Results Of Trial Research Articles

Food allergy in children: treatment challenges and outcome standardization

Relevance. Food allergy (FA) is an important public health concern, particularly among children, with an increasing prevalence. It is associated with a significant decrease in the quality of life for patients and their families due to the need to avoid allergens and the risk of severe allergic reactions, such as anaphylaxis. Despite active research, the primary treatment remains elimination diets, which limit patients’ options and highlight the need for new therapeutic solutions.Aim of the review. This review aims to summarize the current treatment methods for food allergy, discuss the challenges in evaluating the effectiveness of interventions, and highlight the importance of standardizing outcomes in clinical trials to improve comparability and practical relevance.Content. The review discusses modern therapeutic approaches for food allergy, such as oral, epicutaneous, and sublingual immunotherapies, which have shown positive results in achieving tolerance to allergens. Special attention is given to safety concerns, particularly for children, emphasizing the need for further research. The potential use of biological agents, such as omalizumab, in food allergy treatment is also explored. The review addresses challenges in choosing and standardizing endpoints in clinical trials, where most focus on desensitization and immunological markers, while patient-centered outcomes, such as quality of life, remain under-researched. The implementation of “core outcome sets” is highlighted as an important step toward improving data comparability and forming a more objective basis for clinical recommendations.Conclusions. The review emphasizes significant progress in food allergy treatment but notes the need for further research to ensure the safety of new therapies, particularly for children. Standardizing outcomes in clinical trials plays a key role in improving the quality and comparability of research, which will, in turn, help develop more effective clinical guidelines and improve patients’ quality of life.

8753 Efficacy and safety of bempedoic acid for patients with type 2 diabetes and hypercholesterolemia: a meta-analysis of randomized trials and post-hoc studies

Abstract Disclosure: A. Godoi: None. C.H. Silva: None. L.C. Hespanhol: None. P. Romeiro: None. C. Silva: None. C.A. Balieiro: None. T. Texeira: None. Background: Statins, the primary treatment for lowering LDL cholesterol and cardiovascular risk, have been associated with a worsened glycemic control. Moreover, several patients with hypercholesterolemia, including those with type 2 diabetes mellitus (T2DM), are unable to meet treatment goals with statins. Bempedoic acid (BA) has shown promising results in trials with patients with high cholesterol and cardiovascular disease, however, its efficacy in a population restricted to patients with T2DM remains unclear. Purpose: To perform a systematic review and meta-analysis comparing the therapeutic efficacy and safety of BA versus placebo in patients with T2DM and hypercholesterolemia. Methods: PubMed, Cochrane Central and Embase were systematically searched up to January 2024 include randomized controlled studies (RCTs) and post-hoc studies assessing the use of BA in a population of patients with T2DM on prior lipid-lowering therapy. Efficacy outcomes assessed were mean change in low-density lipoprotein C (LDL-C), high-density lipoprotein C (HDL-C), and non-HDL, as well as an increase in HbA1c. Safety outcomes included incidence of hyperglycemia, gout, myalgia and treatment discontinuation due to adverse events. Outcomes were pooled using risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). Statistical analysis was performed with RevMan 5.4.1 and R Studio software. Heterogeneity was assessed with I² statistics. The protocol was registered in PROSPERO. Results: A total of seven RCTs with 7475 patients with T2DM were included, of whom 3842 (51.4%) were allocated to use BA and 3633 (48.6%) were allocated to placebo. Follow-up time ranged from 2 to 52 weeks. The use of BA was associated with a significantly lower LDL-C (MD -30.19mg/dL; -37.56 to -22.82 95% CI; p<0.001), and non-HDL (MD -20.05mg/dL; -20.15 to -19.95 95% CI; p<0.001), although with a lower HDL-C (MD -5.00mg/dL; -5.01 to -4.99 95% CI; p<0.001) compared to placebo. Furthermore, BA use results in significantly lower rates of myalgia (RR 0.74; 0.60 to 0.91 95%CI; p=0.004). There were no differences regarding HbA1c increase (p=0.13), treatment discontinuation (p=0.51), hyperglycemia (p-0.57), or gout (p=0.05) between groups. Conclusion: In this meta-analysis of randomized trials and post-hoc studies, the use of BA was associated with an improved lipid profile without worsening glycemic control or causing significant adverse events, although at the cost of a lower HDL-C. Presentation: 6/1/2024

12542 Results Of The Foresight Trial Support The Efficacy And Safety Of Once-weekly Lonapegsomatropin In Adults With Growth Hormone Deficiency (ghd)

Abstract Disclosure: B.M. Biller: Consulting Fee; Self; HRA Pharmaceuticals, Novartis Pharmaceuticals, Sparrow, Strongbridge Biopharma. Grant Recipient; Self; Strongbridge Biopharma. A. Gilis-Januszewska: Speaker; Self; Ipsen, Novartis Pharmaceuticals, Novo Nordisk, Recordati, Teva Pharmaceutical Industries Ltd.. M. Doknic: None. A.M. Pico: None. M. Fleseriu: Consulting Fee; Self; Ascendis, GlaxoSmithKline, Johnson &Johnson, Karyopharm, Novo Nordisk, Pfizer, Inc., Pharmacosmos. Research Investigator; Self; Ascendis. G. Raverot: None. A.M. Isidori: None. Y. Takahashi: None. J.M. Garcia: None. J.M. Silverstein: None. I. Bancos: None. E. Huang: Employee; Self; Ascendis Pharma, Inc. J. Kang: Employee; Self; Ascendis Pharma, Inc. A.S. Komirenko: Employee; Self; Ascendis Pharma, Inc. L. Domrzalski: Employee; Self; Ascendis Pharma, Inc. A. Shu: Employee; Self; Ascendis Pharma, Inc. K. Yuen: Advisory Board Member; Self; Amryt, Ascendis, Corcept, Crinetics, Novo Nordisk, Recordati, Strongbridge, Xeris. Grant Recipient; Self; Amryt, Ascendis, Corcept, Crinetics. Speaker; Self; Corcept, Novo Nordisk, Recordati. Background: Adult GHD (aGHD) is characterized by metabolic abnormalities due to insufficient growth hormone (GH) production. Lonapegsomatropin was designed to provide sustained release of unmodified somatropin, with the identical amino acid sequence as endogenous GH, and once-weekly injection reduces the burden of daily GH replacement therapy. MethodsForesiGHt was a randomized, parallel-3-arm, placebo(PL)-controlled (double-blind) and active-controlled (open-label) trial designed to establish the efficacy and safety of lonapegsomatropin in aGHD. It evaluated 259 adults with GHD across 21 countries who were GH treatment-naïve or not treated with GH in the prior year, randomized 1:1:1 to receive lonapegsomatropin, once-weekly PL, or daily somatropin (dGH). Fixed dosing was based on age and oral estrogen intake, and designed to be comparable across lonapegsomatropin and dGH arms. Following a 12-week (w) titration period to target maintenance dose, fixed doses were administered for 26w. ResultsBaseline (BL) characteristics were similar between arms. Lonapegsomatropin demonstrated superiority on the primary efficacy endpoint of change from BL in trunk percent fat at Week 38 vs PL (lonapegsomatropin -1.7% vs PL 0.4%, LS mean difference -2.0%, p < 0.0001) and on the key secondary efficacy endpoints of change from BL in total body lean mass (lonapegsomatropin 1.6 kg vs PL -0.1 kg, LS mean difference 1.7 kg, p < 0.0001) and change from BL in trunk fat mass (lonapegsomatropin -0.5 kg vs PL 0.2 kg, LS mean difference -0.7 kg, p = 0.0053). Mean total exposure and maintenance doses were similar for lonapegsomatropin and dGH arms, with larger changes from BL in average IGF-I SDS mean at Week 38 in the lonapegsomatropin arm (1.4) vs dGH arm (0.5). To assess outcomes at comparable weekly IGF-I exposure, a post-hoc analysis was performed in a subset of participants with average IGF-I SDS ≤1.75 SDS at Week 38. Mean IGF-I SDS for these subsets were similar (lonapegsomatropin -0.1, dGH -0.5), and comparable effects in fat and lean tissue compartments were demonstrated (change from BL in trunk percent fat mean -2.4% and -2.6% respectively; change from BL in total body lean mass mean 1.7 kg and 1.4 kg respectively). In the safety population, the incidence of severe AEs was low (lonapegsomatropin, 3.4%; placebo, 1.2%; dGH, 2.3%) and the incidence of treatment-related AEs was similar (lonapegsomatropin 24.7%, dGH 22.1%). Injection site reaction incidence was low and similar for lonapegsomatropin (4.5%), dGH (5.8%) and placebo (4.8%), and A1c levels remained stable in all treatment arms. ConclusionsThe results of the foresiGHt trial indicate that lonapegsomatropin is a safe, efficacious, and tolerable replacement for endogenous GH. Once-weekly dosing may be impactful for adults with GHD who typically manage multiple other medical therapies. Presentation: 6/3/2024

7625 Functional and structural neuronal changes of dulaglutide compared to placebo during smoking cessation - a randomized placebo-controlled trial

Abstract Disclosure: C.O. Sailer: None. S. Lengsfeld: None. D. Coynel: None. F. Baur: None. K. Bologna: None. T. Vukajlovic: None. N.A. Jeanloz: None. C. Bathelt: None. D. Zanchi: None. M. Christ-Crain: None. B.F. Winzeler: None. Introduction: Nicotine activates reward-related brain regions and chronic cigarette smoking can lead to functional and structural neuronal changes. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), known for their anti-obesity effects, have emerged as potential treatments for addictive disorders. A pilot study of exenatide vs placebo revealed increased short-term smoking abstinence rates and reduce smoking craving. We previously reported the results of a clinical trial (n=255) investigating the effect of dulaglutide vs placebo on smoking cessation. Herein, we report the functional magnetic resonance imaging (fMRI) results of a subset of participants. This substudy aimed to investigate the influence of dulaglutide on smoking craving, functional and structural neuronal changes of smokers aiming to quit smoking. Methods: This single-center, randomized, double-blind, placebo-controlled trial enrolled 71 participants with at least a moderate nicotine dependence, all committed to quitting smoking. Of these, 35 participants received 12 weeks dulaglutide 1.5mg, and 36 participants placebo, alongside varenicline treatment and behavioral counselling. An fMRI session was conducted at baseline and 12 weeks. The primary outcomes included smoking craving assessed on a visual analogue scale (VAS, range 0-7), differences in blood oxygen level dependent (BOLD) signal (whole brain and regions of interests, e.g., nucleus accumbens, amygdala, thalamus) and gray matter changes between sessions and groups when exposed to smoking and neutral video cues. Secondary outcomes assessed the above in quitters vs persistent smokers. Results: In line with the primary study findings, abstinence rates at 12 weeks were comparable in the dulaglutide (54%) and placebo (68%) groups (p=0.27). In a mixed effect model, smoking craving significantly decreased at 12 weeks vs baseline (-2.13 (95% CI -2.46, -1.80), p<0.001) and were lower for neutral vs smoking cues (-2.02 (-2.34, 1.70,), p<0.001). However, no significant inter-group difference was observed (-0.09 (-0.53, 0.33), p=0.65). Persistent smokers exhibited higher smoking craving at 12 weeks vs quitters (0.48 (0.06, 0.90), p=0.028), particularly when exposed to smoking cues (2.02 (1.70, 2.34), p<0.001). No significant differences were found in functional or structural analyses between interventions or smoking status. Conclusions: The smoking cessation intervention led to a significant reduction in smoking craving at 12 weeks without in-between group differences in behavioral, functional, or structural outcomes. Our findings challenge the hypothesis that GLP-1 RAs modulates smoking craving and behavior. It is plausible that a potential GLP-1 effect might have been masked by varenicline treatment and the unexpectedly high abstinence rate in the placebo group. Future studies should explore more potent GLP-1 RAs or dual agonists. Presentation: 6/1/2024

Artificial Neural Network Model for Predicting Carrot Root Yield Loss in Relation to Mechanical Heading

Modelling and predicting agricultural production processes have high cognitive and practical values. Plant growth, the threat of pathogens and pests, and the structure of agricultural machinery treatments are mostly non-linear, measurable processes that can be described mathematically. In this paper, a multiple regression analysis was carried out in the first step to check the non-linearity of the data and yielded a coefficient of determination of R2 = 0.9741 and the coefficient of determination corrected for degrees of freedom was R2adj = 0.9739. An artificial neural network model, called CH-NET, is then presented to predict the yield loss of carrot roots by leaving root mass in the field during harvest at the mechanical heading stage. The proposed network model has an architecture consisting of an input layer, three hidden layers with 12 neurons each, and an output layer with one neuron. Twelve input criteria were defined for the analysis and testing of the network, eight of which related to carrot root parameters and four to the heading machine. The training, testing, and validation database of the CH-NET network consisted of the results of field trials and tests of the operation of the patented (P.242097) root heading machine. The proposed CH-NET neural network model achieved global error (GE) values of 0.0931 t·ha−1 for predicting carrot root yield losses for all twelve criteria adopted. However, when the number of criteria is reduced to eight, the error increased to 0.0991 t·ha−1. That is, the prediction was realised with an accuracy of 90.69%. The developed CH-NET model allows the prediction of economic losses associated with root mass left in the field or contamination of the raw material with undercut leaves. The simulations carried out showed that minimum root losses (0.263 t·ha−1) occur at an average root head projection height of 38 mm and a heading height of 20 mm from the ridge surface.

8654 Real-World Performance Of The Medtronic Extended Infusion Set In The United States

Abstract Disclosure: T. Kwa: Employee; Self; Medtronic Minimed. G. Zhang: Employee; Self; Medtronic Minimed. J. Kiehl: Employee; Self; Medtronic Minimed. V. Putcha: Employee; Self; Medtronic Minimed. A. Patel: Employee; Self; Medtronic Minimed. S. Chattaraj: Employee; Self; Medtronic Minimed. O. Cohen: Employee; Self; Medtronic Minimed. R.A. Vigersky: Employee; Self; Medtronic Minimed. Real-World Performance of the Medtronic Extended Infusion Set in the United States Objective: The Medtronic extended infusion set (EIS) is the first and only infusion set approved for up to 7-day use and its pivotal trial established clinical safety and efficacy.[1] The purpose of this retrospective analysis was to assess real-world EIS performance and overall glycemic outcomes based on United States (US) data uploaded by MiniMed™ 770G system (MM770G) users at an aggregate level. Methods: Infusion set occlusion alarm events and time in (TIR, 70-180 mg/dL), below (TBR, <70 mg/dL) and above (TAR, >180 mg/dL) range of EIS-MM770G users (N=393) with >30-day device use in the U.S. were analyzed and compared against the data of a cohort of the same median age of 50 years (N=77219) using the MM770G with a standard 2/3-day infusion set (at an aggregate level). Results: EIS users experienced a lower occlusion alarm rate (median 0.011 alerts/patient day) compared to 0.016 alerts/patient day with the standard set (p = 0.005). TIR for EIS users was 69.4%, which was numerically greater than the 69.1% for standard set users (p = 0.258). While TAR was not significantly different (28.9% for EIS and 29.0% for standard set, p = 0.995), TBR was significantly lower (0.5% for EIS and 1.3% for standard set, p = 0.000). The difference in the total daily dose (TDD) of insulin between the two groups (53.0 units for EIS, 49.4 units for standard set) was not statistically significant (p = 0.961). Conclusion: Since the U.S. launch, the EIS has continued to perform similarly to the pivotal trial results and an early real-world analysis of EIS use outside of the US.2 The decreased burden of fewer set changes comes with a lower occlusion alarm rate and does not compromise time spent in target range.

7380 Qualitative Interviews Describing the Patient Experience of Individuals with Generalized Lipodystrophy Enrolled in a Clinical Trial of Mibavademab

Abstract Disclosure: S. Martin: Other; Self; Employee of RTI Health Solutions, an independent nonprofit research organization retained by Regeneron Pharmaceuticals, Inc. to conduct this research. Compensis unconnected to the studies they work on. K. Kosa: Other; Self; Employee of RTI Health Solutions, an independent nonprofit research organization retained by Regeneron Pharmaceuticals, Inc. to conduct this research. Compensis unconnected to the studies they work on. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A. Garg: Consulting Fee; Self; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals, Third Rock ventures, Kyttaro, Cello Health, Health Advances. Grant Recipient; Self; Aegerion Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Amryt, Ionis Pharmaceuticals Inc. E.A. Oral: Consulting Fee; Self; Regeneron Pharmaceuticals, Third Rock Ventures, Rejuvenate Inc. Grant Recipient; Self; Regeneron Pharmaceuticals, Amryt Pharmaceuticals, Ionis Pharmaceuticals Inc., Gemphire Therapeutics. Other; Self; Amryt Pharmaceuticals, Novo Nordisk, Rhythm Pharmaceuticals, Fractyl Laboratories, GI Dynamics. I. Yildirim Simsir: None. R.J. Brown: Other; Self; Regeneron Pharmaceuticals. S. Ozen: None. O. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. D. Srinivasan: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R.J. Sanchez: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Background: Generalized lipodystrophy (GLD) is characterized by near-total lack of adipose tissue and, consequently, low levels of serum leptin. Mibavademab (REGN4461) is an investigational human monoclonal agonist antibody of the leptin receptor. As part of the phase 2, randomized, double-blind, placebo-controlled study (NCT04159415) of mibavademab, we conducted exit interviews to gather patient experience data specific to GLD and changes experienced during the study. Methods: Between week 52-54, experienced interviewers conducted 45-minute in-depth, semi structured, qualitative phone interviews to understand their GLD-related symptoms/signs, perceptions of any improvements experienced during the study as well as the importance of these improvements. Results: Interviews were conducted with 5 females and 2 males, with a mean age of 19.4 (range:15-23). Most participants reported experiencing hunger-related symptoms (n=6), pain, extreme body temperature sensations (n=5 for each), and fatigue or sleep problems (n=4 for each) prior to them starting the study. While we were interested in symptoms, many participants also reported clinical signs, such as enlarged/fatty liver and hyperglycemia (n=5 for each). Pain was most frequently reported as the most bothersome symptom (n=3) prior to the study. All participants who reported having hunger, pain, extreme body temperatures, hyperglycemia, and fatigue before the study reported improvements after 52 weeks of treatment. Participants generally indicated more than a minimal amount of change. For example, of the 5 participants who reported hunger as a symptom prior to the study and who were asked about the amount of change, all reported either “some” (n=1) or “a lot” of improvement (n=4). Participants, overall, rated each improvement, except body temperature as “very important.” Improvements in extreme body temperature were generally rated by participants as “somewhat important.” When asked which of the reported improvements were most important, changes in hyperglycemia was most frequently reported (n=4) followed by improvements in enlarged or fatty liver (n=2) and pain and hunger (n=1 each). All participants reported they were satisfied (n=2) or very satisfied (n=5) with the study treatment. Conclusions: All participants who reported symptoms of hunger, pain, fatigue, and extreme body temperature, or the clinical biomarker of hyperglycemia before entering the study reported improvements in each of these after treatment. In addition, all participants reported being either satisfied or very satisfied with treatment. This qualitative research provides insight into the patient experience for individuals with GLD and provides an opportunity to further understand and complement the clinical trial results. Presentation: 6/1/2024

Development of Learning Model for Hajj Based on Cooperative Learning in Padang City

The research aimed to produce an appropriate product, namely a cooperative learning model in the rituals of Hajj, to realize an independent Hajj congregation in terms of knowledge, understanding, attitudes, and skills, to specify the level of validity, realism, effectiveness, and attractiveness and so that the problems above can be resolved immediately resolved. This research uses the Research and Development (R&D) approach to achieve the aforementioned objectives. In general, the research and development model is the Four D model. This model consists of four stages of development, i.e., define, design, develop, and develop. The results of the preliminary study / pre-field survey show that in terms of teaching performance of Hajj rituals, it appears that the learning services provided by the instructor/instructor have not been able to accommodate and appreciate the differences in ability (attitude) of Hajj pilgrims. The results of the model development trial show that "(1) it is necessary to improve the teaching performance of the Hajj ritual guide / instructor, (2) the development of the model requires specific teaching performance of Hajj rituals from the supervisor / instructor, and does not want excessive facilities and facilities. (3) there is an increase in the learning activities of Hajj pilgrims in all small groups (high, medium and low), (4) the realization of the optimization of the achievement of learning outcomes for Hajj rituals for Hajj pilgrims, both in the high, medium, and low groups.

Exercising of integrated approach for the specialized meat products development

The principles of the specialized food products development differ from the traditional technologies, which require the integrated approach to their creation, taking into consideration the specified properties, purpose and type of the food product. This article describes the general algorithm for developing the specialized dietary therapeutic and prophylactic nutrition meat products, and demonstrates the implementation of the individual stages of the algorithm on the example of developing the food products for people who suffer from the most socially significant diseases like diabetes and CVD. The algorithm of methodology is a sequence of stages executed during the product development and a description of their content and practical implementation. The modern approaches to creation of healthy food products for people with socially significant diseases, the recommendations of the World Health Organization based on the analysis of scientific literature posted in open sources and publicly available databases were used as the material of the research, as well as the results of our own studies in the field of technologies for dietary therapeutic and prophylactic nutrition meat products. The specialized meat products for therapeutic and prophylactic nutrition, information about their ingredient composition, nutritional value, results of preclinical and clinical trials were used as the objects of the study. The stages of product creation include medical and biological substantiation of the composition, designing of a virtual model of the food product, technology development, evaluation of the safety and efficiency of the resulting product taking into consideration the technological impact, preclinical and clinical evaluation. The study showed the difference in the approaches to the dietary meat products development depending on the purpose — whether its therapeutic nutrition or prophylactic nutrition. The developed methodology can be used as a tool that provides for scientifically justified development of the specialized meat products and substantiation of their efficiency.

Enhancing DHA supplementation adherence: A Bayesian approach with finite mixture models and irregular interim schedules in adaptive trial designs.

Docosahexaenoic acid (DHA) supplementation has proven beneficial in reducing preterm births. However, the challenge lies in addressing nonadherence to prescribed supplementation regimens-a hurdle that significantly impacts clinical trial outcomes. Conventional methods of adherence estimation, such as pill counts and questionnaires, usually fall short when estimating adherence within a specific dosage group. Thus, we propose a Bayesian finite mixture model to estimate adherence among women with low baseline red blood cell phospholipid DHA levels (<6%) receiving higher DHA doses. In our model, adherence is defined as the proportion of participants classified into one of the two distinct components in a normal mixture distribution. Subsequently, based on the estimands from the adherence model, we introduce a novel Bayesian adaptive trial design. Unlike conventional adaptive trials that employ regularly spaced interim schedules, the novelty of our proposed trial design lies in its adaptability to adherence percentages across the treatment arm through irregular interims. The irregular interims in the proposed trial are based on the effect size estimation informed by the finite mixture model. In summary, this study presents innovative methods for leveraging the capabilities of Bayesian finite mixture models in adherence analysis and the design of adaptive clinical trials.

Disparities Between Clinical Trial Recruitment and Real-World Demographics in Macular Edema Secondary to Retinal Vein Occlusion

PurposeClinical trial cohorts frequently differ demographically from the overall population receiving treatment for the condition under study. Our study describes the racial, ethnic, and gender composition of the cohorts of retinal vein occlusion (RVO) macular edema (ME) clinical trials and compares this to the racial, ethnic, and gender composition of patients undergoing treatment for ME secondary to RVO from the (Intelligent Research in Sight) IRIS® Registry. DesignRetrospective observational case series Subjects: Participants in RVO-ME clinical trials that met the following inclusion criteria: conducted in the United States of America, Phase III completed, data reported between Jan 1, 2000, and Jan 1, 2020, and demographic information reported with results. MethodsThis study identified clinical trials by searching PubMed with the following search terms; “retinal vein occlusion” and “clinical trial” and by searching ClinicalTrials.gov with the search term “retinal vein occlusion”. Main Outcome MeasuresThe primary outcome was the enrollment fraction defined as the number of trial enrollees divided by the reference sample size of RVO patients undergoing treatment for ME from published IRIS® Registry (Intelligent Research in Sight) data. Enrollment fraction was compared between different races, ethnicities, and genders. ResultsEight clinical trials met our inclusion criteria. Compared to the enrollment fraction of 7.69% among Whites, lower enrollment fractions were found in Black patients (4.32%, odds ratio [OR] 0.541, confidence interval [CI] 0.468-0.626, P< 0.001) and Hispanic patients (3.38%, OR 0.420, CI 0.351-0.503, P<0.001), and higher enrollment fraction in Asian patients (10.68%, OR 1.436, CI 1.207-1.708, P<0.001). Men were more likely to enroll in the clinical trials compared to women (enrollment fraction, 7.69% vs 5.77%, respectively, OR 1.364, CI 1.273-1.462, P < 0.001). ConclusionsRVO-ME clinical trials have a higher relative proportion of Asian, White and male subjects when compared to the population undergoing treatment for ME secondary to RVO. Further efforts should encourage clinical trial recruitment that is reflective of the RVO population undergoing treatment for ME to ensure generalizability of clinical trial results.

Plasma EGFR mutation ctDNA dynamics in patients with advanced EGFR-mutated NSCLC treated with Icotinib: phase 2 multicenter trial result

Plasma epidermal growth factor receptor mutation (EGFRm) circulating tumor DNA (ctDNA) dynamics exhibit promise in predicting outcomes in patients with EGFRm-advanced non-small cell lung cancer (NSCLC). However, there remains limited trial-level data on integrating ctDNA monitoring into clinical practice. We performed a prospective, multicenter trial to investigate the relationship between EGFRm ctDNA dynamic changes and clinical outcomes in NSCLC patients with EGFRm. Ninety-eight treatment-naive EGFRm-advanced NSCLC patients were recruited and administered icotinib until disease progression. Plasma samples were collected at baseline and four weeks after icotinib administration. ctDNA was analyzed using a droplet-digital polymerase chain reaction. At baseline, 71.4% of patients had detectable EGFRm ctDNA. Among them, 45.9% of patients’ ctDNA became undetectable within four weeks of treatment. These patients demonstrated significantly longer progression-free survival (PFS) and overall survival (OS) than those with detectable ctDNA after treatment (P = 0.004 and < 0.001, respectively) and were comparable to those with undetectable ctDNA at both baseline and four weeks. ctDNA detectable at four weeks emerged as a poor independent risk factor for PFS and OS. Patients whose ctDNA became undetectable after treatment had outcomes similar to those with initially undetectable ctDNA, underscoring the predictive value of ctDNA dynamics in treatment efficacy.Registry and the Registration No. of the study/trial: ChiCTR-DDD-17013131. Date of registration: 2017-10-27.

Routine third-trimester ultrasonography and child neurodevelopmental outcomes: a follow-up of a pragmatic cluster-randomised controlled trial

ABSTRACT Aims/Background Routine third-trimester ultrasonography is increasingly conducted to screen for foetal growth restriction (FGR) and reduce adverse perinatal and child neurodevelopmental outcomes using timely obstetric management. While it did not reduce adverse perinatal outcomes in previous trials, evidence regarding its association with child neurodevelopmental outcome is absent. We examined whether routine third-trimester ultrasonography is positively associated with child developmental and behavioural/emotional outcomes compared to usual care. Design/Methods Dutch mothers with a low-risk pregnancy participating in a subsample (n = 1070) of a nationwide cluster-randomised trial reported infant (age 6 months) and toddler (age 28 months) developmental milestones (Ages and Stages Questionnaire) and toddlers’ internalising and externalising problems (Child Behavior Checklist). Usual care (n = 380) comprised selective ultrasonography. The intervention strategy (n = 690) included two routine third-trimester ultrasounds next to usual care. Both strategies applied the same interdisciplinary protocol for FGR detection and management. Results Adjusted linear mixed-level regressions revealed that routine third-trimester ultrasonography was positively but modestly related to z-standardised infant developmental milestones at 6-month follow-up, B = 0.20, 95%CI [0.07; 0.32], p = 0.003, compared to usual care. At 28-month follow-up, these strategies did not differ in child developmental outcome and internalising and externalising problems. Conclusion Routine third-trimester ultrasonography was positively but modestly associated with infant development. In toddlerhood, routine ultrasonography was not related to child developmental and behavioural/emotional outcomes. Overall, these findings do not support the implementation of routine third-trimester ultrasonography for low-risk pregnant women for reasons concerning children’s early neurodevelopmental outcomes.

Targeting IGF-IR improves neoadjuvant chemotherapy efficacy in breast cancers with low IGFBP7 expression

There has been a long-standing interest in targeting the type 1 insulin-like growth factor receptor (IGF-1R) signaling system in breast cancer due to its key role in neoplastic proliferation and survival. However, no IGF-1R targeting agent has shown substantial clinical benefit in controlled phase 3 trials, and no biomarker has been shown to have clinical utility in the prediction of benefit from an IGF-1R targeting agent. IGFBP7 is an atypical insulin-like growth factor binding protein as it has a higher affinity for the IGF-1R than IGF ligands. We report that low IGFBP7 gene expression identifies a subset of breast cancers for which the addition of ganitumab, an anti-IGF-1R monoclonal antibody, to neoadjuvant chemotherapy, substantially improved the pathological complete response rate compared to neoadjuvant chemotherapy alone. The pCR rate in the chemotherapy plus ganitumab arm was 46.9% in patients in the lowest quartile of IGFBP7 expression, in contrast to only 5.6% in the highest quartile. Furthermore, high IGFBP7 expression predicted increased distant metastasis risk. If our findings are confirmed, decisions to halt the development of IGF-1R targeting drugs, which were based on disappointing results of prior trials that did not use predictive biomarkers, should be reviewed.

The role of selected nutraceuticals in management of prediabetes and diabetes: An updated review of the literature. Part II.

We have already published a review about the results of clinical trials evaluating the effects of selected nutraceuticals on glycemia in humans. In this second part, we describe the role of other nutraceuticals involved in dysglycemia. The available evidence showed promising hypoglycemic effects of the nutraceuticals reviewed both for their efficacy and safety profile. However, contradictory results as regard the efficacy of some supplements such as Allium sativum, Juglans regia, and Lycium barbarum on glucose homeostasis have emerged from some clinical studies. Other nutraceuticals including Aloe vera, Amorphophallus Konjac, Bauhinia forficata, Coccinia, Ganoderma lucidum, Ipomoea batatas, and Lupinus mutabilis require larger and long-term studies rigorously designed to confirm their hypoglycemic effects due to the scarce data available and the poor quality of clinical trials. Further studies are also required for Cinnamomum, Cynara scolymus, Momordica charantia, Olea europaea, and Opuntia streptacantha. Moreover, well-designed large and long-term clinical trials including the use of standardized nutraceutical preparations are necessary for Phaseolus vulgaris and Vaccinium myrtillus.

Diagnostic performance of ultrasound vs. ultrasound-guided FNAc in thyroid nodules: data from the ElaTION trial.

ElaTION is a large multi-centre pragmatic randomised controlled trial, performed in 18 secondary/tertiary hospitals across England, comparing elastography ultrasound-guided fine needle aspiration cytology (EUS-FNAC) with ultrasound-guided FNAC (US-FNAC) alone in the diagnostic assessment of thyroid nodules. Secondary trial outcomes, reported here, assessed the accuracy of ultrasound-alone (US) compared with US-guided FNAC to inform and update current practice guidelines. Adults with single or multiple thyroid nodules who had not undergone previous FNAC were eligible. Radiologists assessed all thyroid nodules using US alone, thereby enabling assessment of its accuracy (sensitivity and specificity) versus US-FNAC. Of the 982 participants, a final definitive diagnosis was obtained in 688, who were included in the final analyses. The sensitivity of US-alone was the same as US-FNAC (0.91, [95% CI 0.85, 0.97] vs 0.87 [95%CI 0.80-0.95], p=0.37). US alone had statistically significant lower specificity than US-FNAC alone (0.48 vs 0.67 respectively, p<0.0001). The malignancy rate on histology in a nodule classified as benign on ultrasound (U2) was 9/263 (3.42%) and on cytology (Thy2) was 15/353 (4.25%), whereas the malignancy rate in a nodule that was benign on both (U2, Thy2) was 3/210 (1.43%). Malignancy risk for U3, U4, and U5 nodules was 68/304 (22.4%), 43/83 (51.8%), and 29/38 (76.3%) respectively (p<0.0001). Yet 80/982 (8%) patients were discharged despite having U3-U5 scans with Thy1 (non-diagnostic) FNAC and no definitive diagnosis.Malignancy risk was higher in smaller nodules: <10mm 23/60 (38.3%), 10-20mm 46/162 (28.4 %), and >20mm 80/466 (17.2%) (p<0.0001). Nodules with indeterminate cytology with atypical features (Thy3a) carried a similar malignancy risk to those with indeterminate cytology (Thy3/3f): 27/95 (28.4%) versus 42/113 (37.2%) respectively (p=0.18). Ultrasound alone appears to be an effective diagnostic modality in thyroid nodules, confirming the recommendations of recent guidelines and the BTA classification. However, findings also suggest caution regarding existing recommendations for conservative management of non-diagnostic (Thy1/Bethesda I) and atypical (Thy3a/Bethesda III) nodules. In those cases, ultrasound (U3-5) features may help identify high-risk subgroups for more proactive management.

Utilising primary care electronic health records to deliver the ALABAMA randomised controlled trial of penicillin allergy assessment

BackgroundUse of electronic health records (EHR) to provide real-world data for research is established, but using EHR to deliver randomised controlled trials (RCTs) more efficiently is less developed. The Allergy AntiBiotics And Microbial resistAnce (ALABAMA) RCT evaluated a penicillin allergy assessment pathway versus usual clinical care in a UK primary care setting. The aim of this paper is to describe how EHRs were used to facilitate efficient delivery of a large-scale randomised trial of a complex intervention embracing efficient participant identification, supporting minimising GP workload, providing accurate post-intervention EHR updates of allergy status, and facilitating participant follow up and outcome data collection. The generalisability of the EHR approach and health economic implications of EHR in clinical trials will be reported in the main ALABAMA trial cost-effectiveness analysis.MethodsA descriptive account of the adaptation of functionality within SystmOne used to deliver/facilitate multiple trial processes from participant identification to outcome data collection.ResultsAn ALABAMA organisation group within SystmOne was established which allowed sharing of trial functions/materials developed centrally by the research team. The ‘ALABAMA unit’ within SystmOne was also created and provided a secure efficient environment to access participants’ EHR data. Processes of referring consented participants, allocating them to a trial arm, and assigning specific functions to the intervention arm were developed by adapting tools such as templates, reports, and protocols which were already available in SystmOne as well as pathways to facilitate allergy de-labelling processes and data retrieval for trial outcome analysis.ConclusionsALABAMA is one of the first RCTs to utilise SystmOne EHR functionality and data across the RCT delivery, demonstrating feasibility and applicability to other primary care RCTs.Trial registrationClinicalTrials.gov: NCT04108637, registered 05/03/2019. ISRCTN: ISRCTN20579216.

Real world clinical outcomes from targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer: data from a large cohort at a national cancer institute.

Randomised evidence supports the use of partial breast irradiation (PBI) with targeted intraoperative radiotherapy (TARGIT-IORT) for early stage breast cancer, but prospective data from real-world adoption of this technique is also important. The aim of this study was to determine if the outcome reported in TARGIT-A trial could be replicated in large cohort of early stage breast cancer treated with TARGIT-IORT. This prospective observational study analysed all patients treated with TARGIT-IORT between 2004 and 2021 in a single national cancer institute. TARGIT-IORT during lumpectomy was performed according to the risk-adapted TARGIT-A protocol using the Intrabeam® device. We analysed the completeness of follow up, 5-year in-breast-tumour-recurrence (IBTR), long term local recurrence free survival, distant disease-free survival, overall survival and breast-cancer-related survival, using the Kaplan-Meier method. A covariate analysis was performed to investigate risk factors for IBTR. We also analysed high grade toxicity events. The study included 814 patients and the a median follow up was 72 months. The majority of patients (60.3%) received TARGIT-IORT as PBI modality ("exclusive IORT" group); 39.7% received additional EBRT. There was no significant difference between the 5 years IBTR for the whole study population and the "exclusive IORT" cohort (1.6% (95%CI=1.1-2.1%) and 2.5% (95%CI=1.7%-3.3%) respectively). 5 years overall survival and tumour related survival were >95%. In 21% of patients with recurrence, breast was preserved. Radiotherapy toxicity (CTCAE Grade>2) was very rare (0.9%). This large single institute study found that breast cancer control and survival outcomes with TARGIT-IORT were consistent with TARGIT-A trial results. This "real world" experience confirmed that the randomised evidence showing the value of TARGIT-IORT as partial breast irradiation modality that can be replicated in routine clinical practice.

Impact of Audio-Visual Complexity on Symptomatology of Laryngeal Dystonia: A Virtual Reality Study.

Laryngeal dystonia (LD) is an isolated focal dystonia characterized by involuntary spasms in laryngeal muscles selectively impairing speech production. Anecdotal observations reported the worsening of LD symptoms in stressful or vocally demanding situations. To examine the impact of surrounding audio-visual complexity on LD symptomatology for a better understanding of disorder phenomenology. We developed well-controlled virtual reality (VR) environments of real-life interpersonal communications to investigate how different levels of audio-visual complexity may impact LD symptoms. The VR experiments were conducted over five consecutive days, during which each patient experienced 10 h of 4100 experimental trials in VR with gradually increasing audio-visual complexity. Daily reports were collected about patients' voice changes, as well as their comfort, engagement, concentration, and drowsiness from using VR technology. After a weekly VR exposure, 82% of patients reported changes in their voice symptoms related to changes in background audio-visual complexity. Significant differences in voice symptoms were found between the first two levels of the audio-visual challenge complexity independent of study sessions or VR environments. This study demonstrated that LD symptoms are impacted by audio-visual background across various virtual realistic settings. These findings should be taken into consideration when planning behavioral experiments or evaluating the outcomes of clinical trials in these patients. Moreover, these data show that VR presents a reliable and useful technology for providing real-life assessments of the impact of various experimental settings, such as during the testing of novel therapeutic interventions in these patients. Level 3 Laryngoscope, 2024.

Improving analysis of cognitive outcomes in cardiovascular trials using different statistical approaches

BackgroundThe Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) questionnaires are commonly used to measure global cognition in clinical trials. Because these scales are discrete and bounded with ceiling and floor effects and highly skewed, their analysis as continuous outcomes presents challenges. Normality assumptions of linear regression models are usually violated, which may result in failure to detect associations with variables of interest.MethodsAlternative approaches to analyzing the results of these cognitive batteries include transformations (standardization, square root, or log transformation) of the scores in the multivariate linear regression (MLR) model, the use of nonlinear beta-binomial regression (which is not dependent on the assumption of normality), or Tobit regression, which adds a latent variable to account for bounded data. We aim to empirically compare the model performance of all proposed approaches using four large randomized controlled trials (ORIGIN, TRANSCEND, COMPASS, and NAVIGATE-ESUS), and using as metrics the Akaike information criterion (AIC). We also compared the treatment effects for the methods that have the same unit of measure (i.e., untransformed MLR, beta-binomial, and Tobit).ResultsThe beta-binomial consistently demonstrated superior model performance, with the lowest AIC values among nearly all the approaches considered, followed by the MLR with square root and log transformations across all four studies. Notably, in ORIGIN, a substantial AIC reduction was observed when comparing the untransformed MLR to the beta-binomial, whereas other studies had relatively small AIC reductions. The beta-binomial model also resulted in a significant treatment effect in ORIGIN, while the untransformed MLR and Tobit regression showed no significance. The other three studies had similar and insignificant treatment effects among the three approaches.ConclusionWhen analyzing discrete and bounded outcomes, such as cognitive scores, as continuous variables, a beta-binomial regression model improves model performance, avoids spurious significance, and allows for a direct interpretation of the actual cognitive measure.Trials registrationORIGIN (NCT00069784). Registered on October 1, 2003; TRANSCEND (NCT00153101). Registered on September 9, 2005; COMPASS (NCT01776424). Registered on January 24, 2013; NAVIGATE-ESUS (NCT02313909). Registered on December 8, 2014.