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Concept: Clinical trial protocol


Indwelling urinary catheters (IUCs) are placed frequently in older adults (age ≥ 65 years) in the emergency department (ED) and carry significant risks. The authors developed, implemented, and assessed a novel clinical protocol to assist ED providers with appropriate indications for placement, reassessment, and removal of IUCs in elders in the ED.

Concepts: Death, Clinical trial protocol, Catheter, Urinary catheterization, Dublin


The paper discusses clinical trial optimization problems in the context of mid- to late-stage drug development. Using the Clinical Scenario Evaluation approach, main objectives of clinical trial optimization are formulated, including selection of clinically relevant optimization criteria, identification of sets of optimal and nearly optimal values of the parameters of interest, and sensitivity assessments. The paper focuses on a class of optimization criteria arising in clinical trials with several competing goals, termed tradeoff-based optimization criteria, and discusses key considerations in constructing and applying tradeoff-based criteria. The clinical trial optimization framework considered in the paper is illustrated using two case studies based on a clinical trial with multiple objectives and a two-stage clinical trial which utilizes adaptive decision rules.

Concepts: Pharmacology, Clinical trial, Evaluation,, Evaluation methods, Pharmaceutical industry, Drug discovery, Clinical trial protocol


To examine the length of time between receiving funding and publishing the protocol and main paper for randomised controlled trials.

Concepts: Experimental design, Clinical trial, Informed consent, Randomized controlled trial,, Clinical trial protocol


Bone morphogenetic protein-2 (BMP-2) appears to be one of the most potent growth factors thus far studied. However, recent publications on the clinical application of BMP-2 revealed that its correct control is the paramount issue in clinical practice. For improving BMP-2 delivery, the cyclic administration might be an alternative. Accordingly, the authors cyclically injected BMP-2 in a cyclic injection model of large cranial defects to maintain the proper dosage during the bone healing process. A 10-mm diameter calvarial bone defect was produced using a round drill in 8-week-old Sprague-Dawley rats. Silk-hydroxyapatite scaffolds soaked in the appropriate concentration of BMP-2 were implanted into the defect. The animals were split into 4 single-injection groups and 3 multiple-injection groups; the latter groups received weekly subcutaneous injections of BMP-2 solution (1, 5, and 10 μg/mL) for 4 weeks, whereas the former groups received a single injection of BMP-2 at these concentrations. Each rat underwent computed tomography at 8 weeks. In terms of total volumes of the new bone, the 5 μg/mL multiple-injection BMP-2 group had significantly greater increases in bone volume than the single-injection groups. In terms of bone thickness, the multiple-injection groups had better outcomes than the single-injection groups. Thus, the cyclic injection protocol restored the original thickness without overgrowth. Cyclic injection of BMP-2 permits more accurate dosage control than single injection and improves thickness and dense bone regeneration. Therefore, it may represent a promising approach for future clinical trials. Further investigation using a greater number of animals is required.

Concepts: Better, Clinical trial, Concentration, Clinical research, Clinical trial protocol, Good clinical practice, Bone healing, Clinical site


Non-retention of participants seriously affects the credibility of clinical trial results and significantly reduces the potential of a trial to influence clinical practice. Non-retention can be defined as instances where participants leave the study prematurely. Examples include withdrawal of consent and loss to follow-up and thus outcome data cannot be obtained. The majority of existing interventions targeting retention fail to describe any theoretical basis for the observed improvement, or lack of improvement. Moreover, most of these interventions lack involvement of participants in their conception and/or design, raising questions about their relevance and acceptability. Many of the causes of non-retention involve people performing a behaviour (e.g. not returning a questionnaire). Behaviour change is difficult, and the importance of a strong theoretical basis for interventions that aim to change behaviour is increasingly recognised. This research aims to develop and pilot theoretically informed, participant-centred, evidence-based behaviour change interventions to improve retention in trials.

Concepts: Clinical trial, Informed consent, The Canon of Medicine, Randomized controlled trial, Avicenna,, Clinical trial protocol, Good clinical practice


IMPORTANCE “Nudges” that influence decision making through subtle cognitive mechanisms have been shown to be highly effective in a wide range of applications, but there have been few experiments to improve clinical practice. OBJECTIVE To investigate the use of a behavioral “nudge” based on the principle of public commitment in encouraging the judicious use of antibiotics for acute respiratory infections (ARIs). DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial in 5 outpatient primary care clinics. A total of 954 adults had ARI visits during the study timeframe: 449 patients were treated by clinicians randomized to the posted commitment letter (335 in the baseline period, 114 in the intervention period); 505 patients were treated by clinicians randomized to standard practice control (384 baseline, 121 intervention). INTERVENTIONS The intervention consisted of displaying poster-sized commitment letters in examination rooms for 12 weeks. These letters, featuring clinician photographs and signatures, stated their commitment to avoid inappropriate antibiotic prescribing for ARIs. MAIN OUTCOMES AND MEASURES Antibiotic prescribing rates for antibiotic-inappropriate ARI diagnoses in baseline and intervention periods, adjusted for patient age, sex, and insurance status. RESULTS Baseline rates were 43.5% and 42.8% for control and poster, respectively. During the intervention period, inappropriate prescribing rates increased to 52.7% for controls but decreased to 33.7% in the posted commitment letter condition. Controlling for baseline prescribing rates, we found that the posted commitment letter resulted in a 19.7 absolute percentage reduction in inappropriate antibiotic prescribing rate relative to control (P = .02). There was no evidence of diagnostic coding shift, and rates of appropriate antibiotic prescriptions did not diminish over time. CONCLUSIONS AND RELEVANCE Displaying poster-sized commitment letters in examination rooms decreased inappropriate antibiotic prescribing for ARIs. The effect of this simple, low-cost intervention is comparable in magnitude to costlier, more intensive quality-improvement efforts. TRIAL REGISTRATION identifier: NCT01767064.

Concepts: Clinical trial, Hospital, Effectiveness,, Pharmaceutical industry, Clinical research, Clinical trial protocol, Clinic


Many investigational drugs fail in late-stage clinical development. A better understanding of why investigational drugs fail can inform clinical practice, regulatory decisions, and future research.

Concepts: Pharmacology, Clinical trial, Pharmaceutical industry, Drug development, Failure, Clinical trial protocol, Good clinical practice, Investigational New Drug


We propose an “efficacy-to-effectiveness” (E2E) clinical trial design, in which an effectiveness trial would commence seamlessly upon completion of the efficacy trial.Efficacy trials use inclusion/exclusion criteria to produce relatively homogeneous samples of participants with the target condition, conducted in settings that foster adherence to rigorous clinical protocols. Effectiveness trials use inclusion/exclusion criteria that generate heterogeneous samples that are more similar to the general patient spectrum, conducted in more varied settings, with protocols that approximate typical clinical care. In E2E trials, results from the efficacy trial component would be used to design the effectiveness trial component, to confirm and/or discern associations between clinical characteristics and treatment effects in typical care, and potentially to test new hypotheses.An E2E approach may improve the evidentiary basis for selecting treatments, expand understanding of the effectiveness of treatments in subgroups with particular clinical features, and potentially foster incorporation of effectiveness information into regulatory processes.Clinical Pharmacology & Therapeutics (2013); Accepted article preview online 23 September 2013; doi:10.1038/clpt.2013.177.

Concepts: Clinical trial, The Canon of Medicine, Effectiveness,, Clinical research, Drug development, Clinical trial protocol, Good clinical practice


Weaning protocols expedite extubation in mechanically ventilated patients, yet the literature investigating the application in tracheostomized patients remains scarce. The primary objective of this parallel randomized controlled pilot trial (RCT) was to assess the feasibility and safety of a nurse-led weaning protocol (protocol) compared to weaning based on physician’s clinical judgment (control) in tracheostomized critically ill patients.

Concepts: Epidemiology, Clinical trial, Patient, The Canon of Medicine, Randomized controlled trial, Pharmaceutical industry, Clinical research, Clinical trial protocol


Clinical trials that led to ibrutinib’s approval in chronic lymphocytic leukemia showed that its side effects differ from traditional chemotherapy toxicities. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at 9 United States cancer centers or the Connec Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. 621 ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, p=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, p=0.8). With a median follow-up of 17 months, an estimated 42% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. Median progression free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib-treated chronic lymphocytic leukemia patients, we show that 42% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not impacted by line of therapy and whether patients were treated on clinical studies or commercially. These data strongly argue to find strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

Concepts: Clinical trial, Informed consent, Avicenna, Leukemia, Pharmaceutical industry, Clinical trial protocol, Good clinical practice, Clinical site