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.

Intravitreal chemotherapy for vitreous seeding in retinoblastoma: Recent advances and perspectives.

For decades intravitreal chemotherapy (IViC) remained virtually banished from the therapeutic armamentarium against retinoblastoma, except as a heroic attempt of salvage before enucleation in only eyes with refractory vitreous seeding. Very recently, we have initiated a reappraisal of this route of administration by (1) profiling eligibility criteria, (2) describing a safety-enhanced injection procedure, (3) adjusting the tumoricidal dose of melphalan, and (4) reporting an unprecedented efficacy in terms of tumor control of vitreous seeding. Since then, intravitreal chemotherapy is being progressively implemented worldwide with great success, but still awaits formal validation by the ongoing prospective phase II clinical trial. As far as preliminary results are concerned, IViC appears to achieve complete vitreous response in 100% of the 35 newly recruited patients irrespective of the previous treatment regimen, including external beam radiotherapy and/or intra-arterial melphalan. In other words, vitreous seeding, still considered as the major cause of primary and secondary enucleation, can now be controlled by IViC. However, sterilization of vitreous seeding does not necessarily translate into eye survival, unless the retinal source of the seeds receives concomitant therapy. In conclusion, IViC, an unsophisticated and cost-effective treatment, is about to revolutionize the eye survival prognosis of vitreous disease in advanced retinoblastoma.

Disc degeneration: current surgical options.

Chronic low back pain attributed to lumbar disc degeneration poses a serious challenge to physicians. Surgery may be indicated in selected cases following failure of appropriate conservative treatment. For decades, the only surgical option has been spinal fusion, but its results have been inconsistent. Some prospective trials show superiority over usual conservative measures while others fail to demonstrate its advantages. In an effort to improve results of fusion and to decrease the incidence of adjacent segment degeneration, total disc replacement techniques have been introduced and studied extensively. Short-term results have shown superiority over some fusion techniques. Mid-term results however tend to show that this approach yields results equivalent to those of spinal fusion. Nucleus replacement has gained some popularity initially, but evidence on its efficacy is scarce. Dynamic stabilisation, a technique involving less rigid implants than in spinal fusion and performed without the need for bone grafting, represents another surgical option. Evidence again is lacking on its superiority over other surgical strategies and conservative measures. Insertion of interspinous devices posteriorly, aiming at redistributing loads and relieving pain, has been used as an adjunct to disc removal surgery for disc herniation. To date however, there is no clear evidence on their efficacy. Minimally invasive intradiscal thermocoagulation techniques have also been tried, but evidence of their effectiveness is questioned. Surgery using novel biological solutions may be the future of discogenic pain treatment. Collaboration between clinicians and basic scientists in this multidisciplinary field will undoubtedly shape the future of treating symptomatic disc degeneration.

The ADVANCE trial: clarifying the role of perindopril/indapamide fixed-dose combination in the reduction of cardiovascular and renal events in patients with diabetes mellitus.

Patients with type 2 diabetes mellitus exhibit a marked increase in cardiovascular and renal risk. A number of interventional trials have shown that these patients benefit greatly from aggressive BP lowering, especially when the drug regimen comprises an inhibitor of the renin-angiotensin system. The results of the placebo-controlled ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) trial, conducted in patients with type 2 diabetes, are exemplary in this respect. The systematic use of a fixed-dose combination containing the ACE inhibitor perindopril and the diuretic indapamide afforded substantial protection against cardiovascular mortality and myocardial infarction, while providing important renoprotection, reducing the development of micro- and macroalbuminuria, and allowing regression of nephropathy. The beneficial effects were obtained regardless of baseline BP and whether or not the patients were receiving antihypertensive therapy.

Randomized comparison of biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents for percutaneous coronary revascularization: Rationale and design of the BIOSCIENCE trial.

BACKGROUND: Biodegradable polymers for release of antiproliferative drugs from metallic drug-eluting stents aim to improve long-term vascular healing and efficacy. We designed a large scale clinical trial to compare a novel thin strut, cobalt-chromium drug-eluting stent with silicon carbide-coating releasing sirolimus from a biodegradable polymer (O-SES, Orsiro; Biotronik, Bülach, Switzerland) with the durable polymer-based Xience Prime/Xpedition everolimus-eluting stent (EES) (Xience Prime/Xpedition stent, Abbott Vascular, IL) in an all-comers patient population. DESIGN: The multicenter BIOSCIENCE trial (NCT01443104) randomly assigned 2,119 patients to treatment with biodegradable polymer sirolimus-eluting stents (SES) or durable polymer EES at 9 sites in Switzerland. Patients with chronic stable coronary artery disease or acute coronary syndromes, including non-ST-elevation and ST-elevation myocardial infarction, were eligible for the trial if they had at least 1 lesion with a diameter stenosis >50% appropriate for coronary stent implantation. The primary end point target lesion failure (TLF) is a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization within 12 months. Assuming a TLF rate of 8% at 12 months in both treatment arms and accepting 3.5% as a margin for noninferiority, inclusion of 2,060 patients would provide more than 80% power to detect noninferiority of the biodegradable polymer SES compared with the durable polymer EES at a 1-sided type I error of 0.05. Clinical follow-up will be continued through 5 years. CONCLUSION: The BIOSCIENCE trial will determine whether the biodegradable polymer SES is noninferior to the durable polymer EES with respect to TLF.

Clinical effectiveness of direct class II restorations: a meta-analysis.

Purpose: More than five hundred million direct dental restorations are placed each year worldwide. In about 55% of the cases, resin composites or compomers are used, and in 45% amalgam. The longevity of posterior resin restorations is well documented. However, data on resin composites that are placed without enamel/dentin conditioning and resin composites placed with self-etching adhesive systems are missing. Material and Methods: The database SCOPUS was searched for clinical trials on posterior resin composites without restricting the search to the year of publication. The inclusion criteria were: (1) prospective clinical trial with at least 2 years of observation; (2) minimum number of restorations at last recall = 20; (3) report on dropout rate; (4) report of operative technique and materials used; (5) utilization of Ryge or modified Ryge evaluation criteria. For amalgam, only those studies were included that directly compared composite resin restorations with amalgam. For the statistical analysis, a linear mixed model was used with random effects to account for the heterogeneity between the studies. P-values under 0.05 were considered significant. Results: Of the 373 clinical trials, 59 studies met the inclusion criteria. In 70% of the studies, Class II and Class I restorations had been placed. The overall success rate of composite resin restorations was about 90% after 10 years, which was not different from that of amalgam. Restorations with compomers had a significantly lower longevity. The main reason for replacement were bulk fractures and caries adjacent to restorations. Both of these incidents were infrequent in most studies and accounted only for about 6% of all replaced restorations after 10 years. Restorations with macrofilled composites and compomer suffered significantly more loss of anatomical form than restorations with other types of material. Restorations that were placed without enamel acid etching and a dentin bonding agent showed significantly more marginal staining and detectable margins compared to those restorations placed using the enamel-etch or etch-and-rinse technique; restorations with self-etching systems were between the other groups. Restorations with compomer suffered significantly more chippings (repairable fracture) than restorations with other materials, which did not statistically differ among each other. Restorations that were placed with a rubber-dam showed significantly fewer material fractures that needed replacement, and this also had a significant effect on the overall longevity. Conclusion: Restorations with hybrid and microfilled composites that were placed with the enamel-etching technique and rubber-dam showed the best overall performance; the longevity of these restorations was similar to amalgam restorations. Compomer restorations, restorations placed with macrofilled composites, and resin restorations with no-etching or self-etching adhesives demonstrated significant shortcomings and shorter longevity.

Anticonvulsants in the treatment of aggression in the demented elderly: an update

Complex psychopathological and behavioral symptoms, such as delusions and aggression against care providers, are often the primary cause of acute hospital admissions of elderly patients to emergency units and psychiatric departments. This issue resembles an interdisciplinary clinically highly relevant diagnostic and therapeutic challenge across many medical subjects and general practice. At least 50% of the dramatically growing number of patients with dementia exerts aggressive and agitated symptoms during the course of clinical progression, particularly at moderate clinical severity. METHODS: Commonly used rating scales for agitation and aggression are reviewed and discussed. Furthermore, we focus in this article on benefits and limitations of all available data of anticonvulsants published in this specific indication, such as valproate, carbamazepine, oxcarbazepine, lamotrigine, gabapentin and topiramate. RESULTS: To date, most positive and robust data are available for carbamazepine, however, pharmacokinetic interactions with secondary enzyme induction limit its use. Controlled data of valproate do not seem to support the use in this population. For oxcarbazepine only one controlled but negative trial is available. Positive small series and case reports have been reported for lamotrigine, gabapentin and topiramate. CONCLUSION: So far, data of anticonvulsants in demented patients with behavioral disturbances are not convincing. Controlled clinical trials using specific, valid and psychometrically sound instruments of newer anticonvulsants with a better tolerability profile are mandatory to verify whether they can contribute as treatment option in this indication.

Tibial tunnel placement in posterior cruciate ligament reconstruction: a systematic review.

PURPOSE: Reconstruction of the posterior cruciate ligament (PCL) yields less satisfying results than anterior cruciate ligament reconstruction with respect to laxity control. Accurate tibial tunnel placement is crucial for successful PCL reconstruction using arthroscopic tibial tunnel techniques. A discrepancy between anatomical studies of the tibial PCL insertion site and surgical recommendations for tibial tunnel placement remains. The objective of this study was to identify the optimal placement of the tibial tunnel in PCL reconstruction based on clinical studies. METHODS: In a systematic review of the literature, MEDLINE, EMBASE, Cochrane Review, and Cochrane Central Register of Controlled Trials were screened for articles about PCL reconstruction from January 1990 to September 2011. Clinical trials comparing at least two PCL reconstruction techniques were extracted and independently analysed by each author. Only studies comparing different tibial tunnel placements in the retrospinal area were included. RESULTS: This systematic review found no comparative clinical trial for tibial tunnel placement in PCL reconstruction. Several anatomical, radiological, and biomechanical studies have described the tibial insertion sites of the native PCL and have led to recommendations for placement of the tibial tunnel outlet in the retrospinal area. However, surgical recommendations and the results of morphological studies are often contradictory. CONCLUSIONS: Reliable anatomical landmarks for tunnel placement are lacking. Future randomized controlled trials could compare precisely defined tibial tunnel placements in PCL reconstruction, which would require an established mapping of the retrospinal area of the tibial plateau with defined anatomical and radiological landmarks.

Anticonvulsants in the treatment of aggression in the demented elderly: an update

Complex psychopathological and behavioral symptoms, such as delusions and aggression against care providers, are often the primary cause of acute hospital admissions of elderly patients to emergency units and psychiatric departments. This issue resembles an interdisciplinary clinically highly relevant diagnostic and therapeutic challenge across many medical subjects and general practice. At least 50% of the dramatically growing number of patients with dementia exerts aggressive and agitated symptoms during the course of clinical progression, particularly at moderate clinical severity. METHODS: Commonly used rating scales for agitation and aggression are reviewed and discussed. Furthermore, we focus in this article on benefits and limitations of all available data of anticonvulsants published in this specific indication, such as valproate, carbamazepine, oxcarbazepine, lamotrigine, gabapentin and topiramate. RESULTS: To date, most positive and robust data are available for carbamazepine, however, pharmacokinetic interactions with secondary enzyme induction limit its use. Controlled data of valproate do not seem to support the use in this population. For oxcarbazepine only one controlled but negative trial is available. Positive small series and case reports have been reported for lamotrigine, gabapentin and topiramate. CONCLUSION: So far, data of anticonvulsants in demented patients with behavioral disturbances are not convincing. Controlled clinical trials using specific, valid and psychometrically sound instruments of newer anticonvulsants with a better tolerability profile are mandatory to verify whether they can contribute as treatment option in this indication.

HIV-1 vaccines and adaptive trial designs.

Developing a vaccine against the human immunodeficiency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although nonhuman primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.

Atherosclerosis screening by noninvasive imaging for cardiovascular prevention: a systematic review.

BACKGROUND: Noninvasive imaging of atherosclerosis is being increasingly used in clinical practice, with some experts recommending to screen all healthy adults for atherosclerosis and some jurisdictions mandating insurance coverage for atherosclerosis screening. Data on the impact of such screening have not been systematically synthesized. OBJECTIVES: We aimed to assess whether atherosclerosis screening improves cardiovascular risk factors (CVRF) and clinical outcomes. DESIGN: This study is a systematic review. DATA SOURCES: We searched MEDLINE and the Cochrane Clinical Trial Register without language restrictions. STUDY ELIGIBILITY CRITERIA: We included studies examining the impact of atherosclerosis screening with noninvasive imaging (e.g., carotid ultrasound, coronary calcification) on CVRF, cardiovascular events, or mortality in adults without cardiovascular disease. RESULTS: We identified four randomized controlled trials (RCT, n=709) and eight non-randomized studies comparing participants with evidence of atherosclerosis on screening to those without (n=2,994). In RCTs, atherosclerosis screening did not improve CVRF, but smoking cessation rates increased (18% vs. 6%, p=0.03) in one RCT. Non-randomized studies found improvements in several intermediate outcomes, such as increased motivation to change lifestyle and increased perception of cardiovascular risk. However, such data were conflicting and limited by the lack of a randomized control group. No studies examined the impact of screening on cardiovascular events or mortality. Heterogeneity in screening methods and studied outcomes did not permit pooling of results. CONCLUSION: Available evidence about atherosclerosis screening is limited, with mixed results on CVRF control, increased smoking cessation in one RCT, and no data on cardiovascular events. Such screening should be validated by large clinical trials before widespread use.

Low incidence of severe respiratory syncytial virus infections in lung transplant recipients despite the absence of specific therapy.

BACKGROUND: Respiratory syncytial virus (RSV) infections in lung transplant recipients (LTRs) have been associated with significant morbidity and mortality. Immunoglobulins, ribavirin, and palivizumab are suggested treatments for both pre-emptive and therapeutic purposes. However, in the absence of randomized, placebo-controlled trials, efficacy is controversial and there is toxicity as well as cost concerns. METHODS: We retrospectively reviewed cases of lower respiratory tract RSV infections in adult LTRs. Diagnosis was based on clinical history, combined with a positive polymerase chain reaction (PCR) and/or viral cultures of bronchoalveolar lavage (BAL) specimens. RESULTS: Ten symptomatic patients were identified (7 men and 3 women, age range 28 to 64 years). All were hospitalized for community-acquired respiratory tract infections. Two patients had a concomitant acute Grade A3 graft rejection, and 1 patient had a concomitant bacterial pneumonia. Eight patients did not receive a specific anti-RSV treatment because of clinical stability and/or improvement at the time of RSV diagnosis. Only 2 patients (1 with Grade A3 allograft rejection and 1 requiring mechanical ventilation) received ribavirin and palivizumab. All patients recovered without complications and with no persistent RSV infection. However, bronchiolitis obliterans (BOS) staging worsened in 6 patients during the mean follow-up of 45 months. CONCLUSIONS: Our data suggest that mild RSV infections in LTRs might evolve favorably in the absence of specific anti-viral therapy. However, this observation needs confirmation in a large clinical trial specifically investigating the development of BOS in untreated vs treated patients.

Clinical effectiveness of direct anterior restorations-A meta-analysis.

OBJECTIVES: This is the first meta-analysis on the efficacy of composite resin restorations in anterior teeth. The objective of the present meta-analysis was to verify whether specific material classes, tooth conditioning methods and operational procedures influence the result for Class III and Class IV restorations. MATERIAL AND METHODS: The database SCOPUS and PubMed were searched for clinical trials on anterior resin composites without restricting the search to the year of publication. The inclusion criteria were: (1) prospective clinical trial with at least 2 years of observation; (2) minimal number of restorations at last recall=20; (3) report on drop-out rate; (4) report of operative technique and materials used in the trial, and (5) utilization of Ryge or modified Ryge evaluation criteria. For the statistical analysis, a linear mixed model was used with random effects to account for the heterogeneity between the studies. p-Values smaller than 0.05 were considered to be significant. RESULTS: Of the 84 clinical trials, 21 studies met the inclusion criteria, 14 of them for Class III restorations, 6 for Class IV restorations and 1 for closure of diastemata; the latter was included in the Class IV group. Twelve of the 21 studies started before 1991 and 18 before 2001. The estimated median overall success rate (without replacement) after 10 years for Class III composite resin restorations was 95% and for Class IV restorations 90%. The main reason for the replacement of Class IV restorations was bulk fractures, which occurred significantly more frequently with microfilled composites than with hybrid and macrofilled composites. Caries adjacent to restorations was infrequent in most studies and accounted only for about 2.5% of all replaced restorations after 10 years irrespective of the cavity class. Class III restorations with glass ionomer derivates suffered significantly more loss of anatomical form than did fillings with other types of material. When the enamel was acid-etched and no bonding agent was applied, significantly more restorations showed marginal staining and detectable margins compared to enamel etching with enamel bonding or the total etch technique; fillings with self-etching systems were in between of these two outcome variables. Bevelling of the enamel was associated with a significantly reduced deterioration of the anatomical form compared to no bevelling but not with less marginal staining or less detectable margins. The type of isolation (absolute/relative) had a statistically significant influence on marginal caries which, however, might be a random finding.

Early transjugular intrahepatic portosystemic shunt in cirrhotic patients with acute variceal bleeding: a systematic review and meta-analysis of controlled trials.

INTRODUCTION: There is conflicting evidence on the benefit of early transjugular intrahepatic portosystemic shunt (TIPSS) on the survival of patients with acute variceal bleeding (AVB). AIM: To assess the effect of early TIPSS on patient prognosis. MATERIALS AND METHODS: We carried out a meta-analysis of trials evaluating early TIPSS in cirrhotic patients with AVB. RESULTS: Four studies were included. Early TIPSS was associated with fewer deaths [odds ratio (OR)=0.38, 95% confidence interval (CI)=0.17-0.83, P=0.02], with moderate heterogeneity between studies (P=0.15, I=44%). Early TIPSS was not significantly associated with fewer deaths among Child-Pugh B patients (OR=0.35, 95% CI=0.10-1.17, P=0.087) nor among Child-Pugh C patients (OR=0.34, 95% CI=0.10-1.11, P=0.074). There was no heterogeneity between studies in the Child-Pugh B analysis (P=0.6, I=0%), but there was a high heterogeneity in the Child-Pugh C analysis (P=0.06, I=60%). Early TIPSS was associated with lower rates of bleeding within 1 year (OR=0.08, 95% CI=0.04-0.17, P<0.001) both among Child-Pugh B patients, (OR=0.15, 95% CI=0.05-0.47, P=0.001) and among Child-Pugh C patients (OR=0.05, 95% CI=0.02-0.15, P<0.001), with no heterogeneity between studies. Early TIPSS was not associated with higher rates of encephalopathy (OR=0.84, 95% CI=0.50-1.42, P=0.5). CONCLUSION: Cirrhotic patients with AVB treated with early TIPSS had lower death rates and lower rates of clinically significant bleeding within 1 year compared with patients treated without early TIPSS. Additional studies are required to identify the potential risk factors leading to a poor prognosis after early TIPSS in patients with AVB and to determine the impact of the degree of liver failure on the patient's prognosis.

Positive Emotions Program for Schizophrenia (PEPS): a pilot intervention to reduce anhedonia and apathy.

BACKGROUND: Recent literature has distinguished the negative symptoms associated with a diminished capacity to experience (apathy, anhedonia) from symptoms associated with a limited capacity for expression (emotional blunting, alogia). The apathy-anhedonia syndrome tends to be associated with a poorer prognosis than the symptoms related to diminished expression. The efficacy of drug-based treatments and psychological interventions for these symptoms in schizophrenia remains limited. There is a clear clinical need for new treatments. METHODS: This pilot study tested the feasibility of a program to reduce anhedonia and apathy in schizophrenia and assessed its impact on 37 participants meeting the ICD-10 criteria for schizophrenia or schizoaffective disorders. Participants were pre- and post-tested using the Scale for the Assessment of Negative Symptoms (SANS) and the Calgary Depression Scale for Schizophrenia (CDSS). They took part in eight sessions of the Positive Emotions Program for Schizophrenia (PEPS)--an intervention that teaches participants skills to help overcome defeatist thinking and to increase the anticipation and maintenance of positive emotions. RESULTS: Thirty-one participants completed the program; those who dropped out did not differ from completers. Participation in the program was accompanied by statistically significant reductions in the total scores for Avolition-Apathy and Anhedonia-Asociality on the SANS, with moderate effect sizes. Furthermore, there was a statistically significant reduction of depression on the CDSS, with a large effect size. Emotional blunting and alogia remain stable during the intervention. DISCUSSION: Findings indicate that PEPS is both a feasible intervention and is associated with an apparently specific reduction of anhedonia and apathy. However, these findings are limited by the absence of control group and the fact that the rater was not blind to the treatment objectives. CONCLUSIONS: PEPS is a promising intervention to improve anhedonia and apathy which need to be tested further in a controlled study. TRIAL REGISTRATION NUMBER: ISRCTN registry ISRCTN74048461, registered 18 may 2015.