Open-label Randomized Clinical Trial Research Articles

Microaxial Flow Pump Hemodynamic and Metabolic Effects in Infarct-Related Cardiogenic Shock

Mechanical circulatory support with a microaxial flow pump (MAFP) has been shown to improve survival in ST-elevation myocardial infarction-induced cardiogenic shock (STEMI-CS). Understanding the impact on hemodynamic stability over time is crucial for optimizing patient treatment. To determine if an MAFP reduces the need for pharmacological circulatory support without compromising hemodynamics compared with standard care in STEMI-CS. This was a substudy of the Danish-German (DanGer) Shock trial, an international, multicenter, open-label randomized clinical trial. Patients from 14 heart centers across Denmark, Germany, and the UK were enrolled. Inclusion criteria for the trial were STEMI and systolic blood pressure less than 100 mm Hg or ongoing vasopressor treatment, left ventricular ejection fraction less than 45%, and arterial lactate level greater than 2.5 mmol/L. Of the enrolled patients, after exclusions from death in the catheterization laboratory or immediately on intensive care unit (ICU) admission, the remaining patients had serial recordings of hemodynamics, arterial lactate, and use of vasoactive drugs. Patients who were in comas after cardiac arrest and patients with mechanical complications or right ventricular failure were excluded. Data were analyzed from May to September 2024. MAFP and standard of care or standard of care alone. Hemodynamic status in terms of heart rate and blood pressure, metabolic status in terms of arterial lactate concentration, and vasoactive-inotropic score (VIS). The clinical events during the first 72 hours were as follows: death from all causes, escalation of mechanical circulatory support, and discharge alive from the ICU. From 355 enrolled patients, 324 (mean [IQR] age, 68 [58-75] years; 259 male [80%]) underwent ICU treatment (169 [52%] in the MAFP group, 155 [48%] in the standard-care group). Baseline characteristics were balanced. There was no difference in heart rate between groups, and mean arterial pressure was above the treatment target of 65 mm Hg in both groups but was achieved with a lower VIS in the MAFP group. No difference in arterial lactate level was found between groups at randomization, but on arrival to the ICU, the MAFP group had significantly lower arterial lactate levels compared with the standard-care group (mean difference, 1.3 mmol/L; 95% CI, 0.7-1.9 mmol/L), a difference that persisted throughout the first 24 hours of observation. The MAFP group achieved lactate normalization (<2 mmol/L) 12 hours (95% CI, 5-18 hours) before the standard-care group. Use of a MAFP reduces the use of vasopressors and inotropic medication while maintaining hemodynamic stability and achieving faster normalization of lactate level in patients with STEMI-CS. ClinicalTrials.gov Identifier: NCT01633502.

Restrictive vs Liberal Transfusion Strategy in Patients With Acute Brain Injury

Blood transfusions are commonly administered to patients with acute brain injury. The optimal hemoglobin transfusion threshold is uncertain in this patient population. To assess the impact on neurological outcome of 2 different hemoglobin thresholds to guide red blood cell transfusions in patients with acute brain injury. Multicenter, phase 3, parallel-group, investigator-initiated, pragmatic, open-label randomized clinical trial conducted in 72 intensive care units across 22 countries. Eligible patients had traumatic brain injury, aneurysmal subarachnoid hemorrhage, or intracerebral hemorrhage; hemoglobin values below 9 g/dL within the first 10 days after injury; and an expected intensive care unit stay of at least 72 hours. Enrollment occurred between September 1, 2017, and December 31, 2022. The last day of follow-up was June 30, 2023. Eight hundred fifty patients were randomly assigned to undergo a liberal (transfusion triggered by hemoglobin <9 g/dL; n = 408) or a restrictive (transfusion triggered by hemoglobin <7 g/dL; n = 442) transfusion strategy over a 28-day period. The primary outcome was occurrence of an unfavorable neurological outcome, defined as a Glasgow Outcome Scale Extended score between 1 and 5, at 180 days following randomization. There were 14 prespecified serious adverse events, including occurrence of cerebral ischemia after randomization. Among 820 patients who completed the trial (mean age, 51 years; 376 [45.9%] women), 806 had available data on the primary outcome, 393 in the liberal strategy group and 413 in the restrictive strategy group. The liberal strategy group received a median of 2 (IQR, 1-3) units of blood, and the restrictive strategy group received a median of 0 (IQR, 0-1) units of blood, with an absolute mean difference of 1.0 unit (95% CI, 0.87-1.12 units). At 180 days after randomization, 246 patients (62.6%) in the liberal strategy group had an unfavorable neurological outcome compared with 300 patients (72.6%) in the restrictive strategy group (absolute difference, -10.0% [95% CI, -16.5% to -3.6%]; adjusted relative risk, 0.86 [95% CI, 0.79-0.94]; P = .002). The effect of the transfusion thresholds on neurological outcome at 180 days was consistent across prespecified subgroups. In the liberal strategy group, 35 (8.8%) of 397 patients had at least 1 cerebral ischemic event compared with 57 (13.5%) of 423 in the restrictive strategy group (relative risk, 0.65 [95% CI, 0.44-0.97]). Patients with acute brain injury and anemia randomized to a liberal transfusion strategy were less likely to have an unfavorable neurological outcome than those randomized to a restrictive strategy. ClinicalTrials.gov Identifier: NCT02968654.

Dapagliflozin cardiovascular effects on end-stage kidney disease (DARE-ESKD-2) trial: rationale and design.

ABSTRACT Background Dapagliflozin prevents myocardial dysfunction in chronic kidney disease patients regardless residual kidney function, We hypothesized that this effect is extensible also to patients on dialysis. Research design and methods The DARE-ESKD-2 is an ongoing, single-center, open-label randomized clinical trial designed to determine the effects of adding dapagliflozin to standard treatment on myocardial function and structure. Eligible patients were adults on a regular dialysis scheme for more than 3 months. Pregnancy, liver failure, allergy to the investigational drug, and prior use of SGLT2i were exclusion criteria. Participants were randomized in a 1:1 ratio to dapagliflozin or standard treatment groups for 24-weeks. The primary goal is to compare the change in NT-proBNP levels between study arms, and secondary goals include comparing the between-group difference in left ventricle global longitudinal strain, indexed mass, ejection fraction, and E/e` ratio, and on symptoms scale and 6-minute walk test distance. An exploratory analysis will evaluate changes in body composition and bone densitometry. Results The trial has finished the enrollment of 80 patients, that are currently being followed-up. Conclusions This trial will provide novel data on myocardial effects of SGLT2i in dialysis recipients. Results from this study may provide evidence to support SGLT2i use in ESKD.

Role of aminophylline in prevention of acute kidney injury in term neonates with severe perinatal asphyxia: a randomized open-label controlled trial.

Acute kidney injury (AKI) is one of the frequently observed complications in neonates with severe perinatal asphyxia. The efficacy of aminophylline in preventing or alleviating renal dysfunction in these neonates remains controversial. The current study aimed to explore whether treatment with aminophylline as adjunctive therapy is superior to standard care alone in preventing AKI in severely asphyxiated term neonates and to delineate the changes in other renal parameters. In this open-label randomized clinical trial, term neonates with severe asphyxia (n = 41) received a 5 mg/kg intravenous dose of aminophylline within the first hour after birth, in addition to standard care for birth asphyxia. The control group (n = 40) received standard care alone. Their daily urine output, weight, serum creatinine, renal functional status, and complications during the first 5 days of life were monitored and compared. The statistical package for social sciences version 25 was used for analysis. Approximately 24.39% of neonates in the aminophylline group developed AKI, compared to 35.0% in the control group (P = .088). Although urine output was generally higher in aminophylline-treated newborns than in the control group, this increase was not statistically significant (P > .05), with the most notable differences observed on the second and third postnatal days. Also, the changes in plasma creatinine levels between the two groups during this time were not statistically significant. Administering a single dose of aminophylline (5 mg/kg) within the first hour of life to severely asphyxiated term neonates might temporarily enhance urine output, but does not reduce the overall incidence of AKI.

Effect of lycopene on prostate cancer among native African men: A protocol for an open-label randomized clinical trial in Tanzania

Background Prostate cancer (PCa) is the most common cancer and the fifth leading cause of death in men worldwide. The treatment of PCa depends on the clinical stage of the disease, prostate-specific antigen (PSA) level, and histology. Lycopene is a bright red carotenoid found in tomatoes, which enhances apoptosis in prostate cells, but its effectiveness has not been studied in East African countries. This study aimed to determine the effectiveness of lycopene from tomato extracts in reducing PSA levels, disease progression, and apoptosis in the prostate glands of men with PCa in Tanzania. Methods This study will be a randomized phase III clinical trial of men diagnosed with PCa in Tanzania. In total, 400 men will be randomized in a 1:1 ratio to receive intervention (n=200) and control (n=200) and followed for 12 months. The intervention arm will receive tomato paste for daily use in addition to the standard treatment, whereas the control arm will only follow the standard of care. The primary endpoints will be a reduction in PSA levels, improved clinical status, and apoptosis of the prostate gland. Data analysis was performed based on the intention-to-treat principle. Descriptive statistics were used to compare average lycopene and PSA levels in the intervention group using T-test and Chi-squared tests. Generalized linear mixed models will be used to further assess the effect of lycopene on PCa progression, urinary symptoms, and PSA reduction. All statistical tests were two-sided at an alpha level of &lt;0.05. Discussion The study used a food supplement as a drug/intervention with minimal or no adverse reactions. However, there is a fear that the control group may not adhere to the protocol after learning the benefits of tomato paste. The study findings will promote the consumption of tomato paste in males diagnosed with PCa to improve the clinical status and reduce disease progression. Trial registration The study has been registered at the Pan African Clinical Trial Registry with registration No PACTR202405488763956.

Partial hepatectomy versus interventional treatment in patients with hepatitis B virus-related hepatocellular carcinoma and clinically significant portal hypertension: a randomized comparative clinical trial.

The widely accepted view that portal hypertension (PHT) is a contraindication to hepatectomy for patients with hepatocellular carcinoma (HCC) is being increasingly challenged. The long-term survival outcomes and safety of partial hepatectomy versus interventional treatment using ablation with or without pre-ablation transarterial chemoembolization (TACE) in patients with HBV-related HCC within the Milan criteria and with clinically significant PHT were compared in this study. This open-label randomized clinical trial was conducted on consecutive patients with clinically PHT and hepatitis B virus (HBV)-related HCC with tumors which were within the Milan criteria. These patients were randomized 1:1 to receive either partial hepatectomy or interventional treatment between December 2012 and June 2018. The primary endpoint was overall survival (OS); secondary endpoints included recurrence-free survival (RFS) and therapeutic safety. Each of the 2 groups had 80 patients. The 1-, 3- and 5-year OS rates in the partial hepatectomy group and the interventional treatment group were 95.0%, 86.2%, 69.5% versus 93.8%, 77.5%, 64.9%, respectively (P = 0.325). The corresponding RFS rates were 78.8%, 55.0%, 46.2% versus 71.3%, 52.5%, 45.0%, respectively (P = 0.783). The partial hepatectomy group had a higher complication rate compared to the interventional group (67.5% vs. 20%, P < 0.001). However, the differences were mainly in Clavien-Dindo Grade I complications (P < 0.001), while not significant in Grade II/III/IV/V (All P > 0.05). This study shows that partial hepatectomy treatment did not meet prespecified significance for improved OS and RFS compared to interventional treatment for patients with HBV-related HCC within the Milan criteria and with clinically significant PHT. However, partial hepatectomy is still a safe procedure and should be considered as a treatment option rather than a contraindication.

Effect of Shoulder Movement Routine on Postoperative Shoulder Pain in Total Laparoscopic Hysterectomy: A Randomized Clinical Trial.

Background and Objectives: Postoperative shoulder pain is a common issue after total laparoscopic hysterectomy (TLH). This study evaluated the impact of a shoulder movement routine on postoperative shoulder pain in women undergoing uncomplicated TLH. Materials and Methods: An open-label randomized clinical trial included women without prior shoulder pain undergoing TLH between 20 January and 20 March 2024. Participants were randomized into two groups: Group 1 (n = 36) received a shoulder movement routine, while Group 2 (control, n = 39) performed a hand movement routine. Shoulder pain was assessed using the visual analog scale (VAS) at 6 h, 24 h, and 7 days postoperatively. Results: Seventy-five women participated. No significant differences were found between the groups regarding demographic variables, surgery duration, or hospital stay. Shoulder pain scores (VAS) at three time points (6 h, 24 h, and 7 days) showed no significant differences between groups (p = 0.57, p = 0.69, and p = 0.91, respectively). Similarly, there were no significant differences in incisional or abdominal pain. Conclusions: The shoulder movement routine did not significantly reduce postoperative shoulder pain in women undergoing uncomplicated TLH.

The Impact of Empagliflozin on Renal Function and Kidney Injury Markers in Patients with Diabetic Nephropathy

Background: Diabetic nephropathy affects approximately 50% of type 2 diabetes patients. Early detection of kidney disease is crucial to reducing the deterioration of renal function. Reversing microalbuminuria towards normal showed beneficial effects in delaying the onset of renal impairment or even reversing the progression of the disease. Recently, empagliflozin, a sodium/glucose cotransporter-2 inhibitor, has received attention for its anti-inflammatory and reno-cardioprotective effects. Objective: This interventional open-label randomized clinical trial aimed to evaluate the clinical outcome of empagliflozin as an add-on therapy for renal function parameters and other injury markers in type 2 diabetic nephropathy patients. Methods: The study enrolled twenty-one type 2 diabetic patients with nephropathy and nineteen without nephropathy. Each group received empagliflozin 10 mg/day for 16 weeks as an add-on to the traditional treatment. Blood and urine samples were collected at baseline and at week 16 to evaluate the glycemic status, renal function, tubular injury markers, and inflammatory and oxidative stress markers. Results: After 16 weeks, empagliflozin significantly reduced glycated hemoglobin A1c and urinary albumin/creatinine ratios in the nephropathy group. Compared with the non-nephropathy group, empagliflozin showed a significant increase in serum creatinine and a significant decrease in eGFRcr. Empagliflozin significantly reduced serum kidney injury molecule-1, cystatin C, interleukin-18, c-reactive protein, and malondialdehyde in both groups. Conclusions: Adding empagliflozin to the traditional oral antidiabetic drugs in diabetic nephropathy improved albuminuria with a mild increment in serum creatinine. Empagliflozin also effectively reduced renal injury markers, as well as inflammatory and oxidative stress markers.

Once-Weekly Insulin Icodec in Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Clinical Trials (ONWARDS Clinical Program).

One hundred years have passed since the discovery of insulin, which is one of the most relevant events of the 20th century. This period resulted in extraordinary progress in the development of novel molecules to improve glucose control, simplify the insulin regimen, and ameliorate the quality of life. In late March 2024, the first once-weekly basal analog Icodec was approved for diabetes mellitus, generating high expectations. Our aim was to systematically review and meta-analyze the efficacy and safety of Icodec compared to once-daily insulin analogs in type 1 (T1D) and type 2 diabetes (T2D). PubMed/MEDLINE, Cochrane Library, and ClinicalTrials.gov were searched for randomized clinical trials (RCTs). Studies were included for the synthesis according to the following prespecified inclusion criteria: uncontrolled T1D or T2D, age ≥ 18 years, insulin Icodec vs. active comparators (Degludec U100, Glargine U100, Glargine U300, and Detemir), phase 3, multicenter, double-blind or open-label RCTs, and a study duration ≥ 24 weeks. The systematic review included 4347 patients with T1D and T2D inadequately controlled (2172 randomized to Icodec vs. 2175 randomized to once-daily basal analogs). Icodec, compared to once-daily basal analogs, slightly reduced the levels of glycated hemoglobin (HbA1c) with an estimated treatment difference (ETD) of -0.14% [95%CI -0.25; -0.03], p = 0.01, and I2 68%. Patients randomized to Icodec compared to those on once-daily basal analogs had a greater probability to achieve HbA1c < 7% without clinically relevant or severe hypoglycemic events in 12 weeks from randomization with an estimated risk ratio (ERR) of 1.17, [95%CI 1.01, 1.36], p = 0.03, and I2 66%. We did not find a difference in fasting glucose levels, time in range, and time above range between Icodec and comparators. Icodec, compared to once-daily basal analogs, resulted in a slight but statistically significant weight gain of 0.62 kg [95%CI 0.25; 0.99], p = 0.001, and I2 25%. The frequency of hypoglycemic events (ERR 1.16 [95%CI 0.95; 1.41]), adverse events (ERR 1.04 [95%CI 1.00; 1.08]), injection-site reactions (ERR 1.08 [95%CI 0.62; 1.90]), and the discontinuation of treatments were similar between the two groups. Icodec was found to work better when used in a basal-only than basal-bolus regimen with an ETD in HbA1c of -0.22%, a probability of achieving glucose control of +33%, a probability of achieving glucose control without clinically relevant or severe hypoglycemia of +28%, more time spent in target (+4.55%) and less time spent in hyperglycemia (-5.14%). The risk of clinically relevant or severe hypoglycemic events was significantly higher when background glinides and sulfonylureas were added to basal analogs (ERR 1.42 [95%CI 1.05; 1.93]). Insulin Icodec is substantially non-inferior to once-daily insulin analogs in T2D, either insulin-naïve or insulin-treated. However, Icodec works slightly better than competitors when used in a basal-only rather than basal-bolus regimen. Weight gain and hypoglycemic risk are substantially low but not negligible. Patients' education, adequate lifestyle and pharmacological interventions, and appropriate therapy adjustments are essential to minimize risks. This systematic review is registered as PROSPERO CRD42024568680.

Effect of silymarin on lipid profile and glycemic control in patients with type 2 diabetes mellitus.

This randomized clinical trial was conducted to evaluate the effects of silymarin supplementation on glycemic indices and serum lipid profile in type 2 diabetes mellitus (T2DM) patients. In this open-label randomized clinical trial study, 48 patients with T2DM were eligible to participate for 12 weeks and were divided into two groups randomly: 24 subjects in the intervention (received three 140 mg silymarin capsules daily and diet plan) and 24 in control (received a diet plan). Fasting blood samples and anthropometric data were collected, and glycemic indices and lipid profiles were determined at baseline and at the end of the study. Out of 60 patients included in the clinical trial, 48 people completed the study. In comparing silymarin and control groups before and after the study, a significant reduction was observed in weight and body mass index. However, after adjustment, no significant difference was seen between the two groups. Furthermore, daily consumption of three capsules of 140 mg silymarin for 12 weeks did not show any significant difference on the level of fasting blood sugar (p = 0.789), HbA1c (p = 0.719), and lipid profile. The findings of the present study show that silymarin did not lead to changes in the level of glycemic index and lipid profile in patients with T2DM.

Medication Optimization Protocol Efficacy for Geriatric Inpatients

There is currently no consensus on clinically effective interventions for polypharmacy among older inpatients. To evaluate the effect of multidisciplinary team-based medication optimization on survival, unscheduled hospital visits, and rehospitalization in older inpatients with polypharmacy. This open-label randomized clinical trial was conducted at 8 internal medicine inpatient wards within a community hospital in Japan. Participants included medical inpatients 65 years or older who were receiving 5 or more regular medications. Enrollment took place between May 21, 2019, and March 14, 2022. Statistical analysis was performed from September 2023 to May 2024. The participants were randomly assigned to receive either an intervention for medication optimization or usual care including medication reconciliation. The intervention consisted of a medication review using the STOPP (Screening Tool of Older Persons' Prescriptions)/START (Screening Tool to Alert to Right Treatment) criteria, followed by a medication optimization proposal for participants and their attending physicians developed by a multidisciplinary team. On discharge, the medication optimization summary was sent to patients' primary care physicians and community pharmacists. The primary outcome was a composite of death, unscheduled hospital visits, and rehospitalization within 12 months. Secondary outcomes included the number of prescribed medications, falls, and adverse events. Between May 21, 2019, and March 14, 2022, 442 participants (mean [SD] age, 81.8 [7.1] years; 223 [50.5%] women) were randomly assigned to the intervention (n = 215) and usual care (n = 227). The intervention group had a significantly lower percentage of patients with 1 or more potentially inappropriate medications than the usual care group at discharge (26.2% vs 33.0%; adjusted odds ratio [OR], 0.56 [95% CI, 0.33-0.94]; P = .03), at 6 months (27.7% vs 37.5%; adjusted OR, 0.50 [95% CI, 0.29-0.86]; P = .01), and at 12 months (26.7% vs 37.4%; adjusted OR, 0.45 [95% CI, 0.25-0.80]; P = .007). The primary composite outcome occurred in 106 participants (49.3%) in the intervention group and 117 (51.5%) in the usual care group (stratified hazard ratio, 0.98 [95% CI, 0.75-1.27]). Adverse events were similar between each group (123 [57.2%] in the intervention group and 135 [59.5%] in the usual care group). In this randomized clinical trial of older inpatients with polypharmacy, the multidisciplinary deprescribing intervention did not reduce death, unscheduled hospital visits, or rehospitalization within 12 months. The intervention was effective in reducing the number of medications with no significant adverse effects on clinical outcomes, even among older inpatients with polypharmacy. UMIN Clinical Trials Registry: UMIN000035265.

The Effect of Uterine Length Measurement before Embryo Transfer versus Transabdominal Ultrasound-Guided Embryo Transfer on FET Cycle Outcome: A Randomised Clinical Trial.

Embryo transfer (ET) is an important step in assisted reproductive technology. Uterine length measurement before ET (ULMbET) enables the determination of catheter length and anatomical variation before the ET. Therefore, in this study, we aim to compare ULMbET and transabdominal ultrasound-guided ET (TAUGET). This open-label randomised clinical trial enrolled 264 women who were scheduled for frozen- thawed ET (FET) cycles. The women were randomised to the ULMbET or TAUGET group for ET. The primary outcome of this study was clinical pregnancy. A total of 132 women were randomly assigned to the ULMbET group and 132 women to the TAUGET group. However, four women in the ULMbET group did not receive the allocated method after randomisation. Finally, 128 women from the ULMbET group and 132 women from the TAUGET group were assessed. No statistically significant differences existed in chemical pregnancy rate (31.3 vs. 36.4%, P=0.384), clinical pregnancy rate (23.4 vs. 28%, P=0.397), and implantation rate (15 vs. 17.8%, P=0.401) between the ULMbET and TAUGET groups, respectively. The results of this clinical trial show no differences in pregnancy outcomes in FET cycles following ULMbET and TAUGET (registration number: IRCT20110509006420N240).

P-476 Barriers and facilitators to nationwide implementation of fertility screening interventions: a qualitative study

Abstract Study question What are the barriers and facilitators to the potential nationwide implementation of Fertility Health Screening (FHS) and/or Fertility Awareness and Education (FAE) in Singapore? Summary answer The study reveals implementation factors that shed light on how advanced societies can adopt evidence-based interventions to deliver fertility education together with behavioural change nudges. What is known already Fertility awareness surveys have consistently shown low public awareness of age-related fertility decline and the limitations of fertility treatments. Furthermore, preventive public health messages to increase fertility awareness are known to produce limited sustained effects. While there is evidence that tailored interventions are more effective than generic ones at increasing fertility awareness, interventional studies targeted at those of reproductive age are scarce. An effectiveness-implementation hybrid type I 3-arm open-label randomized clinical trial (RCT) is underway to evaluate the effects of two theory-based interventions on knowledge, attitudes and practices around childbearing among young married couples in Singapore. Study design, size, duration The present qualitative study was conducted to explore experiences and perspectives on the interventions and their potential implementation among healthcare professionals (HCPs) involved in implementing the interventions and a sub-sample of couples randomized into either treatment group. Recruitment used purposive sampling. Individual semi-structured interviews were conducted from June 2021 to December 2023. The Consolidated Framework for Implementation Research (CFIR) was used to develop the interview guide. Sample size was determined by data saturation. Participants/materials, setting, methods Couples in either treatment group were recruited after completing their final follow-up visit, while HCPs were recruited at their convenience. After taking written informed consent, the interviews were conducted in person or over Zoom and audio recorded. The interviews were transcribed verbatim and inductive thematic analysis was used to evaluate the data. Themes were then mapped to CFIR constructs. The results were reported according to O’Brien et al.’s (2014) Standards for Reporting Qualitative Research. Main results and the role of chance Twenty HCPs (10 doctors, 8 embryologists, 1 nurse and 1 manager) and 29 heterosexual couples (FHS n = 16; FAE n = 13) participated in the interviews. Median age was 30 (women) and 32 (men) years with most participants having post-secondary education. In FHS, couples underwent an Anti-Mullerian Hormone (AMH) test and semen analysis (SA), doctor’s consultation, and standardized counselling by a trained nurse. In FAE, couples watched a video of other couples’ pre-pregnancy experiences, completed an adapted fertility status awareness tool (FertiSTAT), and received an educational brochure. FHS barriers (CFIR constructs n = 6) included the discomfort when producing SA samples, male partners’ reluctance to share personal information with embryologists for SA, stigma associated with undergoing fertility-related tests, lack of time for appointments, limited cost effectiveness, and shortage of human resources due to potential increase in service demand. FHS facilitators (constructs n = 4) included evidence-based testing, increased knowledge of reproductive potential, advice from trained HCPs and comprehensible brochures. Perceived facilitators for FAE (constructs n = 2) included compelling video messages and clearly designed questionnaires. No major barrier was reported for FAE. Overall, insights gained from the interviews can inform strategies to address barriers and leverage facilitators for each intervention. Limitations, reasons for caution Barrers and facilitators may differ between countries. There may also be selection bias in the recruitment strategy, as participants were likely those who wished to have children. Moreover, the lack of diversity in educational qualifications and ethnicity may exclude the influence of class and cultural factors on parenthood intentions. Wider implications of the findings The findings contribute to an understanding of personalised fertility interventions coupled with behavioural change influences by showing how qualitative process indicators could complement research on interventions’ effectiveness. This has implications for other developed countries that are seeking to explore how implementation factors can expedite clinical best practice after research discovery. Trial registration number NCT04647136

Ketamine vs Electroconvulsive Therapy for Treatment-Resistant Depression

The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD. To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT. This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians. Eligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks. Association between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses. Among the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment. In this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.

Evaluating dyNamic myocardial blood flow qUantitation as a Cost-effective care modeL for diabEtic patients with coronary artery diSease (NUCLEuS): A randomized controlled trial – Rationale and Design

BackgroundRecent advancements in quantifying myocardial blood flow (MBF) and coronary flow reserve using dynamic SPECT MPI have demonstrated comparable hemodynamic correlations with invasive angiography and PET. Implementation into routine practice, however, imposes attendant demands on resources. Diabetes mellitus is a rising pandemic associated with accelerated atherosclerosis, yet there is potential for under-detection of significant ischemia. ObjectivesWe postulate that quantifying myocardial blood flow (MBF) by dynamic SPECT reduces post-test resource utilization and improve economic efficiency over conventional SPECT. MethodsNUCLEuS is an ongoing prospective open-label randomized clinical trial that will enroll 300 diabetic patients without known coronary artery disease (CAD) referred clinically for SPECT MPI from March 2022 to March 2025. The aim is to determine the incremental prognostic value and post-test resource utilization of dynamic MBF over conventional SPECT in diabetic patients with suspected CAD. The primary endpoint is diagnostic failure, defined as unnecessary coronary angiography (absence of ≥50% stenosis in ≥1 coronary artery) or additional anatomical testing (e.g., coronary computed tomography angiography) within 90 days. Secondary endpoints are referrals for angiography or revascularization, escalation of anti-anginal medications, and quality-of-life scores at 12 months. Long-term endpoints are major adverse cardiovascular events (cardiac mortality, myocardial infarction, unstable angina, revascularization) within 36 months. The incremental cost-effectiveness ratio will be estimated based on cost and clinical effectiveness. ConclusionsNUCLEuS will be an imaging-directed clinical trial that will compare differences in outcomes and resource utilization of dynamic MBF over conventional SPECT MPI in the routine clinical management of CAD in diabetes mellitus.

Ten-Year Outcomes Following Roux-en-Y Gastric Bypass vs Duodenal Switch for High Body Mass Index

Results from long-term follow-up after biliopancreatic diversion with duodenal switch (DS) are scarce. To compare weight loss, health outcomes, and quality of life 10 years or more after Roux-en-Y-gastric bypass (RYGB) and DS surgery in patients with severe obesity-that is, a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 50 to 60. This open-label randomized clinical trial was conducted at 2 academic bariatric centers in Sweden and Norway. Sixty patients with a BMI of 50 to 60 were included from March 1, 2006, to August 31, 2007. Data were analyzed from August 12, 2022, to January 25, 2023. Laparoscopic RYGB or laparoscopic DS. The main outcome was change in BMI after 10 or more years. Secondary outcomes included anthropometric measures, lipid and glycemic profiles, bone mass density, adverse events, gastrointestinal tract symptoms, and health-related quality of life. Forty-eight of the original 60 patients (80%) were assessed after a median of 12 (range, 9-13) years (mean [SD] age, 48.0 [6.0] years; 35 women [73%]). At follow-up, the mean BMI reductions were 11.0 (95% CI, 8.3-13.7) for RYGB and 20.3 (95% CI, 17.6-23.0) for DS, with a mean between-group difference of 9.3 (95% CI, 5.4-13.1; P < .001). Total weight loss was 20.0% (95% CI, 15.3%-24.7%) for RYGB and 33.9% (95% CI, 27.8%-40.0%) for DS (P = .001). Mean serum lipid levels, except high-density lipoprotein cholesterol and hemoglobin A1c, improved more in the DS group during follow-up. Bone mass was reduced for both groups from 5 to 10 years, with lower bone mass after DS at 10 years. Quality-of-life scores (Obesity-Related Problem Scale and the 36-Item Short Form Health Survey) were comparable across groups at 10 years. The total number of adverse events was higher after DS (135 vs 97 for RYGB; P = .02). More patients in the DS group developed vitamin deficiencies (21 vs 11 for RYGB; P = .008) including 25-hydroxyvitamin D deficiency (19 for DS vs 9 for RYGB; P = .005). Four of 29 patients in the DS group (14%) developed severe protein-caloric malnutrition, of whom 3 (10%) underwent revisional surgery. In this randomized clinical trial, BMI reduction was greater after DS, but RYGB had a better risk profile over 10 years. Biliopancreatic diversion with DS may not be a better surgical strategy than RYGB for patients with a BMI of 50 to 60. ClinicalTrials.gov Identifier: NCT00327912.

Immediate vs Gradual Brace Weaning Protocols in Adolescent Idiopathic Scoliosis

Lack of evidence and consensus for brace weaning protocol in adolescent idiopathic scoliosis (AIS) results in clinicians prescribing gradual weaning in the hope of avoiding curve deterioration after weaning. However, gradual weaning contributes to prolonged brace wear, which can affect spinal stiffness and health-related quality of life (HRQoL). To determine whether gradual weaning results in better curve magnitude and truncal balance maintenance after brace weaning vs immediate brace removal for patients with AIS. This was an open-labeled randomized clinical trial commenced in April 2017 with 24-month follow-up completed in January 2023. Outcome assessors were masked to weaning protocol assigned. The study took place at a territory-wide tertiary scoliosis clinic serving the largest number of referrals in the local population. Patients with AIS ready to wean off of brace wear were eligible (402 were screened; 33 were excluded [15 for <18 hours/day of brace-wear compliance before weaning, 11 were treated with Milwaukee brace, and 7 declined to participate]; and 369 were included), and those who were treated with a custom molded thoracolumbosacral orthosis and had reached skeletal maturity were consecutively recruited. Patients were randomized to gradual weaning protocol (n = 176) with an additional 6 months of nighttime wear before completely stopping or immediate weaning protocol (n = 193) with immediate brace removal at recruitment. Changes in major curve Cobb angle and truncal balance from the time of weaning to 6-month, 12-month, and 24-month follow-up. HRQoL was also assessed using the refined Scoliosis Research Society 22-item and EuroQol 5-dimension questionnaires. A total of 369 patients (mean [SD] age, 14.9 [1.1] years; 304 [83.4%] girls) were randomized with 284 (77.0%) completing 24-month longitudinal follow-up. Immediate and gradual weaning groups had no significant differences in change of major Cobb angle at postweaning 6-month (difference, -0.6°; 95% CI, -1.4 to 0.2; P = .17), 12-month (difference, -0.3°; 95% CI, -1.2 to 0.6; P = .47), and 24-month (difference, -0.3°; 95% CI, -1.2 to 0.7; P = .60) follow-up. The number of curve progression, nonprogression, and rebound cases were comparable (χ22 = 2.123; P = .35). Postweaning changes in truncal balance and HRQoL demonstrated no significant differences between groups. Gradual weaning did not demonstrate superiority to immediate weaning with predefined criteria of Cobb angle and truncal balance maintenance and HRQoL after brace weaning. Gradual and immediate weaning achieved very similar maintenance of brace outcomes in AIS. We therefore recommend the consideration of immediate brace weaning, which aims to benefit patients with earlier time for increased exercises and activity level. ClinicalTrials.gov Identifier: NCT03329716.

An open-label randomized trial comparing addition of olanzapine 5 mg versus olanzapine 10 mg as anti-emetic to standard anti-emetic regime for doxorubicin or epirubicin and cyclophosphamide in breast cancer.

e12531 Background: Chemotherapy-induced nausea and vomiting (CINV) is an important therapy related side effects in the treatment of malignancies. Breast cancer patients receive a highly-emetogenic chemotherapy with Doxorubicin or Epirubicin and Cyclophosphamide. The addition of Olanzapine 10 mg is known to reduce acute and delayed CINV, however, Olanzapine 10 mg is associated with somnolence and fatigue. In this study, the proportion of complete response of CINV to Olanzapine 5 mg was compared to Olanzapine 10 mg that was added to standard antiemetic regime. Methods: This was an open-label randomized clinical trial comparing the effectiveness of Olanzapine 5 mg against Olanzapine 10 mg in preventing acute and delayed phases of CINV. This study was conducted at a tertiary care cancer centre in India between 2020 – 2021. The sample size was calculated 118 subjects that were allocated with simple randomization method. The primary outcome of CINV in acute and delayed phase were collected using the Multinational Association for Supportive Care in Cancer (MASCC) Antiemesis Tool; the intensity of symptoms of nausea, retching and vomiting were assessed using the Rhodes index; the overall patient experience was assessed using the Edmonton Symptom Assessment Scale. The comparison of proportions of CINV in the two groups were compared using Chi-square test while intensity scores were compared using Wilcoxon rank-sum test. All p values &lt;0.05 were considered significant. Ethics approval was obtained from the Institutional Review Board. The trial was registered at the Clinical Trials Registry of India. Results: Of the118 patients randomized, 57 received Olanzapine 5 mg and 61 received Olanzapine 10 mg in addition to standard antiemetic regime. The overall complete response rate was 54.2% in acute phase and 72.0% in delayed phase. The complete response rate of Olanzapine 5 mg was 57.9% in acute phase and 91.2% in delayed phase. The complete response rate of Olanzapine 10 mg was 50.9% in acute phase and 54.1% in delayed phase. The nausea intensity score on day 5 after chemotherapy was significantly lower among those receiving Olanzapine 10 mg. However, there were no difference in the reduction retching and overall symptoms between the groups. In terms of side effect profile, those receiving Olanzapine 10 mg reported significantly higher grades of somnolence and fatigue. There was no difference in the occurrence of pain, depression, anxiety, shortness of beath, appetite and wellbeing. Conclusions: There was no difference in the effectiveness of Olanzapine 5 mg compared to Olanzapine 10 mg in the prevention of CINV. However, Olanzapine 10 mg was associated with higher proportions of somnolence and fatigue. Therefore, it is recommended that Olanzapine 5 mg may replace current antiemetic regimes that contain Olanzapine 10 mg. Clinical trial information: CTRI/2020/01/023076.

An Adaptive Pragmatic Randomized Controlled Trial of Emergency Department Acupuncture for Acute Musculoskeletal Pain Management

Acute musculoskeletal pain in emergency department (ED) patients is frequently severe and challenging to treat with medications alone. The purpose of this study was to determine the feasibility, acceptability, and effectiveness of adding ED acupuncture to treat acute episodes of musculoskeletal pain in the neck, back, and extremities. In this pragmatic 2-stage adaptive open-label randomized clinical trial, Stage 1 identified whether auricular acupuncture (AA; based on the battlefield acupuncture protocol) or peripheral acupuncture (PA; needles in head, neck, and extremities only), when added to usual care was more feasible, acceptable, and efficacious in the ED. Stage 2 assessed effectiveness of the selected acupuncture intervention(s) on pain reduction compared to usual care only (UC). Licensed acupuncturists delivered AA and PA. They saw and evaluated but did not deliver acupuncture to the UC group as an attention control. All participants received UC from blinded ED providers. Primary outcome was 1-hour change in 11-point pain numeric rating scale. Stage 1 interim analysis found both acupuncture styles similar, so Stage 2 continued all 3 treatment arms. Among 236 participants randomized, demographics and baseline pain were comparable across groups. When compared to UC alone, reduction in pain was 1.6 (95% confidence interval [CI]: 0.7 to 2.6) points greater for AA+UC and 1.2 (95% CI: 0.3 to 2.1) points greater for PA+UC patients. Participants in both treatment arms reported high satisfaction with acupuncture. ED acupuncture is feasible and acceptable and can reduce acute musculoskeletal pain better than UC alone.

Comparing pulsed field electroporation and radiofrequency ablation for the treatment of paroxysmal atrial fibrillation: design and rationale of the BEAT PAROX-AF randomized clinical trial.

Using thermal-based energy sources [radiofrequency (RF) energy/cryo energy] for catheter ablation is considered effective and safe when performing pulmonary vein isolation (PVI) in patients with paroxysmal atrial fibrillation (AF). However, treatment success remains limited and complications can occur due to the propagation of thermal energy into non-target tissues. We aim to compare pulsed field ablation (PFA) with RF ablation in terms of efficacy and safety for patients with drug-resistant paroxysmal AF. The BEAT PAROX-AF trial is a European multicentre, superiority, open-label randomized clinical trial in two parallel groups. A total of 292 participants were recruited in 9 high-volume European clinical centres in 5 countries. Patients with paroxysmal AF were randomized to PFA (FARAPULSE Endocardial Ablation System©, Boston Scientific) or RF using the CLOSE protocol with contact force sensing catheter (SmartTouch© catheter and CARTO© Biosense Webster). The primary endpoint will be the 1-year recurrence of atrial arrhythmia, and the major secondary safety endpoint will be the occurrence of acute (<7 days) procedure-related serious adverse events, or pulmonary vein stenosis, or atrio-oesophageal fistula up to 12 months. Additionally, five sub-studies investigate the effect of PFA on oesophageal safety, cerebral lesions, cardiac autonomic nervous system, durability of PVI as assessed during redo ablation procedures, and atrial and ventricular function. The study began on 27 December 2021 and concluded recruitment on 17 January 2024. Results will be available in mid-2025. The BEAT PAROX-AF trial aims to provide critical insights into the optimal treatment approach for patients with paroxysmal AF.