Many agents are being considered for treatment of Parkinson disease (PD). Given the large number of agents and the limited resources to evaluate new agents, it is essential to reduce the likelihood of advancing ineffective agents into large, long-term Phase III trials. Futility design methodology addresses this goal. The authors describe how a single-arm Phase II futility study uses a short-term outcome to compare a treatment group response to a predetermined hypothesized or historically based control response. The authors present advantages and limitations of futility designs along with examples derived from the data archive of a large Phase III efficacy study of treatments to delay PD progression, the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) trial. Using the same control progression rate and treatment effect assumptions used to power the original DATATOP trial, the authors calculated the number of subjects needed to conduct two 12-month futility studies. DATATOP was designed to enroll 800 patients. Using data on 124 consecutive subjects randomized into each of the DATATOP treatment groups, the authors identified tocopherol as futile and deprenyl as worthy of further study. Using Phase II information, DATATOP could have been simplified from a 2 x 2 factorial design to a comparison of deprenyl vs placebo. While not testing efficacy, futility designs provide a strategy for discarding treatments unlikely to be effective in Phase III. A limitation is the dependence on historical data or hypothesized outcomes for untreated controls. Futility studies may decrease the time to identify treatments unworthy of further pursuit and reduce subjects' exposure to futile treatments.
Purpose: To evaluate whether allograft anterior cruciate ligament reconstruction (ACLR) is superior or inferior to autograft ACLR or conservative management in terms of effectiveness and safety. Methods: A systematic review of the evidence for allograft ACLR was conducted. Randomized controlled trials with a minimum mean follow-up time of 5 years were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the EUnetHTA-Core-Model were used as reporting standards. A meta-analysis was conducted for selected crucial outcomes using a random-effects model. The strength of the available evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. Results: Six randomized trials were included comparing allograft with autograft. Patients were on average between 28 and 32.8 years of age (allograft group) and 28.9 and 31.7 years of age (autograft group). Based on the crucial outcomes, the meta-analyses showed no statistically significant differences in Lysholm score, Tegner score, and Cincinnati Knee Score between groups. A small statistical difference favoring autografts was found across studies in the subjective International Knee Documentation Committee score (e2.25; 95% confidence interval e3.02 to e1.47; I 2 ¼ 0%; range of all scores: 73.7-90). Two of six studies reported on graft failure, with a statistically significant difference to the detriment of using allografts (13/49 [26.5%] vs 4/48 [8.3%] in one study, 13/43 [30.2%] vs 3/40 [7.5%] in the other study). Conclusions: Although no substantial difference in patient-reported function, activity level, and symptoms was demonstrated, evidence from the included studies showed a greater risk for graft failure or revision that may make allograft a less safe treatment modality in ACLR. The strength of available evidence is low based on the crucial outcomes due to the lack of high-quality research and the present increased risk of bias in primary studies. Priority should be shifted toward reflecting on whether there is a subpopulation for whom allograft ACLR may still be advantageous in theory (e.g., less-active older patients) and further conduct RCTs in this population. Level of Evidence: Level II, systematic review of Level II evidence studies.
OBJECTIVES: Evaluating whether there is a clinical benefit of using extracorporeal cytokine adsorption therapy in two indications. DESIGN: Systematic review. SETTING: Search on four databases, Medline, Embase, The Cochrane Library, and the European Network for Health Technology Assessment planned and ongoing projects database. PATIENTS: Patients with sepsis/septic shock; patients undergoing cardiac surgery INTERVENTIONS: Cytokine adsorption. MEASUREMENTS AND MAIN RESULTS: Randomized controlled trials and prospective studies with concurrent control were eligible for the evidence synthesis. The quality of the individual studies and the strength of the available evidence were assessed using the Cochrane risk of bias tool and the Grading of Recommendations, Assessment, Development, and Evaluation approach, respectively. For the preventive treatment of extracorporeal cytokine adsorption therapy in patients undergoing cardiac surgery, we found very low-quality inconclusive evidence for mortality (five randomized controlled trials, n = 163), length of stay in the ICU (five randomized controlled trials, n = 163), and length of hospitalization (three randomized controlled trials, n = 101). Very low-quality inconclusive evidence was found for (serious) adverse events (four randomized controlled trials, n = 148). For the therapeutic treatment of extracorporeal cytokine adsorption therapy in patients with sepsis/septic shock, we found very low-quality inconclusive evidence for mortality up to 60-day follow-up (two randomized controlled trials, n = 117), organ function (two randomized controlled trials, n = 117) and length of stay in the ICU (one randomized controlled trial, n = 20). Very low-quality inconclusive evidence was found for (serious) adverse events (two randomized controlled trials, n = 117). CONCLUSIONS: Given the available evidence, the efficacy and safety of extracorporeal cytokine adsorption therapy in combination with standard care in the investigated indications was not established. We strongly recommend considering well-powered studies with patient-relevant endpoints instead of investing further research funds on studies that may not shed light on the clinical benefit of extracorporeal cytokine adsorption therapy.
Background/Aim: Due to the unique physical dose distribution of carbon-ion radiotherapy (CIRT), CIRT can be regarded as a novel tumour irradiation technique-potentially advantageous for various tumour types. Yet it is unclear in how far, superiority or inferiority can be claimed when comparing CIRT to standard irradiation. This study aimed to assess the scientific evidence regarding the effectiveness and safety of CIRT. Materials and Methods: A systematic literature review was performed using the European Network for Health Technology Assessment (EUnetHTA) Core Model ® for rapid relative effectiveness assessment. The literature search for clinical outcome studies on CIRT was performed using four databases [Cochrane (Central), Centre for Research and Dissemination (CRD), Embase and OVID MEDLINE]. The Cochrane Risk of Bias Tool (for randomised controlled trials) and the Institute of Health Economics (IHE-18) Checklist (for observational studies) were used to assess the risk of bias of the included studies. The evidence synthesis was restricted to 54 oncological indications in 12 broad tumour regions and studies with a low or moderate risk of bias, published between 2005 and 2017. Results: Twenty-seven studies were eligible for the qualitative synthesis of the evidence regarding the effectiveness and safety of CIRT: One randomised controlled trial that primarily focused on the feasibility of CIRT, three case-control studies, three before-and after-studies with a focus on quality of life, and 20 further studies of case series. Overall, insufficient scientific evidence was found for superiority or inferiority of CIRT when compared to standard irradiation for 13/54 oncologicaI indications in 7/12 tumour regions (skull base tumours, brain cancer, cancer in the ear-nose-throat region, bone and soft-tissue tumours, lung cancer, prostate cancer, gastrointestinal tumours). No scientific evidence was found for the remaining 41/54 oncological indications. Conclusion: CIRT is undoubtedly, theoretically, a promising cancer treatment. To date, however, it lacks randomised controlled trials assessing the long-term effectiveness and harms associated with the use of CIRT. CIRT must be considered as an experimental treatment due to the lack of high-quality clinical research. Carbon-ion radiotherapy (CIRT) is a novel therapy for treating cancer. CIRT has raised the expectation of achieving higher local control while lowering the probability of damaging surrounding healthy tissues. This is realised by the focused physical distribution of the radiation beams and a high linear energy transfer associated with CIRT (1). CIRT is, however, often described as a two-edged sword (2), highlighting the need to differentiate its application for different oncological indications. That is to say, CIRT may also affect healthy tissues and increase the risk of severe injury to critical organs. Within the past decades, internationally, numerous cancer therapy centres offering CIRT have been established (3). Currently, CIRT is offered at 11 cancer thera...
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