Randomized Clinical Trial Design Research Articles

Risk of bleeding in anticoagulated patients undergoing dental extraction treated with topical tranexamic acid compared to collagen-gelatin sponge: Randomized clinical trial

This two-arm, parallel-group, double-blind, randomized clinical trial design evaluated the risk of postoperative bleeding in anticoagulated patients undergoing dental extraction treated with topical TXA in comparison to collagen-gelatin sponge. Forty patients were randomly included in one of the study groups: (1) topical use of 4.8% TXA solution; and (2) resorbable hydrolyzed collagen-gelatin sponge applied to the surgical alveolus. Primary outcomes were postoperative bleeding episodes and secondary outcomes were thromboembolic events and postoperative INR values. The relative risk (RR), the absolute risk reduction (RAR) and the number needed to treat (NNT) were used as effect estimates and calculated from the counting of bleeding episodes observed during the first postoperative week. The bleeding rate under the TXA treatment was 22.2%, while in the collagen-gelatin sponge group it was 45.7%, resulting in a RR of 0.49 (95% CI 0.24–099; p = 0.046), RAR 23.5% and NNT 4.3. TXA was more effective in reducing bleeding in surgical sites located in the mandible (RR = 0.10; 95% CI 0.01–0.71; p = 0.021) and the posterior region (RR = 0.39; 95% CI 0.18–0.84; p = 0.016). Within the limitations of the study it seems that topical TXA is more effective in controlling bleeding after tooth extractions in anticoagulated patients than collagen-gelatin sponge. Clinical trial registrationRBR-83qw93.

Emulation of Randomized Clinical Trials With Nonrandomized Database Analyses

ImportanceNonrandomized studies using insurance claims databases can be analyzed to produce real-world evidence on the effectiveness of medical products. Given the lack of baseline randomization and measurement issues, concerns exist about whether such studies produce unbiased treatment effect estimates.ObjectiveTo emulate the design of 30 completed and 2 ongoing randomized clinical trials (RCTs) of medications with database studies using observational analogues of the RCT design parameters (population, intervention, comparator, outcome, time [PICOT]) and to quantify agreement in RCT-database study pairs.Design, Setting, and ParticipantsNew-user cohort studies with propensity score matching using 3 US claims databases (Optum Clinformatics, MarketScan, and Medicare). Inclusion-exclusion criteria for each database study were prespecified to emulate the corresponding RCT. RCTs were explicitly selected based on feasibility, including power, key confounders, and end points more likely to be emulated with real-world data. All 32 protocols were registered on ClinicalTrials.gov before conducting analyses. Emulations were conducted from 2017 through 2022.ExposuresTherapies for multiple clinical conditions were included.Main Outcomes and MeasuresDatabase study emulations focused on the primary outcome of the corresponding RCT. Findings of database studies were compared with RCTs using predefined metrics, including Pearson correlation coefficients and binary metrics based on statistical significance agreement, estimate agreement, and standardized difference.ResultsIn these highly selected RCTs, the overall observed agreement between the RCT and the database emulation results was a Pearson correlation of 0.82 (95% CI, 0.64-0.91), with 75% meeting statistical significance, 66% estimate agreement, and 75% standardized difference agreement. In a post hoc analysis limited to 16 RCTs with closer emulation of trial design and measurements, concordance was higher (Pearson r, 0.93; 95% CI, 0.79-0.97; 94% meeting statistical significance, 88% estimate agreement, 88% standardized difference agreement). Weaker concordance occurred among 16 RCTs for which close emulation of certain design elements that define the research question (PICOT) with data from insurance claims was not possible (Pearson r, 0.53; 95% CI, 0.00-0.83; 56% meeting statistical significance, 50% estimate agreement, 69% standardized difference agreement).Conclusions and RelevanceReal-world evidence studies can reach similar conclusions as RCTs when design and measurements can be closely emulated, but this may be difficult to achieve. Concordance in results varied depending on the agreement metric. Emulation differences, chance, and residual confounding can contribute to divergence in results and are difficult to disentangle.

Biomarker-based Bayesian randomized clinical trial design for identifying a target population.

The challenges and potential benefits of incorporating biomarkers into clinical trial designs have been increasingly discussed, in particular to develop new agents for immune-oncology or targeted cancer therapies. To more accurately identify a sensitive subpopulation of patients, in many cases, a larger sample size-and consequently higher development costs and a longer study period-might be required. This article discusses a biomarker-based Bayesian (BM-Bay) randomized clinical trial design that incorporates a predictive biomarker measured on a continuous scale with pre-determined cutoff points or a graded scale to define multiple patient subpopulations. We consider designing interim analyses with suitable decision criteria to achieve correct and efficient identification of a target patient population for developing a new treatment. The proposed decision criteria allow not only the take-in of sensitive subpopulations but also the ruling-out of insensitive ones on the basis of the efficacy evaluation of a time-to-event outcome. Extensive simulation studies are conducted to evaluate the operating characteristics of the proposed method, including the probability of correct identification of the desired subpopulation and the expected number of patients, under a wide range of clinical scenarios. For illustration purposes, we apply the proposed method to design a randomized phase II immune-oncology clinical trial.

Psychoeducational Intervention for Reducing Heart Failure Patients' Rehospitalizations and Promoting Their Quality of Life and Posttraumatic Growth at the 1-Year Follow-Up: A Randomized Clinical Trial.

This study's aim was to verify whether a psychoeducational intervention, with a brief expressive posttraumatic growth (PTG) component, could reduce heart failure (HF) patients' hospital readmissions and promote their quality of life (QoL) and PTG. It adopted a parallel randomized clinical trial design, and its participants comprised HF patients from a hospital in Southern Brazil. All the participants completed the World Health Organization Quality of Life Assessment and Posttraumatic Growth Inventory questionnaires at the pre (T1: baseline) and post (T2) assessments of the intervention. Although patients in the control group (CG) underwent only regular outpatient consultations, those in the intervention group (IG) supplemented their regular consultations, with two additional individual visits to promote health and psychological education. At the 1-year follow-up, hospital readmissions were assessed. Of the 142 patients recruited at baseline (72 and 70 in the CG and IG, respectively), as 19 dropped out at follow-up, only 123 (63 and 60 in the CG and IG, respectively) were reassessed after approximately 378 days. They included 65% men aged 64 (11) years, 58% had low incomes, and 67% had less than high school education. The IG participants' risk of readmission got reduced by 52% ( p = .023), and they also showed significant improvements in their total QoL and positive psychological growth at the 6-month follow-up assessment. The two-session psychoeducational intervention proved to be protective for Southern Brazilian HF patients in the IG, as it effectively reduced their hospital readmission rates by half compared with the CG, as well as improved their QoL and promoted their positive psychological growth. ClinicalTrials.gov identifier: NCT04870918 .

The Determining Effective Testing in Emergency Departments and Care Coordination on Treatment Outcomes (DETECT) for Hepatitis C (Hep C) Linkage-to-Care Trial: rationale and design of an emergency department-based randomized clinical trial of linkage-to-care strategies for hepatitis C

BackgroundHepatitis C (HCV) poses a major public health problem in the USA. While early identification is a critical priority, subsequent linkage to a treatment specialist is a crucial step that bridges diagnosed patients to treatment, cure, and prevention of ongoing transmission. Emergency departments (EDs) serve as an important clinical setting for HCV screening, although optimal methods of linkage-to-care for HCV-diagnosed individuals remain unknown. In this article, we describe the rationale and design of The Determining Effective Testing in Emergency Departments and Care Coordination on Treatment Outcomes (DETECT) for Hepatitis C (Hep C) Linkage-to-Care Trial.MethodsThe DETECT Hep C Linkage-to-Care Trial will be a single-center prospective comparative effectiveness randomized two-arm parallel-group superiority trial to test the effectiveness of linkage navigation and clinician referral among ED patients identified with untreated HCV with a primary hypothesis that linkage navigation plus clinician referral is superior to clinician referral alone when using treatment initiation as the primary outcome. Participants will be enrolled in the ED at Denver Health Medical Center (Denver, CO), an urban, safety-net hospital with approximately 75,000 annual adult ED visits. This trial was designed to enroll a maximum of 280 HCV RNA-positive participants with one planned interim analysis based on methods by O’Brien and Fleming. This trial will further inform the evaluation of cost effectiveness, disparities, and social determinants of health in linkage-to-care, treatment, and disease progression.DiscussionWhen complete, the DETECT Hep C Linkage-to-Care Trial will significantly inform how best to perform linkage-to-care among ED patients identified with HCV.Trial registrationClinicalTrials.govID: NCT04026867Original date: July 1, 2019URL: https://clinicaltrials.gov/ct2/show/NCT04026867

Rationale and design of a multisite randomized clinical trial examining an integrated behavioral treatment for veterans with co-occurring chronic pain and opioid use disorder: The pain and opioids integrated treatment in veterans (POSITIVE) trial

BackgroundChronic pain and opioid use disorder (OUD) individually represent a risk to health and well-being. Concerningly, there is evidence that they are frequently co-morbid. While few treatments exist that simultaneously target both conditions, preliminary work has supported the feasibility of an integrated behavioral treatment targeting pain interference and opioid misuse. This treatment combined Acceptance and Commitment Therapy (ACT) and Mindfulness-Based Relapse Prevention (ACT+MBRP). This paper describes the protocol for the adequately powered efficacy study of this integrated treatment. MethodsA multisite randomized controlled trial will examine the efficacy of ACT+MBRP in comparison to a parallel education control condition, focusing on opioid safety and pain education. Participants include veterans (n = 160; 21–75 years old) recruited from three Veterans Administration (VA) Healthcare Systems with chronic pain who are on a stable dose of buprenorphine. Both conditions include twelve weekly 90 min group sessions delivered via telehealth. Primary outcomes include pain interference (Patient Reported Outcome Measurement Information System - Pain Interference) and hazardous opioid use (Current Opioid Misuse Measure), which will be examined at the end of the active treatment phase and through 12 months post-intervention. Secondary analyses will evaluate outcomes including pain intensity, depression, pain-related fear, and substance use, as well as treatment mechanisms. ConclusionThis study will determine the efficacy of an integrated behavioral treatment program for pain interference and hazardous opioid use among veterans with chronic pain and OUD who are prescribed buprenorphine, addressing a critical need for more integrated treatments for chronic pain and OUD. Trial registrationClinicalTrials.gov Identifier: NCT04648228

Design of a multicenter randomized clinical trial for treatment of Alcohol-Associated Hepatitis

BackgroundMortality is high for severe alcohol-associated hepatitis (AH). Corticosteroids are the standard of care for patients without contraindications. Recent data showed that interleukin-1β receptor antagonist anakinra attenuated inflammation and liver damage. We designed a multicenter, double-blind, randomized controlled trial to assess the safety and efficacy of anakinra compared to prednisone. MethodsPatients meeting the clinical and biochemical criteria for severe AH with MELD scores between 20 and 35 were recruited at eight clinical sites. Eligible patients enrolled in the study were randomized to anakinra, 100 mg subcutaneous injection for 14 days, plus zinc sulfate 220 mg for 90 days, vs. prednisone 40 mg PO daily for 30 days. Matching placebos for anakinra, zinc, and prednisone were provided to mask the treatment. Participants were followed for 180 days. The primary outcome was overall survival at 90 days. An unadjusted log-rank test was used to compare the survival of the two treatments in the first 90 days. Between July 10, 2020, and March 4, 2022, we screened 1082 patients with severe AH, and 147 eligible patients were enrolled and randomized. The average baseline MELD score was 25 [range 20–35], Maddrey discriminant function (MDF) was 59.4 [range 20.2–197.5]. The mean aspartate transaminase (AST)-to-alanine transaminase (ALT) ratio was 3.5. The baseline characteristics were not statistically different between the two treatment groups. ConclusionsThe study provided a direct comparison of the survival benefits and safety profiles of anakinra plus zinc vs. prednisone in patients with severe AH.

Design of an adaptive randomized clinical trial of intravenous citrulline for sickle cell pain crisis in the emergency department

BackgroundVaso-occlusive pain crisis (VOC) is the most frequent cause for Emergency Department (ED) visits and hospital admissions for patients with sickle cell disease (SCD). Nitric oxide plays a critical role in the pathogenesis of vaso-occlusion. The amino acid, citrulline, is the main endothelial nitric oxide booster that offers the potential to ameliorate vaso-occlusion and decrease the risk of hospitalization. ObjectiveIn this two-part study, the goal of the first part is to determine the pharmacokinetic profile of intravenous (IV) l-citrulline and optimal dose for the second part of the study, which is to determine the efficacy and tolerability of the intervention in patients with SCD. DesignA phase I/IIA open-label dose-finding study with subsequent double-blind, placebo-controlled, randomized Study of l-citrulline in children and adolescents with SCD presenting to the ED in VOC. MethodsPart 1: Subjects experiencing VOC are enrolled in an open-label, ascending dose of IV l-citrulline to identify the optimum dose with endpoints of pharmacokinetic parameters, pain scores, reduction of opioid use, quality of life, proportion admitted to the hospital for treatment of pain, readmission rates, and assessment of adverse events. Part 2 of the trial is a double-blind, placebo-controlled adaptive “pick-the-winner” design to evaluate the efficacy and tolerability of IV l-citrulline in patients with SCD while receiving standard of care therapy for VOC. SummaryThis ED based sickle cell adaptive trial will determine the optimal dose for IV citrulline and whether the intervention improves outcome as a potential novel therapy for VOC in SCD.

Effect of Garlic (Allium Sativum) Extract on Hemoglobin Levels in Chronic Hemodialysis Patients

CKD patients undergoing hemodialysis have increased inflammatory biomarkers. Anemia in CKD is associated with an advanced degree of inflammation while undergoing chronic hemodialysis. Garlic (Allium sativum) has anti-inflammatory and antioxidant effects, which are expected to improve the degree of inflammation in CKD patients. This study aims to assess the effect of garlic extract on hemoglobin levels in patients undergoing chronic hemodialysis. This study was an experimental study with a double-blind, randomized clinical trial design. This study was a crossover, randomized, placebo-controlled, double-blind trial. The study subjects were 40 stages 5 CKD patients undergoing chronic hemodialysis, randomly divided into two groups, namely the group that received 1000 mg of garlic extract per day (2x500 mg) for six weeks and the group that received a placebo, then a 2-week wash-out period. And after that, the two groups were given alternate treatment. Statistical analysis was carried out using the SPSS version 25.0 program. A total of 40 subjects participated in the study, 57.5% male. The mean age of the subjects was 48.6 (26-59) years. The results showed that there was a significant difference in Hb levels in the garlic group (p = 0.047), where the increase in Hb was from 10.2 (9.2–11.8) mg/dl to 10.23 (8.9–11.6) mg/dl while in the placebo group, there was a decrease in Hb from 10.18 (9.6 – 11.2) mg/dl to 10.05 ± 0.52 mg/dl. Garlic extract can reduce levels of inflammation which can then increase hemoglobin levels.

Comparison of Oxytocin 10 IU Intravena Dilution of 10 ml Nacl 0.9% Bolus for 15 Seconds and 60 Seconds to Hemodynamics in Sectio Caesaria Patients with Spinal Anesthesia

Introduction: Caesarean section (SC) is defined as the birth of a baby through an incision in the abdomen (laparotomy) and uterus (hysterotomy). Spinal anesthesia is the choice for elective SC because it is considered effective and efficient considering its simple technique and ability to provide adequate surgical anesthesia, easy administration, faster onset, and safety. Spinal anesthesia also provides early skin to skin contact which increases maternal satisfaction although the hypotension risk is higher compared to epidural anesthesia which is countered by sympathomimetic vasopressors administration. The aim to research was to compare the administration of 10 IU oxytocin diluted in 10 cc of 0.9% NaCl for 15 seconds with 60 seconds on hemodynamics in sectio caesarean patients under spinal anesthesia. Method: This study used an RCT (Randomized Clinical Trial) design with double blind, meaning that neither the research subjects nor the observers were aware of the treatment or intervention given. The study sample was patients who underwent Sectio Caesaria at Haji Adam Malik General Hospital Medan, and the Universitas Sumatera Utara Hospital which fulfilled the inclusion and exclusion criteria. Results: It was found that there was not a significant difference in MAP values between the 15-second and 60-second bolus groups with p-values for the 1st, 3rd, 5th, and 10th minutes respectively 0.804, 0.692, 0.568 , 0.216, 0.754, and 0.390. In addition, it is known that there was a significant difference in pulse values between the 15-second and 60-second bolus groups at 1, 3, 5, 10 and 15 minutes, with the results of the p-value before, 1, 3, 5, 10, and 15 minutes are 0.509, 0.464, 0.805, 0.055, 0.475 and 0.857 respectively. In this study, no side effects were found in either group between 15 second and 60 second boluses. Conclusion: There were no significant hemodynamic changes in both test groups (15 second and 60 second boluses), at 1, 3, 5, 10 and 15 minutes.

A Phase 3 Efficacy and Safety Study of Ravulizumab in Adult Patients With Neuromyelitis Optica Spectrum Disorder: Study Design and Methodology

Objective To present the design and rationale for the phase 3 trial ALXN-1210-NMO-307 (NCT04201262). Background Eculizumab is a complement component 5 (C5) inhibitor approved for adults with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab, which binds the same C5 epitope, has a longer half-life with an extended dosing interval (every 8 vs every 2 weeks). We designed an innovative trial without concurrent placebo exposure to assess the efficacy and safety of ravulizumab in adults with AQP4+ NMOSD. Design/Methods NA. Results ALXN1210-NMO-307 is an open-label, multicenter, single-arm study using the placebo group from the PREVENT trial as a comparator. Constancy with PREVENT is maintained, including similar patient populations, adjudication procedures, and endpoints. Sensitivity analyses are prespecified to account for differences in patient characteristics. To measure confounding, an E-value is calculated for the primary endpoint (time-to-first adjudicated on-trial relapse). Given the serious impact of NMOSD attacks, eculizumab approval precluded the use of a concurrent comparator for ethical reasons, as it would require assigning patients to placebo when effective treatments exist. A non-inferiority efficacy trial was also considered but recruiting the very large sample size to adequately power the study was not feasible for this ultra-rare disease. Thus, a standard randomized clinical trial design was used. The trial enrolled 58 adults with EDSS score = 7 to receive an infusion of ravulizumab every 8 weeks after the loading dose. The primary treatment period will end when the last enrolled patient reaches week 50 unless a predefined number of patients have an adjudicated on-trial relapse by that time. The entire treatment period will last up to ∼4.5 years. Conclusions ALXN1210-NMO-307 is an ongoing study evaluating the efficacy and safety of ravulizumab in patients with AQP4+ NMOSD. It is designed to be consistent with PREVENT, and robust statistical methods will address the potential impact of an external comparator.

Comparison of Pre-Loading Fluid With Norepinephrine Toward Mean Arterial Pressure (MAP) In Sepsis Patients In Intensive Care Unit (ICU) of Haji Adam Malik General Hospital, Medan

Introduction: Sepsis is a life-threatening organ dysfunction caused by dysregulation of the host response to infection. Sepsis and septic shock are major health problems, affecting millions of people worldwide each year and killing one in six people affected. Early identification and appropriate management in the early hours after the development of sepsis improves the patient's prognosis. Surviving Sepsis Campaign (SSC) 2021 recommends a fluid dose of 30mL/kgBW, but there are many studies stating that there is no difference in patient outcomes when we resuscitate patients with 10 or 20 mL/kgBW fluids. Norepinephrine is considered as the safest and most potent vasopressor agents than others.
 Methods: This study used a double-blind randomized clinical trial (RCT) design to assess MAP in sepsis patients in intensive care unit (ICU) of Haji Adam Malik General Hospital ,Medan.
 Results: There were more male (56.5%), than female (43.5%). In our study, administration of 10mL/kg and 20mL/kg fluid bolus with vasopressor resulted in increased MAP, and the differences were statistically significant (p < 0.05). Administration of 10 mL/kg fluid gave higher MAP values than the other groups, could be a consideration in choosing fluid in order to avoid fluid overload.
 Conclusion: There is a significant comparison in the ratio of norepinephrine pre-loading fluid toward MAP in sepsis patients. Comparison of the mean MAP value at 15, 20, 25 minutes was the highest in the 10 mL/KgBW group. Meanwhile, the lowest MAP was found in 30mL/KgBW the group.

'What price do you put on your health?': Medical cannabis, financial toxicityand patient perspectives on medication access in advanced cancer.

Following 2016 legislation permitting limited access to cannabis for research and medicinal purposes, the number of randomized clinical trials (RCTs) investigating the effectiveness of medicinal cannabis (MC) on symptom burden relief in cancer contexts has increased in Australia. This study aimed to understand the perceptions, hopes and concerns of people with advanced cancer regarding the future availability and regulation of MC in Australia. This qualitative study draws on semistructured interviews conducted between February 2019 and October 2020 in Brisbane, Australia, as part of an MC RCT substudy. Interviews were undertaken on48 patients with advanced cancer in palliative care eligible to participate in an MC trial (n = 26 participated in an RCT; n = 2 participated in a pilot study; n = 20 declined). Interviews included a discussion of patients' decision-making regarding trial participation, concerns about MC and perceptions of future availability, including cost. Transcribed interviews were analysed inductively and abductively, informed by constructivist thematic analysis conventions. Overall, participants supported making MC legally accessible as a prescription-only medication. Fear of financial toxicity, however, compromised this pathway. Steep posttrial costs of accessing MC prompted several people to decline trial participation, and others to predict-if found effective-that many would either access MC through alternative pathways or reduce their prescribed dosage to enable affordable access. These findings suggest that-despite a relatively robust universal healthcare system-Australians are potentially vulnerable to and fearful of financial toxicity. Prevalent in the United States, financial toxicity occurs when disadvantaged cancer patients access necessary but expensive medications with lasting consequences: bankruptcy, ongoing anxietyand cancer worry. Interview transcripts indicate that financial fears-and the systems sustaining them-may pose a threat to RCT completion and to equitable access to legal MC. Such findings support calls for embedding qualitative substudies and community partnerships within RCTs, while also suggesting the importance of subsidisation to overcoming injustices. A patient advisory committee informed RCT design. This qualitative substudy foregrounds patients' decision-making, perceptions and experiences.

More is exponentially less: marginal utility in critical care research

BACKGROUND: Randomized clinical trials (RCT) in critical care mostly return negative results. The research community discusses strategies to improve RCTs design. METHODS: This paper presents a theoretical framework based on marginal utility to treat the problems of hypothesis generation and treatment effects valuation and presents recently published high-quality studies as instances where such a framework predicts irrelevant findings. RESULTS: Blindness to marginal utility, i.e., inobservance of the marginal utility of the proposed intervention, is common in critical care RCTs. CONCLUSION: Critical care RCTs are usually blind to marginal utility and are, therefore, prone to produce irrelevant findings.

Randomized Clinical Trials of Machine Learning Interventions in Health Care

Despite the potential of machine learning to improve multiple aspects of patient care, barriers to clinical adoption remain. Randomized clinical trials (RCTs) are often a prerequisite to large-scale clinical adoption of an intervention, and important questions remain regarding how machine learning interventions are being incorporated into clinical trials in health care. To systematically examine the design, reporting standards, risk of bias, and inclusivity of RCTs for medical machine learning interventions. In this systematic review, the Cochrane Library, Google Scholar, Ovid Embase, Ovid MEDLINE, PubMed, Scopus, and Web of Science Core Collection online databases were searched and citation chasing was done to find relevant articles published from the inception of each database to October 15, 2021. Search terms for machine learning, clinical decision-making, and RCTs were used. Exclusion criteria included implementation of a non-RCT design, absence of original data, and evaluation of nonclinical interventions. Data were extracted from published articles. Trial characteristics, including primary intervention, demographics, adherence to the CONSORT-AI reporting guideline, and Cochrane risk of bias were analyzed. Literature search yielded 19 737 articles, of which 41 RCTs involved a median of 294 participants (range, 17-2488 participants). A total of 16 RCTS (39%) were published in 2021, 21 (51%) were conducted at single sites, and 15 (37%) involved endoscopy. No trials adhered to all CONSORT-AI standards. Common reasons for nonadherence were not assessing poor-quality or unavailable input data (38 trials [93%]), not analyzing performance errors (38 [93%]), and not including a statement regarding code or algorithm availability (37 [90%]). Overall risk of bias was high in 7 trials (17%). Of 11 trials (27%) that reported race and ethnicity data, the median proportion of participants from underrepresented minority groups was 21% (range, 0%-51%). This systematic review found that despite the large number of medical machine learning-based algorithms in development, few RCTs for these technologies have been conducted. Among published RCTs, there was high variability in adherence to reporting standards and risk of bias and a lack of participants from underrepresented minority groups. These findings merit attention and should be considered in future RCT design and reporting.

Using real-world data for supporting regulatory decision making: Comparison of cardiovascular and safety outcomes of an empagliflozin randomized clinical trial versus real-world data

Aims: In countries where a randomized clinical trial (RCT) is difficult to perform, a real-world evidence (RWE) study with a design similar to an RCT may be an option for drug regulatory decision-making. In this study, the objective was to find out to what extent the safety of empagliflozin from the RWE study in Korea is different from the one in RCT by emulating the design of foreign RCT. The outcome covers various safety outcomes including cardiovascular safety. Methods: The EMPA-REG OUTCOME trial (NCT01131676) was selected for comparison. The inclusion/exclusion criteria and follow-up method for the RWE were matched to the comparison RCT. Major adverse cardiovascular events (MACEs) were used as a primary outcome and 15 other outcomes were also included for analysis. Result: We followed 23,126 matched patients with type 2 diabetes mellitus (11,563 empagliflozin users and 11,563 sitagliptin users) for 2.7 years (median). Empagliflozin use was associated with a significantly decreased risk of MACEs [EMPA-REG DUPLICATE RWE: adjusted HR 0.87, 95% confidence interval (CI) 0.79–0.96]. The predefined estimate agreement, regulatory agreement, and standardized difference for RCT duplication were achieved [EMPA-REG OUTCOME RCT: adjusted HR 0.86, 95% (CI) 0.74–0.99]. According to the predefined criteria for 15 outcomes, 10 outcomes were evaluated as good, and three as moderate. Conclusion: Our study results suggest that RWE in one country in comparison with an RCT has the potential for providing evidence for future regulatory decision-making in an environment where RCT could not be performed.

First STEPS: Primary Outcomes of a Randomized, Stepped-Care Behavioral Clinical Trial for Parents of Young Children With New-Onset Type 1 Diabetes.

Despite the emotional challenges of parental adjustment to a child's type 1 diabetes diagnosis and the unique complexities of early childhood, there are few programs designed to meet the needs of parents of young children at new onset. This study evaluated First STEPS (Study of Type 1 in Early childhood and Parenting Support), a stepped-care behavioral intervention designed to support parents' psychosocial functioning and promote children's glycemic outcomes. Using a two-site randomized clinical trial design, parents (n = 157) of children aged 1-6 years completed baseline data within 2 months of diabetes diagnosis and were randomly assigned to intervention (n = 115) or usual care (n = 42) for 9 months. Intervention steps included: 1) peer parent coaching, with step-ups to 2) structured behavioral counseling and 3) professional consultations with a diabetes educator and psychologist, based on parent mood and child HbA1c. Participants completed follow-ups at 9 and 15 months postrandomization. Primary outcomes were parent depressive symptoms and child HbA1c. Depressive symptoms improved in both groups, and intervention parents had significantly lower depressive symptoms at the 9- and 15-month follow-ups compared with usual care. HbA1c decreased in both groups, but there were no between-group differences at 9 or 15 months. First STEPS improved parents' mood following young children's type 1 diabetes diagnosis. Results indicate likely benefits of parent coach support, supplemented by intervention intensifications, including behavioral intervention and diabetes education. This model has high potential for patient engagement. The absence of a medical intervention component may explain null findings for HbA1c; incorporating targeted behavioral support for intensive diabetes treatment may maximize intervention impact.

Rationale and study design of a double-blinded prospective randomized clinical trial comparing euploidy rates among embryos created from sibling oocytes injected with sperm processed by microfluidics or by density gradient centrifugation

BackgroundDuring the in vitro fertilization (IVF) process, sperm must be processed prior to insemination. While the most common method, density gradient centrifugation, can potentially damage sperm during centrifugation, a recent advancement in sperm processing uses a microfluidics system which selects for the most highly motile sperm. In selecting for these sperm which may be of higher quality, the euploidy rates of embryos created as a result may also be improved. The primary aim of this study is to compare the euploidy rates per mature oocyte between embryos created from sibling oocytes injected with sperm processed by microfluidics sorting or by density gradient centrifugation. MethodsThis is a double-blinded prospective randomized sibling oocyte study including patients undergoing treatment with IVF with intracytoplasmic sperm injection (ICSI) and preimplantation genetic testing (PGT). After controlled ovarian hyperstimulation, oocytes from each patient will be separated into two groups. Each group will be randomized to sperm processed using either microfluidics or density gradient centrifugation and embryos biopsied for PGT to assess euploidy rates. A sample size of 686 oocytes in each group for a total of 1372 oocytes will provide 80% power to detect a significant difference in the euploidy rates per mature oocyte between the two groups. An ancillary study examining the relationship between sperm processing method and sperm DNA fragmentation will be assessed. ConclusionThis study will offer insight into the sperm's contribution to embryo euploidy, and has the potential to provide an alternative method of improving euploidy rates in clinical practice.

A Group Videoconferencing Intervention (C@nnected) to Improve Maternal Sensitivity: Protocol for a Randomized Feasibility Trial.

BackgroundEarly childhood development is highly dependent on the sensitive care provided by caregivers, and interventions focused on supporting parents to improve their sensitivity have shown to be effective. The COVID-19 pandemic has had a significant impact on mental health, with pregnant women and mothers of infants being an especially vulnerable group and maternal sensitivity particularly affected. However, access to face-to-face interventions is restricted; thus, it is important to have remote interventions to support this group of mothers.ObjectiveThe objective of this study is to evaluate the feasibility and acceptability of C@nnected, a group videoconferencing intervention to improve maternal sensitivity aimed at mother-infant dyads attending primary health care centers in vulnerable areas of Santiago, Chile.MethodsThis is a randomized feasibility single-masked (outcome assessor) study with a qualitative component. It will involve a block randomization procedure to generate a 3:2 allocation ratio (with more people allocated to the intervention arm). The intervention consists of 4 group videoconferencing sessions adapted from a face-to-face intervention with proven effectiveness. The control group will receive treatment as usual, along with educational brochures. The feasibility and acceptability of this study will be quantitatively and qualitatively assessed. Changes in clinical outcomes relating to maternal sensitivity, depressive symptoms, postpartum maternal attachment, and infant socioemotional development will also be evaluated.ResultsWe finished adapting the face-to-face intervention to the videoconferencing format in July 2021. The study began recruitment in August 2021, and enrollment is expected to end in August 2022, with final study results expected in December 2022.ConclusionsThis study will contribute evidence for the use of eHealth interventions to promote maternal sensitivity. It will also inform the design and implementation of a future randomized clinical trial.Trial RegistrationClinicalTrials.gov NCT04904861; https://clinicaltrials.gov/ct2/show/NCT04904861International Registered Report Identifier (IRRID)DERR1-10.2196/35881

A qualitative analysis of physician decision making in the use of extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest

Aim of StudyTo prepare for the design of future randomized clinical trials of extracorporeal cardioupulmonary resuscitation (ECPR), we sought to understand physician beliefs regarding the use of ECPR and subsequent management, among physicians who already perform ECPR, as these physicians would be likely to be involved in many planned ECPR trials. MethodsWe performed 12 semi-structured interviews of physicians who already perform ECPR across a variety of medical specialties, centers and geographic regions, but all with 10–50+ cases of ECPR experience. We qualitatively analyzed these interview to identify key characteristics of their experience using ECPR, the tensions involved in patient identification, the complications of subsequent management, and their willingness to enroll potential ECPR patients in randomized trials of ECPR. ResultsPhysicians who routinely perform ECPR have strong beliefs regarding the use of ECPR, and typically have protocols they follow, though they are willing to break these protocols to cannulate young or healthy patients, or patients with immediate pre-hospital CPR and shockable rhythms. We found that physicians lacked equipoise to randomize these types of patients to continued conventional CPR. Future RCTs might be successful in enrolling older patients, younger patients without immediate pre-hospital care/bystander CPR, or patients with obvious comorbidities. ConclusionsRCTs for ECPR will need to avoid targeting patients in whom physicians feel strongly compelled to do ECPR or not do ECPR, instead identifying the middle range of patients in whom the physicians consider ECPR reasonable, but not required or contraindicated.