The German trial on Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE): a multicenter, randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE. METHODS: The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0-2 vs. 3-6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months. RESULTS: The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set (n = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0-2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing). CONCLUSION: GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions. TRIAL REGISTRATION: EudraCT-Nr. 2005-003201-81.

[Mission and tasks of the Coordination Centres for Clinical Trials]. / Aufgaben der Koordinierungszentren für Klinische Studien.

Coordination Centres for Clinical Trials (Koordinierungszentren für Klinische Studien, KKS) were set up to increase the quality and number of clinical trials in Germany as well as to establish clinical trial training programs in order to improve international recognition of German clinical research. Over the past 6 years, 12 KKS have been set up at the respective universities with a public grant from the Federal Ministry of Education and Research (BMBF). Many non-clinical services have been established to ensure successful co-operation in clinical trials with clinical scientists and industry. KKS help researchers to efficiently conduct commercial and non-commercial clinical trials in various disease areas. Their expertise and infrastructure allow the university to assume sponsor responsibility in non-commercial drug trials. Because of their professional work and education activities KKS are well accepted by industry and the scientific community. Central professional trial organisations such as the KKS have been shown to be the pre-requisite for meeting the growing, manifold and complex requirements for clinical trials. Therefore they are considered essential for progress and success in clinical research.

Usage and usability of standard operating procedures (SOPs) among the coordination centers for clinical trials (KKS).

OBJECTIVES: With Standard Operating Procedures (SOPs) the conduction of clinical trials should be standardized so that the results are comparable and traceable. This aim can only be reached if the staff of clinical trials really uses the SOPs. Therefore, we conducted a survey to explore the use and usability of SOPs in clinical trials and to identify problems for their handling. METHOD: Standardized, validated questionnaire among the staff of all 12 coordination centers for clinical trials in Germany (n = 238), anonymous, descriptive analyses RESULTS: A return rate of 58.8% was reached. When having questions about the daily work 18.4% more likely ask a colleague than read the corresponding SOP (13.8%). For the relevance of SOPs 16.9% of the staff regard less than 10% of SOPs as relevant for them. Exclusively working with electronic SOPs are 4%. CONCLUSIONS: The results of the survey indicate that improvements for the handling of SOPs are necessary. They could be used to design a computer-based information retrieval system for SOPs to increase the ease-of-use and usefulness of SOPs in clinical trials.

Comparison of Venae Sectio vs. modified Seldinger Technique for totally implantable access ports; Portas-trial [ISRCTN:52368201].

BACKGROUND: The insertion of a Totally Implantable Access Port (TIAP) is a routinely employed technique in patients who need a safe and permanent venous access. The number of TIAP implantations is increasing constantly mainly due to advanced treatment options for malignant diseases. Therefore it is important to identify the implantation technique which has the optimal benefit/risk ratio for the patient. STUDY DESIGN: A single-centre, randomized, controlled superiority trial to compare two different TIAP implantation techniques. SAMPLE SIZE: 160 patients will be included and randomized intra-operatively. ELIGIBILITY CRITERIA: Age equal or older than 18 years, patients scheduled for primary elective implantation of a TIAP in local anaesthesia and a signed informed consent. Primary endpoint: Primary success rate of the randomized technique. INTERVENTION: Venae Sectio in combination with the Seldinger Technique (guide wire and a peel away sheath) will be used to place a TIAP. Reference treatment: Conventional Venae Sectio will be used with a direct insertion of the TIAP without guide wire or peel away sheath. Duration of study: Approximately 20 months. ORGANISATION/RESPONSIBILITY: The trial will be conducted in compliance with the protocol and in accordance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). The trial will also be carried out in keeping with local and regulatory requirements. The Klinisches Studienzentrum Chirurgie (KSC)--Centre of Clinical Trials in Surgery at the Department of Surgery, University Hospital Heidelberg is responsible for planning and conduction of the trial. Documentation of patient's data will be accomplished via electronical Case Report Files (eCRF) with MACRO-Software by the KSC. Randomization, data management, monitoring and biometry are provided by the independent Koordinierungszentrum für Klinische Studien (KKS)--Coordination Centre for Clinical Trails at the University of Heidelberg.

[Aim, content, evaluation and perspectives of surgical training in randomized trials at the Study Centre of the German Surgical Society]. / Chirurgischer Prüfarztkurs des Studienzentrums der Deutschen Gesellschaft für Chirurgie. Ziel, Inhalte, Evaluationsergebnisse und Ausblick.

BACKGROUND: Clinical research, especially the management of randomized controlled multicentre trials, is a challenge for surgical investigators. To provide the theoretical background and practical knowledge needed for surgical trials, it is necessary to revise standard training programmes, which focus on pharmacological research. The main differences concern regulatory aspects and content, especially in achieving and maintaining comparability, equal treatment, and outcome assessment using special randomisation techniques and standardised surgical procedures. METHODS: In November 2005, in cooperation with the Coordinating Centre for Clinical Trials in Heidelberg, the Study Centre of the German Surgical Society Study Group (SDGC) hosted a clinical investigation course for surgeons. During 3 days, 24 participants were systematically instructed by 16 lecturers on clinical trials (planning, treatment by protocol, data management, biometrics, ethics, and law), followed by participants' evaluation of the course. RESULTS: On a scale of 1 to 6 (excellent to insufficient, respectively) the mean grades for the course were 1.6 for content, 1.55 for clarity, and 1.55 for learning effect. Partial repetition, lack of work in small groups, and not enough materials to take home were the major criticisms. CONCLUSIONS: The evaluation emphasised the necessity and value of the course. Further courses with continued evaluation are necessary and can be based on the same underlying concept. However, the mere qualification of surgeons as clinical investigators without substantial additional improvements in structural problems and increased financial project support will not fundamentally improve clinical research in Germany.

Cost-effectiveness and high patient satisfaction in the elderly: sevoflurane versus propofol anaesthesia.

BACKGROUND AND OBJECTIVE: The use of propofol compared with isoflurane is associated with improved patient comfort and decreased costs. However, as the cost saving, the quicker recovery time and patient comfort may not be evident if sevoflurane is substituted for isoflurane; these two anaesthetic agents were analysed in elderly patients. METHODS: In a prospective randomized study, 96 patients undergoing elective ophthalmic surgery received either total intravenous anaesthesia with propofol (Group P), propofol for induction and sevoflurane for maintenance (Group P/S) or sevoflurane for inhalation induction and maintenance (Group S). Analyses focussed on haemodynamics, the quality of recovery, and the costs for the anaesthetic and the entire procedure. RESULTS: Bradycardia or hypotension, mainly registered in Groups P and P/S, did not influence patients' recovery. In Group S, postoperative nausea and vomiting occurred frequently, and 50% of patients complained of discomfort during induction. In Group P/S, the costs for anaesthetics and total costs were lower than those in Groups P and S. CONCLUSIONS: Propofol- and sevoflurane-based maintenance of anaesthesia were similar with regard to patient comfort and recovery in the elderly. Cost analysis revealed that it was less expensive to use propofol for induction and sevoflurane for maintenance than to use either propofol or sevoflurane as sole agents for anaesthesia.

Assessment of sex hormone-binding globulin and osteocalcin in patients undergoing coronary artery bypass graft surgery.

OBJECTIVE: To determine sex hormone-binding globulin (SHBG) and osteocalcin (OC) levels in patients undergoing coronary artery bypass graft surgery to clarify the status of peripheral thyroid metabolism and to correlate SHBG and OC with thyroid hormones and adverse postoperative events. DESIGN: Prospective study. SETTING: University medical center. PARTICIPANTS: Fifty randomly selected patients undergoing coronary artery bypass graft surgery. INTERVENTIONS: On the morning of surgery before induction of anesthesia; 30 minutes after cross-clamping of the aorta; 2 hours and 6 hours after aortic cross-clamp removal; and on the first, second, third, and seventh postoperative mornings, blood samples were drawn and analyzed for OC, SHBG, triiodothyronine (tT3), free T3 (fT3), thyroxine (tT4), free T4 (fT4), thyroid-stimulating hormone, and thyroid-binding globulin. Adverse postoperative events were recorded. MEASUREMENTS AND MAIN RESULTS: Mean tT3 and fT3 decreased on average by 35% and 18% but remained within the normal range perioperatively. Similarly, mean SHBG and OC remained within the normal range. More than half of the patients investigated (60%) had OC concentrations below the normal range. Patients with pathologically decreased tT3 (n = 6) and tT4 (n = 16) intraoperatively and postoperatively had SHBG and OC concentrations similar to those in patients with normal tT3 and tT4 levels. Patients with postoperative complications had significantly lower OC levels preoperatively and on the first postoperative morning than those with an uneventful postoperative recovery. CONCLUSION: Despite significant intraoperative and postoperative decreases in levels of thyroid hormones, low T3 syndrome was rare in this patient population. Unchanged concentrations of SHBG and OC in patients with pathologically decreased tT3 or tT4 suggest normal local thyroid exposure at the tissue sites in these patients. OC may act as a predictor for postoperative outcome.