Previous Randomized Controlled Trials Research Articles

Generalizability of pharmaceutical randomized controlled trial eligibility criteria for progressive pulmonary fibrosis.

Progressive pulmonary fibrosis (PFF) is of substantial interest for novel pharmacotherapy discovery, but little is known about clinical trial eligibility criteria. We evaluated eligibility criteria of PPF randomized controlled trials (RCTs), their representativeness in registry patients, and forced vital capacity (FVC) changes and mortality according to trial eligibility. A systematic search was used to identify completed and in-progress phase II and III PPF RCTs. Common clinical trial eligibility criteria used in ≥60% of previous PPF RCTs were identified. The most common criteria for PPF used in RCTs ("trial-PPF criteria") and the clinical practice guideline definition of PPF ("guideline-PPF criteria") were both applied to patients enrolled in a prospective multicenter Canadian registry. Common trial eligibility criteria were tested for their frequency and association with health outcomes in registry patients who met trial-PPF and guideline-PPF criteria. Ten different definitions of PPF were used in 16 RCTs. At the time of meeting PPF definitions, 50% of 864 patients with trial-PPF and 44% of 408 patients with guideline-PPF met the common trial eligibility criteria. For both definitions, trial-eligible patients had more rapid 1-year FVC decline but better transplant-free survival than trial-ineligible patients. Patients with unclassifiable interstitial lung disease (ILD) had higher proportion of trial exclusion compared to those with connective tissue disease-associated ILD and fibrotic hypersensitivity pneumonitis. Annual FVC decline (trial-PPF: -67 to -21 mL; guideline-PPF: -116 to -41 mL) and 1-year transplant-free survival (trial-PPF: 90.5 to 97.5%; guideline-PPF: 87 to 96.2%) varied in trial-eligible patients across ILD subtypes. Existing RCTs use a variety of definitions for PPF with eligibility criteria that have limited representativeness. FVC decline and transplant-free survival vary according to trial eligibility and ILD subtypes.

Forecasting Trial Milestones: A Predictive Analysis for Early Termination of the SOUL Study.

Semaglutide, a glucagon-like peptide 1 receptor agonist (GLP1RA), is available in both parenteral and oral preparations. Studies of injectable preparations have convincingly demonstrated its beneficial effect on major adverse cardiac events (MACE). This predictive analysis was undertaken to forecast early termination of the SOUL trial (oral semaglutide) as well as the primary events. SOUL is a multicenter, double-blind, placebo-controlled randomized controlled trial (RCT) evaluating the reduction in MACE associated with oral semaglutide versus placebo in patients with type 2 diabetes (T2D) and cardiovascular (CV) disease. A sample of 9642 participants will be followed for 5years and 5months. A random-effects model meta-analysis, pooling hazard ratios from previous RCTs, was conducted using R software to inform the predictive model. The background CV event rates from the placebo arms of previous RCTs with semaglutide were matched with the pre-adjudicated assumptions of the SOUL trial to create the predictive model. The truncated trial duration, MACE, and its individual components in the intervention and placebo arms were estimated. The predicted difference between the two groups was estimated using the chi-squared test. A pooled analysis of 10,013 patients revealed a significant reduction in the number of MACEs associated with semaglutide (HR 0.79, 95% CI 0.69-0.91). Predictive analysis indicated that 1225 events would be achieved by 3.78years, suggesting premature termination. The mathematical model based on the meta-analysis predicts that the SOUL study on oral semaglutide will be terminated early, with oral semaglutide showing benefits in terms of MACE compared to placebo. If the SOUL study corroborates the findings of this model, it may not only form the basis for the calculation of power but also define the duration of such studies, reducing costs and easing the process of designing cardiovascular outcome trials (CVOTs). INPLASY202460061.

A microbiome-directed therapeutic food for children recovering from severe acute malnutrition.

Severe acute malnutrition (SAM), defined anthropometrically as a weight-for-length z-score more than 3 standard deviations below the mean (WLZ<-3), affects 19 million children under 5-years-old worldwide. Complete anthropometric recovery after standard inventions is rare with children often left with moderate acute malnutrition (MAM; WLZ -2 to -3). Here we conduct a randomized controlled trial (RCT), involving 12-18-month-old Bangladeshi children from urban and rural sites, who after hospital-based treatment for SAM received a 3-month intervention with a microbiota-directed complementary food (MDCF-2) or a ready-to-use supplementary food (RUSF) as they transitioned to MAM. The rate of WLZ improvement was significantly greater with MDCF-2 than the more calorically-dense RUSF, as we observed in a previous RCT of Bangladeshi children with MAM without antecedent SAM. A correlated meta-analysis of aptamer-based measurements of 4,520 plasma proteins in this and the prior RCT revealed 215 proteins positively-associated with WLZ (prominently those involved in musculoskeletal and CNS development) and 44 negatively-associated proteins (related to immune activation), with a significant enrichment in levels of the positively WLZ-associated proteins in the MDCF-2 arm. Characterizing changes in 754 bacterial metagenome-assembled genomes in serially collected fecal samples disclosed the effects of acute rehabilitation for SAM on the microbiome, its transition as each child achieves a state of MAM, and how specific strains of Prevotella copri function at the intersection between MDCF-2 glycan metabolism and the rescue of growth faltering. These results provide a rationale for further testing the generalizability of the efficacy of MDCF and identify biomarkers for defining treatment responses.

Testing the Shamiri Intervention and Its Components With Kenyan Adolescents During the COVID-19 Pandemic: Outcomes of a Universal, 5-Arm Randomized Controlled Trial

Mental health problems are prevalent among African adolescents, but professional treatment capacity is limited. Shamiri, an efficient lay provider-delivered intervention, has significantly reduced depression and anxiety symptoms in previous randomized controlled trials (RCTs). This trial investigated effects of the full Shamiri intervention and its components (growth-only, gratitude-only, and values-only) against a study skills control. In a 5-group RCT with adolescents from Kenyan high schools, anxiety, depression, and well-being were self-reported through 8-month follow-up. The RCT occurred immediately after an unanticipated government-mandated COVID-19 shutdown forced 3 years of schoolwork into 2 years, escalating academic pressures. Participants (N= 1,252; 48.72% female) were allocated to: growth (n= 249), gratitude (n= 237), values (n= 265), Shamiri (n= 250), and study skills (n= 251) conditions. Longitudinal multilevel models showed that, across all conditions, anxiety scores significantly improved at midpoint (B=-0.847), end point (B=-2.948), 1-month (B=-1.587), 3-month (B=-2.374), and 8-month (B=-1.917) follow-ups. Depression scores also improved significantly at midpoint (B=-0.796), end point (B=-3.126), 1-month (B=-2.382), 3-month (B=-2.521), and 8-month (B=-2.237) follow-ups. Well-being scores improved significantly at midpoint (B= 1.73), end point (B= 3.44), 1-month (B= 2.21), 3-month (B= 1.78), and 8-month (B= 1.59) follow-ups. Symptom reduction with Shamiri matched that of pre-COVID-19 trials, but symptom reduction with study skills far outpaced that of trials before the COVID-19-related school shutdown (31% greater anxiety reduction and 60% greater depression reduction). Thus, in contrast to previous RCTs, this COVID-19-era trial showed no significant differences between outcomes in any intervention and active control groups. Our RCT conducted during a post-COVID-19 period of heightened academic pressure produced unexpected results. Improvements in youth-reported anxiety and depression were consistent with previous trials for Shamiri, but markedly larger than in previous trials for study skills. Control interventions teaching life skills may produce mental health benefits when they convey skills of particular contextual relevance. A large five-group randomized controlled trial involved comparing the Shamiri Intervention to its component interventions (growth mindset, gratitude, and values affirmation) and a study-skills control. In contrast to previous studies of Shamiri, similar effects were observed across all groups (p<.05). This trial was conducted right after an unanticipated government-mandated COVID shutdown forced three years of schoolwork into two. Benchmarking analyses against previous trials showed approximately equal effects of Shamiri over time, but a 31% greater anxiety reduction and 60% greater depression reduction for the study-skills condition; this highlights the potential of interventions teaching highly relevant life-skills for improving mental health. Five-Arm Shamiri Trial; https://pactr.samrc.ac.za/; PACTR202104716135752.

#2609 Comparison of baseline patient characteristics of the CONVINCE randomized controlled trial with existing trial and registry populations

Abstract Background and Aims The generalizability of randomized controlled trials (RCTs) results is based on representativeness of the population involved. Trial populations may have different baseline characteristics compared to the general population that could benefit from the intervention. We compare the baseline characteristics of patients involved in the CONVINCE trial with those involved in all previous RCTs and representative registries of patients receiving hemodialysis as renal replacement therapy. Method Based on world class methods for systematic reviews, we identified all RCTs comparing hemodiafiltration (HDF) with hemodialysis (HD) published up to January 2024 and extracted data on baseline patient characteristics. Where data were missing, authors have been contacted and data so far obtained were included in this analysis (Fig. 1). Additional contact attempts are being performed. In addition, a comprehensive search was conducted to identify renal registries from all geographic regions. Those without information in English, without information on HDF and registries focusing on special patient groups (e.g. transplantation only) were excluded. This registry data will not be analyzed in this abstract as we are in progress of extracting the patient data from the latest registry annual reports available up to January 2024 for further analysis. Results We have selected 11 RCTs for further analysis, with the selection criteria and outcomes presented in Fig. 1. Key patient characteristics from RCTs were compared with those of patients in the CONVINCE trial using descriptive statistics and forest plots (Fig. 1). Comparison of differences was analyzed with the Kruskal-Wallis-Test. Interpretation of the results are as follows: • Age: Mean age of 76.5 years noted in Morena et al. (2017) because study inclusion criterion was ≥65 years. Other RCTs ranged from 54.1 to 68 years, which is consistent with 62.4 years in the CONVINCE trial (χ2 = 10, df = 10, p = 0.44). • Sex: 16.7% and 50% female noted in Selby et al. (2006) and Meert et al. (2009) respectively probably due to limited sample size (12 patients and 14 patients respectively). Other RCTs ranges from 30.4% to 42.5%, which is consistent with 36.0% in the CONVINCE trial (χ2 = 11, df = 11, p = 0.44). • Diabetes comorbidities: Ranges from 17.8% to 45%. CONVINCE trial is 35.0% (χ2 = 6, df = 6, p = 0.42). • Cardiovascular diseases comorbidities: Range from 26.4% to 45%. CONVINCE trial is 45% (χ2 = 3, df = 3, p = 0.39). • AVF as vascular access: value of 100% in Pedrini et al. (2011) because it was an inclusion criterion. Other RCTs ranged from 79.4% to 90%, which is consistent with 82% in the CONVINCE trial (χ2 = 7, df = 7, p = 0.43). There were no significant differences between CONVINCE and other RCTs data regarding all 5 patient baseline characteristics. Conclusion Our analysis showed the CONVINCE trial has no significant differences in patient baseline characteristics compared to previous RCTs. For a more comprehensive evaluation of representativeness of the trial's population, we are currently retrieving missing data from the trial authors and analyzing data from hemodialysis registries.

Target trial emulation of carfilzomib safety among patients with relapsed/refractory multiple myeloma using a nationwide observational data in Korea

PurposeCarfilzomib, commonly used for relapsed/refractory multiple myeloma (RRMM), has been associated with various adverse events in randomized controlled trials (RCTs). However, real-world safety data for a more diverse population are needed, as carfilzomib received expedited approval. This study aimed to evaluate carfilzomib’s safety in Korea by comparing new users of KRd (carfilzomib, lenalidomide, and dexamethasone) to Rd (lenalidomide and dexamethasone) using a nationwide administrative claims database.MethodsThe retrospective cohort study utilized target trial emulation, focusing on adverse events in various organ systems similar to the ASPIRE trial.ResultsThis study included 4,580 RRMM patients between 2007 and 2020, and the KRd group showed significantly higher risks of hematologic adverse events (anemia, neutropenia, thrombocytopenia) and some non-hematologic adverse events (cough, hypokalemia, constipation, hypertension, heart failure) compared to the Rd group. Among non-hematologic adverse events, cardiovascular events (heart failure [HR 2.04; 95% CI 1.24–3.35], hypertension [HR 1.58; 95% CI 1.15–2.17]) had the highest risk in the KRd group.ConclusionThe safety profile of carfilzomib in Korean patients was similar to previous RCTs. Therefore, caution should be exercised when using carfilzomib in Asian individuals with RRMM due to the increased risk of cardiovascular adverse events.

Does Early Conversion to Below-elbow Casting for Pediatric Diaphyseal Both-bone Forearm Fractures Adversely Affect Patient-reported Outcomes and ROM?

For distal forearm fractures in children, it has been shown that a below-elbow cast is an adequate treatment that overcomes the discomfort of an above-elbow cast and unnecessary immobilization of the elbow. For reduced diaphyseal both-bone forearm fractures, our previous randomized controlled trial (RCT)-which compared an above-elbow cast with early conversion to a below-elbow cast-revealed no differences in the risk of redisplacement or functional outcomes at short-term follow-up. Although studies with a longer follow-up after diaphyseal both-bone forearm fractures in children are scarce, they are essential, as growth might affect the outcome. In this secondary analysis of an earlier RCT, we asked: (1) Does early conversion from an above-elbow to a below-elbow cast in children with reduced, stable diaphyseal forearm fractures result in worse clinical and radiological outcome? (2) Does a malunion result in inferior clinical outcomes at 7.5 years of follow-up? In this study, we evaluated children at a minimum of 5 years of follow-up who were included in a previous RCT. The median (range) duration of follow-up was 7.5 years (5.2 to 9.9). The patients for this RCT were included from the emergency departments of four different urban hospitals. Between January 2006 and August 2010, we treated 128 patients for reduced diaphyseal both-bone forearm fractures. All 128 patients were eligible; 24% (31) were excluded because they were lost before the minimum study follow-up or had incomplete datasets, leaving 76% (97) for secondary analysis. The loss in the follow-up group was comparable to the included population. Eligible patients were invited for secondary functional and radiographic assessment. The primary outcome was the difference in forearm rotation compared with the uninjured contralateral arm. Secondary outcomes were the ABILHAND-kids and QuickDASH questionnaire, loss of flexion and extension of the elbow and wrist compared with the contralateral forearm, JAMAR grip strength ratio, and radiological assessment of residual deformity. The study was not blinded regarding the children, parents, and clinicians. At 7.5-year follow-up, there were no differences in ABILHAND-kids questionnaire score (above-elbow cast: 41 ± 2.4 versus above/below-elbow cast: 41.7 ± 0.7, mean difference -0.7 [95% confidence interval (CI) -1.4 to 0.04]; p = 0.06), QuickDASH (above-elbow cast: 5.8 ± 9.6 versus 2.9 ± 6.0 for above-/below-elbow cast, mean difference 2.9 [95% CI -0.5 to 6.2]; p = 0.92), and grip strength (0.9 ± 0.2 for above-elbow cast versus 1 ± 0.2 for above/below-elbow cast, mean difference -0.04 [95% CI -1 to 0.03]; p = 0.24). Functional outcomes showed no difference (loss of forearm rotation: above-elbow cast 7.9 ± 17.7 versus 4.1 ± 6.9 for above-/below-elbow cast, mean difference 3.8 [95% CI -1.7 to 9.4]; p = 0.47; arc of motion: above-elbow cast 152° ± 21° versus 155° ± 11° for the above/below-elbow cast group, mean difference -2.5 [95% CI -9.3 to -4.4]; p = 0.17; loss of wrist flexion-extension: above-elbow cast group 1.0° ± 5.0° versus 0.6° ± 4.2° for above/below-elbow cast, mean difference 0.4° [95% CI -1.5° to 2.2°]; p = 0.69). The secondary follow-up showed improvement in forearm rotation in both groups compared with the rotation at 7 months. For radiographical analysis, the only difference was in AP ulna (above-elbow cast: 6° ± 3° versus above/below-elbow cast: 5° ± 2°, mean difference 1.8° [0.7° to 3°]; p = 0.003), although this is likely not clinically relevant. There were no differences in the other parameters. Thirteen patients with persistent malunion at 7-month follow-up showed no clinically relevant differences in functional outcomes at 7.5-year follow-up compared with children without malunion. The loss of forearm rotation was 5.5ׄ° ± 9.1° for the malunion group compared with 6.0° ± 13.9° in the no malunion group, with a mean difference of 0.4 (95% CI of -7.5 to 8.4; p = 0.92). In light of these results, we suggest that surgeons perform an early conversion to a below-elbow cast for reduced diaphyseal both-bone forearm fractures in children. This study shows that even in patients with secondary fracture displacement, remodeling occurred. And even in persistent malunion, these patients mostly showed good-to-excellent final results. Future studies, such as a meta-analysis or a large, prospective observational study, would help to establish the influence of skeletal age, sex, and the severity and direction of malunion angulation of both the radius and ulna on clinical result. Furthermore, a similar systematic review could prove beneficial in clarifying the acceptable angulation for pediatric lower extremity fractures. Level I, therapeutic study.

Efficacy and acceptability of noninvasive brain stimulation for treating posttraumatic stress disorder symptoms: A network meta-analysis of randomized controlled trials.

Despite its high lifetime prevalence rate and the elevated disability caused by posttraumatic stress disorder (PTSD), treatments exhibit modest efficacy. In consideration of the abnormal connectivity between the dorsolateral prefrontal cortex (DLPFC) and amygdala in PTSD, several randomized controlled trials (RCTs) addressing the efficacy of different noninvasive brain stimulation (NIBS) modalities for PTSD management have been undertaken. However, previous RCTs have reported inconsistent results. The current network meta-analysis (NMA) aimed to compare the efficacy and acceptability of various NIBS protocols in PTSD management. We systematically searched ClinicalKey, Cochrane Central Register of Controlled Trials, Embase, ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov to identify relevant RCTs. The targeted RCTs was those comparing the efficacy of NIBS interventions, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and transcutaneous cervical vagal nerve stimulation, in patients with PTSD. The NMA was conducted using a frequentist model. The primary outcomes were changes in the overall severity of PTSD and acceptability (to be specific, rates of dropouts for any reason). We identified 14 RCTs that enrolled 686 participants. The NMA demonstrated that among the investigated NIBS types, high-frequency rTMS over bilateral DLPFCs was associated with the greatest reduction in overall PTSD severity. Further, in comparison with the sham controls, excitatory stimulation over the right DLPFC with/without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms, including depression and anxiety symptoms, and overall PTSD severity. This NMA demonstrated that excitatory stimulation over the right DLPFC with or without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms. PROSPERO CRD42023391562.

Smartphone App-Delivered Mindfulness-Based Intervention for Mild Traumatic Brain Injury in Adolescents: Protocol for a Feasibility Randomized Controlled Trial.

Concussion in children and adolescents is a significant public health concern, with 30% to 35% of patients at risk for prolonged emotional, cognitive, sleep, or physical symptoms. These symptoms negatively impact a child's quality of life while interfering with their participation in important neurodevelopmental activities such as schoolwork, socializing, and sports. Early psychological intervention following a concussion may improve the ability to regulate emotions and adapt to postinjury symptoms, resulting in the greater acceptance of change; reduced stress; and recovery of somatic, emotional, and cognitive symptoms. The primary objective of this study is to assess the feasibility of conducting a parallel-group (1:1) randomized controlled trial (RCT) to evaluate a digital therapeutics (DTx) mindfulness-based intervention (MBI) in adolescents aged 12 to <18 years. The attention-matched comparator intervention (a math game also used in previous RCTs) will be delivered on the same DTx platform. Both groups will be provided with the standard of care guidelines. The secondary objective is to examine intervention trends for quality of life; resilience; self-efficacy; cognition such as attention, working memory, and executive functioning; symptom burden; and anxiety and depression scores at 4 weeks after concussion, which will inform a more definitive RCT. A subsample will be used to examine whether those randomized to the experimental intervention group have different brain-based imaging patterns compared with those randomized to the control group. This study is a double-blind Health Canada-regulated trial. A total of 70 participants will be enrolled within 7 days of concussion and randomly assigned to receive the 4-week DTx MBI (experimental group) or comparator intervention. Feasibility will be assessed based on the recruitment rate, treatment adherence to both interventions, and retention. All outcome measures will be evaluated before the intervention (within 7 days after injury) and at 1, 2, and 4 weeks after the injury. A subset of 60 participants will undergo magnetic resonance imaging within 72 hours and at 4 weeks after recruitment to identify the neurophysiological mechanisms underlying the potential benefits from MBI training in adolescents following a concussion. The recruitment began in October 2022, and the data collection is expected to be completed by September 2024. Data collection and management is still in progress; therefore, data analysis is yet to be conducted. This trial will confirm the feasibility and resolve uncertainties to inform a future definitive multicenter efficacy RCT. If proven effective, a smartphone-based MBI has the potential to be an accessible and low-risk preventive treatment for youth at risk of experiencing prolonged postconcussion symptoms and complications. ClinicalTrials.gov NCT05105802; https://classic.clinicaltrials.gov/ct2/show/NCT05105802. DERR1-10.2196/57226.

Deaddicta® for maintenance treatment of Opioid-dependence: A six-month follow-up.

Opioid dependence, is one of the world's most critical health problems. Deaddicta is a herbal product considered an effective treatment for opioid addiction. Deaddicta's efficacy in the maintenance treatment of patients with opioid use disorder has recently been demonstrated through a double-blind randomized controlled trial (RCT). This study aimed to evaluate the permanence of Deaddicta's efficacy six months after the end of the maintenance treatment for opioid dependence. This study was performed following the previous RCT on the maintenance treatment of opioid addicts. Out of 41 participants who completed the study for three months in the previous research, 15 from the intervention group (Deaddicta capsules, 1500 mg/day) returned for follow-up. They all previously fulfilled the DSM-IV criteria for addiction, were aged 18 to 65, and had discontinued Deaddicta for six months. The outcome measures included addiction severity, depression and anxiety levels, and craving score. The scores of each parameter were compared in three phases: before intervention; after three months of intervention; and six months after the end of the study. Depression, anxiety, and craving scores decreased six months after the end of the previous study. This decrease was significant in the craving score (P = 0.011). No significant increase was observed in the frequency of use. The regression analysis showed a negative relationship between craving and the progression of phases. The Deaddicta product may have desirable and effective properties in decreasing temptation and, as a result, the maintenance treatment of opioid dependence.

Comparative effectiveness of primary tumor resection versus chemotherapy in patients with asymptomatic unresectable metastatic colorectal cancer: a retrospective cohort study using the target trial emulation framework.

Patients who undergo primary tumor resection (PTR) reportedly have significantly higher overall survival (OS) than those who do not undergo this procedure. However, this result is only evident in past retrospective studies, and clinical trial results did not show the same trend. Thus, it remains unclear whether primary tumor resection effectively increases survival in patients with metastatic colorectal cancer (mCRC) across different study designs. We compared the OS of patients with asymptomatic unresectable mCRC who underwent PTR with that of those who did not. This retrospective cohort study was designed to be a target trial emulation of a randomized controlled trial (RCT) that would have compared the effectiveness of PTR versus non-PTR in patients with asymptomatic unresectable mCRC from 2009 to 2017. A systematic review and meta-analysis were conducted to compare the efficacy of PTR and non-PTR in patients with mCRC, and corresponding results were compared. This cohort included 1,132 patients for a per-protocol analysis. The PTR group had non-significantly longer survival (adjusted hazard ratio: 0.70, 95% confidence interval: 0.62-1.01) than the non-PTR group in our cohort. A meta-analysis including five RCTs (1,016 patients) and our cohort found that the PTR group did not have a significantly lower mortality rate than the non-PTR group. The results of this cohort study and previous RCTs suggest that PTR is not associated with improved survival compared to systemic chemotherapy combined with targeted therapy among asymptomatic unresectable mCRC patients. Therefore, routine PTR is not recommended in these patients.

Systematic Literature Review (SLR) of Fatigue in Patients with Sickle Cell Disease (SCD) As Measured By the Patient-Reported Outcomes Measurement Information System (PROMIS Fatigue)

Introduction: Fatigue is a common symptom in patients living with SCD, with 84% reporting its presence within the past year in a recent large multinational survey. Although the exact pathophysiology resulting in fatigue is not fully understood, it is hypothesized that it may be secondary to the underlying abnormal processes of the sickle red blood cells including ongoing hemolysis, vaso-occlusive events, pain, and anemia. PROMIS Fatigue is a widely used, validated tool that utilizes a T-score metric, where 50 represents the average in the general population and scores above/below show worse/better relative outcomes. In this study, the objectives were to conduct an SLR of published evidence to understand 1) the utilization of PROMIS Fatigue in studies of SCD populations, 2) the PROMIS Fatigue scores reported in these studies, and 3) to characterize the estimates of fatigue across the full evidence base in order to assess the usefulness of the tool as a measure of fatigue in this population. Methods: Studies eligible for inclusion in the SLR were clinical trials or observational studies that featured adult and/or pediatric patients with a confirmed diagnosis of SCD and reported PROMIS Fatigue scores (note studies that were not published in the English language were excluded). Structured searches of PubMed, the Excerpta Medica dataBASE, and Cochrane Library (up to February 2022) were conducted. Using the Covidence platform, one reviewer evaluated the eligibility of articles resulting from the database searches, with decisions validated by another more senior reviewer. A similar process was followed for data extraction, whereby data were extracted on study, intervention, and patient characteristics, as well as PROMIS Fatigue scores (both pre and post treatment in interventional studies). Results: The database searches yielded 112 citations, 43 of which were included for full-text screening. Of these, 25 were excluded; one due to population ineligibility, three due to ineligible study designs, and 21 due to not reporting PROMIS Fatigue scores. This resulted in 18 citations, corresponding to 11 unique studies, included in the SLR ( Figure 1). Two studies were randomized controlled trials (RCTs), one was a secondary analysis of patients from a previous RCT, two were non-randomized trials, and the remaining six were cross-sectional observational studies. Although all included studies happened to be conducted in the United States, a high degree of heterogeneity was observed across populations; for example, age groupings were inconsistently defined and treatment interventions differed across studies (e.g. four reported patients received routine blood transfusion; eight reported patients received hydroxyurea). Of note, variation was observed in the specific PROMIS instrument administered (e.g., PROMIS and [pediatric] short forms), as well as schedules of assessment (12 weeks to 24 months follow up, with varying frequency of assessment in between). Mean/median PROMIS Fatigue scores for patients with SCD were generally higher than that of the general population (PROMIS fatigue T-score = 50), although still within one standard deviation (10). Mean/median estimates at baseline ranged from 51.7-55.7/52.8-53.7 in the five interventional studies. The corresponding range of mean estimates from the cross-sectional studies was 46.7-56.3 (one study reported a mean of 19.82, assumed to be the untransformed value), with the two studies with better scores than the general population being conducted in younger populations. The correlation between various factors and PROMIS Fatigue scores was assessed, with pain shown to be associated with worse scores. Conclusion/Summary: Despite the burden of fatigue in people living with SCD, the results from this SLR show that tools such as PROMIS Fatigue are infrequently used and, when used, are implemented inconsistently. The available PROMIS Fatigue scores in patients with SCD were marginally worse than the general population; however, the high degree of heterogeneity makes it challenging to draw strong conclusions from the available data. Further research is required to fully quantify fatigue in patients living with SCD and particular attention should be paid to consistently implementing and optimizing patient-reported outcomes measurement tools, such as PROMIS Fatigue, as well as ensuring potential drivers of changes are fully captured.

1467. Effects Of Oral Antibiotic Prophylaxis For Surgical Site Infections In Colorectal Surgery: Insights From Real World Data

Abstract Background Surgical site infection (SSI) after colorectal surgery is a significant burden on healthcare costs and patient quality of life. Preventive strategies are very important to working on this problem. In a multicenter randomized controlled trial (RCT) published in Annals of Surgery(2016;263:1085-1091), we reported the efficacy of oral antimicrobial prophylaxis in preventing SSI before colorectal surgery. Since the end of the RCT in 2012, we have applied this prophylaxis in our clinical practice and have experienced a large number of cases. Here, we report the incidence of SSIs when this prophylactic measure is applied in real-world clinical practice. Methods We retrospectively evaluated the incidence of SSI in 1192 patients who underwent elective laparoscopic colorectal resection for colorectal tumors between January 2013 and June 2022. We excluded 24 patients who were unable to receive oral prophylaxis. Antimicrobial prophylaxis consisted of oral kanamycin (1 g) and metronidazole (750 mg) twice on the day before surgery and intravenous cefmetazole (1 g) just before and every 3 hours during surgery. The diagnosis of SSI follows the CDC/NHSN definition. Results Our study included 647 males and 545 females, with a mean age of 69.3 years (IQR 63-77) and BMI of 22.6 kg/m2 (IQR 20.2-24.7). The incidence of SSI in all surgical cases was 61/1192 (5.1%; 95% CI 4.0-6.5). The incidence of SSIs in colon surgery was 16/769 (2.1%; 95% CI 1.3-3.4), and in rectal surgery, 45/400 (11.3%; 95% CI 8.5-14.7). The incidence of Clostridioides difficile colitis, which is regarded as a side effect of oral antimicrobial agents, was low at 6/1192 cases (0.5%; 05%CI 0.2-1.1). In our previous RCT, the incidence of SSI was 21/289 (7.26%) in patients treated with oral antibiotics. In a subanalysis of this trial published in the International Journal of Colorectal Disease(2016;31:1775-1784), the incidence of SSI was 9/188 (4.8%) in colon surgery and 13/103 (13%) in rectal surgery. The incidence of SSIs in the present data was similar to or lower than the incidence of SSIs in well-conditioned patients selected in the RCT. Conclusion Our results suggest that preoperative oral antibiotic prophylaxis in colorectal surgery is an effective method to reduce SSIs in a wide variety of patients in real-world clinical practice. Disclosures All Authors: No reported disclosures

Abstract 12199: Mid-Term Survival of Low-Risk Patients Treated With Transcatheter versus Surgical Aortic Valve Replacement: Meta-Analysis of Reconstructed Time-to-Event Data

Background: We performed a meta-analysis of reconstructed time-to-event data from randomized controlled trials (RCTs) and propensity-score matched (PSM) studies comparing transcatheter versus surgical aortic valve replacement (TAVR versus SAVR) to evaluate mid-term outcomes in patients considered low risk for SAVR. Methods and Results: Study-level meta-analysis of Kaplan-Meier-derived time-to-event of RCTs and PSM studies published by December 31, 2022. Eight studies (3 RCTs; 5 PSM studies) met our eligibility criteria and included 5,444 patients (2,639 patients underwent TAVR and 2,805 patients underwent SAVR). TAVR showed a higher risk of all-cause mortality at 8 years of follow-up [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.03-1.43, P=0.018]. Up to 2 years of follow-up, TAVR was not inferior to SAVR (HR 1.08, 95%CI 0.89-1.31, P=0.448); however, we observed a statistically significant difference after 2 years with higher mortality with TAVR (HR 1.51; 95% CI 1.14-2.00; P=0.004). This difference was driven by PSM studies; our sensitivity analysis showed a statistically significant difference between TAVR and SAVR when we included only PSM studies (HR 1.41, 95%CI 1.16-1.72, P=0.001), but no statistically significant difference when we included only RCTs (HR 0.89, 95%CI 0.69-1.16, P=0.398). At 8 years of follow-up after the primary intervention, the treatment difference in restricted mean survival time (RMST) is statistically significant, resulting in a benefit of 187.2 days (95% CI, 85.1-289.2, P&lt;0.001) in the SAVR arm. Conclusion: In comparison with TAVR, SAVR appeared to be associated with improved survival beyond 2 years in low-risk patients. However, the survival benefit of SAVR was only observed in PSM studies and not in RCTs. The addition of data from ongoing RCTs as well as longer follow-up in previous RCTs will help to confirm if there is a difference in mid- and long-term survival between TAVR vs. SAVR in low-risk population.

Midterm Survival of Low-Risk Patients Treated With Transcatheter Versus Surgical Aortic Valve Replacement: Meta-Analysis of Reconstructed Time-to-Event Data.

Background We performed a meta-analysis of reconstructed time-to-event data from randomized controlled trials (RCTs) and propensity-score matched (PSM) studies comparing transcatheter versus surgical aortic valve replacement (TAVR versus SAVR) to evaluate midterm outcomes in patients considered low risk for SAVR. Methods and Results Study-level meta-analysis of reconstructed time-to-event data from Kaplan-Meier curves of RCTs and PSM studies published by December 31, 2022 was conducted. Eight studies (3 RCTs, 5 PSM studies) met our eligibility criteria and included 5444 patients; 2639 patients underwent TAVR, and 2805 patients underwent SAVR. TAVR showed a higher risk of all-cause mortality at 8 years of follow-up (hazard ratio [HR] 1.22, [95% CI, 1.03-1.43], P=0.018). Up to 2 years of follow-up, TAVR was not inferior to SAVR (HR, 1.08 [95% CI, 0.89-1.31], P=0.448); however, we observed a statistically significant difference after 2 years with higher mortality with TAVR (HR, 1.51 [95% CI, 1.14-2.00]; P=0.004). This difference was driven by PSM studies; our sensitivity analysis showed a statistically significant difference between TAVR and SAVR when we included only PSM studies (HR, 1.41 [95% CI, 1.16-1.72], P=0.001) but no statistically significant difference when we included only RCTs (HR, 0.89 [95% CI, 0.69-1.16], P=0.398). Conclusions In comparison with TAVR, SAVR appeared to be associated with improved survival beyond 2 years in low-risk patients. However, the survival benefit of SAVR was observed only in PSM studies and not in RCTs. The addition of data from ongoing RCTs as well as longer follow-up in previous RCTs will help to confirm if there is a difference in mid- and long-term survival between TAVR versus SAVR in the low-risk population.

The Effects of Purslane Consumption on Obesity Indices: A GRADE-Assessed Systematic Review and Meta-Analysis of Randomized Controlled Trials

Obesity and overweight are among the most significant global health challenges that affect both developed and developing countries, leading to various chronic diseases. Previous studies have reported inconsistent results regarding the effects of purslane supplementation on obesity indices. Therefore, the aim of this study was to perform a meta-analysis on the effects of supplementation with purslane on obesity indices among adults. Comprehensive systematic searches were performed throughout Web of Science, EMBASE, PubMed, Scopus, and Cochrane Library databases up to May 30, 2023. All randomized controlled trials (RCTs) that investigated the impact of purslane supplementation on obesity indices were included into the analysis. The I2 and Cochran’s Q tests were used to assess heterogeneity between studies. The effect sizes were reported as the weighted mean difference (WMD) and 95% confidence intervals (CIs) using a random effects model. The initial search yielded 789 studies, of which seven RCTs were included in analysis. Following purslane supplementation, body weight (BW) (WMD: −0.94 kg, 95% CI: −1.57–−0.31, and P = 0.002) and body mass index (BMI) (WMD: −0.53 kg/m2, 95% CI: −0.88–−0.18, and P : 0.001) decreased significantly. However, this meta-analysis could not show any beneficial effect of purslane supplementation on waist circumference (WC) (WMD: −0.28 cm, 95% CI: −1.47–0.91, and P = 0.23). In addition, there was no linear association between the duration of treatment and sample size with BW, BMI, and WC. In conclusion, this meta-analysis showed a significant effect of purslane supplementation on BMI and BW but not on WC in adults, suggesting that it has the potential to be used therapeutically. Moreover, the combined results of previous RCTs indicate that purslane is a safe and effective intervention for reducing obesity indices in subjects with metabolic syndrome or obesity. As such, the consumption of purslane may have indirectly contributed to the amelioration of clinical symptoms in diseases with metabolic disorders, owing to its impact on some obesity indices. However, given the limitations and the low number of included studies in the present meta-analysis, more large-scale RCTs are needed to shed light on this issue.

Reirradiation vs. Systemic Therapy vs. Combination Therapy for Recurrent High-Grade Glioma: A Meta-Analysis of Survival and Toxicity

To compare the effects of reirradiation, systemic therapy and combination therapy (reirradiation + systemic therapy) on overall survival (OS), progression-free survival (PFS) and adverse effects (AEs) in patients with recurrent high-grade glioma (rHGG). A search was performed on PubMed, Scopus, Embase and CENTRAL on 18 March 2022, and repeated on 1 November 2022. Studies comparing OS, PFS and AEs in patients with rHGG, and encompassing the following four groups were included; reirradiation vs systemic therapy, combination therapy vs systemic therapy, combination therapy vs reirradiation, and reirradiation + bevacizumab-based systemic therapy vs reirradiation +/- non-bevacizumab-based systemic therapy. Risk of bias was assessed using the Cochrane RoB 2 tool for randomized control trials (RCTs) and the ROBINS-I tool for non-randomized studies. The logHR and SE (logHR) for OS and PFS, and logRR and SE (logRR) for AEs were extracted or estimated if not reported. Meta-analyses were performed for each comparator group using a random effects model. Subgroup analysis was performed on only RCTs if ≥ 2 studies were available. Thirty-three studies comprising of 2201 participants were included. In the reirradiation vs systemic therapy group, there was no difference in PFS (2 studies, 185 participants; HR 0.87 (95% CI 0.61-1.22)) and OS (3 studies, 237 participants; HR 0.94 (95% CI 0.67-1.31)). In the combination therapy vs systemic therapy group, combination therapy improved PFS (6 studies, 605 participants; HR = 0.70 (95% CI 0.59-0.82)) and OS (6 studies, 537 participants; HR 0.73 (95% CI 0.56-0.96)), and there was no difference in grade 3+ AEs (4 studies, 398 participants; RR 1.03 (95% CI 0.57-1.86)). Subgroup analysis of only RCTs (2 studies, 205 participants) similarly showed no difference in grade 3+ AEs (RR 1.13 (95% CI 0.71-1.82)), though no significant improvements in PFS (HR 0.51 (95% CI 0.22-1.19)) or OS (HR 0.90 (95% CI 0.65-1.26)) were demonstrated. In the combination therapy vs reirradiation group, combination therapy improved PFS (5 studies, 259 participants; HR 0.50 (95% CI 0.37-0.69)) and OS (13 studies, 713 participants; HR 0.59 (95% CI 0.47-0.74)). In the reirradiation + bevacizumab-based systemic therapy vs reirradiation +/- non-bevacizumab-based systemic therapy group, combining reirradiation with bevacizumab improved PFS (2 studies, 104 participants; HR 0.46 (95% CI 0.27-0.77)) and OS (5 studies, 256 participants; HR 0.42 (95% CI 0.24-0.72)), and reduced radionecrosis (RN) (5 studies, 353 participants; RR 0.17 (95% CI 0.06-0.48)). Combination therapy may improve OS and PFS with acceptable toxicity in select patients with rHGG. Further RCTs comparing systemic therapy to combination therapy, particularly with bevacizumab-based systemic therapy, are needed. The limitations of previous RCTs must be addressed; namely inadequate accrual of appropriate patients, and exclusion of FLAIR abnormalities from target delineation.

Lumbar Discectomy With Bone-Anchored Annular Closure Device in Patients With Large Annular Defects: One-Year Results.

Reherniation rates following lumbar discectomy are low for most patients; however, patients with a large defect in the annulus fibrosis have a significantly higher risk of recurrence. Previous results from a randomized controlled trial (RCT) demonstrated that the implantation of a bone-anchored annular closure device (ACD) during discectomy surgery lowered the risk of symptomatic reherniation and reoperation over one year with fewer serious adverse events (SAEs) compared to discectomy alone. The objective of this prospective, post-market, historically controlled study was to evaluate the use of an ACD during discectomy, and to confirm the results of the RCT that was used to establish regulatory approval in the United States. In this post-market study, all patients (N = 55) received discectomy surgery with a bone-anchored ACD. The comparison population was patients enrolled in the RCT study who had discectomy with an ACD (N = 262) or discectomy alone (N = 272). All other eligibility criteria, surgical technique, device characteristics, and follow-up methodology were comparable between studies. Endpoints included rate of symptomatic reherniation or reoperation, SAEs, and patient-reported measures of disability, pain, and quality of life. Fifty-five patients received ACD implants at 12 sites between May 2020 and February 2021. In the previous RCT, 272 control patients had discectomy surgery alone (RCT-Control), and 262 patients had discectomy surgery with an ACD implant (RCT-ACD). Baseline characteristics across groups were typical of the overall population undergoing lumbar discectomy. The proportion of patients who experienced reherniation and/or reoperation was significantly lower in the ACD group compared to RCT-ACD and RCT-Control groups (p < 0.05). In the ACD study, the one-year rate of symptomatic reherniation was 3.7%, compared to 8.5% in the RCT-ACD group and 17.0% in the RCT-Control group. In the ACD group, the risk of reoperation was 5.5%, compared to 6.5% in the RCT-ACD group and 12.5% in the RCT-Control group. There were no device-related SAEs or device integrity failures in the ACD, and there were clinically meaningful improvements in patient-reported measures of disability, pain, and quality of life. In this post-market study of bone-anchored ACD in patients with large annular defects, rates of symptomatic reherniation, reoperation, and SAEs were all low. Compared to theRCT, the post-market ACD study demonstrated lower rates of reherniation and/or reoperation and measures of back pain one-year post-surgery.

Why treatment of proximal humeral fractures remains unresolved despite randomized trials

Most proximal humeral fractures can be treated nonoperatively, but there are specific indications to perform surgery for some of these fractures. Optimal treatment remains subject to debate, since no consensus has been reached for the best therapy for these fractures. This review provides an overview of randomized controlled trials (RCTs) comparing treatment for proximal humeral fractures. Fourteen RCTs comparing different operative and nonoperative types of treatment for PHF are included. Different RCTs comparing the same interventions for PHF have drawn different conclusions. It also highlights reasons why consensus has not been reached based on these data, and how this could be addressed in future research. Previous RCTs have included different patient groups and fracture patterns, may have been prone to selection bias, often were underpowered for subgroup analysis, and showed inconsistency in the outcome measures used. Based on this, and appreciating that treatment may be tailored to specific fracture types and patient characteristic like age, a better way to move forward could be to use a (international) multicenter prospective cohort study. Such a registry-type study should use accurate patient selection and enrollment, well-defined fracture patterns, standardized surgical techniques performed according to the preferences of the surgeon, and with a standardized follow-up.

A multi-center, randomized, parallel-group study to compare the efficacy of enhanced cognitive behavior therapy (CBT-E) with treatment as usual (TAU) for anorexia nervosa: study protocol

BackgroundThe superiority of Enhanced Cognitive Behavior Therapy (CBT-E) with regard to weight gain and improvement of psychopathology of eating disorders for patients with anorexia nervosa (AN) over other psychotherapies and treatment as usual (TAU) has not been demonstrated in randomized controlled trials (RCTs). However, a previous RCT showed that patients with AN whose baseline body mass index (BMI) was less than 17.5 kg/m2 gained more weight when treated with CBT-E than with other psychotherapies. The aim of the study is to compare the efficacy of CBT-E and TAU for patients with AN. It was hypothesized that CBT-E would be superior to TAU, at least in terms of weight gain, as most patients with AN are likely to have a BMI lower than 17.5 kg/m2.Methods/designA randomized parallel-group multicenter trial will be conducted in three teaching hospitals in Japan between January 2023 and March 2026. Patients with DSM-5 AN, aged 16 years and older, with a BMI equal to or above 14.0 and below 18.5 will be eligible to participate. 56 patients will be randomly and evenly assigned to two intervention groups (CBT-E and TAU). Those assigned to CBT-E will be offered 25–40 sessions in accordance with their initial BMI. Patients assigned to TAU will have at least one session every 2 weeks, with the number of sessions and treatment period not fixed in advance. The primary outcome is BMI at 40 weeks after treatment initiation. The secondary outcomes are the results from the Japanese version of the Eating Disorder Examination Questionnaire and Clinical Impairment Assessment questionnaire to measure eating disorder psychopathology and psychological impairment. The follow-up assessment will be performed 6 months after the 40-week assessment.DiscussionThis multi-center randomized controlled study will probably evaluate the efficacy of CBT-E compared with TAU for patients with more severe AN than in previous studies since Japanese patients are likely to have a lower BMI than those in Western countries. While it may be difficult to generalize the results of a study conducted in Japan, it would be valuable to clarify the efficacy of CBT-E as a treatment package.Trial registrationUMIN, UMIN000048847. Registered 12 Sep 2022.