Polymer and Geocomposite Impervious Screen Reliability Assessment

The article examines the operational reliability and technical efficiency assessment of polymer (geomembranes) and geocomposite (bentonite mats) impervious channel coating developed designs. Criteria for impervious channel screen reliability and technical efficiency are proposed based on the domestic and foreign experience generalization in the composite materials use and conducted efficiency studies in terms of water permeability, strength, efficiency, and durability. Two options of developed highly efficient structures for polymer and geocomposite channel linings are presented. The graph of change in screen failure-free operation probability was obtained based on the impervious screen failure-free operation probability calculation results, depending on the survey areas and the failure amount.

Why Are Women Less Represented in Intracerebral Hemorrhage Trials?

Background and Purpose: Fewer women than men tend to be enrolled in clinical trials of intracerebral hemorrhage. It is unclear whether this reflects lower prevalence of intracerebral hemorrhage in women, selection bias, or poor recruitment efforts. We undertook this study to examine differences between men and women in the reasons for exclusion from the iDEF trial (Intracerebral Hemorrhage Deferoxamine). Methods: The screen failure log included 29 different reasons for exclusion. Chi-square statistics were used to evaluate the differences in reasons for exclusion between men and women. Results: A total of 38.2% of participants in iDEF were women. Three thousand nine hundred eighty-two women (45.7%) and 4736 men (54.3%) were screen failures ( P <0.0001). Similar proportions of women (1.28%) and men (1.73%) were excluded due to inability to obtain consent ( P =0.1). Patients or families declined participation in 1.26% of women versus 1.31% of men ( P =0.9). More women than men failed screening because of age>80 (22.40% versus 12.61%; adjusted P =0.0007) and preexisting do-not-resuscitate/do-not-intubate (3.69% versus 2.83%; adjusted P =0.067). Conclusions: Lower rates of women enrollment in the iDEF trial may be attributed to older age. Inability to obtain consent or declining participation was similar between women and men, arguing against selection bias. Our findings should be confirmed in other intracerebral hemorrhage trials to determine best strategies to improve women’s representation in future trials.

Abstract 16677: Real World Screen Failure Rates for Transcatheter Mitral Valve Repair and Replacement for Mitral Regurgitation

Background: Despite an expanding armamentarium of devices, many patients with mitral regurgitation referred for transcatheter mitral valve repair or replacement are not eligible to participate in the clinical trials or receive a commercially available device. We sought to understand the reasons why patients were excluded from receiving therapy. Methods: We retrospectively analyzed the medical charts, and correspondence related to patients referred to our tertiary valve center for transcatheter mitral valve replacement (TMVR) or transcatheter mitral valve repair (TMVr) between June 2016 to September 2019. Patients were screened for eligibility by our structural Heart Team for either TMVR or TMVr. If TMVR or TMVr was not offered the reason for screen failure was recorded and categorized. Results: Over the 3-year period, 564 patients were referred for TMVR/TMVr. Of these, 15.9% were determined to be eligible for and underwent surgical repair or replacement. 440 patients (78.0%) were considered for TMVR/TMVr. 92 patients (16.3%) underwent TMVR/TMVr. The majority of patients (348/564, 61.7%) ultimately did not undergo intervention (Panel A). The reasons for exclusion were clinical in 78%, issues related to patient preference of care delivery in 49% of patients, anatomical in 37% and futility in 25% of patients (Panel B). Conclusions: The majority of patients with mitral regurgitation referred for transcatheter mitral therapy are excluded for a variety of reasons. Clinical trials testing new transcatheter mitral valve devices should be encouraged to follow patients who are excluded to better understand optimal timing of intervention, address challenging anatomies, and ultimately improve penetrance of these novel therapies.

FDA Analysis of Screen Failures By Race in Clinical Trials of Acute Myeloid Leukemia

Background: Ethnic and racial minorities are underrepresented in oncologic clinical trials. One potential barrier to participation may be narrow eligibility criteria which contribute to an increased rate of screen failure among minorities. Prior work in multiple myeloma demonstrated a higher rate of screen failure among black or African-American (AA) patients and lower rate of screen failure among Asian patients compared with white patients (1). Here, we examine screen failure rates by race in patients screened for participation in clinical trials of acute myeloid leukemia (AML). Methods: Trials submitted to the U.S. Food and Drug Administration (FDA) to support approval of new treatments for AML between 2016-2019 were examined. Trials which included information on screen failures and race were included. Trial, screen failure status, basic demographic information (age, gender, race, and ethnicity), country of participant, and reason for screen failure (if relevant) were abstracted from the trials. Screen failure rates were calculated based on this information. Results: Twenty-one trials of AML therapies were identified, of which screen failure and race information were available in fourteen. Of these, information on reason for screen failure was available in nine. A total of 6,471 patients were identified across fourteen trials (Table 1). Race was recorded as unknown for 2,934 (46%) of patients. A total of 3,372 (52%) screen failures occurred. Minorities were more likely to be screen failures at 201/603 (33%) compared to whites at 27%. Of minorities, screen failures occurred in 29% of black/AA patients, 36% of Asians, and 36% of patients of any other race. A total of 579 patients were included in the nine trials that included data on reasons for screen failures (Table 2). Lack of appropriate mutation (i.e. IDH1/2, FLT3) was the most common reason for screen failure overall and was more common in black/AA (41%) and Asian patients (66%) compared to white patients (29%). Other issues related to the disease course (e.g. not at the appropriate point in treatment, not treated within the time limit set in the protocol) led to screen failure in 28% black/AA patients versus 9-22% for other races (19% overall). White patients were more likely than patients of other races to be screen failures due to cardiac issues (4%) and laboratory abnormalities (6%). Conclusions: Minority patients were numerically more likely to be screen failures compared to whites in trials of AML therapeutics, which exemplifies the known issue of lower minority recruitment in clinical trials. Minority patients were more likely to be screen failures due to lack of appropriate mutation and less likely due to lab abnormalities or cardiac issues. The significance of this finding is uncertain given the limited information on reasons for screen failure and the small number of minority patients in the database. Further investigation into screen failures in minority patients with AML is indicated. These results underscore the importance of including racial and ethnic minorities in all phases of translational and clinical research to further precision oncology for all patients since oncogenic driver mutation frequencies may vary among different populations. (1) Kanapuru B, Fernandes L FDA analysis of multiple myeloma trials supporting approval; Presented at FDA-AACR workshop to examine under-representation of African Americans in multiple myeloma clinical trials 2/13/20 Disclosures No relevant conflicts of interest to declare.

FRI0393 BASELINE CHARACTERISTICS OF THE STUDY POPULATION IN ROCCELLA, A PHASE 2 CLINICAL TRIAL EVALUATING THE EFFICACY AND THE SAFETY OF S201086/GLPG1972 IN PATIENTS WITH KNEE OSTEOARTHRITIS

Background:Osteoarthritis (OA) is a degenerative joint disease involving structural pathology of all joint tissues, and most commonly affecting the knee, hip and hand. Degradation of the cartilage extracellular matrix represents a central feature of OA and is widely thought to be mediated by proteinases that degrade primarily aggrecan and collagen. ADAMTS-5, a Disintegrin And Metalloproteinase with ThromboSpondin-motif-5, is a key aggrecan-cleaving enzyme involved in cartilage degradation. S201086/GLPG1972, a potent and highly selective inhibitor of ADAMTS-5, is an oral Disease-Modifying OsteoArthritis Drug (DMOAD) candidate.Objectives:The primary objective of the ROCCELLA phase 2 clinical trial (NCT03595618) is to evaluate the effect of S201086/GLPG1972 over 52 weeks of treatment (3 dose groups compared to placebo) in reducing cartilage loss. Cartilage thickness of the knee is being measured quantitatively by Magnetic Resonance Imaging. Here, we describe the baseline characteristics of patients included in the ROCCELLA clinical trial.Methods:The main inclusion criteria were: male or female, aged 40 to 75, with a diagnosis of knee OA according to the clinical and radiological criteria of the American College of Rheumatology. The target knee had to meet a pain score between 40 and 90 mm on a 100 mm Visual Analog Scale (VAS), and the following radiographic feature upon central radiographic readings: Kellgren/Lawrence (KL) 2 or 3 and OARSI medial joint space narrowing (JSN) 1 or 2 (for more details see Deckxet al. OARSI 2020). The rationale for these specific radiographic inclusion criteria was to ensure sufficient cartilage loss over 12 months to assess the efficacy of S201086/GLPG1972.Results:Across 12 countries, 3319 patients were screened and 932 were finally included in the study. The screen failure of 72% is mainly due to the radiological criteria. The age of the patients was 62.9 ± 7.3 years (mean ± SD) with a majority of women (69.3%). The BMI was 30.5 ± 4.7 kg/m2. The duration of knee OA was 7.2 ± 6.9 years. Five hundred and one (53.8%) patients reported a medical history of musculoskeletal and connective tissue disorders, mainly osteoarthritis in other sites (20.2%), back pain (13.6%), and arthralgia (9.8%). At inclusion, 97.2% of the patients were taking different types of drug treatments, mainly anti-inflammatory and anti-rheumatic products (69.4%) and analgesics (42%). At baseline, 11% of the target knees were KL2 and 89% were KL3; 32% were OARSI medial JSN grade 1 and 68% grade 2. Target knees at inclusion had a pain score on the VAS of 63.5 ± 11.4 mm (range 0-100, with 0 for no and 100 for extreme pain) and a total WOMAC (Likert 3.1) score of 48.0 ± 15.0 (range 0-96). The WOMAC subscores for pain, stiffness and physical function were 10.0 ± 3.2 (range 0-20), 4.2 ± 1.6 (range 0-8) and 33.8 ± 11.2 (range 0-68, indicating functional limitation), respectively.Conclusion:For this clinical trial, patients were selected to present radiological criteria (i.e.OARSI JSN 1 and 2) to ensure sufficient structural progression (cartilage loss) over 12 months, as well as clinical symptoms. These stringent selection criteria were the main cause for the high screen failure rate. These baseline characteristics should warrant the ability to evaluate the efficacy of S201086/GLPG1972 as a DMOAD candidate. The search for an effective pharmacological treatment that can prevent or cure OA remains a major challenge and unmet medical need.Disclosure of Interests:Katy Bernard Employee of: Institut de Recherches Internationales Servier, Sergey GRANKOV Employee of: Institut de Recherches Internationales Servier, Marjolijne van der Stoep Employee of: Galapagos, Agnès Lalande Employee of: Institut de Recherches Internationales Servier, Olivier Imbert Employee of: Institut de Recherches Internationales Servier, De Phung Employee of: Galapagos, Damien Chimits Employee of: Institut de Recherches Internationales Servier, Karine Muller Employee of: Galapagos, Ellen van der Aar Employee of: Galapagos, Henri Deckx Employee of: Galapagos, Maria Pueyo Employee of: Institut de Recherches Internationales Servier, Felix Eckstein Grant/research support from: Merck, Orthotrphix, Servier, Galapagos, Kolon Tissuegene, Samumed, Novartis, Consultant of: Merck, Bioclinica, Servier, Samumed, Roche, Kolon Tissuegene, Galapagos and Novartis, Employee of: co-owner and employment with Chondrometrics

T42. HIGH ADHERENCE TO CURRENT ANTIPSYCHOTIC AND ADJUNCTIVE PIMAVANSERIN IN THE ENHANCE STUDY, A PHASE 3 TRIAL TO EVALUATE THE TREATMENT OF SCHIZOPHRENIA IN PATIENTS WITH AN INADEQUATE RESPONSE TO ANTIPSYCHOTIC TREATMENT

Background Individuals with schizophrenia experience an inadequate response to antipsychotic (AP) treatment at a high rate, up to 70% in some cases (McEvoy et al. 2006). Possible reasons for this include subtherapeutic AP blood levels and medication ineffectiveness. Although patient self-report and clinician opinion are commonly used to identify non-adherence, they are unreliable. AP polypharmacy for inadequate response remains widespread despite a lack of supportive evidence. Few completed trials offer guidance on the optimal trial design and procedures to establish inadequate response at screening/baseline. Adequate treatment is defined as an AP taken at a therapeutic dose for a sufficient duration (Taylor et al. 2012). Confirming treatment stability and adherence, both prior to enrollment and during the trial, is necessary to ensure sufficient exposure to an AP prior to deeming a response inadequate and justifying augmentation. Measuring adherence during the trial is necessary to ensure correct interpretation of trial results. We present the trial design and adherence data from a recently completed Phase 3 clinical trial of an adjunctive therapy in inadequately responding patients with schizophrenia. The trial did not meet the primary endpoint (Bugarski-Kirola, et al. 2019). Methods ENHANCE was a 6-week, randomized, double-blind study of adjunctive pimavanserin (PIM; a 5-HT2A inverse agonist) versus placebo to evaluate the treatment of schizophrenia in patients with an inadequate response to their prescribed AP (aripiprazole, olanzapine, risperidone, and others). During screening, patients provided documentation showing treatment stability for at least 8 weeks prior to screening, a blood sample was tested for adherence, and a telemedicine interview was completed with an independent clinician. After randomization, blood sampling occurred at Baseline, Week 1, Week 3, and Week 6 for pharmacokinetic (PK) assessments of the AP and adjunctive PIM. Results ENHANCE screened 633 patients with 35 rescreens for a total of 668 screenings. Adherence to background AP was high for all patients screened as background AP levels were detected in 90.6% of patients. However, the most common reason for screen failure was still a failure to detect background AP (16.9% of all screen failures). Other common reasons for screen failure included lack of prescription stability/appropriate dosing, investigators determining the patient was inappropriate for the study, and withdrawal of consent, the latter of which often reflected the rigorous screening process required for the study. Proactively screen failing non-adherent patients led to higher levels of adherence at Baseline compared to screening with 94.9% of patients demonstrating adherence at Baseline. Moreover, this is a substantial improvement over the theoretical adherence rate of 84.5% had non-adherent patients been randomized. The high rate of adherence at Baseline for background AP was maintained at Weeks 1, 3 and 6. High adherence was also found for adjunctive PIM. 198 patients were randomized to the PIM treatment arm, 190 had a blood sample at Week 1 with 187 (98.4%) showing measurable levels of PIM, and 182 had a blood sample at Week 3 with 180 (98.9%) showing measurable levels of PIM. Patients leaving the study (either at Week 6 of treatment or as a result of early termination) showed a 96.8% adherence rate. Discussion By employing rigorous screening procedures, including testing for AP treatment adherence, the ENHANCE study enrolled a representative sample of patients with a confirmed inadequate response to their current AP and achieved a high level of treatment adherence (both to patient’s AP treatment and study drug).

Abstract TP299: Association Between Rates of Dysphagia Screening Failure and Short-Term Outcomes in Patients With Mild Stroke

Intro: Guidelines advocate screening all acute stroke patients for dysphagia. However, limited data are available regarding how many patients with mild presentation fail initial screening. We sought to evaluate the rates and predictors of dysphagia screening failure in mild acute ischemic stroke patients (NIHSS < 5). Methods: Using GWTG stroke registry data from three large comprehensive stroke centers in the Northeast, South and West, we analyzed 8,687 stroke admissions from 06/2008 - 12/2018. Patients with mild stroke (NIHSS<5) were identified and dysphagia failure rate was evaluated. Using univariate and multivariable regression (MV) analysis (using factors with p<0.1, in bold), we evaluated factors associated with dysphagia screen failure in mild stroke patients. Results: Of the 8,687 patients, 3,614 (41%) had NIHSS < 5. Dysphagia screening failure was seen in 30.2% in the entire cohort while only 10.3% (373/3,614) in patients with NIHSS < 5. Mild stroke patients who failed dysphagia screening were older, more often had stroke risk factors of hypertension, hyperlipidemia, CAD/MI. They had higher median NIHSS and more often had language disturbance on presentation. Patients who failed dysphagia screening were less likely to be discharged home. On MV analysis, age (1.01, 95% 1.00, 1.02), hypertension (1.45, 95% 1.10, 1.91), NIHSS (1.62 95% 1.48, 1.77) and language disturbance at presentation (1.89 95% 1.13, 2.32) were significantly associated with initial dysphagia. Conclusion: Dysphagia screen failure rates are significantly less frequent in patients with mild symptoms and even lower for those with NIHSS of 0-1 at presentation. Factors associated with failure - older age, higher NIHSS and language disturbance at presentation may help focus efforts to avoid complications in these patients who might otherwise do well. This focused approach of screening patients all patients but targeting mild patients with dysphagia may hold potential for improved outcomes.