Proof Of Concept Trial Research Articles

Mild processing and addition of milk fat globule membrane in infant formula may better mimic intragastric behavior of human milk: A proof of concept trial in healthy males

BackgroundDuring breastfeeding the macronutrient composition of breastmilk changes gradually from relatively low-fat (foremilk) to relatively high-fat (hindmilk), initially exposing the gastrointestinal tract to a relatively low fat concentration. In contrast, infant formulae (IF) are homogenous. Mild processing and addition of milk fat globule membrane (MFGM) may impact gastric emulsion instability, potentially impacting the phased release of nutrients as observed during breastfeeding. ObjectiveTo assess gastric emulsion stability, gastric emptying, and the postprandial plasma metabolome of an experimental minimally processed IF (EF) with an altered fat-globule interface and a control IF (CF). MethodsTwenty healthy males participated in this double-blind randomized crossover trial. Gastric MRI scans and blood samples were obtained before and after consumption of 600 ml CF or EF over a 2-h period. Outcomes included gastric top layer formation, total gastric volume, and blood parameters (free fatty acids (FFA), insulin, glucose, and nuclear magnetic resonance (NMR-)metabolomics). ResultsEF showed an earlier onset (13.4 min, p = 0.017), smaller maximum volume (49.0 ml, p = 0.033), and a shorter time to maximum top layer volume (13.9 min, p = 0.022), but similar AUC (p = 0.915) compared to CF. Total gastric volume did not show a treatment*time effect. Insulin concentrations were lower for EF. FFA and glucose did not differ. EF yielded higher serum concentrations of phospholipid- and cholesterol-related metabolites. ConclusionAn EF displayed faster gastric creaming than a CF, thereby potentially better mimicking the behavior of breastmilk which leads to phased release of nutrients into the intestine. Overall physiological benefits of this difference in gastric behavior remain to be studied further in infants.

The Pyruvate Kinase (PK) Activator AG-946 Improves PK Properties and Red Blood Cell (RBC) Characteristics upon Ex Vivo treatment of RBCs from Patients with Myelodysplastic Syndromes

Background: Myelodysplastic syndromes (MDS) consist of a heterogenous group of clonal myeloid malignancies, characterized by dysplasia, ineffective hematopoiesis and cytopenias. MDS patients frequently suffer from anemia, directly affecting quality of life. The limited therapeutic options often do not result in the desired clinical improvement. Interestingly, in MDS the activity of the red blood cell (RBC) enzyme pyruvate kinase (PK), a key regulatory enzyme of glycolysis, may be decreased. The activation of PK via small molecules is hypothesized to be beneficial in a wide range of anemias. Currently, a phase 2a, open-label, proof of concept trial is running on the use of the PK activator AG-946 in low-risk MDS patients (NCT05490446). In light of these developments, we investigated the effect of ex vivo treatment of MDS RBCs with AG-946. Objectives: To evaluate RBC PK and cellular properties of patients with MDS, and to determine the effect of ex vivo treatment with the PK activator AG-946. Methods: Eleven low-risk non-transfusion dependent MDS patients and six healthy controls (HCs) were studied. Baseline PK activity and PK thermostability were measured in RBC lysates of purified RBCs, under V max conditions (phosphoenolpyruvate (PEP) 5mM final concentration). Hexokinase (HK) activity was included to relate PK activity to mean RBC age. Ex vivo treatment was performed by incubating MDS RBCs for 16 hours at 37 °C in presence or absence of the PK activator AG-946 (10μM or 5μM) using dimethylsulfoxide (DMSO) as a blank. Effect was assessed by measuring PK activity (using a final concentration of PEP 0.5mM) and levels of adenosine triphosphate (ATP) (LC-MS/MS). Functional RBC analysis was performed by osmotic gradient ektacytometry (Lorrca MaxSis). To investigate the effect on PK thermostability, RBC lysates were incubated with AG-946 (2μM or 1μM) or DMSO, after which residual PK activity was measured (PEP 0.5mM). The effect of AG-946 on erythroid development was studied using peripheral blood mononuclear cells, cultured in MethoCult TM H4434 medium for 14 days in the presence or absence of AG-946 (10μM or 625nM, DMSO as blank). Differences between conditions were determined using Unpaired T-test, ANOVA with Dunnett's test or Kruskal-Wallis with Dunn's test via GraphPad Prism. Results: Mean PK/HK ratio was significantly lower in RBCs from MDS patients compared to HCs (6.1 (SD 1.8) versus 10.5 (SD 1.5), p<0.001). Upon ex vivo treatment, PK activity significantly increased (independent of dosage) when compared to DMSO (10μM AG-946, mean increase 30% ( p<0.001); 5μM, 28% ( p<0.0001)) (Figure 1A). MDS RBCs displayed decreased PK thermostability at baseline under V max conditions (HCs 79% residual activity versus 68% in MDS, p<0.01). This was restored by ex vivo treatment with AG-946 (DMSO, 33% residual activity, 2μM AG-946, 85% ( p<0.0001); 1μM, 87% ( p<0.0001)). The increase in PK activity was accompanied by significantly increased ATP levels (N=10, DMSO, mean ATP 14.9 μg/mL RBC; 10μM AG-946, 21.0 μg/mL RBC ( p<0.01); 5μM, 21.1 μg/mL RBC ( p<0.01)) (Figure 1B). Functionally, RBC properties improved upon ex vivo treatment with AG-946 as reflected by the modest yet significant increase in O hyper, indicating improved hydration status (10μM AG-946, mean increase 2.3% ( p<0.001); 5μM, 2.9% ( p<0.0001)). To date, culture assays were performed in 8 patients; 3/8 showed an increase in the number of burst forming units-erythroid (BFU-Es) upon treatment with AG-946 when compared to DMSO. The percentual increases differed per patient: increase of 25% with 10μM AG946 and 150% with 625nM, increase of 40% (10μM) and 39% (625nM), and for the third an increase of 22% (10μM) and 39% (625nM). Conclusion: Our findings show that RBCs from MDS patients have decreased PK activity and thermostability. We demonstrate that ex vivo treatment with AG-946 increases PK activity and ATP levels and restores PK thermostability. Moreover, ex vivo treatment with AG-946 improves RBC hydration, suggesting that improved energy status directly improves RBC functional properties. The preliminary results of the culture assay could indicate that in certain patients, dyserythropoiesis may be ameliorated upon PK activation. To better understand the effects on erythropoiesis additional experiments are required. In conclusion, our data might support a rationale for the use of PK activators as a novel therapeutic option for MDS.

Digital voice analysis as a measure of frailty and distress: A feasibility study (DIVAN).

TPS12139 Background: Assessing of frailty is essential not only in older patients with cancer, because frailty changes management of cancer therapy. Same is true for the routine assessment of distress to identify patient suffering and initiate adequate symptom control or psychosocial interventions. Here we present new potential method of frailty and distress assessment with digital voice analysis as a proof of concept trial. (NCT requested pending, DIVAN-1). Methods: Adult patients with the diagnosis of active incurable cancer can be enrolled into this study. Every participant will describe two to four images presented to him or her on a tablet computer in up to four sessions, and the patient`s voice will be recorded digitally. Baseline characteristics including cancer type, stage, therapy, G8 questionnaire and distress questionnaire (ESAS) will be collected at every session. Acoustic features like mean fundamental frequency (F0) and first few formants (F1, F2, etc.), jitter (variation in F0 from cycle to cycle), shimmer (variation in peak-to-peak amplitude), etc. will be explored digitally along with for example and voice strength (volume). Additionally, a vowel test will conducted and explored. Depending on the distribution of the data, the Pearson R correlation test or the Spearman’s R correlation test will be applied for each variable. The primary research question of this feasibility study is to identify quantitative parameters out of the audio signal to describe the changes in patient’s state in relation to frailty and distress. Trial enrolment has begun in December 2022 and 11 out of 100 patients have been included. Clinical trial information: NCT05783401 .

Post-shock acute electrical parameters of left bundle branch area defibrillation (LBBAD) leads

Abstract Funding Acknowledgements Type of funding sources: None. Background Conduction system pacing is a growing field in bradycardia-treatment. Evidence for His bundle pacing (HBP) and left bundle branch area pacing (LBBAP) to prevent pacing induced cardiomyopathy is growing. Promising data is also emerging to use CSP as an additional tool in cardiac-resynchronisation therapy (CRT). (1-5). Very often patients requiring an ICD also have an indication for bradycardia or resynchronisation pacing. Adding CSP-treatment to these patients requires an additional pacing lead (HBP or LBBAP) and the use of a CRT-D device. As opposed to HBP, in LBBAP atrial oversensing cannot occur. Using an ICD-lead in this position could reduce the number of intracardiac leads needed while maintaining the possibility of sensing and treating ventricular arrhythmias. Purpose We evaluated the acute electrical parameters before and after delivering an ICD shock with an ICD-lead positioned in the left bundle branch area (LBBA). As this ICD-lead position has never been described before, no data is available on dislocation after shock-delivery. We looked at the electrical parameters of the successful LBBAP ICD-lead implants in our LBBAD (Left Bundle Branch Area Defibrillator) pilot-trial which is a proof-of-concept study for LBBA-ICD lead implantation. Methods In the LBBAD pilot trial, we implant an ICD lead in the LBBA to evaluate for feasibility of implantation and functionality of defibrillation. As this is a proof of concept trial, after testing the lead is re-implanted in a conventional ventricular position. In this abstract we report the evaluation of the electrical parameters of the first 3 successfully implanted LBBAD-leads (n=3). Results After LBBA implantation initial electrical parameters were measured. The pacing threshold was 0,8 +/- 0,6 V @ 0,4 ms, while the sensed R-wave and the impedance measured 7,0 +/- 2,7 mV and 512,3 +/- 38,8 Ohms respectively. The shock-coil impedance was 68,0 +/- 7,0 Ohms. All these parameters are in range with the parameters seen in conventional ICD-lead implantation. After performing the defibrillation threshold test (DFT) all electrical parameters were re-evaluated. Sensing, threshold and impedance were 7,6 +/- 2,2 mV, 0,8 +/- 0,7 V @ 0,4 ms, 516,3 +/- 47,8 Ohms and 71,7 +/- 8,2 Ohms respectively. These post-shock measurements remained stable within normal ICD-lead functioning range precluding acute dislocation. Conclusions Our LBBAD pilot trial is the first-in-human experience with ICD-leads implanted in the LBBA. This pilot trial evaluates for implant-feasibility and also looked at the pre- and post shock electrical parameters of the ICD-lead. As the parameters remained in normal working range, precluding acute shock-induced dislocation, these results open the possibility in patients with an LBBAP-indication as well as an ICD-indication, for a follow-up study to implant an LBBAD-lead and perform longer-term evaluation.

Real-time artificial intelligence assisted insulin dosage titration system for glucose control in type 2 diabetic patients: a proof of concept study

ObjectiveThis study aims to develop an insulin dosage adjustment model using machine learning of high quality electronic health records (EHRs) notes and then to form an artificial intelligence-based insulin clinical decision support workflow (iNCDSS) implemented in the HIS system to give a real-time recommendation of insulin dosage titration. The efficacy and safety in clinical practice is evaluated in this proof-of-concept study.Research design and methodsWe extracted patient-specific and time-varying features from the original EHRs data and performed machine learning analysis through 5-fold cross validation. In the patient-blind, single-arm interventional study, insulin dosage was titrated according to iNCDSS in type 2 diabetic inpatients for up to 7 d or until hospital discharge. The primary end point of the trial was the difference in glycemic control as measured by mean daily blood glucose concentration during the intervention period.ResultsA total of 3275 type 2 diabetic patients with 38,406 insulin counts were included for the model analysis. The XGBoost model presented the best performance with root mean square error (RMSE) of 1.06 unit and mean absolute relative difference (MARD) of 6.0% in the training dataset, and RMSE of 1.30 unit and MARD of 6.9% in the testing dataset. Twenty-three patients with T2DM (male 14, 60.9%; age 58.8 ± 10.7 years; duration of diabetes 11.8 ± 8.8 years, HbA1c 9.1 ± 1.1%) were enrolled in the proof of concept trial. The duration of iNCDSS intervention was 7.0 ± 0.1 d. The insulin dose recommended by iNCDSS was accepted by physicians in 97.8%. The mean daily capillary blood glucose was markedly improved during the intervention period, with a reduction of mean daily capillary BG from 11.3(8.0, 13.9) mmol/L in the first 24 h to 7.9(6.5,8.9) mmol/L in the last 24 h of the trial (P < 0.001). In addition, the time range below 3.9 mmol/L was decreased from 1.1% to 0.5%.ConclusionsThe clinical decision support system of insulin dosage titration developed using a machine learning algorithm based on the EHRs data was effective and safe in glycemic control in in type 2 diabetic inpatients.Trial registrationsClinicalTrials.gov Identifier: NCT04053959.

The Safety and Efficacy of Roflumilast Cream 0.15% and 0.05% in Patients With Atopic Dermatitis: Randomized, Double-Blind, Phase 2 Proof of Concept Study.

Patients with atopic dermatitis (AD) need safe and effective topical treatments. To assess safety and efficacy of roflumilast cream in patients with mild to moderate AD. In this phase 2, proof of concept trial, patients (N=136) aged &ge;12 years with AD were randomized to once-daily roflumilast cream 0.15%, roflumilast cream 0.05%, or vehicle cream for 4 weeks. Absolute change from baseline in Eczema Area and Severity Index (EASI) score at week 4 (primary endpoint), percentage change and responder rates, Validated Investigator Global Assessment-AD (vIGA-AD), and safety were assessed. At week 4, mean absolute changes in EASI were &minus;6.4 (P=0.097 vs vehicle), &minus;6.0 (P=0.356), and &minus;4.8 with roflumilast 0.15%, roflumilast 0.05%, and vehicle, respectively. Significant improvements were observed for percentage change from baseline in EASI, patients reaching 75% improvement in EASI, and patients achieving vIGA-AD score of &ldquo;clear&rdquo; or &ldquo;almost clear.&rdquo; Treatment-related adverse events (AEs) occurred in 2 (2.2%) patients receiving roflumilast (mild rash and moderate application site pain). Only 1 (1.1%) patient receiving roflumilast discontinued study/drug due to an AE. Small number of patients. Results support additional larger clinical trials of roflumilast cream to assess its potential as a once-daily, nonsteroidal topical AD treatment. gov identifier NCT03916081 J Drugs Dermatol. 2023;22(2):139-147. doi:10.36849/JDD.7295.

2321. Long-term immunogenicity of Ad26.RSV.preF/RSV preF protein vaccine against RSV in a phase 2b study by age and risk level

Abstract Background Respiratory syncytial virus (RSV) can cause serious lower respiratory tract disease (LRTD) among older adults. There is no licensed RSV vaccine. In CYPRESS (a randomized, double-blind, placebo-controlled, phase 2b proof-of concept trial; NCT03982199), an Ad26.RSV.preF/RSV preF protein vaccine demonstrated 80.0% efficacy for prevention of RSV LRTD and 69.8% efficacy for prevention of any RSV acute respiratory infection in adults aged ≥65 years through the first RSV season. This study evaluated the durability of immune responses elicited by Ad26.RSV.preF/RSV preF protein after two RSV seasons (up to 1.5 years post-vaccination) in the overall study population and in groups of participants stratified by age and risk level for severe RSV LRTD. Methods Participants (N=5782) were randomized 1:1 to receive vaccine or placebo before the RSV season. The primary endpoint was first occurrence of RSV LRTD. RSV A2 virus neutralizing antibodies (VNAs; through Day 365), RSV preF binding antibodies (through Day 533), and RSV-F–specific IFN-γ enzyme-linked immune absorbent spot (ELISpot; through Day 533), were evaluated in an immunogenicity subset (n=195; ages 65–74 years: n=141; 75–84 years: n=47; ≥85 years: n=6; increased risk [chronic heart or lung disease]: n=48; non-increased risk: n=147). Results In the vaccine group of the immunogenicity subset, RSV A2 VNAs peaked at Day 15 and were maintained at 2.8-fold over baseline at 1 year. Similarly, RSV preF-specific binding antibodies peaked at Day 15 and were maintained at 2.1-fold above baseline at 1.5 years. Median RSV-F–specific IFN-γ T-cell frequency increased from 34 spot-forming cells (SFC)/106 peripheral blood mononuclear cells (PBMCs) at baseline to 143 SFC/106 PBMCs at 1.5 years. Comparable immune responses were observed in age/risk subgroups. No relevant changes were observed in the placebo group at any time point. Pre-existing Ad26 VNAs did not appear to impact RSV-specific immune response durability. Conclusion Ad26.RSV.preF/RSV preF protein vaccine was efficacious and elicited robust, durable (to at least 1.5 years) humoral and cellular immune responses in adults aged ≥65 years, older participants (≥75 years), and in participants with increased risk for severe RSV LRTD. Disclosures Christy A. Comeaux, MD, PhD, Janssen Vaccines &amp; Prevention B.V.: Employee Ann R. Falsey, MD, BioFire Diagnostics: Grant/Research Support|Janssen: Grant/Research Support|Merck Sharp &amp; Dohme: Grant/Research Support|Novavax: Advisor/Consultant|Pfizer: Grant/Research Support Kristi Williams, PhD, Janssen Research and Development: Employee John E. Ervin, MD, The Alliance for Multispecialty Research – KCM: Contractual agreement for conduct of study protocol Arangassery R. Bastian, PhD, Janssen Vaccines &amp; Prevention BV: Employee Joris Menten, PhD, Janssen Infectious Diseases: Employee Els De Paepe, MSc, Janssen Infectious Diseases: employee Sjouke Vandenberghe, PhD, Janssen Infectious Diseases: Employee Eric K. H. Chan, PhD, Janssen Global Services, LLC: Employee Jerald Sadoff, MD, Janssen Vaccines &amp; Prevention BV: Employee Macaya Douoguih, MD, MPH, Janssen Vaccines &amp; Prevention B.V.: Employee Benoit Callendret, PhD, Janssen Vaccines &amp; Prevention B.V.: Employee Esther Heijnen, MD, PhD, Janssen Vaccines &amp; Prevention B.V.: Employee.

Understanding multi-modal brain network data: An immersive 3D visualization approach

Understanding the human brain requires the incorporation of functional interaction patterns that depend on a variety of features like experimental setup, strength of directed connectedness or variability between several individuals or groups. In addition to these external factors, there are internal properties of the brain network as for example temporal propagation of connections, or connectivity patterns that only occur in a distinct frequency range of the signal. The visualization of detected networks covering all necessary information poses a substantial problem which is mainly due to the high number of features that have to be integrated within the same view in a natural spatial context.To address this problem, we propose a new tool that transfers the network into an anatomically arranged origin–destination view in a virtual visual analysis lab. This offers the user an opportunity to assess the temporal evolution of connectivity patterns and provides an intuitive and motivating way of exploring the corresponding features via navigation and interaction in virtual reality (VR). The approach was evaluated in a user study including participants with neuroscientific background as well as people working in the field of computer science. As a first proof of concept trial we used functional brain networks derived from time series of electroencephalography recordings evoked by visual stimuli. All participants gave a positive general feedback, notably they saw a benefit in using the VR view instead of the compared 2D desktop variant. This suggests that our application successfully fills a gap in the visualization of high-dimensional brain networks and that it is worthwhile to further follow and enhance the proposed representation method.

Mindfulness-based intervention and aggression and rule-breaking behaviours in elementary school boys: a proof of concept trial

This study investigated the effect of a mindfulness-based intervention on pathological symptoms in boys with externalised disorders. A total of 24 elementary school students with externalising disorders, diagnosed by completing the Child Behavior Checklist (CBCL), were randomly assigned to a mindfulness-based intervention for two months. One session per week was offered and each session lasted one hour ( n = 12) or as a wait-list control group ( n = 12). Data were analysed via a multivariate analysis of covariance (MANCOVA) test. Students from the intervention group showed greater reductions in rule-breaking behaviours than those in the wait-list control group. Also, there was clear superiority of the intervention relative to the wait-list control group for reducing both aggression and rule-breaking behaviours (effect size differences were d = −2.52 and d = −1.88 respectively). These positive results on outcome measures provide initial evidence for a mindfulness-based intervention as a treatment option for boys with externalising disorders.

Immersive Reality Experience Technology for Reducing Social Isolation and Improving Social Connectedness and Well-being of Children and Young People Who Are Hospitalized: Open Trial.

BackgroundChildren and young people who are hospitalized can feel disconnected from their peers and families, which can, in turn, predispose them to psychological problems, including anxiety and depression. Immersive reality experience technology, recently developed by the New Zealand Patience Project Charitable Trust, may help to overcome these issues. Immersive reality experience technology uses immersive 360° live streaming and a virtual reality headset to enable children and young people who are hospitalized to connect through cameras located in either their school or home environment and via SMS text messaging with a designated buddy.ObjectiveThis trial aims to expand qualitative findings from a previous smaller proof of concept trial to ascertain the views of New Zealand children and young people who are hospitalized, their caregivers, and teachers regarding immersive reality experience technology and quantitatively evaluate the effectiveness of immersive reality experience technology in reducing social isolation and improving social connectedness and well-being using validated outcome measures.MethodsAn open trial of immersive reality experience technology was conducted between December 2019 and December 2020 for which 19 New Zealand children and young people aged 13 to 18 years who had been hospitalized at Starship Hospital—a specialist pediatric hospital in Auckland—for at least 2 weeks were recruited. All young people completed the Short Warwick–Edinburgh Mental Well-Being Scale, an abbreviated version of the Social Connectedness Scale, and the Social Inclusion Scale at baseline. Of the 19 participants, 10 (53%) used immersive reality experience technology as often as they wished over a 6-week period and completed postintervention measures. Semistructured interviews with a subset of the 10 young people, 4 caregivers, and 6 teachers were conducted immediately after the intervention.ResultsParticipants reported improvements in social inclusion (mean change 3.9, SD 2.8; P=.06), social connectedness (mean change 14.2, SD 10.0; P=.002), and well-being (mean change 5.7, SD 4.0; P=.001). Key themes from interviews with participants, caregivers, and teachers were the importance of support for using immersive reality experience technology, connecting versus connectedness, choice and connection, and the value of setting it up and getting it right. Recommendations for improving connectedness via immersive reality experience and related technologies were also provided.ConclusionsImmersive reality experience technology can improve the social inclusion, social connectedness, and well-being of New Zealand children and young people who are hospitalized. With some technological modifications and simplified implementation, immersive reality experience and related technology could become part of standard care and support children and young people who are hospitalized in New Zealand and elsewhere to sustain family and peer cohesion, experience fewer psychological problems, and more easily return to normal life following the completion of treatment.Trial RegistrationAustralian New Zealand Clinical Trials Network Registry ACTRN12619000252112; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376837&isReview=true

Advancing HIV prevention using tenofovir-based pre-exposure prophylaxis.

Tenofovir-based pre-exposure prophylaxis (PrEP) revolutionized the global HIV prevention landscape. Prior to the proof-of concept trial in 2010, which demonstrated that tenofovir (TFV) could prevent sexual transmission of HIV, prevention options were largely limited to behavior change, condoms, and circumcision. Several subsequent studies evaluating oral tenofovir disoproxil fumarate (TDF) or the TDF/emtricitabine (FTC) combination as PrEP for HIV prevention provided evidence for regulatory approval and inclusion in national and international guidelines. By 2021, 1.5 million people had initiated oral tenofovir-based PrEP, contributing to declines in HIV incidence in some regions. Here we reflect on how oral tenofovir-based PrEP became an important component of combination HIV prevention programs across the globe.

Post-exercise Warm or Cold Water Immersion to Augment the Cardiometabolic Benefits of Exercise Training: A Proof of Concept Trial

We investigated whether substituting the final half within 60-min bouts of exercise with passive warm or cold water immersion would provide similar or greater benefits for cardiometabolic health. Thirty healthy participants were randomized to two of three short-term training interventions in a partial crossover (12 sessions over 14–16 days, 4 week washout): (i) EXS: 60 min cycling 70% maximum heart rate (HRmax), (ii) WWI: 30 min cycling then 30 min warm water (38–40°C) immersion, and/or (iii) CWI: 30 min cycling then 30 min cold water (10–12°C) immersion. Before and after, participants completed a 20 min cycle work trial, O2max test, and an Oral Glucose Tolerance Test during which indirect calorimetry was used to measure substrate oxidation and metabolic flexibility (slope of fasting to post-prandial carbohydrate oxidation). Data from twenty two participants (25 ± 5 year, BMI 23 ± 3 kg/m2, Female = 11) were analyzed using a fixed-effects linear mixed model. O2max increased more in EXS (interaction p = 0.004) than CWI (95% CI: 1.1, 5.3 mL/kg/min, Cohen’s d = 1.35), but not WWI (CI: −0.4, 3.9 mL/kg/min, d = 0.72). Work trial distance and power increased 383 ± 223 m and 20 ± 6 W, respectively, without differences between interventions (interaction both p > 0.68). WWI lowered post-prandial glucose ∼9% (CI −1.9, −0.5 mmol/L; d = 0.63), with no difference between interventions (interaction p = 0.469). Substituting the second half of exercise with WWI provides similar cardiometabolic health benefits to time matched exercise, however, substituting with CWI does not.

Quantitative Decision Under Unequal Covariances and Post-Treatment Variances: A Kidney Disease Application

Proof-of-concept (PoC) trials enable sponsors decide whether to continue or discontinue a compound’s development based on preliminary evidence of safety and efficacy. Many accounts exist on using quantitative approaches for this decision. Still, these accounts are devoid of quantitative decisions under unequal covariances and post-treatment variances for continuous endpoints. Filling this void is important because randomization to treatment groups only guarantees equal variances before treatment initiation. In this article, I show how unequal covariances and post-treatment variances affect the consider zone when using a three-outcome frequentist decision framework. Results herein suggest that the consider zone decreases with increase in correlation between baseline and post-baseline measurements for any sample size. Compared to decrease in consider zone under equal covariances and post-treatment variances, decrease in consider zone was greater under unequal covariances and post-treatment variances. The results suggest that ignoring a baseline covariate correlated with an outcome robs the study team of an opportunity to effectively minimize uncertain decision in PoC trial scoped to support quantitative decisions. Used for illustration is design of a PoC trial in kidney disease.

Tailoring a dissonance-based body image intervention for adult women in a proof of concept trial: The Women’s Body Initiative

Although historically conceptualized as problems of youth, recent research indicates that women of all ages experience body dissatisfaction and eating disorder (ED) pathology. Despite this, existing body image interventions predominantly target youth. The Body Project (BP) has extensive support for reducing ED risk factors in younger women and girls. The current proof-of-concept study investigated the feasibility, acceptability, and estimates of intervention effect sizes of a modified BP for adult women, the Women’s Body Initiative (WBI). Conducted in the Southwestern United States, adult women (N = 13) aged 29–70 (M = 49.1) participated in 4, 1-h weekly sessions, completing measures at baseline, post-intervention, and 3-month follow-up. Participants rated the program as highly feasible and acceptable. Within-subjects effects sizes were medium to large for primary outcomes (body dissatisfaction, ED pathology) and secondary outcomes (psychosocial impairment, negative affect, quality of life, nutritious food consumption, and sleep) through 3-months. Results suggest preliminary feasibility and acceptability of WBI for adult women, and support proceeding with a larger trial to investigate intervention efficacy.

Effect of denosumab on osteolytic lesion activity after total hip arthroplasty: a single-centre, randomised, double-blind, placebo-controlled, proof of concept trial.

Osteolysis causes recurrent pain and disability after total hip arthroplasty. We investigated the effect of the human monoclonal antibody denosumab on osteolytic lesion activity in patients undergoing revision total hip arthroplasty surgery to show the biological proof of concept for a non-surgical treatment for the disease. We did a phase 2, randomised, double-blind, placebo-controlled, proof of concept superiority trial at Sheffield Teaching Hospitals, Sheffield, UK. Eligible patients aged 30 years or older and scheduled for revision surgery for symptomatic, radiographically confirmed osteolysis were randomly allocated (1:1) to subcutaneous denosumab (60 mg single-dose) or placebo by an independent pharmacist using a random number table. The primary outcome was the between-group difference in osteoclast number per mm of bone surface of biopsies taken from the osteolytic membrane-bone interface at surgery 8 weeks later, measured by quantitative histomorphometry in all patients who underwent revision surgery. Adverse events were analysed in all randomly assigned participants. This trial is registered with the EU Clinical Trials Register (EudraCT 2011-000541-20). Between Dec 12, 2012, and June 24, 2018, 51 patients were assessed for eligibility, of whom 24 were randomly assigned to study treatment. Two patients had their revision surgery cancelled for unrelated reasons, leaving 22 patients (ten in the denosumab group) for analysis of the primary outcome. There were 83% fewer osteoclasts at the osteolysis membrane-bone interface in the denosumab versus the placebo group (median 0·05 per mm [IQR 0·11] vs 0·30 mm [0·40], p=0·011). No deaths or treatment-related serious adverse events occurred. Seven adverse events, including one severe adverse event, occurred in four (36%) of 11 patients in the denosumab group. In the placebo group ten adverse events, including three severe adverse events, occurred in five (38%) of 13 patients. To our knowledge, this is the first clinical trial of an investigational drug for osteolysis that shows tissue-specific biological efficacy. These results justify the need for future trials that target earlier-stage disease to test for clinical efficacy in reducing the need for revision surgery. Amgen.

147. Clinical Safety and Efficacy of Novel Antifungal, Fosmanogepix, in the Treatment of Candidemia: Results from a Phase 2 Proof of Concept Trial

BackgroundFosmanogepix (FMGX) is a first-in-class antifungal agent, with a unique MOA targeting the fungal enzyme Gwt1, that has broad-spectrum activity against both yeasts, molds, and dimorphic fungi, including fungi resistant to other antifungal agents. FMGX has a favorable safety profile, reduced potential for clinically significant drug-drug interactions, and is formulated for IV and oral administration.MethodsThis global, multicenter, open-label, non-comparative study evaluated the safety and efficacy of FMGX for first-line treatment of candidemia. Patients with a recent diagnosis of candidemia defined as positive blood culture for Candida spp. within 96 hrs prior to study entry, with ≤2 days of prior antifungal treatment were eligible. Patients with neutropenia, C. krusei infection, or deep-seated Candida infections were excluded. Patients were treated with FMGX for up to 14 days: 1000 mg IV BID for 1 day, then 600 mg IV QD for at least 2 days, followed by either 600 mg IV QD or 700 mg PO QD. Short-term fluconazole (or appropriate alternative) could follow if treatment was required beyond 14 days. Patients with a diagnosis of candidemia within 96 hrs of start of study drug who received at least 1 dose of FMGX were included in the mITT population. The primary efficacy endpoint was outcome at end of study treatment (EOST) as determined by an independent data review committee (DRC). Successful outcome was defined as clearance of Candida from blood cultures with no additional antifungal treatment and survival at EOST. All Candida isolates were tested for antifungal susceptibility.ResultsA total of 21 subjects were enrolled in the study: 20 were included in the mITT. Median duration of FMGX was 11 days (range 5–14). All subjects received IV FMGX, 48% (10/21) received PO FMGX. The DRC-assessed success rate at EOST was 80% (16/20). Survival at day 30 was 85% (17/20); 3 deaths were not related FMGX. FMGX was well-tolerated with no treatment-related serious adverse events or discontinuations. FMGX had potent in vitro activity against all study Candida spp. (EUCAST MIC range 0.001–0.03 µg/ml) including those resistant to other antifungal agents.ConclusionFMGX was safe, well-tolerated, and demonstrated proof of concept with a high level of treatment success in patients with candidemia.Disclosures Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Bart Jan Kullberg, MD, FRCP, FIDSA, Amplyx (Advisor or Review Panel member) Galia Rahav, MD, AstraZeneca (Scientific Research Study Investigator) Mickaël Aoun, MD, Amplyx Pharmaceuticals (Scientific Research Study Investigator) Pierre Bulpa, MD, Amplyx Pharmaceuticals (Scientific Research Study Investigator) Ricard Ferrer, MD, PhD, Shionogi B.V. (Advisor or Review Panel member) Todd P. McCarty, MD, Amplyx (Scientific Research Study Investigator)Cidara (Scientific Research Study Investigator) Sara Barbat, BSN, RN, Amplyx Pharmaceuticals (Employee) Pamela Wedel, BSc, Amplyx Pharmaceuticals (Employee) Iwonka Oborska, PhD, Amplyx Pharmaceuticals (Consultant, Independent Contractor) Haran T. Schlamm, MD, Amplyx (Consultant) Michael Hodges, BSc. MD, Amplyx Pharmaceuticals Inc. (Employee)

Compassion-Focused Therapy: Proof of Concept Trial on Suicidal Ideation and Cognitive Distortions in Female Survivors of Intimate Partner Violence With PTSD.

This proof of concept trial aimed to assess the pre-post differences in suicidal ideation and cognitive distortions in the compassion-focused therapy (CFT), and to compare the psychological improvement in the experimental group to a control group. A total of 42 women suffering from PTSD due to exposure to intimate partner violence (IPV) were randomized to the experimental and control groups (21 per group). All participants completed the questionnaires of suicidal ideation and cognitive distortions as pretest measures. Subjects of the experimental group received 8 CFT sessions, while the controls did not receive any therapy. Then, all subjects responded to the questionnaires of suicidal ideation and cognitive distortions as the posttest measures. Data were analyzed using one-way repeated measures MANOVA. Subjects of the experimental group indicated a greater reduction in post-test scores of suicidal ideation and its subscales including passive suicidal ideation, preparation for suicide, and active suicidal ideation when compared to the controls. Moreover, the subjects of the experimental group indicated a greater reduction in the post-test scores of cognitive distortions than controls. These results provide support for a larger trial focusing on the efficacy of CFT on psychological outcomes of PTSD following exposure to IPV. This intervention has the potential to be deployed at higher scales for IPV-affected women with PTSD.

Do Cheyne and Stokes have an important message for modern‐day patients with heart failure? Yes, they do

Do <scp>C</scp>heyne and <scp>S</scp>tokes have an important message for modern‐day patients with heart failure? <scp>Y</scp>es, they do

Applications of Bayesian analysis to proof-of-concept trial planning and decision making.

Decision making is a critical component of a new drug development process. Based on results from an early clinical trial such as a proof of concept trial, the sponsor can decide whether to continue, stop, or defer the development of the drug. To simplify and harmonize the decision-making process, decision criteria have been proposed in the literature. One of them is to exam the location of a confidence bar relative to the target value and lower reference value of the treatment effect. In this research, we modify an existing approach by moving some of the "stop" decision to "consider" decision so that the chance of directly terminating the development of a potentially valuable drug can be reduced. As Bayesian analysis has certain flexibilities and can borrow historical information through an inferential prior, we apply the Bayesian analysis to the trial planning and decision making. Via a design prior, we can also calculate the probabilities of various decision outcomes in relationship with the sample size and the other parameters to help the study design. An example and a series of computations are used to illustrate the applications, assess the operating characteristics, and compare the performances of different approaches.

Functionally navigated transcranial magnetic stimulation to evoke lingual pressure in stroke survivors with dysphagia and healthy adults: a proof of concept trial

ABSTRACTBackground: Post-stroke dysphagia is characterized by reduced corticolingual excitability and lingual pressure; however, it remains unknown if transcranial magnetic stimulation (TMS) directly facilitates lingual pressure generation.Objectives: To explore optimal procedures for single pulse TMS using neuronavigation to evoke lingual pressure in intact and disrupted neural networks.Methods: Using co-registered functional magnetic resonance imaging, stimulation sites were determined for five healthy adults (Mage = 67) and four stroke survivors with dysphagia and reduced tongue strength (Mage = 66). Evoked lingual pressures were sampled across 45-65% of maximum stimulator output. Healthy participants repeated TMS with a bite block to isolate lingual pressure from off-target stimulation of mandibular elevators.Results: Only one functionally-guided stimulation site fell within previously reported optimal lateral (8-11cm) and anterior (2–4.25cm) coordinates. Lingual pressure was stable prior to pulse and increased linearly with intensity for both groups (p = .005). Post-stroke active motor thresholds were elevated compared to healthy adults (p = .025). Lingual pressure latency remained stable across intensities (p > .05). Jaw stabilization via bite block reduced the mean magnitude of evoked lingual pressure by approximately 16%.Conclusions: Single pulse TMS directly evokes higher lingual pressure and can define motor thresholds in intact and disordered corticolingual pathways. Stimulation sites using neuronavigation in healthy adults and stroke survivors largely differed from external coordinates in the literature that were predominantly established in young adults. Procedures to investigate motor thresholds for lingual pressure generation are proposed. The therapeutic role of TMS to address post-stroke deficits in lingual pressure and corticolingual excitability warrants continued investigation.