Endpoint Definitions Research Articles

Emerging Role of Autologous CD19 CAR T-Cell Therapies in the Second-Line Setting for Large B-cell Lymphoma: A Game Changer?

Chimeric antigen receptor T-cell (CAR T) therapy has been proven effective in the third-line (and beyond) setting in patients with large B-cell lymphoma (LBCL). Until recently, high-dose chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) was considered the standard of care in the second-line setting in patients demonstrating an objective response before the procedure. The ZUMA-7 and TRANSFORM studies showed the benefit of axicabtagene ciloleucel and lisocabtagene maraleucel, respectively, in patients refractory to or relapsing within 12 months of first-line anthracycline-based chemoimmunotherapy. However, a third trial (BELINDA study) using tisagenlecleucel failed to show a benefit in the same setting compared to standard salvage chemoimmunotherapy followed by auto-HCT. Several differences exist between these trials, including trial designs, patient population, crossover permissibility, bridging therapy, and end-point definitions. In this review, we summarize the current evidence for the treatment of patients with LBCL in the third line and beyond and standard treatment in the second line before CAR T therapy approval and interpret outcomes of the three trials examining the role of CAR T therapy in the second line and their impact in reshaping future practice.

Assessment of the MitraClip Procedure: Reassessing the Goals

THE MITRACLIP (Abbott Laboratories) was first implanted in 2003, was approved in Europe in 2008, and approved by the US Food and Drug Administration in 2013. The MitraClip procedure has reduced hospitalization and mortality compared to medical therapy, with either improved or similar outcomes compared with isolated mitral valve surgery. 1 Shah MA Dalak FA Alsamadi F et al. Complications following percutaneous mitral valve edge-to-edge repair using MitraClip. J Am Coll Cardiol. 2021; 3: 370-376 Google Scholar , 2 Stone GW Lindenfeld JA Abraham WT et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med. 2018; 379: 2307-2318 Crossref PubMed Scopus (1514) Google Scholar , 3 Stone GW Adams DH Abraham WT et al. Clinical trial design principles and endpoint definitions for transcatheter mitral valve repair and replacement: Part 2: Endpoint definitions a consensus document from the mitral valve academic research consortium. J Am Coll Cardiol. 2015; 66: 308-321 Crossref PubMed Scopus (302) Google Scholar In the earlier and preliminary data, proponents of surgery highlighted less mitral regurgitation (MR) and fewer additional procedures after surgical correction of MR; however, the overall major cardiac adverse events were significantly lower (15% v 48%) for percutaneous procedures. 4 Feldman T Foster E Glower DD et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med. 2011; 364: 1395-1406 Crossref PubMed Scopus (1475) Google Scholar Since the initial experiences, all outcomes for MitraClip procedures have improved with greater experience. 5 Chhatriwalla AK Vemulapalli S Holmes DR et al. Institutional experience with transcatheter mitral valve repair and clinical outcomes. J Am Coll Cardiol. 2019; 12: 1342-1352 Crossref Scopus (100) Google Scholar Right Ventricular Failure in Emergent MitraClip Therapy—A Problem Worth InvestigatingJournal of Cardiothoracic and Vascular AnesthesiaPreviewThe MitraClip (Abbott, Santa Clara, CA) has emerged as a safe, effective, and durable treatment for hemodynamically significant mitral regurgitation (MR) refractory to maximally tolerable guideline-directed medical therapy in nonsurgical patients.1-9 Hemodynamically, the MitraClip reduces left ventricular volumes, unloads the left atrium and pulmonary circulation, reduces right ventricular afterload (as long as iatrogenic MitraClip-induced mitral stenosis does not develop), and facilitates biventricular reverse remodeling. Full-Text PDF Invited Commentary: “Assessment of the MitraClip procedure: Reassessing the goals”Journal of Cardiothoracic and Vascular AnesthesiaPreviewAsher and colleagues1 present two interesting cases that not only highlight the use of MitraClip in the urgent setting, but also how intraoperative case management can help facilitate procedural success. Mitral valve disease is one of the most common valvular disorders with an incidence anywhere from 10% to 24%, most commonly affecting people older than 75 years.2,3 Primary mitral regurgitation (MR) is due to a structural or degenerative abnormality while secondary MR is related to left ventricular (LV) or less commonly left atrial disease. Full-Text PDF

Interobserver Reliability of the Nancy Index for Ulcerative Colitis: An Assessment of the Practicability and Ease of Use in a Single-Centre Real-World Setting.

Histological disease severity assessment in ulcerative colitis [UC] has become a mainstay in the definition of clinical endpoints ['histological remission'] in clinical trials of UC. Several scores have been established in the microscopic assessment of disease activity, but the Nancy index [NI] stands out as being the histological index with the fewest scoring items. To what extent histological assessment using the NI is affected by interobserver reliability in a real-word setting is poorly understood. We therefore performed a single-centre retrospective analysis of NI assessment in patients with UC. We retrospectively evaluated the NI in two independent cohorts [total: 1085 biopsies, 547 UC patients] of clinically diagnosed UC patients, who underwent colonoscopy between 2007 and 2020. Cohort #1 consisted of 637 biopsies from 312 patients, while Cohort #2 consisted of 448 biopsies from 235 patients. Two blinded pathologists with different levels of expertise scored all biopsies from each cohort. A consensus conference was held for cases with discrepant scoring results. Finally, an overall consensus scoring was obtained from both cohorts. The interobserver agreement of the NI was substantial after the assessment of 1085 biopsy samples (κ = 0.796 [95% confidence interval, CI: 0.771-0.820]). An improvement of the interobserver agreement was found with increasing numbers of samples evaluated by both observers (Cohort #1: κ = 0.772 [95% CI: 0.739-0.805]; Cohort #2: κ = 0.829 [95% CI: 0.793-0.864]). Interobserver discordance was highest in NI grade 1 [observer 1: n = 128; observer 2: n = 236]. Interobserver discordance was lowest in NI grades 0 [observer 1: n = 504; observer 2: n = 479] and 3 [observer 1: n = 71; observer 2: n = 66]. The NI is an easy-to-use index with high interobserver reliability for assessment of the histological disease activity of UC patients in a real-world setting. While NI grades 0 and 3 had a high level of agreement between observers, NI grade 1 had a poorer level of agreement. This highlights the clinical need to specify histological characteristics leading to NI grade 1.

Primary membranous nephropathy: an endless story.

Primary membranous nephropathy (PMN) is an autoimmune disease caused by the attack of autoantibodies against podocyte antigens leading to the in situ production of immune complexes. However, the etiology is unknown and the pathogenesis is still far from being completely elucidated. MN is prevalently idiopathic or primary, but in about 20-30% of cases it is secondary to chronic infections, systemic diseases, exposure to drugs, or malignancy. The differentiation between primary and secondary MN may be difficult, particularly when MN precedes signs and symptoms of the original disease, as in some cases of cancer or systemic lupus erythematosus. The natural course of PMN is variable, but in the long term 40-60% of patients with nephrotic syndrome progress to end-stage renal disease (ESRD) or die from thrombotic or cardiovascular events. PMN is a treatable disease. Patients with asymptomatic proteinuria should receive supportive care. Immunosuppressive treatments should be given to patients with nephrotic syndrome or risk of progression. The most frequently adopted treatments rely on cyclical therapy alternating steroids with a cytotoxic agent every other month, i.e., rituximab at different doses, or calcineurin inhibitors plus low-dose steroids. A good rate of response may be obtained but relapses can occur. Randomized controlled trials, with adequate size, long-term follow-up, and fair definition of endpoints are needed to identify treatment with the best therapeutic index.

Final Analysis of Diagnostic Endoscopic Resection Followed by Selective Chemoradiotherapy for Stage I Esophageal Cancer: JCOG0508

Final Analysis of Diagnostic Endoscopic Resection Followed by Selective Chemoradiotherapy for Stage I Esophageal Cancer: JCOG0508

Evaluation of non-breath-hold, ultra-fast, low-dose high-pitch (flash) CT scan as a practical alternative to standard spiral scan for pre-TAVI patients: a real-world single-center experience

Abstract Introduction and aim Aortic annulus dimensions change during the cardiac cycle. A retrospective ECG-gated (Spiral) scan is the default technique for pre TAVR evaluation since it includes systolic phases considered optimal for aortic annulus assessment. Ultra-fast, Low-Dose High-Pitch (FLASH) offers faster, potentially low radiation and low contrast dose scans. However, it lacks the ability to time data acquisition to the systole. Therefore, measurements derived from FLASH scan are considered suboptimal for reporting. The effect of this potential annular measurement difference on procedural success and safety was not evaluated. Therefore, we aimed to assess the feasibility and safety of FLASH vs. Spiral scan before TAVI. Methods We conducted a retrospective, single-center study. 409 patients underwent CT-TAVI scan with either FLASH or SPIRAL acquisition. Baseline characteristics, CT study, procedural and f/u data were acquired from the EMR. Outcomes defined by Valve Academic Research Consortium3 (VARC-2) endpoint definitions included in-hospital mortality, bleeding, vascular complications, acute kidney injury (AKI), conduction disorders, mechanical complications, and prosthetic aortic valve regurgitation. Composite endpoints such as device success were also examined. Results Of the 409 patients, 55.7% underwent FLASH scans. The median age was 80 years, and males accounted for 55%. The FLASH-protocol patients had higher rate of chronic kidney disease, their CT-measured aortic annulus area and diameter were smaller, and they were exposed to a smaller amount of contrast agent and radiation than the SPIRAL group. There was no statistically significant difference in primary clinical and safety endpoints between the two groups, including mechanical complications (such as annular rupture and valve malposition) and conduction disorders. Conclusions FLASH CT scan is a pragmatic and safe approach that potentially may replace spiral scan for the evaluation before TAVI procedure in the appropriate patients. Funding Acknowledgement Type of funding sources: None.

S713 Induction and Maintenance Treatment with Risankizumab Leads to Symptomatic Relief in Patients With Moderate to Severe Crohn’s Disease

S713 Induction and Maintenance Treatment with Risankizumab Leads to Symptomatic Relief in Patients With Moderate to Severe Crohn’s Disease

Disease severity and status in Stevens-Johnson syndrome and toxic epidermal necrolysis: Key knowledge gaps and research needs.

Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are on a spectrum of cutaneous drug reactions characterized by pan-epidermal necrosis with SJS affecting < 10% of body surface area (BSA), TEN > 30%, and SJS/TEN overlap between 10 and 30%. Severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is a validated tool to predict mortality rates based on age, heart rate, BSA, malignancy and serum urea, bicarbonate, and glucose. Despite improved understanding, SJS/TEN mortality remains constant and therapeutic interventions are not universally accepted for a number of reasons, including rarity of SJS/TEN; inconsistent definition of cases, disease severity, and endpoints in studies; low efficacy of interventions; and variations in treatment protocols. Apart from mortality, none of the other endpoints used to evaluate interventions, including duration of hospitalization, is sufficiently standardized to be reproducible across cases and treatment centers. Some of the gaps in SJS/TEN research can be narrowed through international collaboration to harmonize research endpoints. A case is made for an urgent international collaborative effort to develop consensus on definitions of endpoints such as disease status, progression, cessation, and complete re-epithelialization in interventional studies. The deficiencies of using BSA as the sole determinant of SJS/TEN severity, excluding internal organ involvement and extension of skin necrosis beyond the epidermis, are discussed and the role these factors play on time to healing and mortality beyond the acute stage is highlighted. The potential role of artificial intelligence, biomarkers, and PET/CT scan with radiolabeled glucose as markers of disease status, activity, and therapeutic response is also discussed.

Cardiac magnetic resonance imaging versus computed tomography to guide transcatheter aortic valve replacement: study protocol for a randomized trial (TAVR-CMR)

BackgroundThe standard procedure for the planning of transcatheter aortic valve replacement (TAVR) is the combination of echocardiography, coronary angiography, and cardiovascular computed tomography (TAVR-CT) for the exact determination of the aortic valve dimensions, valve size, and implantation route. However, up to 80% of the patients undergoing TAVR suffer from chronic renal insufficiency. Alternatives to reduce the need for iodinated contrast agents are desirable. Cardiac magnetic resonance (CMR) imaging recently has emerged as such an alternative. Therefore, we aim to investigate, for the first time, the non-inferiority of TAVR-CMR to TAVR-CT regarding efficacy and safety end-points.MethodsThis is a prospective, randomized, open-label trial. It is planned to include 250 patients with symptomatic severe aortic stenosis scheduled for TAVR based on a local heart-team decision. Patients will be randomized in a 1:1 fashion to receive a predefined TAVR-CMR protocol or to receive a standard TAVR-CT protocol within 2 weeks after inclusion. Follow-up will be performed at hospital discharge after TAVR and after 1 and 2 years. The primary efficacy outcome is device implantation success at discharge. The secondary endpoints are a combined safety endpoint and a combined clinical efficacy endpoint at baseline and at 1 and 2 years, as well as a comparison of imaging procedure related variables. Endpoint definitions are based on the updated 2012 VARC-2 consensus document.DiscussionTAVR-CMR might be an alternative to TAVR-CT for planning a TAVR procedure. If proven to be effective and safe, a broader application of TAVR-CMR might reduce the incidence of acute kidney injury after TAVR and thus improve outcomes.Trial registrationThe trial is registered at ClinicalTrials.gov (NCT03831087). The results will be disseminated at scientific meetings and publication in peer-reviewed journals.

Abstract IA15: Trial Design and Endpoint Definition in intermediate-stage HCC – a Challenge

Abstract Trial Design and Endpoint Definition in general is more complex in hepatocellular carcinoma compared to other solid tumors. It took decades of research until the first systemic treatment was defined in 2007 as a result of the SHARP and the ASIA-Pacific trials. The demonstration of Sorafenib’s anti-tumor efficacy in advanced HCC to a large extend was owing to the concentration on patients with good liver function, avoiding the confounding impact of liver cirrhosis. In intermediate stage HCC trial design is even more challenging: intermediate stage HCC is a heterogeneous disease with a broad spectrum of tumor burden, variable liver function, and radiological intervention with transarterial chemoembolization (TACE) as a standard procedure which is far beyond standardization. Several trials have been launched either combining TACE with systemic therapy or comparing TACE vs. systemic therapy. Several issues in this setting are questioning overall survival as preferred endpoint: with an expected survival in excess of 2.5 years and several systemic therapies available, the competing risks of death (liver disease) and the contribution of post-trial treatments are increasingly impacting OS and obscuring the effectiveness of the trial-specific intervention. This is exemplified by the TACTICS trial, comparing TACE + Sorafenib with TACE, where a solid PFS benefit for the combination (HR: 0.661) did not translate into OS (HR: 0.861), possibly because of a more than 20% higher rate of post-treatment medication in the TACE-only group. Thus, there is an obvious need for surrogate markers, indicative of increased survival time but shifting overall survival analysis into secondary endpoints. We recently started the ABC-HCC trial, a phase IIIb, randomized, multicenter, open-label trial of atezolizumab plus bevacizumab versus transarterial chemoembolization (TACE) in intermediate-stage hepatocellular carcinoma. Here we are using a pragmatic and real-life endpoint, Time to failure of treatment strategy (TTFS) as primary endpoint. TTFS is defined as Time from randomization until failure of strategy, i.e. radiologic progression or lack of radiologic response AND any of the following: the loss of clinical benefit OR unacceptable toxicity OR liver function deterioration OR therapy not further applicable for other reasons Secondary endpoints comprise OS, Overall Survival Rate at 24 months (OS@24), Objective Response Rate (ORR), Time to Progression (TTP), Time to loss of systemic treatment options (TTSYS), Progression free survival (PFS), Duration of Treatment, Duration of Response (DOR), Time to deterioration of liver function, Safety, and QoL (Patient Reported Outcome; PRO). The trial includes an exploratory biomarker analysis. The ABC-HCC and other trials will give us information on the role of systemic therapy in intermediate stage HCC in the upcoming years. Citation Format: Peter R Galle. Trial Design and Endpoint Definition in intermediate-stage HCC – a Challenge [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA15.

SGLT2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials

SGLT2 inhibitors are strongly recommended in guidelines to treat patients with heart failure with reduced ejection fraction, but their clinical benefits at higher ejection fractions are less well established. Two large-scale trials, DELIVER and EMPEROR-Preserved, in heart failure with mildly reduced or preserved ejection fraction have been done, providing power to examine therapeutic effects on cardiovascular mortality and in patient subgroups when combined with the earlier trials in reduced ejection fraction. We did a prespecified meta-analysis of DELIVER and EMPEROR-Preserved, and subsequently included trials that enrolled patients with reduced ejection fraction (DAPA-HF and EMPEROR-Reduced) and those admitted to hospital with worsening heart failure, irrespective of ejection fraction (SOLOIST-WHF). Using trial-level data with harmonised endpoint definitions, we did a fixed-effects meta-analysis to estimate the effect of SGLT2 inhibitors on various clinical endpoints in heart failure The primary endpoint for this meta-analysis was time from randomisation to the occurrence of the composite of cardiovascular death or hospitalisation for heart failure. We assessed heterogeneity in treatment effects for the primary endpoint across subgroups of interest. This study is registered with PROSPERO, CRD42022327527. Among 12 251 participants from DELIVER and EMPEROR-Preserved, SGLT2 inhibitors reduced composite cardiovascular death or first hospitalisation for heart failure (hazard ratio 0·80 [95% CI 0·73-0·87]) with consistent reductions in both components: cardiovascular death (0·88 [0·77-1·00]) and first hospitalisation for heart failure (0·74 [0·67-0·83]). In the broader context of the five trials of 21 947 participants, SGLT2 inhibitors reduced the risk of composite cardiovascular death or hospitalisation for heart failure (0·77 [0·72-0·82]), cardiovascular death (0·87 [0·79-0·95]), first hospitalisation for heart failure (0·72 [0·67-0·78]), and all-cause mortality (0·92 [0·86-0·99]). These treatment effects for each of the studied endpoints were consistently observed in both the trials of heart failure with mildly reduced or preserved ejection fraction and across all five trials. Treatment effects on the primary endpoint were generally consistent across the 14 subgroups examined, including ejection fraction. SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalisations for heart failure in a broad range of patients with heart failure, supporting their role as a foundational therapy for heart failure, irrespective of ejection fraction or care setting. None.

Efficacy of Approved Versus Unapproved Vaccines for Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Randomized Blinded Clinical Trials.

BackgroundFive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are approved in North America and/or Europe: Pfizer/BioNTech, Moderna, Janssen, Oxford-AstraZeneca, and Novavax. Other vaccines have been developed, including Sinopharm, SinoVac, QazVac, Covaxin, Soberana, Zifivax, Medicago, Clover, and Cansino, but they are not approved in high-income countries. This meta-analysis compared the efficacy of US Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved and -unapproved vaccines in randomized clinical trials (RCTs).MethodsA systematic review of trial registries identified RCTs of SARS-CoV-2 vaccines. Risk of bias was assessed using the Cochrane tool (RoB 2). In the meta-analysis, relative risks of symptomatic infection and severe disease were compared for each vaccine versus placebo, using Cochrane-Mantel Haenszel Tests (random effects method).ResultsTwenty-two RCTs were identified and 1 was excluded for high-risk of bias. Ten RCTs evaluated 5 approved vaccines and 11 RCTs evaluated 9 unapproved vaccines. In the meta-analysis, prevention of symptomatic infection was 84% (95% confidence interval [CI], 68%–92%) for approved vaccines versus 72% (95% CI, 66%–77%) for unapproved vaccines, with no significant difference between vaccine types (P = .12). Prevention of severe SARS-CoV-2 infection was 94% (95% CI, 75%–98%) for approved vaccines versus 86% (95% CI, 76%–92%) for unapproved vaccines (P = .33). The risk of serious adverse events was similar between vaccine types (P = .12).ConclusionsThis meta-analysis of 21 RCTs in 390 459 participants showed no significant difference in efficacy between the FDA/EMA-approved and -unapproved vaccines for symptomatic or severe infection. Differences in study design, endpoint definitions, variants, and infection prevalence may have influenced results. New patent-free vaccines could lower costs of worldwide SARS-CoV-2 vaccination campaigns significantly.

Warming up for a better fever: a randomized pilot study in pediatric oncology

BackgroundFever in children is a major problem in pediatric oncology. Usual management leads to immediate antibiotic and antipyretic therapy, although there is consensus that antipyretic therapy should not be utilized with the sole aim of reducing body temperature. Increased body temperature during fever appears to be an effective modifier in terms of viral replication and enhanced host defense mechanisms against pathogens. Therefore, it might be beneficial to support febrile patients by applying gentle heat during the onset of fever to help the body to reach its new thermoregulatory set point.MethodsA randomized pilot study over 6 months will be conducted in a pediatric oncology department in an academic hospital in Germany. This study is a preparation for a multicenter clinical trial with two parallel groups concerning the efficacy of heat application vs. treatment as usual. One of the inclusion criteria is body temperatures ≥ 38.0 °C in n = 24 cases of patients receiving chemotherapy aged 18 months to 17 years. The first intervention consists of gentle heat application with hot water bottles at any sign of illness and onset of fever. The aim is to achieve a warm periphery equilibrated to trunk temperature of less than 0.5 °C. The second intervention is the avoidance of antipyretics. The control group receives the standard antipyretic treatment from the participating hospital. The purposes of this pilot study are proof of principle of intervention, evaluation of safety, feasibility, definition of endpoints, and to receive basic data for sample size calculation and needed resources.DiscussionThe main goal is to improve the care of children with cancer by providing the best possible support for febrile episodes. If fever support by heat reduces discomfort, administration of antipyretics and maybe even antibiotics, this would be an advancement in oncological fever management. This pilot study is intended to provide a basis for a main, multicenter, randomized trial and demonstrate the practicability of heat application in febrile patients in pediatric oncology.Trial registrationGerman Clinical Trials Register (DRKS), DRKS00028273. Registered on 14 April 2022

Global Prevalence and Incidence of Tinnitus

To date, no systematic review has taken a meta-analytic approach to estimating the prevalence and incidence of tinnitus in the general population. To provide frequency estimates of tinnitus worldwide. An umbrella review followed by a traditional systematic review was performed by searching PubMed-MEDLINE and Embase from inception through November 19, 2021. Research data from the general population were selected, and studies based on patients or on subgroups of the population with selected lifestyle habits were excluded. No restrictions were applied according to date, age, sex, and country. Relevant extracted information included type of study, time and location, end point, population characteristics, and tinnitus definition. The study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Pooled prevalence estimates of any tinnitus, severe tinnitus, chronic tinnitus, and diagnosed tinnitus as well as incidence of tinnitus were obtained using random-effects meta-analytic models; heterogeneity between studies was controlled using the χ2 test, and inconsistency was measured using the I2 statistic. Among 767 publications, 113 eligible articles published between 1972 and 2021 were identified, and prevalence estimates from 83 articles and incidence estimates from 12 articles were extracted. The pooled prevalence of any tinnitus among adults was 14.4% (95% CI, 12.6%-16.5%) and ranged from 4.1% (95% CI, 3.7%-4.4%) to 37.2% (95% CI, 34.6%-39.9%). Prevalence estimates did not significantly differ by sex (14.1% [95% CI, 11.6%-17.0%] among male individuals; 13.1% [95% CI, 10.5%-16.2%] among female individuals), but increased prevalence was associated with age (9.7% [95% CI, 7.4%-12.5%] among adults aged 18-44 years; 13.7% [95% CI, 11.0%-17.0%] among those aged 45-64 years; and 23.6% [95% CI, 19.4%-28.5%] among those aged ≥65 years; P < .001 among age groups). The pooled prevalence of severe tinnitus was 2.3% (95% CI, 1.7%-3.1%), ranging from 0.5% (95% CI, 0.3%-0.7%) to 12.6% (95% CI, 11.1%-14.1%). The pooled prevalence of chronic tinnitus was 9.8% (95% CI, 4.7%-19.3%) and the pooled prevalence of diagnosed tinnitus was 3.4% (95% CI, 2.1%-5.5%). The pooled incidence rate of any tinnitus was 1164 per 100 000 person-years (95% CI, 479-2828 per 100 000 person-years). Despite the substantial heterogeneity among studies, this comprehensive systematic review on the prevalence and incidence of tinnitus suggests that tinnitus affects more than 740 million adults globally and is perceived as a major problem by more than 120 million people, mostly aged 65 years or older. Health policy makers should consider the global burden of tinnitus, and greater effort should be devoted to boost research on tinnitus.

Essaying the Impasse

Essaying the Impasse

Statistical Considerations for Analyses of Time-To-Event Endpoints in Oncology Clinical Trials: Illustrations with CAR-T Immunotherapy Studies.

Chimeric antigen receptor T-cell (CAR-T) therapy is an exciting development in the field of cancer immunology and has received a lot of interest in recent years. Many time-to-event (TTE) endpoints related to relapse, disease progression, and remission are analyzed in CAR-T studies to assess treatment efficacy. Definitions of these TTE endpoints are not always consistent, even for the same outcomes (e.g., progression-free survival), which often stems from analysis choices regarding which events to consider as part of the composite endpoint, censoring or competing risk in the analysis. Subsequent therapies such as hematopoietic stem cell transplantation are common but are not treated the same in different studies. Standard survival analysis methods are commonly applied to TTE analyses but often without full consideration of the assumptions inherent in the chosen analysis. We highlight two important issues of TTE analysis that arise in CAR-T studies, as well as in other settings in oncology: the handling of competing risks and assessing the association between a time-varying (post-infusion) exposure and the TTE outcome. We review existing analytical methods, including the cumulative incidence function and regression models for analysis of competing risks, and landmark and time-varying covariate analysis for analysis of post-infusion exposures. We clarify the scientific questions that the different analytical approaches address and illustrate how the application of an inappropriate method could lead to different results using data from multiple published CAR-T studies. Codes for implementing these methods in standard statistical software are provided.

The impact of frailty on adverse outcomes after transcatheter aortic valve replacement in older adults: A retrospective cohort study.

BackgroundTranscatheter aortic valve replacement (TAVR) is an effective alternative to surgical aortic valve replacement for patients who are at increased surgical risk. Consequently, frailty is common in patients undergoing TAVR.ObjectivesThis study aims to investigate the impact of frailty on outcomes following TAVR.MethodsA retrospective cohort study was conducted, including all TAVR candidates who visited the geriatric outpatient clinic for preoperative screening. Frailty status was assessed according to the Groningen Frailty Indicator. The primary outcome of the study was defined as the occurrence of postoperative complications, and this was evaluated according to the Clavien–Dindo classification. An additional analysis was performed to assess the impact of frailty on 1‐year all‐cause mortality and complications within 30 days of TAVR according to the Valve Academic Research Consortium (VARC‐2) criteria. The VARC‐2 criteria provide harmonized endpoint definitions for TAVR studies.ResultsIn total, 431 patients with a mean age of 80.8 ± 6.2 years were included, of whom 56% were female. Frailty was present in 36% of the participants. Frailty was associated with a higher risk of the composite outcome of complications [adjusted odds ratio (OR): 1.55 (95% confidence interval, CI: 1.03–2.34)], 30‐day mortality [adjusted OR: 4.84 (95% CI: 1.62–14.49)], 3‐month mortality [adjusted OR: 2.52 (95% CI: 1.00–6.28)] and 1‐year mortality [adjusted OR: 2.96 (95% CI: 1.46–6.00)].ConclusionsFrailty is common in TAVR patients and is associated with an increased overall risk of postoperative complications, particularly mortality. Increased optimization of screening and treatment of frailty in the guidelines for valvular heart diseases is recommended.

SA40 Indexing Regulatory Documents and Clinical Evidence Publications for Non-Small Cell Lung Cancer (NSCLC) Therapeutics: Establishing a Dataset to Enable the Study of Endpoint Fidelity

Inconsistencies in reporting and defining clinical trial endpoints have been previously documented. In oncology, ongoing debate surrounds the utility of, meaningfulness of, and evidence behind common surrogate endpoints, particularly Progression Free Survival and Overall Response Rate, which hinders design of trials to improve outcomes. Questions emerging from this debate could be answered by comparing endpoint frequency, definition, and application within and across trials, but no data source exists for such analysis.

End-point definition and trial design to advance tuberculosis vaccine development.

Tuberculosis (TB) remains a leading infectious cause of death worldwide and the coronavirus disease 2019 pandemic has negatively impacted the global TB burden of disease indicators. If the targets of TB mortality and incidence reduction set by the international community are to be met, new more effective adult and adolescent TB vaccines are urgently needed. There are several new vaccine candidates at different stages of clinical development. Given the limited funding for vaccine development, it is crucial that trial designs are as efficient as possible. Prevention of infection (POI) approaches offer an attractive opportunity to accelerate new candidate vaccines to advance into large and expensive prevention of disease (POD) efficacy trials. However, POI approaches are limited by imperfect current tools to measure Mycobacterium tuberculosis infection end-points. POD trials need to carefully consider the type and number of microbiological tests that define TB disease and, if efficacy against subclinical (asymptomatic) TB disease is to be tested, POD trials need to explore how best to define and measure this form of TB. Prevention of recurrence trials are an alternative approach to generate proof of concept for efficacy, but optimal timing of vaccination relative to treatment must still be explored. Novel and efficient approaches to efficacy trial design, in addition to an increasing number of candidates entering phase 2-3 trials, would accelerate the long-standing quest for a new TB vaccine.

Keeping up with the guidelines: design changes to the STREAM stage 2 randomised controlled non-inferiority trial for rifampicin-resistant tuberculosis

Results from the STREAM stage 1 trial showed that a 9-month regimen for patients with rifampicin-resistant tuberculosis was non-inferior to the 20-month regimen recommended by the 2011 WHO treatment guidelines. Similar levels of severe adverse events were reported on both regimens suggesting the need for further research to optimise treatment. Stage 2 of STREAM evaluates two additional short-course regimens, both of which include bedaquiline. Throughout stage 2 of STREAM, new drug choices and a rapidly changing treatment landscape have necessitated changes to the trial’s design to ensure it remains ethical and relevant. This paper describes changes to the trial design to ensure that stage 2 continues to answer important questions. These changes include the early closure to recruitment of two trial arms and an adjustment to the definition of the primary endpoint. If the STREAM experimental regimens are shown to be non-inferior or superior to the stage 1 study regimen, this would represent an important contribution to evidence about potentially more tolerable and more efficacious MDR-TB regimens, and a welcome advance for patients with rifampicin-resistant tuberculosis and tuberculosis control programmes globally.Trial registration: ISRCTN ISRCTN18148631. Registered 10 February 2016