Inclusion Criteria For Trials Research Articles

Immune Checkpoint Inhibitors in Patients With Cancer and Infection by Hepatitis B or C Virus: A Perspective Through the Results of a European Survey

IntroductionPatients with cancer and hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are underrepresented in several clinical trials testing immune checkpoint inhibitors (ICIs). Consequently, safety and efficacy of ICI therapy in this population have not been completely defined. We aimed to evaluate the attitudes of oncologists on this topic. MethodsWe conducted a 14-item European anonymous online survey. ResultsPhysicians from 56 oncology departments (26 from Italy, 15 from France, and 15 from Spain) took part in the survey. They mainly used to prescribe ICIs for treating patients with lung cancer, melanoma, and renal cell carcinoma. Of them, 95% recognized the need for specific guidelines addressing the management of patients with cancer and HBV or HCV treated with ICIs. Just 63% of the respondents screened patients for HBV and HCV status before ICIs initiation, although the risk of immune-related hepatotoxicity or viral reactivation was a major concern for most of them. Only 9% of the surveyed oncologists considered HBV and HCV infection a major exclusion criterion for receiving ICIs. Furthermore, 29% of the respondents would start a prophylactic treatment of active infection at ICIs initiation. ConclusionsICIs administration in patients with cancer and HBV or HCV infection is of concern for most of the surveyed European oncologists. Nonetheless, active screening and treatment of viral hepatitis should be improved. Data in this specific setting are needed for an evidence-based management and should be generated by broadening inclusion criteria of clinical trials to allow the enrollment of patients with HBV and HCV.

1109 PULMONARY PRESSUR TREND ANALYSIS IN PATIENTS UNDERGOING MITRACLIP

Abstract Mitral regurgitation (MR) is the second most frequent valve heart disease in Europe and its underlying mechanism primary-organic (due to disease of the mitral leaflets), or secondary-functional (where valve leaflets and chordae are structurally normal and MR results from alterations in left ventricle and left atrium geometry), determines the therapeutic approach. Transcatheter Edge-to-Edge Repair (TEER) with MitraClip implantation is a minimal-invasive treatment that according to 2021 ESC Guidelines should be considered (class of recomandation IIa) in selected symptomatic patients with severe MR despite optimal medical therapy, not eligible for surgery and fulfilling COAPT trial inclusion criteria, suggesting an increased chance of responding to treatment. Optimal valve morphology features for TEER are central pathology (second scallop), no leaflet calcifications, mitral valve area >4cm2, mobile length of posterior leaftel >10 mm, coaptation depth <11mm, normal leaflet strength and mobility, flail width <15 mm, flail gap <10 mm. TEER may be considered (class IIb) only in selected cases when the COAPT criteria are not fulfilled with the aim of improving symptoms and quality of life. MR occurs during systole, that at normal heart rates represents 30-50% of the cardiac cycle. As such, marked left atrial (LA) pressure elevation is present only transiently, representing less of a drive to development of secondary pulmonary hypertension compared to chronic LA pressure elevation seen in severe mitral stenosis. Anyway, in patients with severe MR echocardiography often reveals elevated systolic pulmonary artery pressure (PAPs) and MitraClip implantation usually is associated with a slight increase of the trans-mitral gradient with possible repercussions on pulmonary pressures. To better describe the effect of MitraClip implantation on pulmonary pressures and clinical outcomes we did a retrospective study enrolling in the period 2012-2022 thirty-six patients with severe mitral regurgitation treated with TEER. Compared to the last year presentation, we add eleven patients. The target was still to evaluate the clinical outcomes (symptoms, signs of heart failure, NYHA functional class) and the pulmonary pressures assessed by an echocardiographic examination before and after the intervention. At 6-month follow-up we observed in all patients with repaired mitral regurgitation an improvement in the NYHA class (from IV to II) without re-hospitalization. In addition we notice a more pronounced trend in the reduction of the mean sistolic pulmonary arterial pressure, estimated at around 2.86 mmHg ± 14 mmHg (p 0.24, 95% C.I. -7.69 to 1.94) with an unchanged left ventricle ejection fraction. Moreover, the echocardiographic exam showed a normalization of the S and D waves pattern in the pulmonary veins at the PW Doppler evaluation. These new data reinforced the idea that the clinical improvement and the reduction of dyspnea in these patients underwent TEER is related to a reduction of pressures in the pulmonary circulation regardless of the ejection fraction. This finding could be used as a tool that the cardiologist has to evaluate in the echocardiography lab to reveal a new mitral valve disfunction. Despite the addition of the new patients, the sample is still relatively small. However, considering the improvement of the results with the enlargement of the sample, the goal is to enroll additional patients to make the study even more meaningful.

939 PROGNOSTIC IMPACT OF THE COAPT INCLUSION AND EXCLUSION CRITERIA IN REAL WORLD PATIENTS WITH SECONDARY MITRAL REGURGITATION UNDERGOING MITRACLIP IMPLANTATION

Abstract Background The COAPT randomized trial has shown a huge benefit in the survival of patients with heart failure and functional mitral regurgitation treated with Mitraclip. However, patients in COAPT trial were highly selected and the clinical course in real-world patients with and without fulfilment of the trial inclusion criteria is unclear. Methods and Results The present study examined the clinical outcome in consecutive patients (n=146) with symptomatic moderate-to-severe or severe MR of dominant functional etiology undergoing Mitraclip therapy by the presence of the inclusion criteria of the COAPT trial (left ventricular ejection fraction >20%, left ventricular end-systolic dimension <70 mm, non-commissural primary jet, estimated pulmonary artery systolic pressure <70 mmHg, mitral valve orifice area >4 cm2, no prior mitral valve leaflet surgery or any currently implanted prosthetic mitral valve or any prior transcatheter mitral valve procedure). The primary endpoint was the composite of all-cause mortality or heart failure hospitalization. Secondary endpoints were the single components of the primary endpoint (heart failure hospitalization, all-cause mortality) and cardiovascular mortality. Among 146 patients who underwent Mitraclip implantation 35.6% fulfilled the inclusion criteria of COAPT. The composite endpoint was significantly less frequent in patients fulfilling the COAPT selection criteria than in those not fulfilling the criteria [HR 0.3851 (0.2266 to 0.6642); p=0.0017] (Figure). Conclusion In this single center study the outcome of patients with functional mitral regurgitation undergoing Mitraclip therapy was significantly worse in patients not fulfilling COAPT inclusion criteria, indicating that these criteria might help identify futility.

Enrolling Older Adults Onto National Cancer Institute-Funded Clinical Trials in Community Oncology Clinics: Barriers and Solutions.

In April 2021, the National Cancer Institute (NCI) Division of Cancer Prevention collaborated with the NCI Division of Cancer Treatment and Diagnosis to produce a virtual workshop that developed recommendations for enhancing NCI-sponsored clinical trial accrual of older adults. Prior to the workshop, a multidisciplinary group of stakeholders (eg, community oncologists, advanced practice practitioners, clinic and research staff, and patient advocates) gathered information related to accrual of older adults to clinical trials from the literature. Subsequently, a survey was conducted to detail NCI Community Oncology Research Program members' perspective on accrual barriers for this population; 305 individuals responded to the survey. Barriers to clinical trial accruals included comorbidity-attributed trial ineligibility, transportation and time issues, concern that the proposed regimen is too toxic for older adults, patient or family caregiver declined participation, and lack of trials relevant to older patients. Identified solutions included broadening clinical trial inclusion criteria, increasing the number of clinical trials specifically designed for older adults, simplifying consent forms, improving recruitment materials for older adults and their families, and facilitating transportation vouchers. At the workshop, participants, including stakeholders, used prior literature and survey results to develop recommendations, including interventions to address clinician bias, implement geriatric assessment, and promote clinician and staff engagement as mechanisms to improve accrual of older adults to clinical trials.

Mechanical thrombectomy for large vessel occlusion between 6 and 24 h: outcome comparison of DEFUSE-3/DAWN eligible versus non-eligible patients.

The DEFUSE-3 and DAWN trials showed that mechanical thrombectomy (MT) improves the outcome of selected patients with anterior circulation large vessel occlusions (LVO) up to 24 h after stroke onset. However, it is unknown whether only those patients fulfilling the trial inclusion criteria benefit, or whether benefit is seen in a broader range of patients presenting between 6 and 24 h. We determined whether fulfilling the DEFUSE-3 and DAWN selection criteria affects outcomes in MT patients in clinical practice. We reviewed adult patients with LVO treated with MT between 6 and 24 h after stroke onset at five Swiss stroke centers between 2014 and 2021. We compared two groups: (1) patients who satisfied neither DEFUSE-3 nor DAWN criteria (NDND) and (2) those who satisfied DEFUSE-3 or DAWN criteria (DOD). We used logistic regression to examine the impact of trial eligibility on two safety outcomes (symptomatic intracranial hemorrhage [sICH] and all-cause mortality at 3 months) and two efficacy outcomes (modified Rankin Score [mRS] shift toward lower categories and mRS of 0-2 at 3 months). Of 174 patients who received MT, 102 (59%) belonged to the NDND group. Rates of sICH were similar between the NDND group and the DOD group (3% vs. 4%, p = 1.00). Multivariable regression revealed no differences in 3-month all-cause mortality (aOR 2.07, 95% CI 0.64-6.84, p = 0.23) or functional outcomes (mRS shift: acOR 0.81, 95% CI 0.37-1.79, p = 0.60; mRS 0-2: aOR 0.91, 95% CI 0.31-2.57, p = 0.85). Among adult patients with LVO treated with MT between 6 and 24 h, safety and efficacy outcomes were similar between DEFUSE-3/DAWN eligible and ineligible patients. Our data provide a compelling rationale for randomized trials with broader inclusion criteria for MT.

Multidisciplinary tumor board analysis: validation study of a central tool in tumor centers

The established standard to ensure state-of-the-art cancer treatment is through multidisciplinary tumor boards (TBs), although resource- and time-intensive. In this validation study, the multiple myeloma (MM)-TB was reexamined, aiming to validate our previous (2012–2014) results, now using the TB data from March 2020 to February 2021. We assessed MM-TB protocols, physicians’ documentation, patient, disease, remission status, progression-free survival (PFS), and overall survival (OS) as left-truncated survival times. Moreover, TB-adherence, level of evidence according to grade criteria, time requirements, study inclusion rates, and referral satisfaction were determined. Within a 1-year period, 312 discussed patients were documented in 439 TB protocols. Patient and disease characteristics were typical for comprehensive cancer centers. The percentages of patients discussed at initial diagnosis (ID), with disease recurrence or in need of interdisciplinary advice, were 39%, 28%, and 33%, respectively. Reasons for the MM-TB presentation were therapeutic challenges in 80% or staging/ID-defining questions in 20%. The numbers of presentations were mostly one in 73%, two in 20%, and three or more in 7%. The TB adherence rate was 93%. Reasons for non-adherence were related to patients’ decisions or challenging inclusion criteria for clinical trials. Additionally, we demonstrate that with the initiation of TBs, that the number of interdisciplinarily discussed patients increased, that TB-questions involve advice on the best treatment, and that levels of compliance and evidence can be as high as ≥ 90%. Advantages of TBs are that they may also improve patients’, referrers’, and physicians’ satisfaction, inclusion into clinical trials, and advance interdisciplinary projects, thereby encouraging cancer specialists to engage in them.

Characterization of Oncology Clinical Trials Using Germline Genetic Data

The recent successes of poly-ADP ribose polymerase (PARP) inhibitors and belzutifan support germline genetic data as an exciting, accessible source for biomarkers in cancer treatment. This study hypothesizes, however, that most oncology clinical trials using germline data largely prioritize BRCA1/2 as biomarkers and PARP inhibitors as therapy. To characterize past and ongoing oncology trials that use germline data. This retrospective cross-sectional study of oncology trials used the Informa Trialtrove database to evaluate trial attributes. Trials using germline information (including the terms germline, hereditary, or inherited in the title, treatment plan, interventions, end points, objectives, results, or notes) and conducted globally between December 1, 1990, and April 4, 2022 (data freeze date), were included. Trials by cancer type, phase, participants, sponsor type, end points, outcomes, and locations were described. Associated biomarkers and mechanisms of action for studied therapeutic interventions were counted. How germline data in trial inclusion and exclusion criteria are associated with end points, outcomes, and enrollment were also examined. A total of 887 of 84 297 (1.1%) oncology clinical trials in the Trialtrove database that use germline data were identified. Most trials were conducted in cancer types where PARP inhibitors are already approved. A total of 74.8% (672) of trials were performed in the phase 2 setting or above. Trials were primarily sponsored by industry (523 trials [59.0%]), academia (382 trials [43.1%]), and the government (274 trials [30.9%]), where trials may have multiple sponsor types. Among 343 trials using germline data with outcomes in Trialtrove, 180 (52.5%) reported meeting primary end points. Although BRCA1/2 are the most frequent biomarkers seen (BRCA1, 224 trials [25.3%]; BRCA2, 228 trials [25.7%]), trials also examine pharmacogenomic variants and germline mediators of somatic biomarkers. PARP inhibitors or immunotherapy were tested in 69.9% of trials; PARP inhibition was the most frequently studied mechanism (367 trials [41.4%]). An overwhelming number of trials using germline data were conducted in the US, Canada, and Europe vs other countries, mirroring disparities in cancer genetics data. Germline data in inclusion and exclusion criteria are associated with altered end point, outcomes, and enrollment compared with oncology trials with no germline data use. Examples of inclusion and exclusion criteria regarding germline data that may unintentionally exclude patients were identified. These findings suggest that for germline biomarkers to gain clinical relevance, trials must expand biomarkers, therapies, and populations under study.

Cladribine with Low Dose Cytarabine for Unfit Patients: A Safe and Effective Approach with Low Early Mortality in a Population Ineligible for Clinical Trials

Background Patients with newly diagnosed AML can often present with debilitating medical conditions, active infection, concurrent malignancies, significant cardiovascular disease, and poor performance status. There is a lack of trial options for these patients. Such patients would have been excluded from the VIALE-A trial, that studied HMA + venetoclax in older and unfit patients. Frontline cladribine (Clad) with low dose cytarabine (LDAC) alternating with decitabine yielded an overall response rate (ORR) of 68%, a median overall survival (OS) 13.8 months, and was well-tolerated, with a 4-week mortality of 1% in an older patient population. This combination potentially provides an avenue for therapy in an unfit patient population with significant comorbidities. Here we present the results of this phase II study in unfit patients, ineligible for other clinical trials. Methods Pts over 18 with newly diagnosed AML found to be ineligible for clinical trials due to severe comorbidity, active infection/malignancy, or poor PS were enrolled. To be eligible, pts must have at least 1 of the following: Cr ≥2mg/dL, Bilirubin ≥2 mg/dL, ECOG of 3 or 4, active infection, concurrent active malignancy, or ineligibility for a higher priority protocol. Induction consisted of Clad 5mg/m2 on D1-5 and LDAC 20mg SQ BID on D1-10. Consolidation consisted of Clad 5mg/m2 on D1-3 and LDAC 20mg SQ BID on D1-10 with pts receiving decitabine 20mg/m2 IV monotherapy on D1-5 on alternate cycles. The primary objective was 60-day mortality. Results Between 04/2020 and 05/2022, 33 pts have been enrolled. Baseline characteristics are in Table 1. The median age is 72 yrs (range: 44-82). Fulfilled eligibility criteria for study entry included: comorbidities [acute or chronic renal dysfunction in 7 (21%) pts, cardiac in 2 (6%) , hepatic in 2 (6%), and morbid obesity with advanced PS in 1 (3%) pt] in 12 pts (36%) concomitant (active) malignancy in 9 (27%), poor PS in 6 (18%) pts , active infection in 5 pts (15%), and numerous prior treatments for MDS in 1 pt (3%), making them ineligible for other trials. 15 (45%) had history of ongoing cardiovascular or renal disease. 14 (42%) pts had history of other malignancies. 11 (33%) pts had therapy-related disease. The median blast percent was 31% (range: 12-88). Adverse risk disease based on ELN 2017 criteria was overrepresented in the cohort, occurring in 70% of pts. Complex karyotype and TP53 mutations occurred in 18% and 21% of pts, respectively. The overall response rate (CR/CRi/PR) was 66% (22 pts) with a CR/CRi rate of 63% (21) and a CR rate of 33% (11). 30% (10) attained an MRD negative remission. The median cycles to response was 1 (range: 1-4). Of the pts that responded, 3 (9%) remain on-trial, 2 (6%) went on to allogeneic SCT, 5 (15%) proceeded to post-remission maintenance strategies, 5 (15%) relapsed, 5 (15%) died after infections, 1 (3%) died after falling and developing a subdural hematoma, and 1 (3) was taken off trial due to prolonged myelosuppression. At a median follow up of 14 months, the median OS and median RFS were 8.3 months (95% CI: 0.19-15.7) and 7.9 months (95% CI: 0.45-15.3) respectively. The OS for pts with ECOG 1, 2 and >3 PS was 8.3, 7.6 and 8.8 months respectively. Pts with significant cardiac or renal disease had worse OS at 3.03 months compared to 12.5 months (p = 0.03) in pts without this history. Grade ≥3 adverse events possibly related to this combination occurred in 2 patients: one with Grade 3 nausea and the second with Grade 3 tumor lysis syndrome. The 30-day and 60-day survival were 91% and 82%% respectively. Of the 6 patients (18%) that experienced 60-day mortality, 4 (12%) died from infection (2 with pneumonia and 2 with bacteremia), 1 (3%) patient died due to a heart failure exacerbation with a critical coronary artery stenosis, and 1 (3%) pt died after transitioning to another trial, developing a medullary lesion, and opting for hospice. Conclusions In an unfit patient population with numerous comorbidities, the combination of Clad and LDAC was well tolerated with a 60-day survival of 82%, an ORR of 66%, and a median OS of 8.3 months. Once in remission, patients were able to move onto maintenance therapy or SCT in an improved condition. This combination represents a potential option for treatment in a high-risk, unfit, and undertreated patient population and demonstrates the feasibility of safely expanding trial inclusion criteria for select populations of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparing pregnancy rates following ovarian stimulation with follitropin-Δ to follitropin -α in routine IVF: A retrospective analysis

Study objectivesFollitropin-Δ, a new recombinant follicle stimulation hormone, uses a fixed daily dose producing a predictable ovarian response while using less gonadotropins compared to follitropin-α. We report clinical outcomes comparing each in the routine IVF setting and further compare qualified to disqualified subjects based on previous randomized controlled trial (RCT) inclusion criteria. Study designRetrospective analysis of all cycles performed by a single provider between January 2020 to January 2021. All IVF cycles without patient inclusion–exclusion criteria were considered for the analysis. Clinical outcomes in two groups (follitropin-Δ vs follitropin-α ± 75 IU human menopausal gonadotropin (hMG) in expected poor responders) were compared. In addition, comparisons were made between qualified versus disqualified subgroups. ResultsNo differences in baseline demographics, number of MII oocytes, fertilization/MII oocyte, percent of good quality embryos were noted. Compared to those using follitropin-α, follitropin-Δ resulted in lower daily (170 vs 211 IU/d, p = 0.002) and total Gn used (1739 vs 2194 IU, p = 0.003). Optimal range response (8–14 oocytes) (22/44 [50 %] vs 78/203 [38.6 %]; p = 0.10) and fresh (fCP) and cumulative clinical pregnancy (cCP) rates per transfer (29.5 % vs 24.1 % and 35 % vs 25.1 %, p = 0.08) were similar between groups. Based on previous RCTs, those who would have qualified compared to those who would have disqualified, patients using follitropin-Δ were just as likely to have an optimal oocyte response (qualified: 48 % vs disqualified: 57.1 %) and resulted in similar cCP (41.4 % vs 25 %, p-0.23). ConclusionsWhile follitropin-Δ requires less daily and total dosing compared to follitropin-α, optimal range of retrieved oocytes and clinical outcomes appear to be comparable. Using RCT inclusion criteria, similar findings were noted in those who would have qualified compared to disqualified patients.

Eligibility for 177Lu-PSMA Therapy Depends on the Choice of Companion Diagnostic Tracer: A Comparison of 68Ga-PSMA-11 and 99mTc-MIP-1404 in Metastatic Castration-Resistant Prostate Cancer.

177Lu-prostate-specific membrane antigen-617 (177Lu-PSMA-617) is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC), with evidence of improved survival over standard care. The VISION trial inclusion criteria required a metastatic lesion-to-liver ratio of greater than 1 on 68Ga-PSMA-11 PET scans. We aimed to determine whether an equivalent ratio is suitable for a SPECT tracer, 99mTc-MIP-1404, and to compare lesion and lesion-to-normal-organ ratios between the 2 radiotracers. Methods: Two cohorts of patients with mCRPC matched for age, prostate-specific antigen level, and total Gleason score, with either 99mTc-MIP-1404 SPECT/CT (n = 25) or 68Ga-PSMA-11 PET/CT (n = 25) scans, were included for analysis. Up to 3 lesions in each site (prostate/prostate bed, lymph nodes, bone and soft-tissue metastases) as well as normal liver, parotid gland, spleen, and mediastinal blood-pool SUVmax were measured. Results: 99mTc-MIP-1404 SPECT lesion SUVmax was not significantly different from 68Ga-PSMA-11 PET (median, 18.2 vs. 17.3; P = 0.93). However, 99mTc-MIP-1404 liver SUVmax was higher (median, 8.5 vs. 5.8; P = 0.002) and lesion-to-liver ratios were lower (median, 2.7 vs. 3.5; P = 0.009). There was no significant difference in parotid gland or splenic SUVmax or lesion-to-parotid gland ratios between the 2 tracers although there was a small difference in lesion-to-spleen ratios (P = 0.034). Conclusion: There are differences in biodistribution and, in particular, liver activity, between 68Ga-PSMA-11 and 99mTc-MIP-1404. Therefore, if 99mTc-MIP-1404 is used to assess eligibility for 177Lu-PSMA-617 therapy, a lower adjusted lesion-to-liver ratio should be used.

Cohort Enrichment Strategies for Progressive Interstitial Lung Disease in Systemic Sclerosis From European Scleroderma Trials and Research

Enrichment strategies from clinical trials for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) have not been tested in a real-life cohort. Do enrichment strategies for progressive ILD impact efficacy, representativeness, and feasibility in patients with SSc-ILD from the European Scleroderma Trials and Research (EUSTAR) database? We applied the inclusion criteria of major recent SSc-ILD trials (Study of the Efficacy and Safety of Tocilizumab in Participants With Systemic Sclerosis [focuSSced], Scleroderma Lung Study II [SLS II], and Safety and Efficacy of Nintedanib in Systemic Sclerosis [SENSCIS]) and assessed progressive ILD, which was defined as absolute change in FVC and as significant progression (FVC decline≥10%). Data were compared with all patients and with patients who did not fulfill any inclusion criteria. In total, 2,258 patients with SSc-ILD were included: 31.2%of the patients met SENSCIS criteria; 5.8%of the patients met SLS II criteria; 1.6%of the patients met focuSSced criteria, and 67.7%(1,529) of the patients did not meet any criteria. In the first 12 ± 3months, the absolute FVC decline in all patients and in patients who fulfilled criteria from SENSCIS was -0.1%, in patients who fulfilled criteria from focuSSced was -3.7%, and in patients who fulfilled criteria from SLS II was 2.3%, with accompanying more progressors in focuSSced. The patient populations that fulfilled the different study inclusion criteria significantly differed in various clinical parameters. In the second 12-month period, SENSCIS-enriched patients had a further absolute FVC%decline as described for the total cohort. In contrast, patients who fulfilled the focuSSced and SLS II criteria showed numeric improvement of lung function. There were no significant associations of enrichment criteria and ILD progression. The application of enrichment criteria from previous clinical trials showed enrichment for progression with variable success, which led to selected patient populations reducing feasibility of recruitment. These findings are important for future clinical trial design and interpretation of the results of published trials.

Prevalence of diabetic nephropathy and subsequent cardiovascular outcomes: a nationwide study of 74,014 patients with type 2 diabetes

Abstract Background Nonsteroidal, selective mineralocorticoid receptor antagonists (MRAs) have been shown to reduce cardiovascular events among patients with diabetic nephropathy, a clinical syndrome characterized by persistent albuminuria. However, prior reports have suggested a substantial underuse of MRAs among eligible patients. In real-life, it is unknown how many have urinary excretion of albumin measured, and the cardiovascular outcomes among type 2 diabetes (T2D) patients with versus without albuminuria is relatively unknown. Purpose To identify candidates eligible for treatment with MRAs and compare the risk of cardiovascular events in real-life T2D patients with albuminuria versus without albuminuria. Methods Using the Danish nationwide registers, we identified all patients ≥18 years old with prevalent T2D at index date 1st January 2015 with an albumin-creatinine ratio (ACR) and a creatinine level measured within 365 days prior to the index date. For each patient, the last ACR and estimated glomerular filtration rate (eGFR) registered prior to the index date were used. eGFR was calculated using the CKD-EPI formula. The patients were separated into two groups consisting of patients with T2D with ACR ≥30 mg/g (albuminuria) or ACR<30 mg/g (no albuminuria), respectively. Outcomes for both groups were analyzed as time-to-event as a composite cardiovascular outcome of heart failure (HF), myocardial infarction (MI), stroke, and all-cause death and each component of the composite endpoint was analyzed individually. In both groups, we estimated the 4-year absolute risk of the cardiovascular outcome and the risk of experiencing HF, MI, and stroke. Results A total of 158,904 patients with T2D were identified and of those 74,014 patients (47%) had urinary ACR analyzed within the last year. Of those who had ACR analyzed 29,581 (40%) patients had albuminuria. The absolute 4-year risk of the composite cardiovascular outcome in patients with albuminuria and no albuminuria was 28.6% (95% confidence interval (CI): 28.1–29.1) versus 18.7% (95% CI: 18.4–19.1), respectively. The absolute 4-year risk for the individual components were HF 7.0% (95% CI: 6.7–7.3), MI 4.4% (95% CI: 4.2–4.6), and stroke 7.6% (95% CI: 7.3–7.9) for patients with albuminuria, versus HF 4.0% (95% CI: 3.8–4.2), MI 3.2% (95% CI: 3.1–3.4), and stroke 5.5% (95% CI: 5.3–5.7) for patients with no albuminuria. Conclusion In Denmark, only 47% of patients with T2D had ACR analyzed within a year indicating lack of adherence to the national T2D guidelines. A total of 40% of those who had albuminuria analyzed were eligible for treatment with MRAs based on trial inclusion criteria, and the absolute 4-year risk of experiencing a cardiovascular event was significant. However, patients with no albuminuria still displayed a substantial risk of experiencing a composite event of HF, MI, stroke, and all-cause death. Our analyses may have implications for implementation of new MRAs in patients with T2D. Funding Acknowledgement Type of funding sources: None.

Real-world eligibility and cost-effectiveness analysis for empagliflozin in patients with heart failure

Abstract Background/Introduction Empagliflozin was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for reducing cardiovascular mortality and heart failure (HF) hospitalization in both patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Purpose Limited data are available on the generalizability of empagliflozin to clinical practice. Therefore, we evaluated real-world eligibility and cost-effectiveness based on a nationwide prospective HF registry. Methods For the study, 3108 HFrEF and 2070 HFpEF patients from the Korean Acute Heart Failure (KorAHF) registry were analysed. Eligibility was estimated by FDA and EMA label criteria and by inclusion and exclusion criteria of EMPEROR-Reduced and EMPEROR-Preserved trials. The cost-effectiveness analysis was performed using the decision tree model, where effectiveness was the avoidance of the first hospitalization. Results Among the KorAHF patients, 91.4% met FDA & EMA label criteria, while 44.7% met the clinical trial criteria. The main factor for exclusion in the clinical trial-based empagliflozin eligibility was low systolic blood pressure, including 18.7% of HFrEF and 11.0% of HFpEF patients. Other factors were acute (<4 weeks) myocardial infarction and impaired renal function (eGFR <20 mL/min/1.73 m2 or requiring dialysis). The overall expected hospitalization rate and cost reduction were 3.6 and US$ 14,885 per 100 eligible HF patients per year. In HFrEF patients, hospitalization rate and cost reduction were 4.8 and US$ 28,442. However, in HFpEF, the cost was increased by US$ 7,576, while hospitalization reduction was 1.7. Conclusion(s) There is a large discrepancy of real-world eligibility for empagliflozin between FDA & EMA labels and clinical trial criteria. The cost-effectiveness benefit was more evident in patients with HFrEF than HFpEF. The efficacy and safety of empagliflozin in real-world patients should be further investigated for a broader range of clinical applications. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Minister of Science and Information and Communication Technologies (NRF-2021R1F1A1063430), by the Catholic Medical Center Research Foundation (2022), and by the Research of Korea Centers for Disease Control and Prevention (2010-E63003-00, 2011-E63002-00, 2012-E63005-00, 2013-E6300300, 2014-E63003-01, 2015-E63003-02, 2016-ER6303-00, and 2017-ER6303-01).

The influence of baseline characteristics, treatment and depression on health-related quality of life in patients with multiple myeloma: a prospective observational study

BackgroundMultiple myeloma (MM) is the third most common hematologic malignancy with increasing importance due to improving treatment strategies and long-term outcomes in an aging population. This study aims to analyse influencing factors on health-related quality of life (HRQoL), such as treatment strategies, participation in a clinical trial and patient characteristics like anxiety, depression, gender, and age. A better understanding of the individual factors in context with HRQoL could provide a helpful instrument for clinical decisions.MethodsIn this prospective observational study, the HRQoL of MM patients with different therapies (first-line and relapse) was quantified by standardized questionnaires (EORTC QLQ-C30 and -MY20) in the context of sociodemographic data, individual anxiety and depressiveness (PHQ-4), and a selected number of clinical parameters and symptoms at defined time-points before, during, and after therapy.ResultsIn total, 70 patients were included in the study. The median age of the study cohort was 62 years. 44% were female and 56% were male patients. More than half of the patients were fully active with an ECOG 0. Global health status was significantly higher in patients with first-line treatment and even increased after start of therapy, while the pain level decreased. In contrast, patients with relapsed MM reported a decreasing global health status and increasing pain. Additionally, there was a higher global health status in less anxious/depressive patients. HRQoL decreased significantly after start of chemotherapy in the parameters body image, side effects of treatment, and cognitive functioning. Tandem stem-cell transplantation was not found to be a risk factor for higher impairment of HRQoL. Participation in a clinical study led to an improvement of most aspects of HRQoL. Among others, increased anxiety and depression, female gender, older age, impaired performance status, and recurrent disease can be early indicators for a reduced HRQoL.ConclusionThis study showed the importance of regular longitudinal assessments of patient reported outcomes (PROs) in routine clinical care. For the first time, to our knowledge, we were able to demonstrate a potential impact between participation in clinical trials and HRQoL. However, due to frequently restrictive inclusion criteria for clinical trials, these MM patients might not be directly comparable with patients treated within standard therapy concepts. Further studies are needed to clarify the relevance of this preliminary data in order to develop an individualized, patient-centred, therapy concept.

Qualitative validation of the modified Medical Research Council (mMRC) dyspnoea scale as a patient-reported measure of breathlessness severity

IntroductionThe modified Medical Research Council (mMRC) dyspnoea scale is a measure of breathlessness severity recommended by guidelines and utilised as an inclusion criterion or endpoint for clinical trials. No studies have been conducted to validate the categorical descriptors against the dyspnoea severity grade. MethodsThis study utilised cognitive interviews (Think Aloud method) to assess the content validity of the mMRC scale among 16 participants (13 with cardiac/respiratory disease). Participants were recruited to achieve representation across a variety of demographic factors. Interviews were conducted remotely via video conferencing and participants were presented with all 5 mMRC descriptors on screen in random order then asked to rank the statements “in order from the best breathing to the worst breathing”. ResultsMean age of participants was 57 years (range 22–84 years). Eleven had multimorbidity (≥2 comorbidities) including COPD, asthma, lung cancer, lung infection, interstitial lung disease, heart failure, depression, and anxiety. Length of time with breathlessness ranged between 2 weeks and >25 years. The median rank of the mMRC grade descriptors was concordant for mMRC grades 0, 1 and 4 but not grades 2 and 3. Even so, substantial heterogeneity was found in the distribution of responses for mMRC grade 0. ConclusionOur study found substantial heterogeneity in participant grading of the mMRC descriptors, particularly for grades 0, 2 and 3, indicating that mMRC might not be a good discriminator of difference or change in dyspnoea severity. This study demonstrates the importance of content validation even for long-established PROs like mMRC.

Detecting glaucoma with only OCT: Implications for the clinic, research, screening, and AI development.

A method for detecting glaucoma based only on optical coherence tomography (OCT) is of potential value for routine clinical decisions, for inclusion criteria for research studies and trials, for large-scale clinical screening, as well as for the development of artificial intelligence (AI) decision models. Recent work suggests that the OCT probability (p-) maps, also known as deviation maps, can play a key role in an OCT-based method. However, artifacts seen on the p-maps of healthy control eyes can resemble patterns of damage due to glaucoma. We document in section 2 that these glaucoma-like artifacts are relatively common and are probably due to normal anatomical variations in healthy eyes. We also introduce a simple anatomical artifact model based upon known anatomical variations to help distinguish these artifacts from actual glaucomatous damage. In section 3, we apply this model to an OCT-based method for detecting glaucoma that starts with an examination of the retinal nerve fiber layer (RNFL) p-map. While this method requires a judgment by the clinician, sections 4 and 5 describe automated methods that do not. In section 4, the simple model helps explain the relatively poor performance of commonly employed summary statistics, including circumpapillary RNFL thickness. In section 5, the model helps account for the success of an AI deep learning model, which in turn validates our focus on the RNFL p-map. Finally, in section 6 we consider the implications of OCT-based methods for the clinic, research, screening, and the development of AI models.

Suppression of bile acid synthesis as a tipping point in the disease course of primary sclerosing cholangitis

Background & AimsFarnesoid X receptor (FXR) agonists and fibroblast growth factor 19 (FGF19) analogues suppress bile acid synthesis and are being investigated for their potential therapeutic efficacy in cholestatic liver diseases. We investigated whether bile acid synthesis associated with outcomes in 2 independent populations of people with primary sclerosing cholangitis (PSC) not receiving such therapy.MethodsConcentrations of individual bile acids and 7α-hydroxy-4-cholesten-3-one (C4) were measured in blood samples from 330 patients with PSC attending tertiary care hospitals in the discovery and validation cohorts and from 100 healthy donors. We used a predefined multivariable Cox proportional hazards model to evaluate the prognostic value of C4 to predict liver transplantation-free survival and evaluated its performance in the validation cohort.ResultsThe bile acid synthesis marker C4 was negatively associated with total bile acids. Patients with fully suppressed bile acid synthesis had strongly elevated total bile acids and short liver transplantation-free survival. In multivariable models, a 50% reduction in C4 corresponded to increased hazards for liver transplantation or death in both the discovery (adjusted hazard ratio [HR] = 1.24, 95% CI 1.06–1.43) and validation (adjusted HR = 1.23, 95% CI 1.03–1.47) cohorts. Adding C4 to established risk scores added value to predict future events, and predicted survival probabilities were well calibrated externally. There was no discernible impact of ursodeoxycholic acid treatment on bile acid synthesis.ConclusionsBile acid accumulation-associated suppression of bile acid synthesis was apparent in patients with advanced PSC and associated with reduced transplantation-free survival. In a subset of the patients, bile acid synthesis was likely suppressed beyond a tipping point at which any further pharmacological suppression may be futile. Implications for patient stratification and inclusion criteria for clinical trials in PSC warrant further investigation.Lay summaryWe show, by measuring the level of the metabolite C4 in the blood from patients with primary sclerosing cholangitis (PSC), that low production of bile acids in the liver predicts a more rapid progression to severe disease. Many people with PSC appear to have fully suppressed bile acid production, and both established and new drugs that aim to reduce bile acid production may therefore be futile for them. We propose C4 as a test to find those likely to respond to these treatments.

COVID-19 Vaccine Clinical Trials: A Bird's Eye Perspective.

Several Phase-III clinical studies investigating vaccine safety and effectiveness have been published a year following the first breakout of the COVID-19 pandemic. These vaccine candidates were produced using a variety of vaccination technologies, including mRNA, recombinant protein, adenoviral vector, and inactivated virus-based platforms, by various research organizations and pharmaceutical firms. Despite many successful clinical studies, participants are restricted by trial inclusion and exclusion criteria, geographic location, and the current state of the virus epidemic. Many concerns remain, particularly for specific populations such as the elderly, women who are pregnant or nursing, and teenagers. Vaccine effectiveness against asymptomatic infection and particular viral variations, on the other hand, is still largely unclear. This review will focus on vaccination candidates that have completed Phase-III clinical trials and will examine the scientific evidence that has been gathered so far for these vaccine candidates for various subgroups of individuals and virus variations.

Towards a validated definition of the clinical transition to secondary progressive multiple sclerosis: A study from the Italian MS Register

Background: Definitions for reliable identification of transition from relapsing-remitting multiple sclerosis (MS) to secondary progressive (SP)MS in clinical cohorts are not available. Objectives: To compare diagnostic performances of two different data-driven SPMS definitions. Methods: Data-driven SPMS definitions based on a version of Lorscheider’s algorithm (DDA) and on the EXPAND trial inclusion criteria were compared, using the neurologist’s definition (ND) as gold standard, in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Akaike information criterion (AIC) and area under the curve (AUC). Results: A cohort of 10,240 MS patients with ⩾5 years of follow-up was extracted from the Italian MS Registry; 880 (8.5%) patients were classified as SPMS according to the neurologist definition, 1806 (17.6%) applying the DDA and 1134 (11.0%) with the EXPAND definition. The DDA showed greater discrimination power (AUC: 0.8 vs 0.6) and a higher sensitivity (77.1% vs 38.0%) than the EXPAND definition, with similar specificity (88.0% vs 91.5%). PPV and NPV were higher using the DDA than considering EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%). Conclusion: Data-driven definitions demonstrated greater ability to capture SP transition than neurologist’s definition and the global accuracy of DDA seems to be higher than the EXPAND definition.

Tau positron emission tomography in preclinical Alzheimer's disease.

Rates of tau accumulation in cognitively unimpaired older adults are subtle, with magnitude and spatial patterns varying in recent reports. Regional accumulation also likely varies in the degree to which accumulation is amyloid-β-dependent. Thus, there is a need to evaluate the pattern and consistency of tau accumulation across multiple cognitively unimpaired cohorts and how these patterns relate to amyloid burden, in order to design optimal tau end points for clinical trials. Using three large cohorts of cognitively unimpaired older adults, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and companion study, Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (n = 447), the Alzheimer's Disease Neuroimaging Initiative (n = 420) and the Harvard Aging Brain Study (n = 190), we attempted to identify regions with high rates of tau accumulation and estimate how these rates evolve over a continuous spectrum of baseline amyloid deposition. Optimal combinations of regions, tailored to multiple ranges of baseline amyloid burden as hypothetical clinical trial inclusion criteria, were tested and validated. The inferior temporal cortex, fusiform gyrus and middle temporal cortex had the largest effect sizes of accumulation in both longitudinal cohorts when considered individually. When tau regions of interest were combined to find composite weights to maximize the effect size of tau change over time, both longitudinal studies exhibited a similar pattern-inferior temporal cortex, almost exclusively, was optimal for participants with mildly elevated amyloid β levels. For participants with highly elevated baseline amyloid β levels, combined optimal composite weights were 53% inferior temporal cortex, 31% amygdala and 16% fusiform. At mildly elevated levels of baseline amyloid β, a sample size of 200/group required a treatment effect of 0.40-0.45 (40-45% slowing of tau accumulation) to power an 18-month trial using the optimized composite. Neither a temporal lobe composite nor a global composite reached 80% power with 200/group with an effect size under 0.5. The focus of early tau accumulation on the medial temporal lobe has resulted from the observation that the entorhinal cortex is the initial site to show abnormal levels of tau with age. However, these abnormal levels do not appear to be the result of a high rate of accumulation in the short term, but possibly a more moderate rate occurring early with respect to age. While the entorhinal cortex plays a central role in the early appearance of tau, it may be the inferior temporal cortex that is the critical region for rapid tau accumulation in preclinical Alzheimer's disease.