Impact of pharmacist care in the management of cardiovascular disease risk factors: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Pharmacists may improve the clinical management of major risk factors for cardiovascular disease (CVD) prevention. A systematic review was conducted to determine the impact of pharmacist care on the management of CVD risk factors among outpatients. METHODS: The MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials databases were searched for randomized controlled trials that involved pharmacist care interventions among outpatients with CVD risk factors. Two reviewers independently abstracted data and classified pharmacists' interventions. Mean changes in blood pressure, total cholesterol, low-density lipoprotein cholesterol, and proportion of smokers were estimated using random effects models. RESULTS: Thirty randomized controlled trials (11 765 patients) were identified. Pharmacist interventions exclusively conducted by a pharmacist or implemented in collaboration with physicians or nurses included patient educational interventions, patient-reminder systems, measurement of CVD risk factors, medication management and feedback to physician, or educational intervention to health care professionals. Pharmacist care was associated with significant reductions in systolic/diastolic blood pressure (19 studies [10 479 patients]; -8.1 mm Hg [95% confidence interval {CI}, -10.2 to -5.9]/-3.8 mm Hg [95% CI,-5.3 to -2.3]); total cholesterol (9 studies [1121 patients]; -17.4 mg/L [95% CI,-25.5 to -9.2]), low-density lipoprotein cholesterol (7 studies [924 patients]; -13.4 mg/L [95% CI,-23.0 to -3.8]), and a reduction in the risk of smoking (2 studies [196 patients]; relative risk, 0.77 [95% CI, 0.67 to 0.89]). While most studies tended to favor pharmacist care compared with usual care, a substantial heterogeneity was observed. CONCLUSION: Pharmacist-directed care or in collaboration with physicians or nurses improve the management of major CVD risk factors in outpatients.

Influence of CYP2D6 activity on pre-emptive analgesia by the N-methyl-D-aspartate antagonist dextromethorphan in a randomized controlled trial of acute pain.

BACKGROUND: There is some evidence that dextromethorphan (DM) is effective as a pre-emptive analgesic agent.  DM is mainly metabolized to dextrorphan (DOR) by CYP2D6 whose activity can be inhibited by pharmacologic intervention. OBJECTIVES: To investigate the efficacy of DM as a pre-emptive analgesic agent and describe the population pharmacokinetics in the presence of normal and poor CYP2D6 metabolism in acute post-operative pain. STUDY DESIGN: Double blind, randomized, placebo-controlled trial SETTING: Post-surgical analgesic consumption after knee ligament surgery, a setting of acute pain. METHODS: Forty patients were randomized to a single oral dose of 50 mg quinidine or placebo, administered 12 hours before 50 mg DM. Patients were genotyped for the major CYP2D6 and ABCB1 variants and phenotyped for CYP2D6 using urine DM/DOR metabolic ratios and blood samples for population pharmacokinetic modeling. RESULTS: Quinidine was effective in inhibiting CYP2D6 activity, with 2-fold reduction of DM to DOR biotransformation clearance, prolonged DM half-life, and increased DM systemic availability. Patients in the quinidine group required significantly less often NSAIDs than patients in the placebo group (35.3% vs. 75.0%, P = 0.022). The odds ratio for NSAID consumption in the placebo vs. quinidine group was 5.5 (95% confidence interval (CI) 1.3 - 22.7) at 48 hours after surgery. LIMITATIONS: While this study shows an impact of DM on pre-emptive analgesia and is mechanistically interesting, the findings need to be confirmed in larger trials. CONCLUSION: CYP2D6 inhibition by quinidine influenced the pre-emptive analgesic effectiveness of DM confirming that CYP2D6 phenotypic switch increases the neuromodulatory effect of oral dextromethorphan.

The synthetic Plasmodium falciparum circumsporozoite peptide PfCS102 as a malaria vaccine candidate: a randomized controlled phase I trial.

BACKGROUND: Fully efficient vaccines against malaria pre-erythrocytic stage are still lacking. The objective of this dose/adjuvant-finding study was to evaluate the safety, reactogenicity and immunogenicity of a vaccine candidate based on a peptide spanning the C-terminal region of Plasmodium falciparum circumsporozoite protein (PfCS102) in malaria naive adults. METHODOLOGY AND PRINCIPAL FINDINGS: Thirty-six healthy malaria-naive adults were randomly distributed into three dose blocks (10, 30 and 100 microg) and vaccinated with PfCS102 in combination with either Montanide ISA 720 or GSK proprietary Adjuvant System AS02A at days 0, 60, and 180. Primary end-point (safety and reactogenicity) was based on the frequency of adverse events (AE) and of abnormal biological safety tests; secondary-end point (immunogenicity) on P. falciparum specific cell-mediated immunity and antibody response before and after immunization. The two adjuvant formulations were well tolerated and their safety profile was good. Most AEs were local and, when systemic, involved mainly fatigue and headache. Half the volunteers in AS02A groups experienced severe AEs (mainly erythema). After the third injection, 34 of 35 volunteers developed anti-PfCS102 and anti-sporozoite antibodies, and 28 of 35 demonstrated T-cell proliferative responses and IFN-gamma production. Five of 22 HLA-A2 and HLA-A3 volunteers displayed PfCS102 specific IFN-gamma secreting CD8(+) T cell responses. Responses were only marginally boosted after the 3(rd) vaccination and remained stable for 6 months. For both adjuvants, the dose of 10 microg was less immunogenic in comparison to 30 and 100 microg that induced similar responses. AS02A formulations with 30 microg or 100 microg PfCS102 induced about 10-folds higher antibody and IFN-gamma responses than Montanide formulations. CONCLUSIONS/SIGNIFICANCE: PfCS102 peptide was safe and highly immunogenic, allowing the design of more advanced trials to test its potential for protection. Two or three immunizations with a dose of 30 microg formulated with AS02A appeared the most appropriate choice for such studies. TRIAL REGISTRATION: Swissmedic.ch 2002 DR 1227.

Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.

PURPOSE: This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM). METHODS: Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395). RESULTS: Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml). CONCLUSIONS: This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.

Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: Results from the randomized controlled I-COME Trial

Introduction: Imatinib trough plasma concentrations (Cmin) have been correlated with treatment response in chronic myeloid leukemia (CML) patients. The use of Cmin monitoring for optimizing imatinib dosage (therapeutic drug monitoring [TDM]) is therefore proposed for patients with unsatisfying response or tolerance ("rescue TDM"). A cycle of "routine TDM" for dosage individualization could also be beneficial to prevent unfavorable events, yet its clinical usefulness has not been evaluated. We aimed to assess prospectively whether a "routine TDM" intervention targeting imatinib Cmin of 1000 ng/mL (tolerance, 750-1500 ng/mL) could improve efficacy, tolerance, and persistence on treatment compared with "rescue TDM" use only. Patients (or Materials) and Methods: The Swiss Imatinib COncentration Monitoring Evaluation (I-COME) study was a multicenter randomized controlled trial (ISRCTN31181395). Adult patients in chronic or accelerated phase CML receiving imatinib ≤5 years were eligible. Patients were randomly (1:1) allocated to receive "routine TDM" intervention or to serve as controls with access only to "rescue TDM". All had 1-year follow-up. The primary endpoint was a combined efficacy-safety outcome (failure- and toxicity-free survival without imatinib discontinuation), analyzed in intention-to-treat. Results: Among 56 CML recruited patients, 55 had their molecular and cytogenetic response measured. 14/27 of patients receiving "routine TDM" (52% [33%-71%]) remained event-free versus 16/28 of control patients with "rescue TDM" only (57% [39%-75%]; P=0.69). In the "routine TDM" group, dosage recommendations were adopted entirely in 50% of patients (median Cmin at study end, 895 ng/mL; CV = 33%). These patients had fewer unfavorable events (28% [5%-52%]) compared with patients not receiving the advised dosage (77% [54%-99%]; P = 0.03; median Cmin at study end, 648 ng/mL; CV = 38%). Conclusion: This first prospective target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" of imatinib, especially due to a small patient number and limited prescriber's adherence to dosage recommendations. Nevertheless, the patients receiving the advised dosage more often met target concentrations and the combined outcome (efficacy, tolerance, and persistence). A cycle of routine TDM could thus be favorable, at least in patients eligible for dosage adjustment. Its usefulness should, however, be further confirmed in larger trials.

Randomized controlled trial of interventions for young people at ultra-high risk of psychosis: study design and baseline characteristics.

OBJECTIVE: Intervention during the pre-psychotic period of illness holds the potential of delaying or even preventing the onset of a full-threshold disorder, or at least of reducing the impact of such a disorder if it does develop. The first step in realizing this aim was achieved more than 10 years ago with the development and validation of criteria for the identification of young people at ultra-high risk (UHR) of psychosis. Results of three clinical trials have been published that provide mixed support for the effectiveness of psychological and pharmacological interventions in preventing the onset of psychotic disorder. METHOD: The present paper describes a fourth study that has now been undertaken in which young people who met UHR criteria were randomized to one of three treatment groups: cognitive therapy plus risperidone (CogTher + Risp: n = 43); cognitive therapy plus placebo (CogTher + Placebo: n = 44); and supportive counselling + placebo (Supp + Placebo; n = 28). A fourth group of young people who did not agree to randomization were also followed up (monitoring: n = 78). Baseline characteristics of participants are provided. RESULTS AND CONCLUSION: The present study improves on the previous studies because treatment was provided for 12 months and the independent contributions of psychological and pharmacological treatments in preventing transition to psychosis in the UHR cohort and on levels of psychopathology and functioning can be directly compared. Issues associated with recruitment and randomization are discussed.

Effect of a governmentally-led physical activity program on motor skills in young children attending child care centers: a cluster randomized controlled trial.

OBJECTIVE: To assess the effect of a governmentally-led center based child care physical activity program (Youp'la Bouge) on child motor skills.Patients and methods: We conducted a single blinded cluster randomized controlled trial in 58 Swiss child care centers. Centers were randomly selected and 1:1 assigned to a control or intervention group. The intervention lasted from September 2009 to June 2010 and included training of the educators, adaptation of the child care built environment, parental involvement and daily physical activity. Motor skill was the primary outcome and body mass index (BMI), physical activity and quality of life secondary outcomes. The intervention implementation was also assessed. RESULTS: At baseline, 648 children present on the motor test day were included (age 3.3 +/- 0.6, BMI 16.3 +/- 1.3 kg/m2, 13.2% overweight, 49% girls) and 313 received the intervention. Relative to children in the control group (n = 201), children in the intervention group (n = 187) showed no significant increase in motor skills (delta of mean change (95% confidence interval: -0.2 (-0.8 to 0.3), p = 0.43) or in any of the secondary outcomes. Not all child care centers implemented all the intervention components. Within the intervention group, several predictors were positively associated with trial outcomes: 1) free-access to a movement space and parental information session for motor skills 2) highly motivated and trained educators for BMI 3) free-access to a movement space and purchase of mobile equipment for physical activity (all p < 0.05). CONCLUSION: This "real-life" physical activity program in child care centers confirms the complexity of implementing an intervention outside a study setting and identified potentially relevant predictors that could improve future programs.Trial registration: Trial registration number: clinical trials.gov NCT00967460 http://clinicaltrials.gov/ct2/show/NCT00967460.

Early mobilization out of bed after ischaemic stroke reduces severe complications but not cerebral blood flow: a randomized controlled pilot trial.

OBJECTIVE: To evaluate whether early mobilization after acute ischaemic stroke is better than delayed mobilization with regard to medical complications and if it is safe in relation to neurological function and cerebral blood flow. DESIGN: Randomized controlled pilot trial of early versus delayed mobilization out of bed with incidence of severe complications as the primary outcome. SETTING: Acute stroke unit in the neurology department of a University Hospital. PARTICIPANTS: Fifty patients after ischaemic stroke with a National Institutes of Health Stroke Scale (NIHSS) score >6 were recruited. INTERVENTION: All patients were treated with physiotherapy immediately after their admission. In the early protocol patients were mobilized out of bed after 52 hours, in the delayed protocol after seven days. RESULTS: Eight out of 50 randomized patients were excluded from the per-protocol analysis because of early transfer to other hospitals. There were 2 (8%) severe complications in the 25 early mobilization patients and 8 (47%) in the 17 delayed mobilization patients (P < 0.006). There were no differences in the total number of complications or in clinical outcome. In the 26 patients (62%) who underwent serial transcranial Doppler ultrasonography, no blood flow differences were found. CONCLUSION: We found an apparent reduction in severe complications and no increase in total complications with an early mobilization protocol after acute ischaemic stroke. No influence on neurological three-month outcomes or on cerebral blood flow was seen. These results justify larger trials comparing mobilization protocols with possibly even faster mobilization out of bed than explored here.

Afatinib versus placebo as adjuvant therapy after chemoradiation in a double-blind, phase III study (LUX-Head & Neck 2) in patients with primary unresected, clinically intermediate-to-high-risk head and neck cancer: study protocol for a randomized controlled trial.

BACKGROUND: Over 50% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced disease. Those at intermediate-to-high risk of recurrence after definitive therapy exhibit advanced disease based on tumour size or lymph node involvement, non-oropharynx primary sites, human papillomavirus (HPV)-negative oropharyngeal cancer, or HPV-positive oropharynx cancer with smoking history (>10-pack-years). Non-surgical approaches include concurrent chemoradiotherapy, induction chemotherapy followed by definitive radiotherapy or chemoradiotherapy, or radiotherapy alone. Following locoregional therapies (including surgical salvage of residual cervical nodes), no standard intervention exists. Overexpression of epidermal growth factor receptor (EGFR), an ErbB family member, is associated with poor prognosis in HNSCC. EGFR-targeted cetuximab is the only targeted therapy that impacts overall survival and is approved for HNSCC in the USA or Europe. However, resistance often occurs, and new approaches, such as targeting multiple ErbB family members, may be required. Afatinib, an irreversible ErbB family blocker, demonstrated antiproliferative activity in preclinical models and comparable clinical efficacy with cetuximab in a randomized phase II trial in recurrent or metastatic HNSCC. LUX-Head & Neck 2, a phase III study, will assess adjuvant afatinib versus placebo following chemoradiotherapy in primary unresected locoregionally advanced intermediate-to-high-risk HNSCC. METHODS/DESIGN: Patients with primary unresected locoregionally advanced HNSCC, in good clinical condition with unfavourable risk of recurrence, and no evidence of disease after chemoradiotherapy will be randomized 2:1 to oral once-daily afatinib (40 mg starting dose) or placebo. As HPV status will not be determined for eligibility, unfavourable risk is defined as non-oropharynx primary site or oropharynx cancer in patients with a smoking history (>10 pack-years). Treatment will continue for 18 months or until recurrence or unacceptable adverse events occur. The primary endpoint measure is duration of disease-free survival; secondary endpoint measures are disease-free survival rate at 2 years, overall survival, health-related quality of life and safety. DISCUSSION: Given the unmet need in the adjuvant treatment of intermediate-to-high-risk HNSCC patients, it is expected that LUX-Head & Neck 2 will provide new insights into treatment in this setting and might demonstrate the ability of afatinib to significantly improve disease-free survival, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT01345669.

Learning from failure - rationale and design for a study about discontinuation of randomized trials (DISCO study).

BACKGROUND: Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. METHODS/DESIGN: Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs.We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. DISCUSSION: Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

SWIVIT - Swiss video-intubation trial evaluating video-laryngoscopes in a simulated difficult airway scenario: study protocol for a multicenter prospective randomized controlled trial in Switzerland.

BACKGROUND: Video-laryngoscopes are marketed for intubation in difficult airway management. They provide a better view of the larynx and may facilitate tracheal intubation, but there is no adequately powered study comparing different types of video-laryngoscopes in a difficult airway scenario or in a simulated difficult airway situation. METHODS/DESIGN: The objective of this trial is to evaluate and to compare the clinical performance of three video-laryngoscopes with a guiding channel for intubation (Airtraq?, A. P. Advance?, King Vision?) and three video-laryngoscopes without an integrated tracheal tube guidance (C-MAC?, GlideScope?, McGrath?) in a simulated difficult airway situation in surgical patients. The working hypothesis is that each video-laryngoscope provides at least a 90% first intubation success rate (lower limit of the 95% confidence interval >0.9). It is a prospective, patient-blinded, multicenter, randomized controlled trial in 720 patients who are scheduled for elective surgery under general anesthesia, requiring tracheal intubation at one of the three participating hospitals. A difficult airway will be created using an extrication collar and taping the patients' head on the operating table to substantially reduce mouth opening and to minimize neck movement. Tracheal intubation will be performed with the help of one of the six devices according to randomization. Insertion success, time necessary for intubation, Cormack-Lehane grade and percentage of glottic opening (POGO) score at laryngoscopy, optimization maneuvers required to aid tracheal intubation, adverse events and technical problems will be recorded. Primary outcome is intubation success at first attempt. DISCUSSION: We will simulate the difficult airway and evaluate different video-laryngoscopes in this highly realistic and clinically challenging scenario, independently from manufacturers of the devices. Because of the sufficiently powered multicenter design this study will deliver important and cutting-edge results that will help clinicians decide which device to use for intubation of the expected and unexpected difficult airway. TRIAL REGISTRATION: NCT01692535.

A pilot feasibility, safety and biological efficacy multicentre trial of therapeutic hypercapnia after cardiac arrest: study protocol for a randomized controlled trial.

BACKGROUND: Cardiac arrest causes ischaemic brain injury. Arterial carbon dioxide tension (PaCO2) is a major determinant of cerebral blood flow. Thus, mild hypercapnia in the 24 h following cardiac arrest may increase cerebral blood flow and attenuate such injury. We describe the Carbon Control and Cardiac Arrest (CCC) trial. METHODS/DESIGN: The CCC trial is a pilot multicentre feasibility, safety and biological efficacy randomized controlled trial recruiting adult cardiac arrest patients admitted to the intensive care unit after return of spontaneous circulation. At admission, using concealed allocation, participants are randomized to 24 h of either normocapnia (PaCO2 35 to 45 mmHg) or mild hypercapnia (PaCO2 50 to 55 mmHg). Key feasibility outcomes are recruitment rate and protocol compliance rate. The primary biological efficacy and biological safety measures are the between-groups difference in serum neuron-specific enolase and S100b protein levels at 24 h, 48 h and 72 h. Secondary outcome measure include adverse events, in-hospital mortality, and neurological assessment at 6 months. DISCUSSION: The trial commenced in December 2012 and, when completed, will provide clinical evidence as to whether targeting mild hypercapnia for 24 h following intensive care unit admission for cardiac arrest patients is feasible and safe and whether it results in decreased concentrations of neurological injury biomarkers compared with normocapnia. Trial results will also be used to determine whether a phase IIb study powered for survival at 90 days is feasible and justified. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000690853 .

Thromboxane prostaglandin receptor antagonist and carotid atherosclerosis progression in patients with cerebrovascular disease of ischemic origin: a randomized controlled trial.

BACKGROUND AND PURPOSE: Thromboxane prostaglandin receptors have been implicated to be involved in the atherosclerotic process. We assessed whether Terutroban, a thromboxane prostaglandin receptor antagonist, affects the progression of atherosclerosis, as measured by common carotid intima-media thickness and carotid plaques. METHODS: A substudy was performed among 1141 participants of the aspirin-controlled Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin with Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) trial. Common carotid intima-media thickness and carotid plaque occurrence was measured during a 3-year period. RESULTS: Baseline characteristics did not differ between Terutroban (n=592) and aspirin (n=549) treated patients and were similar as in the main study. Mean study and treatment duration were similar (28 and 25 months, respectively). In the Terutroban group, the annualized rate of change in common carotid intima-media thickness was 0.006 mm per year (95% confidence interval, -0.004 to 0.016) and -0.005 mm per year (95% confidence interval, -0.015 to 0.005) in the aspirin group. There was no statistically significant difference between the groups in the annualized rate of change of common carotid intima-media thickness (0.011 mm per year; 95% confidence interval, -0.003 to 0.025). At 12 months of follow-up, 66% of Terutroban patients had no emergent plaques, 31% had 1 to 2 emergent plaques, and 3% had ≥3 emergent plaques. In the aspirin group, the corresponding percentages were 64%, 32%, and 4%. Over time, there was no statistically significant difference in the number of emergent carotid plaques between treatment modalities (rate ratio, 0.91; 95% confidence interval, 0.77-1.07). CONCLUSIONS: Compared with aspirin, Terutroban did not beneficially affect progression of carotid atherosclerosis among well-treated patients with a history of ischemic stroke or transient ischemic attacks with an internal carotid stenosis <70%. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN66157730.

Internet-Based Brief Intervention to Prevent Unhealthy Alcohol Use among Young Men: A Randomized Controlled Trial.

Alcohol use is one of the leading modifiable morbidity and mortality risk factors among young adults. 2 parallel-group randomized controlled trial with follow-up at 1 and 6 months. Internet based study in a general population sample of young men with low-risk drinking, recruited between June 2012 and February 2013. Intervention: Internet-based brief alcohol primary prevention intervention (IBI). The IBI aims at preventing an increase in alcohol use: it consists of normative feedback, feedback on consequences, calorific value alcohol, computed blood alcohol concentration, indication that the reported alcohol use is associated with no or limited risks for health. Intervention group participants received the IBI. Control group (CG) participants completed only an assessment. Alcohol use (number of drinks per week), binge drinking prevalence. Analyses were conducted in 2014-2015. Of 4365 men invited to participate, 1633 did so; 896 reported low-risk drinking and were randomized (IBI: n = 451; CG: n = 445). At baseline, 1 and 6 months, the mean (SD) number of drinks/week was 2.4(2.2), 2.3(2.6), 2.5(3.0) for IBI, and 2.4(2.3), 2.8(3.7), 2.7(3.9) for CG. Binge drinking, absent at baseline, was reported by 14.4% (IBI) and 19.0% (CG) at 1 month and by 13.3% (IBI) and 13.0% (CG) at 6 months. At 1 month, beneficial intervention effects were observed on the number of drinks/week (p = 0.05). No significant differences were observed at 6 months. We found protective short term effects of a primary prevention IBI. Controlled-Trials.com ISRCTN55991918.

Premature Discontinuation of Randomized Trials in Critical and Emergency Care: A Retrospective Cohort Study.

OBJECTIVES: Randomized clinical trials that enroll patients in critical or emergency care (acute care) setting are challenging because of narrow time windows for recruitment and the inability of many patients to provide informed consent. To assess the extent that recruitment challenges lead to randomized clinical trial discontinuation, we compared the discontinuation of acute care and nonacute care randomized clinical trials. DESIGN: Retrospective cohort of 894 randomized clinical trials approved by six institutional review boards in Switzerland, Germany, and Canada between 2000 and 2003. SETTING: Randomized clinical trials involving patients in an acute or nonacute care setting. SUBJECTS AND INTERVENTIONS: We recorded trial characteristics, self-reported trial discontinuation, and self-reported reasons for discontinuation from protocols, corresponding publications, institutional review board files, and a survey of investigators. MEASUREMENTS AND MAIN RESULTS: Of 894 randomized clinical trials, 64 (7%) were acute care randomized clinical trials (29 critical care and 35 emergency care). Compared with the 830 nonacute care randomized clinical trials, acute care randomized clinical trials were more frequently discontinued (28 of 64, 44% vs 221 of 830, 27%; p = 0.004). Slow recruitment was the most frequent reason for discontinuation, both in acute care (13 of 64, 20%) and in nonacute care randomized clinical trials (7 of 64, 11%). Logistic regression analyses suggested the acute care setting as an independent risk factor for randomized clinical trial discontinuation specifically as a result of slow recruitment (odds ratio, 4.00; 95% CI, 1.72-9.31) after adjusting for other established risk factors, including nonindustry sponsorship and small sample size. CONCLUSIONS: Acute care randomized clinical trials are more vulnerable to premature discontinuation than nonacute care randomized clinical trials and have an approximately four-fold higher risk of discontinuation due to slow recruitment. These results highlight the need for strategies to reliably prevent and resolve slow patient recruitment in randomized clinical trials conducted in the critical and emergency care setting.