Trial Participants Research Articles

Perceptions about dementia clinical trials among underrepresented populations: a nationally representative survey of U.S. dementia caregivers

BackgroundThe research community has historically failed to enroll diverse groups of participants in dementia clinical trials. A unique aspect of dementia care research is the requirement of a study partner, who can attest to the care recipient’s clinical and functional capacity. The aim of this study is to assess racial and ethnic differences and the importance of various trial considerations among dementia caregivers, in their decision to participate in clinical research as study partners.MethodWe embedded a vignette about a hypothetical dementia clinical trial in a nationally representative survey of U.S. dementia caregivers, oversampling non-Hispanic Black and Hispanic caregivers. Dementia caregivers were asked about their willingness to participate in the trial with their care recipient and rated the importance of nine considerations in hypothetical decisions to participate. Caregiver demographic characteristics were analyzed as predictors of trial participation in a base demographic model. In a second reasons model caregiver demographic characteristics and the rated importance of the nine considerations were separately analyzed as predictors; both models used survey-weighted logistic regression.ResultThe sample consisted of 610 dementia caregivers, including 156 non-Hispanic Black and 122 Hispanic caregiver participants. In the base demographic model, hypothetical trial participation was negatively associated with older caregiver age (OR (odds ratio) = 0.72, p = < 0.001). In the reasons model, the rated importance of a social responsibility to help others by participating in research was significantly associated with participation (OR = 1.56, p = 0.049), while the importance of the possibility of the care recipient experiencing serious side effects was negatively associated with participation (OR = 0.51, p = 0.003). In both models there was no significant difference in hypothetical participation between non-Hispanic Black and non-Hispanic White caregivers, or between Hispanic and non-Hispanic White caregivers.ConclusionHispanic and non-Hispanic Black dementia caregivers were not less likely than non-Hispanic White dementia caregivers to participate in a hypothetical dementia clinical trial. Our study suggests that failures to recruit diverse populations in dementia clinical research are not attributable to less willingness among members of underrepresented groups but may instead reflect structural barriers and historic exclusion from trial participation.

Advance Consent for Participation in Acute Stroke Trials: A Focus Group Study with People with Lived Experience of Stroke.

Advance consent could address many of the limitations traditional consenting methods pose to participation in acute stroke trials. We conducted a series of five focus groups with people with lived experience of stroke. Using an inductive thematic approach, two themes were developed: factors in favour of, and against, advance consent. Participants supported the idea of advance consent and highlighted trust, transparent communication and sufficient time as major factors that would positively affect their decision to provide advance consent. The results will be used to finalise a model of advance consent suitable for testing the feasibility in stroke prevention clinics.

How to make cardiology clinical trials more inclusive.

Cardiovascular clinical trials continue to under-represent children, older adults, females and people from ethnic minority groups relative to population disease distribution. Here we describe strategies to foster trial representativeness, with proposed actions at the levels of trial funding, design, conduct and dissemination. In particular, trial representativeness may be increased through broad recruitment strategies and site selection criteria that reflect the diversity of patients in the catchment area, as well as limiting unjustified exclusion criteria and using pragmatic designs that minimize research burden on patients (including embedded and decentralized trials). Trial communications ought to be culturally appropriate; engaging diverse people with lived experience in the co-design of some trial elements may foster this. The demographics of trialists themselves are associated with participant demographics; therefore, trial leadership must be actively diversified. Funding bodies and journals increasingly require the reporting of sociodemographic characteristics of trial participants, and regulatory bodies now provide guidance on increasing trial diversity; these steps may increase the momentum towards change. Although this Perspective focuses on the cardiovascular trial context, many of these strategies could be applied to other fields.

The scanning CONfoCal Ophthalmoscopy foR DIAbetic eye screening (CONCORDIA) study paper 2.

To determine if the Eidon white light 60-degree field Scanning Confocal Ophthalmoscope (SCO) camera was safe to use with staged mydriasis in a Diabetic Eye Screening Programme (DESP). The trial participants were recruited from people with diabetes attending appointments in DESP or Virtual Eye clinics for post-Covid delayed hospital appointments. Using staged mydriasis, the SCO images were taken before the pupils were dilated and compared to two-field 45 degrees mydriatic digital photography (the reference standard). Mydriatic SCO images were only compared to the reference standard if the non-mydriatic SCO images were unassessable. 1050 patients were recruited, 35 individuals were withdrawn, the majority (18) due to an imaging protocol deviation leaving 1015 individuals (2029 eyes). Using staged mydriasis, the sensitivity and specificity for any retinopathy was 97.5% (95% CI: 96.4-98.4%) and 82.3% (95% CI: 79.6-84.7%) respectively. The sensitivity and specificity for referable retinopathy was 92.7% (95% CI: 89.9-94.9%) and 85.4% (95% CI: 83.6-87.2%) respectively. The total number of eyes that were unassessable with the Eidon without mydriasis was 85/2029 (4.2%), and after mydriasis was 34/2029 (1.7%) and, with the reference standard, 34/2029 (1.7% - not always the same images) were unassessable. This study provides promising early results of the performance of the Eidon camera using staged mydriasis in a DESP which needs further evidence from a non-Caucasian population and from cost-effectiveness analyses.

Application and clinical effects in lung bullae resection of CT 3-dimensional reconstruction.

To investigate the value and clinical effect of computed tomography (CT) 3-dimensional reconstruction technology in lung bullae resection. Ninety-eight patients who underwent thoracoscopic surgical resection of lung bullae in our hospital from February 2019 to February 2023 were selected and divided into 2 groups according to the principle of voluntary participation in the clinical trial, of which 43 cases underwent preoperative spiral CT for thin-layer enhancement or planar CT scanning of lung bullae (control group), and 43 cases were imaged with MimicsMedical 21 software for 3-dimensional reconstruction to develop a surgical plan (observation group). To compare the surgery-related indexes, postoperative complications, pain, and analgesic use between the 2 groups, we measured serum creatine phosphokinase and myoglobin levels. The amount of surgical bleeding, drainage volume, hospital stay, and postoperative visual analog scale score of the research group were lower than those of the control group (P < .05), and the duration of analgesic medication was shorter than that of the control group (P < .05), and the levels of serum creatine phosphokinase and myoglobin were lower than those of the control group at 1 and 3 days postoperatively, and the differences were statistically significant (P < .05). Preoperative CT 3-dimensional reconstruction technique can clearly show the anatomical structures around the lung bullae and has its application value for precise lung bullae.

Financial toxicity in early-phase cancer clinical trial participants.

Little is known about financial toxicity in early-phase clinical trial (EP-CT) participants. This study sought to describe financial toxicity in EP-CT participants and assess associations with patient characteristics and patient-reported outcomes (PROs). Prospectively enrolled EP-CT participants from were followed from April 2021 through January 2023. Participants completed the Comprehensive Score for Financial Toxicity (<26=financial toxicity) at time of treatment. Quality of life (QOL), symptoms, coping, and resource concerns were surveyed. Associations of financial toxicity with patient characteristics, PROs, and clinical outcomes were explored. Of 261 eligible patients, 197 completed baseline assessments (75.5%, median age=63.4 years [31.8-88.6], 57.4% female). Most common cancers were gastrointestinal (33.0%) and breast (20.8%). More than one third (34.0%) of patients reported financial toxicity. Patients with financial toxicity were more likely to be<65 years (70.2% vs 48.5%, p=.004), unemployed (45.5% vs 16.9%, p<.001), not have attended college (53.1% vs 26.4%, p=.002), and have income <$60,000 (59.7% vs 25.4%, p<.001). In adjusted models, patients with financial toxicity reported lower QOL (B=-6.66, p=.004) and acceptance (B=-0.78, p=.002), and increased self-blame (B=0.87, p<.001). They were more likely to have concerns regarding housing (10.6% vs 2.3%, p=.025), bills (31.8% vs 3.8%, p<.001), food (9.1% vs 0.8%, p=.006), and employment (21.2% vs 1.5%, p<.001). There was no difference in time on trial (hazard ratio, 1.03; p=.860) or survival (hazard ratio, 1.16; p=.496). More than one third of EP-CT participants reported financial toxicity. Factors associated with financial toxicity and demonstrated novel associations among financial toxicity with QOL, coping, and resource concerns were identified, highlighting the need to address financial toxicity among this population.

Acute ingestion of caffeinated chewing gum reduces fatigue index and improves 400-meter performance in trained sprinters: a double-blind crossover trial.

This study investigated the effects of caffeinated chewing gum on fatigue index and 400-meter performance in trained sprinters. Nineteen participants (age: 20.9 ± 1.0 years; height: 175.6 ± 4.9 cm; mass: 66.5 ± 5.6 kg; training age: 7.9 ± 1.0 years) were randomly assigned to either a caffeine trial (CAF) or a placebo trial (PL) using a double-blind, randomized crossover design. The participants in the CAF trial chewed a gum containing 3 mg/kg of caffeine for a period of 10 minutes, while those in the PL trial chewed a gum containing a placebo with no caffeine. Following a 15-minute period of rest, the fatigue index was tested by six maximal 35-meter sprints with a 10-second rest between efforts. After this, at least 30 minutes of rest was permitted, during which time the participants engaged in brief warm-up activities prior to the commencement of the 400-meter sprint test. Saliva samples were collected before chewing gum, before the fatigue test and before 400-meters sprinting. The fatigue index was significantly lower in the CAF trial compared to the PL trial (CAF: 8.1 ± 2.5%; PL: 9.6 ± 4.8%; p = 0.046, Cohen's d = 039). The CAF trial demonstrated significantly lower sprint time for the 300-400 meter segment (CAF: 14.73 ± 1.35 seconds; PL: 15.23 ± 1.30 seconds; p = 0.019, Cohen's d = 0.37) and total sprint time compared to the PL trial (CAF: 53.87 ± 2.88 seconds; PL: 54.68 ± 3.37 seconds; p = 0.003, Cohen's d = 0.27). Saliva caffeine and α-amylase concentration were significantly higher in the CAF trial compared to the PL trial (p < 0.05). The present study demonstrated that caffeine gum supplementation prior to exercise significantly reduced the fatigue index and increased the capacity to maintain speed, particularly in the final 300 to 400 meters, as well as enhancing 400-meter sprint performance.

Comparison of brief olfactory and cognitive assessments to neuroimaging biomarkers in the prediction of cognitive decline and dementia in the MCSA cohort.

We evaluated impaired odor identification and global cognition as simple, cost-effective alternatives to neuroimaging biomarkers to predict cognitive decline and dementia in the Mayo Clinic Study of Aging. Six hundred forty-seven participants (mean 8.1, standard deviation 3.4 years' follow-up) had the following baseline procedures: modified Blessed Information Memory Concentration Test (BIMCT), 12-item Brief Smell Identification Test (BSIT), structural brain magnetic resonance imaging (MRI), and positron emission tomography (PET) imaging with 11C-Pittsburgh compound B (11C-PiB) and fluorodeoxyglucose (FDG; subset). Cognitive decline developed in 102 participants and dementia in 34 participants. In survival analyses, PiB PET showed robust prediction for cognitive decline. Impaired BSIT, impaired BIMCT, MRI, and FDG measures were also significant predictors. The combination of demographics + BSIT + BIMCT showed strong predictive utility (C-index 0.81), similar to demographics + PiB PET (C-index 0.80). Similar but stronger results were obtained for prediction of dementia. Impairment in both odor identification test and global cognition was comparable to PiB PET for predicting cognitive decline and dementia. In 647 participants in the population-based Mayo Clinic Study of Aging, several clinical markers and biomarkers each predicted cognitive decline or dementia during an average 8 years of follow-up. The combination of the demographic variables of age, sex, and education with a brief odor identification test (BSIT) and a global cognitive test (Blessed Information Memory Concentration Test) showed strong predictive utility (C-index 0.81) for cognitive decline that was similar to the demographic variables combined with Pittsburgh Compound B amyloid imaging (C-index 0.80). Combining a brief odor identification test with a brief cognitive test needs consideration as a simple, cost-effective option in the clinical assessment of individuals at risk of cognitive decline and dementia, as well as a potential tool to identify individuals who may benefit from disease-modifying treatments and to screen participants for prevention trials.

Transoral Laser or Robotic Surgery Outcomes for Oropharyngeal Carcinoma

Transoral robotic surgery (TORS) or transoral laser microsurgery (TLM) offer excellent oncological outcomes for oropharyngeal squamous cell carcinoma caused by human papillomavirus (HPV) infection. TORS may offer greater margin clearance around tumors than TLM. To determine whether the differing energy sources used and surgical technique of TORS or TLM is associated with postoperative early swallowing function, feeding tube use, and specific factors related to quality of life. This prespecified cohort study was performed within the Postoperative Adjuvant Treatment for HPV-Positive Tumours (PATHOS) randomized clinical trial at 40 centers in the UK, Germany, France, the US, and Australia between November 1, 2015, and August 31, 2023. PATHOS trial participants with HPV-positive oropharyngeal carcinoma of stages T1 to T3 and N0 to N2b M0 (TNM7) who underwent TLM or TORS were eligible. Of 989 consecutively recruited patients on the PATHOS trial, 508 were eligible for this substudy. The exposure of interest was TORS or TLM. Preplanned outcome measures included nasogastric tube insertion rates within 4 weeks after surgery, length of in-hospital stay following surgery, specific scales from the MD Anderson Dysphagia Inventory (MDADI), 35-item European Organization for Research and Treatment of Cancer Head and Neck Questionnaire (H&N35), and 30-item Quality of Life Questionnaire (QLQ C30), water swallow test results, and videofluoroscopy scores. Of the 508 patients included in the analysis (390 [76.8%] male; median age, 58.3 [IQR, 52.8-63.6] years), 195 had TLM and 313 had TORS. Nasogastric tube insertion rates were higher after TORS than TLM (85 of 189 [45.0%] vs 10 of 126 [7.9%]; adjusted odds ratio [OR], 4.41 [95% CI, 1.01-19.32]). Mean scores favored TLM with small effect sizes in all MDADI domains and the H&N35 swallowing item at 4 weeks after surgery; between-group difference for the MDADI composite score was -4.89 (95% CI, -8.27 to -1.50); for the MDADI physical functioning score, -6.37 (95% CI, -10.15 to -2.59); for the MDADI global score, -10.02 (95% CI, -16.50 to -3.54); and for H&N35 swallowing score, 7.24 (95% CI, 2.17-12.30). No other measures showed evidence of clinically meaningful differences. In this cohort study, functional outcomes were moderately less impaired 4 weeks following TLM compared with TORS. Once the longer-term outcomes for these patients are known, these findings could aid the design and use of future head and neck-specific surgical robots. ClinicalTrials.gov Identifier: NCT02215265.

Telemedicine and Access to Elective Cholecystectomy for Socially Vulnerable Adults

Socially vulnerable patients with symptomatic cholelithiasis are more likely to face barriers to accessing surgical care. This barrier to access can lead to delays in treatment, the need for emergent cholecystectomy, and worse outcomes. To determine the effectiveness of telemedicine vs in-person surgical consultation on access to elective cholecystectomy in socially vulnerable populations and to evaluate the association of scheduling navigation with access to elective cholecystectomy in these populations. This pilot randomized clinical trial conducted in a single academic center enrolled 60 adults from February 1, 2023, to February 21, 2024, with 3-month follow-up of clinical outcomes. Data were also collected retrospectively on a comparison group of 32 patients referred from June 30 to December 29, 2022. Adults with social vulnerability, such as being non-White or Hispanic or having nonprivate insurance or low income, with a diagnosis of symptomatic cholelithiasis and referral for outpatient surgical consultation were included. All trial participants were randomized to the telemedicine or in-person surgical consultation group, and received professional scheduling navigation. The latter intervention was compared with a historical cohort without navigation assistance. The primary outcome was completion of outpatient surgical consultation. Secondary outcomes included receipt of treatment and operative urgency. The trial enrolled 60 participants (30 per arm). Their mean (SD) age was 48.2 (18.2) years, 50 (83.3%) were female, 2 (3.3%) were Asian, 39 (65.0%) were Black, 8 (13.3%) were Hispanic, 11 (18.3%) were White, and 41 (68.3%) had no private insurance. The historical patient cohort included 32 participants (mean [SD] age, 45.9 [3.2] years; 27 [84.4%] female; 3 [9.4%] Asian, 15 [46.9%] Black, 10 [31.3%] Hispanic, and 6 [18.8%] White; and 18 [56.3%] without private insurance). In total, 18 trial participants assigned to telemedicine (60.0%) completed surgical consultations compared with 23 trial participants assigned to in-person visits (76.7%; P = .17). For telemedicine participants who underwent cholecystectomy, 3 of 7 (42.9%) underwent emergent cholecystectomy compared with 0 of 14 (0%) participants with in-person consultations (P = .03). Of 30 trial participants who received scheduling navigation, 23 (76.7%) completed surgical consultations compared with 15 of 32 patients in the historical cohort who did not receive scheduling navigation (46.9%; P = .02). Of 14 trial participants who received scheduling navigation and cholecystectomy, no participants underwent emergent cholecystectomy compared with 4 of 16 (25.0%) participants in the historical cohort without scheduling navigation (P = .04). In this pilot randomized clinical trial of socially vulnerable adults with symptomatic cholelithiasis, telemedicine consultation compared with in-person visits did not improve access to elective outpatient surgical care. However, scheduling navigation services may improve access to elective outpatient surgical care. Future large-scale studies are needed to identify possible barriers to virtual health care and mechanisms to address inequities. ClincialTrials.gov Identifier: NCT05745077.

Can systemic antibiotics reduce the need for surgical intervention in treating peri-implantitis?

A retrospective cohort design was used to assess the long-term clinical effectiveness of systemic amoxicillin and metronidazole, used adjunctively with non-surgical peri-implantitis treatment (NST) and whether it prevents the need for further surgical interventions. Of the 57 peri-implantitis patients examined, 45 patients were included in this study. The participants were divided into two subgroups in accordance to who had received NST with or without systemic antibiotics. Selection was based on prior participation in a three-month randomised control trial, ensuring comparability of data regarding peri-implantitis severity and treatment history. Data were extracted pre-treatment, 3-months post-treatment and at a long-term follow-up interval of 36 months. The primary outcome was the need for additional surgical intervention and was analysed via Kaplan-Meier analysis and Cox regression. A multitude of secondary clinical outcomes were evaluated using parametric and non-parametric tests, including peri- implant probing depth, bleeding scores and treatment success. Overall, 62.2% of the 45 NST patients did not need surgical peri-implantitis treatment: 73.9% of the subgroup with antibiotics and 50% of the subgroup without antibiotics respectively. However, the difference between the two groups was not statistically significant (log-rank test, p = 0.110). The Cox regression analysis also displayed no significance over the first three years post-treatment (p = 0.115). Additionally, the study found that deeper peri- implant pockets at baseline significantly predicted the need for future surgical treatment (p = 0.031), highlighting the importance of initial disease severity in treatment outcomes. The study concludes that the adjunctive use of systemic amoxicillin and metronidazole with NST may delay but not statistically reduce or prevent a future surgical need. Although a short-term reduction in clinical inflammatory parameters was evident, the long-term effectiveness in altering the progression of peri-implantitis remains limited.

From the Beginning of the Korean Gynecologic Oncology Group to the Present and Next Steps.

The Korean Gynecologic Oncology Group (KGOG) was established in 2002 and is the only organization in Korea conducting multi-center clinical trials for gynecologic cancers. Since its re-establishment as a non-profit organization in 2021, KGOG has grown significantly, now including 207 gynecologic oncology specialists from 76 hospitals. This growth is a testament to the dedication and hard work of all those involved in the organization. KGOG is committed to maximizing the activation of multi-center clinical research through policies that support patients with rare diseases and gynecologic cancer research, focusing on strengthening institutional capacity, equalizing participation opportunities, and enhancing information sharing. A significant milestone for KGOG was becoming a member of the US Gynecologic Oncology Group (GOG) in 2005, allowing participation in GOG clinical trials. KGOG later joined the Gynecologic Cancer InterGroup (GCIG) and strengthened its capabilities by hosting the first Endometrial Cancer Consensus Conference-Clinical Research (ECCC-CR) in 2023. KGOG holds biannual meetings and symposia, as well as 224 operating committee meetings annually to review the discussions of the Tumor Site Committee. KGOG has conducted 156 investigator-initiated trial (IIT) or sponsor-initiated trial (SIT) studies as KGOG-led or participated in research. Currently, 18 studies are registered, and 10 are in preparation. To date, 68 papers have been published. KGOG conducts six national projects and collaborates with external organizations such as the NRG Oncology Foundation, Gynecologic Oncology Group Partners (GOG-P), GCIG, East Asian Gynecologic Oncology Trial group (EAGOT), and the Japanese Gynecologic Oncology Group (JGOG). Through collaboration with renowned international research institutions, KGOG has significantly expanded the scope of its research, achieving noteworthy clinical outcomes. This report not only introduces the history and recent status of KGOG but also presents the exciting future direction of the organization, filled with potential breakthroughs and advancements in gynecologic oncology research.

The Scanning CONfoCal Ophthalmoscopy foR DIAbetic eye screening (CONCORDIA) study paper 1.

This project was to determine the performance of the Zeiss Clarus 700 (Clarus) and the Optos California (Optos) with staged mydriasis in a Diabetic Eye Screening Programme (DESP). Trial participants were recruited from people attending appointments in DESP or Virtual Eye clinics for delayed hospital appointments. Non-mydriatic photographs from the Clarus and Optos cameras were compared to 2-field 45 degrees mydriatic digital photography (the reference standard) and mydriatic photographs compared if the non-mydriatic photos were unassessable (staged mydriasis). 1573 patients were recruited. 76 individuals were withdrawn, leaving 1497 individuals (2993 eyes). For the Clarus and the Optos, the sensitivity for any retinopathy were 94.2% (95% CI: 92.9-95.3%) and 91.9% (95% CI: 90.5-93.2%) with specificities of 87.3% (95% CI: 85.4-89.0%) and 78.1% (95% CI: 75.7-80.3%) respectively. For referable DR the sensitivities for the Clarus and Optos were 86.0% (95% CI: 82.9-88.8%) and 77.6% (95% CI: 73.9-80.9%) with specificities of 92.8% (95% CI: 91.7-93.8%) and 95.4% (95% CI: 94.5-96.2%) respectively. The Clarus and Optos without mydriasis produced 100 (3.3%) and 152 (5.1%) unassessable eyes respectively, and after staged mydriasis 51 (1.7%) and 102 (3.4%) respectively with 52 (1.7%) reference standard images unassessable. This study reports the performance of the Clarus and the Optos using staged mydriasis in DR screening with wider fields detecting more referable retinopathy peripherally with some reduction in sensitivity centrally for macular lesions.

Clinical trial knowledge among cancer survivors in the United States: the role of health information technology.

Clinical trials are essential to the advancement of cancer care. However, clinical trial knowledge and participation remain critically low among adult patients with cancer. Health information technology (HIT) could play an important role in improving clinical trial knowledge and engagement among cancer survivors. We used data from 3,794 adults who completed the 2020 Health Information National Trends Survey, 626 (16.2%) of whom were cancer survivors. We examined the prevalence of HIT use in the study population and by cancer history using chi-squared tests. We used multivariable logistic regression models to examine the impact of HIT use on clinical trial knowledge for cancer survivors and respondents with no cancer history, respectively. Approximately 63.8% of cancer survivors reported having some knowledge of clinical trials. Almost half of the cancer survivors used HIT to communicate with doctors (47.1%) and make health appointments (49.4%), 68.0% used HIT to look up health information online and 42.2% used it to check test results. In the adjusted models, the use of HIT in communicating with doctors [OR 2.79; 95% CI (1.41, 5.54)], looking up health information online [OR 2.84; 95% CI (1.04, 7.77)], and checking test results [OR 2.47; 95% CI (1.12, 5.43)] was associated with having some knowledge of clinical trials. HIT use for engaging with the healthcare team and health information gathering is associated with higher clinical trial knowledge in cancer survivors. Given the rapid increase in mobile technology access globally and the increased use of HIT, digital technology can be leveraged to improve clinical trial knowledge and engagement among cancer survivors.

Radio-opaque contrast agents for liver cancer targeting with KIM during radiation therapy (ROCK-RT): an observational feasibility study.

This observational study aims to establish the feasibility of using x-ray images of radio-opaque chemoembolisation deposits in patients as a method for real-time image-guided radiation therapy of hepatocellular carcinoma. This study will recruit 50 hepatocellular carcinoma patients who have had or will have stereotactic ablative radiation therapy and have had transarterial chemoembolisation with a radio-opaque agent. X-ray and computed tomography images of the patients will be analysed retrospectively. Additionally, a deep learning method for real-time motion tracking will be developed. We hypothesise that: (i) deep learning software can be developed that will successfully track the contrast agent mass on two thirds of cone beam computed tomography (CBCT) projection and intra-treatment images (ii), the mean and standard deviation (mm) difference in the location of the mass between ground truth and deep learning detection are ≤ 2mm and ≤ 3mm respectively and (iii) statistical modelling of study data will predict tracking success in 85% of trial participants. Developing a real-time tracking method will enable increased targeting accuracy, without the need for additional invasive procedures to implant fiducial markers. Registered to ClinicalTrials.gov (NCT05169177) 12th October 2021.

Forced randomization: the what, why, and how.

When running a randomized controlled trial (RCT), a clinical site may face a situation when an eligible trial participant is to be randomized to the treatment that is not available at the site. In this case, there are two options: not to enroll the participant, or, without disclosing to the site, allocate the participant to a treatment arm with drug available at the site using a built-in feature of the interactive response technology (IRT). In the latter case, one has employed a "forced randomization" (FR). There seems to be an industry-wide consensus that using FR can be acceptable in confirmatory trials provided there are "not too many" instances of forcing. A better understanding of statistical properties of FR is warranted. We described four different IRT configurations with or without FR and illustrated them using a simple example. We discussed potential merits of FR and outlined some relevant theoretical risks and risk mitigation strategies. We performed a search using Cortellis Regulatory Intelligence database (IDRAC) ( www.cortellis.com ) to understand the prevalence of FR in clinical trial practice. We also proposed a structured template for development and evaluation of randomization designs featuring FR and showcased an application of this template for a hypothetical multi-center 1:1 RCT under three experimental settings ("base case", "slower recruitment", and "faster recruitment") to explore the effect of four different IRT configurations in combination with three different drug supply/re-supply strategies on some important operating characteristics of the trial. We also supplied the Julia code that can be used to reproduce our simulation results and generate additional results under user-specified experimental scenarios. FR can eliminate refusals to randomize patients, which can cause frustration for patients and study site personnel, improve the study logistics, drug supply management, cost-efficiency, and recruitment time. Nevertheless, FR carries some potential risks that should be reviewed at the study planning stage and, ideally, prospectively addressed through risk mitigation planning. The Cortellis search identified only 9 submissions that have reported the use of FR; typically, the FR option was documented in IRT specifications. Our simulation evidence showed that under the considered realistic experimental settings, the percentage of FR is expected to be low. When FR with backfilling was used in combination with high re-supply strategy, the final treatment imbalance was negligibly small, the proportion of patients not randomized due to the lack of drug supply was close to zero, and the time to complete recruitment was shortened compared to the case when FR was not allowed. The drug overage was primarily determined by the intensity of the re-supply strategy and to a smaller extent by the presence or absence of the FR feature in IRT. FR with a carefully chosen drug supply/re-supply strategy can result in quantifiable improvements in the patients' and site personnel experience, trial logistics and efficiency while preventing an undesirable refusal to randomize a patient and a consequential unblinding at the site. FR is a useful design feature of multi-center RCTs provided it is properly planned for and carefully implemented.

Predicting the sample size of randomized controlled trials using natural language processing.

Extracting the sample size from randomized controlled trials (RCTs) remains a challenge to developing better search functionalities or automating systematic reviews. Most current approaches rely on the sample size being explicitly mentioned in the abstract. The objective of this study was, therefore, to develop and validate additional approaches. 847 RCTs from high-impact medical journals were tagged with 6 different entities that could indicate the sample size. A named entity recognition (NER) model was trained to extract the entities and then deployed on a test set of 150 RCTs. The entities' performance in predicting the actual number of trial participants who were randomized was assessed and possible combinations of the entities were evaluated to create predictive models. The test set was also used to evaluate the performance of GPT-4o on the same task. The most accurate model could make predictions for 64.7% of trials in the test set, and the resulting predictions were equal to the ground truth in 93.8%. GPT-4o was able to make a prediction on 94.7% of trials and the resulting predictions were equal to the ground truth in 90.8%. This study presents an NER model that can extract different entities that can be used to predict the sample size from the abstract of an RCT. The entities can be combined in different ways to obtain models with different characteristics. Training an NER model to predict the sample size from RCTs is feasible. Large language models can deliver similar performance without the need for prior training on the task although at a higher cost due to proprietary technology and/or required computational power.

An Open-Label Extension Study Assessing the Long-Term Safety and Efficacy of Viloxazine Extended-Release Capsules in Adults with Attention-Deficit/Hyperactivity Disorder.

Viloxazine ER (extended-release capsules; Qelbree®) is a nonstimulant medication that has been approved by the United States Food and Drug Administration (FDA) for treatment of attention-deficit/hyperactivity disorder (ADHD) in children (> 6 years old) and adults. This phase 3 open-label extension to a pivotal phase 3, double-blind trial evaluated the long-term safety and continued efficacy of viloxazine ER in adults with ADHD. This was a multicenter, flexible-dose, open-label extension to a phase III, double-blind, placebo-controlled trial (NCT04016779). Viloxazine ER was initiated at 200 mg/day and adjusted (between 200 and 600 mg/day) to achieve optimal efficacy and tolerability. Trial enrollment was halted temporarily (24 March 2020 to 23 July 2020) due to the coronavirus disease 2019 (COVID-19) pandemic. Participants completing double-blind treatment during that time were offered delayed enrollment upon trial requalification. Safety outcomes were the primary objectives. Secondary objectives were efficacy outcomes, including the ADHD Investigator Symptom Rating Scale (AISRS), and were assessed relative to double-blind baseline (or trial re-entry baseline for those whose enrollment was delayed by the COVID-19 pandemic). Overall, 159 participants (133 immediate and 26 delayed rollover) received viloxazine ER, with a mean exposure of 265 ± 254.9 days. Adverse events (AEs) included (> 10% incidence) insomnia (13.8%), nausea (13.8%), headache (10.7%), and fatigue (10.1%). AEs led to discontinuation for 17.6% of participants [most commonly insomnia (2.5%), nausea (2.5%), and fatigue (1.9%)]. AISRS total score [baseline mean ± standard deviation (SD): 37.9 ± 6.3] improved by the first follow-up visit (-11.4 ± 9.5; week 2) with continued improvement at subsequent visits (last on-study visit: -18.2 ± 11.54). Similar patterns of improvement were seen for other measures of efficacy, including quality of life and executive function. Following initial dose optimization, most participants (73%) used viloxazine ER doses ≥ 400 mg/day, with 36% using doses of 600 mg/day. Long-term viloxazine ER use was well tolerated, with no new long-term safety findings. Improvements in ADHD symptoms and associated measures were sustained throughout trial participation. In total, 73% percent of adult participants in this long-term study used viloxazine ER doses of 400 mg or more during maintenance treatment. Clinicaltrials.gov Identifier: NCT04143217.

The use of focal therapy for the treatment of prostate cancer in Canada: Where are we, how did we get here, and where are we going?

Focal therapy is an emerging treatment for localized prostate cancer. The objectives of this review were to: 1) review how focal therapies are regulated and approved; 2) summarize the scope and quality of the literature regarding safety, efficacy, and side-effects; and 3) outline ongoing clinical trials of focal therapy in Canada. Using the PRISMA framework for scoping reviews, we searched PubMed, Embase, and Cochrane from 2021-2024, complementing Hopstaken et al's search up functional and oncologic outcomes. Additionally, we examined the FDA database for regulatory details and ongoing trials in Canada via ClinicalTrial.gov. FDA approval for prostate tissue ablation was granted to high-intensity focused ultrasound (HIFU) in 2015 via the de novo pathway; other therapies followed the 510(k) route, citing equivalence to predicate devices. Most studies are in early stages, primarily single-arm, prospective cohort designs. Oncologic outcomes like cancer detection and survival rates, alongside functional data, such as adverse events and erectile function, were assessed. Recurrence-free survival at 48 months ranged from 58-92%, pad-free rates were greater than 95%, and rates of new-onset erectile dysfunction were variable, ranging from no change to 50%. Rates of serious adverse events (SAEs) were low, ranging from 0-14%. Three Canadian clinical trials are actively enrolling participants, and five private clinics were found offering private HIFU, irreversible electroporation (IRE), or transurethral ultrasound ablation (TULSA). Focal therapy technologies have gained regulatory approval for prostate tissue ablation, and, aside from provincial support for cryoablation in Alberta, are available to Canadians through private payment or clinical trials. Many studies demonstrate promising cancer control and impressive functional outcomes but are limited by their short followup and lack of comparator group. Clinical trial or registry participation should be prioritized to ensure an evidence-based integration into current prostate cancer treatment approaches.

Exploring desirability of outcome ranking and generalised pairwise comparisons as endpoints in serious infections: Post hoc application with the MERINO trial

ObjectivesRandomised controlled trials in serious infections typically use a single primary endpoint such as mortality. Ordinal or rank-based composite endpoints that evaluate mortality and other measures are a novel approach in clinical trials. Desirability of outcome ranking (DOOR) has been increasingly used in infectious disease trials and generalised pairwise comparisons (GPC) in cardiovascular trials. MethodsWe undertook a post hoc analysis of the MERINO trial, comparing piperacillin-tazobactam (PTZ) with meropenem in bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp. to demonstrate and compare the DOOR and GPC approaches. The primary composite endpoint included mortality, microbiological relapse and secondary infection. A further analysis was performed by adding length of stay as a tiebreaker. We applied DOOR to evaluate the DOOR distribution, probability and conducted partial credit analyses. We applied GPC to estimate the win statistics: win ratio, win odds and net benefit. A secondary analysis with both approaches was conducted with trial participants with PTZ susceptible isolates only as recorded by a central laboratory. ResultsThe DOOR probability was 44.3 % (95 % CI: 40.8 %, 47.9 %), indicating superiority of meropenem. Partial credit analyses demonstrated similar conclusions across different patient preferences. The win ratio, win odds and net benefit were 0.40 (95 % CI: 0.23, 0.70; p = 0.001), 0.80 (95 % CI: 0.69, 0.92; p = 0.002) and −11.3 % (95 % CI:18.7 %, −4.0 %; p = 0.003), also indicating superiority of meropenem. With the addition of length of stay, the DOOR probability was 43.7 % (95 % CI: 37.9 %, 49.6 %) and the win ratio, win odds and net benefit were 0.77 (95 % CI: 0.60, 0.99; p = 0.04), 0.78 (95 % CI: 0.62, 0.99; p = 0.04), −12.1 % (95 % CI:23.8 %, −0.3 %; p = 0.04). Superiority of meropenem was not able to be demonstrated in the secondary analysis where only patients with PTZ susceptible isolates were assessed. ConclusionsThough the functionality and interpretation of DOOR and GPC differ, both approaches can enhance the overall understanding of treatment effect in survivors beyond a single endpoint such as mortality.