Randomized Clinical Trial Design Research Articles

A nurse-led coaching intervention with home telemonitoring for patients with heart failure: Protocol for a feasibility randomized clinical trial

Poor treatment adherence and lack of self-care behaviors are significant contributors to hospital readmissions of people with heart failure (HF). A transitional program with non-invasive telemonitoring may help sustain patients and their caregivers to timely recognize signs and symptoms of exacerbation.We will conduct a Randomized Clinical Trial (RCT) to evaluate the feasibility and acceptability of a 6-month supportive intervention for patients discharged home after cardiac decompensation. Forty-five people aged 65 years and over will be randomized to either receive a supportive intervention in addition to standard care, which combines nurse-led telephone coaching and a home-based self-monitoring vital signs program, or standard care alone. Four aspects of the feasibility will be assessed using a mixed-methods approach: process outcomes (e.g., recruitment rate), resources required (e.g., adherence to the intervention), management data (e.g., completeness of data collection), and scientific value (e.g. 90- and 180-day all-cause and HF-related readmissions, self-care capacity, quality of life, psychological well-being, mortality, etc.). Participants will be interviewed to explore preferences and satisfaction with the intervention. The study is expected to provide valuable insight into the design of a definitive RCT.

Challenging the Concept of Statistical Fragility: Is There Any Value Added?

Today, well-designed randomized clinical trials (RCTs) are considered the pinnacle of clinical research, and they inform many practices in orthopaedics. When designing these studies, researchers conduct a power analysis, which allows researchers to strike a balance between (1) enrolling enough patients to detect a clinically important treatment effect (i.e., researchers can be confident that the effect is unlikely due to chance) and (2) cost, time, and risk to patients, which come with enrolling an excessive number of patients. Because researchers will have a desire to conduct resource-efficient RCTs and protect patients from harm, many studies report a p value that is close to the threshold for significance. The concept of the fragility index (FI) was introduced as a simple way to interpret RCT findings, but it does not account for RCT design. The adoption of the FI conflicts with researchers' goals of designing efficient RCTs that conserve resources and limit ineffective or harmful treatments to patients. The use of the FI may reflect many clinicians' lack of familiarity with interpreting p values beyond "significant" or "nonsignificant." Instead of inventing new metrics to convey the same information provided by the p value, greater emphasis should be placed on educating clinicians on how to interpret p values and, more broadly, statistics, when reading scientific studies.

The Effects of a Cool Saline Solution Irrigation on Mandibular Third Molar Extraction Site: A Postoperative Split-Mouth Evaluation.

This study aimed to evaluate the effects of sterile saline solution irrigation (lavage) performed after mandibular third molar extraction on postoperative complications, utilizing a split-mouth randomized clinical trial design. Seventeen healthy participants requiring bilateral mandibular third molar extraction were enrolled in this single-center study. In each participant, one impacted third molar was designated as the experimental group and subjected to saline lavage at 4 °C. In contrast, the control group was the other impacted third molar, undergoing saline lavage at 25 °C. Various parameters, including postoperative pain, mouth opening, and facial swelling, were assessed using standardized measures and three-dimensional facial scanning at multiple time points. The average age of participants was 26.66 ± 4.1 years, with no postoperative complications observed in either group. The duration of surgery did not significantly differ between groups. Postoperative pain was significantly reduced in the experimental group during the immediate postoperative period compared with the control group, but this difference diminished over time. No significant differences were observed in mouth opening or facial swelling between groups at any time. In site 4 °C, sterile saline solution irrigation after mandibular third molar extraction may effectively reduce early postoperative complications, particularly pain, without prolonging surgical duration.

Impact of prenatal maternal depression on gestational length: post hoc analysis of a randomized clinical trial

Shortened gestation is a leading cause of childhood morbidity and mortality with lifelong consequences for health. There is a need for public health initiatives on increasing gestational age at birth. Prenatal maternal depression is a pervasive health problem robustly linked via correlational and epidemiological studies to shortened gestational length. This proof-of-concept study tests the impact of reducing prenatal maternal depression on gestational length with analysis of a randomized clinical trial (RCT). Participants included 226 pregnant individuals enrolled into an RCT and assigned to receive either interpersonal psychotherapy (IPT) or enhanced usual care (EUC). Recruitment began in July 2017 and participants were enrolled August 10, 2017 to September, 8 2021. Depression diagnosis (Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; DSM 5) and symptoms (Edinburgh Postnatal Depression Scale and Symptom Checklist) were evaluated at baseline and longitudinally throughout gestation to characterize depression trajectories. Gestational dating was collected based on current guidelines via medical records. The primary outcome was gestational age at birth measured dichotomously (≥39 gestational weeks) and the secondary outcome was gestational age at birth measured continuously. Posthoc analyses were performed to test the effect of reducing prenatal maternal depression on gestational length. This trial is registered with ClinicalTrials.gov (NCT03011801). Steeper decreases in depression trajectories across gestation predicted later gestational age at birth, specifically an increase in the number of full-term babies born ≥39 gestational weeks (EPDS linear slopes: OR=1.54, 95% CI 1.10-2.16; and SCL-20 linear slopes: OR=1.67, 95% CI 1.16-2.42). Causal mediation analyses supported the hypothesis that participants assigned to IPT experienced greater reductions in depression symptom trajectories, which in turn, contributed to longer gestation. Supporting mediation, the natural indirect effect (NIE) showed that reduced depression trajectories resulting from intervention were associated with birth ≥39 gestational weeks (EPDS, OR=1.65, 95% CI 1.02-2.66; SCL-20, OR=1.85, 95% CI 1.16-2.97). We used a RCT design and found that reducing maternal depression across pregnancy was associated with lengthened gestation. This research was supported by the NIH (R01 HL155744, R01 MH109662, R21 MH124026, P50 MH096889).

The Mexican dataset of a repetitive transcranial magnetic stimulation clinical trial on cocaine use disorder patients: SUDMEX TMS

Cocaine use disorder (CUD) is a global health problem with severe consequences, leading to behavioral, cognitive, and neurobiological disturbances. While consensus on treatments is still ongoing, repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising approach for medication-resistant disorders, including substance use disorders. In this context, here we present the SUDMEX-TMS, a Mexican dataset from an rTMS clinical trial involving CUD patients. This longitudinal dataset comprises 54 CUD patients (including 8 females) with data collected at five time points: baseline (T0), two weeks (T1), three months (T2), six months (T3) follow-up, and twelve months (T4) follow-up. The clinical rTMS treatment followed a double-blinded randomized clinical trial design (n = 24 sham/30 active) for 2 weeks, followed by an open-label phase. The dataset includes demographic, clinical, and cognitive measures, as well as magnetic resonance imaging (MRI) data collected at all time points, encompassing structural (T1-weighted), functional (resting-state fMRI), and multishell diffusion-weighted (DWI-HARDI) sequences. This dataset offers the opportunity to investigate the impact of rTMS on CUD participants, considering clinical, cognitive, and multimodal MRI metrics in a longitudinal framework.

Patterns of Care in the Diagnosis and Management of Intracranial Atherosclerosis‐Related Large‐Vessel Occlusion: The Rescue‐LVO Survey

Background We aimed to determine the current practice patterns among neurointerventional practitioners frequently involved in treating intracranial atherosclerosis‐related large‐vessel occlusion (ICAS‐LVO) during mechanical thrombectomy. Methods We conducted an international online survey of neurointerventionalist members of the Society of Vascular and Interventional Neurology and Society of Neurointerventional Surgery. The 28‐question poll evaluated the preferences on diagnosis, treatment, and endovascular approach to ICAS‐LVO. Results A total of 184 individual survey responses were obtained from practicing neurointerventional physicians. Overall, 38.3% reported an incidence of 6% to 10% of ICAS‐LVO during mechanical thrombectomy. Most neurointerventionalists (91%) diagnose ICAS‐LVO after a continued or recurrent occlusion or by the presence of fixed focal stenosis after multiple mechanical thrombectomy attempts. Most respondents (86%) preferred acute treatment of ICAS‐LVO with rescue stenting (RS)±angioplasty. However, in patients who achieved recanalization with a severe fixed focal stenosis, most (58%) recommended primary medical management. The preferred medication during acute RS was intravenous antiplatelet therapy (65%), and after acute RS, it was dual oral antiplatelet therapy (65%). Fear of hemorrhagic complications (74%) was the most compelling reason not to perform RS±angioplasty. Of respondents, 24% were hesitant to randomize patients to acute RS versus medical therapy in a future randomized trial because of the lack of sensitive and specific biomarkers to diagnose ICAS‐LVO before mechanical thrombectomy treatment. Conclusions The findings of this survey highlight the variations in practice in the medical and endovascular management of ICAS‐LVO. In addition, it informs the situation of equipoise in the treatment decision in ICAS‐LVO, which can then be incorporated into the design of future randomized clinical trials.

Placebo-controlled randomized clinical trials of antidepressants for major depressive disorder: Analysis of ClinicalTrials.gov, 2008–2022

The purpose of this study was to analyze the key aspects of the design of contemporary placebo-controlled randomized clinical trials (RCTs) of antidepressants enrolling patients with major depressive disorder (MDD) aged 18 years or older, especially the outcome measures and the eligibility criteria. The study included 122 RCTs registered with ClinicalTrials.gov and started from 2008 through 2022. Most RCTs assessed only clinical remission, with proportion of trials with outcome measures related to functional remission being rather low (n = 34; 28 %). Clinical remission was mostly evaluated in acute phase of depression, and only 7 (6 %) trials assessed the prevention of relapse. Proportion of trials utilizing self-report questionnaires that provide important information complementary to clinician-rated scales was moderate (n = 66; 54 %). Another problem in included RCTs was common use of stringent eligibility criteria. For instance, minimal symtpom severity required for the patient's inclusion was listed in 104 RCTs (85 %), and 41 RCTs (34 %) excluded patients based on comorbid anxiety disorders. Most RCTs (n = 103; 84 %) excluded older patients, and only 6 (5 %) trials were dedicated exclusively to them. To ensure optimal development of clinical pharmacotherapy of MDD, the investigators should consider modification of some of the key aspects of the design of RCTs of antidepressants.

Prophylactic pectoralis major flap to compensate for increased risk of pharyngocutaneous fistula in laryngectomy patients with low skeletal muscle mass (PECTORALIS): study protocol for a randomized controlled trial

BackgroundTotal laryngectomy (TL) is a surgical procedure commonly performed on patients with advanced laryngeal or hypopharyngeal carcinoma. One of the most common postoperative complications following TL is the development of a pharyngocutaneous fistula (PCF), characterized by a communication between the neopharynx and the skin. PCF can lead to extended hospital stays, delayed oral feeding, and compromised quality of life. The use of a myofascial pectoralis major flap (PMMF) as an onlay technique during pharyngeal closure has shown potential in reducing PCF rates in high risk patients for development of PCF such as patients undergoing TL after chemoradiation and low skeletal muscle mass (SMM). Its impact on various functional outcomes, such as shoulder and neck function, swallowing function, and voice quality, remains less explored. This study aims to investigate the effectiveness of PMMF in reducing PCF rates in patients with low SMM and its potential consequences on patient well-being.MethodsThis multicenter study adopts a randomized clinical trial (RCT) design and is funded by the Dutch Cancer Society. Eligible patients for TL, aged ≥ 18 years, mentally competent, and proficient in Dutch, will be enrolled. One hundred and twenty eight patients with low SMM will be centrally randomized to receive TL with or without PMMF, while those without low SMM will undergo standard TL. Primary outcome measurement involves assessing PCF rates within 30 days post-TL. Secondary objectives include evaluating quality of life, shoulder and neck function, swallowing function, and voice quality using standardized questionnaires and functional tests. Data will be collected through electronic patient records.DiscussionThis study’s significance lies in its exploration of the potential benefits of using PMMF as an onlay technique during pharyngeal closure to reduce PCF rates in TL patients with low SMM. By assessing various functional outcomes, the study aims to provide a comprehensive understanding of the impact of PMMF deployment. The anticipated results will contribute valuable insights into optimizing surgical techniques to enhance patient outcomes and inform future treatment strategies for TL patients.Trial registrationNL8605, registered on 11-05-2020; International Clinical Trials Registry Platform (ICTRP).

Endovascular Ablation of the Right Greater Splanchnic Nerve in Heart Failure With Preserved Ejection Fraction: Rationale, Design and Lead-in Phase Results of the REBALANCE-HF Trial

IntroductionSplanchnic vasoconstriction augments transfer of blood volume from the abdomen into the thorax, which may increase filling pressures and hemodynamic congestion in patients with noncompliant hearts. Therapeutic interruption of splanchnic nerve activity holds promise to reduce hemodynamic congestion in patients with heart failure with preserved ejection fraction (HFpEF). Here we describe (1) the rationale and design of the first sham-controlled randomized clinical trial (RCT) of splanchnic nerve ablation for HFpEF; and (2) the 12-month results of the lead-in (open-label) trial participants. MethodsREBALANCE-HF is a prospective, multicenter, randomized, double-blinded, sham-controlled clinical trial of endovascular, transcatheter right-sided greater splanchnic nerve ablation for volume management (SAVM) in patients with HFpEF. The primary objectives are to evaluate the safety and efficacy of SAVM and identify responder characteristics to inform future studies. The trial consists of an open-label lead-in phase followed by the randomized, sham-controlled phase. The primary efficacy endpoint is the reduction in pulmonary capillary wedge pressure (PCWP) at 1-month follow-up compared to baseline during passive leg raise and 20W exercise. Secondary and exploratory endpoints include health status (Kansas City Cardiomyopathy Questionnaire), 6-minute walk test distance, New York Heart Association, and NTproBNP at 3, 6, and 12 months. The primary safety endpoint is device- or procedure-related serious adverse events at 1-month follow-up. ResultsThe lead-in phase of the study, which enrolled 26 HFpEF patients who underwent SAVM, demonstrated favorable safety outcomes and reduction in exercise PCWP at 1-month post-procedure; and improvements in all secondary endpoints at 6 and 12 months of follow-up. The randomized phase of the trial (n=44 SAVM, n=46 sham) has completed enrollment, and follow-up is ongoing. ConclusionREBALANCE-HF is the first sham-controlled RCT of greater splanchnic nerve ablation in HFpEF. Initial 12-month open-label results are promising, and the results of the randomized portion of the trial will inform the design of a future pivotal clinical trial. SAVM may offer a promising therapeutic option for patients with HFpEF. Trial RegistrationNCT04592445

Efficacy of Consolidation Therapy with Ponatinib 15mg on Treatment-Free Remission Rate in Patients with Chronic Myeloid Leukemia. Results of the Ponazero Trial

Introduction: Discontinuation of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has become part of routine clinical practice in recent years, thanks to growing evidence on their feasibility and safety. However, and despite adequate patient selection based on current recommendations, loss of response is observed in approximately 50% of patients. In this scenario, efforts are focused on finding strategies to increase the rate of successful discontinuations. Ponatinib has shown to induce deeper molecular responses compared with imatinib, but its risk of arterial occlusive events (AOE) limits its use in first line at its standard dose of 45mg. The risk of AOEs appears to be dose-related and following the results of the OPTIC study, dose reduction to 15mg in patients with good response is an increasingly popular strategy. Under these premises it has been postulated that a consolidation with ponatinib 15mg may increase the proportion of patients who could discontinue treatment successfully. Our aim is to evaluate the efficacy and safety of one year of consolidation therapy with ponatinib 15mg on treatment-free remission (TFR) rate in patients with CML who have achieved a deep molecular response with imatinib. Material and Methods: A multicenter open-label, single-arm, phase II, exploratory, prospective clinical trial (NCT 04043676) was conducted including patients with philadelphia-positive CML who met discontinuation criteria according to European LeukemiaNet recommendations, had received 4 years or more of imatinib therapy, with a documented grade 4 molecular response (MR4) at least 12 months prior to study entry. Uncontrolled arterial hypertension, active cardiovascular disease, or concomitant medication with potential for QTc prolongation were exclusion criteria. The study has two main phases: ponatinib consolidation (48 weeks), and ponatinib TFR phase (48 weeks); where patients remain without treatment. During the TFR phase, patients with a confirmed loss of MR4 or a single value above major molecular response (MMR) were scheduled to restart treatment with a TKI at investigator's discretion. The present abstract reports the results of the primary endpoint of the study; the proportion of patients with no loss of MR4 at the end of the TFR phase. Results: A total of 23 patients started treatment with ponatinib 15mg. One patient subsequently failed screening due to a major protocol deviation. Baseline patient characteristics were as follows: median age was 51.8 years (range 26-74), 65.2% were male. Ninety-five percent were Caucasian and 5% were Hispanic, ECOG was 0 in 83% and 1 in 17%, Sokal was low in 69.5%, intermediate in 17.5% and unknown in 13%. Eighteen patients were receiving imatinib 400mg daily (82%) at study entry, 2 patients 800mg and two 200mg. Median time on prior imatinib was 10 years (range 4-17), with a median time on MR4 of 3.6 years (range 1.9-13.3). Prior to initiation 13 patients (56.5%) had a grade 5 molecular response, 4 had a 4.5 molecular response (26%) and the remainder had a MR4. The adverse events (AEs) reported with ponatinib are summarized in Table 1, the most frequent being constipation (30%), asthenia (26%), myalgias and arthralgias (26% respectively) and skin rash (17%). A high rate of SARS-CoV2 infections was reported during the treatment period (26%), which should be interpreted considering that the study took place during the COVID-19 pandemic. Three patients out of 22 (13.6%) had serious AEs with ponatinib leading to treatment discontinuation; thrombophlebitis, erectile dysfunction, and intermittent claudication. Of the patients who entered the TFR phase, 14/19 (74%) continue with MMR without requiring treatment after a median follow-up of 12 months (68% with MR4) (table 1). Six patients (31%) lost MR4, five of them required reintroduction of an TKI (4 imatinib, 1 dasatinib; median time to reintroduction 5.4 months). All patients with MR4 loss were receiving the 400 mg dose of imatinib at study entry. All patients who restarted treatment recovered MMR. The sixth patient lost MR4 while maintaining an MMR without requiring treatment reinduction to date. Conclusions: Consolidation with 12 months of ponatinib 15mg in this study shows a high discontinuation success rate with an adequate safety profile, although not free of AEs. The results make this approach attractive for the design of further randomized clinical trials.

Group-based PFMT programme for preventing and/or treating UI in pregnant women: protocol of a randomized controlled feasibility study

BackgroundUrinary incontinence (UI) is a prevalent health problem in women worldwide. Many women experience UI during pregnancy. The National Institute for Health and Care Excellence (NICE) recommended pelvic floor muscle training (PFMT) as the first-line conservative treatment for UI. However, it is not widely implemented due to the limited number of healthcare trainers. Group-based PFMT has been used with older women and a limited number of maternity studies. But the effectiveness of the group-based PFMT needs to be investigated because the overall quality of the studies is low. Therefore, this study aims to assess the feasibility of delivering a group-based PFMT programme for pregnant women in Nanjing city.MethodsThis feasibility study will be conducted in Nanjing Maternity and Child Health Care Hospital in China, using a mixed methods design to investigate the feasibility and acceptability of delivering group-based PFMT to pregnant women. Pregnant women with or without the symptoms of UI will be included. This study aims to recruit 48 pregnant women with 24 in each arm. Participants will receive either the group-based PFMT delivered by a midwife or usual antenatal care which includes only verbal instruction on PFMT. The study will assess the completion rates, acceptability of outcome measures, recruitment and retention rate and calculate an appropriate sample size for a future study.DiscussionThe results of this study will inform the design and implementation of a definitive randomized clinical trial to explore the effectiveness of the intervention.Trial registrationClinicalTrials.gov, NCT05242809.

TROG 15.03/ANZUP International Multicenter Phase II Trial of Focal Ablative STereotactic RAdiotherapy for Cancers of the Kidney (FASTRACK II)

Stereotactic body radiotherapy (SBRT) is an emerging non-invasive alternative for primary renal cell cancer (RCC) in patients unsuitable for surgery. The objective of the FASTRACK II clinical trial was to investigate the efficacy of SBRT for primary RCC. This non-randomized, intergroup multi-institutional phase II study was activated in 7 Australian centers and 1 Dutch center, through the Trans Tasman Radiation Oncology Group (TROG) and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). Eligible patients had biopsy confirmed diagnosis of primary RCC with a single lesion within a kidney, ECOG performance ≤2 and were medically inoperable, high risk or declined surgery. For tumors ≤4 cm a single fraction of 26 Gy was prescribed, for tumors > 4 cm, 42 Gy in three fractions was prescribed. The primary outcome of the study was to estimate the efficacy of SBRT for primary RCC, defined as local control based on RECIST criteria. The study was powered assuming that 1-year local control would be 90%, with the null hypothesis of ≤80% considered undesirable and not worthy of proceeding to a future randomized controlled trial. Between July 2016 and February 2020, 70 patients were enrolled with a median follow-up of 42 months. Median age was 77 years. Forty-nine patients were male (70%), median BMI was 32 and median Charlson comorbidity score was 7. The median [IQR] RENAL complexity score was 8 [7-10]. Biopsy confirmation was 100%. Twenty-three patients (33%) had T1a disease. The median (interquartile range [IQR]) tumor size was 4.6cm [3.7-5.5]; it was 3.3cm [3.0-3.6] in those receiving single fraction (n = 23), and 5.3cm [4.6-6.0] in those receiving 3-fraction SBRT (n = 47). During real-time pre-treatment quality assurance review, 10 cases (14.3%) required resubmission for protocol deviation, 2119 variables were assessed at final review, and final protocol compliance was 99.3%. Seven (10%) patients experienced grade 3 treatment-related adverse events, with no grade 4 or 5 events observed. Eleven (16%) patients reported no adverse events. Local control was 100% throughout the lifetime of the trial (p<0.001). Cancer-specific survival was also 100% throughout the lifetime of the trial. Freedom from distant failure (95% CIs) at 1 and 3 years was 99% (90-100%). Overall survival (95% CIs) at 1 and 3 years was 99% (90-100%) and 82% (70-89%), respectively. Baseline mean eGFR (95% CI) was 61.1 mLs/min (56.6; 65.6) and reduced by -10.8 mLs/min (-13.0; -8.6) by 1-year, by -14.6 mLs/min (-17.0; -12.2) by 2-years and plateaued thereafter. In the first multicenter prospective trial of a non-surgical primary RCC cohort, enrolling mostly T1b+ disease, SBRT was an effective treatment strategy with no observed local failures. We observed an acceptable side effect profile and renal function after SBRT. These outcomes support the design of a future randomized clinical trial of SBRT versus surgery for primary RCC. The trial was registered with ID: NCT02613819.

The Effect of Giving Vitamin D Supplements on Improving Ejection Fraction in Heart Failure Patients at Dr. Mohammad Hoesin General Hospital, Palembang, Indonesia

Background: The role of vitamin D as an inflammation modulator, regulation system renin-angiotensin-aldosterone (RAAS), inhibits the production of parathyroid hormone (PTH), thereby causing left ventricular hypertrophy, causing hypocalcemia which induces hypertrophy in cardiac myocytes and can reduce cardiac contractility. This study aimed to determine the effect of giving vitamin D supplements on improving ejection fraction in heart failure patients at Dr. Mohammad Hoesin General Hospital (RSMH) Palembang, Indonesia.&#x0D; Methods: This study is an experimental study with a double-blind, randomized clinical trial design and uses primary data obtained from clinical examinations and supporting examinations of research subjects. A total of 40 research subjects participated in this study.&#x0D; Results: In this study, the median vitamin D level in the vitamin D supplementation group before treatment was 19.92 ng/dl (18.65-20.22), and in the placebo group was 19.74 ng/dl (18.14 - 20.13). After treatment with 1000 iu of vitamin D given for 3 months, the results showed that in the vitamin D supplementation group, there was an increase in vitamin D levels to 33.06 ng/dl (an increase of 13.14) with statistically significant results (p &lt; 0 .05). In the vitamin D supplementation group, there was an increase in ejection fraction to 37.9% (an increase of 3.65%) with statistically significant results (p&lt;0.05). Contrasting results were shown in the group that received a placebo, where there was a decrease in ejection fraction to 33.15% (2.25% decrease).&#x0D; Conclusion: There is an improving effect of giving vitamin D supplements on increasing ejection fraction in heart failure patients at Dr. Mohammad Hoesin General Hospital, Palembang, Indonesia.

A prospective randomized clinical trial to assess antibiotic pocket irrigation on tissue expander breast reconstruction.

Bacterial infection is the most common complication following staged post-mastectomy breast reconstruction initiated with a tissue expander (TE). To limit bacterial infection, antibiotic irrigation of the surgical site is commonly performed despite little high-quality data to support this practice. We performed a prospective randomized control trial to compare the impact of saline irrigation alone to a triple antibiotic irrigation regimen (1 g cefazolin, 80 mg gentamicin, and 50,000 units of bacitracin in 500 mL of saline) for breast implant surgery. The microbiome in breasts with cancer (n = 16) was compared to those without (n = 16), as all patients (n = 16) had unilateral cancers but bilateral mastectomies (n = 32). Biologic and prosthetic specimens procured both at the time of mastectomy and during TE removal months later were analyzed for longitudinal comparison. Outcomes included clinical infection, bacterial abundance, and relative microbiome composition. No patient in either group suffered a reconstructive failure or developed an infection. Triple antibiotic irrigation administered at the time of immediate TE reconstruction did not reduce bacterial abundance or impact microbial diversity relative to saline irrigation at the time of planned exchange. Implanted prosthetic material adopted the microbial composition of the surrounding host tissue. In cancer-naïve breasts, relative to saline, antibiotic irrigation increased bacterial abundance on periprosthetic capsules (P = 0.03) and acellular dermal matrices (P = 0.04) and altered the microbiota on both. These data show that, relative to saline only, the use of triple antibiotic irrigation in TE breast reconstruction does impact the bacterial abundance and diversity of certain biomaterials from cancer-naïve breasts. IMPORTANCE The lifetime risk of breast cancer is ~13% in women and is treated with a mastectomy in ~50% of cases. The majority are reconstructed, usually starting with a tissue expander to help restore the volume for a subsequent permanent breast implant or the women's own tissues. The biopsychosocial benefits of breast reconstruction, though, can be tempered by a high complication rate of at least 7% but over 30% in some women. Bacterial infection is the most common complication, and can lead to treatment delays, patient physical and emotional distress and escalating health care cost. To limit this risk, plastic surgeons have tried a variety of strategies to limit bacterial infection including irrigating the pocket created after removing the breast implant with antibiotic solutions, but good-quality data are scarce. Herein, we study the value of antibiotics in pocket irrigation using a robust randomized clinical trial design and molecular microbiology approaches.

Palliative care for persons with late-stage Alzheimer’s and related dementias and their caregivers: protocol for a randomized clinical trial

BackgroundLimited access to specialized palliative care exposes persons with late-stage Alzheimer’s disease and related dementias (ADRD) to burdensome treatment and unnecessary hospitalization and their caregivers to avoidable strain and financial burden. Addressing this unmet need, the purpose of this study was to conduct a randomized clinical trial (RCT) of the ADRD-Palliative Care (ADRD-PC) program.MethodsThe study will use a multisite, RCT design and will be set in five geographically diverse US hospitals. Lead investigators and outcome assessors will be masked. The study will use 1:1 randomization of patient-caregiver dyads, and sites will enroll N = 424 dyads of hospitalized patients with late-stage ADRD with their family caregivers. Intervention dyads will receive the ADRD-PC program of (1) dementia-specific palliative care, (2) standardized caregiver education, and (3) transitional care. Control dyads will receive publicly available educational material on dementia caregiving. Outcomes will be measured at 30 days (interim) and 60 days post-discharge. The primary outcome will be 60-day hospital transfers, defined as visits to an emergency department or hospitalization ascertained from health record reviews and caregiver interviews (aim 1). Secondary patient-centered outcomes, ascertained from 30- and 60-day health record reviews and caregiver telephone interviews, will be symptom treatment, symptom control, use of community palliative care or hospice, and new nursing home transitions (aim 2). Secondary caregiver-centered outcomes will be communication about prognosis and goals of care, shared decision-making about hospitalization and other treatments, and caregiver distress (aim 3). Analyses will use intention-to-treat, and pre-specified exploratory analyses will examine the effects of sex as a biologic variable and the GDS stage.DiscussionThe study results will determine the efficacy of an intervention that addresses the extraordinary public health impact of late-stage ADRD and suffering due to symptom distress, burdensome treatments, and caregiver strain. While many caregivers prioritize comfort in late-stage ADRD, shared decision-making is rare. Hospitalization creates an opportunity for dementia-specific palliative care, and the study findings will inform care redesign to advance comprehensive dementia-specific palliative care plus transitional care.Trial registrationClinicalTrials.gov NCT04948866. Registered on July 2, 2021.

Comparing Intravenous Labetalol and Intravenous Hydralazine for Managing Severe Gestational Hypertension.

Background Hypertensive disorders of pregnancy are the leading causes of both maternal morbidity and maternal mortality. Hypertensive disorders are acute obstetric emergencies, which refer to various life-threatening medical challenges known to develop during pregnancy, labor, and delivery,requiring urgent attention to reduce blood pressure (BP) for the benefit ofthe affected mothers and infants. Hydralazine and labetalol have been widely used as the first-line medications in themanagement of severe hypertension during pregnancy. However, the choice between these two drugs lacks clear evidence regarding their safety and superiority. Several studies have attempted to study intravenous (IV) labetalol versus hydralazine, but very fewsuch comparison studies havebeen conducted in Africa. Objective To compare the effectiveness of IV labetalol and IV hydralazine in reducing systolic and diastolic BP in pregnant women with severe hypertension. Also, to determine thetime required for hydralazine and labetalol to lower BP to ≤150/100 mmHg, the number of doses needed for each drug, and evaluating maternal and perinatal outcomes. Study design This study employed an open-label randomized clinical trial design conducted in the labor, delivery, and antenatal ward of the Central and Stella Obasanjo Hospital in Benin City. A total of 120 women with severe pregnancy-induced hypertension were randomly assigned to two groups: Group X, consisting of 60 pregnant women, received IV hydralazine at a slow rate of 5 mg for five minutes, repeated every 20 minutes (maximum of five doses) until a blood pressure of ≤150/100 mmHg was achieved. Group Y, also consisting of 60 pregnant women, received IV labetalol in escalating doses of 25, 50, 75, 75, and 75 mg (maximum of 300 mg) every 20 minutes until the blood pressure reached ≤150/100 mmHg. Statistical analysis was performed using SPSS version 23(IBMInc., Armonk, New York). Result IV hydralazine achieved the target BP in an average time of 45.80 +/- 25.17 minutes, while IV labetalol took an average of 72.67 +/- 41.80 minutes (p=0.001). The number of doses required to reach the target BP differed significantly between the two drugs. Hydralazine required an average of 1.72 +/- 0.904 doses, whereas labetalol required an average of 3.72 +/- 1.782 doses (p=0.0001). While 45% of women in the hydralazine group attained the target BP with a single dose of hydralazine, only 31.1% of women in the labetalol group were able to attain the target BP with asingle doseof labetalol(p=0.02). Overall, target BP was achieved in 55 out of 60 women (91.7%) who were randomized to receive IV hydralazine, whereas 45 out of 60 women (75%) who received IV labetalol achieved the target blood pressure. While hydralazine demonstrated more favorable results in terms of achieving target blood pressure, there were higher incidences of maternal adverse effects in the hydralazine group compared to the labetalol group. However, these adverse effects were not severe enough to warrant discontinuation of the medication. Conclusion IV hydralazine showed faster achievement of the target BP and a lower number of doses required compared to IV labetalol. Additionally, a higher percentage of women in the hydralazine group achieved the target BP with a single dose. However, there were more maternal adverse effects associated with hydralazine, although they were not severe. Perinatal outcomes did not differ significantly between the two groups.

Multicenter, dual fractionation scheme, single core lab comparison of rectal volume dose reduction following injection of two biodegradable perirectal spacers.

A multicenter, double-arm, central core lab, retrospective study was performed to compare the rectal dosimetry of patients implanted with two injectable, biodegradable perirectal spacers, in conventional fractionation (CF), as well as ultrahypofractionation (UH) treatment plans. Fifty-nine patients were enrolled into the study in five centers: two centers in Europe, which implanted a biodegradable balloon spacer in a total of 24 subjects and three centers in the US, which implanted the SpaceOAR in 35 subjects. Anonymized CTs (pre and post-implantation) were reviewed by the central core lab. For VMAT CF plans rectal V50, V60, V70, and V80 were calculated. For UH plans, a corresponding rectal V22.6, V27.1, V31.37, and V36.25 were established representing 62.5%, 75%, 87.5%, and 100% of the 36.25Gy prescribed dose. For CF VMAT, a comparison between the balloon spacer and the SpaceOAR revealed a significant difference of 33.4% decrease in mean rectal V50 (71.9%vs. 38.5%, p<0.001), 27.7% in mean rectal V60 (79.6%vs. 51.9%, p<0.001), 17.1% difference in mean rectal V70 (84.1%vs. 67.0%, p=0.001), and a significant difference of 3.0% (p=0.019) in mean rectal V80 (87.2%vs. 84.2%). With UH analysis, the mean rectal dose reduction for the balloon spacer compared to the SpaceOAR was 79.2% and 53.3% for V27.1 (p<0.001), 84.1% and 68.1% for V31.71 (p=0.001), and 89.7% and 84.8% for V36.25 (p=0.012), respectively. Rectal dosimetry is more favorable for treatment with the balloon spacer compared with SpaceOAR. Further research, particularly in the context of a prospective randomized clinical trial design, is needed to assess the acute and late toxicity experience as well as physician satisfaction with achieving symmetrical implantation, and ease of use in light of increasing clinical use.

Characteristics of Design and Analysis of Ophthalmic Randomized Controlled Trials: A Review of Ophthalmic Papers 2020-2021.

To evaluate the recent practice of design and statistical analysis of ophthalmic randomized clinical trials (RCTs). Review of 96 ophthalmic RCTs. Two authors (R.D., G.S.Y.) reviewed primary result papers published from January 2020 through December 2021 in Ophthalmology, JAMA Ophthalmology, American Journal of Ophthalmology, and British Journal of Ophthalmology. Data were extracted and analyzed for the characteristics of design (1-eye design, 2-eye design, paired-eye design, and subject design), sample size and power, and statistical analysis for intereye correlation adjustment, missing data, and correction for multiplicity. Characteristics of trial design and statistical analysis. Among 96 RCTs, 50 (52%) used 1-eye design, 21 (22%) 2-eye design, 10 (10%) paired-eye design, and 15 (16%) subject design. In 31 trials of 2-eye design or paired-eye design, 18 (58%) trials had suboptimal analysis of data from both eyes by analyzing data from 1 eye (n= 10), taking the average of 2 eyes (n= 2), analyzing 2 eyes separately (n= 1), ignoring intereye correlation (n= 3), or not specifying how 2-eye data were analyzed (n= 2), and 13 trials (42%) properly adjusted the intereye correlation by using the mixed-effects model (n= 6), paired t test (n= 5), generalized estimating equations (n= 1), or marginal Cox regression model (n= 1). Among 96 trials, 75 (78%) provided both sample size and statistical power estimation, and 16 (17%) trials described statistical test for sample size or power estimation. Missing data in primary outcome occurred in 86 (90%) trials with a median missing data rate of 8%, 32 (37%) trials applied statistical methods for missing data, including last value carried forward (n= 10), multiple imputation (n= 14), or other approaches (n= 8). Among 25 trials with > 2 arms, 16 (64%) corrected for multiplicity using the Bonferroni procedure (n= 8), Hochberg procedure (n= 2), Gatekeeping procedure (n= 2), or hierarchical procedure (n= 4). Among 16 trials with multiple primary outcomes, 4 (25%) corrected for multiplicity by the Bonferroni procedure. There are opportunities for improvement in the design and statistical analyses of ophthalmic trials, particularly in the aspects of adjustment for intereye correlation, missing data, and multiplicity. Continuing education in ophthalmology and vision research community may improve the quality of ophthalmic trials. Proprietary or commercial disclosure may be found after the references.

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.