Successful Trials Research Articles

Peripheral perfusion index as a predictor of reintubation in critically ill surgical patients

PurposeWe aimed to evaluate the ability of the peripheral perfusion index (PPI) to predict reintubation of critically ill surgical patients.MethodsThis prospective observational study included mechanically ventilated adults who were extubated after a successful spontaneous breathing trial (SBT). The patients were followed up for the next 48 h for the need for reintubation. The heart rate, systolic blood pressure, respiratory rate, peripheral arterial oxygen saturation (SpO2), and PPI were measured before-, at the end of SBT, 1 and 2 h postextubation. The primary outcome was the ability of PPI 1 h postextubation to predict reintubation using area under the receiver operating characteristic curve (AUC) analysis. Univariate and multivariate analyses were performed to identify predictors for reintubation.ResultsData from 62 patients were analysed. Reintubation occurred in 12/62 (19%) of the patients. Reintubated patients had higher heart rate and respiratory rate; and lower SpO2 and PPI than successfully weaned patients. The AUC (95%confidence interval) for the ability of PPI at 1 h postextubation to predict reintubation was 0.82 (0.71–0.91) with a negative predictive value of 97%, at a cutoff value of ≤ 2.5. Low PPI and high respiratory rate were the independent predictors for reintubation.ConclusionPPI early after extubation is a useful tool for prediction of reintubation. Low PPI is an independent risk factor for reintubation. A PPI > 2.5, one hour after extubation can confirm successful extubation.

Design analysis and development of a gantry robot for multi-layer 3-D concrete printing with simulation and experimental validation

The present study investigates the design analysis and development of a framed gantry robot (FGR) for 3-D concrete printing. Finite element simulations are performed for design validation and parameter estimation to conduct detailed analysis of the concrete printer. The kinematic and dynamic models of FGR are used for workspace analysis, motion control study, and motor sizing for printer development. The motion trajectory of the printer nozzle tip is evaluated using MATLAB simulations. An integrated programmable logic controller (PLC) with an in-built human-machine interface (HMI) through control algorithms has been implemented for interactive, user-friendly, and precise motion control. A separate control system is developed to monitor the pumping power and feed rate of mortar mix during printing. The simulated control scheme is validated experimentally using trajectory tracking for various input printing paths through HMI, with a maximum tracking error of 1 mm. Successful concrete printing trials have been conducted using various mix-design, following extensive evaluation of different printer and material parameters at the laboratory scale. The proposed design concept, mechanisms, interactive control interface, and tracking accuracy have been validated through simulation and experimental results, for ensuring quality concrete prints by the developed printer. Material testing parameters have been evaluated experimentally for modeling various mix-designs. To further evaluate printing performance, simulations of layer deformation in printed structures are conducted using finite element analysis, incorporating non-linear material models and various contact layer interactions. The simulated results of printed layers of different shapes of structures show a close resemblance with the experimental concrete printing trials.

Neuromodulation in Management of Patients with Failed Back Surgery Syndrome. An Outcome Assessment Study

Abstract Background Failed back surgery syndrome (FBSS) is a constellation of conditions that describes persistent or recurring low back pain following spine surgeries with a reported point prevalence in the general adult population of 37% and a lifetime prevalence of between 60% and 85%. It always has a significant impact on patients’ quality of life. Neuromodulation such as spinal cord stimulation has been showing significant effect and improvement in pain scores and functional capacity of the FBSS patients with a reflected effect on their daily activities and quality of life. Aim and Objectives Our aim in this study is to assess the change in pain scores, quality of life and opioid medications intake as an outcome of neuromodulation procedures performed to patients diagnosed with failed back surgery syndrome, and to detect the post procedure complications. Subjects and Methods This is a mixed prospective-retrospective study conducted at Ain Shams University (ASU) hospital and Oregon Health and Science University (OHSU) hospital during the period from September 2019 till December 2022. Patients who are 18 years old or older diagnosed with FBSS for more than 6 months and treated with spinal cord stimulation with successful trials during this time frame were included in the study. Results 34 patients were included in this study who had successful SCS trials and underwent a permanent implantation of SCS devices with post procedure follow up period of 12 months. Patients showed median pain numerical rating scale (NRS) of 7/10 at baseline with median NRS of 4/10 through the follow up period, also, there was a significant improvement of functional capacity using metabolic equivalent assessment with 74% of patients became moderate capacity compared to 32% at baseline. Quality of life assessed by activity measure of post-acute care (AM-PAC) showed significant improvement from mean of 16.87 ± 2.74 at baseline to mean of 19.97 ± 2.93 through follow up. Also there was a significant reduction of opioid medication usage. Post procedure complications was of low percentage with the most commonly detected were battery dysfunction in 7 patients and pocket pain in 6 patients. Reoperation was needed in 13 patients with 4 needed just revision and 9 patients required a complete removal of the device. Conclusion Failed back surgery syndrome is a widely described chronic pain condition which has a negative impact on the patients’ quality of life and daily activities with an evidenced effect on chronic use and abuse of opioid analgesic medications. We presented in our study that SCS could be offered as an effective modality of treatment with a statistically significant reduction in pain scores and a significant improvement in functional capacity and quality of life. Also, it has a recognizable but not statistically significant reduction in opioid analgesic medications and a very low percentage of procedure related complications.

Conducting a successful diet trial for the diagnosis of food allergy in dogs and cats.

A limited antigen diet trial and subsequent food provocation is currently the optimal method of confirming a diagnosis of food allergy in dogs and cats. However, performing an effective diet trial can be challenging as it requires a high level of client and pet compliance, appropriate diet selection and correct interpretation of the provocative challenge. This narrative guides the clinician through the process, highlights potential pitfalls and specifies how these can be avoided to achieve a successful outcome.

Proportion of treatment effect explained: An overview of interpretations.

The selection of the primary endpoint in a clinical trial plays a critical role in determining the trial's success. Ideally, the primary endpoint is the clinically most relevant outcome, also termed the true endpoint. However, practical considerations, like extended follow-up, may complicate this choice, prompting the proposal to replace the true endpoint with so-called surrogate endpoints. Evaluating the validity of these surrogate endpoints is crucial, and a popular evaluation framework is based on the proportion of treatment effect explained (PTE). While methodological advancements in this area have focused primarily on estimation methods, interpretation remains a challenge hindering the practical use of the PTE. We review various ways to interpret the PTE. These interpretations-two causal and one non-causal-reveal connections between the PTE principal surrogacy, causal mediation analysis, and the prediction of trial-level treatment effects. A common limitation across these interpretations is the reliance on unverifiable assumptions. As such, we argue that the PTE is only meaningful when researchers are willing to make very strong assumptions. These challenges are also illustrated in an analysis of three hypothetical vaccine trials.

Non-invasive Transcutaneous Spinal Cord Stimulation Programming Recommendations for the Treatment of Upper Extremity Impairment in Tetraplegia

ObjectivesThis study analyzes the stimulation parameters implemented during two successful trials that used non-invasive transcutaneous spinal cord stimulation (tSCS) to effectively improve upper extremity function after chronic spinal cord injury (SCI). It proposes a framework to guide stimulation programming decisions for the successful translation of these techniques into the clinic. Materials and MethodsProgramming data from 60 participants who completed the Up-LIFT trial and from 17 participants who subsequently completed the LIFT Home trial were analyzed. All observations of stimulation amplitudes, frequencies, waveforms, and electrode configurations were examined. The incidence of adverse events and relatedness to stimulation parameters is reported. A comparison of parameter usage across the American Spinal Injury Association Impairment Scale (AIS) subgroups was conducted to evaluate stimulation strategies across participants with varying degrees of sensorimotor preservation. ResultsActive (cathodal) electrodes were typically placed between the C3/C4 and C6/C7 spinous processes. Most sessions featured return (anodal) electrodes positioned bilaterally over the anterior superior iliac spine, although clavicular placement was frequently used by 12 participants. Stimulation was delivered with a 10-kHz carrier frequency and typically a 30-Hz burst frequency. Biphasic waveforms were used in 83% of sessions. Average stimulation amplitudes were higher for biphasic waveforms. The AIS B subgroup required significantly higher amplitudes than did the AIS C and D subgroups. Device-related adverse events were infrequent, and not correlated with specific waveforms or amplitudes. Within the home setting, participants maintained their current amplitudes within 1% of the preset values. The suggested stimulation programming framework dictates the following hierarchical order of parameter adjustments: current amplitude, waveform type, active/return electrode positioning, and burst frequency, guided by clinical observations as required. ConclusionsThis analysis summarizes effective stimulation parameters from the trials and provides a decision-making framework for clinical implementation of tSCS for upper extremity functional restoration after SCI. The parameters are aligned with existing literature and proved safe and well tolerated by participants.

The Role of Resveratrol in Aging and Senescence: A Focus on Molecular Mechanisms.

Resveratrol (Res), a polyphenol found in red wine, has been shown to decelerate aging, the progressive loss of physiological integrity and cellular senescence, characterized by the inability to progress through the cell cycle. No successful clinical trials have yet to be completed in humans on dose limitations. Yet, the potent anti-aging and anti-senescence efficacy of Res has been documented in several in vivo animal models. In this review, we highlight the molecular mechanisms of Res efficacy in antiaging disorders, such as diabetes, neurodegenerative disorders, eye diseases, and cardiovascular diseases.

Downhole Hydrogen-Generation System Stimulates Challenging Formations in Kuwait

_ This article, written by JPT Technology Editor Chris Carpenter, contains highlights of paper OTC 34832, “Successful Trial of Innovative Downhole Hydrogen-Generator System To Stimulate Hard-to-Recover Formations: First in Onshore Kuwait,” by Mustafa Al-Hussaini, Hamad S. Al-Rashedi, and Nada Al-Saleh, SPE, Kuwait Oil Company, et al. The paper has not been peer reviewed. Copyright 2024 Offshore Technology Conference. _ The objective of the pilot trial described in the complete paper was to provide an economic solution to develop tight and hard-to-recover formations within the operator’s fields. These assets represent a major challenge because of their low recovery factor (1–3%), the high cost of available conventional stimulation technologies, low revenue, and inability to sustain production rates. Introduction To establish an integrated stimulation solution for tight and heavy oil formations, the concept of using active single-atom hydrogen power to enhance near-wellbore permeability was evolved. This technology is based on downhole hydrogen generation from an in-situ exothermic multistage chemical reaction between two unique hydroreacting agents (HRAs). This reaction generates a huge amount of thermal energy, active hydrogen, and other hot active gases and acid vapors. The selection of HRA compounds, and their amount and concentration, is customized for each field. Development of Business Cases West Kuwait (WK) Business Case. The M formation in the WK region is a carbonate, multifractured tight reservoir that had been producing for years but had begun experiencing a low recovery factor. Some of its wells had low-productivity issues related to tight formation characteristics and low pressure. Production could not be sustained for long periods of time even after conventional acid stimulation. The reservoir featured a carbonate reservoir thickness of 300 ft, with 70% of oil in place at the top section. The reservoir is classified as tight (less than 0.1–10 md average permeability and 10–25% porosity), with 10 fractured multilayers. Only 1–3% recovery could be achieved despite many vertical, horizontal, and multilateral wells having been drilled in the M formation. Oil is considered nonviscous (28 cp, 21 °API). Current stimulation approaches included conventional acid stimulation, which elicited a poor response, and multistage fracturing, which encountered mixed results at best. North Kuwait (NK) Business Case. The tight T formation in this region featured poor reservoir connectivity. Minimal aquifer support led to a rapid decline in reservoir pressure. In general, low mobility of oil, poor API gravity, and low permeability were the main obstacles in draining oil from the T formation, in addition to reservoir heterogeneities such as facies distribution, fracture patterns, and pressure regimes. The formation consisted of tight limestone deposited on a carbonate ramp. The reservoir is divided into three main stratigraphic units (Upper, of approximately 110 ft; Middle, of approximately 60 ft; and Lower, of approximately 16 ft). The reservoir exhibits porosity of approximately 14% and permeability of approximately 14 md and is filled with relatively-low-API hydrocarbon (19–22 °API).

Nonmetallic-Based Tubulars Provide Superior Integrity, Cost Savings

_ This article, written by JPT Technology Editor Chris Carpenter, contains highlights of paper SPE 214647, “Operational Experience From the Implementation of 21 Wells With Nonmetallic-Based Downhole Tubing: From Pilot to Large-Scale Implementation,” by Mohamad H. Ahmad, ADNOC. The paper has not been peer reviewed. _ Tubular glass-reinforced-epoxy (GRE) lining technology has been applied globally since the 1960s in eliminating downhole tubular corrosion. Compared with conventional carbon steel, which can experience frequent failure, GRE-lined carbon steel provides long-lasting protection, resulting in huge savings in life-cycle cost. The operator implemented this technology for a successful trial of water-disposal wells. In the complete paper, the authors share the data from caliper logs run into, and the inspection of tubing pulled from, these disposal wells after 4 years in service. Tubular Corrosion in Operator Assets A growing emphasis on water disposal was inevitable because so much water was being produced with increased water cut and production. ADNOC Onshore operates almost 200 water-disposal wells. However, corrosion has been a common problem in these wells, such that a failure has been reported every 1–2 years. Use of corrosion-prone carbon steel for disposal strings has led to integrity issues and the need for expensive workover jobs that could cost between $1.5 million and $2 million per job. Fiberglass GRE Lining Since 2014, the operator has run 19 water-disposal wells with GRE-lined carbon steel strings. No failures have been reported, and inspections have been successful. Fiberglass tubular lining protects the internal surface of the tubing or casing inside the steel joint. Cement is pumped into the annulus between the GRE-liner outer diameter (OD) and the steel‑pipe inner diameter (ID). The final product is a completely corrosion-protected string, even under the connection area, where accessories called flares and corrosion barrier rings (CBRs) are installed (Fig. 1). The mechanical capability of the system is maintained by the steel pipe, while the internal fiberglass liner provides reliable corrosion resistance. Fiberglass Liner. The fiberglass liner shows excellent resistance in corrosive environments. As per tested and as per the manufacturer’s data sheets, the fiberglass lining system can be used in temperatures of up to 145°C, depending on hydrogen sulfide and CO2 levels in the flowing fluid. Besides being corrosion‑resistant, fiberglass lining improves the flow rate of the flowing water or oil because of the superior surface-energy properties and manufacturing quality of the liner material. The thickness of the liner varies according to the tubing size (diameter). Cement. The cement transfer applies pressure directly to the steel pipe. The cement does not bond the fiberglass liner to the steel and allows relative micromovement between the fiberglass liner and the steel pipe resulting from the difference in the thermal expansion coefficient of these two materials. Being alkaline, the cement tends to neutralize the possible presence of acid gases migrating in the fiberglass‑steel annulus; this further reduces the possibility of carbon-steel-pipe corrosion.

Roles of the oncometabolite enantiomers of 2-hydroxyglutarate and their metabolism by diverse dehydrogenases.

2-Hydroxyglutarate (2HG) is an oncometabolite that can contribute to tumor progression. Two enantiomer forms, L-2HG and D-2HG, arise from independent pathways starting from the precursor α-ketoglutarate (αKG). L-2HG production occurs through the promiscuous activities of malate dehydrogenase (MDH) and lactate dehydrogenase (LDH) under acidic and/or hypoxic conditions. D-2HG frequently accumulates by gain-of-function mutations in the genes encoding two isoforms of isocitrate dehydrogenase (IDH1 and IDH2). Cognate metabolite repair enzymes, L- and D-2-hydroxyglutarate dehydrogenases, oxidize the enantiomers and cause abnormally high 2HG accumulation and disease when mutated. Elevated levels of either oncometabolite affect redox homeostasis, metabolism, and immune system functioning. Moreover, the oncometabolites inhibit several α-ketoglutarate-dependent dioxygenases resulting in epigenetic changes such as DNA and histone hypermethylation as well as deficiencies in DNA repair. L-2HG, and D-2HG in some cases, inhibit degradation of hypoxia-inducible factor (HIF1α), a transcription factor that alters gene expression to adapt to hypoxic conditions, favoring tumorigenesis. Patients with the rare disease 2-hydroxyglutaric aciduria (2HGA) have exceedingly high levels of 2HG, which is neurotoxic, causing developmental delays and brain abnormalities. D-2HG also has specific effects on collagen production and NADPH pools. Recently, D-2HG has been targeted in new chemotherapies aimed at disrupting the gain-of-function IDH1 and IDH2 mutants, resulting in successful clinical trials for several cancers.

Field Trials of Live and Inactivated Camelpox Vaccines in Kazakhstan.

An outbreak of camelpox occurred in the Mangistau region of Kazakhstan in 2019. To control the outbreak of camelpox and to prevent its further spread to other regions, camels were vaccinated using live and inactivated camelpox vaccines produced in Kazakhstan. To evaluate the efficacy of these camelpox vaccines in the field, vaccine trials used 172 camels on camel farms in the Beineu district. Of these, 132 camels were vaccinated using a live attenuated camelpox vaccine and 40 camels were vaccinated using an inactivated vaccine to observe immunogenicity and safety. The live vaccine was inoculated into camels by scarification at a dose of 5 × 104 EID50, and the inactivated vaccine was injected intramuscularly at 5 mL twice, with an interval of 35 days. During the safety evaluation, camels administered either vaccine displayed no clinical signs of illness or any adverse effects. Post-vaccination seroconversion demonstrated that the live attenuated vaccine started to elicit antibody responses in some animals as early as day seven, while, by day 28, 99% of vaccinated camels responded. For camels immunized with the inactivated vaccine, seroconversion began on day 21 at low titers ranging from 1:2 to 1:4. Ninety days post vaccination, 77% of the camels demonstrated an immune response that was up to a titer of 1:16. The antibody response waned six months post vaccination in camels vaccinated with two types of vaccine. Nonetheless, both vaccines were 100% effective at preventing clinical disease in vaccinated camels during the camelpox outbreak. All unvaccinated camels became ill, with manifestations of clinical signs characteristic of camelpox. Following these successful field trials in Kazakhstan, a vaccination program for camels, to control camelpox using the domestically produced live attenuated camelpox vaccine, has started.

Efficacy and durability of holmium laser enucleation of the prostate in the management of acute and chronic urinary retention A retrospective study.

Our study aimed to assess the efficacy and durability of holmium laser enucleation of the prostate (HoLEP) in managing acute urinary retention (AUR), neurogenic chronic urinary retention (NCUR), and non-neurogenic chronic urinary retention (NNCUR). We also sought to compare outcomes in patients with preoperative urinary retention (UR) to those without. We conducted a retrospective analysis using prospectively gathered data from men who underwent HoLEP at our institution between October 2017 and July 2022. Patient demographics and outcome measures were recorded, including indications for the procedure, median urinary volume drained, or median postvoid residual urine volume (PVR) before catheterization or HoLEP. Chronic urinary retention (CUR) was defined as PVR >300 mL in males able to void; and initial catheter drainage >1000 mL in males unable to void, in the absence of pain. NCUR and NNCUR were differentiated based on the presence of any significant illness or injury with a neurologic impact on the bladder. All patients had postoperative followup visits at one, three, six, and 12 months. Our evaluation included the International Prostate Symptom Score (IPSS), quality of life (QoL) assessment, maximum urinary flow rate (Qmax), PVR, and catheter-free status. Three hundred sixty-eight males who underwent HoLEP were included in our study. The UR group consisted of 189 patients (70 AUR, 42 NCUR, and 77 NNCUR), and the lower urinary tract symptoms (LUTS) group was comprised of 179 individuals. There were no statistically significant differences between the NCUR and NNCUR subgroups regarding demographics and outcomes. At 12 months postoperative, the AUR group had a higher catheter-free rate than the CUR group (p=0.04), and other outcome variables were comparable between the two cohorts. The UR group had a significantly lower QoL score at one month (p=0.01) and a significantly lower IPSS score at one and 12 months (p=0.034 and p=0.018, respectively) than the LUTS cohort. During all followup visits, the UR group had a significantly higher PVR than the LUTS cohort. The successful first trial of void (TOV) rate for the UR and LUTS groups was 81% and 83.2%, respectively. At 12 months postoperative, the catheter-free rate for the UR and LUTS cohorts was 96.3% and 99.4%, respectively. HoLEP is an effective and durable treatment for UR with a high catheter-free rate and comparable outcomes when performed to manage LUTS.

Implementation of statistical features of a Bayesian two-armed responsive adaptive randomization trial with post hoc analysis of time trend drift

ABSTRACT Bayesian adaptive designs with response adaptive randomization (RAR) have the potential to benefit more participants in a clinical trial. While there are many papers that describe RAR designs and results, there is a scarcity of works reporting the details of RAR implementation from a statistical point exclusively. In this paper, we introduce the statistical methodology and implementation of the trial Changing the Default (CTD). CTD is a single-center prospective RAR comparative effectiveness trial to compare opt-in to opt-out tobacco treatment approaches for hospitalized patients. The design assumed an uninformative prior, conservative initial allocation ratio, and a higher threshold for stopping for success to protect results from statistical bias. A particular emerging concern of RAR designs is the possibility that time trends will occur during the implementation of a trial. If there is a time trend and the analytic plan does not prespecify an appropriate model, this could lead to a biased trial. Adjustment for time trend was not pre-specified in CTD, but post hoc time-adjusted analysis showed no presence of influential drift. This trial was an example of a successful two-armed confirmatory trial with a Bayesian adaptive design using response adaptive randomization.

Exposure to humans and task difficulty levels affect wild raccoons (Procyon lotor) learning.

Cognition helps wildlife exploit novel resources and environments. Raccoons (Procyon lotor) have successfully adapted to human presence, in part due to their cognitive abilities. However, interactions between humans and wildlife can create conflict. A better understanding of the raccoon's behavioral flexibility and learning ability could mitigate some conflicts. Our objective was to evaluate wild raccoons learning in contexts varying in terms of exposure to humans (recreational and preservation zoning within protected areas) and task difficulty. Learning can be evaluated over multiple exposures to a cognitive task. Across three years of experiment, we employed 2 food extraction tasks to gauge the change in problem-solving performance over trials. This assessment considered the success probability (the number of successful trials divided by the total number of trials) and the time taken to solve the puzzles. We also looked at the effects of 2 behavioral traits, exploratory diversity and persistence. We found strong evidence for learning over consecutive trials in terms of improved success probability. Improvement in terms of success probability and solving time was more pronounced with the initially easier task. We detected an increase in success probability over trials only in the recreation zones, and there was no evidence of an effect of behavioral traits. The improved performance attributed to learning was also maintained over consecutive years. We provide additional evidence that raccoons can learn how to solve a problem, resulting in a more effective solution in consecutive trials. Finally, we consider the management implications of dealing with raccoons accessing anthropogenic resources.

Recalled through this day but forgotten next week?—retrieval activity predicts durability of partly consolidated memories

Abstract Even partly consolidated memories can be forgotten given sufficient time, but the brain activity associated with durability of episodic memory at different time scales remains unclear. Here, we aimed to identify brain activity associated with retrieval of partly consolidated episodic memories that continued to be remembered in the future. Forty-nine younger (20 to 38 years; 25 females) and 43 older adults (60 to 80 years, 25 females) were scanned with functional magnetic resonance imaging during associative memory retrieval 12 h post-encoding. Twelve hours is sufficient to allow short-term synaptic consolidation as well as early post-encoding replay to initiate memory consolidation. Successful memory trials were classified into durable and transient source memories based on responses from a memory test ~6 d post-encoding. Results demonstrated that successful retrieval of future durable vs. transient memories was supported by increased activity in a medial prefrontal and ventral parietal area. Individual differences in activation as well as the subjective vividness of memories during encoding were positively related to individual differences in memory performance after 6 d. The results point to a unique and novel aspect of brain activity supporting long-term memory, in that activity during retrieval of memories even after 12 h of consolidation contains information about potential for long-term durability.

Advancing Transthyretin Amyloidosis Drug Development in an Evolving Treatment Landscape: Amyloidosis Forum Meeting Proceedings.

Hereditary transthyretin amyloidosis (ATTRv, also referred to as hATTR; ORPHA 271861) and wild-type ATTR amyloidosis (ATTRwt; ORPHA 330001) are rare, progressive, systemic protein misfolding disorders with heterogeneous clinical presentations. ATTRv and ATTRwt amyloidosis are characterized by the deposition of amyloid fibrils in multiple organs including the heart, nerves, eyes, and soft tissues. The management of ATTR amyloidosis is complex because of its multisystemic nature and progression despite available treatment options. Morbidity is high and there are many unmet medical needs for patients. While contemporary ATTR amyloidosis cohorts are diagnosed earlier, have lower risk disease and lower mortality compared with the previous era, these advances coupled with the emergence of effective disease-modifying therapies have confounded the design of future prospective clinical trials and interpretation of historical control data. The Amyloidosis Forum is a public-private partnership between the US Food and Drug Administration Center for Drug Evaluation and Research and the nonprofit Amyloidosis Research Consortium ( www.arci.org ). This article summarizes proceedings from the 21 June 2023 Amyloidosis Forum on advancing drug development in ATTR amyloidosis in an evolving treatment landscape. The Forum focused on elements of clinical trial design to address these challenges and discussed their strengths and weaknesses from multiple stakeholder perspectives (i.e., patient, sponsor, statistician, clinician, and regulatory authorities). Given rapid evolution of natural history in ATTR amyloidosis, the utility of historical control data is limited. Leveraging contemporary real-world data is essential for clinical trial design. Evidence generation from clinical trials should address clinically relevant questions. Key factors in successful trial design must be informed by up-to-date data on natural history, prognostic factors, clinically meaningful thresholds, and sharing available clinical trial data. The Amyloidosis Forum includes the community of patients with ATTR amyloidosis, the physicians who treat them, and the sponsors and regulators who collectively stand ready to support further studies in order to develop novel effective therapies.

Characterizing the authorship of phase 3 randomized clinical trials in oncology, 1960-2023.

11079 Background: Phase 3 randomized clinical trials (RCTs) inform the standard of care in cancer treatment yet have a mixed track record of success. In this study, we sought to 1) determine the overall success rate of phase 3 RCTs; 2) assess whether authorship patterns differ between successful (positive) and unsuccessful (negative) trials; and 3) explore if individual authors have distinct track records of success. Methods: The HemOnc knowledgebase (KB) was queried for initial publications of phase 3 RCTs of systemic anticancer therapy; those without primary outcome described were excluded. RCTs were labeled positive if the primary endpoint was met per HemOnc standard criteria (P value ≤ 0.05 or hazard ratio upper bound ≤ 1 for any experimental arm[s]) and negative if they did not meet these criteria or if the experimental arm was statistically inferior. Trial metadata and author information were extracted from the HemOnc KB. Author positive publication rate (PPR) was defined as % of publications reporting a positive result divided by total number of eligible publications. Prolific authors were defined as those with 6+ eligible publications. Author count for manuscripts reporting positive vs negative results was evaluated with the Mann-Whitney U test; other statistics were descriptive. Results: 3328 studies met criteria as of February 5, 2024; these were associated with 3305 initial publications between 1960-2023, involving 25,412 unique authors. 1474 (44.3%) of the studies were positive. Publications reporting positive trial results had, on average, 3 more authors, median (interquartile range) of 18 (12-23) vs 15 (11-20), p<0.0001. The mean (±SD) PPR for n=1967 prolific authors was 47.7% (±22.3%). The PPR was not related to individual author output; mean PPR for non-prolific authors was 48.0% (SD not reported). Differences in PPR were apparent by the disease under study and the years of publication (Table). Among the 46 prolific authors who had a PPR 2+ SD above the mean, 26 (55%) were from China followed by Italy with 3 (6%). Conclusions: Despite known positive publication bias, the success rate of published phase 3 RCTs remains <50%. Publications reporting positive results had significantly more authors; this finding requires further study including adjustment for trial sample size. Significant variation in PPR amongst fields could be due to watershed therapeutic advances, differential selection of primary endpoints, and/or selective reporting of results. Finally, a signal for geographic association of outlier PPRs suggests the need for further investigation. [Table: see text]

Pediatric and Adolescent Hodgkin Lymphoma: Paving the Way for Standards of Care and Shared Decision Making.

Hodgkin lymphoma (HL) is a treatable cancer with an incidence peak in adolescent and young adult years. Treatment strategies have been developed to balance the intensity of therapy needed to maintain disease-free survival while simultaneously preserving overall survival. Risk-based, response-adapted frontline therapy has long used a combination of chemotherapy and radiotherapy (RT). Successive clinical trials over the past three decades have safely reduced cumulative alkylator, anthracycline, and RT exposures for many patients. The advent of checkpoint inhibitors and the CD30-targeted antibody drug conjugate, brentuximab vedotin, has provided new options for de-escalation of conventional therapies associated with late effects in survivors treated at a young age. The ability to evaluate novel agents has been accelerated in collaborative trials inclusive of children and adolescents within the US National Clinical Trials Network and between the Children's Oncology Group and the EuroNet Pediatric Hodgkin Lymphoma Consortium. With numerous treatment options, patients with HL and their clinicians have an opportunity for shared decision making from diagnosis, through cancer treatment, and into survivorship. Given excellent survival outcomes, decisions about treatment in classic HL should be collaborative and attention to long-term survivorship needs should remain a high priority. Patient-reported outcomes remain an important tool to aid clinicians working with survivors to optimize health status and related quality of life for decades after HL therapy.

Simulation as a potential tool for successful clinical trial initiation

Simulation as a potential tool for successful clinical trial initiation

Redefining feasibility in clinical trials: Collaborative approaches for improved site selection

BackgroundThis Site Feasibility Task Force convened to assess the complex and burdensome process of site feasibility in clinical trials. The objective was to create mutual understanding of challenges and provide suggestions for improving collaboration among sponsors, contract research organizations (CROs), and sites. MethodsThe task force was composed of representatives from sponsors, CROs and sites (43 % Sites, 20 % Site Networks, 10 % Small/mid-size sponsors, 10 % Small/mid-size CROs, 10 % Large sponsors, 7 % Large CROs). The group collaborated to define the scope of the problem, identify challenges in the current process, and provide suggestions for improving the process. ResultsThe group found there is a need for better differentiation between the three main stages of feasibility, and the four sub-phases of Site Feasibility. The discussion brought to light emerging trends like early initiation of Site Feasibility and premature engagement of sites by CROs. To fully explain these challenges, the group analyzed the current practices and documented their downstream impact on clinical trial execution for all stakeholders. A list of best practices emerged naturally from this analysis. These findings are aggregated into short and actionable best practice guides. ConclusionThe task force suggests practical changes for the feasibility process and raises awareness of emerging trends and their associated risks. This awareness can begin to drive change in the site feasibility process, although industry-wide transformation will require new levels of collaboration, data standardization and automation tools. The potential benefits of evolving this process are significant and meaningful for more efficient and successful clinical trials.