articles by this author Aldo Brassetti More articles by this author Mariaconsiglia Ferriero More articles by this author Leonardo Misuraca More articles by this author Salvatore Guaglianone More articles by this author Michele Gallucci More articles by this author Giuseppe Simone More articles by this author Expand All Advertisement PDF downloadLoading ...

MP56-05 IMPACT OF COMPREHENSIVE MEASUREMENT OF SURGICAL OUTCOMES ON SUBJECTIVE ASSESSMENT OF HEALTH RELATED QUALITY OF LIFE IN PATIENTS RECEIVING RADICAL CYSTECTOMY WITH ORTHOTOPIC PADUA ILEAL BLADDER: SINGLE CENTER RANDOMIZED CONTROLLED TRIAL

You have accessJournal of UrologyCME1 May 2022MP56-05 IMPACT OF COMPREHENSIVE MEASUREMENT OF SURGICAL OUTCOMES ON SUBJECTIVE ASSESSMENT OF HEALTH RELATED QUALITY OF LIFE IN PATIENTS RECEIVING RADICAL CYSTECTOMY WITH ORTHOTOPIC PADUA ILEAL BLADDER: SINGLE CENTER RANDOMIZED CONTROLLED TRIAL Riccardo Mastroianni, Gabriele Tuderti, Umberto Anceschi, Alfredo Maria Bove, Leonardo Misuraca, Aldo Brassetti, Mariaconsiglia Ferriero, Salvatore Guaglianone, Michele Gallucci, and Giuseppe Simone Riccardo MastroianniRiccardo Mastroianni More articles by this author , Gabriele TudertiGabriele Tuderti More articles by this author , Umberto AnceschiUmberto Anceschi More articles by this author , Alfredo Maria BoveAlfredo Maria Bove More articles by this author , Leonardo MisuracaLeonardo Misuraca More articles by this author , Aldo BrassettiAldo Brassetti More articles by this author , Mariaconsiglia FerrieroMariaconsiglia Ferriero More articles by this author , Salvatore GuaglianoneSalvatore Guaglianone More articles by this author , Michele GallucciMichele Gallucci More articles by this author , and Giuseppe SimoneGiuseppe Simone More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002639.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Functional outcomes of Radical Cystectomy (RC) with orthotopic padua ileal bladder (PIB) are poorly reported and their impact on HRQoL underivestigated. We evaluated impact of trifecta and tetrafecta achievement on global health status from an ongoing RCT (NCT03434132). METHODS: Inclusion criteria were: diagnostic TURBt with cT2-4cN0cM0, or recurrent HG NMIBC and no anesthesiologic contraindications to RARC. Between Jan 2018 and Sept 2020 patients were enrolled with a covariate adaptive randomization process based on BMI, ASA, baseline hgb, UD, neoadjuvant chemo and cTstage. We previously described Trifecta as the combination of day continence, no major complication (CD ≥3) and recurrence-free status, at 1yr. Tetrafecta also included night continence. Global health status/QoL (QL) was evaluated from EORTC QLQC30 questionnaires. Satisfactory HRQoL outcome was defined as 1yr QL decrease <10% from baseline. Continuous and categorical variables were compared using Student t and Chi-Square tests. Logistic regression analysis was performed to assess the role of trifecta achievement on HRQoL. RESULTS: Out of 116 patients enrolled 88 underwent PIB and 75 reached a minimum follow-up of 1yr. Baseline clinical features were reported Table 1. Trifecta was achieved in 41 patients (55%) while tetrafecta in 17 (23%). Trifecta achievement had a significant impact on QL patients who achieved trifecta had a lower probability (34%) to observe a QL decrease≥10% compared with patients who did not achieve trifecta (62%) (p=0.021). Tetrafecta achievement had a negligible impact on QL (29% and 52%, tetrafecta achieved vs tetrafecta not achieved p=0.166) suggesting a minor impact of night continence on HRQoL (Figure 1). At logistic regression analysis patients who achieved trifecta had 68% lower probability to experience an overall QL decrease ≥10% (OR 0.321, 95% CI 0.125-0.827; p=0.019). CONCLUSIONS: This study described a significant impact of trifecta on HRQoL, providing a strict correlation between objective evaluation of surgical outcomes and self reported HRQoL. Tetrafecta seems to play a negligible role on HRQoL, even if a larger cohort is needed to establish the HRQoL impact of night urinary continence. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e972 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Riccardo Mastroianni More articles by this author Gabriele Tuderti More articles by this author Umberto Anceschi More articles by this author Alfredo Maria Bove More articles by this author Leonardo Misuraca More articles by this author Aldo Brassetti More articles by this author Mariaconsiglia Ferriero More articles by this author Salvatore Guaglianone More articles by this author Michele Gallucci More articles by this author Giuseppe Simone More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP23-02 EARLY ONCOLOGIC OUTCOMES OF OPEN VS ROBOT-ASSISTED RADICAL CYSTECTOMY WITH TOTALLY INTRACORPOREAL URINARY DIVERSION: SINGLE CENTRE PROSPECTIVE RANDOMISED CONTROLLED TRIAL

You have accessJournal of UrologyCME1 May 2022MP23-02 EARLY ONCOLOGIC OUTCOMES OF OPEN VS ROBOT-ASSISTED RADICAL CYSTECTOMY WITH TOTALLY INTRACORPOREAL URINARY DIVERSION: SINGLE CENTRE PROSPECTIVE RANDOMISED CONTROLLED TRIAL Riccardo Mastroianni, Gabriele Tuderti, Umberto Anceschi, Alfredo Maria Bove, Aldo Brassetti, Mariaconsiglia Ferriero, Leonardo Misuraca, Salvatore Guaglianone, Michele Gallucci, and Giuseppe Simone Riccardo MastroianniRiccardo Mastroianni More articles by this author , Gabriele TudertiGabriele Tuderti More articles by this author , Umberto AnceschiUmberto Anceschi More articles by this author , Alfredo Maria BoveAlfredo Maria Bove More articles by this author , Aldo BrassettiAldo Brassetti More articles by this author , Mariaconsiglia FerrieroMariaconsiglia Ferriero More articles by this author , Leonardo MisuracaLeonardo Misuraca More articles by this author , Salvatore GuaglianoneSalvatore Guaglianone More articles by this author , Michele GallucciMichele Gallucci More articles by this author , and Giuseppe SimoneGiuseppe Simone More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002562.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Radical Cystectomy (RC) with urinary diversion (UD) is still considered a complex surgery associated with significant morbidity. Open radical cystectomy (ORC) remains the reference option of treatment, even if adoption of robot-assisted RC (RARC) is rapidly increasing. Two-yrs oncologic outcomes proved to be predictive of long term oncologic outcomes in historical series. In this study, we assessed early oncologic outcomes from a randomised controlled trial (RCT) comparing ORC and RARC with totally intracorporeal (i) urinary diversion (UD) (Clinical Trials: NCT03434132). METHODS: Institutional review board approval was obtained. Patients were eligible for randomization if they had a diagnostic TURBt with cT2-4, cN0, cM0, or recurrent HG NMIBC and no anesthesiologic contraindications to robotic surgery. Between January 2018 and September 2020, patients were enrolled with a covariate adaptive randomization process based on the following variables: BMI, ASA score, preoperative haemoglobin, UD (Padua ileal bladder or ileal conduit), neoadiuvant chemotherapy and cT-stage. Aim of this study was to evaluate oncologic outcomes: overall survival (OS), cancer specific survival (CSS), disease free survival (DFS) and metastasis free survival (MFS). Continuous and categorical variables were compared using Student t and Chi-Square tests, respectively. Kaplan-Meier (KM) method and the log-rank test were applied to assess survival outcomes. RESULTS: Overall, 116 patients were enrolled (RARC: 58 vs ORC: 58). Both groups were homogeneous for all clinical features (all p >0.15) (Tab.1). In the robotic group, UD was performed in all cases with a totally intracorporeal approach, with no need of open conversion. Pathologic data were reported (Tab.2). Overall, 23 (19.9%) patients had a high-risk non-muscle invasive BC. Homogeneous distribution of cT stages was confirmed at final pT-stages (p=0.78) and pN-stages (p=0.91). Soft tissue surgical margins were negative in all cases. Two patients were lost to follow-up, one for each arm. At a median follow-up of 22 mo (IQR 15-31), KM analysis displayed comparable OS, CSS, DFS and MFS probabilities (Fig.1). CONCLUSIONS: This RCT confirms comparable oncologic outcomes between ORC and RARC with totally iUD. Source of Funding: none © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e380 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Riccardo Mastroianni More articles by this author Gabriele Tuderti More articles by this author Umberto Anceschi More articles by this author Alfredo Maria Bove More articles by this author Aldo Brassetti More articles by this author Mariaconsiglia Ferriero More articles by this author Leonardo Misuraca More articles by this author Salvatore Guaglianone More articles by this author Michele Gallucci More articles by this author Giuseppe Simone More articles by this author Expand All Advertisement PDF downloadLoading ...

Toward Better Practice of Covariate Adjustment in Analyzing Randomized Clinical Trials

In randomized clinical trials, adjustments for baseline covariates at both design and analysis stages are highly encouraged by regulatory agencies. A recent trend is to use a model-assisted approach for covariate adjustment to gain credibility and efficiency while producing asymptotically valid inference even when the model is incorrect. In this article we present three considerations for better practice when model-assisted inference is applied to adjust for covariates under simple or covariate-adaptive randomized trials: (a) guaranteed efficiency gain: a model-assisted method should often gain but never hurt efficiency; (b) wide applicability: a valid procedure should be applicable, and preferably universally applicable, to all commonly used randomization schemes; (c) robust standard error: variance estimation should be robust to model misspecification and heteroscedasticity. To achieve these, we recommend a model-assisted estimator under an analysis of heterogeneous covariance working model that includes all covariates used in randomization. Our conclusions are based on an asymptotic theory that provides a clear picture of how covariate-adaptive randomization and regression adjustment alter statistical efficiency. Our theory is more general than the existing ones in terms of studying arbitrary functions of response means (including linear contrasts, ratios, and odds ratios), multiple arms, guaranteed efficiency gain, optimality, and universal applicability. Supplementary materials for this article are available online.

Open Radical Cystectomy versus Robot-Assisted Radical Cystectomy with Intracorporeal Urinary Diversion: Early Outcomes of a Single-Center Randomized Controlled Trial.

Radical cystectomy (RC) with urinary diversion (UD) is still considered a complex surgery associated with significant morbidity. Open RC (ORC) remains the reference option of treatment, even if adoption of robot-assisted RC (RARC) is rapidly increasing. To date, all the available randomized controlled trials were characterized by an extracorporeal approach in performing UD, undermining potential benefits of a totally minimally invasive procedure. In this study, we aimed to report perioperative and 6-month outcomes from the first RCT comparing ORC and RARC with totally intracorporeal UD. Patients were eligible for randomization if they had a diagnostic transurethral resection of bladder tumor with cT2-4, cN0, cM0 or recurrent high-grade nonmuscle-invasive bladder cancer and no anesthesiological contraindications to robotic surgery. Patients were enrolled with a covariate adaptive randomization process based on the following variables: body mass index, American Society of Anesthesiologists® score, baseline hemoglobin, planned UD, neoadjuvant chemotherapy and cT stage. The primary end point was to demonstrate the superiority of RARC with intracorporeal UD in terms of a 50% transfusion rate reduction. Overall, 116 consecutive patients (58 RARC, 58 ORC) were enrolled. Among primary endpoint, overall perioperative transfusion rates were significantly lower in the RARC cohort (RARC: 22% vs ORC: 41%; p=0.046). This prospective randomized trial observed 22% and 41% overall perioperative transfusion rates in patients treated by RARC and ORC, respectively, confirming a significant benefit in favor of RARC with intracorporeal UD. However, perioperative complications, hospital stay and 6-month health-related quality of life were largely comparable between groups. Oncologic and functional outcomes will be assessed at longer followup to observe potential differences between arms.

BIOM-17. DIFFERENCES IN THE IMMUNE MICROENVIRONMENT OF GLIOMAS HARBORING IDH2 VERSUS IDH1 MUTATIONS

Abstract INTRODUCTION IDH mutations are a defining feature of lower-grade glioma and secondary glioblastoma. Approximately 95% of glioma-associated IDH mutations are in codon 132 of IDH1, but a small proportion are in IDH2. IDH mutations produce the oncometabolite 2-hydroxyglutarate, which induces global DNA hypermethylation and is associated with an immunosuppressive tumor microenvironment. IDH1 is localized in the cytosol while IDH2 is found in the mitochondrial matrix, and mutations in these genes may have differing effects on the tumor microenvironment. METHODS Formalin-fixed, paraffin-embedded tissue from 633 IDH-mutant gliomas (615 IDH1-mutant, 18 IDH2-mutant) underwent whole-exome and whole-transcriptome sequencing at Caris Life Sciences (236 grade 2/3 astrocytoma, 158 grade 2/3 oligodendroglioma, 202 IDH-mutant glioblastoma, 37 glioma, NOS). QuantiSEQ was used to infer tumor-infiltrating immune cell populations from RNAseq data, and gene-set enrichment analyses (GSEA) were performed using Wikipathway. RESULTS IDH1-mutant gliomas had higher levels of pro-inflammatory M1 macrophages (P=0.04), modestly higher levels of monocytes (P=0.08), and lower levels of neutrophils (P=0.04) – typically considered immunosuppressive – compared with IDH2-mutant gliomas. No differences were observed in levels of B cells, dendritic cells, NK cells, or T cell subsets (Treg, CD4+, CD8+). IDH2-mutant gliomas were enriched for hallmark oligodendroglioma mutations (TERT promoter, CIC, FUBP1), while IDH1-mutant gliomas were enriched for hallmark astrocytoma mutations (ATRX, TP53). However, associations with tumor-infiltrating immune cells persisted after excluding 1p/19q co-deleted oligodendroglioma from analyses. GSEA revealed upregulation of the microglial TYROBP signaling pathway, the microglial phagocytic pathway, and of Type II Interferon signaling in IDH1-mutant gliomas versus IDH2-mutant gliomas. CONCLUSIONS Although IDH2 mutations are generally thought to function similarly to IDH1 mutations, we observe differences in tumor-infiltrating immune cells across groups. IDH2-mutant gliomas appeared to have a more immunosuppressive tumor microenvironment than their IDH1-mutant counterparts. Early-phase immunotherapy trials should consider covariate-adaptive randomization approaches to equally allocate IDH2-mutant gliomas across treatment arms.

Estimating Conditional Power for Sequential Monitoring of Covariate Adaptive Randomized Designs: The Fractional Brownian Motion Approach

Conditional power based on classical Brownian motion (BM) has been widely used in sequential monitoring of clinical trials, including those with the covariate adaptive randomization design (CAR). Due to some uncontrollable factors, the sequential test statistics under CAR procedures may not satisfy the independent increment property of BM. We confirm the invalidation of BM when the error terms in the linear model with CAR design are not independent and identically distributed. To incorporate the possible correlation structure of the increment of the test statistic, we utilize the fractional Brownian motion (FBM). We conducted a comparative study of the conditional power under BM and FBM. It was found that the conditional power under FBM assumption was mostly higher than that under BM assumption when the Hurst exponent was greater than 0.5.

MP13-05 IMPACT OF MICTURITION HABITS ON FUNCTIONAL OUTCOMES OF PATIENTS WITH ORTHOTOPIC NEOBLADDER: RESULTS FROM A SINGLE CENTER PROSPECTIVE RANDOMISED CONTROLLED TRIAL

You have accessJournal of UrologyBladder Cancer: Invasive I (MP13)1 Sep 2021MP13-05 IMPACT OF MICTURITION HABITS ON FUNCTIONAL OUTCOMES OF PATIENTS WITH ORTHOTOPIC NEOBLADDER: RESULTS FROM A SINGLE CENTER PROSPECTIVE RANDOMISED CONTROLLED TRIAL Riccardo Mastroianni, Gabriele Tuderti, Umberto Anceschi, Alfredo Maria Bove, Aldo Brassetti, Mariaconsiglia Ferriero, Leonardo Misuraca, Salvatore Guaglianone, Ashanti Zampa, Michele Gallucci, and Giuseppe Simone Riccardo MastroianniRiccardo Mastroianni More articles by this author , Gabriele TudertiGabriele Tuderti More articles by this author , Umberto AnceschiUmberto Anceschi More articles by this author , Alfredo Maria BoveAlfredo Maria Bove More articles by this author , Aldo BrassettiAldo Brassetti More articles by this author , Mariaconsiglia FerrieroMariaconsiglia Ferriero More articles by this author , Leonardo MisuracaLeonardo Misuraca More articles by this author , Salvatore GuaglianoneSalvatore Guaglianone More articles by this author , Ashanti ZampaAshanti Zampa More articles by this author , Michele GallucciMichele Gallucci More articles by this author , and Giuseppe SimoneGiuseppe Simone More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001994.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Functional outcomes of radical cystectomy (RC) with orthotopic ileal neobladder and their predictive variables remain underinvestigated. We aimed to evaluate the impact of voiding time-intervals on both day (d)- and night (n)-time continence in a randomised controlled trial (RCT) cohort of patients comparing open RC (ORC) and robot-assisted RC (RARC) with totally intracorporeal (i) urinary diversion (UD) (NCT03434132). METHODS: Patients were eligible if they had a diagnostic TURBt with cT2-4, cN0, cM0, or recurrent high-grade NMIBC and no anesthesiologic contraindications to robotic surgery. Between Jan 2018 and Sept 2020, 116 patients were enrolled with a covariate adaptive randomization process based on the following variables: BMI, ASA score, preoperative hgb, UD [Padua ileal bladder (PIB) or ileal conduit], neoadjuvant chemotherapy and cT-stage. Logistic regression (LR) was performed to build a model to predict d- and n-time continence using a voiding cut-off time. RESULTS: Out of 116 patients enrolled, 88 received PIB and 71 were included in the study (12 patients died, 1 was lost to follow-up, 1 was hypercontinent, 1 had a stroke and 2 had permanent catheter). Baseline clinical data were reported in Table 1. RARC with iPIB was performed with no need of open conversion. At a median follow-up of 16 months (IQR: 11-28), 60 patients (85%) were d-time continent, and 45 (63%) were n-time continent. Patients who had d-time voiding intervals <3h had higher probability to be d-time continent (88%vs64%;p=0.04); similarly, n-time continence probabilities were higher when n-time voiding intervals were <3h (76%vs47%;p=0.01). At LR analysis, for each hour increase in voiding intervals, d-time and n-time continence probabilities decreased of 41% (HR: 0.587; 95%CI 0.424-0.813;p=0.001). In d-time continent patients, LR demonstrated that for each hour increase n-time continence probability decreased of 49% (HR: 0.514; 95%CI 0.353-0.749; p=0.001). CONCLUSIONS: This study supports the key role of micturition habits on functional outcomes of neobladder patients. Patients should be preoperatively counseled about the need to respect voiding cut-off time of 3h to achieve optimal functional results. Source of Funding: none © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e244-e244 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Riccardo Mastroianni More articles by this author Gabriele Tuderti More articles by this author Umberto Anceschi More articles by this author Alfredo Maria Bove More articles by this author Aldo Brassetti More articles by this author Mariaconsiglia Ferriero More articles by this author Leonardo Misuraca More articles by this author Salvatore Guaglianone More articles by this author Ashanti Zampa More articles by this author Michele Gallucci More articles by this author Giuseppe Simone More articles by this author Expand All Advertisement Loading ...

Testing for treatment effect in covariate-adaptive randomized trials with generalized linear models and omitted covariates.

Concerns have been expressed over the validity of statistical inference under covariate-adaptive randomization despite the extensive use in clinical trials. In the literature, the inferential properties under covariate-adaptive randomization have been mainly studied for continuous responses; in particular, it is well known that the usual two-sample t-test for treatment effect is typically conservative. This phenomenon of invalid tests has also been found for generalized linear models without adjusting for the covariates and are sometimes more worrisome due to inflated Type I error. The purpose of this study is to examine the unadjusted test for treatment effect under generalized linear models and covariate-adaptive randomization. For a large class of covariate-adaptive randomization methods, we obtain the asymptotic distribution of the test statistic under the null hypothesis and derive the conditions under which the test is conservative, valid, or anti-conservative. Several commonly used generalized linear models, such as logistic regression and Poisson regression, are discussed in detail. An adjustment method is also proposed to achieve a valid size based on the asymptotic results. Numerical studies confirm the theoretical findings and demonstrate the effectiveness of the proposed adjustment method.

A Retrospective Analysis to Determine Whether Training-Induced Changes in Muscle Thickness Mediate Changes in Muscle Strength.

To investigate the role of muscle thickness changes on changes in strength following 6weeks of unaccustomed resistance training, via retrospective analysis. 151 participants completed 6weeks of no intervention (CONTROL), one-repetition maximum training (1RM-TRAIN), or traditional resistance training (TRAD-TRAIN). Groups were assigned by covariate adaptive randomization. 1RM-TRAIN and TRAD-TRAIN performed elbow flexion exercise on the dominant arm 3 times/week. One-repetition maximum strength and muscle thickness (B-mode ultrasound at 50, 60, and 70% of the anterior upper arm) were assessed pre- and post-training. Direct and indirect effects on strength via each training modality were quantified relative to CONTROL using indicator-coded, change-score mediation analyses for each muscle thickness site. Values are presented as regression coefficients (95% CI). The effect of 1RM-TRAIN on muscle thickness was greater than CONTROL for 60% [0.09 (0.01, 0.17) cm] and 70% [0.09 (0.01,0.18) cm] models. All muscle thickness changes for TRAD-TRAIN were greater than CONTROL: 50% [0.24 (0.16, 0.33) cm], 60% [0.25 (0.17, 0.33) cm], 70% [0.23 (0.14, 0.32) cm]. All direct effects on strength were greater for 1RM-TRAIN versus CONTROL: 50% [1.90 (1.21, 2.58) kg], 60% [1.89 (1.19, 2.58) kg], 70% [1.81 (1.12, 2.51) kg]; and TRAD-TRAIN versus CONTROL: 50% [2.04 (1.29, 2.80) kg], 60% [1.98 (1.22, 2.75) kg], 70% [1.79 (1.05, 2.53) kg]. Compared to CONTROL, there was no indication of an effect of 1RM-TRAIN on strength through muscle thickness (i.e., indirect effect) for 50% [- 0.03 (- 0.17, 0.10)], 60% [- 0.01 (- 0.17, 0.17)], or 70% [0.07 (- 0.09, 0.28)] sites, nor of TRAD-TRAIN for 50% [- 0.11 (- 0.48,0.29)], 60% [- 0.04 (- 0.42, 0.40)], and 70% sites [0.17 (-0.23,0.58)]. Training-induced changes in muscle thickness do not appear to appreciably mediate training-induced changes in the strength of untrained individuals during the first 6weeks of training.

Rejoinder on ‘Inference after covariate-adaptive randomization: aspects of methodology and theory’

I would like to thank all discussants for their insightful discussions on the topic of statistical inference after covariate-adaptive randomisation, especially for including reviews of some new res...

Sample size re-estimation for covariate-adaptive randomized clinical trials.

Covariate-adaptive randomization (CAR) procedures have been developed in clinical trials to mitigate the imbalance of treatments among covariates. In recent years, an increasing number of trials have started to use CAR for the advantages in statistical efficiency and enhancing credibility. At the same time, sample size re-estimation (SSR) has become a common technique in industry to reduce time and cost while maintaining a good probability of success. Despite the widespread popularity of combining CAR designs with SSR, few researchers have investigated this combination theoretically. More importantly, the existing statistical inference must be adjusted to protect the desired type I error rate when a model that omits some covariates is used. In this article, we give a framework for the application of SSR in CAR trials and study the underlying theoretical properties. We give the adjusted test statistic and derive the sample size calculation formula under the CAR setting. We can tackle the difficulties caused by the adaptive features in CAR and prove the asymptotic independence between stages. Numerical studies are conducted under multiple parameter settings and scenarios that are commonly encountered in practice. The results show that all advantages of CAR and SSR can be preserved and further improved in terms of power and sample size.

A randomized and comparative study to assess safety and efficacy of supplemental treatment of a herbal formulation - Aayudh Advance comprising essential oils in patients with corona virus 2019 (COVID-19)

ObjectiveThe purpose of this study was to examine the effect of herbal formulation - Aayudh Advance on viral load as well as recovery duration in mild symptomatic patients diagnosed with Corona Virus Disease 2019 (COVID-19). It also aimed to study the effect of Herbal formulation – Aayudh Advance in terms of clinical improvement of various sign and symptoms in mild symptomatic COVID-19 patients. MethodOnce the patient suffice the requirement of inclusion, exclusion criteria of the study than as per the method of ‘Covariate Adaptive Randomization’ technique, patient was assigned in either Aayudh Advance arm (Test arm) or Control Arm. Here standard of Care treatment was given to all patients of both the arms. Treatment was given for the period of 14 days or till patient turned COVID-19 negative, which ever was earlier. Clinical signs and symptoms viz. body temperature, SpO 2, Scoring of Cough & Scoring of Shortness of breath were recorded on all 5 Clinical visits along with biochemical testing like RT-PCR (with CT value of E gene and RDRP gene), serum ferritin, CRP and NLR observed on weekly Visit. ResultTotal 74 patients were enrolled in the present study. Out of which 60 patients (30 patients in each group) have completed study as per the protocol, whereas 14 patients have voluntarily withdrawn from the study due to getting early discharge from the hospital. All patients in Aayudh Advance treatment group recovered (100%) after 14 days. This observed recovery was 15.38% more as compared to Standard of Care treatment alone. Further, there was statistically significant reduction (p < 0.05) in viral load as indicated by significant increase in CT value of E-gene and RDRP gene. Further, no patients reported any Adverse Reaction as well as no drug to drug interaction was observed with supplemental treatment with Aayudh Advance. ConclusionThe Aayudh Advance was found safe as well as more effective in terms of reduction of viral load. % recovery was more in Treatment arm as compared to Control arm in mild symptomatic COVID-19 patients.

Inference on the average treatment effect under minimization and other covariate-adaptive randomization methods

Summary Covariate-adaptive randomization schemes such as minimization and stratified permuted blocks are often applied in clinical trials to balance treatment assignments across prognostic factors. The existing theory for inference after covariate-adaptive randomization is mostly limited to situations where a correct model between the response and covariates can be specified or the randomization method has well-understood properties. Based on stratification with covariate levels utilized in randomization and a further adjustment for covariates not used in randomization, we propose several model-free estimators of the average treatment effect. We establish the asymptotic normality of the proposed estimators under all popular covariate-adaptive randomization schemes, including the minimization method, and we show that the asymptotic distributions are invariant with respect to covariate-adaptive randomization methods. Consistent variance estimators are constructed for asymptotic inference. Asymptotic relative efficiencies and finite-sample properties of estimators are also studied. We recommend using one of our proposed estimators for valid and model-free inference after covariate-adaptive randomization.

Inference under covariate-adaptive randomization: A simulation study.

In clinical trials, several covariate-adaptive designs have been proposed to balance treatment arms with respect to key covariates. Although some argue that conventional asymptotic tests are still appropriate when covariate-adaptive randomization is used, others think that re-randomization tests should be used. In this manuscript, we compare by simulation the performance of asymptotic and re-randomization tests under covariate-adaptive randomization. Our simulation study confirms results expected by the existing theory (e.g. asymptotic tests do not control type I error when the model is miss-specified). Furthermore, it shows that (i) re-randomization tests are as powerful as the asymptotic tests if the model is correct; (ii) re-randomization tests are more powerful when adjusting for covariates; (iii) minimization and permuted blocks provide similar results.