Screening Failure Research Articles

Brexpiprazole and Sertraline Combination Treatment in Posttraumatic Stress Disorder: A Phase 3 Randomized Clinical Trial.

New pharmacotherapy options are needed for posttraumatic stress disorder (PTSD). To investigate the efficacy, safety, and tolerability of brexpiprazole and sertraline combination treatment (brexpiprazole + sertraline) compared with sertraline + placebo for PTSD. This was a parallel-design, double-blind, randomized clinical trial conducted from October 2019 to August 2023. The study had a 1-week, placebo run-in period followed by an 11-week, double-blind, randomized, active-controlled, parallel-arm period (with 21-day follow-up) and took place at 86 clinical trial sites in the US. Adult outpatients with PTSD were enrolled (volunteer sample). Oral brexpiprazole 2 to 3 mg per day (flexible dose) + sertraline 150 mg per day or sertraline 150 mg per day + placebo (1:1 ratio) for 11 weeks. The primary end point was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score (which measures the severity of 20 PTSD symptoms) from randomization (week 1) to week 10 for brexpiprazole + sertraline vs sertraline + placebo. Safety assessments included adverse events. A total of 1327 individuals were assessed for eligibility. After 878 screen failures, 416 participants (mean [SD] age, 37.4 [11.9] years; 310 female [74.5%]) were randomized. Completion rates were 137 of 214 participants (64.0%) for brexpiprazole + sertraline and 113 of 202 participants (55.9%) for sertraline + placebo. At week 10, brexpiprazole + sertraline demonstrated statistically significant greater improvement in CAPS-5 total score (mean [SD] at randomization, 38.4 [7.2]; LS mean [SE] change, -19.2 [1.2]; n = 148) than sertraline + placebo (randomization, 38.7 [7.8]; change, -13.6 [1.2]; n = 134), with LS mean difference, -5.59 (95% CI, -8.79 to -2.38; P < .001). All key secondary and other efficacy end points were also met. Treatment-emergent adverse events with incidence of 5% or greater for brexpiprazole + sertraline (and corresponding incidences for sertraline + placebo) were nausea (25 of 205 [12.2%] and 23 of 196 [11.7%]), fatigue (14 of 205 [6.8%] and 8 of 196 [4.1%]), weight increase (12 of 205 [5.9%] and 3 of 196 [1.5%]), and somnolence (11 of 205 [5.4%] and 5 of 196 [2.6%]). Discontinuation rates due to adverse events were 8 of 205 participants (3.9%) for brexpiprazole + sertraline and 20 of 196 participants (10.2%) for sertraline + placebo. Results of this randomized clinical trial show that brexpiprazole + sertraline combination treatment statistically significantly improved PTSD symptoms vs sertraline + placebo, indicating its potential as a new efficacious treatment for PTSD. Brexpiprazole + sertraline was tolerated by most participants, with a safety profile consistent with that of brexpiprazole in approved indications. ClinicalTrials.gov Identifier: NCT04124614.

School-based hearing screening of first-grade students in Saudi Arabia: A pilot study.

Hearing loss in children is a global concern. Early identification and intervention are critical for minimising the adverse effects of hearing loss. Despite the implementation of hearing screening programmes in Saudi Arabia, more research is needed on the audiological profiles of first-grade students. This study aimed to characterize the audiological profile of first-grade students in Saudi Arabia and to raise awareness among parents, schools, and decision-makers about the need for hearing screening programs and the implementation of an effective monitoring and management system in the country. This cross-sectional descriptive study assessed the audiological profile of 308 first-grade students in Riyadh, the capital of Saudi Arabia, using pure-tone audiometry (PTA) and tympanometry. Additionally, two questionnaire-based assessments, one for parents and one for the home teacher, were developed to predict students who failed PTA. Among the students screened, 26.3% failed PTA. Tympanometry identified abnormal middle ear function in 30.5% of the students. The discrimination capacity of both questionnaires in identifying students who failed PTA screening was poor. A 26.3% prevalence rate of PTA screening failure, and a 30.5% of middle ear pathologies were noted. Both parent and teacher questionnaires were ineffective tools for identifying hearing loss among first-grade children who failed PTA screening.Contribution:This pilot study recommends that primary schools incorporate hearing screening as a regular practice of their preventative healthcare system. The study emphasises the importance of establishing international standards for school-based hearing screening to enhance its efficacy and develop more effective hearing screening questionnaires.

Risk Factors for Hearing Screen Failure in a Single Family Room Neonatal Intensive Care Unit.

To determine hearing screen outcomes and identify clinical and environmental risk factors for hearing screen failure in very preterm infants at a level IV single family room (SFR) neonatal intensive care unit (NICU). We conducted a retrospective study of infants <33wks gestational age admitted to a level IV SFR NICU who survived to discharge and had automated auditory brainstem response results available. Demographics, antenatal and postnatal factors, and respiratory support modes and their duration were collected from the electronic medical record. Of 425 eligible infants with documented hearing screen results, 353 (83%) passed and 72 (17%) failed the hearing screen [unilateral, N= 44 (61%); bilateral, N= 28 (39%)]. Compared to infants who passed the hearing screen, infants with hearing screen failure were lower gestational age and birthweight, male sex, were screened at later postnatal and postmenstrual ages, had lower 1 and 5 min Apgar scores, longer duration of furosemide therapy, early hypotension, IVH≥ Grade 3, and BPD at 36 weeks PMA. Infants with hearing screen failure experienced longer exposures to invasive and non-invasive respiratory support. Heated, humidified, high flow nasal cannula >2LPM exposure was significantly longer in infants with bilateral hearing screen failure (18.4±18.4 d) compared to duration in infants who passed (7.4±12.8 d) and those with unilateral failure (9±13 d), (mean ± SD, p<0.001). In the final logistic model, IVH ≥Grade 3 (OR 3.22, 95% CI 1.15-8.98, p=0.026) and BPD (OR 2.27, 95% CI 1.25-4.11, p=0.007) were the factors with greatest risk for hearing screen failure. We speculate that the association of BPD with hearing screen failure may be mediated, in part, by chronic noise exposure, including from respiratory support devices. Attention to hearing protection in at-risk infants during respiratory support may mitigate the risk of hearing loss.

Associations between School-Based Vision Program Outcomes and School Characteristics in 410 Schools.

School-based vision programs (SBVPs) deliver vision care services directly to students at school, helping address disparities in access to pediatric vision care. We aim to evaluate the associations between SBVP outcomes and school-level characteristics. Retrospective cross-sectional data analysis PARTICIPANTS: Public schools with at least 50 SBVP-enrolled students 5 to 22 years old with complete demographic data. Schools with fewer than 60% of total grade levels served by the SBVP were excluded, resulting in a sample of 410 schools. Vision screening and eye exam data were extracted from Helen Keller International's United States Vision Program dataset from 2016 through 2022. Individual student data were aggregated to characterize each school's SBVP outcomes and analyzed with schools' publicly available socioeconomic and demographic data (student body race and ethnicity composition, proportion of students qualifying for free and reduced-price meals [FARM%], and proportion of English Language Learners). Descriptive statistics summarized SBVP outcomes. Fractional regression models were utilized to understand associations between SBVP outcomes and school characteristics. SBVP outcomes were rates of vision screening failure, eyeglasses prescription, and community eye care referral among each school's SBVP-enrolled students. We evaluated 151 (36.8%) elementary, 155 (37.8%) middle, and 104 (25.4%) high schools, with a median FARM% of 87.4% and a plurality of Hispanic students in 61.0% of schools. Overall median rates of vision screening failure, eyeglasses prescription, and referral were 38.4%, 25.2%, and 5.4%, respectively. High schools were associated with increased screening failure and eyeglasses prescription rates and a decrease in referral rate, compared with elementary schools. In multivariate analysis, each 10% increase in FARM% was associated with a 2.6% (95% confidence interval [CI]: 1.54-3.65), 1.8% (CI: 0.87-2.74), and 0.86% (CI: 0.36-1.36) increase in screening failure, eyeglasses prescription, and referral rates, respectively. There is significant vision care demand among public schools, especially those with student populations from lower socioeconomic backgrounds. SBVPs are important in bridging the gap in pediatric vision care access in such populations. Our findings demonstrated opportunities to allocate program staffing and equipment resources according to schools' anticipated needs, thus maximizing SBVPs' impact in delivering pediatric vision care.

Implementation of a Multidisciplinary Cardiogenic Shock Team in a non-academic Canadian Heart Center: An Implementation Study

BACKGROUNDWe evaluated our ability to implement a cardiogenic shock (CS-Team) focussing on i) early screening, ii) CS-Team activation and iii) use of invasive monitoring to guide therapy. METHODSAll patients admitted to the Coronary Care Unit (CCU) over 12-months were screened for CS. A diagnosis of CS was made when both hypotension and hypoperfusion was present. The CS-team was composed of CCU attending, Interventional Cardiologist and Cardiac Surgeon. Multivariate analysis was carried out with mortality as the outcome of interest. RESULTSScreening was documented in 74% of patients admitted to the CCU (1160/1562); of these, 1080 were not in CS. We identified 80 patients in CS (SCAI stages C-E) which represented 6.9% of all screened patients. CS patients had significantly higher in-hospital mortality (35% vs. 2%, p<0.0001). CS-Team was activated in 35/80 patients (44%). CS-Team activation resulted in significantly higher use of invasive monitoring (pulmonary artery catheter (PAC) = 49% vs. 7%, p<0.0001), cardiac catheterization (94% vs. 76%, p<0.032) and mechanical circulatory support (51% vs. 2%, p<0.001). Independent predictors of mortality were severity of CS (SCAI D or E) (OR 18.78 (4.89-96.65)) and age in years (OR 1.07(1.01-1.14)) while CS-Team was not predictive of mortality (OR 0.66 (0.16-2.41)). CONCLUSIONWe demonstrate that i) early screening by front line staff is feasible but has limitations (26% screening failure), ii) CS-Team activation appears discretionary (limited activation to 45% of patients), and iii) CS-Team activation resulted in significant increase in the use of invasive monitoring that helped guide therapy.

Transcatheter mitral replacement: what are the outcomes of un-eligible patients compared to treated?

Abstract Background/Introduction Transcatheter mitral valve replacement (TMVR) is emerging in recent years as a promising tool to treat mitral regurgitation, however its applicability in the real world remains limited. Purpose The aim of the study is to assess the real-world screening success rate of TMVR in native anatomy and the 1-year outcomes of both accepted and refused patients as well as clinical results. Methods Retrospective analysis was performed on all patients screened for TMVR at our Valve Center, eligible for 1-year follow-up. In-hospital data of all patients admitted to our Department are prospectively collected. Follow-up was done through outpatient visits and/or telephone calls. Results Out of 3400 patients referred to mitral treatment at our department between January 2016-January 2022, 92 were submitted to screening for TMVR. Among these, 48 patients (49%) were accepted and treated with TMVR while 44 (44.8%) were refused (RG). The main reasons for rejection were anatomy unfeasibility in 25 patients (59%) and frailty in 5(11%). Main reasons for anatomy unfeasibility were risk LVOT obstruction (n=15; 60%), annular dimension (n=8; 33%) and ventricular dimension (n=2; 8,3%).Major baseline characteristics between groups were similar including age (85 vs 84), STS (12 vs 13), ejection fraction and LVEDD. However, refused patients had higher filtration rate than TMVR (80 vs 45 ml/min respectively (p=0.001)).All patients accepted were treated with TMVR: 7 patients received Tiara and 24 Tendyne. Procedure success in the TMVR group was 96% (46/48). Patients refused from TMVR were treated with Mitraclip in 5(11%) cases, 37(84%) were left in medical therapy and 2 (4,5%) underwent surgery. 1-year overall survival 65.2±51.3 vs 54.8±36.5 in TMVR and refused group respectively (p=0.002)(Figure 1). 6 deaths (2 cardiac, 33%) occurred in the TMVR compared to 37 (32 cardiac, 86%) in the refused group. Freedom from Cardiac death was 98±19% TMVR vs 75±65% (p&amp;lt;0.001)(Figure 2). NYHA class improved in 98% of cases in TMVR group but worsened in 80% in refused group, (p&amp;lt;0.001). TMVR screening failure is associated with increased cardiac death (HR 12 [1,51;95], p&amp;lt;0,019) and death for any causes (HR 17,5 [6,02;51], p&amp;lt;0,001). Conclusion(s) In the present experience, approximately 50% of patients screened for TMVR were accepted. The most frequent reasons for screening failure were anatomical issues. With a baseline similar clinical profile, treatment with TMVR provided significant 1-year survival and symptoms improvement compared to those of patients refused, whose prognosis is indeed remarkably poor. These data underline the importance of proper patient selection for TMVR to achieve good outcomes but also the need for technological improvement of devices to expand the proportion of patients who can be treated. Given the small numbers currently available, more data are needed to confirm the present findings, which must be considered hypothesis-generating.Figure 1Figure 2

Combination of the chemokine receptor type 2 (CCR2) antagonist DMX-200 and candesartan for COVID-19: a randomised controlled trial

ObjectiveTo determine whether a chemokine receptor type 2 antagonist, DMX-200 (repagermanium), in combination with an angiotensin receptor blocker, candesartan, improves clinical outcomes in people with COVID-19.DesignProspective, multicentre, double-blind, placebo-controlled trial.SettingTen...

Screen Failures and Causes in Inflammatory Bowel Disease Randomized Controlled Trials: A Study of 16913 Screened Patients.

While recruitment rates in inflammatory bowel disease (IBD) trials are continuously decreasing, the underlying reasons are likely multifactorial but remain poorly defined. Screen failure (SF) proportions and causes have not been extensively explored in IBD. We assessed SF proportions and underlying SF reasons in IBD phase 2 and 3 clinical trials. We analyzed SF-related data from 17 randomized controlled phase 2 or 3 IBD trials. Twelve trials were in ulcerative colitis (UC) and 5 trials were in Crohn's disease (CD) operated by a single contract research organization, IQVIA. Differences between patient groups were tested for significance by Mann-Whitney and Fisher's tests when appropriate. We analyzed a total of 11 161 patients with UC and 5752 patients with CD. The mean SF proportion was 0.43 per trial in UC. The primary reason for SFs in UC was not meeting the overall (modified) Mayo score inclusion threshold and/or the endoscopic subscore of at least 2 (33.8% of all SF). In CD clinical trials, the mean SF proportion was at 0.53. The primary cause for SFs was not meeting the CDAI eligibility criteria (23.1% of all SFs). SF proportions were significantly higher in CD versus UC trials (P = .027). Clostridium difficile or any other intestinal infection and not meeting tuberculosis screening criteria were other major reasons for SFs both in UC and CD. High SF proportion in IBD clinical trials, particularly for CD studies, pose obstacles to patient recruitment. While underlying causes are diverse, arbitrarily defined clinical and/or endoscopic eligibility criteria remain the major limiting factors.

Risk of Hearing Loss in Neonates and Toddlers with in Utero Exposure to SARS-CoV-2.

Given the prevalence of neonatal hearing loss (HL) associated with intrauterine viral exposures, the goal of this study is to provide information on neonatal HL in the context of the COVID-19 pandemic. Data were drawn from the COVID-19 Mother Baby Outcomes (COMBO) Initiative. 1007 participants completed the newborn hearing screen as part of routine clinical care (COMBO-EHR cohort) and 555 completed the National Survey of Children's Health (NSCH) at 2 and/or 3 years of age for research purposes (COMBO-RSCH cohort). Maternal SARS-CoV-2 infection status during pregnancy was determined through electronic health records and maternal-reported questionnaires. In adjusted multivariate logistic regression models covarying for newborn age at assessment, mode of delivery, and gestational age at delivery, there was no significant association between intrauterine SARS-CoV-2 exposure and newborn hearing screening failure (OR = 1.05, 95% CI = 0.39-2.42, p = 0.91) in the COMBO-EHR cohort. In the COMBO-RSCH cohort, there were similar non-significant associations between intrauterine exposure to SARS-CoV-2 and maternal-reported concern for HL on the NSCH (OR = 1.19 [95% CI = 0.30-4.24], p = 0.79). There is no association between intrauterine exposure to SARS-CoV-2 and failed hearing screen in neonates. Similarly, based on the NSCH, there is no association between intrauterine exposure to SARS-CoV-2 and maternal-reported concern for hearing in toddlers. These results offer reassurance given the widespread nature of this pandemic with tens of millions of fetuses having a history of intrauterine exposure. Level 4 Laryngoscope, 2024.

Uterine fibroids and non-informative cell-free DNA screening results.

Uterine fibroids are monoclonal tumors, which are often genetically abnormal and associated with false-positive genome-wide cell-free DNA (cfDNA) screening results, particularly when large. It is plausible that fibroids may also increase the risk of cfDNA failure by affecting fetal fraction or due to their genetic anomalies confounding cfDNA algorithms. We aimed to investigate a possible association between fibroids and cfDNA non-informative results. This was a retrospective cohort study of women undergoing cfDNA screening for fetal chromosomal abnormalities between 2013 and 2020, comparing pregnancies with vs without uterine fibroids recorded on any obstetric ultrasound before 24 weeks' gestation. Univariable and multivariable logistic regression models were used to investigate the association between fibroids and cfDNA failure, adjusting for gestational age, maternal age, weight and height at blood sampling, mode of conception, multiple gestation and test platform (chromosome-selective or genome-wide). Analyses were stratified according to the number of fibroids and total fibroid volume. The impact of fibroids on fetal fraction was assessed using linear regression, adjusting for the same covariates. Among 19 818 pregnancies undergoing cfDNA screening, fibroids were reported in 2038 (10.28%) and cfDNA failure at the first screening attempt occurred in 228 (1.15%) pregnancies. Non-informative results occurred in 1.96% of pregnancies with fibroids and 1.06% of pregnancies without fibroids (adjusted odds ratio (aOR), 2.40 (95% CI, 1.65-3.48)). The risk of failure in the first screening attempt increased progressively with the number of fibroids (aOR, 5.05 (95% CI, 2.29-11.13) in women with four or more fibroids) and total fibroid volume, with greater than a 5-fold and 14-fold increase in risk among women with fibroid volumes of 100.1-400 mL (aOR, 5.52 (95% CI, 2.30-13.25)) and > 400 mL (aOR, 14.80 (95% CI, 4.50-48.69)), respectively. Although test failure was more common with chromosome-selective than genome-wide screening, fibroids similarly increased the risk of failure of both screening platforms. Compared to pregnancies without fibroids, those with fibroids had a fetal fraction on average 0.61% lower (adjusted mean difference, -0.61% (95% CI, -0.77% to -0.45%)). Uterine fibroids are associated with lower fetal fraction and an increased risk of cfDNA screening failure. The strength of this association increases with increasing fibroid number and volume. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Pharmaceutical care in the screening process of phase I oncohaematological clinical trials

ObjectiveTo determine the pharmaceutical interventions in patients eligible for phase I cancer clinical trials, focusing specifically on exclusion criteria related to medication or relevant interactions.MethodDescriptive, observational study conducted at a...

Newborn concurrent hearing and genetic screening for hearing impairment: A systematic review and meta‑analysis.

Hearing loss is the most prevalent neurosensory disorder in humans, with significant implications for language, social and cognitive development if not diagnosed and treated early. The present systematic review and meta-analysis aimed to determine the rate of hearing screening pass and genetic screening failure [universal newborn hearing screening (UNHS) pass/genetic failure] and to investigate the advantages of combining newborn hearing and genetic screening for newborn hearing impairment. The PubMed, Embase and Cochrane databases were searched from inception to September 2023 to identify studies reporting the combination of neonatal hearing screening with genetic screening. Duplicate literature, unpublished literature, studies with incomplete data, animal experiments, literature reviews and systematic studies were excluded. All the data were processed by STATA15.1 statistical software. A total of nine cross-sectional studies were included in this meta-analysis. The sample sizes ranged from 1,716 to 180,469, and there were a total of 377,688 participants. The pooled results revealed that the prevalence of passing the UNHS while failing genetic screening was 0.31% (95% CI, 0.22-0.41%). The prevalence of UNHS pass and gap junction protein beta 2 and solute carrier family 26 member 4 variant screen failure was 0.01% (95% CI, 0.00-0.02%) and 0.00% (95% CI, 0.00%), respectively, while the prevalence of mitochondrially encoded 12S RRNA variant screening failure and UNHS pass was 0.21% (95% CI, 0.18-0.26%). Combined screening has a significant advantage over pure hearing screening, especially in terms of identifying newborns with mitochondrial gene mutations that render them sensitive to certain medications. In clinical practice, decision-makers can consider practical circumstances and leverage the benefits of combined newborn hearing and genetic screening for early diagnosis, early counseling, and early intervention in patients with hearing loss.

Efficacy and safety of the subcutaneous implantable cardioverter-defibrillator in patients with and without obesity: A meta-analysis

BackgroundThe subcutaneous implantable cardioverter-defibrillator (S-ICD) has emerged as an alternative to transvenous systems for prevention of sudden cardiac death. However, concerns have been raised regarding its efficacy and safety in obese individuals. ObjectiveThe purpose of this study was to perform a meta-analysis to evaluate the efficacy and safety of the S-ICD in patients with obesity by assessing the relationship between body mass index (BMI) and clinical outcomes. MethodsA comprehensive search of multiple databases was conducted for English-language peer-reviewed studies reporting clinical outcomes in S-ICD recipients with (BMI ≥30 kg/m2) and without obesity (BMI <30 kg/m2). Data on preimplantation screening failure, defibrillation testing, complications, appropriate and inappropriate shocks, and survival were analyzed using standard, random-effects, meta-analytical techniques. ResultsTwenty-nine studies involving 20,486 patients were included. There was no statistically significant difference in mean BMI values of patients with failed or successful preimplantation screening (mean difference –0.60 kg/m2; 95% confidence interval [CI] –2.06 to 0.86). Obesity was associated with higher rates of failed defibrillation testing at ≤65 J (odds ratio [OR] 2.16; 95% CI 1.39–3.35), and malpositioning/suboptimal positioning occurred more frequently in obese compared to nonobese patients (OR 3.37; 95% CI 1.76–6.44). Increased BMI as a continuous variable (per increase in 1 kg/m2 BMI) was associated with elevated defibrillation thresholds (OR 1.05; 95% CI 1.03–1.08); higher risk of complications (hazard ratio [HR] 1.04; 95% CI 1.02–1.05); a trend toward an increased number of appropriate shocks (HR 1.02; 95% CI 1.00–1.04); and no significant increase in the risk of inappropriate shocks (HR 1.01; 95% CI 0.99–1.03). ConclusionThis meta-analysis underscores the importance of considering obesity in S-ICD implantation decisions. Although S-ICD remains effective in obese patients, attention to potential technical challenges and higher complication rates is warranted.

Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers. A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration. A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing. Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.

Screening failure in clinical trials for patients with head and neck squamous cell carcinoma: A retrospective analysis.

e18009 Background: Clinical trials drive improvements in patient care with head and neck squamous cell carcinoma (HNSCC), presenting opportunities for optimizing clinical outcomes. However, a significant number of patients (pts) miss out on new therapeutic opportunities due to screen failure (SF) after signing the informed consent form. Understanding the circumstances leading to SF might improve enrollment processes. Methods: Retrospective cohort analysis of pts with HNSCC intended for treatment within a clinical trial at the Royal Marsden Cancer Centre but who experienced SF between Jan 2016 and Jan 2024. Demographic and cancer-related characteristics, comorbidities, consent and SF dates, SF causes, and subsequent outcomes after SF were analyzed. Results: 76 pts who experienced SF were identified across 33 different trials. Cohort characteristics and type of trials offered are described in the table. The largest number of SFs was due to exclusion criteria being met in screening tests in 37 pts (49%): Pathology sample did not meet the quality standards in 11 pts (14%); abnormal laboratory tests in 5pts (6%); abnormal echocardiogram/reduced ejection fraction in 5 pts (6%); vessel invasion/ encasement in 4 pts (5%); non-measurable disease in 2 pts (3%); abnormal audiometry in 1pt (1%) among other reasons. The next commonest cause of SF was rapid progression during screening in 28 pts (37%): 11% compromised airway; 11% active bleeding; 5% central nervous system progression and 7% other rapid progression causes. Other causes of SF included: withdrawn consent in 7 pts (9%), comorbidity-related complication in 3 pts (5%) and study termination by sponsor in 2 pts (3%). The median time between consenting and SF was 20 days (range 4-42). After SF, 8% reconsented for the same trial, 56% received standard therapy, and 36% received best supportive care. Conclusions: This study reveals abnormal screening tests and rapid progression as primary causes for SF in patients with HNSCC. Timely referral , airway assessments and improved tissue acquisition could improve enrollment and minimize SF. [Table: see text]

A phase IV trial to confirm the efficacy of olaparib in combination with bevacizumab as maintenance frontline treatment of HRD-positive ovarian tumours (IOlanTHe).

TPS5628 Background: PAOLA-1/ENGOT-ov25 trial demonstrated that Olaparib (O) plus Bevacizumab (B) determined a significant survival benefit in patients (pts) with advanced, high-grade, epithelial ovarian, peritoneal and/or fallopian-tube cancer (HEOC) presenting defects of homologous recombination repair system (HRD+) in clinical response after first-line platinum-based chemotherapy (CT) plus B. Methods: IOLANTHE is a multicenter Italian phase IV trial (sponsored by the MaNGO group, Protocol Number IRFMN-OVA-8542) aiming to confirm in a setting close to clinical practice the efficacy of this combination in pts with HRD+HEOC. As the study includes a consistent translational component, all suspicious advanced cases will be considered for study enrollment. Pts with a confirmed pathological diagnosis of HEOC will be included in the step 1 of the trial which main inclusion criteria are the following: -availability of formalin-fixed, paraffin-embedded samples for the central testing of HRD status (performed by Myriad Mychoice CDx Plus assay) - suitability to receive CT + B. Only HRD+ pts responding to first line CT plus at least one cycle of B will be enrolled in the step 2 of the trial and will be treated with B 15 mg/kg every 3 weeks plus O 300 mg twice daily. Considering the PAOLA-1 median progression free survival (PFS) of 37.2 months (mo) in the B-O arm, with a sample size of 90 pts followed for 24 months and setting a one-side error of 5%, we will have a statistical power of 80% to demonstrate a PFS-24mo≥64% with an upper critical value of 61%. In order to have 90 patients eligible for the step 2 of the study, 190 pts are needed to be enrolled in the step 1 of the clinical study (as approximately 80% of pts with HEOC will respond to CT and out of these, 60% will be HRD+). The translational subproject 1 will consist of the analysis of circulating-tumor (ctDNA), using whole genome sequencing aiming - to correlate residual tumour after surgery and ctDNA levels - to anticipate the diagnosis of progression - to monitor the mutational status of HR-related genes and other genes such as Tp53BP1, POLQ, REV7 probably involved in PARPi resistance during the maintenance therapy. The translational subproject 2 will be developed to compare pts’ response to therapy with that of cancer cells, tested by organotypic model treated with the combination. These models will be generated using fresh tumor tissue and ascitic fluid for the isolation of the tumor cells and macroscopically healthy omentum for the isolation of the mesothelial cells and fibroblasts. Eight centers have been activated and other 6 are waiting for the activation with 19 patients registered and 3 screening failures. The enrollment is continuing, according to protocol timeline (12 months for enrollment, 6 months for surgery and CT and 24 months for maintenance treatment). Clinical trial information: NCT06121401 .

Genomics to select treatment for patients (pts) with metastatic cancer: Final analysis of Molecular Tumor Board (MTB) evaluations in the ROME trial.

3157 Background: The ROME trial (NCT04591431) investigates the efficacy of a tailored treatment (TT), driven by extensive genomic tests and Molecular Tumor Board (MTB) evaluation, compared to standard treatment (SoC) in patients (pts) with refractory metastatic cancer. Here we report the prevalence of actionable variants identified and the personalized treatment received by the patients enrolled. Methods: A centralized extensive NGS test (FoundationOne CDx and Liquid CDx) was performed on both tissue and blood samples. Pts with at least one potentially targetable alteration matched to the available drugs were discussed at the MTB. MTB evaluation criteria were: genomic variant type, tumor mutational burden (TMB), VAF, availability of preclinical or clinical data of efficacy and patients’ clinical characteristics. COSMIC, ClinVar, OncoKB and VarSome datasets were used to evaluate the clinical actionability of genomic alterations. MTB indications were: randomization to TT vs SoC, screening failure (SF), or indication to other trial/access to the drug. Results: From November 2020 to August 2023, 1794 pts were screened. A total of 127 weekly MTB meetings were conducted and 899 cases were discussed (7 cases/meeting on average). After MTB discussion, a targetable genomic alteration was identified in 425 pts, who received an indication to be randomized. MTB assigned ICIs to 190 pts (155 to ipilimumab plus nivolumab; 8 to nivolumab) due to high (≥10 mut/mb) TMB. 234 pts had indications to target therapy: 86 pts (37%) to PI3K/AKT/mTOR inhibitors(i), 59 (25%) anti-HER2 agents, 34 (15%) FGFRi, 31 (13%) BRAF/MEKi, 7 (3%) PARPi, 5 (2%) CDK4/6i, 4 (2%) ALKi, 2 (&gt;1%) NTRKi, 2 (&gt;1%) RETi, 2 (&gt;1%) Hedgehog-i, 1 (&gt;1%) JAKi, 1 (&gt;1%) MEKi. 27 pts had indication to ICIs plus target therapy combinations. Additionally, 150 pts with potentially hereditary variants were addressed to genetic counselling and germline testing. Finally, according to the genomic evaluation, 63 pts were referred by MTB to other clinical trial even if considered SF for the ROME trial, 34 patients received from the MTB a modification of the initially proposed standard therapy and 4 had both suggestions. Overall, 652 pts (36%) received an indication following NGS test and MTB evaluation. Conclusions: Our study provides evidence that MTB discussion of comprehensive genomic profiling data identifies a personalized treatment in a large (36%) fraction of patients, thus outperforming the traditional histological approach. Clinical trial information: NCT04591431 .

Screen Failures in Clinical Trials in Retina

PurposeDisparities in clinical trials are a major problem due to significant underrepresentation of certain gender, racial and ethnic groups. Several factors including stringent eligibility criteria and recruitment strategies hinder our understanding of retinal disease. Thus, we aimed to study the various reasons of screen failures and specific patient and study characteristics among screen failures. DesignThis is a cross-sectional retrospective study MethodsScreening data of 87 trials from 6 centers were analyzed. Study characteristics (disease studied, phase of trial, route of drug administration) and patient demographics (age, gender, race, ethnicity, and employment status) were compared among different causes of screen failures. Screen failures were broadly classified into six categories: exclusion due to vision-based criteria, exclusion due to imaging findings, exclusion due to other factors, patient-related criteria, physician related criteria and miscellaneous. Descriptive statistics, Pearson Chi-square test and ANOVA were used for statistical analysis. Main outcome measuresDetermine the prevalence of various reasons for screen failures in multiple trials and its trend among different study and patient characteristics. ResultsAmong 87 trials and 962 patients, 465(48.2%) patients were successfully randomized and 497(51.8%) patients were classified as screen failures. The trials were conducted for various retinal diseases. Mean age was 76.50 ±10.45 years and 59.4% were females. Predominantly whites(93.4%) and unemployed/retired patients(66.6%) were screened. Of the 497 screen failures, most were due to patients not meeting inclusion criteria of imaging findings (n=221[44.5%]) followed by inclusion of vision-based criteria (n=73 [14.7%]), exclusion due to other factors (n=75[15.1%]), patient-related (n=34[6.8%]), physician-related (n=28[5.6%]) and miscellaneous reasons (n= 39[17.8%]). Reason for screen failure was not available for 27(5.4%) patients. A higher proportion of patients screened for surgical trials (15%) declined to participate in the study compared to non-invasive trials involving topical drugs and photobiomodulation (0%).(p=0.02) ConclusionPatients not meeting the imaging and vision-cased criteria were the most common reasons for screen failures. Whites and unemployed patients predominantly participated in clinical trials. Patients are more inclined to continue participation in non-invasive clinical trials compared to surgical trials. Better recruitment strategies and careful consideration of study criteria can aid in decreasing the rate of screen failures.

Randomised clinical trial: Design of the SYNERGY-NASH phase 2b trial to evaluate tirzepatide as a treatment for metabolic dysfunction-associated steatohepatitis and modification of screening strategy to reduce screen failures.

The use of histological inclusion criteria for clinical trials of at-risk metabolic dysfunction-associated steatohepatitis (MASH) is often associated with high screen failure rates. To describe the design of a trial investigating tirzepatide treatment of MASH and to examine the effect of new inclusion criteria incorporating the use of the FibroScan-AST (FAST) score on the proportion of patients meeting histological criteria. SYNERGY-NASH is a Phase 2b, multicentre, randomised, double-blinded, placebo-controlled trial in patients with biopsy-confirmed MASH, F2-F3 fibrosis and NAFLD Activity Score ≥4. New inclusion criteria (FAST score >0.35 and an increase in AST inclusion criterion from >20 to >23 U/L) were adopted during the trial, allowing us to examine its impact on the qualification rate. 1583 participants were screened, 651 participants proceeded to liver biopsy and 190 participants were randomised with an overall screen fail rate of 87%. Following the protocol amendment, the overall qualification rate for per-protocol biopsies was minimally changed from 27.5% to 28.9% with considerable variation among different investigator medical speciality types: endocrinology: from 37.5% to 39.3%; gastroenterology/hepatology: from 26.0% to 23.3%; other specialities: from 21.3% to 29.7%. At 29 sites that performed per-protocol biopsies before and after the amendment, qualification rates changed as follows: all: 26.1% to 29.1%; endocrinology: from 35.0% to 40.9%; gastroenterology/hepatology: 25.6% to 20.0%; other specialities: from 16.1% to 27.8%. For at-risk MASH trials based on liver histology, the implementation of inclusion criteria with the proposed FAST score and AST cut-offs in this trial was most effective at non-specialist sites.

Participant characteristics and exclusion from phase 3/4 industry funded trials of chronic medical conditions: meta-analysis of individual participant level data

ObjectivesTo assess whether age, sex, comorbidity count, and race and ethnic group are associated with the likelihood of trial participants not being enrolled in a trial for any reason (ie,...