The challenge of running trials in advanced angiosarcoma: A systematic review of the literature from EORTC/STBSG to guide the development of angiosarcoma-specific trials.

INTRODUCTION: While available systemic treatments have modest long term efficacy in advanced angiosarcoma, immunotherapy represents an interesting new therapeutic opportunity. To establish its benefit, it is required to conduct a clinical trial assessing its efficacy and toxicity compared to standard treatments. MATERIAL AND METHODS: This is a literature review from PubMed search. RESULTS: Several systemic treatments (chemotherapy and TKI) are currently used in advanced angiosarcoma with ORR ranging from 12.5 to 68 % and PFS from 2 to 7 months. However, few randomized trials, mainly phase II, has been conducted to compare these treatments. While most centers propose doxorubicin containing regimens or paclitaxel in 1st or 2nd line, a high heterogeneity of regimens administered in this setting is observed even across sarcoma specialized centers with no consensual standard treatment. Encouraging signals of immunotherapy activity have been reported in angiosarcoma from several retrospective and phase II studies assessing anti-PD1 either alone or in combination with anti CTLA4 or TKI. Although cutaneous and head and neck location seems to benefit more from immunotherapy, response may be observed in any angiosarcoma subtype. In sarcoma in general and AS in particular, no biomarker has been clearly established to predict the efficacy of immunotherapy: high tumor mutational burden and presence of tertiary lymphoid structures are under assessment. DISCUSSION: Even essential, developing a randomized clinical trial in AS struggles with the heterogeneity of the disease, the lack of consensual standard regimen, the uncertainty on optimal immunotherapy administration and the absence of established predictive biomarkers. CONCLUSION: International collaboration is essential to run randomized trial in advanced AS and asses the efficacy of immune therapy in this rare and heterogeneous disease.

Pediatric dentistry systematic reviews using the GRADE approach: methodological study.

BACKGROUND: To assess the reporting of the certainty of the evidence using the GRADE approach in systematic reviews of interventions in pediatric dentistry. METHODS: The inclusion criteria were systematic reviews of randomized clinical trials (RCTs) and non-randomized studies of interventions (NRSIs) in pediatric dentistry that reported the certainty of the evidence through the GRADE approach. Paired independent reviewers screened the studies, extracted data, and appraised the methodological quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR 2) tool. The certainty of the evidence was extracted for each outcome. A descriptive analysis was conducted. RESULTS: Around 28% of pediatric dentistry reviews of interventions used the GRADE approach (n = 24). Twenty reviews reported 112 evidence outcomes from RCTs and 13 from NRSIs using GRADE evidence profile tables. The methodological quality was high (16.7%), moderate (12.5%), low (37.5%), and critically low (33.3%), fulfilling the majority of the AMSTAR 2 criteria. The certainty of the evidence for outcomes generated from RCTs and NRSIs was very low (40.2% and 84.6%), low (33.1% and 7.7%), moderate (17.8% and 7.7%), and high (9.8% and 0.0%). The main reasons to downgrade the certainty were due to (for RCTs and NRSIs, respectively): risk of bias (68.8% and 84.6%), imprecision (67.8% and 100.0%), inconsistency (18.8% and 23.1%), indirectness (17.8% and 0.0%), and publication bias (7.1% and 0.0%). CONCLUSION: The proportion of systematic reviews assessing the certainty of the evidence using the GRADE approach was considered small, considering the total initial number of published pediatric dentistry reviews of intervention. The certainty of the evidence was mainly very low and low, and the main problems for downgrading the certainty of evidence were due to risk of bias and imprecision. REGISTRATION: PROSPERO database #CRD42022365443.

INfluenza VaccInation To mitigate typE 1 Diabetes (INVITED): a study protocol for a randomised, double-blind, placebo-controlled clinical trial in children and adolescents with recent-onset type 1 diabetes.

INTRODUCTION: Children and adolescents with recent-onset type 1 diabetes (T1D) commonly maintain a certain level of insulin production during the remission phase, which can last months to years. Preserving ß-cell function can reduce T1D complications and improve glycaemic control. Influenza vaccination has pleiotropic effects and administration of the vaccine during the early phases of T1D may offer ß-cell protection. This study aims to assess the effect of influenza vaccination on preserving ß-cell function in children and adolescents with recent-onset T1D. METHODS AND ANALYSIS: The INfluenza VaccInation To mitigate typE 1 Diabetes trial is a randomised, double-blind, placebo-controlled, multicentre trial in paediatric patients with recent-onset T1D aged 7-17 years. 100 participants will be randomised in a 1:1 ratio to receive either a standard inactivated quadrivalent influenza vaccine or a placebo within 14 days of diagnosis. The primary outcome is a difference in mean change (from baseline to 12 months) in C-peptide level between groups during a 2-hour mixed-meal tolerance test. Secondary outcomes include mean change (from baseline to 6 months) in C-peptide levels, haemoglobin A1c, ambulatory glucose profiles and insulin requirements. Exploratory outcomes are diabetes-related autoantibodies, inflammatory markers and serum haemagglutinin inhibition antibody titres against the influenza viruses. The current treatment for T1D is largely symptomatic, relying on insulin administration. There is a pressing need for novel pharmacological approaches aimed at modulating the immune system to preserve residual ß-cell function. Existing immunotherapies are cost-prohibitive and associated with multiple side effects, whereas influenza vaccination is inexpensive and generally well tolerated. A positive outcome of this study holds potential for immediate implementation into standard care for children and adolescents with recent-onset T1D and may guide future research on immune modulation in T1D. ETHICS AND DISSEMINATION: Ethical approval was obtained from Danish Health Authorities prior to participant enrollment. The trial results will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05585983 and EudraCT Number 2022-500906-17-01.

Efficacy and safety of alpha-pinene capsule in the management of functional dyspepsia and eradication of helicobacter pylori: a randomized clinical trial.

Aim: Our objective was to assess the efficacy and safety of adding alpha-pinene (a herbal terpenoid) to quadruple therapy compared to a placebo in improving symptoms and Helicobacter pylori (H. pylori) eradication rates in Functional dyspepsia (FD) patients. Background: FD is a prevalent upper gastrointestinal condition, and no definitive pharmacological treatment is available for its management. Methods: We conducted a randomized, double-blinded, placebo-controlled trial on FD patients diagnosed with H. pylori infection. We collected baseline demographic data and assessed FD symptoms in the participants. Patients were randomly allocated to receive either standard quadruple therapy with α-pinene capsules (0.25 mg/day) or quadruple therapy with a placebo for two weeks. We employed a validated questionnaire, the Short Form Leeds Dyspepsia Questionnaire (SF-LDQ), to evaluate FD symptoms. The eradication rate of H. pylori was compared between the two groups one month after completing the treatment regimens. Any reported adverse drug reactions (ADRs) were documented throughout the trial. Results: Over four months, a total of 66 patients completed the trial. Notably, there were no significant differences in baseline SF-LDQ scores between the two groups (p=0.83); however, a significant divergence emerged at the trial's conclusion (p=0.03). The H. pylori eradication rates did not show notable differences between the two treatment arms (p=0.43). Importantly, there were no dropouts from the trial due to ADRs. Among reported ADRs, participants experienced abdominal pain, headache, diarrhea, and a metallic taste, with no significant variance in incidence rates observed between the two groups (p=0.62). Conclusion: These findings suggest that α-pinene could be an effective and safe agent for reducing FD symptoms.

Systems-level computational modeling in ischemic stroke: from cells to patients.

Ischemic stroke, a significant threat to human life and health, refers to a class of conditions where brain tissue damage is induced following decreased cerebral blood flow. The incidence of ischemic stroke has been steadily increasing globally, and its disease mechanisms are highly complex and involve a multitude of biological mechanisms at various scales from genes all the way to the human body system that can affect the stroke onset, progression, treatment, and prognosis. To complement conventional experimental research methods, computational systems biology modeling can integrate and describe the pathogenic mechanisms of ischemic stroke across multiple biological scales and help identify emergent modulatory principles that drive disease progression and recovery. In addition, by running virtual experiments and trials in computers, these models can efficiently predict and evaluate outcomes of different treatment methods and thereby assist clinical decision-making. In this review, we summarize the current research and application of systems-level computational modeling in the field of ischemic stroke from the multiscale mechanism-based, physics-based and omics-based perspectives and discuss how modeling-driven research frameworks can deliver insights for future stroke research and drug development.

Underrepresentation of black individuals in pivotal trials for novel anticancer drugs: Potential consequence of using estimated creatinine clearance to assess kidney function?

BACKGROUND: Black individuals are historically underrepresented in oncology clinical trials. One potential reason for this is the prevalence of kidney disease in Black individuals, utilization of estimated creatinine clearance as a surrogate for glomerular filtration rate (GFR) in oncology, and GFR-based trial eligibility criteria. We characterized the representation of racial minorities in anticancer agent pivotal trials and examined if GFR-based trial eligibility criteria impact the proportion of Black individuals in trial populations. METHODS: We constructed a data repository for anticancer drugs FDA-approved 2015-2019 and associated pivotal trials, from which we extracted trial population racial compositions and GFR-based trial eligibility criteria. We calculated the participation-to-incidence ratio (PIR) and participation-to-mortality ratio (PMR) for a variety of cancer sites, where PIR or PMR >1.2 and < 0.8 indicate overrepresentation and underrepresentation, respectively. We evaluated the relationship between GFR eligibility cutoffs and the proportion of Black enrollees with Spearman rank correlation coefficient. RESULTS: We assessed 24,698 patients in 74 trials. Black individuals were underrepresented in all trials (PIR ≤0.48, PMR ≤0.50). For trials with GFR-based eligibility criteria (n = 49), a lower GFR cutoff was modestly associated with a higher proportion of Black enrollees (r = -0.29, p = 0.039). This relationship was strengthened for trials that only used estimated creatinine clearance to estimate GFR (r = -0.43, p = 0.004). CONCLUSIONS: GFR-related eligibility, and specifically the use of estimated creatinine clearance, may contribute to Black individuals being disproportionately excluded from cancer clinical trials. This highlights the need for implementation of contemporary GFR equations and other interventions to boost racial minority trial enrollment.

Engagement and partnership with consumers and communities in the co-design and conduct of Research: Lessons from the INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on haemodialysis (INFERR) clinical trial.

BACKGROUND: Engagement and partnership with consumers and communities throughout research processes produces high quality research meeting community needs and promoting translation of research into improved policy and practice. Partnership is critical in research involving Aboriginal and/or Torres Strait Islander people (First Nations Peoples) to ensure cultural safety. We present lessons from the design, implementation and progress of the National Health and Medical Research Council funded INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on hemodialysis (INFERR) clinical trial. MAIN BODY: The trial was designed to understand the benefits and harms of iron therapy in First Nations Australians on haemodialysis with anaemia and hyperferritinaemia. The lack of evidence for treatment was discussed with patients who were potential participants. A key element ensuring safe conduct of the INFERR trial was the establishment of the Indigenous Reference Groups (IRGs) comprising of dialysis patients based in the Top End of Australia and Central Australia. Two IRGs were needed based on advice from First Nations communities and researchers/academics on the project regarding local cultural differences and approaches to trial conduct. The IRGs underpin culturally safe trial conduct by providing input into study materials and translating study findings into effective messages and policies for First Nations dialysis patients. Throughout the trial conduct, the IRGs' role has developed to provide key mechanisms for advice and guidance regarding research conduct both in this study and more broadly. Support provided to the IRGs by trial First Nations Research Officers and independent First Nations researchers/academics who simplify research concepts is critical. The IRGs have developed feedback documents and processes to participants, stakeholders, and the renal units. They guarantee culturally safe advice for embedding findings from the trial into clinical practice guidelines ensuring evidence-based approaches in managing anaemia in haemodialysis patients with hyperferritinaemia. CONCLUSION: Active consumer and community partnership is critical in research conduct to ensure research impact. Strong partnership with consumers in the INFERR clinical trial has demonstrated that First Nations Consumers will engage in research they understand, that addresses health priorities for them and where they feel respected, listened to, and empowered to achieve change.

In this paper, we present the importance of actively involving consumers in the planning, implementation and conduct of research using the example of a clinical trial among Aboriginal and/or Torres Strait Australians (First Nations Australians) who have kidney disease and are currently receiving haemodialysis. The study assesses how safe and effective it is for people on dialysis to receive iron given through the vein during dialysis when they have anaemia and high levels of a blood test called ferritin, a test used routinely to measure iron levels. Two consumer reference groups of First Nations patients on dialysis, one based in the Top End of Australia and the other based in Central Australia, are supported by First Nations Research Officers and Research Academics to make sure that the research is performed in a way that involves, respects and values First Nations participation, culture, and knowledge. Active consumer and community partnership in this study has supported robust research governance processes which we believe are crucial for knowledge translation to have a positive impact for patients.

Prompt closure versus gradual weaning of external ventricular drain for hydrocephalus following aneurysmal subarachnoid haemorrhage: a statistical analysis plan for the DRAIN randomised clinical trial.

BACKGROUND: Insertion of an external ventricular drain (EVD) is a first-line treatment of acute hydrocephalus caused by aneurysmal subarachnoid haemorrhage (aSAH). Once the patient is clinically stable, the EVD is either removed or replaced by a permanent internal shunt. The optimal strategy for cessation of the EVD is unknown. Prompt closure carries a risk of acute hydrocephalus or redundant shunt implantations, whereas gradual weaning may increase the risk of EVD-related infections. METHODS: DRAIN (Danish RAndomised Trial of External Ventricular Drainage Cessation IN Aneurysmal Subarachnoid Haemorrhage) is an international multicentre randomised clinical trial comparing prompt closure versus gradual weaning of the EVD after aSAH. The primary outcome is a composite of VP-shunt implantation, all-cause mortality, or EVD-related infection. Secondary outcomes are serious adverse events excluding mortality and health-related quality of life (EQ-5D-5L). Exploratory outcomes are modified Rankin Scale, Fatigue Severity Scale, Glasgow Outcome Scale Extended, and length of stay in the neurointensive care unit and hospital. Outcome assessment will be performed 6 months after ictus. Based on the sample size calculation (event proportion 80% in the gradual weaning group, relative risk reduction 20%, alpha 5%, power 80%), 122 participants are required in each intervention group. Outcome assessment for the primary outcome, statistical analyses, and conclusion drawing will be blinded. Two independent statistical analyses and reports will be tracked using a version control system, and both will be published. Based on the final statistical report, the blinded steering group will formulate two abstracts. CONCLUSION: We present a pre-defined statistical analysis plan for the randomised DRAIN trial, which limits bias, p-hacking, and data-driven interpretations. This statistical analysis plan is accompanied by tables with simulated data, which increases transparency and reproducibility. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03948256. Registered on May 13, 2019.

A randomized, double-blind, placebo-controlled study of Cistanche tubulosa and Ginkgo biloba extracts for the improvement of cognitive function in middle-aged and elderly people.

Mild cognitive impairment poses an increasing challenge to middle-aged and elderly populations. Traditional Chinese medicinal herbs like Cistanche tubulosa and Ginkgo biloba (CG) have been proposed as potential agents to improve cognitive and memory functions. A randomized controlled trial involving 100 Chinese middle-aged and elderly participants was conducted to investigate the potential synergistic effects of CG on cognitive function in individuals at risk of neurodegenerative diseases. Over 90 days, both CG group and placebo group received two tablets daily, with each pair of CG tablets containing 72 mg echinacoside and 27 mg flavonol glycosides. Cognitive functions were assessed using multiple scales and blood biomarkers were determined at baseline, Day 45, and Day 90. The CG group exhibited significant improvements in the scores of Mini-Mental State Examination (26.5 at baseline vs. 27.1 at Day 90, p < 0.001), Montreal Cognitive Assessment (23.4 at baseline vs. 25.3 at Day 90, p < 0.001), and World Health Organization Quality of Life (81.6 at baseline vs. 84.2 at Day 90, p < 0.001), all surpassing scores in placebo group. Notably, both the Cognitrax matrix test and the Wechsler Memory Scale-Revised demonstrated enhanced memory functions, including long-term and delayed memory, after CG intervention. Moreover, cognitive-related blood biomarkers, including total tau, pT181, pS199, pT231, pS396, and thyroid-stimulating hormone, significantly decreased, whereas triiodothyronine and free triiodothyronine significantly increased. No treatment-related adverse events were reported, and routine blood and urine tests remained stable. These findings indicated that CG supplementation could potentially serve as an effective supplementary solution for enhancing cognitive and memory functions.

Efficacy and Safety of TAS-303 in Female Patients With Stress Urinary Incontinence: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE: We aimed to evaluate the therapeutic efficacy and safety of TAS-303, a highly selective noradrenaline reuptake inhibitor, in Japanese women with stress urinary incontinence (SUI). MATERIALS AND METHODS: A double-blind, placebo-controlled, phase 2 study randomized women with SUI symptoms to once-daily oral administration of TAS-303 18 mg or placebo for 12 weeks. The primary endpoint was percent change from baseline to Week 12 in mean SUI episode frequency per 24 hours (SUIEF) in the per-protocol set. The secondary endpoints were the proportion of patients with ≥ 50% reduction in mean SUIEF, incontinence episode frequency, incontinence amount, health-related quality of life, and safety in the full analysis set. RESULTS: In total, 231 patients were randomized to TAS-303 (n = 116) or placebo (n = 115). At Week 12, TAS-303 had superior efficacy to placebo, with a least squares mean percent change in mean SUIEF of -57.7% vs -46.9%, respectively, in the per-protocol set (least squares mean difference -10.8%; P = .036). TAS-303 showed some evidence of improved incontinence episode frequency, incontinence amount, and health-related quality of life (although not statistically significant) at Week 12 vs placebo in the full analysis set. The between-group difference in SUIEF improvement was more clearly confirmed in patients with ≥ 2 SUI episodes daily at baseline. All adverse events (AEs) with TAS-303 were mild or moderate; there were no serious AEs, AEs leading to discontinuation, or nervous system- or gastrointestinal-related (eg, nausea or vomiting) adverse drug reactions. CONCLUSIONS: Once-daily TAS-303 18 mg showed superior efficacy to placebo for the treatment of SUI in Japanese women, with an adequate safety profile. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04512053; Japan Registry of Clinical Trials: jRCT2080225307 (JapicCTI-205403 before site integration).

A 52-week follow-up, multi-center, randomized, double-blinded comparison of efficacy and safety of two hyaluronic acid fillers for the treatment of moderate-to-severe nasolabial folds in Chinese population.

INTRODUCTION: To investigate the efficacy and safety of Cutegel® MAX (Cutegel) in the correction of moderate-to-severe nasolabial folds (NLFS) compared to Restylane® (Restylane, control). METHODS: This study was a 52-week, multicenter, randomized, double-blinded, active-controlled clinical trial. Qualified participants with moderate-to-severe NLFs were randomly assigned in a 1:1 ratio to receive Cutegel or Restylane. For the primary efficacy endpoint, the response rate was defined as the percentage of subjects exhibiting an improvement of at least one-point based on blinded evaluation of Wrinkle Severity Rating Scale (WSRS) at 24 weeks after injection. Other secondary efficacy endpoints and treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Of 340 subjects randomized, 317 completed the week 52 visit. In the per protocol set (PPS), the blinded evaluator-assessed response rates at week 24 were 81.17% for Cutegel versus 77.56% for Restylane (p = 0.327). The between-group treatment differences in response rates were 3.60% [95% confidence interval (CI) = (-5.39%, 12.60%)], which demonstrated the noninferiority of Cutegel. Other secondary efficacy endpoints supported this. No significant differences were observed in the occurrence of adverse events between the two groups. CONCLUSION: Similar to Restylane, Cutegel was effective and well tolerated in correcting moderate-to-severe NLFs among the Chinese population.

Nasolabial folds (NLFs) are among the early indicators of facial aging process. In the past, rhytidectomy has been considered a safe procedure, yet it continues to carry risks such as hematoma, skin necrosis, nerve injury, and infection. With the ongoing development of biomaterials including hyaluronic acid (HA), minimally invasive injection procedures for the aesthetic correction of NLFs have become the preferred choice in recent years. The widespread use of HA has resulted in the development of various types of commercial HA fillers, such as Cutegel and Restylane. It is well known that HA filler products produce varying effects, attributable to differences in their components and physical properties. Previous studies have established that Restylane is a safe and effective HA dermal filler for the correction of NLFs. However, there is a lack of studies on both the cosmetic results and safety data for Cutegel in the published literature. Therefore, a randomized, double-blinded, active-controlled clinical trial was conducted at seven Chinese hospitals to evaluate the efficacy and safety of Cutegel for the correction of moderate-to-severe NLFs, compared to the approved Restylane in China. Among the 340 randomized subjects, 170 subjects received Cutegel, and 169 subjects received Restylane. Both groups reported similar improvements in WSRS (the between-group treatment differences in response rates exceeded the prespecified noninferiority margins), and also in other efficacy evaluations. Additionally, the two treatment groups showed similar safety profiles. In summary, Cutegel proved to be well tolerated and effective in this randomized, active-controlled clinical study, demonstrating its noninferiority to Restylane and validating its use as an alternative treatment for Chinese subjects with moderate-to-severe NLFs.

Combined Hip and Knee Strengthening Compared With Knee Strengthening for Individuals With Lateral Patellar Dislocation: A Single-blind, Superiority, Randomized Controlled Trial.

Objective: To investigate whether a combined hip and knee muscle strengthening program is superior to a knee strengthening program for people after lateral patellar dislocation (LPD). Design: Single-blind, superiority, randomized controlled trial with 48 weeks follow-up. Setting: Physiotherapy out-patient clinic. Participants: Forty individuals aged 16 or older, with a history of non-traumatic LPD were randomized to a knee-based strengthening (KBSG) or quadriceps and hip strengthening exercise (HQSG) program (N=40). Inclusion criteria included a positive apprehension sign, pain on palpation along the medial retinaculum, and J sign. Exclusion criteria included restricted range of motion (<90° knee flexion), and traumatic or postsurgical LPD. Interventions: Concealed randomization was performed using random permuted blocks of size 4. Individuals received their corresponding exercise program according to randomization and group allocation: knee-based strengthening (n=20) or combined hip and quadriceps strengthening (n=20) twice weekly for 8 weeks over 16 appointments. Main Outcome Measures: Primary outcome was the Lysholm Knee Score. Secondary outcomes included Numerical Pain Ratings Scale (NPRS) at rest and during effort, Norwich Patellar Instability Score (NPIS), Kujala Anterior Knee Pain Scale (AKPS), Lower Extremity Functional Scale (LEFS), 4 domains of the WHOQOL-Bref, and recurrence rate. Patient-reported outcome measures were assessed from the baseline to 48 weeks. Assessments were performed by a physiotherapist who was blinded to the group allocation. Data were analyzed by using a repeated-measures ANOVA model with Tukey's post hoc test after an intention-to-treat principle. Results: At the primary time-point of 8 weeks, there were no substantial between-group differences in the Lysholm Knee Score: mean difference=-6.8 (95% CI -14.3 to 3.7); NPIS: mean difference=23.5 (95% CI 5.6 to 41.3); AKPS: mean difference=-1.54 (95% CI -8.6 to 5.6), NPRS at rest and during effort (mean difference=0.32 (95% CI -0.37 to 1); and mean difference=0.68 (95% CI -0.9 to 1.86); LEFS mean difference=-1.08 (95% CI -5.9 to 2.4), WHOQOL-Bref domains (physical health: mean difference=-0.12, (95% CI -1.26 to 1.02); psychological: mean difference=-0.32 (95% CI -2.04 to 1.4); social relations: mean difference=-0.7 (95% CI -2.2 to 0.82); environment: mean difference=0.44 (95% CI -1 to 1.9), and recurrence rate (P=.69). Conclusion: This study indicates that combined hip and knee muscle strengthening is not superior to knee-based strengthening for LPD treatment. The limitations stemming from the underpowered nature of the trial must be acknowledged, concerning the potential oversight of moderate intervention effects.

Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis: A potential model for rare diseases.

Background: Neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments. Methods: Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts. Results: The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF. Conclusions: These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials.

Correction of omega-3 fatty acid deficiency and improvement in disease activity in patients with systemic lupus erythematosus treated with krill oil concentrate: a multicentre, randomised, double-blind, placebo-controlled trial.

OBJECTIVE: Omega-3 polyunsaturated fatty acids (PUFAs) play a critical role in regulating inflammation and lipid metabolism. This study sought to ascertain the frequency of omega-3 deficiency in patients with SLE and investigate whether supplementation with krill oil concentrate (KOC) could replenish omega-3 levels and decrease SLE disease activity. METHODS: A multicentre, randomised, double-blind, placebo-controlled trial was conducted in adult patients with active SLE. Eligible patients were randomised to receive 4 g/day KOC or placebo (vegetable oil mixture) for the first 24 weeks, and thereafter patients could opt to enter an open-label extension. The primary end point was improvement of the red blood cell Omega-3 Index from baseline to week 24. Changes in clinical features, including SLE Disease Activity Index 2000 (SLEDAI-2K) disease activity scores, were also monitored. RESULTS: Seventy-eight patients met eligibility criteria and were randomised to a treatment group (n=39 per group). The baseline Omega-3 Index in the total SLE cohort was a mean 4.43% (±SD 1.04%). After 4 weeks of KOC treatment, the Omega-3 Index rapidly increased to 7.17%±1.48% (n=38) and after 24 weeks to 8.05%±1.79% (n=25) (each p<0.001 vs baseline), whereas no significant change from baseline was noted in patients receiving placebo. Increases in the Omega-3 Index in KOC-treated patients persisted through week 48. After patients switched from placebo to KOC at 24 weeks, the mean Omega-3 Index showed a rapid and significant increase (from 4.63%±1.39% at week 24 (n=26) to 7.50%±1.75% at week 48 (n=12); p<0.001). Although there were no changes in disease activity in the study population overall, SLEDAI-2K scores decreased significantly in the KOC group during the 24-week randomised period among those who had high disease activity at baseline (SLEDAI-2K ≥9) (p=0.04, p=0.02 and p=0.01 vs placebo at 4, 8 and 16 weeks, respectively; n=9 per group). KOC was well-tolerated, with no significant safety concerns. CONCLUSION: KOC corrected omega-3 deficiency in patients with SLE. Supplementation with KOC was safe and decreased disease activity in those with more active disease. These findings warrant further evaluation of omega-3 fatty acid supplementation with KOC in the management of SLE. TRIAL REGISTRATION NUMBER: NCT03626311.

Risk assessment of clinical trial protocols: a tool for hospital pharmacists to reduce human error in experimental drug management.

BACKGROUND AND OBJECTIVES: Hospital pharmacists collaborate in clinical trials by managing the reception, conservation, distribution, return and destruction of the investigational medical products (IMP). However, errors can happen during the simultaneous management of multiple trials because each clinical trial stipulates its own method for managing the drug under study. In order to promote optimal management by hospital pharmacists, we developed a method for calculating a risk of error index for each experimental protocol, and wrote standard procedures for managing trials assigned low, moderate and high risk levels, to provide hospital pharmacists with a systematic tool for reducing human error in the management of IMPs for multiple clinical trials. METHODS: Calculation of this risk of error index (ρ) entails four factors: the pharmacological risk of error (φ) inherent in the pharmacological characteristics and route of administration of the IMP (carcinogenic, mutagenic, cytotoxic nature of the drug, parental or non-parenteral administration), the technological risk of error (α) involved should drug compounding be required, the risk of error related to the number of patients enrolled (np) and the risk of error intrinsic to the protocol (π) when it involves placebos, randomisation or other factors. We developed the formula [Formula: see text] to define trials as low (ρ<50), moderate (51<ρ<150) and high risk (ρ>151) for hospital pharmacist error. RESULTS: Calculations of this formula for 60 active trials indicated that seven (11.7%) of the protocols were low risk of hospital pharmacist error, 43 (71.7%) were moderate risk and 10 (16.6%) were high risk. For each of these categories (low, moderate and high risk) we have outlined standard procedures in order to minimise the occurrence of any errors. CONCLUSIONS: Following validation of our formula and standard procedures by the ISMETT Research Institute, we are promoting the use of the tool in other clinical centres as we believe it can help hospital pharmacists minimise the risk of error in managing experimental drugs for clinical trials.

Hematological Malignancies in Older Patients: Focus on the Potential Role of a Geriatric Assessment Management.

Geriatric assessment management is a multidimensional tool used to evaluate prognosis for clinical outcomes and targets for interventions in older adults with cancer receiving chemotherapy. In this review, we evaluated the possible application of geriatric assessment management (GAM) in hematological malignancies. In older patients with Diffuse Large B Cell Lymphoma, GAM might be helpful in both predicting planned hospital admissions and improving quality of life. In chronic myeloid leukemia, the Charlson Comorbidity Index demonstrates how comorbidities could affect treatment compliance and overall outcomes. In multiple myeloma, the application of different scores such as the International Myeloma Working Group Frailty Index and the Revised Myeloma Comorbidity Index can identify frail patients who need suitable interventions in treatment plan (reducing drug dose or changing treatment). Therefore, including GAM in the management plan of older patients with hematological malignancies may direct and optimize cancer care.

Short-term effects of 448 kilohertz radiofrequency stimulation on plantar fascia measured by quantitative ultrasound elastography and thermography on active healthy subjects: an open controlled clinical trial.

Objective: This study is an open clinical trial. The aim of this study was to show the changes that occur in the viscoelastic properties of the plantar fascia (twenty healthy volunteers) measured by SEL and the changes in the plantar fascia temperature measured by thermography after the application of a 448 kHz capacitive resistive monopolar radiofrequency (CRMR) in active healthy subjects immediately after treatment and at the 1-week follow-up.Methods: Furthermore, to analyze if an intervention with 448 kHz CRMR in the plantar fascia of the dominant lower limb produces a thermal response in the plantar fascia of the non-dominant lower limb. The final objective was to analyze the level of association between the viscoelastic properties of the PF and the temperature before and after the intervention with 448 kHz CRMR.Results: Our results showed that a temperature change, which was measured by thermography, occurred in the plantar fascia after a single intervention (T0-T1) and at the 1-week follow up (T1-T2).Conclusion: However, no changes were found in the viscoelastic properties of the plantar fascia after the intervention or at the 1-week follow up. This is the first study to investigate changes in both plantar fascia viscoelastic properties and in plantar fascia temperature after a radiofrequency intervention.

Cognitive Behavioral Psychotherapy as an Add-on in Comprehensive Outpatient Care of Non-affective Psychoses: A Multicenter Randomized-Controlled Effectiveness Trial in a Naturalistic Setting.

BACKGROUND AND HYPOTHESIS: Non-affective psychoses (NAP) are associated with severe consequences with regard to social functioning, physical health, employment, and suicidality. Treatment guidelines recommend cognitive behavioral therapy for psychosis (CBTp) as an effective additional treatment strategy to psychopharmacology. We hypothesized that outpatient CBTp has an add-on effect in individuals with NAP who already receive comprehensive outpatient care (COC) in Germany. STUDY DESIGN: In a randomized-controlled effectiveness trial, 6 months of COC + CBTp were compared to COC. The primary outcomes were change of symptom severity as assessed by the Positive and Negative Symptom Scale (pre-/post-treatment and 6-month follow-up). Mixed linear models and effect sizes were used to compare changes across treatment groups. Additionally, the number of readmissions was compared. STUDY RESULTS: N = 130 individuals with chronic NAP were recruited (COC + CBTp: n = 64, COC: n = 66). COC + CBTp participants significantly improved more regarding positive symptom severity (estimated mean difference at follow-up: -2.33, 95% CI: -4.04 to -0.61, P = .0083, d = 0.32) and general psychopathology (estimated mean difference at follow-up: -4.55, 95% CI: -7.30 to -1.81, P = .0013, d = 0.44) than the COC group. In both groups, negative symptom severity did not change significantly over time nor did groups differ regarding readmissions. CONCLUSION: The results underline an add-on benefit of CBTp in chronically ill individuals with NAP. Superiority of CBTp was demonstrated in comparison with high-quality comprehensive care and may also be true in different comprehensive care settings. CLINICAL TRIALS REGISTRATION: DRKS00015627.