Science and ethics of sham surgery: a survey of Parkinson disease clinical researchers

BACKGROUND: Sham surgery is used in neurosurgical clinical trials in Parkinson disease (PD) but remains controversial. The controversy may be compounded when gene-transfer technologies are tested in sham surgical trials. OBJECTIVE: To determine the perspective of PD clinical researchers on the science and ethics of sham-surgery controls when used to test novel interventions such as gene transfer for PD. DESIGN: Internet survey eliciting both quantitative and qualitative responses. PARTICIPANTS: Investigator members of the Parkinson Study Group. RESULTS: Overall response rate was 103 (61.3%) of 168 researchers. A large majority (97%) of PD clinical researchers believe sham-surgery controls are better than unblinded controls for testing the efficacy of neurosurgical interventions such as gene transfer for PD. Half of the researchers believe an unblinded control efficacy trial would be unethical because it may lead to a falsely positive result. A minority (less than 22%) believe that an invasive sham condition that involves penetration of brain tissue is justified. CONCLUSION: It appears unlikely that the PD clinical research community will perceive future neurosurgical interventions for PD, such as gene-transfer therapies, as truly efficacious unless a sham-control condition is used to test it.     

Combination therapies for multiple sclerosis: scientific rationale, clinical trials, and clinical practice

PURPOSE OF REVIEW: To outline the scientific rationale for combination therapy in multiple sclerosis and to discuss the evidence for combination treatment strategies from animal models and clinical trials of multiple sclerosis. RECENT FINDINGS: Experiments conducted in experimental autoimmune encephalomyelitis have recently shown beneficial effects of numerous combination therapies. The combination of approved and experimental drugs and two or more experimental agents may positively impact clinical disease activity, inflammation within the central nervous system, and neurorepair. Clinical trials are currently underway to establish the therapeutic efficacy and safety of various combination therapies for multiple sclerosis patients. SUMMARY: More effective therapies are needed to treat multiple sclerosis. There are good scientific rationales for the use of combination therapy in multiple sclerosis, and the pharmacologic principles for evaluating and understanding their actions are available. The evaluation of specific combination therapies in the controlled setting of clinical trials should be a priority in clinical multiple sclerosis research.     

Combination rapid transcranial magnetic stimulation in treatment refractory depression

High frequency (>1 Hz) repetitive transcranial magnetic stimulation (rTMS) applied to the left prefrontal cortex and low frequency (≤1 Hz) rTMS applied to the right prefrontal cortex have shown antidepressant effects. However, the clinical significance of these effects has often been modest. It was hypothesized that a combination of these two techniques might act synergistically and result in more clinically relevant antidepressant effects. Sixty-two subjects with treatment-resistant major depression (an average of 8 failed medication trials) were randomized to receive combination right low frequency (1 Hz)/left high frequency (10 Hz) rTMS over the dorsolateral prefrontal cortex at 110% of the motor threshold vs sham rTMS. Subjects were treated for 2 weeks (10 weekday sessions) and received 1600 stimulations during each treatment session. Subjects receiving combination treatment were further randomized to receive different orders of treatment: right low frequency first (Slow Right) vs left high frequency first (Fast Left). There were no statistical differences in the active vs sham treatment arms in the primary outcome variable, the Hamilton Depression Rating Scale (HDRS). However compared with subjects in the Sham and Slow Right arms, there was a trend for subjects in the Fast Left arm to show improvement in the HDRS, the Beck Depression Inventory, and the Brief Psychotic Rating Scale with increased number of treatments. The Fast Left arm also showed significant improvement in both blinded clinician and self-ratings of global improvement. These differences were hypothesized to be due to the decreased number of failed medication trials for subjects in Fast Left arm. Neuropsychological performance was not significantly different between the sham and active rTMS arms. Future studies should increase the number of treatment sessions and focus on subjects with moderate treatment resistance.     

Neurosurgical suite of the future. III

The neurosurgical suite of the future will continue to incorporate developing technologies so that lesion localization, surgical dissection, electrode placement, and cell/drug delivery will be optimized. In this article it was shown that MR technology can be placed into a neurosurgical operating room and used as a surgical adjunct in such a way that surgical, anesthetic, and nursing techniques are not [figure: see text] compromised. Essential to the success was the high magnetic field strength and system mobility. It is now hypothesized that MR technology, coupled to advances in molecular therapies, endovascular techniques, and transplantation, will continue to improve neurosurgical outcome not only for benign pathology but also malignant neoplastic and degenerative CNS disorders. Although these technologies are intriguing and ultimately will improve neurosurgical outcome, it is likely that for the foreseeable future, neurosurgery will continue to require sound clinical judgment and surgical dexterity.     

Combination therapy for multiple sclerosis

To improve the partial benefit of approved monotherapies in multiple sclerosis (MS), over 25 combined therapies have been tested in recent years, either as fixed-dose or sequential combination regimes. The main therapeutic targets for combination therapy in MS are the same as for monotherapy: the immune-mediated inflammatory cascade, oxidative toxicity and excitotoxicity. There are numerous reasons to consider combination therapy in MS, including to improve the benefit and/or tolerance in patients responding to approved treatments, stop frequent disabling relapses and/or rapid progression in patients who do not respond to approved therapies, and maintain the benefit of immunosuppressive treatments. Preliminary clinical trials suggest that combination therapy in MS does not increase the side-effects of approved monotherapy; its efficacy over monotherapy should therefore be tested. Statistically robust trials would need to involve many patients for each combination, so the first step in determining the efficacy of combination therapy should be to perform safety studies, followed by proof-of-concept efficacy studies.     

Placebo or active control trials of antipsychotic drugs?

The placebo-controlled trial has been the standard method to demonstrate efficacy and safety of antipsychotic drugs. We reviewed the scientific and ethical advantages and disadvantages of the placebo-controlled trial and an alternative method, the active-control trial, focusing more specifically on the active-control noninferiority trial. Recent meta-analyses indicate that a therapeutic dose of second-generation antipsychotic will very likely be statistically superior to placebo in an adequate trial, and that the average improvement of schizophrenia symptoms in a placebo arm will be small. These findings strengthen the scientific and ethical justification for the active-control noninferiority trial. New drugs in the pharmacotherapy for schizophrenia are often claimed to differ from their marketed competitors in their safety profile rather than in antipsychotic efficacy. Thus, in many cases, it appears sufficient to demonstrate mere noninferiority (rather than superiority) of antipsychotic efficacy in comparison with a standard antipsychotic. The active-control noninferiority trial is suitable for such demonstration. Sample size requirements for various equivalence margins in noninferiority trials are provided. Scientific and ethical arguments should lead to a more frequent use of the active-control noninferiority trial design.     

Was ist wissenschaftlich fundierte Psychotherapie? Zur Diskussion um Leitlinien für die Psychotherapieforschung

The scientific nature of psychotherapy can be defined by two partially interrelated criteria: validity of the theory underlying a therapy and efficacy or effectiveness of a therapy. To enhance the scientific basis of a psychotherapeutic approach, research is needed on therapeutic objectives, principles, and processes, measuring methods, process-outcome relationships, and efficacy and effectiveness of therapies. Determination of efficacy requires randomized clinical trials (RCT). The scientific basis must be seen as the continuous development of a psychotherapeutic approach. In contrast, the question of whether a psychotherapeutic approach is well established is dichotomous. In addition to scientific criteria, those deriving from mental health policy and economics are also important. This paper presents various approaches to ascertaining efficacy. According to the criteria of the American Psychological Association Task Force, to be "well-established," treatments for specific disorders must be shown efficacious in at least two independent randomized clinical trials. Although comparability is limited, we propose that psychotherapeutic research be conceptualized into phases, as in pharmacotherapeutic research.     

颅内动脉瘤治疗措施的临床证据评价

目的 评价不同治疗方案对颅内动脉瘤的疗效及不良后果.以为颅内动脉瘤的循证治疗制定最佳治疗方案.方法 以颅内动脉瘤、治疗、血管内栓塞治疗、手术夹闭治疗等英文词组作为检索词.分别检索MEDLINE、PubMed、Cochrane图书馆等数据库,并辅助手工检索获得临床指南、随机对照临床试验、系统评价、回顾性病例分析、临床对照试验及病例观察研究等方面的相关文献,采用Jadad量表对文献质量进行评价.结果 经筛选共纳入与颅内动脉瘤治疗有关的临床指南4篇、随机对照临床试验4篇、系统评价7篇、回顾性病例分析9篇、临床对照试验1篇、病例观察研究1篇;其中20篇被评为高质量文献(2篇7分、2篇6分、4篇5分、12篇4分),6篇为低质量文献.经对各项临床试验治疗原则和不同治疗方法 的疗效及安全性评价显示:(1)血管内栓塞和手术夹闭治疗是目前治疗颅内动脉瘤的主要外科手术方法,但哪种方法 更具优势仍存在争议.(2)对于未破裂颅内动脉瘤的治疗,有症状者建议积极治疗;但对于无症状的小动脉瘤,是否需要治疗尚有争议,应根据各种影响因素如年龄、既往病史、家族史.以及动脉瘤大小、部位、形态和预期寿命等综合考虑.(3)对于已破裂的颅内动脉瘤.建议尽快施行手术治疗,除非急性期不能耐受手术者外,不宜采取延期治疗方案.手术方法 的选择也应结合患者具体情况具体分析.(4)动脉瘤破裂后的药物治疗,除尼莫地平已获得大犁随机对照临床试验证据外,其他药物治疗效果仍有待研究.结论 借助循证医学评价方法 可为颅内动脉瘤患者的治疗提供最佳的临床证据.     

Use of gene therapy in central nervous system repair

Recent advances have increased our molecular understanding of the central nervous system (CNS), in both health and disease. In order to realize the clinical benefits of these findings, new molecular-based therapies need to be developed, such as CNS gene therapy. Although the field has suffered setbacks, it remains an attractive technology for providing new therapies in the post-genomic world. The development of new vectors, and their extensive application in animal models of CNS disease, provides evidence suggesting that gene therapy will eventually become an accepted clinical option. In fact, the first gene therapy clinical trial for Parkinson's disease has recently begun. This review discusses how gene therapy has been applied in animal models, and how it may be used to repair the damage caused by CNS diseases and trauma in human beings. Furthermore, it explores how such treatments may be combined with, and augment, more conventional therapeutic approaches.     

Neurosurgical convection-enhanced delivery of treatments for Parkinson’s disease

Convection-enhanced delivery (CED) is a promising neurosurgical technique for the delivery of potential therapeutic agents to the Parkinson’s disease (PD)-affected striatum. CED utilises stereotactic insertion of a catheter to the striatum and continuous infusion to distribute agents in the brain parenchyma. Insufficient attention to the details of CED may have contributed to early failures of translating candidate therapeutic agents from the laboratory to PD patients. A literature review was performed to examine the factors that govern CED in the laboratory as well as translation in PD and we found that although there have been significant developments in implant design, infusion parameters and infusate composition, there have not been enough comparative trials of different technologies. Further optimisation of CED is required before it can be applied in the clinical setting and this will require a step-by-step breakdown of the different elements of delivery for independent testing. We conclude that CED is a promising technique for delivering therapeutic agents to the striatum for the treatment of PD but further refinements are necessary for successful clinical translation. The risk is that early clinical translation of exciting new therapies may lead to therapeutic failure which is not due to the agent in question but simply the neurosurgical delivery.     

Developing dopaminergic cell therapy for Parkinson's disease—give up or move forward?

Despite 3 decades of basic and clinical studies, there is still no dopaminergic cell therapy for Parkinson's disease. Several arguments have been put forward why this approach, so far tested with transplantation of human fetal mesencephalic dopamine‐rich tissue, will never be of clinical use and should be abandoned: (1) Lack of efficacy in 2 sham surgery‐controlled trials; (2) occurrence of troublesome off‐medication dyskinesias in a subgroup of grafted patients; (3) disease process destroys grafted neurons; and (4) non‐motor symptoms will not be influenced by intrastriatal dopaminergic grafts. Here, the author argues that, based on recent scientific advancements, the development of a dopaminergic cell therapy for Parkinson's disease should continue. Factors influencing the outcome after transplantation have now been identified, and dopaminergic neurons can be generated in large numbers from stem cells. Mechanisms of graft‐induced dyskinesias are much better understood, and patients with well functioning grafts can exhibit long‐term motor recovery of therapeutic value even in the presence of non‐motor symptoms. © 2013 Movement Disorder Society     

Drug Insight: interferon treatment in multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. Between 1987 and 1997, clinical trials of three preparations of recombinant interferon-beta were conducted in patients with MS, ushering in a new therapeutic era. These medications have demonstrable benefits and seem to be safe; they represent an important advance in MS treatment. All three formulations of interferon-beta had modest effects on relapses and short-term progression of disability, but the effects on MRI lesion parameters were more substantial. The benefits were greater in clinically isolated syndromes and relapsing-remitting MS than in secondary progressive MS. Although these drugs have been shown to be effective, however, their long-term impact on clinically relevant disability progression is uncertain, and there are many areas of controversy in the MS field regarding the use of these products. There is still a need for more effective treatments, which might include new agents or combination therapies.     

Combination therapy in multiple sclerosis

Multiple sclerosis is an inflammatory/demyelinating and neurodegenerative disease. Treatment of MS is currently based on various different therapeutic algorithms of a sequential or escalating therapy with immunomodulators or immunosuppressants, generated partly from evidence based medicine and partly from expert's consensus. However, these therapies are not always effective as monotherapies. An alternative would be the combination of agents which already have some proven efficacy in MS therapy, are directed against different mechanisms of the pathogenic chain, and ideally result in synergic effects and a profile of reduced toxicity. Combination therapy in multiple sclerosis can be: Combination of two or more anti-inflammatory agents or combination of anti-inflammatory agents plus neuroprotective agents. Many combinations of drugs have been or are being tested in multiple sclerosis. Clinical trials have included a low number of patients for short periods of time. Preliminary studies on safety suggest that some combination therapies might be safe and efficacious. Ongoing and new phase III clinical trials involving a greater number of patients for longer periods of time are needed to verify this hypothesis. A wise balance between efficacy and safety and extremely clear information to patients should drive clinical decisions.     

The numbers needed to treat for neurological disorders

BACKGROUND: Numerous therapeutic interventions have been developed in the neurosciences. Clinicians need summary measures about efficacy of therapies that derive from the best available evidence, and that can be readily extrapolated to clinical practice. The number needed to treat (NNT) is intuitive and clinically applicable. We provide clinicians with a single source that summarizes important therapies in the main neurological and neurosurgical areas. METHODS: Critically appraised evidence about therapies in the neurosciences was obtained from meta-analyses in all neurosciences groups in the Cochrane library, and from critically appraised topics at the University of Western Ontario. Therapies were included if they were deemed relevant and if outcomes were dichotomous. For each therapy, we obtained absolute risk differences and their 95% confidence intervals (CI), the corresponding NNTs, control and experimental event rates, and the time-frame of the outcome assessment. RESULTS: We assembled a table of NNTs for 87 interventions in ten disease categories, deriving from meta-analyses (70%) or randomized controlled trials (30%), and assessing surgical interventions (7%), procedures (9%) or pharmacological treatments (84%). The NNTs varied widely, ranging from 1 in the use of epidural blood patch for post-dural puncture headache to 4608 for meningococcal vaccination. Preventative interventions had substantially larger NNTs. Time-frames were inappropriately short for many chronic conditions. CONCLUSIONS: Large collections of NNTs provide useful, updateable summaries of therapeutic effects in the neurosciences, an increasingly interventional clinical field.     

When will Alzheimer's disease be cured? A pharmaceutical perspective

Alzheimer's disease (AD) continues to be one of most difficult human diseases to treat. The past 18 months have been a cruel reminder of the challenges of finding new and effective treatments. In 2010, several large Phase III clinical trials were terminated for lack of therapeutic efficacy. Concurrently, an NIH expert review panel was resigned to conclude that there was insufficient scientific evidence to recommend any treatment choices for slowing the progression of AD. Why has this disease proved so daunting? The answer is complex. To begin, it is still not clear whether AD is one disease with a single cause or multiple syndromes with common symptoms and/or a common pathology. Resolving this question is a prerequisite for forecasting whether to expect a 'magic bullet' therapy or only incremental progress in select patient populations. This review will explore some of the details of recent clinical trials and consider some of the lessons learned. As therapies approach clinical trials, it is essential to understand the expectations of regulatory agencies such as the FDA and EMA to obtain approval. Lastly, we will cover some of the essential gaps in our scientific understanding about the disease process and the impact this has on target validation. The hope of finding of a quick cure for AD without a complete understanding of the disease may have been too optimistic. However, a prudent review of the scientific evidence, a clear understanding of the expectations of regulators, and careful attention to patient needs may still lead to good therapies in the foreseeable future.     

Designing Clinical Trials for Dystonia

With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs.     

Neural stem cells and their use as therapeutic tool in neurological disorders

Spontaneous neural tissue repair occurs in patients affected by inflammatory and degenerative disorders of the central nervous system (CNS). However, this process is not robust enough to promote a functional and stable recovery of the CNS architecture. The development of cell-based therapies aimed at promoting brain repair, through damaged cell-replacement, is therefore foreseen. Several experimental cell-based strategies aimed at replacing damaged neural cells have been developed in the last 30 years. Although successful in promoting site-specific repair in focal CNS disorders, most of these therapeutic approaches have failed to foster repair in multifocal CNS diseases where the anatomical and functional damage is widespread. Stem cell-based therapies have been recently proposed and might represent in the near future a plausible alternative strategy in these disorders. However, before envisaging any human applications of stem cell-based therapies in neurological diseases, we need to consider some preliminary and still unsolved issues: (i) the ideal stem cell source for transplantation, (ii) the most appropriate route of stem cell administration, and, last but not least, (iii) the best approach to achieve an appropriate, functional, and long-lasting integration of transplanted stem cells into the host tissue.     

How can we improve the pre-clinical development of drugs for stroke?

The development of stroke drugs has been characterized by success in animal studies and subsequent failure in clinical trials. Animal studies might have overstated efficacy, or clinical trials might have understated efficacy; in either case we need to better understand the reasons for failure. Techniques borrowed from clinical trials have recently allowed the impact of publication and study-quality biases on published estimates of efficacy in animal experiments to be described. On the basis of these data, we propose minimum standards for the range and quality of pre-clinical animal data. We believe the adoption of these standards will lead to improved effectiveness and efficiency in the selection of drugs for clinical trials in stroke and in the design of those trials.     

Focused ultrasound opening of the blood–brain barrier for treatment of Parkinson's disease

The expanding landscape of options for Parkinson's disease (PD) therapeutics calls for novel ways to improve delivery of treatments to counteract neurodegeneration or enhance symptomatic control. This unmet need is particularly relevant for opportunities in gene therapy, which, in recent PD clinical trials, has required invasive neurosurgical approaches into the CNS. One of the promising techniques to bring new therapies into the brain for PD therapeutics involves an evolving technology, focused ultrasound. Focused ultrasound has been used to alleviate tremor by thermal ablation with high‐energy sonication. Using similar equipment but much lower sonication energy, focused ultrasound assisted with micro‐bubbles can temporarily open the blood–brain barrier at specific brain targets to facilitate real‐time magnetic resonance–guided delivery of therapeutic agents. To explore the current status and future of focused ultrasound in transvascular therapeutics for PD, a November 2018 workshop reviewed its accomplishments and challenges. This report summarizes key points of discussion and provides further background to the promising roles focused ultrasound offers. © 2019 International Parkinson and Movement Disorder Society     

Pharmacological approaches to the treatment of complicated grief: rationale and a brief review of the literature

Complicated grief (CG) is a common and often under-acknowledged cause of profound impairment experienced after the loss of a loved one. Although both clinical and basic research suggests that pharmacological agents might be of use in the treatment of CG, research on pharmacological approaches to this condition is still scarce. Three open-label trials and one randomized trial on bereavement-related depression suggest that tricyclic antidepressants may be effective, although they may be more efficacious for depressive symptoms than for grief-specific symptoms. Four open-label trials (total number of participants, 50) of selective serotonin reuptake inhibitors (SSRIs) have yielded results, providing very preliminary support that they might be effective in the treatment of CG, both as a standalone treatment and in conjunction with psychotherapeutic interventions. These more recent studies have shown an effect on both depression and grief-specific scales. Furthermore, therapeutic interventions for CG may be more effective in conjunction with SSRI administration. Given the small number of pharmacological studies to date, there is a need for randomized trials to test the potential efficacy of pharmacological agents in the treatment of CG.