Trial Network Research Articles

ProTarget: a Danish Nationwide Clinical Trial on Targeted Cancer Treatment based on genomic profiling – a national, phase 2, prospective, multi-drug, non-randomized, open-label basket trial

BackgroundAn increasing number of trials indicate that treatment outcomes in cancer patients with metastatic disease are improved when targeted treatments are matched with druggable genomic alterations in individual patients (pts). An estimated 30–80% of advanced solid tumors harbor actionable genomic alterations. However, the efficacy of personalized cancer treatment is still scarcely investigated in larger, controlled trials due to the low frequency and heterogenous distribution of druggable alterations among different histologic tumor types. Therefore, the overall effect of targeted cancer treatment on clinical outcomes still needs investigation.Study design/methodsProTarget is a national, non-randomized, multi-drug, open-label, pan-cancer phase 2 trial aiming to investigate the anti-tumor activity and toxicity of currently 13 commercially available, EMA-approved targeted therapies outside the labeled indication for treatment of advanced malignant diseases, harboring specific actionable genomic alterations. The trial involves the Danish National Molecular Tumor Board for confirmation of drug-variant matches. Key inclusion criteria include a) measurable disease (RECIST v.1.1), b) ECOG performance status 0–2, and c) an actionable genomic alteration matching one of the study drugs. Key exclusion criteria include a) cancer type within the EMA-approved label of the selected drug, and b) genomic alterations known to confer drug resistance. Initial drug dose, schedule and dose modifications are according to the EMA-approved label. The primary endpoint is objective response or stable disease at 16 weeks. Pts are assigned to cohorts defined by the selected drug, genomic alteration, and tumor histology type. Cohorts are monitored according to a Simon’s two-stage-based design. Response is assessed every 8 weeks for the first 24 weeks, then every 12 weeks. The trial is designed similar to the Dutch DRUP and the ASCO TAPUR trials and is a partner in the Nordic Precision Cancer Medicine Trial Network. In ProTarget, serial fresh tumor and liquid biopsies are mandatory and collected for extensive translational research including whole genome sequencing, array analysis, and RNA sequencing.DiscussionThe ProTarget trial will identify new predictive biomarkers for targeted treatments and provide new data and essential insights in molecular pathways involved in e.g., resistance mechanisms and thereby potentially evolve and expand the personalized cancer treatment strategy.Protocol version: 16, 09-MAY-2022.Trial registrationClinicalTrials.gov Identifier: NCT04341181.Secondary Identifying No: ML41742.EudraCT No: 2019–004771-40.

More and better clinical trials in health care: focusing on people, not just systems and processes.

More and better clinical trials in health care: focusing on people, not just systems and processes.

Secondary prevention with a structured semi-interactive stroke prevention package in INDIA (SPRINT INDIA): a multicentre, randomised controlled trial

There is a high burden of stroke, including recurrent stroke, in India. We aimed to assess the effect of a structured semi-interactive stroke prevention package in patients with subacute stroke to reduce recurrent strokes, myocardial infarction, and death. This was a multicentre, randomised, clinical trial conducted in 31 centres of the Indian Stroke Clinical Trial Network (INSTRuCT). Adult patients with first stroke and access to a mobile cellular device were randomly allocated (1:1) to intervention and control groups by the research coordinators at each centre using a central, in-house, web-based randomisation system. The participants and research coordinators at each centre were not masked to group assignment. The intervention group received regular short SMS messages and videos that promoted risk factor control and medication adherence and an educational workbook, in one of 12 languages, and the control group received standard care. The primary outcome was a composite of recurrent stroke, high-risk transient ischaemic attack, acute coronary syndrome, and death at 1 year. The outcome and safety analyses were done in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03228979 and Clinical Trials Registry-India (CTRI/2017/09/009600) and was stopped for futility after interim analysis. Between April 28, 2018, and Nov 30, 2021, 5640 patients were assessed for eligibility. 4298 patients were randomised to the intervention group (n=2148) or control group (n=2150). 620 patients were not followed up at 6 months and a further 595 patients were not followed up at 1 year because the trial was stopped for futility after interim analysis. 45 patients were lost to follow-up before 1 year. Acknowledgment of receipt of the SMS messages and videos by the intervention group patients was low (17%). The primary outcome occurred in 119 (5·5%) of 2148 patients in the intervention group and 106 (4·9%) of 2150 patients in the control group (adjusted odds ratio 1·12; 95% CI 0·85-1·47; p=0·370). Among the secondary outcome measures, alcohol cessation and smoking cessation were higher in the intervention group than in the control group (alcohol cessation 231 [85%] of 272 in the intervention group vs 255 [78%] of 326 in the control group; p=0·036; smoking cessation 202 [83%] vs 206 [75%]; p=0·035). Medication compliance was better in the intervention group than in the control group (1406 [93·6%] of 1502 vs 1379 [89·8%] of 1536; p<0·001). There was no significant difference between the two groups in other secondary outcome measures at 1 year: blood pressure, fasting blood sugar (mg/dL), low-density lipoprotein cholesterol (mg/dL), and triglycerides (mg/dL), BMI, modified Rankin Scale, and physical activity. A structured semi-interactive stroke prevention package did not reduce vascular events when compared with standard care. However, there was an improvement in some lifestyle behavioural factors, including adherence to medication, which might have long-term benefits. There was a possibility of type 2 error owing to reduced power since there were fewer events and a high number of patients could not be followed up. Indian Council of Medical Research.

Informatics infrastructure in a rural pediatric clinical trials network: Matching specific clinical research needs with best practices and industry guidelines

Children have historically been underrepresented in randomized controlled trials and multi-center studies. This is particularly true for children who reside in rural and underserved areas. Conducting multi-center trials in rural areas presents unique informatics challenges. These challenges call for increased attention towards informatics infrastructure and the need for development and application of sound informatics approaches to the collection, processing, and management of data for clinical studies. By modifying existing local infrastructure and utilizing open source tools, we have been able to successfully deploy a multi-site data coordinating and operations center. We report our implementation decisions for data collection and management for the IDeA States Pediatric Clinical Trial Network (ISPCTN) based on the functionality needed for the ISPCTN, our synthesis of the extant literature in data collection and management methodology, and Good Clinical Data Management Practices.

An Exploratory Trial of EPI-589 in Amyotrophic Lateral Sclerosis (EPIC-ALS): Protocol for a Multicenter, Open-Labeled, 24-Week, Single-Group Study

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, with its currently approved drugs, including riluzole and edaravone, showing limited therapeutic effects. Therefore, safe and effective drugs are urgently necessary. EPI-589 is an orally available, small-molecule, novel redox-active agent characterized by highly potent protective effects against oxidative stress with high blood-brain barrier permeability. Given the apparent oxidative stress and mitochondrial dysfunction involvement in the pathogenesis of ALS, EPI-589 may hold promise as a therapeutic agent. This protocol aims to describe the design and rationale for the EPI-589 Early Phase 2 Investigator-Initiated Clinical Trial for ALS (EPIC-ALS). EPIC-ALS is an explorative, open-labeled, single-arm trial that evaluates the safety and tolerability of EPI-589 in patients with ALS. This trial consists of 12-week run-in, 24-week treatment, and 4-week follow-up periods. Patients will receive 500 mg of EPI-589 3 times daily over the 24-week treatment period. Clinical assessments include the mean monthly change of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score. The biomarkers are selected to analyze the effect on oxidative stress and neuronal damage. The plasma biomarkers are 8-hydroxy-2'-deoxyguanosine (8-OHdG), 3-nitrotyrosine (3-NT), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), homocysteine, and creatinine. The cerebrospinal fluid biomarkers are 8-OHdG, 3-NT, NfL, pNfH, and ornithine. The magnetic resonance biomarkers are fractional anisotropy in the corticospinal tract and N-acetylaspartate in the primary motor area. This trial began data collection in September 2021 and is expected to be completed in October 2023. This study can provide useful data to understand the characteristics of EPI-589. Japan Primary Registries Network jRCT2061210031; tinyurl.com/2p84emu6. DERR1-10.2196/42032.

Impact of Chill and Heat Exposures under Diverse Climatic Conditions on Peach and Nectarine Flowering Phenology.

The present study aims to generalize cultivar-specific tree phenology responses to winter and spring temperatures and assess the effectiveness of the Tabuenca test and various chill and heat accumulation models in predicting bloom dates for a wide range of climatic conditions and years. To this end, we estimated the dates of rest completion and blooming and correlated them with observed bloom dates for 14 peach and nectarine cultivars that were evaluated in 11 locations across Europe (Greece, France, Italy, Romania and Spain), within the EUFRIN cultivar testing trial network. Chill accumulation varied considerably among the studied sites, ranging from 45 Chill Portions (CP) in Murcia-Torre Pacheco (Spain) to 97-98 CP in Cuneo (Italy) and Bucharest (Romania). Rest completion occurred latest or was not achieved at all for some cultivars in the southern sites in Murcia. Dormancy release happened earliest in Bucharest and Cuneo, sites where heat accumulation had a strong influence on the regulation of bloom time. Blooming occurred earliest in the moderately cold regions of Lleida (Spain) and Bellegarde (France), and 7-11 days later in the warmer locations of Rome (Italy) and Naoussa (Greece), suggesting that bloom timing is strongly influenced by delayed rest completion in these locations. The Dynamic Model resulted in both more homogeneous chill accumulation across years and better predictions of bloom dates, compared with the Utah, Positive Utah and Chilling Hours models. Prediction of bloom dates was less successful for low-chill cultivars than for medium- and high-chill cultivars. Further climatic and experimental data are needed to make estimates of the climatic needs of peach cultivars more robust and to generate reliable advice for enhancing the resilience of peach production under varying and changing climatic conditions.

The Teaching Quality Evaluation of Chinese-Foreign Cooperation in Running Schools from the Perspective of Education for Sustainable Development

As one of the important ways to cultivate internationalized and highly competitive talents, Chinese-foreign cooperation in running schools (CFCRS) is very significant to education for sustainable development (ESD). From the perspective of ESD, we developed a teaching quality evaluation model using 18 indicators in 4 dimensions: resource input, faculty environment, teaching process, and teaching outcome. The DANP (Decision-Making Trial and Evaluation Laboratory-Based Analytic Network Process) method is used to explore the mutual influence relationship of teaching quality in CFCRS, and the TOPSIS (Technique for Order Preference by Similarity to an Ideal Solution) method is used in this empirical study. The results show that the evaluation dimensions listed by impact level from big to small are as follows: teaching outcome, teaching process, faculty environment, and resource input. Among them, resource input and faculty environment are the cause dimensions, while teaching process and teaching outcome are the result dimensions. Academic support is the most influential indicator, followed by teaching resource and teaching management, and the teacher’s nationality is the least influential indicator. The CFCRS A of a comprehensive university in the developed region of China has the highest comprehensive score, followed by the CFCRS C of an applied science and technology university and CFCRS B of a comprehensive university in the underdeveloped region. The teaching quality of CFCRS can be improved by increasing the frequency of academic activities, strengthening teacher training, reinforcing curriculum and discipline management, and encouraging students to participate in competitions and paper publications.

Identification of Eco-Climatic Factors Driving Yields and Genotype by Environment Interactions for Yield in Early Maturity Soybean Using Crop Simulation

Deploying crops in regions bordering their initial distribution area requires adapting existing cultivars to particular environmental constraints. In this study, we revealed the main Eco-climatic Factors (EFs)—climatic factors recorded over specific phenological periods—impacting both yields and Genotype by Environment Interactions (GEI) for yield in early maturity soybeans (Glycine max (L.) Merrill) under high latitudes. A multi-year (2017–2021) and multi-environment (n = 112) database was built based on the official post-inscription French soybean trial network “SOJA Terres Inovia-GEVES-Partenaires”. Yields of 57 cultivars covering MG00 and MG000 maturity groups were considered. For each environment, 126 EFs were calculated using a Crop Growth Model (CGM) based on observed weather data and simulated developmental stages. Partial Least Square (PLS) regression analyses using the Variable Importance in Projection (VIP) score were used to sort out the most relevant EFs for their impact on yield levels on the one side and on GEI for yield on the other side. Our results confirmed that yield levels for both maturity groups were greatly influenced by climatic factors from the seed filling phenophases, mainly End of Pod to Physiological Maturity. The cumulative potential evapotranspiration during the End of Pod to Physiological Maturity period was the main EF affecting yield levels positively for both maturity groups (VIP = 2.86; R2 = 0.64). Interestingly, EFs explaining yield levels strongly differed from those explaining GEI, in terms of both climatic factors and phenophases. GEI were mostly influenced by climatic factors from First Flower to End of Pod; these factors were maximum temperatures and solar radiation intensity. Cold stress from Sowing to First Seed also appeared to be a critical driver for GEI in MG00 soybeans. The contrasted responses of several cultivars to the main GEI-drivers highlighted a potential genetic variability that could be exploited in early maturity soybean breeding. This study revealed the complexity of GEI ecophysiology, and our results should help breeding strategies to deliver germplasm that outperforms the existing genetic material for expanding the crop to northern European regions.

Consider new options for treating OUD in designing trials

Although there are already three approved medications to treat opioid use disorder (OUD) — methadone, buprenorphine, and naltrexone — “novel treatments” are needed, according to a review published this month in JAMA Psychiatry. Partly because of long‐standing barriers to treatment with methadone and buprenorphine, the review looked at possible treatments that go “beyond the endogenous mu‐opioid receptor [MOR] system. For the review, a public–private partnership including members of the federal Food and Drug Administration (FDA) and the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) group met to look at potential treatments for OUD, including cannabinoids, psychedelics, sedative‐hypnotics and vaccines. The consensus recommendations for clinical trial design included targeting the stage of treatment (e.g., seeking treatment, early abstinence, long‐term recovery), looking at the role of treatment, looking at primary outcomes informed by patient preferences, and considering adverse events, including the potential for relapse or overdose in the case of relapse. The study, “Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder,” is by Brian D. Kulik, Ph.D., and colleagues, and funded by the ACTTION public–private partnership with the FDA.

Approaches for enhancing the informativeness and quality of clinical trials: Innovations and principles for implementing multicenter trials from the Trial Innovation Network.

One challenge for multisite clinical trials is ensuring that the conditions of an informative trial are incorporated into all aspects of trial planning and execution. The multicenter model can provide the potential for a more informative environment, but it can also place a trial at risk of becoming uninformative due to lack of rigor, quality control, or effective recruitment, resulting in premature discontinuation and/or non-publication. Key factors that support informativeness are having the right team and resources during study planning and implementation and adequate funding to support performance activities. This communication draws on the experience of the National Center for Advancing Translational Science (NCATS) Trial Innovation Network (TIN) to develop approaches for enhancing the informativeness of clinical trials. We distilled this information into three principles: (1) assemble a diverse team, (2) leverage existing processes and systems, and (3) carefully consider budgets and contracts. The TIN, comprised of NCATS, three Trial Innovation Centers, a Recruitment Innovation Center, and 60+ CTSA Program hubs, provides resources to investigators who are proposing multicenter collaborations. In addition to sharing principles that support the informativeness of clinical trials, we highlight TIN-developed resources relevant for multicenter trial initiation and conduct.

The Trial Innovation Network Liaison Team: building a national clinical and translational community of practice.

In 2016, the National Center for Advancing Translational Science launched the Trial Innovation Network (TIN) to address barriers to efficient and informative multicenter trials. The TIN provides a national platform, working in partnership with 60+ Clinical and Translational Science Award (CTSA) hubs across the country to support the design and conduct of successful multicenter trials. A dedicated Hub Liaison Team (HLT) was established within each CTSA to facilitate connection between the hubs and the newly launched Trial and Recruitment Innovation Centers. Each HLT serves as an expert intermediary, connecting CTSA Hub investigators with TIN support, and connecting TIN research teams with potential multicenter trial site investigators. The cross-consortium Liaison Team network was developed during the first TIN funding cycle, and it is now a mature national network at the cutting edge of team science in clinical and translational research. The CTSA-based HLT structures and the external network structure have been developed in collaborative and iterative ways, with methods for shared learning and continuous process improvement. In this paper, we review the structure, function, and development of the Liaison Team network, discuss lessons learned during the first TIN funding cycle, and outline a path toward further network maturity.

Decentralized clinical trials in the trial innovation network: Value, strategies, and lessons learned.

New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or "hybrid" trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.

East Asian Gynecologic Oncology Trial Group (EAGOT): founding history and future perspective.

Racial and regional differences exist in morbidity, histology, drug response, toxicity, and prognosis of gynecologic cancer. However, most large-scale phase III studies have been conducted in Western countries, and these data on Asians, who account for more than half of the world's population, are limited. To build a global clinical trial network in Asia, four clinical trial groups with high expertise and international competitiveness in East Asia, namely the Japanese Gynecologic Oncology Group in Japan, the Korean Gynecologic Oncology Group in Korea, the Taiwanese Gynecologic Oncology Group in Taiwan, and the Chinese Gynecologic Cancer Society in the People's Republic of China, established a new group called the East Asia Gynecologic Oncology Trial Group (EAGOT) on November 19, 2021. It includes four committees: the Cervical Cancer Committee, Uterine Corpus Cancer Committee, Ovarian Cancer Committee, and Translational Research Committee. The purpose of EAGOT is to conduct international clinical trials in an effort to provide the best treatments for Asian women affected by gynecologic cancer. Discussions on new collaborative clinical trials have already begun. The first Annual EAGOT Meeting was held on May 25-27, 2023 in Niigata, Japan. EAGOT, the largest healthcare/investigational innovation network in Asia in the area of gynecologic cancers, will become a platform for establishing standards of care and lead to guidelines for Asian women suffering from gynecologic cancer. The harmonization of regulatory/investigator-initiated clinical trials, simultaneous approval of unapproved drugs in the four countries under a common protocol, and expansion of indications will improve the prognosis of gynecologic cancers in Asia in the near future.

New developments in targeted therapy for metastatic colorectal cancer.

Colorectal cancer (CRC) is the second most lethal cancer worldwide and the prognosis of metastatic CRC (mCRC) remains poor. Recent advancements in translational research have led to the identification of several new therapeutic targets and improved the treatment outcome of patients with tumours harbouring BRAF V600E mutation, (HER2) ErBB2 alterations, NTRK gene fusions and KRAS(G12C) mutation. Improved understanding towards the mechanism of resistance to targeted therapy such as anti-epidermal growth factor receptor antibodies and the evolving role of therapeutic monitoring with circulating tumour DNA (ctDNA) has enabled the longitudinal tracking of clonal evolution during treatment and the individualization of subsequent treatments. To broaden the community-based implementation of precision oncology in directing targeted therapies for patients with gastrointestinal cancers including mCRC, the feasibility of 'Master Protocols' that utilizes ctDNA-based genotyping platforms is currently being evaluated. Such protocols encompass both observational and interventional clinical trials of novel targeted therapies conducted within a large clinical trial network. In this review, we will discuss the latest developments in targeted therapies, and therapeutic strategies for overcoming acquired drug resistance in patients with mCRC.

Mechanisms to expedite pediatric clinical trial site activation: The DOSE trial experience

BackgroundTimely trial start-up is a key determinant of trial success; however, delays during start-up are common and costly. Moreover, data on start-up metrics in pediatric clinical trials are sparse. To expedite trial start-up, the Trial Innovation Network piloted three novel mechanisms in the trial titled Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multi-site, randomized, double-blind, placebo-controlled trial in the pediatric intensive care setting. MethodsThe three novel start-up mechanisms included: 1) competitive activation; 2) use of trial start-up experts, called site navigators; and 3) supplemental funds earned for achieving pre-determined milestones. After sites were activated, they received a web-based survey to report perceptions of the DOSE start-up process. In addition to perceptions, metrics analyzed included milestones met, time to start-up, and subsequent enrollment of subjects. ResultsTwenty sites were selected for participation, with 19 sites being fully activated. Across activated sites, the median (quartile 1, quartile 3) time from receipt of regulatory documents to site activation was 82 days (68, 113). Sites reported that of the three novel mechanisms, the most motivating factor for expeditious activation was additional funding available for achieving start-up milestones, followed by site navigator assistance and then competitive site activation. ConclusionStudy start-up is a critical time for the success of clinical trials, and innovative methods to minimize delays during start-up are needed. Milestone-based funds and site navigators were preferred mechanisms by sites participating in the DOSE study and may have contributed to the expeditious start-up timeline achieved.ClinicalTrials.gov #: NCT03938857

International variability in the diagnosis and management of disorders of consciousness

This manuscript explores the international variability in the diagnosis and management of disorders of consciousness (DoC). The identification, evaluation, intervention, exploration, prognostication and limitation of therapy for patients with DoC is reviewed through an international lens. The myriad factors that impact the diagnosis and management of DoC including 1) financial, 2) legal and regulatory, 3) cultural, 4) religious and 5) psychosocial considerations are discussed. As data comparing patients with DoC internationally are limited, findings from the general critical care or neurocritical care literature are described when information specific to patients with DoC is unavailable.There is a need for improvements in clinical care, education, advocacy and research related to patients with DoC worldwide. It is imperative to standardize methodology to evaluate consciousness and prognosticate outcome. Further, education is needed to 1) generate awareness of the impact of the aforementioned considerations on patients with DoC and 2) develop techniques to optimize communication about DoC with families. It is necessary to promote equity in access to expertise and resources for patients with DoC to enhance the care of patients with DoC worldwide. Improving understanding and management of patients with DoC requires harmonization of existing datasets, development of registries where none exist and establishment of international clinical trial networks that include patients in all phases along the spectrum of care. The work of international organizations like the Curing Coma Campaign can hopefully minimize international variability in the diagnosis and management of DoC and optimize care.

Clinical, methodology, and patient/carer expert advice in pediatric drug development by conect4children.

Many medicines are used "off-label" in children outside the terms of the license. Feasible pediatric clinical trials are a challenge to design. Conect4children (c4c) is an Innovative Medicines Initiative project to set up a pan-European pediatric clinical trial network aiming to facilitate the development of new medicines for children. To optimize pediatric trial development by promoting innovative trial design, c4c set up a European multidisciplinary advice service, including the voice of young patients and families, tailored to industry and academia. A network of experts was established to provide multidisciplinary advice to trial sponsors. Experts were selected to join clinical and innovative methodology expert groups. A patient and public involvement (PPI) database, to include the expert opinion of patients and parents/carers was formed. A stepwise process was developed: (1) sponsors contact c4c, (2) scoping interview takes place, (3) ad hoc advice group formed, (5) advice meeting held, and (6) advice report provided. Feedback on the process was collected. Twenty-four clinical and innovative methodology expert groups (>400 experts) and a PPI database of 135 registrants were established. As of September 30, 2022, 36 advice requests were received, with 25 requests completed. Clinical and methodology experts and PPI representatives participated in several advice requests. Sponsors appreciated the advice quality and the multidisciplinary experts from different countries, including experts not known before. Experts and PPI participants were generally satisfied with the process. The c4c project has shown successful proof of concept for a service that presents a new framework to plan innovative and feasible pediatric trials.

Inhibition of bone erosion, determined by high-resolution peripheral quantitative computed tomography (HR-pQCT), in rheumatoid arthritis patients receiving a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) plus denosumab vs csDMARD therapy alone: an open-label, randomized, parallel-group study

BackgroundThis exploratory study compared the inhibition of bone erosion progression in rheumatoid arthritis (RA) patients treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) plus denosumab versus csDMARD therapy alone and investigated the effects of denosumab on bone micro-architecture and other bone-related parameters using high-resolution peripheral quantitative computed tomography (HR-pQCT).MethodsIn this open-label, randomized, parallel-group study, patients with RA undergoing treatment with a csDMARD were randomly assigned (1:1) to continue csDMARD therapy alone or to continue csDMARDs with denosumab (60-mg subcutaneous injection once every 6 months) for 12 months. The primary endpoint was the change from baseline in the depth of bone erosion, measured by HR-pQCT, in the second and third metacarpal heads at 6 months after starting treatment. Exploratory endpoints were also evaluated, and adverse events (AEs) were monitored for safety.ResultsIn total, 46 patients were enrolled, and 43 were included in the full analysis set (csDMARDs plus denosumab, N = 21; csDMARD therapy alone, N = 22). Most patients were female (88.4%), and the mean age was 65.3 years. The adjusted mean (95% confidence interval) change from baseline in the depth of bone erosion, measured by HR-pQCT, in the 2–3 metacarpal heads at 6 months was − 0.57 mm (− 1.52, 0.39 mm) in the csDMARDs plus denosumab group vs − 0.22 mm (− 0.97, 0.53 mm) in the csDMARD therapy alone group (between-group difference: − 0.35 mm [− 1.00, 0.31]; P = 0.2716). Similar results were shown for the adjusted mean between-group difference in the width and volume of bone erosion of the 2–3 metacarpal heads. Significant improvements in bone micro-architecture parameters were shown. The incidence of AEs and serious AEs was similar between the csDMARDs plus denosumab and the csDMARD therapy alone groups (AEs: 52.2% vs 56.5%; serious AEs: 4.3% vs 8.7%).ConclusionsAlthough the addition of denosumab to csDMARDs did not find statistically significant improvements in bone erosion after 6 months of treatment, numerical improvements in these parameters suggest that the addition of denosumab to csDMARDs may be effective in inhibiting the progression of bone erosion and improving bone micro-architecture.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry, UMIN000030575. Japan Registry for Clinical Trials, jRCTs071180018

Evolving Profile of Acute Spinal Cord Injury Demographics, Outcomes, and Surgical Treatment in North America: Analysis of a Prospective Multi-Center Dataset of 989 Patients.

Changes in demography and injury patterns have altered the profile and outcome of acute spinal cord injury (SCI) over time. This study sought to describe recent trends in epidemiology and early clinical outcomes using the multi-center North American Clinical Trial Network (NACTN) for Spinal Cord Injury Registry. All participants with blunt acute traumatic SCI (n = 782) were grouped into three five-year time intervals from 2005 to 2019 (2005-2009, 2010-2014, and 2015-2019). Baseline demographics, clinical scores, medical co-morbidities, as well as early clinical outcomes were extracted. Categorical and continuous variables were analyzed to determine between-group differences. Subgroup analysis was performed for participants <50 and ≥50 years of age. Over the duration of the study period, there was an increase in age at presentation (p = 0.0077) as well as a greater incidence of falls as the mechanism of injury. Participants who were ≥50 years of age were more likely to sustain incomplete SCI (<0.0003) and central cord syndrome (< 0.0001). In the most recent period (2015-2019), a greater proportion of NACTN participants underwent surgery within 24 h of injury (63% vs. 41% vs. 41%, p = 0.0001). There was a statistically significant increase in cardiac complications (p < 0.0001) and decrease in pulmonary complications (p < 0.0001) during the study period. Data from the NACTN registry shows that the age of participants with acute SCI is increasing, falls have become the major mechanism of injury, and central cord injury is becoming increasingly prevalent. While early surgical intervention for acute SCI is more common in recent years, cardiac complications are more prevalent while pulmonary complications are less prevalent.

Identification of adapted breeding lines to improve barley hybrids for Spain

AbstractThis study explores the potential of Spanish germplasm for the development of hybrids adapted to southern Europe, a new region for hybrid barley (Hordeum vulgare). A set of 140 locally adapted, advanced breeding lines, developed in a Spanish public breeding program, were evaluated for their potential to widen the germplasm available for hybrid barley development. A subset of 24 lines was introduced into three‐way hybrid combinations and tested in a field trial network of four locations and 2 yr. The hybrid performance of the rest of the lines was estimated based on genomic prediction models. No three‐way hybrid exceeded the best check. We succeeded in identifying lines with high general combining ability, which could produce promising two‐way hybrids. Some were among those tested in the field, whereas others resulted from genomic predictions, validating the strategy followed of mining locally adapted breeding lines. Rachis brittleness detected in field trials revealed a low but detrimental effect of the presence of alternative brittle mutations in the hybrid combination. The success of hybrid breeding in southern Europe requires further investigation of the underlying heterotic patterns, and appropriate management of brittle genes through prebreeding, to widen the germplasm accessible for hybrid barley breeding.