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Trials Dec 2022To support the primary care sector in delivering high-quality type 2 diabetes (T2D), literature reviews emphasize the need for implementing models of collaboration that...
The effect of virtual specialist conferences between endocrinologists and general practitioners about type 2 diabetes: study protocol for a pragmatic randomized superiority trial.
BACKGROUND
To support the primary care sector in delivering high-quality type 2 diabetes (T2D), literature reviews emphasize the need for implementing models of collaboration that in a simple and effective way facilitate clinical dialogue between general practitioners (GPs) and endocrinologists. The overall aim of the project is to evaluate if virtual specialist conferences between GPs and endocrinologists about patients living with T2D is clinically effective and improves diabetes competences and organization in general practice in comparison to usual practice.
METHODS
A prospective, pragmatic, and superiority RCT with two parallel arms of general practices in the Municipality of Aarhus, Denmark. All general practices are invited (n = 100). The intervention runs for 12 months and consists of four virtual conferences between endocrinologists and an individual general practice. Before the first conference, an introductory webinar teaches GPs about how to use an IT-platform to identify and manage T2D patients. The main analysis (month 12) concerns the difference between the intervention and control arm. It is expected that the virtual conferences at the patient level will improve adherence to international recommendations on diabetes medication for T2D patients and improve the risk profile with a reduction in glycated haemoglobin, blood pressure, and cholesterol. The study design allows for identifying a significant difference between the intervention (n = 15) and control group (n = 15) regarding the three primary clinical outcomes with a power of 0.8870-0.9941. At the general practice level, it is expected that general practitioners and practice staff in the intervention group will improve self-reported diabetes competence and organization. The control arm will get the intervention when the primary intervention ends (months 12-24), and the intervention arm transitions to a maintenance phase.
DISCUSSION
The potential of virtual conferences is yet to be fully tapped because of methodological limitations. Studies have also not yet systematically evaluated virtual conferences in the context of chronic care using a high-quality research design. Given the nature of this real-life intervention, general practitioners and endocrinologists cannot be blinded to their allocation to either the intervention or comparison arm.
TRIAL REGISTRATION
ClinicalTrials.gov, United States National Institutes of Health trial ID: NCT05268081. Registered on 4 March 2022.
Topics: Humans; Diabetes Mellitus, Type 2; Endocrinologists; General Practitioners; Glycated Hemoglobin; Prospective Studies; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Equivalence Trials as Topic
PubMed: 36578024
DOI: 10.1186/s13063-022-06961-y -
Trials Dec 2019Antibiotic exposure is often inadequate in critically ill patients with severe sepsis or septic shock and this is associated with worse outcomes. Despite markedly...
Right Dose Right Now: bedside data-driven personalized antibiotic dosing in severe sepsis and septic shock - rationale and design of a multicenter randomized controlled superiority trial.
BACKGROUND
Antibiotic exposure is often inadequate in critically ill patients with severe sepsis or septic shock and this is associated with worse outcomes. Despite markedly altered and rapidly changing pharmacokinetics in these patients, guidelines and clinicians continue to rely on standard dosing schemes. To address this challenge, we developed AutoKinetics, a clinical decision support system for antibiotic dosing. By feeding large amounts of electronic health record patient data into pharmacokinetic models, patient-specific predicted future plasma concentrations are displayed graphically. In addition, a tailored dosing advice is provided at the bedside in real time. To evaluate the effect of AutoKinetics on pharmacometric and clinical endpoints, we are conducting the Right Dose Right Now multicenter, randomized controlled, two-arm, parallel-group, non-blinded, superiority trial.
METHODS
All adult intensive care patients with a suspected or proven infection and having either lactatemia or receiving vasopressor support are eligible for inclusion. Randomization to the AutoKinetics or control group is initiated at the bedside when prescribing at least one of four commonly administered antibiotics: ceftriaxone, ciprofloxacin, meropenem and vancomycin. Dosing advice is available for patients in the AutoKinetics group, whereas patients in the control group receive standard dosing. The primary outcome of the study is pharmacometric target attainment during the first 24 h. Power analysis revealed the need for inclusion of 42 patients per group per antibiotic. Thus, a total of 336 patients will be included, 168 in each group. Secondary pharmacometric endpoints include time to target attainment and fraction of target attainment during an entire antibiotic course. Secondary clinical endpoints include mortality, clinical cure and days free from organ support. Several other exploratory and subgroup analyses are planned.
DISCUSSION
This is the first randomized controlled trial to assess the effectiveness and safety of bedside data-driven automated antibiotic dosing advice. This is important as adequate antibiotic exposure may be crucial to treat severe sepsis and septic shock. In addition, the trial could prove to be a significant contribution to clinical pharmacometrics and serve as a stepping stone for the use of big data and artificial intelligence in the field.
TRIAL REGISTRATION
Netherlands Trial Register (NTR), NL6501/NTR6689. Registered on 25 August 2017. European Clinical Trials Database (EudraCT), 2017-002478-37. Registered on 6 November 2017.
Topics: Adult; Anti-Bacterial Agents; Artificial Intelligence; Big Data; Dose-Response Relationship, Drug; Drug Monitoring; Equivalence Trials as Topic; Female; Humans; Intensive Care Units; Kaplan-Meier Estimate; Male; Multicenter Studies as Topic; Netherlands; Randomized Controlled Trials as Topic; Research Design; Severity of Illness Index; Shock, Septic; Treatment Outcome
PubMed: 31852491
DOI: 10.1186/s13063-019-3911-5 -
BMC Medical Research Methodology Feb 2022Adaptive designs offer added flexibility in the execution of clinical trials, including the possibilities of allocating more patients to the treatments that turned out...
BACKGROUND
Adaptive designs offer added flexibility in the execution of clinical trials, including the possibilities of allocating more patients to the treatments that turned out more successful, and early stopping due to either declared success or futility. Commonly applied adaptive designs, such as group sequential methods, are based on the frequentist paradigm and on ideas from statistical significance testing. Interim checks during the trial will have the effect of inflating the Type 1 error rate, or, if this rate is controlled and kept fixed, lowering the power.
RESULTS
The purpose of the paper is to demonstrate the usefulness of the Bayesian approach in the design and in the actual running of randomized clinical trials during phase II and III. This approach is based on comparing the performance of the different treatment arms in terms of the respective joint posterior probabilities evaluated sequentially from the accruing outcome data, and then taking a control action if such posterior probabilities fall below a pre-specified critical threshold value. Two types of actions are considered: treatment allocation, putting on hold at least temporarily further accrual of patients to a treatment arm, and treatment selection, removing an arm from the trial permanently. The main development in the paper is in terms of binary outcomes, but extensions for handling time-to-event data, including data from vaccine trials, are also discussed. The performance of the proposed methodology is tested in extensive simulation experiments, with numerical results and graphical illustrations documented in a Supplement to the main text. As a companion to this paper, an implementation of the methods is provided in the form of a freely available R package 'barts'.
CONCLUSION
The proposed methods for trial design provide an attractive alternative to their frequentist counterparts.
Topics: Bayes Theorem; Clinical Trials as Topic; Computer Simulation; Humans; Medical Futility; Probability; Research Design
PubMed: 35184731
DOI: 10.1186/s12874-022-01526-8 -
Trials Apr 2021Surgical site infections (SSI) are frequent complications after elective abdominal surgery. We designed the Enhanced PeriOperative Care and Health Protection programme... (Randomized Controlled Trial)
Randomized Controlled Trial
Enhanced PeriOperative Care and Health protection programme for the prevention of surgical site infections after elective abdominal surgery (EPOCH): statistical analysis plan of a randomised controlled multicentre superiority trial.
BACKGROUND
Surgical site infections (SSI) are frequent complications after elective abdominal surgery. We designed the Enhanced PeriOperative Care and Health Protection programme (EPOCH) care bundle, comprising of intraoperative high fractional inspired oxygen; intraoperative goal-directed fluid therapy; active preoperative, intraoperative and postoperative warming; glucose control and treatment of hyperglycaemia (> 10 mmol L) in diabetics as well as non-diabetics; and wound irrigation before closure using an aqueous antiseptic. We hypothesise that EPOCH added to standard care reduces the incidence of SSI compared to standard care alone for elective abdominal surgery.
METHODS
This trial is designed as an open label, pragmatic randomised controlled parallel-group multicentre superiority trial. The primary endpoint is the incidence of SSI, defined by the Centers for Disease Control and prevention, within 30 days after surgery. The incidence of SSI is assessed using the Dutch national complication register and medical chart review. Secondary endpoints include the SSI incidence within 90 days, incidence of anastomotic leakage at 30 and 90 days, the incidence of incisional hernia within 1 year, mortality within 1 year and 5 years, quality of life, health and disability, and cost-effectiveness. Primarily, an intention-to-treat analysis will be performed to estimate the relative risk using a log binomial model. If not feasible, a logistic regression will be used to estimate the odds ratio. A per-protocol analysis will also be performed. Furthermore, the attributive effect of the distinct interventions will be explored.
DISCUSSION
The results of the EPOCH trial will determine if the EPOCH bundle is effective to prevent SSI incidence for patients undergoing elective abdominal surgery. Details of the statistical analysis are described in this Statistical Analysis Plan (SAP).
TRIAL REGISTRATION
Registration number: Dutch Trial Register Trial NL5572 . Registered on March 3, 2016. SAP version: V1.0, January 8, 2020. This SAP has been written based on study protocol V10.
Topics: Abdomen; Elective Surgical Procedures; Humans; Perioperative Care; Quality of Life; Surgical Wound Infection
PubMed: 33883024
DOI: 10.1186/s13063-021-05202-y -
Clinical Colorectal Cancer Mar 2021Biosimilars - biological medicines highly similar to a licensed reference product (RP) - can mitigate the risk of drug shortages by providing treatment alternatives and,... (Review)
Review
Biosimilars - biological medicines highly similar to a licensed reference product (RP) - can mitigate the risk of drug shortages by providing treatment alternatives and, with their lower costs, increase patient access to medication and reduce health care expenditure. However, limited knowledge of biosimilar approval processes and lack of confidence in their quality and efficacy can limit their uptake. Importantly, biosimilars are approved based on tightly controlled regulatory pathways to demonstrate that the physical, chemical, and biological properties of the proposed biosimilar are highly similar to the RP, with no clinically meaningful differences. Initially, a battery of highly sensitive in vitro studies are performed, comparing critical quality attributes between the proposed biosimilar and RP. Subsequently, in vivo pharmacodynamic studies compare the activity and physiologic effects of the biosimilar and RP. Finally, clinical studies are conducted, including a pharmacokinetic equivalence study and a confirmatory comparative clinical trial. The latter is performed in the most sensitive patient population for which the RP is licensed, to provide the greatest possibility of identifying any clinically meaningful differences between the proposed biosimilar and RP. When equivalent safety and efficacy have been demonstrated in one setting, the totality of evidence, together with scientific justification that there are no anticipated differences between the RP and proposed biosimilar in mechanism of action, pharmacokinetics, immunogenicity or toxicity, allows extrapolation into indications where clinical studies were not performed with the proposed biosimilar. Here, we review the approval process for biosimilars, focusing on the licensing of bevacizumab biosimilars and their extrapolation to metastatic colorectal cancer.
Topics: Antineoplastic Agents, Immunological; Bevacizumab; Biosimilar Pharmaceuticals; Colorectal Neoplasms; Drug Approval; Equivalence Trials as Topic; Humans; Neoplasm Staging; Progression-Free Survival
PubMed: 33243618
DOI: 10.1016/j.clcc.2020.10.005 -
Trials Dec 2023Low back pain (LBP) is the leading cause of years lived with disability worldwide. Public safety workers are highly exposed to physically demanding activities and...
Effectiveness of m-health-based core strengthening exercise and health education for public safety workers with chronic non-specific low back pain: study protocol for a superiority randomized controlled trial (SAFEBACK).
BACKGROUND
Low back pain (LBP) is the leading cause of years lived with disability worldwide. Public safety workers are highly exposed to physically demanding activities and inappropriate postures, increasing the risk of experiencing LBP. Smartphone app-based self-managed interventions may be an alternative for chronic non-specific LBP (CNSLBP) treatment. This study aims to evaluate the effectiveness of a smartphone app-based self-managed exercise program plus health education, compared to a health education program alone, on neuromuscular and perceptual outcomes in police officers and firefighters with CNSLBP.
METHODS
This is a parallel, two-armed, blinded evaluator randomized clinical trial. Police officers and firefighters (from public safety institutions in the Rio Grande do Sul state, Brazil) will be randomly assigned to a m-health self-managed exercise program (twice a week) plus health education or health education alone. Self-management exercise program components are mobility and core resistance exercises, available on the app. Follow-ups will be conducted post-treatment (8 weeks) and 16 weeks after randomization. The co-primary outcomes will be pain intensity and disability post-treatment (8 weeks). Secondary outcomes will be biopsychosocial factors related to CNSLBP.
DISCUSSION
We hypothesize that the effects of a smartphone app-based self-managed exercise program on co-primary and secondary outcomes will be superior, compared to the health education only in public safety workers with CNSLBP.
TRIAL REGISTRATION
The study was prospectively registered at ClinicalTrials.gov (NCT05481996. Registered on August 01, 2022).
Topics: Humans; Chronic Pain; Exercise; Exercise Therapy; Health Education; Low Back Pain; Telemedicine; Treatment Outcome; Equivalence Trials as Topic
PubMed: 38041180
DOI: 10.1186/s13063-023-07833-9 -
Trials May 2021Most people with mental disorders, including those with severe and chronic disorders, are treated solely by their general practitioner (GP). Nevertheless, specialised...
Mental health specialist video consultations versus treatment as usual in patients with depression or anxiety disorders in primary care: study protocol for an individually randomised superiority trial (the PROVIDE-C trial).
BACKGROUND
Most people with mental disorders, including those with severe and chronic disorders, are treated solely by their general practitioner (GP). Nevertheless, specialised mental health care may be required for specific patients. Notably, the accessibility of mental health specialist care is mainly complicated by (a) long waiting times for an appointment with specialists, (b) long travel distances to specialists, particularly in rural and remote areas, and (c) patients' reservations about mental health specialist care (including fear of being stigmatised by seeking such care). To mitigate those barriers, technology-based integrated care models have been proposed. The purpose of this study is to examine the effectiveness and cost-effectiveness of a mental health specialist video consultations model versus treatment as usual in patients with depression or anxiety disorders in primary care.
METHODS
In an individually randomised, prospective, two-arm superiority trial with parallel group design, N = 320 patients with anxiety and/or depressive disorder will be recruited in general practices in Germany. The intervention includes a newly developed treatment model based on video consultations with focus on diagnostics, treatment planning, and short-term intervention by mental health specialists. We will systematically compare the effectiveness, cost-effectiveness, and adverse effects of this new model with usual care by the GP: the primary outcome is the absolute change in the mean depressive and anxiety symptom severity measured on the Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS) from baseline to 6 months after baseline assessment. Follow-up in both groups will be conducted by blinded outcome assessors at 6 months and 12 months after baseline. The main analysis will be based on the intention-to-treat principle. We will optimise the likelihood of treatment effectiveness by strict inclusion criteria for patients, enhanced intervention integrity, and conducting a process evaluation.
DISCUSSION
To the best of our knowledge, this is the first confirmatory study on a video-based, integrated care model for the treatment of anxiety and depressive disorders in GP patients in Germany.
TRIAL REGISTRATION
ClinicalTrials.gov, United States National Institutes of Health NCT04316572 . Prospectively registered on 20 March 2020.
Topics: Anxiety Disorders; Cost-Benefit Analysis; Depression; Germany; Humans; Mental Health; Primary Health Care; Prospective Studies; Specialization; Telemedicine; Treatment Outcome
PubMed: 33952313
DOI: 10.1186/s13063-021-05289-3 -
Journal of General Internal Medicine Jan 2018Noninferiority trials are increasingly common, though they have less standardized designs and their interpretation is less familiar to clinicians than superiority trials. (Review)
Review
BACKGROUND
Noninferiority trials are increasingly common, though they have less standardized designs and their interpretation is less familiar to clinicians than superiority trials.
OBJECTIVE
To empirically evaluate a cohort of noninferiority trials to determine 1) their interpretation as recommended by CONSORT, 2) choice of alpha threshold and its sidedness, and 3) differences between methods of analysis such as intention-to-treat and per-protocol.
DESIGN
We searched MEDLINE for parallel-group randomized controlled noninferiority trials published in the five highest-impact general medical journals between 2011 and 2016.
MAIN MEASURES
Data abstracted included trial design parameters, results, and interpretation of results based on CONSORT recommendations.
KEY RESULTS
One hundred sixty-three trials and 182 noninferiority comparisons were included in our analysis. Based on CONSORT-recommended interpretation, 79% of experimental therapies met criteria for noninferiority, 13% met criteria for superiority, 20% were declared inconclusive, and 2% met criteria for inferiority. However, for 12% of trials, the experimental therapy was statistically significantly worse than the active control, but CONSORT recommended an interpretation of inconclusive or noninferior. A two-sided alpha equivalent of greater than 0.05 was used in 34% of the trials, and in five of these trials, the use of a standard two-sided alpha of 0.05 led to changes in the interpretation of results that disfavored the experimental therapy. In four of the five comparisons where different methods of analysis (e.g., intention-to-treat and per-protocol) yielded different results, the intention-to-treat analysis was the more conservative. In 11% of trials, a secondary advantage of the new therapy was neither reported nor could it be inferred by reviewers.
CONCLUSIONS
In this cohort, the design and interpretation of noninferiority trials led to significant and systematic bias in favor of the experimental therapy. Clinicians should exercise caution when interpreting these trials. Future trials may be more reliable if design parameters are standardized.
Topics: Empirical Research; Equivalence Trials as Topic; Humans; Randomized Controlled Trials as Topic; Research Design
PubMed: 28875400
DOI: 10.1007/s11606-017-4161-4 -
Annals of Medicine Dec 2021Atrial fibrillation globally affects roughly 33.5 million people, making it the most common heart rhythm disorder. It is a crucial arrhythmia, as it is linked with a... (Review)
Review
Atrial fibrillation globally affects roughly 33.5 million people, making it the most common heart rhythm disorder. It is a crucial arrhythmia, as it is linked with a variety of negative outcomes such as strokes, heart failure and cardiovascular mortality. Atrial fibrillation can reduce quality of life because of the potential symptoms, for instance exercise intolerance, fatigue, and palpitation. There are different types of treatments aiming to prevent atrial fibrillation and improve quality of life. Currently, the primary treatment for atrial fibrillation is pharmacology therapy, however, these still show limited effectiveness, which has led to research on other alternative strategies. Catheter ablation is considered the second line treatment for atrial fibrillation when the standard treatment has failed. Moreover, catheter ablation continues to show significant results when compared to standard therapy. Hence, this review will argue that catheter ablation can show superiority over current pharmacological treatments in different aspects. It will discuss the most influential aspects of the treatment of atrial fibrillation, which are recurrence and burden of atrial fibrillation, quality of life, atrial fibrillation in the setting of heart failure and mortality and whether catheter ablation can be the first line treatment for patients with atrial fibrillation.
Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Catheter Ablation; Equivalence Trials as Topic; Heart Failure; Humans; Quality of Life; Recurrence; Secondary Prevention; Stroke
PubMed: 33783271
DOI: 10.1080/07853890.2021.1905873 -
The Lancet. Infectious Diseases Sep 2019Plasmodium falciparum and Plasmodium vivax infections are important causes of adverse pregnancy outcomes in the Asia-Pacific region. We hypothesised that monthly...
Efficacy and safety of intermittent preventive treatment and intermittent screening and treatment versus single screening and treatment with dihydroartemisinin-piperaquine for the control of malaria in pregnancy in Indonesia: a cluster-randomised, open-label, superiority trial.
BACKGROUND
Plasmodium falciparum and Plasmodium vivax infections are important causes of adverse pregnancy outcomes in the Asia-Pacific region. We hypothesised that monthly intermittent preventive treatment (IPT) or intermittent screening and treatment (IST) with dihydroartemisinin-piperaquine is more effective in reducing malaria in pregnancy than the existing single screening and treatment (SST) strategy, which is used to screen women for malaria infections at the first antenatal visit followed by passive case detection, with management of febrile cases.
METHODS
We did an open-label, three-arm, cluster-randomised, superiority trial in Sumba (low malaria transmission site) and Papua (moderate malaria transmission site), Indonesia. Eligible participants were 16-30 weeks pregnant. Clusters (antenatal clinics with at least ten new pregnancies per year matched by location, size, and malaria risk) were randomly assigned (1:1:1) via computer-generated lists to IPT, IST, or SST clusters. In IPT clusters, participants received the fixed-dose combination of dihydroartemisinin-piperaquine (4 and 18 mg/kg per day). In IST clusters, participants were screened with malaria rapid diagnostic tests once a month, whereas, in SST clusters, they were screened at enrolment only. In all groups, participants with fever were tested for malaria. Any participant who tested positive received dihydroartemisinin-piperaquine regardless of symptoms. The primary outcome was malaria infection in the mother at delivery. Laboratory staff were unaware of group allocation. Analyses included all randomly assigned participants contributing outcome data and were adjusted for clustering at the clinic level. This trial is complete and is registered with ISRCTN, number 34010937.
FINDINGS
Between May 16, 2013, and April 21, 2016, 78 clusters (57 in Sumba and 21 in Papua) were randomly assigned to SST, IPT, or IST clusters (26 clusters each). Of 3553 women screened for eligibility, 2279 were enrolled (744 in SST clusters, 681 in IPT clusters, and 854 in IST clusters). At enrolment, malaria prevalence was lower in IST (5·7%) than in SST (12·6%) and IPT (10·6%) clusters. At delivery, malaria prevalence was 20·2% (128 of 633) in SST clusters, compared with 11·6% (61 of 528) in IPT clusters (relative risk [RR] 0·59, 95% CI 0·42-0·83, p=0·0022) and 11·8% (84 of 713) in IST clusters (0·56, 0·40-0·77, p=0·0005). Conditions related to the pregnancy, the puerperium, and the perinatal period were the most common serious adverse events for the mothers, and infections and infestations for the infants. There were no differences between groups in serious adverse events in the mothers or in their infants.
INTERPRETATION
IST was associated with a lower prevalence of malaria than SST at delivery, but the prevalence of malaria in this group was also lower at enrolment, making interpretation of the effect of IST challenging. Further studies with highly sensitive malaria rapid diagnostic tests should be considered. Monthly IPT with dihydroartemisinin-piperaquine is a promising alternative to SST in areas in the Asia-Pacific region with moderate or high transmission of malaria.
FUNDING
Joint Global Health Trials Scheme of the Medical Research Council, Department for International-Development, and the Wellcome Trust.
Topics: Adult; Antimalarials; Artemisinins; Drug Combinations; Female; Humans; Indonesia; Malaria, Falciparum; Malaria, Vivax; Parturition; Postpartum Period; Pregnancy; Pregnancy Complications, Parasitic; Prevalence; Quinolines; Young Adult
PubMed: 31353217
DOI: 10.1016/S1473-3099(19)30156-2