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Nature Medicine Oct 2023Measurement of natriuresis has been suggested as a reliable, easily obtainable biomarker for assessment of the response to diuretic treatment in patients with acute... (Randomized Controlled Trial)
Randomized Controlled Trial
Measurement of natriuresis has been suggested as a reliable, easily obtainable biomarker for assessment of the response to diuretic treatment in patients with acute heart failure (AHF). Here, to assess whether natriuresis-guided diuretic therapy in patients with AHF improves natriuresis and clinical outcomes, we conducted the pragmatic, open-label Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure trial, in which 310 patients (45% female) with AHF requiring treatment with intravenous loop diuretics were randomly assigned to natriuresis-guided therapy or standard of care (SOC). In the natriuresis-guided arm, natriuresis was determined at set timepoints, prompting treatment intensification if spot urinary sodium levels were <70 mmol l. The dual primary endpoints were 24 h urinary sodium excretion and a combined endpoint of time to all-cause mortality or adjudicated heart failure rehospitalization at 180 days. The first primary endpoint was met, as natriuresis in the natriuresis-guided and SOC arms was 409 ± 178 mmol arm versus 345 ± 202 mmol, respectively (P = 0.0061). However, there were no significant differences between the two arms for the combined endpoint of time to all-cause mortality or first heart failure rehospitalization, which occurred in 46 (31%) and 50 (31%) of patients in the natriuresis-guided and SOC arms, respectively (hazard ratio 0.92 [95% confidence interval 0.62-1.38], P = 0.6980). These findings suggest that natriuresis-guided therapy could be a first step towards personalized treatment of AHF. ClinicalTrials.gov registration: NCT04606927 .
Topics: Female; Humans; Male; Acute Disease; Diuretics; Heart Failure; Natriuresis; Sodium; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 37640861
DOI: 10.1038/s41591-023-02532-z -
JAMA Oct 2023Universal nasal mupirocin plus chlorhexidine gluconate (CHG) bathing in intensive care units (ICUs) prevents methicillin-resistant Staphylococcus aureus (MRSA)... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Universal nasal mupirocin plus chlorhexidine gluconate (CHG) bathing in intensive care units (ICUs) prevents methicillin-resistant Staphylococcus aureus (MRSA) infections and all-cause bloodstream infections. Antibiotic resistance to mupirocin has raised questions about whether an antiseptic could be advantageous for ICU decolonization.
OBJECTIVE
To compare the effectiveness of iodophor vs mupirocin for universal ICU nasal decolonization in combination with CHG bathing.
DESIGN, SETTING, AND PARTICIPANTS
Two-group noninferiority, pragmatic, cluster-randomized trial conducted in US community hospitals, all of which used mupirocin-CHG for universal decolonization in ICUs at baseline. Adult ICU patients in 137 randomized hospitals during baseline (May 1, 2015-April 30, 2017) and intervention (November 1, 2017-April 30, 2019) were included.
INTERVENTION
Universal decolonization involving switching to iodophor-CHG (intervention) or continuing mupirocin-CHG (baseline).
MAIN OUTCOMES AND MEASURES
ICU-attributable S aureus clinical cultures (primary outcome), MRSA clinical cultures, and all-cause bloodstream infections were evaluated using proportional hazard models to assess differences from baseline to intervention periods between the strategies. Results were also compared with a 2009-2011 trial of mupirocin-CHG vs no decolonization in the same hospital network. The prespecified noninferiority margin for the primary outcome was 10%.
RESULTS
Among the 801 668 admissions in 233 ICUs, the participants' mean (SD) age was 63.4 (17.2) years, 46.3% were female, and the mean (SD) ICU length of stay was 4.8 (4.7) days. Hazard ratios (HRs) for S aureus clinical isolates in the intervention vs baseline periods were 1.17 for iodophor-CHG (raw rate: 5.0 vs 4.3/1000 ICU-attributable days) and 0.99 for mupirocin-CHG (raw rate: 4.1 vs 4.0/1000 ICU-attributable days) (HR difference in differences significantly lower by 18.4% [95% CI, 10.7%-26.6%] for mupirocin-CHG, P < .001). For MRSA clinical cultures, HRs were 1.13 for iodophor-CHG (raw rate: 2.3 vs 2.1/1000 ICU-attributable days) and 0.99 for mupirocin-CHG (raw rate: 2.0 vs 2.0/1000 ICU-attributable days) (HR difference in differences significantly lower by 14.1% [95% CI, 3.7%-25.5%] for mupirocin-CHG, P = .007). For all-pathogen bloodstream infections, HRs were 1.00 (2.7 vs 2.7/1000) for iodophor-CHG and 1.01 (2.6 vs 2.6/1000) for mupirocin-CHG (nonsignificant HR difference in differences, -0.9% [95% CI, -9.0% to 8.0%]; P = .84). Compared with the 2009-2011 trial, the 30-day relative reduction in hazards in the mupirocin-CHG group relative to no decolonization (2009-2011 trial) were as follows: S aureus clinical cultures (current trial: 48.1% [95% CI, 35.6%-60.1%]; 2009-2011 trial: 58.8% [95% CI, 47.5%-70.7%]) and bloodstream infection rates (current trial: 70.4% [95% CI, 62.9%-77.8%]; 2009-2011 trial: 60.1% [95% CI, 49.1%-70.7%]).
CONCLUSIONS AND RELEVANCE
Nasal iodophor antiseptic did not meet criteria to be considered noninferior to nasal mupirocin antibiotic for the outcome of S aureus clinical cultures in adult ICU patients in the context of daily CHG bathing. In addition, the results were consistent with nasal iodophor being inferior to nasal mupirocin.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03140423.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Administration, Intranasal; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Infective Agents, Local; Baths; Chlorhexidine; Cross Infection; Intensive Care Units; Iodophors; Methicillin-Resistant Staphylococcus aureus; Mupirocin; Pragmatic Clinical Trials as Topic; Sepsis; Staphylococcal Infections; Staphylococcus aureus; United States
PubMed: 37815567
DOI: 10.1001/jama.2023.17219 -
Journal of Medical Internet Research Jun 2023Urinary incontinence (UI) is a highly prevalent health concern commonly observed during and after pregnancy that can substantially impact women's physical and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Urinary incontinence (UI) is a highly prevalent health concern commonly observed during and after pregnancy that can substantially impact women's physical and psychological well-being and quality of life. Owing to its numerous advantages, mobile health may be a promising solution; however, it is unclear whether the app-based intervention can effectively improve UI symptoms during and after pregnancy.
OBJECTIVE
This study aimed to evaluate the effectiveness of the Urinary Incontinence for Women (UIW) app-based intervention for UI symptom improvement among pregnant women in China.
METHODS
Singleton pregnant women without incontinence before pregnancy who were aged ≥18 years and between 24 and 28 weeks of gestation were recruited from a tertiary public hospital in China and were randomly allocated (1:1) to either an experimental group (n=63) or a control group (n=63). The experimental group received the UIW app intervention and oral pelvic floor muscle training (PFMT) instructions, whereas the control group received oral PFMT instructions alone. Neither the participants nor the researchers were blinded to the intervention. The primary outcome was UI severity. The secondary outcomes included quality of life, self-efficacy with PFMT, and knowledge of UI. All data were collected at baseline, 2 months after randomization, and 6 weeks post partum through electronic questionnaires or by checking the electronic medical record system. Data analysis followed the intention-to-treat principle. A linear mixed model was used to examine the intervention effect on primary and secondary outcomes.
RESULTS
Participants in the experimental and control groups were comparable at baseline. Of the 126 overall participants, 117 (92.9%) and 103 (81.7%) women completed follow-up visits at 2 months after randomization and 6 weeks after delivery, respectively. A statistically significant difference in UI symptom severity was observed between the experimental group and control group (2 months after randomization: mean difference -2.86, 95% CI -4.09 to -1.64, P<.001; 6 weeks post partum: mean difference -2.68, 95% CI -3.87 to -1.49, P<.001). For the secondary outcomes, a statistically significant intervention effect on the quality of life, self-efficacy, and UI knowledge was found at the 2-month follow-up (all P<.05) and 6 weeks post partum (all P<.001).
CONCLUSIONS
The app-based UI self-management intervention (UIW) effectively improved UI symptom severity, quality of life, self-efficacy with PFMT, and knowledge of UI during the late pregnancy and early postnatal periods. Larger multicenter studies with a longer postpartum follow-up are required to further extend these findings.
TRIAL REGISTRATION
Chinese Clinical Trial Registry ChiCTR1800016171; http://www.chictr.org.cn/showproj.aspx?proj=27455.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
RR2-10.2196/22771.
Topics: Adolescent; Adult; Female; Humans; Male; Pregnancy; China; Exercise Therapy; Mobile Applications; Pelvic Floor; Pregnant Women; Quality of Life; Self-Management; Treatment Outcome; Urinary Incontinence
PubMed: 37368465
DOI: 10.2196/43528 -
American Society of Clinical Oncology... Jun 2024Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past... (Review)
Review
Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past decades. Traditional explanatory trials, focused on establishing intervention efficacy in ideal settings, often lack generalizability and may not reflect real-world patient care scenarios. Furthermore, increasing complexity in cancer clinical trial design has led to challenges such as protocol deviations, slow enrollment leading to lengthened durations of trial, and escalating costs. By contrast, pragmatic trials aim to assess intervention effectiveness in more representative patient populations under routine clinical conditions. Here, we review the principles, methodologies, challenges, and advantages of incorporating pragmatic features (PFs) into cancer clinical trials. We illustrate the application of pragmatic trial designs in oncology and discuss the QUASAR collaborative, TAPUR study, and the ongoing PRAGMATICA-LUNG trial. Although not all oncology trials may be amenable to adopting fully pragmatic designs, integration of PFs when feasible will enhance trial generalizability and real-world applicability. Project Pragmatica and similar initiatives advocate for the integration of real-world practice with clinical trials, fostering a nuanced approach to oncology research that balances efficacy and effectiveness assessments, ultimately with a goal of improving patient outcomes.
Topics: Humans; Neoplasms; Clinical Trials as Topic; Research Design; Pragmatic Clinical Trials as Topic; Medical Oncology
PubMed: 38771997
DOI: 10.1200/EDBK_100040 -
BMJ (Clinical Research Ed.) Jan 2024To assess the effects of an additional programme of physiotherapy in adults with a first-time traumatic shoulder dislocation compared with single session of advice,... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To assess the effects of an additional programme of physiotherapy in adults with a first-time traumatic shoulder dislocation compared with single session of advice, supporting materials, and option to self-refer to physiotherapy.
DESIGN
Pragmatic, multicentre, randomised controlled trial (ARTISAN).
SETTING AND PARTICIPANTS
Trauma research teams at 41 UK NHS Trust sites screened adults with a first time traumatic anterior shoulder dislocation confirmed radiologically, being managed non-operatively. People were excluded if they presented with both shoulders dislocated, had a neurovascular complication, or were considered for surgical management.
INTERVENTIONS
One session of advice, supporting materials, and option to self-refer to physiotherapy (n=240) was assessed against the same advice and supporting materials and an additional programme of physiotherapy (n=242). Analyses were on an intention-to-treat basis with secondary per protocol analyses.
MAIN OUTCOME MEASURES
The primary outcome was the Oxford shoulder instability score (a single composite measure of shoulder function), measured six months after treatment allocation. Secondary outcomes included the QuickDASH, EQ-5D-5L, and complications.
RESULTS
482 participants were recruited from 40 sites in the UK. 354 (73%) participants completed the primary outcome score (n=180 allocated to advice only, n=174 allocated to advice and physiotherapy). Participants were mostly male (66%), with a mean age of 45 years. No significant difference was noted between advice compared with advice and a programme of physiotherapy at six months for the primary intention-to-treat adjusted analysis (between group difference favouring physiotherapy 1.5 (95% confidence interval -0.3 to 3.5)) or at earlier three month and six week timepoints. Complication profiles were similar across the two groups (P>0.05).
CONCLUSIONS
An additional programme of current physiotherapy is not superior to advice, supporting materials, and the option to self-refer to physiotherapy.
TRIAL REGISTRATION
Current Controlled Trials ISRCTN63184243.
Topics: Adult; Female; Humans; Male; Middle Aged; Cost-Benefit Analysis; Joint Instability; Physical Therapy Modalities; Quality of Life; Shoulder Dislocation; Shoulder Joint
PubMed: 38233068
DOI: 10.1136/bmj-2023-076925 -
Journal of the American College of... May 2024Most patients with atherosclerotic cardiovascular disease fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals. Twice-yearly inclisiran... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Most patients with atherosclerotic cardiovascular disease fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals. Twice-yearly inclisiran lowers LDL-C by ∼50% when added to statins.
OBJECTIVES
This study evaluated the effectiveness of an "inclisiran first" implementation strategy (adding inclisiran immediately upon failure to reach LDL-C <70 mg/dL despite receiving maximally tolerated statins) vs representative usual care in U.S. patients with atherosclerotic cardiovascular disease.
METHODS
VICTORION-INITIATE, a prospective, pragmatically designed trial, randomized patients 1:1 to inclisiran (284 mg at days 0, 90, and 270) plus usual care (lipid management at treating physician's discretion) vs usual care alone. Primary endpoints were percentage change in LDL-C from baseline and statin discontinuation rates.
RESULTS
We randomized 450 patients (30.9% women, 12.4% Black, 15.3% Hispanic); mean baseline LDL-C was 97.4 mg/dL. The "inclisiran first" strategy led to significantly greater reductions in LDL-C from baseline to day 330 vs usual care (60.0% vs 7.0%; P < 0.001). Statin discontinuation rates with "inclisiran first" (6.0%) were noninferior vs usual care (16.7%). More "inclisiran first" patients achieved LDL-C goals vs usual care (<70 mg/dL: 81.8% vs 22.2%; <55 mg/dL: 71.6% vs 8.9%; P < 0.001). Treatment-emergent adverse event (TEAE) and serious TEAE rates compared similarly between treatment strategies (62.8% vs 53.7% and 11.5% vs 13.4%, respectively). Injection-site TEAEs and TEAEs causing treatment withdrawal occurred more commonly with "inclisiran first" than usual care (10.3% vs 0.0% and 2.6% vs 0.0%, respectively).
CONCLUSIONS
An "inclisiran first" implementation strategy led to greater LDL-C lowering compared with usual care without discouraging statin use or raising new safety concerns. (A Randomized, Multicenter, Open-label Trial Comparing the Effectiveness of an "Inclisiran First" Implementation Strategy to Usual Care on LDL Cholesterol [LDL-C] in Patients With Atherosclerotic Cardiovascular Disease and Elevated LDL-C [≥70 mg/dL] Despite Receiving Maximally Tolerated Statin Therapy [VICTORION-INITIATE]; NCT04929249).
Topics: Humans; Female; Male; Middle Aged; Prospective Studies; Cholesterol, LDL; Aged; Atherosclerosis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Oligonucleotides; Treatment Outcome
PubMed: 38593947
DOI: 10.1016/j.jacc.2024.03.382 -
Pain Jul 2023Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled...
Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions.
Topics: Humans; Analgesics; Consensus; Pain; Pain Management; Research Design; Pragmatic Clinical Trials as Topic
PubMed: 36943273
DOI: 10.1097/j.pain.0000000000002888 -
Multiple Sclerosis (Houndmills,... Aug 2023Phase 3 clinical trials for disease-modifying therapies in relapsing-remitting multiple sclerosis (RRMS) have utilized a limited number of conventional designs with a... (Review)
Review
BACKGROUND
Phase 3 clinical trials for disease-modifying therapies in relapsing-remitting multiple sclerosis (RRMS) have utilized a limited number of conventional designs with a high degree of success. However, these designs limit the types of questions that can be addressed, and the time and cost required. Moreover, trials involving people with progressive multiple sclerosis (MS) have been less successful.
OBJECTIVE
The objective of this paper is to discuss complex innovative trial designs, intermediate and composite outcomes and to improve the efficiency of trial design in MS and broaden questions that can be addressed, particularly as applied to progressive MS.
METHODS
We held an international workshop with experts in clinical trial design.
RESULTS
Recommendations include increasing the use of complex innovative designs, developing biomarkers to enrich progressive MS trial populations, prioritize intermediate outcomes for further development that target therapeutic mechanisms of action other than peripherally mediated inflammation, investigate acceptability to people with MS of data linkage for studying long-term outcomes of clinical trials, use Bayesian designs to potentially reduce sample sizes required for pediatric trials, and provide sustained funding for platform trials and registries that can support pragmatic trials.
CONCLUSION
Novel trial designs and further development of intermediate outcomes may improve clinical trial efficiency in MS and address novel therapeutic questions.
Topics: Child; Humans; Bayes Theorem; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Sample Size; Clinical Trials as Topic
PubMed: 37555492
DOI: 10.1177/13524585231189671 -
Clinical and Experimental Emergency... Mar 2024The goal of a clinical study is to determine the factors associated with a disease and to assess the efficacy and safety of an investigational drug, procedure, or...
The goal of a clinical study is to determine the factors associated with a disease and to assess the efficacy and safety of an investigational drug, procedure, or device. Since clinical study designs vary due to unique requirements of individual studies, the aims of this report are to educate researchers on the different types of studies and to assist researchers in choosing the optimal study type to fulfill their individual requirements. Clinical studies are classified into the two main types, observational studies and clinical trials, depending on the presence or absence of an intervention. Observational studies include case-control studies, cohort studies, and cross-sectional studies. Case-control and cohort studies may be prospective or retrospective, and case-control studies may be nested or not. Clinical trials may be pragmatic and may be controlled or noncontrolled; randomized or nonrandomized; open label or blinded; and parallel, crossover, or factorial. These observational and clinical trial designs are reviewed. Each type of clinical study has advantages and disadvantages. Therefore, researchers must consider these in choosing the design best suited for achieving their study objectives.
PubMed: 37280050
DOI: 10.15441/ceem.23.036 -
International Journal of Nursing Studies Jan 2024Older nursing home residents are prone to develop different skin conditions at the same time, including xerosis cutis, skin tears, pressure ulcers,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Older nursing home residents are prone to develop different skin conditions at the same time, including xerosis cutis, skin tears, pressure ulcers, incontinence-associated dermatitis or intertrigo. Guidelines and recommendations mainly address these skin conditions separately. The overall aim of this study was to measure the effects of the implementation of a skincare and prevention package.
TRIAL DESIGN
A two-arm cluster-randomised controlled trial was conducted.
METHODS
In nursing homes being assigned to the intervention group, an evidence-based and structured skincare and prevention programme was implemented for six months. Nursing home residents in the control group received standard care as usual. Blinded dermatologists conducted head-to-toe skin assessments, and the researchers assessed skin barrier parameters including stratum corneum hydration and transepidermal water loss at the upper and lower extremities after three and six months. Outcomes included the cumulative incidence of incontinence-associated dermatitis, skin tears, pressure ulcers and intertrigo, and were presented as intention-to-treat and per protocol analysis. Skin dryness and resident-reported outcomes (pain, itch, quality of life) were assessed.
RESULTS
A random sample of 17 nursing homes in the federal state of Berlin, Germany, was drawn and randomised in intervention (n = 9) and control groups (n = 8). In total, 165 participants were allocated to the intervention, and 149 participants were allocated to the control group. The cumulative incidence of skin tears (19.2 %, 95 % CI 12.8-27.8), pressure ulcers (13.6 %, 95 % CI 8.1-21.9) and intertrigo (27.0 %, 95 % CI 18.4-37.7) was lower in the intervention compared to the control group, with cumulative incidences of 27.2 % (95 % CI 19.3-36.9) for skin tears, 16.9 % (95 % CI 10.6-25.9) for pressure ulcer, and 37.8 % (95 % CI 27.5-49.4) for intertrigo. The incidence of incontinence-associated dermatitis was higher in the intervention group (26.3 %, 95 % CI 17.9-36.8) compared to the control group (23.1 %; 95 % CI 14.6-34.5). Mean skin dryness was lower in the intervention group but showed variation. The impact on pain, itch, and quality of life was trivial.
CONCLUSIONS
The present study results indicate that the implementation of tailored and evidence-based nursing routines improves skin health and safety in residential long-term care. Evidence suggests that multiple adverse skin conditions can be prevented by regular skin assessments and individually tailored skincare routines. Positive effects on skin dryness were observed, but skin physiology parameters did not indicate changes of the skin barrier function.
TRIAL REGISTRATION
This study is registered at the German Clinical Trials Register (registration number: DRKS00015680; date of registration: January 29, 2019) and ClinicalTrials.gov (NCT03824886; date of registration: January 31, 2019).
Topics: Humans; Aged; Pressure Ulcer; Quality of Life; Skin; Intertrigo; Pain
PubMed: 37956524
DOI: 10.1016/j.ijnurstu.2023.104627