Late Trials Research Articles

Streamlining the Conduct of Cancer Clinical Trials: New Standard Data Collection Practices for National Cancer Institute Late Phase Clinical Studies.

The increase in the complexity of cancer clinical trials over the past several decades has led to a dramatic growth in trial cost and operational burden. The extent and frequency of data collection, particularly in late phase trials which enroll many participants, have been major contributors to this problem. The Clinical Trials and Translational Research Advisory Committee of the National Cancer Institute (NCI) recently assessed the impact of these stressors on the NCI National Clinical Trials Network (NCTN) and recommended that data collection in late phase NCTN trials be limited to data elements essential to address the primary and secondary objectives of the trial. The purpose of this commentary is to describe the rationale for this recommendation, progress towards implementation, and the development of new streamlined standard practices for data collection for late phase NCTN trials effective January 1, 2025.

A - 137 An Item-Level Analysis of the Boston Naming Test in a Sample of Veterans as it Relates to Age and Education

Abstract Objective The Boston Naming Test (Kaplan et al., 1983) is a 60-item test designed to measure confrontational naming ability. Word-finding difficulty is a prominent feature of aphasias, with picture-naming ability being a reliable predictor of lexical retrieval ability (Herbert et al., 2008). Lower performance on the BNT is found among older age groups and individuals with lower educational attainment (Zec et al., 2007). Notably, an item-level analysis of the BNT has not been analyzed in a Veteran population. There is great importance in properly accounting for demographic variables when interpreting patient test results. Methods An item-level confirmatory factor analysis examined mean BNT scores in a veteran sample (n = 517) ages 20–79 (M = 51) with years of educational attainment (M = 13). The purpose of this study was to conduct an item-level factor analysis of the unique cohort effects of both age and education on the Boston Naming Test within a Veteran population. Results The BNT solution explained 60.95% of the variance, and components reflected early and late trials. Within the rotated components matrix, education contributed to late items (36–60) whereas age contributed to early items (11–45). Conclusions These results indicate the importance of properly accounting for demographic variables such as age and educational attainment when interpreting test results unique to a Veteran population. Higher educational attainment is associated with increased performance on later items, whereas older age is associated with decreased performance on earlier items. It may be informative to consider item-level performance when assessing confrontational naming ability.

Expanding RNAi to Kidneys, Lungs, and Spleen via Selective ORgan Targeting (SORT) siRNA Lipid Nanoparticles.

Inhibition of disease-causing mutations using RNA interference (RNAi) has resulted in clinically approved medicines with additional candidates in late stage trials. However, targetable tissues currently in preclinical development are limited to liver following systemic intravenous (IV) administration because predictable delivery of siRNA to non-liver tissues remains an unsolved challenge. Here, evidence of durable extrahepatic gene silencing enabled by siRNA Selective ORgan Targeting lipid nanoparticles (siRNA SORT LNPs) to the kidneys, lungs, and spleen is provided. LNPs excel at dose-dependent silencing of tissue-enriched endogenous targets resulting in 60%-80% maximal knockdown after a single IV injection and up to 88% downregulation of protein expression in mouse lungs after two doses. To examine knockdown potency and unbiased organ targeting, B6.129TdTom/EGFP mice that constitutively express the TdTomato transgene across all cell types are utilized to demonstrate 58%, 45%, and 15% reduction in TdTomato fluorescence in lungs, spleen, and kidneys, respectively. Finally, physiological relevance of siRNA SORT LNP-mediated gene silencing is established via acute suppression of endogenous Tie2 which induces lung-specific phenotypic alteration of vascular endothelial barrier. Due to plethora of extrahepatic diseases that may benefit from RNAi interventions, it is anticipated that the findings will expand preclinical landscape of therapeutic targets beyond the liver.

Enrollment of underserved racial and ethnic populations in pediatric asthma clinical trials

BackgroundLimited data exist on enrollment trends of historically underserved racial and ethnic children in clinical trials. ObjectiveWe sought to evaluate documentation and representation of race and ethnicity in pediatric asthma clinical trials in the US. MethodsThis is a cross-sectional study of US-based interventional trials studying pediatric asthma completed between 2008 and 2022 and registered on ClinicalTrials.gov. Enrollment disparities were assessed using the enrollment prevalence difference (EPD) measure – the median difference between the proportion of participants enrolled and asthma prevalence in the US population by race and ethnicity. ResultsOf the 67 trials reviewed, 53 (79.2%) and 36 (53.7%) reported on race and ethnicity in ClinicalTrials.gov, respectively. Most participants were White (39.1%), Black (37.1%), and non-Hispanic (66.1%). Black, Hispanic, Multiracial, and White children were enrolled in expected proportions based on their contribution to asthma burden. However, American Indian or Alaska Native (AI/AN) (EPD: -1, 95% CI: -1, -1) and Asian children (EPD: -3, 95% CI: -3, -3) were underrepresented, relative to disease burden in these respective groups. Fewer Black children were enrolled in drug or device trials (β=-0.80; 95% CI -1.60, -0.01) than in other trials. Fewer Hispanic children were enrolled in early phase than late phase trials (β=-2.42; 95% CI -3.66, -1.19). ConclusionsEnrollment in pediatric asthma trials conducted in the US was commensurate with the demographics of children affected by asthma for most racial and ethnic groups, but AI/AN and Asian children were underrepresented. Concerted efforts are needed to promote inclusion of these underserved groups in future trials.

QOL-37. THE CREATION OF A PLAY PREPARATION CLINIC FOR CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMOURS TO REGAIN CONTROL ONCE MORE

Abstract Targeted therapies are becoming more readily available for children with Central Nervous System (CNS) tumours, not only for early phase but also late phase trials. With this knowledge, we have created a play preparation clinic whereby all children with a CNS tumour diagnosis are invited to attend. Initially the play preparation clinic was solely a programme to train children to take tablets using a technique created at The Great North Children’s Hospital called ‘Kidzmeds’. On average children are successful in achieving the ‘Kidzmeds’ technique within ten minutes so we were able to expand the programme and incorporate two other areas of play preparation. Firstly, we have been able to include play preparation for children undergoing procedures without sedation or general anaesthesia such as MRI scans and lumbar punctures. Secondly, we have been able to use play preparation to teach children how to achieve cannulation or blood taking using a specific technique we have called the ‘GNCH way’. Our aim is that children leave our hospital having a positive experience and regain control and choice in how procedures take place, feeling they have ownership of their bodies. There is an added incentive of cost saving for our hospital, for example converting medication from liquid to tablet form. Forty-eight children have took part in the clinic so far. Every child has been able to achieve two of the play preparation techniques we offer and eighty-three percent of children have been successful in achieving all three. The youngest child in achieving all three play preparation techniques has been four years old. All forty-eight children continue to be successful in their achievements. Within our service, the feedback from children and families have been overwhelmingly positive and our hope is that other hospitals across the world can benefit from our experience.

Impact of the COVID-19 pandemic mitigation strategies on cancer treatment trials: A meta-analysis of industry and NCI studies.

11021 Background: ASCO and Friends of Cancer Research established a task force to evaluate trial mitigation strategies allowed by US regulators during the COVID-19 pandemic, including the use of telemedicine and remote monitoring. We report the results of a meta-analysis quantifying the impact of these strategies on quality metrics and the recovery time to pre-COVID levels. Methods: We invited 41 sponsors with active US cancer treatment trials from January 2015-May 2022 to contribute deidentified trial-level aggregate data on major protocol deviations (PDs), dropouts, severe or worse toxicity (CTCAE Grade 3-5), and enrollment. We examined outcomes as proportions of participants at-risk during the pre-COVID, initial wave (IW), initial recovery (IR), and secondary recovery (SR) assessment times (Table). Multi-level beta-regression analyses were adjusted for trial phase (“early”, phases I, II, or I/II, vs. “late”, phase III) with study and sponsor as random effects. Indicator variables were used for post-COVID time periods with pre-COVID as the reference. Results: Ten sponsors (9 industry and 1 NCI Cooperative Group) contributed 82 evaluable studies: 63 early and 19 late phase trials. Among the 15,679 participants, enrollment odds decreased 64% in the IW and 45% in the IR but recovered to approximately pre-COVID levels by the SR (Table). Major PDs, dropouts, and severe or worse toxicity all had lower incidence in the IW compared to pre-COVID; these outcomes were also less frequent in IR (p<.05 for each), but not in the SR (p>.05 for each) compared to pre-COVID. Conclusions: Large declines in enrollment rates during the IW rebounded to pre-COVID levels by 2021-2022. We found steep reductions in the rates of reported occurrence of major PDs, dropouts, and severe or worse toxicity during the initial outbreak, which also recovered to pre-COVID levels by 2021-2022. Findings suggest pandemic-related procedural flexibility did not lead to increased reporting of PDs or dropouts and highlight how use of mitigation strategies likely corresponded with the temporary disruption to trial conduct during the pandemic’s peak. Sponsors could consider broader adaptation of trial flexibilities moving forward. [Table: see text]

The impact of large core and late treatment trials: An update on the modelled annual thrombectomy eligibility of UK stroke patients.

To support decisions about thrombectomy provision, we have previously estimated the annual UK population eligible for treatment as ∼10% of stroke admissions. Since then, eight further randomised trials that could alter the eligibility rate have reported in 2021-23. We updated our estimates of the eligible population from these trials and other recent studies. An updated decision tree describing the EVT eligible population for UK stroke admissions was produced. Decision criteria were derived from the highest level of evidence available. For nodes where no specific RCT data existed, evidence was obtained from the latest systematic review(s) or the highest quality observational data. We estimate that 15,420 (approximately 15%) of admitted UK stroke patients are now eligible for thrombectomy, or 14,930 if advanced brain imaging using MRI/CT perfusion or collateral assessment were used in all patients. This is a 54% increase in our previous estimate in 2021. Over 50% of LAO strokes are now potentially eligible for thrombectomy. The increase in eligibility is principally due to a much larger cohort of later presenting and/or larger ischaemic core patients. Most previously independent LAO stroke patients presenting within 24 h, even in the presence of a large ischaemic core on initial non-contrast CT, should be considered for thrombectomy with use of advanced brain imaging in those presenting beyond 12 h to identify salvageable penumbral brain tissue. Treatment in most patients remains critically time-dependent and our estimates should be interpreted with this in mind.

Probability of Regulatory Approval Over Time: A Cohort Study of Cancer Therapies.

New cancer therapies are frequently evaluated in multiple disease indications. We evaluated whether the probability of achieving US Food and Drug Administration (FDA) approval for a new cancer therapy changes with time. We identified a cohort of anticancer drugs with a first registered efficacy trial from 2007 to 2011 on ClinicalTrials.gov. We downloaded all clinical trials for each included drug from the initiation of efficacy testing to January 11, 2021. Each trial was categorized by cancer indication and assigned to investigational trajectories on the basis of unique drug-indication pairings. We performed a univariate Cox's proportional hazards regression to assess the probability of a trajectory leading to regulatory approval over time since initiation of the first efficacy trial for a given drug. We included 213 drugs in our cohort, of which 37 (17.4%) received FDA approval in at least one oncology indication. In our primary analysis, we found a 15% decrease in the probability of approval for every year since initiation of the first efficacy trial (hazard ratio [HR], 0.85 [95% CI, 0.73 to 0.99]; P = .032). We found a 45% increase in the probability of approval for the first trajectory launched for a given drug in comparison with all others (HR, 0.55 [95% CI, 0.33 to 0.91]; P = .021). Drug-indication pairings pursued years after initial testing for efficacy have lowered probability of affecting care. Clinical trial investigators, sponsors, and regulatory bodies may benefit from awareness of this trend when considering both early and late trajectory trials in a drug's development.

B - 100 Principal Component Analysis of WAIS-IV Indices with the Serial Digit Learning Test.

Previous studies have evaluated the construct validity of the Serial Digit Learning Test (SDL) using principal component analysis (PCA; Larrabee et al., 1995; Greenman & Moses, 2016). In this study, we sought to re-investigate the SDL construct using a similar methodological approach with the Weschler Adult Intelligence Scale-4th ed. (WAIS-IV) and a performance validity measure. Sample consisted of diagnostically diverse veterans referred for clinical neuropsychological assessment as part of their standard clinical care (N = 411). SDL-8-digit raw scores were submitted to PCA where a forced three factor solution was derived. Those derived factors were submitted to a second PCA using the four WAIS-IV index scores. The SDL8 solution explained 83% of the variance, and factors reflected early, middle, and late trials. The second PCA produced an unforced four-factor solution explaining 71% of the variance. Excluding loading coefficients below +/-0.3, Component 1 showed loadings on WMI (0.805) and early trials (0.813), Component 2 showed loadings on PSI (0.800) and middle trials (0.789), Component 3 loaded on PRI (0.685) and late trials (0.829), and Component 4 loaded on VCI (0.951) and PSI (-0.348). These results replicated earlier research demonstrating that earlier SDL8 trials load on attentional/working memory measures and middle trials on processing speed. Unexpectedly, late trials loaded onto the Perceptual Reasoning Index, whereas they had previously loaded onto Verbal Comprehension of the WAIS-III. As these results may reflect the updated theoretical model underlying the WAIS-IV, further research replicating results which incorporated earlier WAIS-III perceptual reasoning (POI) measures is warranted.

Casting Justice Before Swine: Late Mediaeval Pig Trials as Instances of Human Exceptionalism

In recent years, several cases about the legal personhood of nonhuman animals garnered global attention, e.g. the recognition of ‘basic rights’ for the Argentinian great apes Sandra and Cecilia. Legal scholars have embraced the animal turn, blurring the once sovereign boundaries between persons and objects, recognising nonhuman beings as legal subjects. The zoonotic origins of the Covid-19 pandemic stress the urgency of establishing ‘global animal law’ and deconstructing anthropocentrism. To this end, it is vital to also consider the extensive premodern legal history that humans share with other animals. Over 200 so-called animal trials have been documented in premodern Europe. In these proceedings, certain nonhuman animals—particularly domestic pigs—were prosecuted, often resulting in their capital punishment or anathema. This paper takes a history of ideas approach to these historical instances where Western philosophy of law and philosophical anthropology intersect, problematising the notion that such trials constitute wholesome precedents of the kind of legal personhood presently debated in jurisprudence. My counter-hegemonic analysis of the legal prosecution and execution of several pigs in fifteenth-century France demonstrates that late mediaeval notions of criminality transcended the alleged human-nonhuman divide whilst reaffirming and reifying human distinctiveness. I propose that pig trials were local laboratories where Christian communities reflected upon the natural hierarchy of God’s creation. Ensuing the apparent breach of the prescribed boundaries of nature, these communities renegotiated and re-naturalised everyday interspecies sociability by utilising the offending animals to exemplify particular norms about what it means to be human, generally to the animals’ detriment.

Late breaking trials in heart failure.

Late breaking trials in heart failure.

Carbon footprint of industry-sponsored late-stage clinical trials

ObjectivesTo quantify the carbon footprint from a sample of pharma industry sponsored phase III trials. To develop an approach that can readily be applied to future trials by AstraZeneca and...

Validation of the Human Arm Stiffness Estimation Method Developed for Overground Physical Interaction Experiments.

To build a physically interactive robot for overground applications, it is crucial to first understand the biomechanics of humans underlying overground physical human-robot interaction (pHRI) tasks. Estimating human arm stiffness during overground interactive tasks is a promising first step toward this goal. For this, an arm stiffness estimation technique was developed in our previous works that consider the unique challenges involving overground pHRI, such as the need to estimate the arm stiffness from a short duration of data with fewer repetitions. In this work, our stiffness estimation method is further validated with a passive spring setup with known stiffness values, as well as with a human experiment setup that resembles the widely used seated reaching tasks. Results show that our method can estimate the passive spring stiffness within 0.5% of error. We also show that the human arm stiffness measured through our method is comparable to those reported in well-known literature. In addition, our method was able to discern experimental conditions such as early vs. late trials or differences in arm movement conditions. Implications of these results are discussed further.Clinical Relevance- This method can aid the design and development of overground interactive robots for human movement assistance and rehabilitation.

Examining clinical trial eligibility for oncology patients with human immunodeficiency virus (HIV): A global cross-sectional analysis.

6554 Background: People Living with HIV (PLWH) are at higher risk of developing cancer, and malignancy is the most common cause of death in PLWH in the USA . In 2017 a joint research statement by the American Society of Clinical Oncology and Friends of Cancer Research (ASCO-FCR) examined trial inclusivity, stating PLWH should not be excluded from clinical trials due to HIV positivity alone without justification. It also provided guidance for designing trial inclusion criteria using CD4 count, use of antiretroviral therapy (ART), ART-related drug interactions and HIV-associated complications. To review incorporation of ASCO-FCR recommended wording and current compliance, we examined global eligibility for PLWH in clinical trials. Methods: Clinicaltrials.gov was searched on 15 Nov 2022 for open and recruiting trials worldwide, using terms ‘advanced cancer’ and ‘interventional’. Trials lacking systemic treatment were deemed non-evaluable. Evaluable studies’ eligibility criteria were manually reviewed for specific criterion excluding PLWH or diagnosis/history of immunodeficiency (outright exclusion). Therapy type and study phase were captured and their relationships to outright exclusion were significance tested using odds ratios (OR) with 95% confidence intervals (CI). Results: The search rendered 2388 evaluable clinical trials. Eligibility criteria outrightly excluded PLWH in 1194 (50%) , of which 1113 (93%) were early phase trials (Phase 0-2). 206 evaluable trials (8.6%) permitted inclusion of PLWH aligned with ASCO-FCR guidance, including 3 (0.1%) with a cohort for PLWH. AIDS-defining illness was an exclusion criterion in 27 trials (1%), and specific interactions to ART in 10 (0.4%). Early phase trials had a significantly higher likelihood of outright exclusion of PLWH when compared with late phase trials (OR 2.98; 95% CI 2.16-4.11, p<0.0001). Trials investigating immunomodulatory agents were more likely to outrightly exclude PLWH than those investigating other drug classes (OR 1.60; 95% CI 1.36-1.88, p<0.0001). Criteria which may implicitly exclude PLWH were identified, including 204 (8.5%) citing active/chronic/severe infection, 189 (7.9%) listing CYP and P-gp interaction criteria and 3 (0.1%) "immunodeficiency". Conclusions: Despite adequate time to incorporate, most currently recruiting oncology clinical trials do not use ASCO-FCR guidance for including PLWH. Half of evaluated trials excluded PLWH without reason. Early phase and immunotherapy trials were significantly more likely to exclude PLWH without exception, despite data to support immunotherapy use for PLWH. Covert inclusionary barriers exist in criteria that lack HIV-specific guidance, and this may further exclude PLWH. Consideration of recommendations and guidance in eligibility criteria for oncology trials is critical to address current inequities in care for PLWH and cancer.

Immature human engineered heart tissues engraft in a guinea pig chronic injury model.

Engineered heart tissue (EHT) transplantation represents an innovative, regenerative approach for heart failure patients. Late preclinical trials are underway, and a first clinical trial started recently. Preceding studies revealed functional recovery after implantation of in vitro-matured EHT in the subacute stage, whereas transplantation in a chronic injury setting was less efficient. When transplanting matured EHTs, we noticed that cardiomyocytes undergo a dedifferentiation step before eventually forming structured grafts. Therefore, we wanted to evaluate whether immature EHT (EHTIm) patches can be used for transplantation. Chronic myocardial injury was induced in a guinea pig model. EHTIm (15×106 cells) were transplanted within hours after casting. Cryo-injury led to large transmural scars amounting to 26% of the left ventricle. Grafts remuscularized 9% of the scar area on average. Echocardiographic analysis showed some evidence of improvement of left-ventricular function after EHTIm transplantation. In a small translational proof-of-concept study, human scale EHTIm patches (4.5×108 cells) were epicardially implanted on healthy pig hearts (n=2). In summary, we provide evidence that transplantation of EHTIm patches, i.e. without precultivation, is feasible, with similar engraftment results to those obtained using matured EHT.

Different Control Strategies Drive Interlimb Differences in Performance and Adaptation during Reaching Movements in Novel Dynamics.

Humans exhibit lateralization such that most individuals typically show a preference for using one arm over the other for a range of movement tasks. The computational aspects of movement control leading to these differences in skill are not yet understood. It has been hypothesized that the dominant and nondominant arms differ in terms of the use of predictive or impedance control mechanisms. However, previous studies present confounding factors that prevented clear conclusions: either the performances were compared across two different groups, or in a design in which asymmetrical transfer between limbs could take place. To address these concerns, we studied a reach adaptation task during which healthy volunteers performed movements with their right and left arms in random order. We performed two experiments. Experiment 1 (18 participants) focused on adaptation to the presence of a perturbing force field (FF) and experiment 2 (12 participants) focused on rapid adaptations in feedback responses. The randomization of the left and right arm led to simultaneous adaptation, allowing us to study lateralization in single individuals with symmetrical and minimal transfer between limbs. This design revealed that participants could adapt control of both arms, with both arms showing similar performance levels. The nondominant arm initially presented a slightly worst performance but reached similar levels of performance in late trials. We also observed that the nondominant arm showed a different control strategy compatible with robust control when adapting to the force field perturbation. EMG data showed that these differences in control were not caused by differences in co-contraction across the arms. Thus, instead of assuming differences in predictive or reactive control schemes, our data show that in the context of optimal control, both arms can adapt, and that the nondominant arm uses a more robust, model-free strategy likely to compensate for less accurate internal representations of movement dynamics.

Safety-Related Drug Label Changes Following Large Post-Marketing Cardiometabolic Trials: A Review of European Public Assessment Reports.

Selective safety data collection may simplify late-stage clinical trials and improve their feasibility. However, the impact on increasing overall drug safety knowledge is unknown. The aim of this study is to evaluate how much safety information is added to the drug label based on large trials after initial authorization. Changes made to the "undesirable effects" section of the drug label of cardiometabolic agents approved between 2000 and 2020 based on the results of large (> 1,000 patient) clinical trials submitted to the European Medicines Agency (EMA) were evaluated. The study focused on glucose lowering, antithrombotic, and lipid-modifying agents. The primary outcome was the number of changes in adverse drug reactions in the drug label. The EMA reviewed 55 large trials concerning 25 cardiometabolic agents after the initial marketing authorization, which included 402,444 patients. Ultimately, 38 trials (69%) resulted in a safety section update, whereas 17 trials (31%) did not. Changes in listed adverse drug reactions were made following 19 trials (35%) for 12 agents: 77 adverse drug reactions were added, 11 were deleted, and the frequencies of 43 were changed. Most changes in adverse drug reactions arose from trials with antithrombotic agents (88%) and trials performed in a new population (92%). Large trials for cardiometabolic agents reported after authorization add limited new safety information on adverse drug reactions, especially when performed in the population studied prior to approval. This suggests that selective safety data collection does not reduce learnings from late stage cardiometabolic trials in populations comprehensively studied before.

A novel, efficient and seamless Phase 2A‐2B design to test varoglutamstat in early AD: the VIVA‐MIND study

AbstractBackgroundImproved Phase 2 study designs may increase success rates in late stage AD trials. Varoglutamstat (PQ912) is an oral small molecule glutaminyl cyclase inhibitor designed to address several key disease mechanisms. A Phase 2A study (NCT02389413) of 120 early AD patients treated for 12 weeks provided preliminary evidence of safety and tolerability, and effects on working memory, CSF biomarkers, and synaptic function (EEG theta‐power).ObjectiveTo design a well‐powered, safe, and efficient study of varoglutamstat in early AD incorporating adaptive dose selection in Phase 2A, a futility analysis testing pharmacological, biological and cognitive criteria, and a seamless transition to a larger Phase 2B study investigating longer‐term efficacy and safety.MethodsAn efficient and safe selection rule across 3 descending doses (600mg, 300mg, 150 mg BID) was established using a continuously monitored Pocock safety boundary targeting a set of treatment emergent AE’s of interest. Well‐powered stage‐gate criteria at a planned interim futility analysis included thresholds for target occupancy in plasma, and would detect negative effects on a cognitive composite or absence of benefit on EEG theta‐power. The Phase 2B study was powered to detect an effect size of 0.7 points on the Clinical Dementia Rating – Sum of Boxes score at 18 months, an established approvable endpoint.ResultsThe on‐going Phase 2A adaptive dose‐finding trial (NCT03919162) is randomizing 180 subjects with MCI or mild probable AD, initially to 24+ weeks of 600mg varoglutamstat dose or placebo, BID. If the safety boundary is hit, the dose will be discontinued and all subjects titrated down, with similar sequential testing of lower doses as needed. The interim futility analysis will occur when the first 180 randomized subjects have been on study for at least 24 weeks. If this stage‐gate is passed, Phase 2B will enroll 234 additional patients to achieve 414 total patients treated for 72 weeks at full dose of varoglutamstat or placebo.ConclusionThis novel study design enables adaptive dose selection, an early interim futility analysis, and longer‐term determination of cognitive and functional efficacy, and should support robust proof‐of‐concept for varoglutamstat using a total sample of 414 subjects treated for 72 weeks.

Fedratinib: a pharmacotherapeutic option for JAK-inhibitor naïve and exposed patients with myelofibrosis

ABSTRACT Introduction Ruxolitinib is the most commonly used JAK-inhibitor (JAKi) for the management of symptoms related to splenomegaly and cytokine-mediated inflammation in patients with myelofibrosis (MF), but is limited by variable durability of response with most patients experiencing failure after 2–3 years. Long-term data on other approved JAKi, fedratinib and pacritinib, are not available due to the clinical hold put on pivotal trials for toxicity concerns. Areas covered Following the initial hold for concern of Wernicke’s encephalopathy, fedratinib was approved by the Food and Drug Administration (FDA) in 2019 for MF. We review the data available from early, and late phase critical trials, outline a role for fedratinib in the current treatment landscape of MF, and highlight the knowledge gaps in optimizing use of fedratinib. Expert opinion The JAKARTA and JAKARTA2 trials established efficacy in spleen volume response (SVR) and symptom reduction in JAKi-naïve and ruxolitinib-exposed MF patients, respectively. Further trials, FREEDOM and FREEDOM2, are in progress to understand long-term effects of fedratinib; and include strategies to mitigate gastrointestinal toxicity, monitor thiamine levels and surveil for encephalopathy. We use fedratinib for symptomatic MF following ruxolitinib failure in patients without significant cytopenias; with practical strategies for monitoring and managing potential toxicity.

Large scale clinical trials: lessons from the COVID-19 pandemic

BackgroundThe COVID-19 pandemic has presented substantial new challenges to clinical and research teams. Our objective was to analyse the experience of investigators and research delivery staff regarding the research response...