EGFR-ErbB2 dual kinase inhibitor lapatinib decreases autoantibody levels and worsens renal disease in Interferon α-accelerated murine lupus.

Glomerulonephritis remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). We have reported that expression of HER2/ErbB2, a member of the EGFR family, is increased in kidneys of patients and mice with lupus nephritis. We therefore asked if EGFR-family inhibition could ameliorate murine lupus nephritis. We used lapatinib, an EGFR-ErbB2 dual kinase inhibitor in female lupus-prone NZBxW/F1 mice, in which lupus onset was accelerated by injecting an IFN-α-expressing adenovirus. Mice received lapatinib (75 mg/Kg) or vehicle from the beginning of the acceleration or after the mice developed severe proteinuria (>300 mg/dL). Autoantibodies, kidney disease and markers of fibrosis and wound healing were analyzed. Exposure to IFNα induced ErbB2 expression in the kidney of lupus prone mice. Lapatinib, administered before but not after renal disease onset, lowered autoantibody titers and lessened immune complex deposition in the kidney. However, lapatinib increased proteinuria, kidney fibrosis and mouse mortality. Lapatinib also inhibited an in vitro wound healing assay testing renal cells. Our results suggest that EGFR-ErbB2 dual kinase inhibitor lapatinib decreases autoimmunity but worsens renal disease in IFNα-accelerated lupus, by increasing fibrosis and inhibiting wound healing. Type I Interferons are highlighted as important regulators of HER2/ErbB2 expression in the kidney. Further studies are required to parse the beneficial aspects of EGFR inhibition on autoimmunity from its negative effects on wound healing in lupus nephritis.

Medical Malpractice Claims Related to Performance of Transesophageal Echocardiography by Anesthesiologists.

More than 300,000 adults have cardiac surgery in the United States annually, and most undergo intraoperative transesophageal echocardiography (TEE). This patient population is often older with multiple comorbidities, increasing their risk for complications for even routine procedures. Major morbidity or mortality caused by TEE is rare, and it is unknown how often such complications lead to malpractice lawsuits. The authors identified 13 cases out of 2,564 in a closed claims database that involved TEE and reviewed their etiology. Esophageal injury accounted for most of the suits, and only 2 were related to diagnosis. Most expert reviews deemed the care provided by the anesthesiologist to be appropriate.

Variation in Hospitalization Costs, Charges, and Lengths of Hospital Stay for Coronavirus Disease 2019 Patients Treated With Venovenous Extracorporeal Membrane Oxygenation in the United States: A Cohort Study.

OBJECTIVES: The aim was to characterize hospitalization costs, charges, and lengths of hospital stay for COVID-19 patients treated with venovenous (VV) extracorporeal membrane oxygenation (ECMO) in the United States during 2020. Secondarily, differences in hospitalization costs, charges, and lengths of hospital stay were explored based on hospital-level factors. DESIGN: Retrospective cohort study. SETTING: Multiple hospitals in the United States. PARTICIPANTS: Adult patients with COVID-19 who were on VV ECMO in 2020 and had data in the national inpatient sample. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics and baseline comorbidities were recorded for patients. Primary study outcomes were hospitalization costs, charges, and lengths of hospital stay. Study outcomes were compared after stratification by hospital region, bed size, and for-profit status. The median hospitalization cost for the 3,315-patient weighted cohort was $200,300 ($99,623, $338,062). Median hospitalization charges were $870,513 ($438,228, $1,553,157), and the median length of hospital stay was 30 days (17, 46). Survival to discharge was 54.4% for all patients in the cohort. Median hospitalization cost differed by region (p = 0.01), bed size (p < 0.001), and for-profit status (p = 0.02). Median hospitalization charges also differed by region (p = 0.04), bed size (p = 0.002), and for-profit status (p < 0.001). Length of hospital stay differed by region (p = 0.03) and bed size (p < 0.001), but not for-profit status (p = 0.40). Hospitalization costs were the lowest, and charges were highest in private-for-profit hospitals. Large hospitals also had higher costs, charges, and hospital stay lengths than small hospitals. CONCLUSIONS: In this retrospective cohort study, hospitalization costs and charges for patients with COVID-19 on VV ECMO were found to be substantial but similar to what has been reported previously for patients without COVID-19 on VV ECMO. Significant variation was observed in costs, charges, and lengths of hospital stay based on hospital-level factors.

Challenges in Implementing Futility Schemes, with Reference to Aducanumab.

Stopping an ongoing clinical trial based on an interim analysis that shows poor outcomes, often referred to as a judgment of "futility", is a familiar feature in current clinical trials practice. Interim data can be misleading, and the implications of prematurely terminating a trial that should not stop are severe. It is thus critical that designs allowing futility stopping be planned and implemented carefully and cautiously. A recent Phase III development program for aducanumab in Alzheimer's disease was halted based on a pre-defined futility guideline, yet based upon updated data and closer examination, the terminated studies became the basis for a regulatory submission. Not surprisingly, this situation generated much controversy and discussion. It provides a good basis for illustrating important principles governing the planning and implementation of futility schemes.

Persistent Bacteriuria and Antibodies Recognizing Curli/eDNA Complexes From Escherichia coli Are Linked to Flares in Systemic Lupus Erythematosus.

OBJECTIVE: Infections contribute to morbidity and mortality in systemic lupus erythematosus (SLE). Uropathogenic Escherichia coli (UPEC) are known to trigger urinary tract infections (UTIs) and form biofilms, which are multicellular communities of bacteria that are strengthened by amyloids such as curli. We previously reported that curli naturally form complexes with bacterial extracellular DNA (eDNA), and these curli/eDNA complexes induce hallmark features of lupus in mouse models. The present study was undertaken to investigate whether anti-curli/eDNA complex antibodies play a role in the pathogenesis of SLE or development of flares in SLE. METHODS: In total, 96 SLE patients who met at least 4 Systemic Lupus International Collaborating Clinics disease criteria were investigated. Anti-curli/eDNA complex antibodies in the plasma were tested for both IgG and IgA subclasses. Results were compared to that in 54 age-, sex-, and race/ethnicity-matched healthy controls. Correlations of the levels of anti-curli/eDNA antibodies with clinical parameters, lupus disease status, and frequency of bacteriuria were assessed. RESULTS: Anti-curli/eDNA antibodies were detected in the plasma of SLE patients and healthy controls, and their levels correlated with the presence of asymptomatic persistent bacteriuria and occurrence of disease flares in lupus patients. Persistent bacteriuria contained curli-producing UPEC, and this was associated with an inflammatory phenotype. Finally, curli/eDNA complexes cross-reacted with lupus autoantigens, such as double-stranded DNA, in binding autoantibodies. CONCLUSION: These results suggest that UTIs and persistent bacteriuria are environmental triggers of lupus and its flares. Antibodies against curli/eDNA could serve as a sign of systemic exposure to bacterial products in SLE.

Lessons Learned From Multi-regional Trials With Signals of Treatment Effect Heterogeneity.

Inconsistent results across regions have been reported in a number of recent large trials. In this research, by reviewing results from studies that showed inconsistent treatment effects, and summarizing lessons learned, we provide some recommendations for minimizing the chance of inconsistency and allowing more accurate interpretation when such signs of heterogeneity arise, for example: keep the number of regions for consistency evaluation at a minimum to avoid observing false inconsistency signals; proactively address in the protocol the differences in culture, medical practices, and other factors that are potentially different across regions; closely monitor the blinded data from early-enrolled patients to more effectively identify and address issues such as imbalance of baseline covariates or inconsistency of primary outcome rates across regions. For treatments of life-threatening conditions, the stakes for accurate interpretation of MRCT results are high; the criteria for decisions warrant careful consideration.

Presenting Risks and Benefits: Helping the Data Monitoring Committee Do Its Job.

Data monitoring committees (DMCs), or data and safety monitoring boards, protect clinical trial participants by conducting benefit-risk assessments during the course of a clinical trial. These evaluations may be improved by broader access to data and more effective analyses and presentation. Data monitoring committees should have access to all data, including efficacy data, at each interim review. The DMC reports should include graphical presentations that summarize benefits and harms in efficient ways. Benefit-risk assessments should include summaries that are consistent with the intention-to-treat principle and have a pragmatic focus. This article provides examples of graphical summaries that integrate benefits and harms, and proposes that such summaries become standard in DMC reports.

Challenges in Assessing the Impact of the COVID-19 Pandemic on the Integrity and Interpretability of Clinical Trials.

Abstract-The COVID-19 pandemic has a global impact on the conduct of clinical trials of medical products. This article discusses implications of the COVID-19 pandemic on clinical research methodology aspects and provides points to consider to assess and mitigate the risk of seriously compromising the integrity and interpretability of clinical trials. The information in this article will support discussions that need to occur cross-functionally on an ongoing basis to "integrate all available knowledge from the ethical, the medical, and the methodological perspective into decision making." This article aims at facilitating: (i) risk assessments of the impact of the pandemic on trial integrity and interpretability; (ii) identification of the relevant data and information related to the impact of the pandemic on the trial that needs to be collected; (iii) short-term decision making impacting ongoing trial operations; (iv) ongoing monitoring of the trial conduct until completion, including the possible involvement of data monitoring committees, and adequately documenting all measures taken to secure trial integrity throughout and after the pandemic, and (v) proper analysis and interpretation of the eventual interim or final trial data.

An additive boundary for group sequential designs with connection to conditional error.

Group sequential designs allow stopping a clinical trial for meeting its efficacy objectives based on interim evaluation of the accumulating data. Various methods to determine group sequential boundaries that control the probability of crossing the boundary at an interim or the final analysis have been proposed. To monitor trials with uncertainty in group sizes at each analysis, error spending functions are often used to derive stopping boundaries. Although flexible, most spending functions are generic increasing functions with parameters that are difficult to interpret. They are often selected arbitrarily, sometimes using trial and error, so that the corresponding boundaries approximate the desired behavior numerically. Lan and DeMets proposed a spending function that approximates in a natural way the O'Brien-Fleming boundary based on the Brownian motion process. We extend this approach to a general family that has an additive boundary for the Brownian motion process. The spending function and the group sequential boundary share a common parameter that regulates how fast the error is spent. Three subfamilies are considered with different additive terms. In the first subfamily, the parameter has an interpretation as the conditional error rate, which is the conditional probability to reject the null hypothesis at the final analysis. This parameter also provides a connection between group sequential and adaptive design methodology. More choices of designs are allowed in the other two subfamilies. Numerical results are provided to illustrate flexibility and interpretability of the proposed procedures. A clinical trial is described to illustrate the utility of conditional error in boundary determination.

The cytokine network type I IFN-IL-27-IL-10 is augmented in murine and human lupus.

IL-10 is elevated in the autoimmune disease systemic lupus erythematosus (SLE). Here, we show that conventional dendritic cells (cDCs) from predisease lupus-prone B6.NZM Sle1/Sle2/Sle3 triple congenic (TCSle) mice produce more IL-10 than wild-type congenic cDCs upon TLR stimulation, and this overproduction is prevented by blocking the type I IFN receptor (IFNAR) with specific Abs. Priming wild-type cDCs with type I IFN mimics the IL-10 overproduction of TCSle cDCs. The MAPK ERK is more phosphorylated in lupus cDCs, partially contributing to IL-10 overproduction. Moreover, we found that TCSle cDCs express higher levels of IL-27 upon TLR7/TLR9 stimulation, and IFNAR blockade reduced IL-27 levels in TCSle cDCs. These results suggest that dysregulated type I IFNs in cDCs contribute to the increased IL-10 and IL-27 in SLE. Since IL-27 neutralization did not inhibit TLR-induced IL-10 production, we propose that type I IFNs enhanced IL-10 in TCSle cDCs independently from IL-27. Moreover, RNA sequencing analysis of a cohort of SLE patients reveals higher gene expression of these cytokines in SLE patients expressing a high IFN signature. Since IL-27 and IL-10 have both pro- and anti-inflammatory effects, our results also suggest that these cytokines can be modulated by the therapeutic IFN blockade in trials in SLE patients and have complex effects on the autoimmune response.

A proof-of-concept-to-confirmatory multiple adaptation design in the development of an anti-viral treatment.

In the clinical development of some new infectious disease drugs, early clinical pharmacology trials may predict with high confidence that the efficacious doses are well below the range of the safety margin. In this case, a dose-ranging study may be unnecessary after a proof-of-concept (PoC) study testing the highest dose. A multi-stage adaptive design spanning both PoC and confirmatory stages is proposed in this context. The design incorporates two interim analyses allowing strategies for stopping, continuing, or expanding the study. A conditional power threshold for a binary endpoint is proposed to assess futility. Additional components of early efficacy and sample size adjustment are also included to enhance the design's flexibility and robustness. Design operating characteristics are evaluated by numerical calculation. We show that the proposed streamlined trial design has the same statistical rigor as a conventional phase 3 clinical trial with adequate power and a properly controlled type 1 error rate. Additional adaptive design options are also investigated and discussed.

The changing landscape of data monitoring committees-Perspectives from regulators, members, and sponsors.

Data Monitoring Committees (DMCs) are an integral part of clinical drug development. Their use has evolved along with changing study designs and regulatory expectations, which has associated statistical and ethical implications. Although there is guidance from the different regulatory agencies, there are opportunities to bring more consistency to address practical issues of establishing and operating a DMC. Challenging issues include defining the scope of DMC decisions, the regulatory requirements and expectations, the perceived independence of DMCs, the specific focus primarily on safety, etc. Wider use of adaptive clinical trial designs in recent years introduce additional challenges in terms of trial governance and the complexity of DMC activities. A panel comprised of clinical and statistical experts from across academia, industry, and regulatory agencies shared their experience and thoughts on the importance of these aspects and offered perspectives on the future of the DMCs. This paper documents the thinking from the panel session at the CEN-ISBS conference held in Vienna, Austria, 2017.

A Misguided Contraindication: International Normalized Ratio in Acute Liver Failure Precluding Thrombolysis for Massive Pulmonary Embolism: A Case Report.

Massive pulmonary embolism and its treatment with thrombolysis both carry grave risks. Optimal management hinges on determining the risk-to-benefit ratio of thrombolytic administration. For patients with liver dysfunction, assessing bleeding risk is challenging because they may have elevations in the international normalized ratio yet be hypercoagulable. We describe a patient with massive pulmonary embolism and new-onset liver failure, who-absent contraindications-warranted thrombolysis. Initial laboratory values, however, revealed an elevated international normalized ratio, which precluded lysis, despite a hypercoagulable Thromboelastogram. We believe that viscoelastic testing of coagulation is essential for evaluating coagulation in liver dysfunction, particularly when considering thrombolysis.

What makes a group fitness program for people with Parkinson's disease endure? A mixed-methods study of multiple stakeholders.

OBJECTIVE: Identify key features of an enduring group exercise program for people with Parkinson's disease (PD) by exploring experiences of participants, student assistants and the exercise instructor through a convergent mixed methods design. METHODS: Fourteen people with PD (modified Hoehn & Yahr: 1-3.5) who regularly participated in a group exercise program (≥ 50% of classes for ≥ 1 year) were interviewed to explore their perceptions of the program. The exercise instructor was also interviewed and weekly written reflections were collected from 18 undergraduate student assistants. Using a grounded theory approach, interviews and written reflections were thematically analyzed via qualitative content analysis. Quantitative data from the Physical Fitness and Exercise Activity Levels of Older Adults Scale were used as part of a convergent mixed-methods design to move towards theory formation. RESULTS: Thematic analysis of the PD participant interviews revealed 4 themes: 1) Quality of the program, 2) Social interactions, 3) Facilitators to exercise, 4) Barriers to exercise. The exercise instructor interview revealed 2 themes: individualization and functionality of exercises, and creating a nurturing atmosphere. Themes from students' data included student learning, and positive in-class experiences. Means (sd) were 1.6 (0.5) for facilitators and 3.0 (0.5) for barriers subscales (1=strongly agree to 4=strongly disagree). CONCLUSION: These varied sources of data converge to identify and characterize key features of an enduring group exercise program for people with PD: a positive and nurturing environment, varied and individually tailored exercise content, and the importance of social cohesion. These findings also highlight the critical role of multiple stakeholders in fostering an environment that facilitates long-term adherence to group exercise.

Adaptive designs: The Swiss Army knife among clinical trial designs?

There has been considerable progress in the development and implementation of adaptive designs over the past 30 years. A major driver for this class of novel designs is the possibility to increase the information value of clinical trial data to enable better decisions, leading to more efficient drug development processes and improved late-stage success rates. In the first part of this article, we review the development of adaptive designs from different perspectives. We trace back key historical papers, report on landmark adaptive design clinical trials, review major cross-industry collaborations, and highlight key regulatory guidance documents. In the second, more technical part of this article, we address the question of whether it is possible to define factors which guide the choice between a fixed or an adaptive design for a given trial. We show that in non-linear regression models with a moderate variance of the responses, the first-stage sample size of an adaptive design should be chosen sufficiently large in order to address variability in the interim parameter estimate. In conclusion, the choice between an adaptive and a fixed design depends in a sensitive manner on the specific statistical problem under investigation.

Addressing Challenges and Opportunities of "Less Well-Understood" Adaptive Designs.

The draft adaptive design guidance released by FDA in 2010 included references to adaptive study designs that were described as "less well-understood." At that time, there was relatively little regulatory experience with such designs, and their properties were felt to be insufficiently understood. In order to promote greater use of adaptive designs, especially those categorized as less well-understood, the Best Practice Subteam of the DIA Adaptive Designs Scientific Working Group (ADSWG) has worked on describing and characterizing these designs, identifying challenges associated with them and suggesting improvements to design or study conduct aspects that might make them more acceptable. This paper summarizes the work from the subteam.

DIA's Adaptive Design Scientific Working Group (ADSWG): Best Practices Case Studies for "Less Well-understood" Adaptive Designs.

Adaptive design (AD) clinical trials use accumulating subject data to modify the parameters of the design of an ongoing study, without compromising the validity and integrity of the study. The 2010 US Food and Drug Administration (FDA) Draft Guidance on Adaptive Design Clinical Trials described a subset of 7 primary design types as "less well-understood." FDA defined these designs as those with limited regulatory experience. To better understand the properties of these less well-understood ADs and to promote their use when applicable, the Best Practices Subteam for DIA's Adaptive Design Scientific Working Group conducted an extensive nonsystematic search and reviewed trials from multiple sponsors who had employed these designs. Here, we review 10 specific case studies for which less well-understood ADs were employed and share feedback about their challenges and successes, as well as details about the regulatory interactions from these trials. We learned that these designs and associated statistical methodologies can make difficult research situations more amenable for study and, therefore, are needed in our toolbox. While they can be used to study many diseases, they are particularly valuable for rare diseases, small populations, studies involving terminal illnesses, and vaccine trials, in which it is important to find efficient ways to bring effective treatments to market more rapidly. It is imperative, however, that these methodologies be utilized appropriately, which requires careful planning and precise operational execution.

Simultaneous inference on treatment effects in survival studies with factorial designs.

A clinical trial with a 2×2 factorial design involves randomization of subjects to treatment A or A‾ and, within each group, further randomization to treatment B or B‾. Under this design, one can assess the effects of treatments A and B on a clinical endpoint using all patients. One may additionally compare treatment A, treatment B, or combination therapy AB to A‾B‾. With multiple comparisons, however, it may be desirable to control the overall type I error, especially for regulatory purposes. Because the subjects overlap in the comparisons, the test statistics are generally correlated. By accounting for the correlations, one can achieve higher statistical power compared to the conventional Bonferroni correction. Herein, we derive the correlation between any two (stratified or unstratified) log-rank statistics for a 2×2 factorial design with a survival time endpoint, such that the overall type I error for multiple treatment comparisons can be properly controlled. In addition, we allow for adjustment of prognostic factors in the treatment comparisons and conduct simultaneous inference on the effect sizes. We use simulation studies to show that the proposed methods perform well in realistic situations. We then provide an application to a recently completed randomized controlled clinical trial on alcohol dependence. Finally, we discuss extensions of our approach to other factorial designs and multiple endpoints.