Need For Trial Designs Research Articles

The Dose-Related Efficacy of Acupuncture on Endometrial Receptivity in Infertile Women: A Systematic Review and Meta-Analysis.

BackgroundProgress has been achieved by using acupuncture widely for poor endometrial receptivity (PER). However, different acupuncture dosages may lead to controversy over efficacy.ObjectiveTo evaluate the evidence-based conclusions of dose-related acupuncture on infertile women with PER.MethodReferences were retrieved from nine databases from inception to 26 February 2022. This meta-analysis included randomized controlled trials (RCTs) that investigated the dose-related efficacy of acupuncture for PER with outcomes of endometrium receptivity (ER) parameters by transvaginal sonography (TVS) and the subsequent pregnancy outcomes in three acupuncture-dose groups: the high-dosage group (three menstrual cycles), the moderate-dosage group (one menstrual cycle), and the low-dosage group (two or four days). Since there remained sufficient heterogeneity among the three subsets, we prespecified seven subgroup variables (four clinical and three methodological) to investigate the heterogeneities.ResultsA total of 14 RCTs (1,564 women) of moderate or low overall quality were included. The results were different when the dosage of acupuncture was restricted. For the moderate or high-dosage group, CPR and part of ER parameters were improved in the acupuncture group (i.e., CPR: OR = 2.00, 95% CI [1.24, 3.22], p = 0.004, I2 = 0% in one menstrual cycle; OR = 2.49, 95%CI [1.67, 3.72], p < 0.05, I2 = 0% in three menstrual cycles). However, for the low-dosage group, no statistical difference was observed in CPR (OR = 0.07, 95% CI [−0.10, 0.23], p = 0.44, I2 = 82%) and a part of the ER parameters. In subgroup analysis, four subgroup variables (the routine treatment, risk of performance bias, duration of acupuncture treatment, and the age of participants) could explain some of the heterogeneities across all trials.ConclusionThe finding indicated that the trend of relatively more acupuncture dosage showed better effects for poor endometrial receptivity among PER women. It remains a potential heterogeneity in our studies. Further high-quality trials with a homogeneity trial design need to be conducted.

Critical appraisal of clinical trials in multiple system atrophy: Toward better quality.

Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause. Although many clinical trials have been conducted, there is still no treatment that cures the disease or slows its progression. We sought to assess the clinical trials, methodology, and quality of reporting of clinical trails conducted in MSA patients. We conducted a systematic review of all trials with at least 1 MSA patient subject to any pharmacological/nonpharmacological interventions. Two independent reviewers evaluated the methodological characteristics and quality of reporting of trials. A total of 60 clinical trials were identified, including 1375 MSA patients. Of the trials, 51% (n = 31) were single-arm studies. A total of 28% (n = 17) had a parallel design, half of which (n = 13) were placebo controlled. Of the studies, 8 (13.3%) were conducted in a multicenter setting, 3 of which were responsible for 49.3% (n = 678) of the total included MSA patients. The description of primary outcomes was unclear in 60% (n = 40) of trials. Only 10 (16.7%) clinical trials clearly described the randomization process. Blinding of the participants, personnel, and outcome assessments were at high risk of bias in the majority of studies. The number of dropouts/withdrawals was high (n = 326, 23.4% among the included patients). Overall, the design and quality of reporting of the reviewed studies is unsatisfactory. The most frequent clinical trials were small and single centered. Inadequate reporting was related to the information on the randomization process, sequence generation, allocation concealment, blinding of participants, and sample size calculations. Although improved during the recent years, methodological quality and trial design need to be optimized to generate more informative results. © 2017 International Parkinson and Movement Disorder Society.

GOST: A generic ordinal sequential trial design for a treatment trial in an emerging pandemic.

BackgroundConducting clinical trials to assess experimental treatments for potentially pandemic infectious diseases is challenging. Since many outbreaks of infectious diseases last only six to eight weeks, there is a need for trial designs that can be implemented rapidly in the face of uncertainty. Outbreaks are sudden and unpredictable and so it is essential that as much planning as possible takes place in advance. Statistical aspects of such trial designs should be evaluated and discussed in readiness for implementation.Methodology/Principal findingsThis paper proposes a generic ordinal sequential trial design (GOST) for a randomised clinical trial comparing an experimental treatment for an emerging infectious disease with standard care. The design is intended as an off-the-shelf, ready-to-use robust and flexible option. The primary endpoint is a categorisation of patient outcome according to an ordinal scale. A sequential approach is adopted, stopping as soon as it is clear that the experimental treatment has an advantage or that sufficient advantage is unlikely to be detected. The properties of the design are evaluated using large-sample theory and verified for moderate sized samples using simulation. The trial is powered to detect a generic clinically relevant difference: namely an odds ratio of 2 for better rather than worse outcomes. Total sample sizes (across both treatments) of between 150 and 300 patients prove to be adequate in many cases, but the precise value depends on both the magnitude of the treatment advantage and the nature of the ordinal scale. An advantage of the approach is that any erroneous assumptions made at the design stage about the proportion of patients falling into each outcome category have little effect on the error probabilities of the study, although they can lead to inaccurate forecasts of sample size.Conclusions/SignificanceIt is important and feasible to pre-determine many of the statistical aspects of an efficient trial design in advance of a disease outbreak. The design can then be tailored to the specific disease under study once its nature is better understood.

A Bayesian adaptive design for biomarker trials with linked treatments.

Background:Response to treatments is highly heterogeneous in cancer. Increased availability of biomarkers and targeted treatments has led to the need for trial designs that efficiently test new treatments in biomarker-stratified patient subgroups.Methods:We propose a novel Bayesian adaptive randomisation (BAR) design for use in multi-arm phase II trials where biomarkers exist that are potentially predictive of a linked treatment's effect. The design is motivated in part by two phase II trials that are currently in development. The design starts by randomising patients to the control treatment or to experimental treatments that the biomarker profile suggests should be active. At interim analyses, data from treated patients are used to update the allocation probabilities. If the linked treatments are effective, the allocation remains high; if ineffective, the allocation changes over the course of the trial to unlinked treatments that are more effective.Results:Our proposed design has high power to detect treatment effects if the pairings of treatment with biomarker are correct, but also performs well when alternative pairings are true. The design is consistently more powerful than parallel-groups stratified trials.Conclusions:This BAR design is a powerful approach to use when there are pairings of biomarkers with treatments available for testing simultaneously.

Evidence‐Based Medicine: The Design and Interpretation of Noninferiority Clinical Trials in Veterinary Medicine

Noninferiority trials are clinical studies designed to demonstrate that an investigational drug is at least as effective as an established treatment within a predetermined margin. They are conducted, in part, because of ethical concerns of administering a placebo to veterinary patients when an established effective treatment exists. The use of noninferiority trial designs has become more common in veterinary medicine with the increasing number of established veterinary therapeutics and the desire to eliminate potential pain or distress in a placebo-controlled study. Selecting the appropriate active control and an a priori noninferiority margin between the investigational and active control drug are unique and critical design factors for noninferiority studies. Without reliable historical knowledge of the disease response in the absence of treatment and of the response to the selected active control drug, proper design and interpretation of a noninferiority trial is not possible. Despite the appeal of conducting noninferiority trials to eliminate ethical concerns of placebo-controlled studies, there are real limitations and possible ethical conundrums associated with noninferiority trials. The consequences of incorrect study conclusions because of poor noninferiority trial design need careful attention. Alternative trial designs to typical noninferiority studies exist, but these too have limitations and must also be carefully considered.

The Impact of Recent Data on the Optimization of Standards of Care in Newly Diagnosed Glioblastoma

Glioblastoma is an aggressive form of brain cancer with a poor long-term prognosis. Treatment regimens for newly diagnosed disease range from surgical resection alone to surgery followed by radiotherapy with concurrent and adjuvant chemotherapy. Ongoing investigations are focused on optimization of chemotherapy by improving dosing and duration schedules and utilization of biomarkers for patient selection. Our understanding of glioblastoma tumor biology, the role of molecular signaling pathways, cellular repair mechanisms, and angiogenesis has increased greatly over the past few years, leading to the investigation of a variety of targeted therapies. In addition, advances in radiographic assessment have significantly impacted not only improvement in diagnosis, but interpretation of response to therapy. In order to effectively evaluate the clinical utility of new agents, as well as incorporate advances in radiographic assessment, changes to current clinical trial design need to be considered. This article reviews the care for newly diagnosed glioblastoma, as well as how recent findings might be incorporated into patient care.

Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines

Until the early 1990s six major compounds (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid) were available for the treatment of epilepsy. However, these drugs have pharmacokinetic limitations, teratogenic potential, and a negative effect on cognitive functions that impairs the quality of patients' lives and limits the use of these drugs in some patients. In addition, 20-30% of patients are refractory to these drugs. The development of ten new antiepileptic drugs (vigabatrin, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide, and pregabalin) has expanded treatment options. The newer drugs may be better tolerated, have fewer drug interactions, and seem to affect cognitive functions to a lesser extent than old drugs. Guidelines on the use of new antiepileptic drugs have been developed in the USA and in the UK. Both guidelines offer a clear picture of the efficacy, safety, and tolerability of the new antiepileptic drugs and agree on their use as add-on treatment in patients who do not respond to conventional drugs. The guidelines differ in the type and strength of recommendations. Whereas the US guidelines recommend treatment in newly diagnosed epilepsy with a standard drug or a new drug depending on the individual patient's characteristics, the UK guidelines recommend that a new antiepileptic drug should be considered only if there is no benefit from an old antiepileptic drug, an old drug is contraindicated, there is a previous negative experience with the same drug, or the patient is a woman of childbearing potential. The limited amount of information on the new antiepileptic drugs may explain the discrepancies among the two guidelines and between these and other recommendations. Comparative, pragmatic, long-term and open trials should be done to show long-term efficacy and comparative features of the new antiepileptic drugs, and to better assess the effect on quality-of-life, cost-effectiveness, tolerability, and teratogenic potential. In addition, the conflicts should be resolved between the needs of the regulatory bodies and those of the treating physicians. Finally, there is a need for trial designs to be standardised.

Usefulness and limitations of monitoring serum levels of antiepileptic drugs

Until the early 1990s six major compounds (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid) were available for the treatment of epilepsy. However, these drugs have pharmacokinetic limitations, teratogenic potential, and a negative effect on cognitive functions that impairs the quality of patients' lives and limits the use of these drugs in some patients. In addition, 20–30% of patients are refractory to these drugs.The development of ten new antiepileptic drugs (vigabatrin, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide, and pregabalin) has expanded treatment options. The newer drugs may be better tolerated, have fewer drug interactions, and seem to affect cognitive functions to a lesser extent than old drugs. Guidelines on the use of new antiepileptic drugs have been developed in the USA and in the UK. Both guidelines offer a clear picture of the efficacy, safety, and tolerability of the new antiepileptic drugs and agree on their use as add-on treatment in patients who do not respond to conventional drugs. The guidelines differ in the type and strength of recommendations. Whereas the US guidelines recommend treatment in newly diagnosed epilepsy with a standard drug or a new drug depending on the individual patient's characteristics, the UK guidelines recommend that a new antiepileptic drug should be considered only if there is no benefit from an old antiepileptic drug, an old drug is contraindicated, there is a previous negative experience with the same drug, or the patient is a woman of childbearing potential.The limited amount of information on the new antiepileptic drugs may explain the discrepancies among the two guidelines and between these and other recommendations. Comparative, pragmatic, long-term and open trials should be done to show long-term efficacy and comparative features of the new antiepileptic drugs, and to better assess the effect on quality-of-life, cost-effectiveness, tolerability, and teratogenic potential. In addition, the conflicts should be resolved between the needs of the regulatory bodies and those of the treating physicians. Finally, there is a need for trial designs to be standardised.