The closure of the abdomen after median laparotomy is still a matter of debate among surgeons. Further well designed and performed randomised controlled trials determining the optimal method of abdominal fascial closure are needed.
This is a three armed, multi-centre, intra-operatively randomised, controlled, patient blinded trial. Over 20 surgical departments will enrol 600 patients who are planned for an elective primary abdominal operation. The objective of this study is to compare the frequency of abdominal incisional hernias between two continuous suture techniques with different, slowly absorbable monofilament materials and an interrupted suture using an absorbable braided suture material at one year postoperatively.
This trial will answer the question whether the continuous abdominal wall closure with a slowly absorbable material with longitudinal elasticity is superior to the continuous suture with a material lacking elasticity and to interrupted sutures with braided thread.
There are two ways to open the abdominal cavity in elective general surgery: vertically or transversely. Various clinical studies and a meta-analysis have postulated that the transverse approach is superior to other approaches as regards complications. However, in a recent survey it was shown that 90 % of all abdominal incisions in visceral surgery are still vertical incisions. This discrepancy between existing recommendations of clinical trials and clinical practice could be explained by the lack of acceptance of these results due to a number of deficits in the study design and analysis, subsequent low internal validity, and therefore limited external generalisability. The objective of this study is to address the issue from the patient's perspective.
This is an intraoperatively randomized controlled observer and patient-blinded two-group parallel equivalence trial. The study setting is the Department of General-, Visceral-, Trauma Surgery and Outpatient Clinic of the University of Heidelberg, Medical School. A total of 172 patients of both genders, aged over 18 years who are scheduled for an elective abdominal operation and are eligible for either a transverse or vertical incision. To show equivalence of the two approaches or the superiority of one of them from the perspective of the patient, a primary endpoint is defined: the pain experienced by the patient (VAS 0–100) on day two after surgery and the amount of analgesic required (piritramide [mg/h]). A confidence interval approach will be used for analysis. A global α-Level of 0.05 and a power of 0.8 is guaranteed, resulting in a size of 86 patients for each group. Secondary endpoints are: time interval to open and close the abdomen, early-onset complications (frequency of burst abdomen, postoperative pulmonary complications, and wound infection) and late complications (frequency of incisional hernias). Different outcome variables will be ranked by patients and surgeons to assess the relevance of possible endpoints from the patients' and surgeons' perspective.
This is a randomized controlled observer and patient-blinded two-group parallel trial to answer the question if the transverse abdominal incision is equivalent to the vertical one due to the described endpoints.
The optimal strategy for abdominal wall closure has been an issue of ongoing debate. Available studies do not specifically enroll patients who undergo emergency laparotomy and thus do not consider the distinct biological characteristics of these patients. The present randomized controlled trial evaluates the efficacy and safety of two commonly applied abdominal wall closure strategies in patients undergoing primary emergency midline laparotomy.
The CONTINT trial is a multicenter, open label, randomized controlled trial with a two-group parallel design. Patients undergoing a primary emergency midline laparotomy are enrolled in the trial. The two most commonly applied strategies of abdominal wall closure after midline laparotomy are compared: the continuous, all-layer suture technique using slowly absorbable monofilament material (two Monoplus® loops) and the interrupted suture technique using rapidly absorbable braided material (Vicryl® sutures). The primary endpoint within the CONTINT trial is an incisional hernia within 12 months or a burst abdomen within 30 days after surgery. As reliable data on this primary endpoint is not available for patients undergoing emergency surgery, an adaptive interim analysis will be conducted after the inclusion of 80 patients, allowing early termination of the trial if necessary or modification of design characteristics such as recalculation of sample size.
This is a randomized controlled multicenter trial with a two-group parallel design to assess the efficacy and safety of two commonly applied abdominal wall closure strategies in patients undergoing primary emergency midline laparotomy.
Several randomized controlled trials have compared different suture materials and techniques for abdominal wall closure with respect to the incidence of incisional hernias after midline laparotomy and shown that it remains, irrespective of the methods used, considerably high, ranging from 9% to 20%. The development of improved suture materials which would reduce postoperative complications may help to lower its frequency.
This is a historically controlled, single-arm, multi-centre, prospective trial to evaluate the safety of MonoMax® suture material for abdominal wall closure in 150 patients with primary elective midline incisions. INSECT patients who underwent abdominal closure using Monoplus® and PDS® will serve as historical control group. The incidences of wound infections and of burst abdomen are defined as composite primary endpoints. Secondary endpoints are the frequency of incisional hernias within one year after operation and safety. To ensure adequate comparability in surgical performance and recruitment, the 4 largest centres of the INSECT-Trial will participate. After hospital discharge, the investigators will examine the enrolled patients again at 30 days and at 12 ± 1 months after surgery.
This historically controlled, single-arm, multi-centre, prospective ISSAAC trial aims to assess whether the use of an ultra-long-lasting absorbable monofilament suture material is safe and efficient.
To examine the current ethical review process (ERP) of ethics committees in a non‐pharmacological trial from the perspective of a clinical investigator.
Prospective collection of data at the Study Centre of the German Surgical Society on the duration, costs and administrative effort of the ERP of a randomised controlled multicentre surgical INSECT Trial (INterrupted or continuous Slowly absorbable sutures—Evaluation of abdominal Closure Techniques Trial, ISRCTN 24023541) between November 2003 and May 2005.
18 ethics committees, including the ethics committee handling the primary approval, responsible overall for 32 clinical sites throughout Germany. 8 ethics committees were located at university medical schools (MSU) and 10 at medical chambers. Duration was measured as days between submission and receipt of final approval, costs in euros and administrative effort by calculation of the product of the total number of different types of documents and the mean number of copies required (primary approval acting as the reference standard).
The duration of the ERP ranged from 1 to 176 (median 31) days. The median duration was 26 days at MSUs compared with 34 days at medical chambers. The total cost was €2947. 1 of 8 ethics committees at universities (€250) and 8 of 10 at medical chambers charged a median fee of €162 (mean €269.70). The administrative effort for primary approval was 30. Four ethics committees required a higher administrative effort for secondary approval (37, 39, 42 and 104).
The ERP for non‐pharmacological multicentre trials in Germany needs improvement. The administrative process has to be standardised: the application forms and the number and content of the documents required should be identical or at least similar. The fees charged vary considerably and are obviously too high for committees located at medical chambers. However, the duration of the ERP was, with some exceptions, excellent. A centralised ethics committee in Germany for multicentre trials such as the INSECT Trial can simplify the ERP for clinical investigators in and outside the country.
After its introduction, laparoscopic cholecystectomy rapidly expanded around the world and was accepted the procedure of choice by consensus. However, analysis of evidence shows no difference regarding primary outcome measures between laparoscopic and small-incision cholecystectomy. In absence of clear clinical benefit it may be interesting to focus on the resource use associated with the available techniques, a secondary outcome measure. This study focuses on a difference in costs between laparoscopic and small-incision cholecystectomy from a societal perspective with emphasis on internal validity and generalisability
A blinded randomized single-centre trial was conducted in a general teaching hospital in The Netherlands. Patients with reasonable to good health diagnosed with symptomatic cholecystolithiasis scheduled for cholecystectomy were included. Patients were randomized between laparoscopic and small-incision cholecystectomy. Total costs were analyzed from a societal perspective.
Operative costs were higher in the laparoscopic group using reusable laparoscopic instruments (difference 203 euro; 95% confidence interval 147 to 259 euro). There were no significant differences in the other direct cost categories (outpatient clinic and admittance related costs), indirect costs, and total costs. More than 60% of costs in employed patients were caused by sick leave.
Based on differences in costs, small-incision cholecystectomy seems to be the preferred operative technique over the laparoscopic technique both from a hospital and societal cost perspective. Sick leave associated with convalescence after cholecystectomy in employed patients results in considerable costs to society.
ISRCTN Register, number ISRCTN67485658.
Concomitant treatment in addition to intervention may influence the primary outcome, especially in complex interventions such as surgical trials. Evidence-based standards for perioperative care after distal pancreatectomy, however, have been rarely defined. This study's objective was therefore to identify and analyse the current basis of evidence for perioperative management in distal pancreatectomy.
A standardised questionnaire was sent to 23 European centres recruiting patients for a randomized controlled trial (RCT) on open distal pancreatectomy that would compare suture versus stapler closure of the pancreatic remnant (DISPACT trial, ISRCTN 18452029). Perioperative strategies (e.g., bowel preparation, pain management, administration of antibiotics, abdominal incision, drainages, nasogastric tubes, somatostatin, mobilisation and feeding regimens) were assessed. Moreover, a systematic literature search in the Medline database was performed and retrieved meta-analyses and RCTs were reviewed.
All 23 centres returned the questionnaire. Consensus for thoracic epidural catheters (TECs), pain treatment and transverse incisions was found, as well as strong consensus for the placement of intra-abdominal drainages and perioperative single-shot antibiotics. Also, there was consensus that bowel preparation, somatostatin application, postoperative nasogastric tubes and intravenous feeding might not be beneficial. The literature search identified 16 meta-analyses and 19 RCTs demonstrating that bowel preparation, somatostatin therapy and nasogastric tubes can be omitted. Early mobilisation, feeding and TECs seem to be beneficial for patients. The value of drainages remains unclear.
Most perioperative standards within the centres participating in the DISPACT trial are in accordance with current available evidence. The need for drainages requires further investigation.
Clinical trial registration: ISRCTN 18452029
Hepatic resection is still associated with significant morbidity. Although the period of parenchymal transection presents a crucial step during the operation, uncertainty persists regarding the optimal technique of transection. It was the aim of the present randomized controlled trial to evaluate the efficacy and safety of hepatic resection using the technique of stapler hepatectomy compared to the simple clamp-crushing technique.
The CRUNSH Trial is a prospective randomized controlled single-center trial with a two-group parallel design. Patients scheduled for elective hepatic resection without extrahepatic resection at the Department of General-, Visceral- and Transplantation Surgery, University of Heidelberg are enrolled into the trial and randomized intraoperatively to hepatic resection by the clamp-crushing technique and stapler hepatectomy, respectively. The primary endpoint is total intraoperative blood loss. A set of general and surgical variables are documented as secondary endpoints. Patients and outcome-assessors are blinded for the treatment intervention.
The CRUNSH Trial is the first randomized controlled trial to evaluate efficacy and safety of stapler hepatectomy compared to the clamp-crushing technique for parenchymal transection during elective hepatic resection.
Controlled clinical trials of health care interventions are either explanatory or pragmatic. Explanatory trials test whether an intervention is efficacious; that is, whether it can have a beneficial effect in an ideal situation. Pragmatic trials measure effectiveness; they measure the degree of beneficial effect in real clinical practice. In pragmatic trials, a balance between external validity (generalizability of the results) and internal validity (reliability or accuracy of the results) needs to be achieved. The explanatory trial seeks to maximize the internal validity by assuring rigorous control of all variables other than the intervention. The pragmatic trial seeks to maximize external validity to ensure that the results can be generalized. However the danger of pragmatic trials is that internal validity may be overly compromised in the effort to ensure generalizability. We are conducting two pragmatic randomized controlled trials on interventions in the management of hypertension in primary care. We describe the design of the trials and the steps taken to deal with the competing demands of external and internal validity.
External validity is maximized by having few exclusion criteria and by allowing flexibility in the interpretation of the intervention and in management decisions. Internal validity is maximized by decreasing contamination bias through cluster randomization, and decreasing observer and assessment bias, in these non-blinded trials, through baseline data collection prior to randomization, automating the outcomes assessment with 24 hour ambulatory blood pressure monitors, and blinding the data analysis.
Clinical trials conducted in community practices present investigators with difficult methodological choices related to maintaining a balance between internal validity (reliability of the results) and external validity (generalizability). The attempt to achieve methodological purity can result in clinically meaningless results, while attempting to achieve full generalizability can result in invalid and unreliable results. Achieving a creative tension between the two is crucial.
Postoperative surgical site infections cause substantial morbidity, prolonged hospitalization, costs and even mortality and remain one of the most frequent surgical complications. Approximately 14% to 30% of all patients undergoing elective open abdominal surgery are affected and methods to reduce surgical site infection rates warrant further investigation and evaluation in randomized controlled trials.
To investigate whether the application of a circular plastic wound protector reduces the rate of surgical site infections in general and visceral surgical patients that undergo midline or transverse laparotomy by 50%. BaFO is a randomized, controlled, patient-blinded and observer-blinded multicenter clinical trial with two parallel surgical groups. The primary outcome measure will be the rate of surgical site infections within 45 days postoperative assessed according to the definition of the Center for Disease Control. Statistical analysis of the primary endpoint will be based on the intention-to-treat population. The global level of significance is set at 5% (2 sided) and sample size (n = 258 per group) is determined to assure a power of 80% with a planned interim analysis for the primary endpoint after the inclusion of 340 patients.
The BaFO trial will explore if the rate of surgical site infections can be reduced by a single, simple, inexpensive intervention in patients undergoing open elective abdominal surgery. Its pragmatic design guarantees high external validity and clinical relevance.
http://www.clinicaltrials.gov NCT01181206. Date of registration: 11 August 2010; date of first patient randomized: 8 September 2010
Abdominal dressing; Abdominal surgery; Randomized trial; Surgical site infection; Wound edge protector; Wound infection
Development of incisional hernia after open abdominal surgery remains a major cause of post-operative morbidity. The aim of this study was to determine the current practice of surgeons in terms of access to and closure of the abdominal cavity in elective open surgery.
Twelve surgical departments of the INSECT-Trial group documented the following variables for 50 consecutive patients undergoing abdominal surgery: fascial closure techniques, applied suture materials, application of subcutaneous sutures, subcutaneous drains, methods for skin closure. Descriptive analysis was performed and consensus of treatment variables was categorized into four levels: Strong consensus >95%, consensus 75–95%, overall agreement 50–75%, no consensus <50%.
157 out of 599 patients were eligible for analysis (85 (54%) midline, 54 (35%) transverse incisions). After midline incisions the fascia was closed continuously in 55 patients (65%), using slowly absorbable (n = 47, 55%), braided (n = 32, 38%) sutures with a strength of 1 (n = 48, 57%). In the transverse setting the fascia was closed continuously in 39 patients (72%) with slowly absorbable (n = 22, 41%) braided sutures (n = 27, 50%) with a strength of 1 (n = 30, 56%).
In the present evaluation midline incision was the most frequently applied access in elective open abdominal surgery. None of the treatments for abdominal wall closure (except skin closure in the midline group) is performed on a consensus level.
The RASCAL (Refractory Angina Spinal Cord stimulation and usuAL care) pilot study seeks to assess the feasibility of a definitive trial to assess if addition of spinal cord stimulation (SCS) to usual care is clinically superior and more cost-effective than usual care alone in patients with refractory angina.
This is an external pilot, patient-randomized controlled trial.
The study will take place at three centers in the United Kingdom - South Tees Hospitals NHS Foundation Trust (The James Cook University Hospital), Dudley Group of Hospitals NHS Foundation Trust, and Basildon and Thurrock University Hospitals NHS Foundation Trust.
The subjects will be 45 adults with refractory angina, that is, limiting angina despite optimal anti-angina therapy, Canadian Cardiovascular Society Functional Classification Class III and IV, angiographically documented coronary artery disease not suitable for revascularization, satisfactory multidisciplinary assessment and demonstrable ischemia on functional testing.
The study will be stratified by center, age and Canadian Cardiovascular Society Functional Classification.
Interventions will involve spinal cord stimulation plus usual care (‘SCS group’) or usual care alone (‘UC group’). Usual care received by both groups will include consideration of an education session with a pain consultant, trial of a transcutaneous electrical neurostimulation, serial thoracic sympathectomy and oral/systemic analgesics.
Expected outcomes will be recruitment and retention rates; reasons for agreeing/declining participation; variability in primary and secondary outcomes (to inform power calculations for a definitive trial); and completion rates of outcome measures. Trial patient-related outcomes include disease-specific and generic health-related quality of life, angina exercise capacity, intake of angina medications, frequency of angina attacks, complications and adverse events, and satisfaction.
The RASCAL pilot trial seeks to determine the feasibility and design of a definitive randomized controlled trial comparing the addition of spinal cord stimulation to usual care versus usual care alone for patients with refractory angina.
Fifteen patients have been recruited since recruitment opened in October 2011. The trial was originally scheduled to end in April 2013 but due to slow recruitment may have to be extended to late 2013.
Randomized controlled trial; Pilot study; Refractory angina; Spinal cord stimulation
Clinical studies on cognitive behavioral therapy (CBT) that include schizophrenia patients primarily on the basis of negative symptoms are uncommon. However, those studies are necessary to assess the efficacy of CBT on negative symptoms. This article first gives an overview of CBT on negative symptoms and discusses the methodological problems of selecting an adequate control group. Furthermore, the article describes a clinical study (the TONES-Study, ISRCTN 25455020), which aims to investigate whether CBT is specifically efficacious for the reduction of negative symptoms. This multicenter randomized clinical trial comparing CBT with cognitive remediation (CR) for control of nonspecific effects is depicted in detail. In our trial, schizophrenia patients (n = 198) participated in manualized individual outpatient treatments. Primary outcome is the negative syndrome assessed with the positive and negative syndrome scale, analyzed with multilevel linear mixed models. Patients in both groups moderately improved regarding the primary endpoint. However, against expectation, there was no difference between the groups after treatment in the intention to treat as well as in the per-protocol analysis. In conclusion, psychotherapeutic intervention may be useful for the reduction of negative symptoms. However, there is no indication for specific effects of CBT compared with CR.
schizophrenia; cognitive behavioral therapy; cognitive remediation; negative symptoms; randomized clinical trial
We investigated cosmetic outcomes of the midline sternotomy incision. A randomized clinical trial was conducted in 60 patients who underwent surgery through a midline sternotomy incision. Patients were divided into groups A (n=30) and B (n=30). In addition, the incision line was also divided into 2 regions (upper and lower halves) in each group. In group A, the upper half of the skin was closed with absorbable 4-0 braided polyglycolic acid sutures (Sentesor®, Boz; Ankara, Turkey), and the lower half was closed with 4-0 nonabsorbable monofilamentous polypropylene suture (Monoplen®, Boz), and vice versa in group B. Scar width and height were measured and photographed at the 6th postoperative month.
In both groups, the lower part of the incision showed inferior cosmetic results, regardless of the suture material (P < 0.05). On the other hand, the upper part of the incision in group A (the area of absorbable polyglycolic acid sutures) was significantly more hypertrophic.
We conclude that monofilament nylon sutures diminish the risk of hypertrophic scarring, in comparison with absorbable sutures. In the lower half of the sternotomy scar, increased tension and relative mobility of the skin over the xiphoid process lead to inferior cosmetic results, regardless of the suture material used.
Cardiac surgical procedures; cicatrix, hypertrophic/etiology/pathology; keloid/etiology; skin/injuries; sternum/surgery; surgical procedures, operative/methods; sutures
In recent years some studies have been published supporting the efficacy of light exposure, physical activity, sleep control and a Mediterranean diet pattern on the improvement or prevention of Depression. However, to our knowledge, there have been no studies using all these measures together as an adjuvant antidepressant strategy.
Multicenter, randomized, controlled, two arm-parallel, clinical trial. Eighty depressed patients undergoing standard antidepressant treatment will be advised to follow four additional hygienic-dietary recommendations about exercise, diet, sunlight exposure and sleep. Outcome measures will be assessed before and after the 6 month intervention period.
We expect the patients in the active recommendations group to experience a greater improvement in their depressive symptoms. If so, this would be a great support for doctors who might systematically recommend these simple and costless measures, especially in primary care.
Severe dental caries and the treatment thereof are reported to affect growth and well-being of young children. The objective of this study was to assess the effects of extraction of severely decayed pulpally involved primary teeth on weight and height in underweight preschool Filipino children.
Underweight preschool Filipino children with severe dental decay had their pulpally involved primary teeth extracted during a stepped wedge cluster randomized clinical trial. Day care centers were randomly divided into two groups; children from Group A day care centers received treatment as soon as practical, whereas children from Group B day care centers were treated four months after Group A. Clinical oral examinations using WHO criteria and the pufa-index were carried out. Anthropometric measurements were done on both groups immediately before treatment of Group A and at follow-up four months later. Height and weight z-scores were calculated using 2006 and 2007 WHO Growth Standards. Multilevel analysis was used to assess the effect of dental extractions on changes in anthropometric measurements after dental treatment.
Data on 164 children (85 in Group A and 79 in Group B), mean age 59.9 months, were analyzed. Both groups gained weight and height during the trial period. Children in Group A significantly increased their BMI (p < 0.001), and their weight-for-age (p < 0.01) and BMI-for-age z-scores (p < 0.001) after dental treatment, whereas untreated children in Group B did not. Children in Group A had significantly more weight gain (p < 0.01) compared to untreated children in Group B. However, children in Group A had an inverse change in height gain (p < 0.001). Adjustment for the time interval between the two visits had little effect on the results.
The extraction of severely decayed primary teeth resulted in significant weight gain in underweight Filipino children. Untreated dental decay should be considered an important co-factor affecting child growth and should be considered when planning for interventions to improve child growth.
Underweight; Weight gain; Growth; Dental caries; Dental decay; Tooth extraction; Dental extraction; Stepped wedge design; Cluster randomized trial; Clinical trial
In September 2004, the International Committee of Medical Journal Editors (ICMJE) issued a Statement requiring that all clinical trials be registered at inception in a public register in order to be considered for publication. The World Health Organization (WHO) and ICMJE have identified 20 items that should be provided before a trial is considered registered, including contact information. Identifying those scientifically responsible for trial conduct increases accountability. The objective is to examine the proportion of registered clinical trials providing valid scientific leadership information.
We reviewed clinical trial entries listing Canadian investigators in the two largest international and public trial registers, the International Standard Randomized Controlled Trial Number (ISRCTN) register, and ClinicalTrials.gov. The main outcome measures were the proportion of clinical trials reporting valid contact information for the trials' Principal Investigator (PI)/Co-ordinating Investigator/Study Chair/Site PI, and trial e-mail contact address, stratified by funding source, recruiting status, and register. A total of 1388 entries (142 from ISRCTN and 1246 from ClinicalTrials.gov) comprised our sample. We found non-compliance with mandatory registration requirements regarding scientific leadership and trial contact information. Non-industry and partial industry funded trials were significantly more likely to identify the individual responsible for scientific leadership (OR = 259, 95% CI: 95–701) and to provide a contact e-mail address (OR = 9.6, 95% CI: 6.6–14) than were solely industry funded trials.
Despite the requirements set by WHO and ICMJE, data on scientific leadership and contact e-mail addresses are frequently omitted from clinical trials registered in the two leading public clinical trial registers. To promote accountability and transparency in clinical trials research, public clinical trials registers should ensure adequate monitoring of trial registration to ensure completion of mandatory contact information fields identifying scientific leadership
Incisional hernia is a frequent complication in abdominal surgery. This article describes the development of a prospective randomized clinical trial designed to determine whether watchful waiting is an acceptable alternative to surgical repair for patients with oligosymptomatic incisional hernia.
This clinical multicenter trial has been designed to compare watchful waiting and surgical repair for patients with oligosymptomatic incisional hernia. Participants are randomized to watchful waiting or surgery and followed up for two years. The primary efficacy endpoint is pain/discomfort during normal activities as a result of the hernia or hernia repair two years after enrolment, as measured by the hernia-specific Surgical Pain Scales (SPS). The target sample size of six hundred thirty-six patients was calculated to detect non-inferiority of the experimental intervention (watchful waiting) in the primary endpoint. Sixteen surgical centers will take part in the study and have submitted their declaration of commitment giving the estimated number of participating patients per year. A three-person data safety monitoring board will meet annually to monitor and supervise the trial.
To date, we could find no published data on the natural course of incisional hernias. To our knowledge, watchful waiting has never been compared to standard surgical repair as a treatment option for incisional hernias. A trial to compare the outcome of the two approaches in patients with oligosymptomatic incisional hernias is urgently needed to provide data that can facilitate the choice between treatment options. If watchful waiting was equal to surgical repair, the high costs of surgical repair could be saved. The design for such a trial is described here.
This multicenter trial will be funded by the German Research Foundation (DFG). The ethics committee of the Charité has approved the study protocol. Approval has been obtained from ten study sites at time of this submission. The electronic Case Report Forms have been created. The first patient was to be randomized November 14th, 2011. An initiation meeting took place in Berlin January 9th, 2012.
oligosymptomatic incisional hernia; watchful waiting; surgical repair; prospective randomized trial
A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial.
The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm.
The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up.
This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen.
To compare the performance of community- vs university-based clinical centers in 3 multicenter randomized clinical trials of intraocular surgery.
Each Submacular Surgery Trials clinical center was classified as a university-based center, if the contract to perform as a center was signed by a university official, or as a community-based center. The 2 groups of centers were compared on performance, assessed cumulatively by the Submacular Surgery Trials Quality Assurance and Monitoring Subcommittee.
Patient accrual, completion of scheduled examinations, completion of masked vision examinations 2 years after enrollment (the designated primary study end point evaluation time), timeliness of submission of retinal photographs required by protocol to the Photograph Reading Center, completion of health- and vision-related quality-of-life interviews, and timeliness of submission of the primary outcome data to the Coordinating Center after completion of the examination.
Almost all centers performed at a very high (good) level, although there was a trend for some community-based centers to be at the lower end of most distributions.
Most community- and university-based centers performed well in these multicenter clinical trials. Monitoring performance and periodically providing feedback to clinical center investigators may encourage excellent performance in areas critical to the success of clinical trials, regardless of whether the center is community or university based.
The treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major unsolved problem in Neurology. Current gold standard for therapy is acyclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains up to 15%, less than 20% of patients are able to go back to work, and the majority of patients suffer from severe disability. This is a discouraging, unsatisfactory situation for treating physicians, the disabled patients and their families, and constitutes an enormous burden to the public health services. The information obtained from experimental animal research and from recent retrospective clinical observations, indicates that a substantial benefit in outcome can be expected in patients with HSVE who are treated with adjuvant dexamethasone. But currently there is no available evidence to support the routine use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter trial is the only useful instrument to address this question.
GACHE is a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with HSVE. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaptation in the last stage.
372 patients with proven HSVE (positive HSV-DNA-PCR), aged 18 up to 85 years; with focal neurological signs no longer than 5 days prior to admission, and who give informed consent will be recruited from Departments of Neurology of academic medical centers in Germany, Austria and The Netherlands. Sample size will potentially be extended after the second interim analysis up to a maximum of 450 patients.
Current Controlled Trials
Studies of type 2 translation, the adaption of evidence-based interventions to real-world settings, should include representative study sites and staff to improve external validity. Sites for such studies are, however, often selected by convenience sampling, which limits generalizability. We used an optimized probability sampling protocol to select an unbiased, representative sample of study sites to prepare for a randomized trial of a weight loss intervention.
We invited North Carolina health departments within 200 miles of the research center to participate (N = 81). Of the 43 health departments that were eligible, 30 were interested in participating. To select a representative and feasible sample of 6 health departments that met inclusion criteria, we generated all combinations of 6 from the 30 health departments that were eligible and interested. From the subset of combinations that met inclusion criteria, we selected 1 at random.
Of 593,775 possible combinations of 6 counties, 15,177 (3%) met inclusion criteria. Sites in the selected subset were similar to all eligible sites in terms of health department characteristics and county demographics.
Optimized probability sampling improved generalizability by ensuring an unbiased and representative sample of study sites.
Randomized clinical trials are considered to be the gold standard of evidence‐based medicine nowadays. However, it is important that we point out some limitations of randomized clinical trials relating to surgical interventions. There are limitations that affect the external and internal validity of many surgical study designs. Some limitations can be bypassed, but can make it more difficult for the study to be carried out. Other limitations cannot be bypassed. When it is intended to extrapolate the result of a randomized clinical trial, the premise is that the performed or to be performed intervention will be similar wherever applied and/or for every doctor using it. However, no matter how standardized the technique may be, the results are not similar for all surgeons, which implies a significant limitation to surgical randomized clinical trials concerning external validity. When considering the various limitations presented for performing surgical trials capable of generating scientific evidence within the patterns currently proposed in the evidence level classifications of medical publications, it is necessary to rethink whether those scientific evidence levels are similarly applicable to surgical works and to nonsurgical trials. We currently live in a time of supposed “inferiority” of surgical scientific works under the optics of the current quality criteria for a “suitable” clinical trial.
Clinical Trial; Surgery; Randomization; Blinding; Evidence Level
No randomised, controlled trials have been conducted to date on the efficacy of psychological and pharmacological treatments of pain catastrophising (PC) in patients with fibromyalgia. Our aim in this study was to assess the effectiveness of cognitive-behaviour therapy (CBT) and the recommended pharmacological treatment (RPT) compared with treatment as usual (TAU) at the primary care level for the treatment of PC in fibromyalgia patients.
We conducted a six-month, multicenter, randomized, blinded, parallel group, controlled trial in which patients were randomly assigned to one of three study arms: CBT (n = 57), RPT (n = 56) and TAU at the primary care level (n = 56). The major outcome of this study was PC in patients with fibromyalgia. The secondary variables were pain acceptance, depression, anxiety, pain, global function and quality of life.
CBT significantly decreased global PC at the six-month follow-up examination with effect sizes of Cohen's d = 0.73 and 1.01 compared with RPT and TAU, respectively. CBT was also more effective than RPT and TAU at increasing pain acceptance at the six-month follow-up examination (effect sizes of Cohen's d = 0.77 and 0.80, respectively). Compared with RPT and TAU, CBT was more effective at improving global function based on the Fibromyalgia Impact Questionnaire (six-month effect sizes Cohen's d = 0.44 and 0.53, respectively) and quality of life based on the European Quality of Life Scale (six-month effect sizes Cohen's d = 0.11 and 0.40, respectively). There were no differences among the three treatments with regard to pain and depression.
CBT shows higher efficacy than RPT and TAU not only in key outcomes in FM, such as function and quality of life, but also in relevant mediators of treatment effects, such as pain catastrophising and pain acceptance.
catastrophisation; fibromyalgia; randomised controlled trial; cognitive-behaviour therapy
Asthma Control Questionnaire (ACQ) is a validated tool to measure asthma control. Cut-off points that best discriminate “well-controlled” or “not well-controlled” asthma have been suggested from the analysis of a large randomized clinical trial but they may not be adequate for daily clinical practice.
To establish cut-off points of the ACQ that best discriminate the level of control according to Global Initiative for Asthma (GINA) 2006 guidelines in patients with asthma managed at Allergology and Pulmonology Departments as well as Primary Care Centers in Spain.
Patients and methods
An epidemiological descriptive study, with prospective data collection. Asthma control following GINA-2006 classification and 7-item ACQ was assessed. The study population was split in two parts: 2/3 for finding the cut-off points (development population) and 1/3 for validating the results (validation population).
A total of 1,363 stable asthmatic patients were included (mean age 38 ± 14 years, 60.3% women; 69.1% non-smokers). Patient classification according to GINA-defined asthma control was: controlled 13.6%, partially controlled 34.2%, and uncontrolled 52.3%. The ACQ cut-off points that better agreed with GINA-defined asthma control categories were calculated using receiver operating curves (ROC). The analysis showed that ACQ < 0.5 was the optimal cut-off point for “controlled asthma” (sensitivity 74.1%, specificity 77.5%) and 1.00 for “uncontrolled asthma” (sensitivity 73%, specificity 88.2%). Kappa index between GINA categories and ACQ was 0.62 (p < 0.001).
The ACQ cut-off points associated with GINA-defined asthma control in a real-life setting were <0.5 for controlled asthma and ≥1 for uncontrolled asthma.
Asthma control; GINA guidelines; Asthma control questionnaire; Validation study