Rationale and design of the RE-LATED AF--AFNET 7 trial: REsolution of Left atrial-Appendage Thrombus--Effects of Dabigatran in patients with Atrial Fibrillation.

BACKGROUND: Dabigatran etexilate, a direct thrombin inhibitor and non-vitamin K antagonist oral anticoagulant (NOAC), has been shown to effectively prevent thromboembolic events in patients with non-valvular atrial fibrillation (AF). However, there is a paucity of data on the antithrombotic efficacy and safety of dabigatran in the resolution of left atrial appendage (LAA) thrombi in AF patients. OBJECTIVE: The primary objective of the RE-LATED AF trial is to assess whether dabigatran results in a faster complete LAA thrombus resolution as compared to vitamin K antagonist phenprocoumon. Secondary objectives are to assess the impact of dabigatran on complete LAA thrombus resolution rate within 6 weeks of treatment and change in LAA thrombus volume under treatment. Furthermore, this study aims to assess and compare safety and tolerability of dabigatran vs. phenprocoumon. METHODS: The study is designed as a prospective, randomized, open-label, controlled, explorative, blinded endpoint (PROBE) trial. Patients with AF and left atrial appendage thrombus confirmed by transoesophageal echocardiography (TEE) will be randomized to receive either dabigatran (150 mg bid) or phenprocoumon (INR 2-3) for the resolution of LAA thrombus formation for at least 21 days. Thrombus resolution will be determined by TEE 3 weeks after treatment initiation and subsequently at weeks 4 and 6, if the LAA thrombus has not been resolved before. A total of 110 patients are planned to be randomized. CONCLUSION: This is the first prospective, multicentre, randomized controlled clinical trial investigating safety and efficacy of a NOAC for the resolution of LAA thrombi in patients with non-valvular AF.

Randomized controlled trials: part 17 of a series on evaluation of scientific publications.

BACKGROUND: In clinical research, randomized controlled trials (RCTs) are the best way to study the safety and efficacy of new treatments. RCTs are used to answer patient-related questions and are required by governmental regulatory bodies as the basis for approval decisions. METHODS: To help readers understand and evaluate RCTs, we discuss the methods and qualitative requirements of RCTs with reference to the literature and an illustrative case study. The discussion here corresponds to expositions of the subject that can be found in many textbooks but also reflects the authors' personal experience in planning, conducting and analyzing RCTs. RESULTS: The quality of an RCT depends on an appropriate study question and study design, the prevention of systematic errors, and the use of proper analytical techniques. All of these aspects must be attended to in the planning, conductance, analysis, and reporting of RCTs. RCTs must also meet ethical and legal requirements. CONCLUSION: RCTs cannot yield reliable data unless they are planned, conducted, analyzed, and reported in ways that are methodologically sound and appropriate to the question being asked. The quality of any RCT must be critically evaluated before its relevance to patient care can be considered.

Rationale and design of the randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with major depressive disorder--the EMC trial.

BACKGROUND: In major depressive disorder (MDD), the traditional belief of a delayed onset of antidepressants' effects has lead to the concept of current guidelines that treatment durations should be between 3-8 weeks before medication change in case of insufficient outcome. Post hoc analyses of clinical trials, however, have shown that improvement usually occurs within the first 10-14 days of treatment and that such early improvement (Hamilton Depression Rating Scale [HAMD] decrease >or=20%) has a substantial predictive value for final treatment outcome. Even more important, non-improvement (HAMD decrease <20%) after 14 days of treatment was found to be highly predictive for a poor final treatment outcome. METHODS/DESIGN: The EMC trial is a phase IV, multi-centre, multi-step, randomized, observer-blinded, actively controlled parallel-group clinical trial to investigate for the first time prospectively, whether non-improvers after 14 days of antidepressant treatment with an early medication change (EMC) are more likely to attain remission (HAMD-17

German Paediatric Research Network (PAED-Net).

Clinical trials in children are mandatory to generate data on new drugs as well as on drugs used off-label or for unlicensed indications. The EU Paediatric Regulation introduced in 2007 provides the background, goals, and requirements for pediatric clinical trials. The German Paediatric Network (PAED-Net) was established in 2002 with a public grant from the German Ministry of Education and Research with the aim of developing competence, infrastructure, networking, and education for pediatric clinical trials. The network, consisting of six pediatric clinical units and a coordinating office, has progressed very well and has achieved valuable improvements concerning the conduct of pediatric clinical trials. In addition, training programs have encouraged knowledge about clinical trials in investigators and nurses and have made medical professionals as well as the public aware of the need and advantages of trials in children. Although these trials are still challenging from the ethical, scientific, and clinical points of view, quality-controlled data are the prerequisite for sharing therapeutic innovations for children and for applying the principles of evidence-based medicine to the youngest patient population.

Kinetics and dynamics of the peripheral neurokinin-1 receptor antagonist SLV317 in healthy individuals.

AIMS: To investigate the pharmacokinetics and the pharmacodynamic effects in dorsal hand veins of the neurokinin-1 receptor antagonist SLV317. METHODS: In a randomized, double-blind, placebo-controlled cross-over study 19 healthy men received a single oral dose of SLV317 or placebo. Blood samples were collected for analysis of SLV317 plasma concentrations and the inhibition of the venodilator response to substance P was evaluated using the hand vein compliance method. RESULTS: Administration of 250 mg SLV317 as an oral solution was well tolerated and resulted in mean peak plasma concentrations (+/- SEM) of 77 +/- 9 ng ml(-1) within 47 +/- 3 min; the mean half-life was 9.9 +/- 1.6 h. In hand veins preconstricted with phenylephrine, local infusion of substance P resulted in a mean venodilation of 56 +/- 8% and 49 +/- 6% (P = 0.91) before administration of SLV317 or placebo, respectively. SLV317 caused a substantial inhibition of substance P-induced venodilation, whereas placebo had no effect (P < 0.001). The maximum antagonizing effect of SLV317 averaged 95 +/- 8% and was observed after 1.47 +/- 00.24 h. Correspondingly, the mean area under the effect curve after administration of SLV317 [278 +/- 67% h(-1); 95% confidence interval (CI) 198, 358] was significantly higher compared with placebo (49 +/- 12% h(-1); 95% CI -24, 122; P < 0.001). CONCLUSIONS: This study demonstrates that the neurokinin-1 receptor antagonist SLV317 is an orally active and highly effective antagonist of substance P-induced effects in humans.

HEGPOL: randomized, placebo controlled, multicenter, double-blind clinical trial to investigate hepatoprotective effects of glycine in the postoperative phase of liver transplantation [ISRCTN69350312].

BACKGROUND: Kupffer cell-dependent ischemia/reperfusion (I/R) injury after liver transplantation is still of high clinical relevance, as it is strongly associated with primary dysfunction and primary nonfunction of the graft. Glycine, a non-toxic, non-essential amino acid has been conclusively shown in various experiments to prevent both activation of Kupffer cells and reperfusion injury. Based on both experimental and preliminary clinical data this study protocol was designed to further evaluate the early effect of glycine after liver transplantation. METHODS/DESIGN: A prospective double-blinded randomized placebo-controlled multicenter study with two parallel groups in a total of 130 liver transplant recipients was designed to assess the effect of multiple intravenous doses of glycine after transplantation. Primary endpoints in hierarchical order are: peak levels of both aspartat-amino-transaminase (AST) and alanine-amino-transaminase (ALT) as surrogates for the progression of liver related injury, as well as both graft and patient survival up to 2 years after transplantation. Furthermore, the effect of glycine on cyclosporine A-induced nephrotoxicity is evaluated. DISCUSSION: The ongoing clinical trial represents an advanced element of the research chain, along which a scientific hypothesis has to go by, in order to reach the highest level of evidence; a randomized, prospective, controlled double-blinded clinical trial. If the data of this ongoing research project confirm prior findings, glycine would improve the general outcome after liver transplantation.