Trial Population Research Articles

Infrequent Resolution of Vaso-Occlusive Crises in Routine Clinical Care Among Patients Mimicking the Exa-Cel Trial Population: A Cohort Study of Medicaid Enrollees.

The CRISPR-based gene editing therapy exagamglogene autotemcel (exa-cel) recently received FDA approval for patients with severe sickle cell disease (SCD). The approval was based on a phase III trial (CLIMB SCD 121), which showed 97% efficacy of this treatment in eliminating vaso occlusive crises (VOCs) for 12 consecutive months. To help contextualize results from this trial, we aimed to investigate the proportion of patients with severe SCD who remain VOC-free for a 1-year period in routine clinical care. Using Medicaid claims data (2000-2018), we identified a cohort of patients, 12-35 years old with severe SCD, defined by ≥ 2 VOCs per year for 2 consecutive years, who met other exa-cel trial inclusion criteria to mimic a trial-like population. A VOC was identified using ICD diagnosis codes during hospitalization and ER visits. The primary outcome was the proportion of patients with no VOCs during a 1-year follow-up. A total of 7,425 patients with severe SCD [mean (SD) age: 20.5 (6.0) years, 54.6% females, 84% African Americans], had a mean of 5.2 VOCs, 5.1 ER visits and 3.5 hospitalizations per year during the baseline period. The proportion of patients with no VOCs during the 1-year follow-up was 7.7% (95% confidence interval: 7.1%-8.3%). In conclusion, less than one in 12 patients with severe SCD achieved VOC-free status within 1 year in routine clinical care. These findings suggest that the high efficacy observed for exa-cel in the trial, if replicated in routine clinical care, could translate into a significant public health impact.

Applying the SOUND Trial for Omitting Axillary Surgery in Patients With Early Breast Cancer in Bahrain.

The Sentinel Node vs. Observation After Axillary Ultra-Sound (SOUND) trial reported that omission of axillary surgery was not inferior to sentinel lymph node biopsy (SLNB) in those with cT1 breast cancer and negative preoperative axillary ultrasound. The aim of our study was to evaluate the clinical characteristics of early breast cancer patients undergoing breast conserving surgery (BCS) at our institution in order to investigate the exportability of SOUND criteria to our patient population. We retrospectively reviewed patients with cT1N0 breast cancer undergoing BCS and adjuvant radiotherapy according to the SOUND trial criteria. Comparison was made between the eligible group of our cohort and the SLNB arm of the SOUND trial. The proportion of younger patients was higher in our eligible cohort (37.7% vs. 17.5%, p = 0.002). Postmenopausal patients were more prevalent in the SOUND trial (79.4% vs. 56.6%, p = 0.004). On final pathology, tumours were more likely to be upgraded to T2 in our group (26.4% vs. 4.4%, p = 0.001). Patients in our cohort were more likely to receive adjuvant chemotherapy (37.7% vs. 20.1%, p = 0.002). The clinicopathological differences between our cohort and the SOUND trial population could be attributed to aggressive tumours in Bahrain compared to Western countries. Our study may influence others to investigate the applicability of the SOUND trial in clinical practice. Nevertheless, it is a study that should generate multidisciplinary discussion in the de-escalation of axillary surgery.

Efficacy and Safety of Etrasimod in Patients with Ulcerative Colitis in Japan: Data from the Phase 3 ELEVATE UC 12 and ELEVATE UC 40 JAPAN Trials

Introduction: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Here, we report the primary analysis of a phase 3 trial evaluating the efficacy and safety of etrasimod in patients from Japan with moderately to severely active UC. Methods: Patients from Japan who completed the 12-week ELEVATE UC 12 induction trial could enroll in the 40-week ELEVATE UC 40 JAPAN maintenance trial for a combined 52-week treatment period. Patients in this Japan cohort continued their baseline assigned treatment (etrasimod 2 mg QD or placebo) from ELEVATE UC 12. Efficacy was assessed at week 12 and week 52. Treatment-emergent adverse events (TEAEs) pooled from both trials were assessed up to 52 weeks of exposure. Results: The Japan cohort comprised 32 and 16 patients who received etrasimod and placebo, respectively. A numerically greater proportion of patients who received etrasimod versus placebo achieved clinical remission at week 12 (etrasimod: 14.3%; placebo: 7.1%) and week 52 (etrasimod: 25.0%; placebo: 7.1%); a similar trend was observed for all key secondary efficacy endpoints. TEAEs occurred in 84.4% (27/32) and 62.5% (10/16) of patients who received etrasimod and placebo, respectively. No new safety signals were detected. Conclusion: In these induction and maintenance trials evaluating etrasimod in patients from Japan with UC, numerically higher proportions of patients who received etrasimod versus placebo achieved efficacy endpoints. Efficacy and safety findings were consistent with those from the global ELEVATE UC trial populations.

Abstract B058: Preliminary findings of a multilevel community-based clinical trials and genomic navigation program implemented in the southern United States

Abstract Introduction: Advances in genomics have increased our understanding of the interplay between genetics, environment, behavior, and disease. However, these scientific advances are hampered by the inadequate representation of African American (AA) and Hispanic populations in genomic studies and clinical trials; thus, it is important to identify effective engagement and navigation strategies. The goal of the MSM/TU/UAB OCCC Partnerships to Advance Cancer Health Equity (PACHE) Outreach Core is to implement and evaluate an evidence-based, theory-informed, multi-level, clinical trial and cancer genomics education program (CTC-GEP) to address the determinants for AA and Hispanic participation in clinical trials and genomic research. The program consists of a clinical and genomic navigator and a high and low-tech toolkit. We will present preliminary data characterizing the feasibility phase of this two-arm behavioral trial. Methods: The Attitudes and Intentions to Enroll in a Therapeutic Trial (AIET) questionnaire and a culturally tailored social and demographic questionnaire were used by navigators to obtain participants information. Cumulative logistic regression was used to assess the correlation of age, race, education, and type of health insurance with attaining a higher score on the Likert scale used in AIET survey questions at pre- and post-test. Results: Younger participants (18-49 years) were significantly more likely than older participants (ages 50 and above) to hold several positive views about participating in clinical trials. Specifically, they were 3.6 times as likely to believe that participating in a clinical trial could help advance science to improve community health (P-value = 0.0393); 4.6 times as likely to think there are benefits for others like them (P-value = 0.25); 5.6 times as likely to trust that clinical trial centers have rules to protect their records (P-value = 0.024); and 3.9 times as likely to trust health workers (P-value = 0.002). Additionally, participants with a high school education or less were 3.2 times as likely to consider themselves at risk of cancer compared to those with a college education or higher (P- value = 0.0015). Medicare & Medicaid recipients, compared to those with private insurance, viewed privacy as a major concern when participating in research (P-value = 0.008). Furthermore, Black/AA participants were more likely than White participants to believe that Blacks are used in research without their knowledge (P-value = 0.005). Conclusions: CTC- GEP was demonstrated to be feasible and acceptable among study participants. Findings from the AIET survey highlight privacy concerns are more pronounced among Medicare & Medicaid recipients, indicating a need for better communication about privacy protections. As well, age and racial disparities exist in trust regarding the ethical conduct of research, with older and AA participants expressing significant concern about being used in research inappropriately and without their knowledge. Citation Format: Mohamed Mubasher, Osato Eke, Victoria Churchill, Vivian Carter, Yu-Mei Schoenberger, Desiree Rivers, Jamirah Chevrin, Stephen Sodeke, Christina Wilkerson, Makeeta Rayton, Teresa Hall, Illeana Barrios Zermeno, Angela Morris, Jennifer Culbertson, Roland Matthews, Brian Rivers. Preliminary findings of a multilevel community-based clinical trials and genomic navigation program implemented in the southern United States [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B058.

Abstract A107: Be Part of the Cure Clinical Trials Campaign: Koreans, Hispanic/Latino/a/e/x, and Black/African Americans living in Los Angeles County

Abstract Background. There is negative perception and lack of participation in clinical trials among Koreans, Hispanic/Latino/a/e/x, and Black/African Americans living in Los Angeles County, which may be attributed to cultural beliefs, language barriers, historical mistrust of medical research, and lack of awareness about the benefits of participation. Without representation from diverse groups, there may be missed opportunities to develop personalized treatment approaches tailored to specific genetic, cultural, and lifestyle factors. Methods. Cedars Sinai Cancer Community Outreach and Engagment (COE) developed a multi-level approach to increase representation of minority populations in clinical trials. With active Community Advisory Board involvement in the development and implementation, a culturally sensitive clinical trials awareness campaign, “Be Part of the Cure”, was developed to offer in-language cancer information, education on clinical trials, and navigation through the cancer care continuum. To support patients and facilitate access to trials, COE has developed bi-directional engagement between CCSC physicians, nurses and Clinical Trials Office representatives, FQHCs, and community and faith-based organizations to ensure a seamless navigation process to care. Additionally, our multicultural and multilingual COE staff have trained Community Health Workers and navigators to expand our outreach efforts and effectively engage our target communities. Results. In total, COE has facilitated 7 health education workshops and attended 3 community outreach events with 501 people educated (37% or 184 Black/African American; 25% or 123 Asians; 17% or 87 Hispanic/Latinx; and 21% or 107 White). Pre/post-tests administered to 73 Koreans during health education workshops showed significant increase in positive perception on clinical trials from 57% to 95%. Korean (n=9) cancer patients have expressed interest in clinical trials, and 1 have been enrolled in Neoadjuvant HER2-Targeted Therapy and Immunotherapy with Pembrolizumab clinical trial. Among Hispanic/Latinx/a/o community, 1 clinical trials health awareness workshop was convened with clinicians who presented to promotores, patients, caregivers, survivors and community members. There were 25 people who completed the pre/post test. There was an increase in positive perception on clinical trials from 52% to 100%, willingness to participate from 60% to 96%, and likelihood of encouraging others to participate from 60% to 96%. In the Black/African American community, 1 clinical trials health awareness workshop was also convened. Among attendees, 21 people completed Pre/Post Test and positive perception on clincal trials increased from 47% to 85%, willingness to participate from 43% to 81%, and likehood on encouraging others to participate from 52% to 81%. Conclusion. Efforts to increase diversity and inclusion in clinical trials should focus on culturally sensitive recruitment strategies, language accessibility, community engagement, and building trust between researchers and communities. Citation Format: Ghecemy Lopez, Dong Hee Kim, Zul Surani, Lourdes Barajas. Be Part of the Cure Clinical Trials Campaign: Koreans, Hispanic/Latino/a/e/x, and Black/African Americans living in Los Angeles County [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A107.

Abstract C164: Underrepresentation of Black and elderly populations in immunotherapy-based clinical trials for gynecologic cancers: Trends over the past two decades

Abstract BACKGROUND: Race-based disparities in gynecologic oncology (GYN-ONC) clinical trials are well-documented. In 2012, the FDA introduced the Safety and Innovation Act (FDASIA) to improve the reporting and inclusion of demographic minorities in clinical trials. Also, the first immune checkpoint inhibitor (ICI), Ipilimumab, received FDA approval in 2011, which opened a new era of ICI-based clinical trials in several cancer types, including Gyn cancers. Here we assessed trends in race- and age-based disparities pre- and post-introduction of the FDASIA in a subset of GYN-ONC clinical trials investigating immunotherapy. METHODS: Phase 1-3 trials were identified using the following search terms on ClincialTrials.gov: ovarian cancer (OvCa), endometrial cancer (EnCa), cervical cancer (CxCa), immunotherapy, adoptive cell therapy, vaccine, ICI. Trials without posted/published results were excluded. Enrollment, race, ethnicity, and age data were extracted from the clinical trials page and/or associated manuscripts. Using CxCa, EnCa and OvCa prevalence data from the 2021 SEER database, we calculated expected enrollment proportions by race and age, respectively, and compared these to actual clinical trial enrollment data. Binomial and chi-squared tests were used for statistical analyses. RESULTS: 252 clinical trials were initially identified. 123 trials (48.8%), opened between 2002-2020, remained after removing ongoing trials without published/posted results. Of the 123 trials, 58 (47%) reported both race and ethnicity (RAE) data; 26 (21.1%) reported only racial demographics; and 39 (31.7%) did not report RAE data. 71.2% (71/99) of studies that opened from 2013-2020 reported RAE data compared to 50% (12/24) from 2002-2012 (OR: 2.54, 95% CI: 1.04-6.18, p=0.05). 84 trials (58 with RAE, and 26 with only race) had evaluable data for 12,433 participants. Black patients had lower enrollment (3.9%; 47% of expected enrollment) vs. White patients (69.7%; 81% of expected enrollment, P<0.0001) compared to the distribution of race (White: 86.3%, Black: 8.4%, Asian: 4.9%) of all three GYN cancers in the US. In trials that opened between 2013-2020 vs. 2002-2012, the proportion of Whites entering trials decreased (68.6% vs. 94.1%, OR: 0.14, 95% CI: 0.10-0.19, p<0.0001), while there was no change in the proportion of Black enrollment ( 4.0% vs. 3.1%, OR: 1.32, 95% CI: 0.82 to 2.14, p=0.27). On the other hand, there was an increase in the proportion of Asian participants (17.7% vs. 2.0%, OR: 10.65, 95% CI: 5.93-19.28, p<0.0001) and the proportion of other/unknown participants (9.8% vs. 0.9%, OR: 11.96, 95% CI: 5.17-27, p<0.0001). Enrollment of elderly groups did not change significantly between 2002-2012 (37.2%) vs. 2013-2020 (27.0%, OR: 0.78, 95% CI: 0.50-1.24, p=0.27). CONCLUSIONS: RAE reporting trended to increase after the introduction of the 2012 FDASIA, however, Black and elderly populations were still underrepresented. Continued efforts should be made to improve RAE reporting as well as enrollment of Black and elderly populations in Gyn cancer immunotherapy trials. Citation Format: Maheen Khan, Kristen Ibanez, Duncan Donohue, Courtney Bowen, Jung-Min Lee. Underrepresentation of Black and elderly populations in immunotherapy-based clinical trials for gynecologic cancers: Trends over the past two decades [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C164.

Abstract A087: Clinical outcomes in Black patients with EGFR-mutated NSCLC treated with osimertinib

Abstract Introduction: Epidermal growth factor receptor (EGFR) gene mutations are present in about 15% of non–small cell lung cancer (NSCLC) cases in the U.S. The FLAURA study, in which the tyrosine kinase inhibitor (TKI) Osimertinib demonstrated a median PFS of 18.9 months, set the current standard in the U.S. for front-line treatment of advanced NSCLC with sensitizing EGFR mutations. However, Black patients were greatly underrepresented in the FLAURA study (<1% of trial population) and two retrospective single-institution studies suggest inferior survival in Black patients with EGFR-mutant NSCLC treated with TKIs versus (vs.) other races. Research is needed using large real-world cohorts to evaluate real-world progression-free survival (rwPFS) and overall survival (OS) in Black patients with EGFR-mutant NSCLC to determine whether they derive comparable benefit from Osimertinib as other races. Methods: The nationwide Flatiron Health Electronic Health Record (EHR)-derived de-identified database was used to analyze data from 1503 patients with advanced NSCLC bearing an EGFR exon 19 deletion or L858R mutation who received front-line Osimertinib. The de-identified data originated from 280 US cancer clinics (∼800 sites of care). Patients were stratified by race (Black vs. White) and characteristics were compared using chi-square, Fisher’s exact, and t-tests. Kaplan-Meier curves estimated rwPFS (based on clinician documentation of progression) and OS in months (m). Differences in survival were assessed between Black and White patients using multivariable Cox proportional hazards models that adjusted for age, gender, EGFR subtype, histology, diagnosis year, smoking history, performance status, insurance status, and socioeconomic index. Results: In our cohort, comprised of 179 Black and 1324 White patients with EGFR-mutant NSCLC, median age and percentage with a smoking history did not differ by race. However, Black patients were more likely to be female (74.3% vs. 66.4%, p=0.03), possess an exon 19 deletion tumor (74.3% vs. 58.3%, p<0.001) or be in a low socioeconomic index category (30.2% vs. 8.7%, p<0.001) than White patients. Median rwPFS did not significantly differ between Black and White patients treated with Osimertinib (15.1 m vs. 14.1 m, HR 0.91, p=0.39). Similarly, no significant difference in OS was observed among Black patients treated with Osimertinib as compared to Whites (29.2 m vs. 32.5 m, HR 1.07, p=0.57). Conclusion: This real-world analysis of one of the largest cohorts of Black patients with EGFR-mutant NSCLC to date, did not observe differences in rwPFS and OS as compared to White patients following front-line Osimertinib therapy. Efforts should be made to ensure all patients receive mutational testing upfront so they can receive optimal first line therapy. Citation Format: Neel Belani, Farsha Rizwan, Jill Hasler, Jessica Bauman, Khadijah Mitchell, Hossein Borghaei, Joseph N Bodor. Clinical outcomes in Black patients with EGFR-mutated NSCLC treated with osimertinib [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A087.

Abstract B160: Assessing patient experience in cancer clinical trial participants: Results from a rapid umbrella review with an equity lens

Abstract Introduction: Clinical trials are an important part of cancer care, yet research assessing patient experience in cancer clinical trials is sparse. Ensuring that the patient voice is heard and valued in the context of clinical trials is critical to the delivery of high-quality, patient-centered, and equitable cancer care. Furthermore, understanding the aspects of cancer clinical trials that are important to and reported by patients may inform strategies to address barriers to clinical trial participation, improve diversity in clinical trials, and advance health equity, particularly among populations underrepresented in clinical research. This rapid umbrella review sought to understand how patient experience is assessed in cancer clinical trials and to identify opportunities to integrate an equity lens. Methods: PubMed, Embase, Cochrane, and CINAHL databases were searched for systematic reviews that identify and describe development, use, or testing of tools/instruments assessing patient experience of cancer clinical trial patients. The search strategy was collaboratively developed with an NIH Librarian, using a combination of key terms to describe: 1) patient experience, 2) clinical trials, 3) healthcare delivery, and ) systematic reviews. The search was limited to publications in the English language and a date range of 2018-2024. One co-author completed the title and abstract review based on the inclusion criteria. Two reviewers will then independently completed the full text review, quality appraisal, and data abstraction for all included studies. All authors will synthesize data into matrix tables and narratively summarize into key themes. Discrepancies were resolved through discussion. Results: Out of 1,751 yielded search results, 151 articles were preliminarily identified. Upon further reading of the full texts, the final list of included articles meeting inclusion criteria will be reported using Covidence. Summary findings from this rapid umbrella review will include the number of studies identified, clinical trials population, a description of the patient experience measures, domains, findings, as well as opportunities for health equity integration using the PROGRESS-Plus Framework. Conclusion: Equitable representation in clinical trials will require intentional efforts to understand and enhance the experience of patients on clinical trials across diverse patient populations, as well as address barriers to participation. However, there are several research gaps that limit our understanding in this area, including a lack of consistent definitions, patient experience domains; availability and use of standardized, validated measures for clinical trial populations, and knowledge about what factors differ and influence patients’ experiences, particularly among populations underrepresented in clinical research. Attention to these gaps will facilitate a greater understanding of patient needs, experiences, and barriers, and may promote actionable strategies to increase access to, inclusion of, and diversity in cancer clinical trials. Citation Format: Brenda Adjei, Katrina Makres, Eric Juarez, Sae-Jin E Lee, Lynne Padgett. Assessing patient experience in cancer clinical trial participants: Results from a rapid umbrella review with an equity lens [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B160.

Racial and Sex Differences in Genomic Profiling of Intrahepatic Cholangiocarcinoma.

Racial and sex disparities in the incidence and outcomes of patients with intrahepatic cholangiocarcinoma (iCCA) exist, yet potentialgenomic variations of iCCA based on race and sex that might be contributing to disparate outcomeshave not been well studied. Data from the American Association for Cancer ResearchProject GENIE registry (version 15.0) were analyzed to assess genetic variations in iCCA. Adult patients (age >18 years) with histologically confirmed iCCA who underwent next-generation sequencing were included in the analytic cohort. Racial and sex variations in genomic profiling of iCCA were examined. The study enrolled 1068 patients from 19 centers (White, 71.9%; Black, 5.1%; Asian, 8.4%, other, 14.6%). The male-to-female ratio was 1:1. The majority of the patients had primary tumors (73.7%), whereas 23.0% had metastatic disease sequenced. While IDH1 mutations occurred more frequently in White versus Black patients (20.8% vs. 5.6%; p = 0.021), FGFR2 mutations tended to be more common among Black versus White populations (27.8% vs. 16.1%; p = 0.08). Males were more likely to have TP53 mutations than females (24.3% vs. 18.2%, p = 0.016), whereas females more frequently had IDH1 (23.3% vs 16.0 %), FGFR2 (21.0% vs. 11.3%), and BAP1 (23.4% vs. 14.5%) mutations than males (all p < 0.05). Marked variations in the prevalence of other common genomic alterations in iCCA were noted across different races and sexes. Distinct genomic variations exist in iCCA across race and sex. Differences in mutational profiles of iCCA patients highlight the importance of including a diverse patient population in iCCA clinical trials as well as the importance ofrecognizing different genetic drivers that may be targetable to treatdistinct patient cohorts.

Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial.

Background: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene (EDN1) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. Methods: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. Results: A total of 118 participants (mean ±SD; years of age 63.5 [9.2 ]; 71 [60.2% ] females; 25 [21.2% ] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95 ] CI, -19.60 to 11.06] P=0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P<0.001). Conclusions: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common.

Semaglutide and blood pressure: an individual patient data meta-analysis.

Randomized clinical trials (RCTs) assessing semaglutide reported reductions of systolic blood pressure (SBP) in trial populations with baseline blood pressure in the normotensive range. This study aimed to determine whether this SBP reduction is greater in hypertensive groups. Individual patient data (IPD) from three RCTs examining the effect of semaglutide 2.4 mg on body weight over 68 weeks were included. Trial participants were categorized according to a hypertension diagnosis, treatment or baseline measurement (HTN), baseline SBP > 130 mmHg (HTN130) or >140 mmHg (HTN140), and those with apparent resistant hypertension (RH). The primary analysis compared the in-trial change in SBP in the semaglutide and placebo arms. Alterations of anti-hypertensive medications were quantified by treatment intensity score and compared between arms. These analyses were performed using analysis of covariance. Overall, 3136 participants were included. The difference in SBP change between the treatment (n = 2109) and placebo (n = 1027) groups was -4.95 mmHg [95% confidence interval (CI) -5.86 to -4.05] overall. This difference was -4.78 mmHg (95% CI -5.97 to -3.59) for HTN, -4.93 mmHg (95% CI -6.75 to -3.11) for HTN130, -4.09 mmHg (95% CI -7.12 to -1.06) for HTN140, and -3.16 mmHg (95% CI -8.69-2.37) for RH. Reduction in SBP was mediated substantially by weight loss. The anti-hypertensive treatment intensity score decreased for those on semaglutide compared to placebo (-0.51; 95% CI -0.71 to -0.32). This IPD analysis of three large RCTs found blood pressure reductions with semaglutide in participants with hypertension that were similar to those seen in all trial participants. This finding may in part be due to concurrent reductions to anti-hypertensive medications. These results suggest that semaglutide is a useful adjunctive treatment for patients with hypertension and obesity.

1543MO Analysis of concordance between trial and target populations for cancer drugs in the US, EU, and Switzerland (2014-2023)

1543MO Analysis of concordance between trial and target populations for cancer drugs in the US, EU, and Switzerland (2014-2023)

Aging is associated with reduced inflammatory disease activity independent of disease duration in relapsing multiple sclerosis trial populations

Background: Higher age is associated with less inflammatory disease activity in relapsing-remitting multiple sclerosis (RRMS). It is unknown whether age itself or disease duration underlies this association. Objectives: This study investigated the effects of age, disease duration, and inflammatory disease activity in people with RRMS. Methods: Individual patient-level data from five large phase III randomized controlled trials (RCTs) was utilized to investigate the association of both age and disease duration with annualized relapse rate (ARR), contrast-enhancing lesions (CELs), and new T2 lesions on magnetic resonance imaging (MRI) at baseline and follow-up. Results: The data set included 5626 participants. Higher age was associated with lower ARRs, lower CEL number on MRI at baseline and follow-up, and lower new T2 lesion numbers at follow-up. This effect was present in all disease duration groups. For example, we found a lower number of new T2 lesions on MRI during follow-up in higher age groups compared to lower age groups, independent of disease duration. Conclusion: Aging in RRMS is associated with a lower risk of inflammatory disease activity, across different disease durations. Age should be taken into account when designing clinical trials and future research should investigate how age should be integrated into personalized predictions of treatment response and risk profiling.

Effects of Semaglutide on Heart Failure Outcomes in Diabetes and Chronic Kidney Disease in the FLOW Trial

BackgroundPeople with type 2 diabetes (T2D) and chronic kidney disease (CKD) are at high risk for heart failure (HF) and premature death from cardiovascular (CV) causes. The FLOW (Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease), which enrolled participants with T2D and CKD, demonstrated that semaglutide, a glucagon-like peptide-1 receptor agonist, reduced the incidence of the primary composite outcome (persistent ≥50% decline in estimated glomerular filtration rate, persistent estimated glomerular filtration rate <15 mL/min/1.73 m2, kidney replacement therapy, and kidney or CV death) by 24%. ObjectivesThis prespecified analysis examined the effects of semaglutide on HF outcomes in this high-risk population. MethodsParticipants were randomized (1:1) to once-weekly subcutaneous semaglutide 1 mg or placebo. The prespecified main outcome was a composite of HF events (new onset or worsening of HF leading to an unscheduled hospital admission or an urgent visit, with initiation of or intensified diuretic/vasoactive therapy) or CV death. HF data were collected by the investigator. CV death was adjudicated by an independent committee. ResultsA total of 3,533 randomized participants were followed for a median of 3.4 years. HF was present at baseline in 342 participants (19.4%) in the semaglutide group and 336 (19.0%) in the placebo group. In the overall trial population, semaglutide increased time to first HF events or CV death (HR: 0.73; 95% CI: 0.62-0.87; P = 0.0005), HF events alone (HR: 0.73; 95% CI: 0.58-0.92; P = 0.0068), and CV death alone (HR: 0.71; 95% CI: 0.56-0.89; P = 0.0036). The risk reduction for the composite HF outcome was similar in those with (HR: 0.73; 95% CI: 0.54-0.98; P = 0.0338) and without (HR: 0.72; 95% CI: 0.58-0.89; P = 0.0028) HF at baseline. The risk of HF outcomes (HF events or CV death) was generally higher in participants categorized as NYHA functional class III and those with the HF reduced ejection fraction subtype, regardless of treatment. ConclusionsSemaglutide substantially reduced the risk of time to first composite outcome of HF events or CV death, as well as HF events and CV death alone, in a high-risk population with T2D and CKD. These effects were consistent regardless of history of HF. (A Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease [FLOW]; NCT03819153)

Unraveling innovative treatments for spinal muscular atrophy: a brief review

In the past few years, there have been amazing breakthroughs in treating spinal muscular atrophy (SMA), which is a big deal considering it's been studied for over a hundred years. Now, there are three approved therapies that all work to increase SMN protein production. They do this by fixing the genetic problem either by replacing the faulty SMN1 gene or by helping the SMN2 gene produce more of the right kind of protein. One way they do this is by using a special virus called adeno- associated viral vectors (AAV9) to deliver the gene therapy because the SMN1 gene is small enough to fit inside. The paper discusses the evolution of SMA treatment, focusing on advancements like gene therapy and new drug treatments. It highlights challenges in interpreting efficacy, especially regarding disease classification. Despite successes, issues like limited trial populations and varying disease stages pose complexities in care. With expanding treatment options, including those in advanced development stages, the landscape of SMA management grows more intricate. However, the importance of timely diagnosis and interdisciplinary clinical management remains crucial, recognizing that despite drug treatments, many patients still face significant disease burdens. This article aims to give a quick rundown of spinal muscular atrophy, starting from when people first noticed the disease up until now, when there are some really cool new treatments that are changing how the disease affects people.

Cost-effectiveness analysis of dupilumab among patients with uncontrolled severe asthma using LIBERTY ASTHMA QUEST Korean data

BackgroundA sub-analysis of the Korean population in the LIBERTY ASTHMA QUEST trial (NCT02414854) revealed that dupilumab effectively treated severe uncontrolled asthma. This study aimed to assess the cost-effectiveness of add-on therapy with dupilumab to background therapy in patients ≥ 12 years of age with uncontrolled severe asthma compared to that of background therapy in South Korea.MethodsThe cost-effectiveness analysis was conducted using a Markov model over a lifetime from the Korean healthcare system perspective. Clinical efficacy and utility weights were obtained from post-hoc analyses of the Korean population in the QUEST trial. Data on the costs and treatment setting of exacerbation in a real-world setting were retrospectively collected using the administrative medical database from a single tertiary hospital.ResultsThe base-case results indicated that add-on dupilumab therapy increases costs ($112,924 for add-on dupilumab versus $29,545 for background therapy alone). However, add-on dupilumab increased quality-adjusted life years (QALYs, 8.03 versus 3.93, respectively), with fewer events of severe exacerbations per patient compared to using the background therapy alone (17.920 versus 19.911, respectively). The incremental cost-effectiveness ratio was $20,325 per QALY. Various sensitivity analyses supported the robustness of the base-case results. Probabilistic sensitivity analysis showed that the probability of add-on dupilumab being cost-effective was 87% at a threshold willingness-to-pay of $26,718 (KRW 35 million) per QALY gained.ConclusionsDupilumab is cost-effective for adolescents and adults with uncontrolled severe asthma in South Korea. Our study provides evidence to support clinicians and policymakers in making informed decisions for severe asthma management.

Role of the dengue vaccine TAK-003 in an outbreak response: Modeling the Sri Lanka experience.

Outbreaks of dengue can overburden hospital systems, drastically reducing capacity for other care. The 2017 dengue serotype 2 (DENV-2) outbreak in Sri Lanka coincided with vaccination in an ongoing phase 3 efficacy trial of a tetravalent dengue vaccine, TAK-003 (NCT02747927). Here, we present data on the efficacy of TAK-003 following two doses of the vaccine administered 3 months apart in participants aged 4-16 years in Sri Lanka. In addition, we have used the 2017 outbreak dynamics to model the potential impact of TAK-003 on virologically confirmed dengue (VCD) cases and hospitalizations during an outbreak situation. Modeling was performed using an age-structured, host-vector, spatial and stochastic transmission model, assuming 65% vaccine coverage and 30 days until initiation of vaccination. Efficacy of TAK-003 against VCD and hospitalized VCD cases was based on data against DENV-2 from the first year of the phase 3 trial. Vaccine efficacy and safety findings in Sri Lanka were in line with those of the overall trial population. The efficacy estimates in Sri Lanka up to the first 12 months after the second dose of TAK-003 were 94.7% and 95.7% against VCD and hospitalized VCD cases, respectively. Modeling of the trial data over an extended geographic area showed a substantial reduction in cases and a flattening of outbreak curves from TAK-003 use. The baseline vaccination scenario (initiation at 30 days, 65% target coverage, vaccine effective at 14 days, 70% hospitalization rate, VE of 95% for VCD and 97% for hospitalized VCD, and 47% for asymptomatic) resulted in a 69.1% reduction in VCD cases and 72.7% reduction in VCD hospitalizations compared with no vaccination. An extreme high scenario (vaccination initiated at Day 15, 80% coverage rate, baseline VE) resulted in 80.3% and 82.3% reduction in VCD and VCD hospitalizations, respectively. Vaccine performance, speed of vaccination campaign initiation, and vaccine coverage were key drivers in reducing VCD cases and hospitalizations. Overall, the study and modeling results indicate that TAK-003 has the potential of meaningful utility in dengue outbreaks in endemic areas.

Risk factors for development of hyper-reflective foci overlying drusen in eyes with intermediate age-related macular degeneration

AimsThe aim of this study is to assess baseline characteristics of drusen preceding the development of intraretinal hyper-reflective foci (IHRF) in eyes with intermediate age-related macular degeneration (AMD).MethodsIn this retrospective...

Simultaneous Inference Using Multiple Marginal Models.

This tutorial describes single-step low-dimensional simultaneous inference with a focus on the availability of adjusted p values and compatible confidence intervals for more than just the usual mean value comparisons. The basic idea is, first, to use the influence of correlation on the quantile of the multivariate t-distribution: the higher the less conservative. In addition, second, the estimability of the correlation matrix using the multiple marginal models approach (mmm) using multiple models in the class of linear up to generalized linear mixed models. The underlying maxT-test using mmm is discussed by means of several real data scenarios using selected R packages. Surprisingly, different features are highlighted, among them: (i) analyzing different-scaled, correlated, multiple endpoints, (ii) analyzing multiple correlated binary endpoints, (iii) modeling dose as qualitative factor and/or quantitative covariate, (iv) joint consideration of several tuning parameters within the poly-k trend test, (v) joint testing of dose and time, (vi) considering several effect sizes, (vii) joint testing of subgroups and overall population in multiarm randomized clinical trials with correlated primary endpoints, (viii) multiple linear mixed effect models, (ix) generalized estimating equations, and (x) nonlinear regression models.

Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer

Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking. To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer. This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022. Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses. Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively. In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.