START NOW: a cognitive behavioral skills training for adolescent girls with conduct or oppositional defiant disorder - a randomized clinical trial.

BACKGROUND: Conduct disorder (CD) and oppositional defiant disorder (ODD) both convey a high risk for maladjustment later in life and are understudied in girls. Here, we aimed at confirming the efficacy of START NOW, a cognitive-behavioral, dialectical behavior therapy-oriented skills training program aiming to enhance emotion regulation skills, interpersonal and psychosocial adjustment, adapted for female adolescents with CD or ODD. METHODS: A total of 127 girls were included in this prospective, cluster randomized, multi-center, parallel group, quasi-randomized, controlled phase III trial, which tested the efficacy of START NOW (n = 72) compared with standard care (treatment as usual, TAU, n = 55). All female adolescents had a clinical diagnosis of CD or ODD, were 15.6 (±1.5) years on average (range: 12-20 years), and were institutionalized in youth welfare institutions. The two primary endpoints were the change in number of CD/ODD symptoms between (1) baseline (T1) and post-treatment (T3), and (2) between T1 and 12-week follow-up (T4). RESULTS: Both treatment groups showed reduced CD/ODD symptoms at T3 compared with T1 (95% CI: START NOW = -4.87, -2.49; TAU = -4.94, -2.30). There was no significant mean difference in CD/ODD symptom reduction from T1 to T3 between START NOW and TAU (-0.056; 95% CI = -1.860, 1.749; Hedge's g = -0.011). However, the START NOW group showed greater mean symptom reduction from T1 to T4 (-2.326; 95% CI = -4.274, -0.378; Hedge's g = -0.563). Additionally, secondary endpoint results revealed a reduction in staff reported aggression and parent-reported irritability at post assessment. CONCLUSIONS: Although START NOW did not result in greater symptom reduction from baseline to post-treatment compared with TAU, the START NOW group showed greater symptom reduction from baseline to follow-up with a medium effect size, which indicates a clinically meaningful delayed treatment effect.

Quality-of-life outcomes of the ROBOtic-assisted versus Conventional Open Partial nephrectomy (ROBOCOP) II trial.

OBJECTIVES: To comprehensively compare quality-of-life (QoL) outcomes between open partial nephrectomy (OPN) and robot-assisted PN (RAPN) from the randomised ROBOtic-assisted versus Conventional Open Partial nephrectomy (ROBOCOP) II trial, as QoL data comparing OPN and RAPN are virtually non-existent, especially not from randomised controlled trials (RCTs). PATIENTS AND METHODS: The ROBOCOP II was a single-centre, open-label RCT between OPN and RAPN. The pre-planned analyses of QoL outcomes are presented. Data were analysed descriptively in a modified intention-to-treat population. RESULTS: A total of 50 patients underwent surgery. At postoperative Day 90 (POD90), there was no significant difference for the Kidney Disease Quality of Life-Short Form questionnaire score (mean [sd] OPN 72 [20] vs RAPN 76 [15], P = 0.850), while there were advantages for RAPN in the subdomains of 'Pain' (P = 0.006) and 'Physical functioning' (P = 0.011) immediately after surgery. For the European Organisation for Research and Treatment of Cancer quality of life questionnaire 30-item core there were overall advantages directly after surgery (mean [sd] score OPN 63 [20] vs RAPN 75 [17], P = 0.031), as well as for the subdomains 'Fatigue' (P = 0.026), 'Pain' (P = 0.002) and 'Constipation' (P = 0.045) but no differences at POD90. There were no differences for the EuroQoL five Dimensions five Levels questionnaire at POD90 (mean [sd] score OPN 70 [22] vs RAPN 72 [17], P = 1.0) or at any other time point. Finally, no significant differences were found for the overall Convalescence and Recovery Evaluation questionnaire score at POD90 (mean [sd] OPN 84 [13] vs RAPN 86 [10], P = 0.818) but less pain in the RAPN group (P = 0.017) directly after surgery. CONCLUSIONS: Pain and physical functioning as subdomains of QoL are improved after RAPN compared to OPN in the early postoperative course, while there are no differences anymore after 3 months.

Dyslipidemia in children with chronic kidney disease-findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study.

BACKGROUND: Dyslipidemia is an important and modifiable risk factor for CVD in children with CKD. METHODS: In a cross-sectional study of baseline serum lipid levels in a large prospective cohort study of children with stage 3-5 (predialysis) CKD, frequencies of abnormal lipid levels and types of dyslipidemia were analyzed in the entire cohort and in subpopulations defined by fasting status or by the presence of nephrotic range proteinuria. Associated clinical and laboratory characteristics were determined by multivariable linear regression analysis. RESULTS: A total of 681 patients aged 12.2 ± 3.3 years with a mean eGFR of 26.9 ± 11.6 ml/min/1.73 m2 were included. Kidney diagnosis was classified as CAKUT in 69%, glomerulopathy in 8.4%, and other disorders in 22.6% of patients. Nephrotic range proteinuria (defined by a urinary albumin/creatinine ratio > 1.1 g/g) was present in 26.9%. Dyslipidemia was found in 71.8%, and high triglyceride (TG) levels were the most common abnormality (54.7%). Fasting status (38.9%) had no effect on dyslipidemia status. Except for a significant increase in TG in more advanced CKD, lipid levels and frequencies of dyslipidemia were not significantly different between CKD stages. Hypertriglyceridemia was associated with younger age, lower eGFR, shorter duration of CKD, higher body mass index (BMI-SDS), lower serum albumin, and higher diastolic blood pressure. CONCLUSIONS: Dyslipidemia involving all lipid fractions, but mainly TG, is present in the majority of patients with CKD irrespective of CKD stage or fasting status and is significantly associated with other cardiovascular risk factors.

Optimal sample size allocation for two-arm superiority and non-inferiority trials with binary endpoints.

The sample size of a clinical trial has to be large enough to ensure sufficient power for achieving the aim the study. On the other side, for ethical and economical reasons it should not be larger than necessary. The sample size allocation is one of the parameters that influences the required total sample size. For two-arm superiority and non-inferiority trials with binary endpoints, we performed extensive computations over a wide range of scenarios to determine the optimal allocation ratio that minimizes the total sample size if all other parameters are fixed. The results demonstrate, that for both superiority and non-inferiority trials the optimal allocation may deviate considerably from the case of equal sample size in both groups. However, the saving in sample size when allocating the total sample size optimally as compared to balanced allocation is typically small.

Estimation of treatment effects in early-phase randomized clinical trials involving external control data.

There are good reasons to perform a randomized controlled trial (RCT) even in early phases of clinical development. However, the low sample sizes in those settings lead to high variability of the treatment effect estimate. The variability could be reduced by adding external control data if available. For the common setting of suitable subject-level control group data only available from one external (clinical trial or real-world) data source, we evaluate different analysis options for estimating the treatment effect via hazard ratios. The impact of the external control data is usually guided by the level of similarity with the current RCT data. Such level of similarity can be determined via outcome and/or baseline covariate data comparisons. We provide an overview over existing methods, propose a novel option for a combined assessment of outcome and baseline data, and compare a selected set of approaches in a simulation study under varying assumptions regarding observable and unobservable confounder distributions using a time-to-event model. Our various simulation scenarios also reflect the differences between external clinical trial and real-world data. Data combinations via simple outcome-based borrowing or simple propensity score weighting with baseline covariate data are not recommended. Analysis options which conflate outcome and baseline covariate data perform best in our simulation study.

Persistent Symptoms in Adult Patients 1 Year After Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study.

BACKGROUND: Long COVID is defined as the persistence of symptoms beyond 3 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To better understand the long-term course and etiology of symptoms we analyzed a cohort of patients with COVID-19 prospectively. METHODS: Patients were included at 5 months after acute COVID-19 in this prospective, noninterventional, follow-up study. Patients followed until 12 months after COVID-19 symptom onset (n = 96; 32.3% hospitalized, 55.2% females) were included in this analysis of symptoms, quality of life (based on an SF-12 survey), laboratory parameters including antinuclear antibodies (ANAs), and SARS-CoV-2 antibody levels. RESULTS: At month 12, only 22.9% of patients were completely free of symptoms and the most frequent symptoms were reduced exercise capacity (56.3%), fatigue (53.1%), dyspnea (37.5%), and problems with concentration (39.6%), finding words (32.3%), and sleeping (26.0%). Females showed significantly more neurocognitive symptoms than males. ANA titers were ≥1:160 in 43.6% of patients at 12 months post-COVID-19 symptom onset, and neurocognitive symptom frequency was significantly higher in the group with an ANA titer ≥1:160 versus <1:160. Compared with patients without symptoms, patients with ≥1 long-COVID symptom at 12 months did not differ significantly with respect to their SARS-CoV-2 antibody levels but had a significantly reduced physical and mental life quality compared with patients without symptoms. CONCLUSIONS: Neurocognitive long-COVID symptoms can persist ≥1 year after COVID-19 symptom onset and reduce life quality significantly. Several neurocognitive symptoms were associated with ANA titer elevations. This may indicate autoimmunity as a cofactor in etiology of long COVID.

An adaptive design for early clinical development including interim decision for single-arm trial with external controls or randomized trial.

In early clinical development, randomized controlled trials (RCT) or single-arm trials with external controls (SATwEC) are design options, which allow adjustment for confounding: RCT via design, SATwEC via analysis using propensity score methods. SATwEC requires less investment than RCT. However, if the confounder space substantially differs between the experimental and external control group, the SATwEC might lead to inappropriate decisions for further development. We develop an adaptive two-stage design (ATD) for early clinical development that reduces the risk of unreliable decision-making at the end of a SATwEC. In Stage I, subjects are solely assigned to the experimental group. If at the interim the propensity score distributions of internal and external data are comparable based on the preference score, the subjects in stage II will again be solely assigned to the experimental arm; if not, a randomized stage II will be conducted. In a simulation study guided by a motivating example, data is generated using a time-to-event model with observable and unobservable confounders. The confounder space is varied to investigate the impact on false go/stop probabilities as well as a loss function, which reflects the quality of treatment effect estimates and decision-making. The proposed ATD provides a compromise between optimizing quality (as expressed by false go/stop probabilities and the loss function) and investment (defined by sample size and trial duration).

Robotic-Assisted Versus Conventional Open Partial Nephrectomy (Robocop): A Propensity Score-Matched Analysis of 249 Patients.

OBJECTIVES: The objective of this study was to compare open partial nephrectomy (OPN) and robotic-assisted PN (RAPN) based on a propensity score-matched sample and to test the Comprehensive Complication Index (CCI) as an end point for complications. METHODS: Patients undergoing PN from 2010 to 2018 at a university care center were included. OPN and RAPN cases were matched in a 2:1 ratio using propensity score-matching with age, gender, BMI, RENAL score, and tumor size as confounders. The primary end point was complications measured with the CCI as continuous score (0-100, 100 indicating death). RESULTS: Data of 570 patients were available. After matching, both cohorts (OPN = 166; RAPN = 83) showed no baseline differences. For the primary end point, CCI, RAPN was superior (RAPN 2.6 ± 7.9 vs. OPN 8.7 ± 13.9; p < 0.001). Additionally, RAPN was superior for length of stay (RAPN 6.5 ± 4.0 vs. OPN 7.4 ± 3.5 days; p < 0.001), hemoglobin drop (RAPN 2.8 ± 1.4 vs. OPN 3.8 ± 1.6 g/dL; p < 0.001), and drop of glomerular filtration rate (RAPN 11.4 ± 14.2 vs. OPN 19.5 ± 14.3 mL/min; p < 0.001). OPN had shorter operating times (RAPN 157 ± 43 vs. OPN 143 ± 45 min; p = 0.014) and less ischemia (RAPN 13% vs. OPN 28%; p = 0.016). CONCLUSIONS: RAPN provides superior short-term results regarding overall complications without compromising renal function for small and less complex tumors. However, OPN remains an important option for more complex and larger tumors.

Optimal designs for phase II/III drug development programs including methods for discounting of phase II results.

BACKGROUND: Go/no-go decisions after phase II and sample size chosen for phase III are usually based on phase II results (e.g., the treatment effect estimate of phase II). Due to the decision rule (only promising phase II results lead to phase III), treatment effect estimates from phase II that initiate a phase III trial commonly overestimate the true treatment effect. Underpowered phase III trials are the consequence. Optimistic findings may then not be reproduced, leading to the failure of potentially expensive drug development programs. For some disease areas these failure rates are described to be quite high: 62.5%. METHODS: We integrate the ideas of multiplicative and additive adjustment of treatment effect estimates after go decisions in a utility-based framework for optimizing drug development programs. The design of a phase II/III program, i.e., the "right amount of adjustment", the allocation of the resources to phase II and III in terms of sample size, and the rule applied to decide whether to stop or to proceed with phase III influences its success considerably. Given specific drug development program characteristics (e.g., fixed and variable per patient costs for phase II and III, probable gain in case of market launch), optimal designs with respect to the maximal expected utility can be identified by the proposed Bayesian-frequentist approach. The method will be illustrated by application to practical examples characteristic for oncological studies. RESULTS: In general, our results show that the program set-ups with adjusted treatment effect estimate used for phase III planning are superior to the "naïve" program set-ups with respect to the maximal expected utility. Therefore, we recommend considering an adjusted phase II treatment effect estimate for the phase III sample size calculation. However, there is no one-fits-all design. CONCLUSION: Individual drug development planning for a specific program is necessary to find the optimal design. The optimal choice of the design parameters for a specific drug development program at hand can be found by our user friendly R Shiny application and package (both assessable open-source via [1]).

Rotational thrombelastometry (ROTEM) improves hemostasis assessment compared to conventional coagulation test in ACLF and Non-ACLF patients.

BACKGROUND: Patients with liver cirrhosis typically exhibit abnormal coagulation parameters in conventional coagulation tests (CCTs). Rotational thromboelastometry (ROTEM) is a holistic blood coagulation assay. This method provides an insight into the global hemostatic capabilities and has been suggested to provide a better overview of the coagulation system in liver cirrhosis. METHODS: The goal of this study was to examine hemostasis in patients with stable liver cirrhosis (Non-ACLF) and in acute-on-chronic liver failure (ACLF) by CCT and ROTEM including agreement of both tests and the prospective assessment of test performance based on clinical outcomes in ACLF patients. Therefore, ACLF patients were additionally subgrouped by bleeding events. Fifty-five Non-ACLF patients and twenty-two patients with ACLF were analysed in this prospective cohort study. RESULTS: Coagulation parameters analysed by CCT were outside the normal range in Non-ACLF and ACLF patients, but were significantly more aberrant in ACLF patients. Non-ACLF patients analysed by ROTEM revealed parameters largely within the normal limits, while significantly more ROTEM parameters in ACLF patients were affected. Maximum clot firmness (MCF) was significantly divergent between both patient groups and correlated well with levels of fibrinogen and platelet count. Using Cohen's Kappa coefficient κ, the strength of agreement between CCT and ROTEM analyses was determined to be fair for Non-ACLF patients and moderate for ACLF patients. Bleeding events occurred significantly more often in ACLF group with significantly reduced A10 and MCF. CONCLUSIONS: For assessing hemostasis in Non-ACLF and ACLF patients the underlying dataset shows advantages of ROTEM over CCT. A10 and MCF represent suitable prognostic parameters in predicting bleeding events in ACLF group.

Plasma Lipidome, PNPLA3 polymorphism and hepatic steatosis in hereditary hemochromatosis.

BACKGROUND: Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder with increased intestinal iron absorption and therefore iron Overload. iron overload leads to increased levels of toxic non-transferrin bound iron which results in oxidative stress and lipid peroxidation. The impact of iron on lipid metabolism is so far not fully understood. The aim of this study was to investigate lipid metabolism including lipoproteins (HDL, LDL), neutral (triglycerides, cholesterol) and polar lipids (sphingo- and phospholipids), and PNPLA3 polymorphism (rs738409/I148M) in HH. METHODS: We conducted a cohort study of 54 subjects with HH and 20 healthy subjects. Patients were analyzed for their iron status including iron, ferritin, transferrin and transferrin saturation and serum lipid profile on a routine follow-up examination. RESULTS: HH group showed significantly lower serum phosphatidylcholine (PC) and significantly higher phosphatidylethanolamine (PE) compared to healthy control group. The ratio of PC/PE was clearly lower in HH group indicating a shift from PC to PE. Triglycerides were significantly higher in HH group. No differences were seen for HDL, LDL and cholesterol. Hepatic steatosis was significantly more frequent in HH. PNPLA3 polymorphism (CC vs. CG/GG) did not reveal any significant correlation with iron and lipid parameters including neutral and polar lipids, grade of steatosis and fibrosis. CONCLUSION: Our study strengthens the hypothesis of altered lipid metabolism in HH and susceptibility to nonalcoholic fatty liver disease. Disturbed phospholipid metabolism may represent an important factor in pathogenesis of hepatic steatosis in HH.

Optimal decision-making in oncology development programs based on probability of success for phase III utilizing phase II/III data on response and overall survival.

In clinical development, there is a trade-off between investment and level of confidence in the potential of the drug before going into phase III. Reduced investment requires the use of short-term endpoints. On new compounds, only limited information about the relationship between treatment effects of short- and long-term endpoints is usually available. Therefore, decision-making solely based on short-term endpoints does not seem desirable. Our goal is to plan an efficient development program, which uses short- and long-term endpoints data for decision-making. We found that with limited prior information and restrictions on maximum sample size, decision-making after phase II cannot be substantially improved. We follow the concept of a "phase 2+" design where after a go-to-phase-III-decision, further follow-up data from phase II are employed to make interim decisions on phase III. The program will be stopped early when additional phase II and/or available phase III data lead to a low probability of success (PoS). We utilize information from a multi-categorical short-term endpoint (response status) and a long-term endpoint (overall survival (OS)) to determine the PoS in phase III with OS as the primary endpoint. Optimal combinations of decision boundaries and time points are demonstrated in a simulation study. Our results show that the proposed second look using additional follow-up data from phase II/III improves PoS estimates compared to the first look, especially when prior data about the control arm is available. The proposed planning strategy allows a customized compromise between the quality of decision-making and program duration.

Adjustment for exploratory cut-off selection in randomized clinical trials with survival endpoint.

Defining the target population based on predictive biomarkers plays an important role during clinical development. After establishing a relationship between a biomarker candidate and response to treatment in exploratory phases, a subsequent confirmatory trial ideally involves only subjects with high potential of benefiting from the new compound. In order to identify those subjects in case of a continuous biomarker, a cut-off is needed. Usually, a cut-off is chosen that resulted in a subgroup with a large observed treatment effect in an exploratory trial. However, such a data-driven selection may lead to overoptimistic expectations for the subsequent confirmatory trial. Treatment effect estimates, probability of success, and posterior probabilities are useful measures for deciding whether or not to conduct a confirmatory trial enrolling the biomarker-defined population. These measures need to be adjusted for selection bias. We extend previously introduced Approximate Bayesian Computation techniques for adjustment of subgroup selection bias to a time-to-event setting with cut-off selection. Challenges in this setting are that treatment effects become time-dependent and that subsets are defined by the biomarker distribution. Simulation studies show that the proposed method provides adjusted statistical measures which are superior to naïve Maximum Likelihood estimators as well as simple shrinkage estimators.

Low levels of urinary epidermal growth factor predict chronic kidney disease progression in children.

Urinary epidermal growth factor (uEGF) has recently been identified as a promising biomarker of chronic kidney disease (CKD) progression in adults with glomerular disease. Low levels of uEGF predict CKD progression and appear to reflect the extent of tubulointerstitial damage. We investigated the relevance of uEGF in pediatric CKD. We performed a post hoc analysis of the Cardiovascular Comorbidity in Children with CKD (4C) study, which prospectively follows children aged 6-17 years with baseline estimated glomerular filtration rate (eGFR) of 10-60 ml/min/1.73 m2. uEGF levels were measured in archived urine collected within 6 months of enrollment. Congenital abnormalities of the kidney and urinary tract were the most common cause of CKD, with glomerular diseases accounting for <10% of cases. Median eGFR at baseline was 28 ml/min/1.73 m2, and 288 of 623 participants (46.3%) reached the composite endpoint of CKD progression (50% eGFR loss, eGFR < 10 ml/min/1.73 m2, or initiation of renal replacement therapy). In a Cox proportional hazards model, higher uEGF/Cr was associated with a decreased risk of CKD progression (HR 0.76; 95% CI 0.69-0.84) independent of age, sex, baseline eGFR, primary kidney disease, proteinuria, and systolic blood pressure. The addition of uEGF/Cr to a model containing these variables resulted in a significant improvement in C-statistics, indicating better prediction of the 1-, 2- and 3-year risk of CKD progression. External validation in a prospective cohort of 222 children with CKD demonstrated comparable results. Thus, uEGF may be a useful biomarker to predict CKD progression in children with CKD.

Indoxyl sulfate associates with cardiovascular phenotype in children with chronic kidney disease.

BACKGROUND: Cardiovascular disease is the leading cause of death in children with chronic kidney disease (CKD). Serum levels of gut-derived uremic toxins increase with deterioration of kidney function and are associated with cardiac comorbidities in adult CKD patients. METHODS: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) were measured by high-performance liquid chromatography in serum of children participating in the Cardiovascular Comorbidity in Children with CKD (4C) Study. Results were correlated with measurements of the carotid intima-media thickness (cIMT), central pulse wave velocity (PWV), and left ventricular mass index (LVMI) in children aged 6-17 years with initial eGFR of 10-60 ml/min per 1.73 m2. RESULTS: The median serum levels of total IS and of pCS, measured in 609 patients, were 5.3 µmol/l (8.7) and 17.0 µmol/l (21.6), respectively. In a multivariable regression model, IS and pCS showed significant positive associations with urea and negative associations with eGFR and uric acid. Furthermore, positive associations of pCS with age, serum albumin, and non-Mediterranean residency and a negative association with glomerular disease were observed. By multivariable regression analysis, only IS was significantly associated with a higher cIMT SDS at baseline and progression of PWV SDS within 12 months, independent of other risk factors. CONCLUSIONS: Serum levels of gut-derived uremic toxins IS and pCS correlated inversely with eGFR in children. Only IS was significantly associated with surrogate markers of cardiovascular disease in this large pediatric CKD cohort.

"What would you like to achieve?" Goal-Setting in Patients with Dementia in Geriatric Rehabilitation.

BACKGROUND: Setting meaningful, individualized rehabilitation goals is an essential part of the rehabilitation process. Even though patients with dementia are a drastically increasing patient group in geriatric rehabilitation, empirical data about meaningful rehabilitation goals and collaborative goal-setting in this target group is missing. Cognitive impairment and lack of insight in current deficits have been discussed as barriers for participation in goal-setting, but require empirical examination. This study investigated the feasibility of a semi-structured versus a structured goal-setting approach and the types of goals, rehabilitation patients with mild to moderate dementia perceive as personally relevant. Insights in acute functional and motor deficits, differentiated by cognitive status were explored. METHODS: Cohort study in a geriatric rehabilitation center. Semi-structured and ICF-based, structured interviews were applied to explore patients` rehabilitation goals. Patients` insight in deficits was operationalized as the relationship of self-ratings and objective measures of linked clinical assessments for the same functional construct. RESULTS: Patients (n = 101, MMSE 22 ± 2.6, age 83.9 ± 5.9 years) stated the improvement of mobility-related functions and self-care activities (> 70%) but also psychological well-being such as handling stress or mood (> 38%) as most important rehabilitation goals. The structured interview facilitated goal-setting and provided a broader view of rehabilitation needs. Correlations between self-ratings and clinical assessments were medium to high (rho = 0.29 to 0.83) with highest associations for key motor features. Trend tests identified a significant trend between values of the clinical assessment and categories of self-ratings (p ≤ 0.01) with lower cognitive status derogating this relationship. CONCLUSIONS: Collaborative goal-setting was feasible, especially when supported by a structured approach and yielded a large spectrum of functional but also psychological rehabilitation needs from the patients` perspective. Patients showed sustained insight in their actual functional impairments, limited in a subgroup of patients with more advanced cognitive impairment.

Optimal sample size allocation and go/no-go decision rules for phase II/III programs where several phase III trials are performed.

The conduct of phase II and III programs is costly, time-consuming and, due to high failure rates in late development stages, risky. There is a strong connection between phase II and III trials as the go/no-go decision and the sample size chosen for phase III are based on the results observed in phase II. An integrated planning of phase II and III is therefore reasonable. The success of phase II/III programs crucially depends on the allocation of the resources to phase II and III in terms of sample size and the rule applied to decide whether to stop or to proceed with phase III. Recently, a utility-based approach was proposed, where optimal planning of phase II/III programs is achieved by taking fixed and variable costs of the drug development program and potential gains after a successful launch into account. However, this method is restricted to programs with a single phase III trial, while regulatory authorities usually require statistical significance in two or more phase III trials. We present a generalization of this procedure to programs where two or more phase III trials are performed. Optimal phase II sample sizes and go/no-go decision rules are provided for time-to-event outcomes and cases, where at least one, two, or three phase III trials need to be successful. Different drug development program strategies (e.g. one large vs. two phase III trials) are compared within these different cases. Application to practical examples typically met in oncology trials illustrates the proposed method.

Implementation of a novel efficacy score to compare sealing and cutting devices in a porcine model.

BACKGROUND: In general surgery, minimally invasive laparoscopic procedures have been steadily increasing over the last decade. The application of advanced bipolar and ultrasonic energy devices for sealing and cutting of blood vessels plays a vital role in routine clinical procedures. The advantages of energy-based instruments are enhanced sealing capability combined with both fast sealing time and minimal thermal injury. The purpose of this study was to compare the safety and efficacy profiles of nine laparoscopic sealing and cutting devices in a porcine model, with a new scoring system. METHODS: Comparative studies in a porcine model were performed to assess vessel sealing, burst pressure, thermal spread, maximum heat, sealing/cooling time, and compression strength over the full jaw. Nine different devices from five manufacturers were tested in this study. The sealing and cutting devices (SCD) score has been developed to enable standardized comparisons of various devices. For this purpose, the most important parameters were identified through a consensus approach. RESULTS: All sealed vessels with different devices could withstand a median pressure of more than 300 mmHg (range 112-2046 mmHg). The time for the sealing procedure was 7.705 s (range 5.305-18.38 s) for the ultrasonic and 7.860 s (range 5.08-10.17 s) for the bipolar devices. The ultrasonic instruments reached a median temperature of 218.1 °C (range 81.3-349.75 °C) and the bipolar devices a temperature of 125.5 °C (range 94.1-133.35 °C). The tissue reached a median temperature of 61.9 (range 47.1-80.6 °C) after ultrasonic sealing and 76.7 °C (range 63.1-94.2 °C) after bipolar sealing. The median SCD score was 10.47 (range 7.16-13.72). CONCLUSION: All the instruments used seemed safe for use on the patient. The SCD score allows an indirect comparability of the instruments.

Optimal planning of phase II/III programs for clinical trials with multiple endpoints.

Owing to increased costs and competition pressure, drug development becomes more and more challenging. Therefore, there is a strong need for improving efficiency of clinical research by developing and applying methods for quantitative decision making. In this context, the integrated planning for phase II/III programs plays an important role as numerous quantities can be varied that are crucial for cost, benefit, and program success. Recently, a utility-based framework has been proposed for an optimal planning of phase II/III programs that puts the choice of decision boundaries and phase II sample sizes on a quantitative basis. However, this method is restricted to studies with a single time-to-event endpoint. We generalize this procedure to the setting of clinical trials with multiple endpoints and (asymptotically) normally distributed test statistics. Optimal phase II sample sizes and go/no-go decision rules are provided for both the "all-or-none" and "at-least-one" win criteria. Application of the proposed method is illustrated by drug development programs in the fields of Alzheimer disease and oncology.

The Value of PSA Density in Combination with PI-RADS™ for the Accuracy of Prostate Cancer Prediction.

PURPOSE: Multiparametric magnetic resonance imaging has an emerging role in prostate cancer diagnostics. In addition, clinical information is a reliable predictor of significant prostate cancer. We analyzed whether the negative predictive value of multiparametric magnetic resonance imaging to rule out significant prostate cancer could be improved using clinical factors, especially prostate specific antigen density. MATERIALS AND METHODS: A total of 1,040 consecutive men with suspicion of prostate cancer underwent multiparametric magnetic resonance imaging first, followed by transperineal systematic and magnetic resonance imaging-transrectal ultrasound fusion guided biopsy. Logistic regression analyses were performed to test different clinical factors as predictors of significant prostate cancer and build nomograms. To simplify these nomograms for clinical use patients were stratified into 3 prostate specific antigen density groups, including group 1-less than 0.07, group 2-0.07 to 0.15 and group 3-greater than 0.15 ng/ml/ml. After stratification we calculated the negative predictive value of a PI-RADS (Prostate Imaging Reporting and Data System) Likert score of less than 3. Significant prostate cancer was defined as a Gleason score of 3 + 4 or greater. High grade prostate cancer was defined as a Gleason score of 4 + 3 or greater. RESULTS: Overall 451 men were diagnosed with significant prostate cancer, including 187 with a Gleason score of 4 + 3 or greater. On ROC curve analyses the predictive power of the developed nomogram for significant prostate cancer showed a higher AUC than that of PI-RADS alone (0.79 vs 0.75, p <0.001). The negative predictive value of harboring significant prostate cancer increased in men with unsuspicious magnetic resonance imaging from 79% up to 89% when prostate specific antigen density was 0.15 ng/ml/ml or less. In the repeat biopsy setting the negative predictive value of significant prostate cancer increased from 83% to 93%. The negative predictive value to harbor high grade prostate cancer increased from 92% up to 98% in the entire cohort. CONCLUSIONS: Using prostate specific antigen density combined with multiparametric magnetic resonance imaging improved the negative predictive value of PI-RADS scoring. By increasing the probability of ruling out significant prostate cancer approximately 20% of unnecessary biopsies could be avoided safely.