Completed Trials Research Articles

Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial.

Data describing the long-term efficacy and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials. Following completion of the parent trial, adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent, or heterozygous familial hypercholesterolaemia received open-label inclisiran twice yearly (after initial and 3-month doses) until Day 990, followed by an end-of-study visit at Day 1080 or ≥ 90 days after the last dose. The study endpoints included the proportion of patients achieving pre-specified low-density lipoprotein cholesterol (LDL-C) goals [ASCVD: < 1.8 mmol/L (< 70 mg/dL); ASCVD risk equivalent: < 2.6 mmol/L (< 100 mg/dL)], percentage and absolute changes in LDL-C at end-of-study, and safety of inclisiran. Of 3274 patients, 2446 (74.7%) were followed until end-of-study. Mean age was 64.9 ± 9.9 years, 82.7% (n = 2709) had ASCVD, and mean baseline LDL-C was 2.9 ± 1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% [95% confidence interval (CI): 76.8, 80.0] of patients achieved pre-specified LDL-C goals and mean percentage change in LDL-C was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at injection site (all mild/moderate) occurred in 5.9% of the patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified. In the largest and longest follow-up to date with >12 000 patient-years exposure, inclisiran demonstrated consistent and effective LDL-C lowering with a favourable long-term safety and tolerability profile. ClinicalTrials.gov identifier: NCT03814187.

A qualitative analysis of post-hoc interviews with multilevel participants of a randomized controlled trial of a community-based intervention.

Community-based health interventions often demonstrate efficacy in clinical trial settings but fail to be implemented in the real-world. We sought to identify the key operational and contextual elements of the Los Angeles Barbershop Blood Pressure Study (LABBPS), an objectively successful community-based health intervention primed for real-world implementation. LABBPS was a cluster randomized control trial that paired the barbers of Black-owned barbershops with clinical pharmacists to manage uncontrolled hypertension in Black male patrons, demonstrating a substantial 21.6 mmHg reduction in systolic blood pressure. Despite this success, the LABBPS intervention has not expanded beyond the original clinical trial setting. The aim of this study was to determine the facilitating and limiting factors to expansion of the LABBPS intervention. We undertook a qualitative assessment of semi-structured interviews with study participants performed after trial completion. Interviews included a total of 31 participants including 20 (6%) of the 319 LABBPS program participants ("patrons"), 10 (19%) barbers, and one (50%) clinical pharmacist. The semi-structured interviews were focused on perceptions of the medical system, study intervention, and influence of social factors on health. Several common themes emerged from thematic analysis of interview responses including: importance of care provided in a convenient and safe environment, individual responsibility for health and health-related behaviors, and engagement of trusted community members. In particular, patrons reported that receiving the intervention from their barber in a familiar environment positively influenced the formation of relationships with clinical pharmacists around shared efforts to improve medication adherence and healthy habits. All interviewee groups identified the trust diad, comprising the familiar environment and respected community member, as instrumental in increasing health-related behaviors to a degree not usually achieved by traditional healthcare providers. In conclusion, participants of an objectively successful community-based intervention trial consistently identified key features that could facilitate wider implementation and efficacy: social trust relationships, soliciting insights of trust bearers, and consistent engagement in a familiar community setting. These findings can help to inform the design and operations of future community-based studies and programs aiming to achieve a broad and sustainable impact.

The most effective corticosteroid dose in the treatment of glenohumeral osteoarthritis: Feasibility pilot and protocol for double blinded randomized controlled trial

ObjectiveOsteoarthritis affects over 5.4 million people in the United States. A common treatment is to perform intra-articular corticosteroid injections. However, the ideal steroid dose is unknown. This study aimed to pilot a corticosteroid injection protocol for primary glenohumeral OA. MethodsWe conducted a double blinded randomized feasibility pilot study. Patients with primary osteoarthritis of the glenohumeral joint were recruited and randomized to receive 20 ​mg, 40 ​mg, or 80 ​mg of triamcinolone. The primary outcome was the feasibility of the protocol and change in the Shoulder Pain and Disability Index (SPADI) 6 months following injection. Results300 patients were screened for participation with 78 meeting inclusion criteria. 19 subjects completed the study. The most common reason for not participating was concern they would receive a smaller dose than previous injections. There was a 26% dropout rate, with 2 patients undergoing a total shoulder arthroplasty. There was no clinically significant difference (p ​= ​0.090) between the groups at 6-months for the SPADI although all treatment groups showed a reduction of SPADI from baseline at 6 months. There was one adverse event in the 20 ​mg group, with a patient experiencing facial flushing after the injection. ConclusionWe were successful in developing a feasible protocol. In the future excluding those who have received previous injections would be helpful for a higher enrollment rate. This patient concern highlights the need to complete clinical trials to guide medical decisions surrounding corticosteroid administration. NCT03586687.

The Role of Fresh Beef Intake and Mediterranean Diet Adherence during Pregnancy in Maternal and Infant Health Outcomes.

Beef is an excellent source of nutrients important for maternal health and fetal development. It is also true that the Mediterranean diet is beneficial for the health of both the mother and offspring; however, the relative value of fresh beef intake within Mediterranean diet patterns during pregnancy is unknown. The objective of this project was two-fold: (1) assess the relationship between beef intake and nutrient intake in a pregnant population; (2) assess the relationship between maternal beef consumption among varying degrees of Mediterranean diet adherence with maternal risk of anemia and infant health outcomes. This is a secondary analysis of an existing cohort of pregnant women (n = 1076) who participated in one of two completed clinical trials examining the effect of a docosahexaenoic acid supplementation on birth and offspring outcomes. Women were enrolled between 12 and 20 weeks of gestation and were followed throughout their pregnancies to collect maternal and infant characteristics, food frequency questionnaires [providing beef intake and Mediterranean diet (MedD) adherence], and supplement intake. Women with the highest fresh beef intake had the highest intake of many micronutrients that are commonly deficient among pregnant women. Fresh beef intake alone was not related to any maternal or infant outcomes. There was a reduced risk of anemia among women with medium to high MedD quality and higher fresh beef intake. Women in the medium MedD group had 31% lower odds of anemia, and women in the high MedD group had 38% lower odds of anemia with every one-ounce increase in fresh beef intake, suggesting that diet quality indices may be misrepresenting the role of fresh beef within a healthy diet. These findings show that beef intake increases micronutrient intake and may be protective against maternal anemia when consumed within a healthy Mediterranean diet pattern.

Upstrapping to determine futility: predicting future outcomes nonparametrically from past data

BackgroundClinical trials often involve some form of interim monitoring to determine futility before planned trial completion. While many options for interim monitoring exist (e.g., alpha-spending, conditional power), nonparametric based interim monitoring methods are also needed to account for more complex trial designs and analyses. The upstrap is one recently proposed nonparametric method that may be applied for interim monitoring.MethodsUpstrapping is motivated by the case resampling bootstrap and involves repeatedly sampling with replacement from the interim data to simulate thousands of fully enrolled trials. The p-value is calculated for each upstrapped trial and the proportion of upstrapped trials for which the p-value criteria are met is compared with a pre-specified decision threshold. To evaluate the potential utility for upstrapping as a form of interim futility monitoring, we conducted a simulation study considering different sample sizes with several different proposed calibration strategies for the upstrap. We first compared trial rejection rates across a selection of threshold combinations to validate the upstrapping method. Then, we applied upstrapping methods to simulated clinical trial data, directly comparing their performance with more traditional alpha-spending and conditional power interim monitoring methods for futility.ResultsThe method validation demonstrated that upstrapping is much more likely to find evidence of futility in the null scenario than the alternative across a variety of simulations settings. Our three proposed approaches for calibration of the upstrap had different strengths depending on the stopping rules used. Compared to O’Brien-Fleming group sequential methods, upstrapped approaches had type I error rates that differed by at most 1.7% and expected sample size was 2–22% lower in the null scenario, while in the alternative scenario power fluctuated between 15.7% lower and 0.2% higher and expected sample size was 0–15% lower.ConclusionsIn this proof-of-concept simulation study, we evaluated the potential for upstrapping as a resampling-based method for futility monitoring in clinical trials. The trade-offs in expected sample size, power, and type I error rate control indicate that the upstrap can be calibrated to implement futility monitoring with varying degrees of aggressiveness and that performance similarities can be identified relative to considered alpha-spending and conditional power futility monitoring methods.

60 Effects of phase feeding rolled hybrid rye on feedlot performance in backgrounded beef steers

Abstract The objective of this study was to evaluate the effects of phase-fed rolled hybrid rye on feedlot performance and carcass characteristics of finishing steers. Backgrounded steers [n = 110; initial shrunk (4% of body weight; BW) = 391 ± 1.3 kg] were assigned to 1 of 14 pens at the Southeast Research Farm, Beresford, SD in a randomized complete block design. Pens were blocked by location with four blocks of dirt-surfaced, outside pens (8 pens; 10 steers/pen) and three blocks of concrete-surfaced, partially covered pens (6 pens; 5 steers/pen). Pens were randomly assigned to one of two dietary treatments (7 pens/treatment): dry rolled corn (DRC) included at 66% diet dry matter (DM) or rolled hybrid rye (RRYE) included at 66% diet DM for the initial 46 d of the experiment followed by the DRC diet from d 47 to trial completion on d 144. One steer was removed from the study because of lameness. During the rye feeding period (d1 to d 46), RRYE decreased average daily gain (ADG) by 13% (P = 0.01; 1.59 and 1.83 kg, respectively) and DMI by 18% (P = 0.01; 8.45 and 10.30 kg, respectively) with no effect (P = 0.15) on gain to feed ratio (G:F) compared with DRC. Negative effects of RRYE were more pronounced during the first 20 d of the experiment with ADG reduced by 29% (P = 0.01; 1.13 and 1.60 kg, respectively), DMI by 15% (P = 0.01; 8.20 and 9.61 kg, respectively), and G:F by 17% (P = 0.01; 0.139 and 0.167, respectively). Dietary net energy values for RRYE were increased (P ≤ 0.03) from d 1 to 46. Feeding rye reduced BW on d 46 by 10 kg compared with DRC (P = 0.01; 474 and 464 kg, respectively). From d 47 to 144 when all steers were fed a common diet there were no differences (P ≥ 0.38) in any growth performance responses or measures of dietary net energy utilization. When measured over the entire experiment, DMI tended to be less (P = 0.08) for RRYE compared with DRC with no effect on ADG or G:F (P ≥ 0.19). Final BW was numerically reduced in the RRYE treatment compared with DRC (P = 0.21; 614 and 623 kg, respectively). Cumulative observed-to-expected ratios for NEm and NEg were increased (P = 0.05) for RRYE compared with DRC. Dietary treatments did not affect (P ≥ 0.29) carcass characteristics, distribution of USDA yield or quality grades, or liver abscess incidence or severity. Feeding rolled rye decreased ADG, DMI, and G:F during the first 46 DOF with similar growth performance when fed a DRC-based diet for the final 98 d.

Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura

BackgroundCongenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known.MethodsIn this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment.ResultsA total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy.ConclusionsDuring prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.)

Abstract PO4-11-09: Feasibility of physical activity behaviour change for women living with metastatic breast cancer, a randomised controlled trial

Abstract Background Physical activity benefits women living with metastatic breast cancer by improving outcomes such as physical function, health-related quality of life and fatigue. These findings have been reported within well-resourced trials that involve exercise equipment and supervision. Home or community-based settings, however, may be preferable and more accessible. This trial evaluated the feasibility of a remotely delivered behaviour change intervention for increasing physical activity for women living with metastatic breast cancer, and evaluated the program’s efficacy. Methods A 12-week randomised controlled trial was conducted in which 20 women living with metastatic breast cancer were recruited from a metropolitan outpatient cancer clinic. Inclusion criteria were over 18 years old, English speaking, ambulatory, and not regularly active at time of recruitment. Participants were randomised 1:1 to an intervention or attention control group. Both groups received a recommendation for 150 minutes of physical activity, a wrist-worn activity monitor, a physical activity diary, and nine phone or video call sessions (six weekly, three fortnightly). The intervention group received individualised behaviour change advice on topics such as physical activity benefits, motivation, barriers and social support; the attention control group received a recurring symptom questionnaire and no behavioural advice. Feasibility outcomes included recruitment, dropout and session adherence rates, and acceptability of methods was evaluated with an interview at trial completion. Baseline and 12-week outcomes included: i) physical activity minutes measured with a 5-day Actigraph wear, ii) 6-minute walk distance, iii) 30-second sit-to-stands, iv) questionnaires for self-reported physical activity, health-related quality of life, fatigue, behavioural factors (stage of change, self-efficacy, decisional balance, processes of change, social support), and patient-specific function. Questionnaires were measured again at 18 weeks. Results Recruitment, baseline measures and within-trial sessions are completed; 12 and 18-week measures will conclude late August. Thirty-two women were approached to enrol the target sample of 20, with exclusion reasons being disinterest (n=5), health problems (n=4), loss of contact (n=2) and already physically active (n=1). Median age was 62 years (IQR: 60-69), and median time since metastatic diagnosis was 4 years (IQR: 1-5). Twelve women had bone metastases, and ten had a musculoskeletal comorbidity. Session delivery through video or phone calls were equally preferred (n=10 each). Participants completed 84% of the sessions, with reasons for missed sessions consisting of forgetting (55%), feeling unwell (24%), IT problems (7%), holiday (7%), and work commitments (7%). Median session duration for the intervention group was 23 minutes (IQR: 20-28), and control group was 17 minutes (IQR: 14-21). The preferred type of physical activity was predominantly walking, and no adverse events were reported. Four women dropped out after loss of contact. Compared to age-matched normative values, baseline outcomes varied: actigraphy-measured physical activity was low (median: 68 minutes/day, IQR: 45-88), self-reported physical activity was high (median: 289 MET-minutes/day, IQR: 52-728), 6-minute walk distance was equal (median: 529m, IQR: 416-579), 30-second sit-to-stands were low (median: 11, IQR: 8-14), health-related quality of life was high (median: 80, IQR: 70-100), and fatigue was equal (median: 30, IQR 20-40). Conclusions Women living with metastatic breast cancer were generally receptive of the trial, and recruitment, dropout and session adherence rates were positive. The women who dropped out were more physically active, physically functional and/or rated higher on the questionnaires, indicating that the trial may be more suited to those with limited physical activity experience. Citation Format: Mark Liu, Sharon Kilbreath, Elizabeth Dylke, Jasmine Yee, Jane Beith. Feasibility of physical activity behaviour change for women living with metastatic breast cancer, a randomised controlled trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-11-09.

Abstract PS05-07: Early prediction of response to Neoadjuvant Immunotherapy in Triple Negative Breast Cancer (TNBC) with DCE-MRI

Abstract Purpose: Neoadjuvant immunotherapy (NIT) in combination with neoadjuvant chemotherapy (NCT) was recently approved for treatment of TNBC patients with increased rates of pathologic complete response (pCR) compared to NCT alone. The aim of this study was to evaluate if dynamic contrast-enhanced (DCE)-MRI performed after 2 and/or 4 cycles of NIT + NCT, can predict which patients will achieve pCR, potentially triaging them to continuation of NIT+NCT or, when appropriate, to de-escalation trials. Alternatively, identified chemoresistant tumors who are unlikely to achieve pCR may be directed to other treatment strategies, including novel targeted trials, and avoid the unnecessary toxicity of NIT. Methods and Materials: Preliminary analysis included 64 patients from prospective IRB-approved study (NCT02276443) with stage I-III TNBC who underwent DCE-MRI at baseline (BL), after 2 cycles (C2), and 4 cycles (C4) of NIT combined with standard of care NCT (Paclitaxel +/- carboplatin). Tumor volumes were calculated using 3 axis measurements of the index lesion at the DCE MRI and percent tumor volume reduction (TVR) between BL, C2, and C4 was calculated. pCR was assessed at surgery after completion of neoadjuvant treatment. Correlation between pCR and TVR was evaluated using ROC analysis. Results: 59% (38/64) of TNBC patients achieved pCR after NIT+NCT. DCE-MRI after 2 cycles of NIT+NCT was able to predict pCR with an AUC of 0.71 (95% CI: 0.57-0.84). TVR &amp;gt;90% at C2 predicted pCR with PPV 86%, and TVR &amp;lt; 35% predicted chemoresistance with NPV 100%. Following 4 cycles of treatment DCE-MRI was able to predict pCR with an AUC of 0.81 (95% CI: 0.69-0.92). TVR &amp;gt;95% at C4 was predictive of chemosensitivity with PPV 82%, while TVR &amp;lt; 75% was predictive of chemoresistance with NPV 100%. Conclusions: DCE-MRI volumetric changes early during NIT + NCT were able to predict pCR status of TNBC patients as either excellent responders or nonresponders, triaging them to SOC neoadjuvant therapy with option for de-escalation trials, or targeted therapies, respectively. These preliminary results will be validated in the larger cohort after completion of the ongoing prospective clinical trial. Citation Format: Gaiane Rauch, Mary Guirguis, Miral Patel, Rosalind Candelaria, Rania Mohamed, Tanya Moseley, H. T. Carisa Le-Petross, Jessica Leung, Gary Whitman, Deanna Lane, Marion Scoggins, Frances Perez, Jia Sun, Sanaz Pashapoor, Zhan Xu, Jason White, Peng Wei, Brandy Reed, Jong Bum Son, Ken-Pin Hwang, Bikash Panthi, Anil Korkut, Lei Huo, Kelly Hunt, Alyson Clayborn, Jennifer Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Wei Yang, Jingfei Ma, Beatriz Adrada. Early prediction of response to Neoadjuvant Immunotherapy in Triple Negative Breast Cancer (TNBC) with DCE-MRI [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS05-07.

Pediatric immunotherapy and HIV control.

Highlighting opportunities/potential for immunotherapy by understanding dynamics of HIV control during pediatric HIV infection with and without antiretroviral therapy (ART), as modeled in Simian immunodeficiency virus (SIV) and Simian-human immunodeficiency virus (SHIV)-infected rhesus macaques and observed in clinical trials. This review outlines mode of transmission, pathogenesis of pediatric HIV, unique aspects of the infant immune system, infant macaque models and immunotherapies. During the earliest stages of perinatal HIV infection, the infant immune system is characterized by a unique environment defined by immune tolerance and lack of HIV-specific T cell responses which contribute to disease progression. Moreover, primary lymphoid organs such as the thymus appear to play a distinct role in HIV pathogenesis in children living with HIV (CLWH). Key components of the immune system determine the degree of viral control, targets for strategies to induce viral control, and the response to immunotherapy. The pursuit of highly potent broadly neutralizing antibodies (bNAbs) and T cell vaccines has revolutionized the approach to HIV cure. Administration of HIV-1-specific bNAbs, targeting the highly variable envelope improves humoral immunity, and T cell vaccines induce or improve T cell responses such as the cytotoxic effects of HIV-1-specific CD8+ T cells, both of which are promising options towards virologic control and ART-free remission as evidenced by completed and ongoing clinical trials. Understanding early events during HIV infection and disease progression in CLWH serves as a foundation for predicting or targeting later outcomes by harnessing the immune system's natural responses. The developing pediatric immune system offers multiple opportunities for specific long-term immunotherapies capable of improving quality of life during adolescence and adulthood.

Abstract PO1-10-11: Illuminating Breast Cancer Clinical Trials: Unpublication Rates, Causes , and Recommendations

Abstract Introduction: Breast cancer stands as the most prevalent cancer among women worldwide. Recent years have witnessed remarkable improvements in patient’s outcome, primarily attributed to advancements in management strategies. However, the introduction of novel management approaches necessitates rigorous evaluation through clinical trials, ensuring both their safety and effectiveness. Conducting these trials entails significant financial investments and time commitments, making them susceptible to termination for various reasons. This study aims to investigate the factors that contribute to an increased likelihood of breast cancer clinical trial termination. Methodology: A thorough and extensive exploration of ClinicalTrials.gov was undertaken in order to discover completed clinical trials focused on treating breast cancer from 2000 to 2020. By employing the distinctive National Clinical Trial number (NCT) identifier, trial's status; whether completed or terminated, was determined. Subsequently, a meticulous evaluation was carried out on these trials to ascertain the factors that contributed to their termination. In order to unveil the noteworthy factors linked to publication, a comprehensive analysis encompassing both univariate and multivariate approaches was conducted. Results: During the specified period, a noteworthy number of oncology clinical trials, totaling 9,145, were conducted. Among them, 12.3% (n=1,127) were focused on breast cancer. These breast cancer trials managed to recruit an impressive 2,669,749 patients. However, it is concerning to note that a significant portion, 38.1% (n=429), of the breast cancer trials did not result in published findings, despite enrolling a considerable number of patients (n= 2,397,179). Our comprehensive univariate analysis revealed several significant associations between the characteristics of clinical trials and their likelihood of going unpublished (P&amp;lt; 0.001). Factors such as funding, phase, masking, center type (single vs multi), and country of conduct were all found to have a statistically significant impact on the publication status. Furthermore, our meticulous multivariate analysis demonstrated that certain criteria were associated with higher odds of publication. These included trials that recruited &amp;gt;50 patients, multicenter trials, studies implemented masking, phase-3 trials and those that included low- and middle-income countries (LMIC), Table. Conclusion: Our findings indicate that the unpublication rate of clinical trials was alarmingly high. We identified that the sample size, masking, multicenter involvement and phase of the trial impact significantly on publication rate . This knowledge can be valuable for researchers, funding agencies, and other stakeholders who can prioritize resource allocations and improve patients care. Table: Multivariate analysis, factors that impact publication rate Citation Format: Abdulrahman Alhajahjeh, Ghayda’ Bader, Saji Aweidah, Taima’ Bader, Basil Abdin, Layla El-Amayreh, Hikmat Abdel-Razeq. Illuminating Breast Cancer Clinical Trials: Unpublication Rates, Causes , and Recommendations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-10-11.

LEGACY EFFECT OF EXERCISE TRAINING TRIALS ON COGNITION IN OLDER ADULTS: SYSTEMATIC REVIEW AND META-ANALYSIS

INTRODUCTION &amp; AIMS Exercise training trials consistently show efficacy for improving cognitive outcome in older adults, especially when the intervention is supervised. However, whether this improvement in cognition is sustained long-term (i.e. a legacy effect) is unknown. While this is likely impacted by long-term adherence to exercise, the legacy effect of exercise training trials on cognition has not been established. Therefore, the aim of this study was to review the literature and investigate the legacy effect of an exercise trial on cognitive function in older adults. METHODS A systematic review of the literature published in English was conducted in PubMed, Scopus, CINAHL, SPORTdiscus, Web of Science and Cochrane Central Register of Controlled Trials electronic databases. Study screening and data extraction were undertaken by two independent researchers. The main inclusion criteria were randomised controlled trial design with non-exercise control, older adult cohort (average age ≥50 years), supervised exercise intervention and cognitive assessments at post-trial and follow up (≥3 months). Pairwise random-effects restricted maximum likelihood meta-analysis estimated the standardised mean difference (Hedges’ g) between intervention and control groups for each cognitive function outcomes at post-trial and follow-up. RESULTS A total of 12,539 articles were screened with 21 trials (n=2,504 participants aged 75.2±6.4 and mostly (56%) female) included in a meta-analysis. After 5.2±3.2 months, a legacy effect was seen with a small-to-moderate between-group effect for the cognitive domain of executive function favouring the exercise interventions (SMD=0.30, 95% CI 0.11 to 0.49; p=0.002). No effect was observed for other cognitive domains. The Cochrane risk-of-bias tool for randomized trials (RoB2) tool identified that 73.7% of the trials had “some concerns” and 26.3% had high risk for bias. CONCLUSION In older adults who received an exercise intervention there was a small-to-moderate legacy effect for improved executive function compared to controls, five months after trial completion.

The role of systemic therapy in advanced skull base chordomas: overview of the current state and the MD Anderson protocol.

The role of systemic therapy in primary or advanced and metastatic chordoma has been traditionally limited because of the inherent resistance to cytotoxic therapies and lack of specific or effective therapeutic targets. Despite resection and adjuvant radiation therapy, local recurrence rates in clival chordoma remain high and the risk of systemic metastases is not trivial, leading to significant morbidity and mortality. Recently, molecular targeted therapies (MTTs) and immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic avenues in chordoma. In recent years, preclinical studies have identified potential targets based on intrinsic genetic dependencies, epigenetic modulators, or newly identified tumor-associated cell populations driving treatment resistance and recurrence. Nonetheless, the role of systemic therapies in the neoadjuvant or adjuvant setting for primary, locally progressive, and distant metastatic chordomas is still being investigated. Herein, an overview of current and emerging systemic treatment strategies in advanced clival chordoma is provided. Furthermore, several molecular biomarkers have been recently uncovered as potential predictors of the response to specific molecular therapeutics. The authors describe the recently discovered role of 1p36 and 9p21 deletions as biomarkers capable of guiding drug selection. Then they discuss completed and ongoing clinical trials of MTTs, including several tyrosine kinase inhibitors used as monotherapy or in combination, such as imatinib, sorafenib, dasatinib, and lapatinib, among others, as well as mammalian target of rapamycin inhibitors such as everolimus and rapamycin. They present their experience and other recent studies demonstrating vast benefits in advanced chordoma from ICIs. Additionally, they provide a brief overview of novel systemic strategies such as adoptive cell transfer (CAR-T and NK cells), oncolytic viruses, epigenetic targeting (KDM6, HDAC, and EZH2 inhibitors), and several promising preclinical studies with high translational potential. Finally, the authors present their institutional multidisciplinary protocol for the incorporation of systemic therapy for both newly diagnosed and recurrent chordomas based on molecular studies including upfront enrollment in MTT trials in patients with epidermal growth factor receptor upregulation or INI-1 deficiency or enrollment in ICI clinical trials for patients with high tumor mutational burden or high PD-L1 expression on tumor cells or in the tumor microenvironment.

Regulatory gaps and research waste in clinical trials involving women with metastatic breast cancer in Germany

Background Non-publication, incomplete publication and excessively slow publication of clinical trial outcomes contribute to research waste and can harm patients. While research waste in German academic trials is well documented, research waste in Germany related to a specific disease area across non-commercial and commercial sponsors has not previously been assessed. Methods In this cohort study, we used public records from three clinical trial registries to identify 70 completed or terminated clinical trials involving women with metastatic breast cancer with trial sites in Germany. We then searched registries and the literature for trial outcomes and contacted sponsors about unreported studies. Results We found that 66/70 trials (94.3%) had made their results public. Only 13/70 (18.6%) trials had reported results within one year of completion as recommended by the World Health Organisation (WHO). The outcomes of 4/70 trials (5.7%) had not been made public at all, but only one of those trials had recruited a significant number of patients. Conclusions Discussions about research waste in clinical trials commonly focus on weakly designed or unreported trials. We believe that late reporting of results is another important form of research waste. In addition, a discussion regarding the appropriate ethical and legal rules for reporting the results of terminated trials might add value. German legislation now requires sponsors to upload the results of some clinical trials onto a trial registry within one year of trial completion, but these laws only cover around half of all trials. Our findings highlight the potential benefits of extending the scope of national legislation to cover all interventional clinical trials involving German patients.

Low-rank human-like agents are trusted more and blamed less in human-autonomy teaming.

If humans are to team with artificial teammates, factors that influence trust and shared accountability must be considered when designing agents. This study investigates the influence of anthropomorphism, rank, decision cost, and task difficulty on trust in human-autonomous teams (HAT) and how blame is apportioned if shared tasks fail. Participants (N = 31) completed repeated trials with an artificial teammate using a low-fidelity variation of an air-traffic control game. We manipulated anthropomorphism (human-like or machine-like), military rank of artificial teammates using three-star (superiors), two-star (peers), or one-star (subordinate) agents, the perceived payload of vehicles with people or supplies onboard, and task difficulty with easy or hard missions using a within-subject design. A behavioural measure of trust was inferred when participants accepted agent recommendations, and a measure of no trust when recommendations were rejected or ignored. We analysed the data for trust using binomial logistic regression. After each trial, blame was apportioned using a 2-item scale and analysed using a one-way repeated measures ANOVA. A post-experiment questionnaire obtained participants' power distance orientation using a seven-item scale. Possible power-related effects on trust and blame apportioning are discussed. Our findings suggest that artificial agents with higher levels of anthropomorphism and lower levels of rank increased trust and shared accountability, with human team members accepting more blame for team failures.

Viral Kinetics Model of SARS-CoV-2 Infection Informs Drug Discovery, Clinical Dose, and Regimen Selection.

Quantitative systems pharmacology (QSP) has been an important tool to project safety and efficacy of novel or repurposed therapies for the SARS-CoV-2 virus. Here, we present a QSP modeling framework to predict response to antiviral therapeutics with three mechanisms of action (MoA): cell entry inhibitors, anti-replicatives, and neutralizing biologics. We parameterized three distinct model structures describing virus-host interaction by fitting to published viral kinetics data of untreated COVID-19 patients. The models were used to test theoretical behaviors and map therapeutic design criteria of the different MoAs, identifying the most rapid and robust antiviral activity from neutralizing biologic and anti-replicative MoAs. We found good agreement between model predictions and clinical viral load reduction observed with anti-replicative nirmatrelvir/ritonavir (Paxlovid®) and neutralizing biologics bamlanivimab and casirivimab/imdevimab (REGEN-COV®), building confidence in the modeling framework to inform a dose selection. Finally, the model was applied to predict antiviral response with ensovibep, a novel DARPin therapeutic designed as a neutralizing biologic. We developed a new in silico measure of antiviral activity, area under the curve (AUC) of free spike protein concentration, as a metric with larger dynamic range than viral load reduction. By benchmarking to bamlanivimab predictions, we justified dose levels of 75, 225, and 600 mg ensovibep to be administered intravenously in a Phase 2 clinical investigation. Upon trial completion, we found model predictions to be in good agreement with the observed patient data. These results demonstrate the utility of this modeling framework to guide the development of novel antiviral therapeutics.

E070 Sustained and consistent efficacy of bimekizumab in patients with active psoriatic arthritis regardless of prior TNF-inhibitor status: results from the phase 3 BE OPTIMAL and BE COMPLETE trials

Abstract Background/Aims Bimekizumab (BKZ), a humanised monoclonal IgG1 antibody that inhibits IL-17A and IL-17F, has demonstrated rapid efficacy in joint and skin outcomes for patients with active psoriatic arthritis (PsA) who are bDMARD-naïve (BE OPTIMAL; NCT03895203) and TNFi-inadequate responders (TNFi-IR) (BE COMPLETE; NCT03896581). Here we report longer-term PsA response criteria (PsARC) response, along with health-related quality of life (HRQoL) outcomes in BE OPTIMAL and BE COMPLETE. Methods BE OPTIMAL and BE COMPLETE were randomised multicentre, double-blind, placebo (PBO)-controlled, parallel-group, phase 3 trials. BE OPTIMAL included a 16-week (Wk) double-blind, PBO-controlled period and a 36-Wk active-treatment period. Patients were randomised (3:2) to receive BKZ 160mg Q4W, or PBO. At Wk16, PBO patients switched to BKZ. In BE COMPLETE, patients with inadequate response or intolerance to TNFis were randomised (2:1) to receive either BKZ 160mg Q4W or PBO for 16Wks after which they were eligible for entry into BE VITAL (NCT04009499; open-label extension). We report PsARC response rates at Wk52 (BE OPTIMAL) and Wk40 (BE COMPLETE). Additionally, the association of PsARC responders with HRQoL-related outcomes (HAQ-DI, FACIT-Fatigue and SF-36) for the randomised set are also reported. Data are reported as non-responder imputation (NRI) and observed cases (OC). Results In BE OPTIMAL, 821/852 (96.4%) patients completed Wk16 and 761 (89.3%) completed Wk52. In BE COMPLETE, 388/400 (97%) patients completed Wk16, 377 (94.3%) entered BE VITAL and 360 (90.0%) completed Wk40. Baseline characteristics were comparable between groups within both trials. In BE OPTIMAL, PsARC response (NRI) was achieved by 80.3% BKZ and 40.2% PBO patients at Wk16 and was sustained or increased at Wk52 to 79.1% BKZ and 79.7% PBO/BKZ patients. In BE COMPLETE, PsARC response (NRI) was achieved by 85.4% BKZ and 30.8% PBO at Wk16 and was sustained or increased at Wk40 to 77.9% BKZ and 75.2% PBO/BKZ patients. Clinically meaningful improvements in HAQ-DI and SF 36-PCS scores, and FACIT-Fatigue were achieved from baseline among PsARC responders compared to non-responders (Table). Conclusion Improvements in PsARC were sustained up to 1 year in BKZ-treated patients and associated with improvement in HRQoL and fatigue, regardless of whether patients were bDMARD-naïve (BE OPTIMAL) or TNFi-IR (BE COMPLETE). Disclosure W.R. Tillett: Other; WRT has received Research funding, consulting and or speaker fees from: Abbvie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer and UCB Pharma. B. Ink: Shareholder/stock ownership; BI is a shareholder of AbbVie, GlaxoSmithKline and UCB Pharma. R. Bajracharya: Other; RB is an employee and shareholder of UCB Pharma. V. Taieb: Other; VT is an employee of UCB Pharma. P. Sharma: Other; PS has done Advisory Board for UCB Pharma. D. McGonagle: Grants/research support; DM has received research grants/research support from AbbVie, Celgene, Janssen, Merck, and, Pfizer. Other; DM has received honoraria or consultation fees and has been paid as a speaker for AbbVie, Celgene, Janssen, Merck, Novartis, Pfizer, and UCB Pharma. L.C. Coates: Consultancies; LCC has worked as a paid consultant for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Moonlake, Novartis, Pfizer and UCB Pharma. Grants/research support; LCC has received grants/research support from AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer and UCB Pharma. Other; LCC has been paid as a speaker for AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Medac, Novartis, Pfizer and UCB Pharma. I.B. McInnes: Grants/research support; IM has received grants/research support from Astra Zeneca, Abbvie, BMS, Compugen, Cabaletta, EveloBio, Eli Lilly, GSK, Janssen, Novartis, Moonlake, Novartis, Sanofi, UCB Pharma, XinThera.

Factor XI: structure, function and therapeutic inhibition.

Arterial and venous thromboembolism is a major medical concern that requires therapeutic anticoagulation in various medical fields to prevent its drastic consequences. Despite significant advances in anticoagulant therapy, thrombosis remains a leading cause of morbidity and mortality worldwide. Traditional anticoagulants like heparin and vitamin K antagonists (VKAs) have shown efficacy in preventing and treating thrombosis but come with an inherent risk of bleeding due to their non-specific inhibition of multiple coagulation factors. Subsequent direct oral anticoagulants (DOACs), targeting specific factors such as Xa or thrombin, demonstrated improved safety profiles compared to VKAs, yet bleeding remains a concern. Accordingly, research is focused on developing anticoagulants with improved safety profiles. A safer class of anticoagulants would have broad appeal. The intrinsic pathway of coagulation, involving factor XI (FXI), has attracted attention as a potential target for safer anticoagulants. Preclinical studies and epidemiological data indicate that FXI deficiency or inhibition protects against thrombosis with minimal bleeding. Current research involves evaluating various FXI-directed strategies, and phase 2 studies have shown promising results in orthopedic surgery, atrial fibrillation, end-stage renal disease (ESRD), myocardial infarction, and ischemic stroke. Several agents, such as antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers, have been developed to inhibit FXI at different stages, offering potentially safer alternatives to traditional anticoagulants. However, the optimal balance between preventing thrombosis and the risk of bleeding associated with FXI inhibitors requires validation through extensive phase 3 clinical trials using definite clinical endpoints. Several of such trials are currently underway or planned to define the role of FXI inhibitors in clinical practice and determine the most suitable FXI inhibitor for each specific indication. The current review highlightsthe rationale behind developing FXI inhibitors, presenting the most advanced agents in development, summarizing completed clinical trials, and discussing ongoing research efforts.

Applying Exercise Capacity and Physical Activity as Single vs Composite Endpoints for Trials of Cardiac Rehabilitation Interventions: Rationale, Use-case, and a Blueprint Method for Sample Size Calculation

ObjectiveTo conceptualize a composite primary endpoint for parallel-group RCTs of exercise-based cardiac rehabilitation (CR) interventions and to explore its application and statistical efficiency. DesignWe conducted a statistical exploration of sample size requirements. We combined exercise capacity and physical activity for the composite endpoint (CE), both being directly related to reduced premature mortality in patients with cardiac diseases. Based on smallest detectable and minimal clinically important changes (change in exercise capacity of 15 W and change in physical activity of 10 min/day), the CE combines 2 dichotomous endpoints (achieved/not achieved). To examine statistical efficiency, we compared sample size requirements based on the CE to single endpoints using data from 2 completed CR trials. SettingCardiac rehabilitation phase III. ParticipantsPatients in cardiac rehabilitation. InterventionsNot applicable. Main Outcome Measure(s)Exercise capacity (Pmax assessed by incremental cycle ergometry) and physical activity (daily minutes of moderate to vigorous physical activity assessed by accelerometry). ResultsExpecting, for example, a 10% between-group difference and improvement in the clinical outcome, the CE would increase sample size by up to 21% or 61%, depending on the dataset. When expecting a 10% difference and designing an intervention with the aim of non-deterioration, the CE would allow to reduce the sample size by up to 55% or 70%. ConclusionsTrialists may consider the utility of the CE for future studies in exercise-based CR to reduce sample size requirements. However, perhaps surprisingly at first, the CE could also lead to an increased sample size needed, depending on the observed baseline proportions in the trial population and the aim of the intervention.

Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.

Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.