-
1.
Approaches to Disease Modification for Parkinson's Disease: Clinical Trials and Lessons Learned.
Hung, AY, Schwarzschild, MA
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2020;(4):1393-1405
-
-
Free full text
-
Abstract
Despite many clinical trials over the last three decades, the goal of demonstrating that a treatment slows the progression of Parkinson's disease (PD) remains elusive. Research advances have shed new insight into cellular pathways contributing to PD pathogenesis and offer increasingly compelling therapeutic targets. Here we review recent and ongoing clinical trials employing novel strategies toward disease modification, including those targeting alpha-synuclein and those repurposing drugs approved for other indications. Active and passive immunotherapy approaches are being studied with the goal to modify the spread of alpha-synuclein pathology in the brain. Classes of currently available drugs that have been proposed to have potential disease-modifying effects for PD include calcium channel blockers, antioxidants, anti-inflammatory agents, iron-chelating agents, glucagon-like peptide 1 agonists, and cAbl tyrosine kinase inhibitors. The mechanistic diversity of these treatments offers hope, but to date, results from these trials have been disappointing. Nevertheless, they provide useful lessons in guiding future therapeutic development.
-
2.
Pivotal clinical trials, meta-analyses and current guidelines in the treatment of hyperkalemia.
Bianchi, S, Regolisti, G
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2019;(Suppl 3):iii51-iii61
Abstract
Hyperkalemia (HK) is the most common electrolyte disturbance observed in patients with advanced stages of chronic kidney disease (CKD), is a potentially life-threatening clinical condition due to an increased risk of fatal arrhythmias, and strongly impacts the quality of life and prognosis of CKD patients. Moreover, while renin-angiotensin-aldosterone system inhibitors (RAASIs) represent the most cardio-nephro-protective drugs used in clinical practice, the treatment with these drugs per se increases serum potassium (sK) values, particularly when heart failure and diabetes mellitus coexist. In fact, the onset or recurrence of HK is frequently associated with not starting, down-titrating or withdrawing RAASIs, and is an indication to begin renal replacement treatment in end-stage renal disease. Current strategies aimed at preventing and treating chronic HK are still unsatisfactory, as evidenced by the relatively high prevalence of HK also in patients under stable nephrology care, and even in the ideal setting of randomized clinical trials. Indeed, dietary potassium restriction, the use of sodium bicarbonate or diuretics, the withdrawal or down-titration of RAASIs, or the administration of old potassium binders, namely sodium polystyrene sulphonate and calcium polystyrene sulphonate, have limited efficacy and are poorly tolerated; therefore, these strategies are not suitable for long-term control of sK. As such, there is an important unmet need for novel therapeutic options for the chronic management of patients at risk for HK. The development of new potassium binders may change the treatment landscape in the near future. This review summarizes the current evidence on the treatment of chronic HK in cardio-renal patients.
-
3.
Children of a lesser god: exclusion of chronic kidney disease patients from clinical trials.
Zoccali, C, Blankestijn, PJ, Bruchfeld, A, Capasso, G, Fliser, D, Fouque, D, Goumenos, D, Ketteler, M, Massy, Z, Rychlık, I, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2019;(7):1112-1114
Abstract
The exclusion of chronic kidney disease (CKD) patients from clinical trials-particularly cardiovascular trials-remains a long-standing, unsolved problem, which prevents the optimization of clinical care in these patients. The situation recalls the insufficient recruitment of women in cardiovascular trials until the 1980s, a problem that was only resolved following regulatory interventions. Regulatory agencies are in a unique position to promote recruitment of CKD patients in clinical trials. The main stakeholders, namely patients' associations and scientific societies, should make major lobbying efforts to persuade these agencies that the issue is an absolute public health priority.
-
4.
Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD.
Rinella, ME, Tacke, F, Sanyal, AJ, Anstee, QM, ,
Journal of hepatology. 2019;(4):823-833
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a global public health concern. Its natural history, the development of non-alcoholic steatohepatitis (NASH) and fibrosis, is highly variable, prone to endogenous (e.g., genetics, microbiota) and exogenous (e.g., nutrition, alcohol, physical activity) disease modifiers, and can fluctuate over time. The complexity of its pathophysiology is reflected by the multitude of pharmacological targets in development. NASH clinical trials have provided valuable insight that is applicable to future trial design. Endpoints for NASH have evolved over the past decade and will continue to be refined. Currently accepted endpoints for conditional approval include resolution of NASH without worsening of fibrosis and/or improvement in fibrosis without worsening of NASH by standardized evaluation of paired liver histology. In pediatric NASH, practical obstacles, pubertal hormonal changes, and stringent safety requirements mandate adaptations in trial design. In adult patients with NASH-related cirrhosis, decrease in portal pressure as well as clinical events (e.g. decompensation, hepatocellular carcinoma, transplantation, death) are more prevalent and thereby are viable primary endpoints for clinical trials. Consideration of the natural fluctuation of disease, the clinical implication of the chosen primary endpoint, and factors that may affect placebo response will facilitate an accurate determination of efficacy of emerging therapeutics for NASH. Conclusion: The June 2018 American Association for the Study of Liver Diseases and European Association for the Study of the Liver joint workshop on NAFLD endpoints summarized important findings from ongoing and completed trials, defined the scientific evidence supporting distinct endpoints, and provided guidance for future trial design.
-
5.
Physics aspects of setting up a multicenter clinical trial involving internal dosimetry of radioiodine treatment of differentiated thyroid cancer.
Taprogge, J, Leek, F, Flux, GD
The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of.... 2019;(3):271-277
Abstract
The field of molecular radiotherapy is expanding rapidly, with the advent of many new radiotherapeutics for the treatment of common as well as for rare cancers. Treatment outcome is dependent on the absorbed doses delivered to target volumes and to healthy organs-at-risk, which are shown to vary widely from fixed administrations of activity. There have been significant developments in quantitative imaging and internal dosimetry in recent years, although clinical implementation of these methods has been slow in comparison with external beam radiotherapy, partly due to there being relatively few patients treated at single centers. Multicenter clinical trials are therefore essential to acquire the data required to ensure best practice and to develop the personalized treatment planning that this area is well suited to, due to the unrivalled opportunity to image the therapeutic drug in vivo. Initial preparation for such trials requires a significant effort in terms of resources and trial design. Imaging systems in participating centers must be characterized and set up for quantitative imaging to allow for collation of data. Data transfer for centralized processing is usually necessary but is hindered in some cases by data protection regulations and local logistics. Recent multicenter clinical trials involving radioiodine therapy have begun to establish the procedures necessary for quantitative SPECT imaging in a multicenter setting using standard and anthropomorphic phantoms. The establishment of national and international multicenter imaging and dosimetry networks will provide frameworks to develop and harmonize best practice with existing therapeutic procedures and to ensure rapid and optimized clinical implementation of new radiotherapeutics across all centers of excellence that offer molecular radiotherapy. This will promote networks and collaborations that can provide a sound basis for further developments and will ensure that nuclear medicine maintains a key role in future developments.
-
6.
Heart Failure End Points in Cardiovascular Outcome Trials of Sodium Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Critical Evaluation of Clinical and Regulatory Issues.
Butler, J, Packer, M, Greene, SJ, Fiuzat, M, Anker, SD, Anstrom, KJ, Carson, PE, Cooper, LB, Fonarow, GC, Hernandez, AF, et al
Circulation. 2019;(25):2108-2118
-
-
Free full text
-
Abstract
Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.
-
7.
PARADIGM-HF Trial: Secondary Analyses Address Unanswered Questions.
Smith, KR, Hsu, CC, Berei, TJ, Aldemerdash, A, Hollis, IB, Vardeny, O, Rodgers, JE
Pharmacotherapy. 2018;(2):284-298
Abstract
Our aim was to summarize published secondary analyses of the PARADIGM-HF trial. In the original trial, published in September 2014, sacubitril/valsartan significantly reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared to enalapril. This summary provides a resource for clinicians to review subsequent analyses of the landmark trial evaluating the benefit of sacubitril/valsartan in various subgroups and providing information regarding optimal use of this new therapy in the broader heart failure population. A full list of publications of the existing PARDADIGM-HF post hoc analyses was obtained and summarized, grouped by focus (e.g., severity of illness, tolerability). Twenty-six publications and one abstract analyzing the PARADIGM-HF trial were reviewed, summarizing the most important results that compared the benefits of sacubitril/valsartan to enalapril, including pertinent subgroup information from each analysis. Key publications evaluated the treatment effect of sacubitril/valsartan based on heart failure severity (i.e., ejection fraction or heart failure risk scores), impact on alternate outcomes, influence of additional therapies, tolerability in patients with comorbidities (i.e., diabetes), long-term benefits, and cost-effectiveness. In addition, nine ongoing phase III and phase IV clinical trials with sacubitril/valsartan were briefly summarized to address potential future uses in more extensive heart failure settings. The benefit of sacubitril/valsartan over enalapril for the primary endpoint in the PARADIGM-HF trial is maintained throughout numerous secondary analyses. Though the subgroups analyzed are based on participants from a single clinical trial, clinicians can more confidently incorporate this novel therapy into practice with expanded knowledge of these existing analyses as well as ongoing prospective trials.
-
8.
Emerging outcome measures for nutrition trials in the critically ill.
Bear, DE, Griffith, D, Puthucheary, ZA
Current opinion in clinical nutrition and metabolic care. 2018;(6):417-422
Abstract
PURPOSE OF REVIEW Mortality has long been the gold-standard outcome measure for intensive care clinical trials. However, as the critical care community begins to understand and accept that survivorship is associated with functional disability and a health and socioeconomic burden, the clinical and research focus has begun to shift towards long-term physical function RECENT FINDINGS To use mortality as a primary outcome measure, one would either have to choose an improbable effect (e.g. a difference of 5-10% in mortality as a result of a single intervention) or recruit a larger number of patients, the latter being unfeasible for most critical care trials.Outcome measures will need to match interventions. As an example, amino acids, or intermittent feeding, can stimulate muscle protein synthesis, and so prevention of muscle wasting may seem an appropriate outcome measure when assessing the effectiveness of these interventions. Testing the effectiveness of these interventions requires the development of novel outcome measures that are targeted and acceptable to patients. We describe advancements in dual-energy X-ray absorptiometry scanning, bio-impedence analysis, MRI and muscle ultrasound in this patient group that are beginning to address this development need. SUMMARY New approaches to outcome assessment are beginning to appear in post-ICU research, which promise to improve our understanding of nutrition and exercise interventions on skeletal muscle structure, composition and function, without causing undue suffering to the patient.
-
9.
Evaluating Whole Grain Intervention Study Designs and Reporting Practices Using Evidence Mapping Methodology.
Sawicki, CM, Livingston, KA, Ross, AB, Jacques, PF, Koecher, K, McKeown, NM
Nutrients. 2018;(8)
Abstract
Consumption of whole grains have been associated with reduced risk of chronic diseases in many observational studies; yet, results of intervention studies are mixed. We aimed to use evidence mapping to capture the methodological and reporting variability in whole grain intervention studies that may contribute to this inconsistency. We conducted a reproducible search in OVID Medline for whole grain human intervention studies (published 1946 to February 2018). After screening based on a priori criteria, we identified 202 publications describing a total of 213 unique trials. Over half (55%) were acute trials, lasting ≤1 day, 30% were moderate duration studies (up to 6 weeks) and 15% were of longer duration (more than 6 weeks). The majority of acute trials (75%) examined measures of glycaemia and/or insulinemia, while most of the longer trials included measures of cardiometabolic health (71%), appetite/satiety (57%) and weight/adiposity (56%). Among the moderate and long duration trials, there was a wide range of how whole grains were described but only 10 publications referenced an established definition. Only 55% of trials reported the actual amount of whole grains (in grams or servings), while 36% reported the amount of food/product and 9% did not report a dose at all. Of the interventions that provided a mixture of whole grains, less than half (46%) reported the distribution of the different grain types. Reporting of subject compliance also varied and only 22% used independent biomarkers of whole grain intake. This evidence map highlights the need to standardize both study protocols and reporting practices to support effective synthesis of study results and provide a stronger foundation to better inform nutrition scientists and public health policy.
-
10.
How to set the stage for a full-fledged clinical trial testing 'incremental haemodialysis'.
Casino, FG, Basile, C
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2018;(7):1103-1109
Abstract
Most people who make the transition to maintenance haemodialysis (HD) therapy are treated with a fixed dose of thrice-weekly HD (3HD/week) regimen without consideration of their residual kidney function (RKF). The RKF provides an effective and naturally continuous clearance of both small and middle molecules, plays a major role in metabolic homeostasis, nutritional status and cardiovascular health, and aids in fluid management. The RKF is associated with better patient survival and greater health-related quality of life. Its preservation is instrumental to the prescription of incremental (1HD/week to 2HD/week) HD. The recently heightened interest in incremental HD has been hindered by the current limitations of the urea kinetic model (UKM), which tend to overestimate the needed dialysis dose in the presence of a substantial RKF. A recent paper by Casino and Basile suggested a variable target model (VTM), which gives more clinical weight to the RKF and allows less frequent HD treatments at lower RKF as opposed to the fixed target model, based on the wrong concept of the clinical equivalence between renal and dialysis clearance. A randomized controlled trial (RCT) enrolling incident patients and comparing incremental HD (prescribed according to the VTM) with the standard 3HD/week schedule and focused on hard outcomes, such as survival and health-related quality of life of patients, is urgently needed. The first step in designing such a study is to compute the 'adequacy lines' and the associated fitting equations necessary for the most appropriate allocation of the patients in the two arms and their correct and safe follow-up. In conclusion, the potentially important clinical and financial implications of the incremental HD render it highly promising and warrant RCTs. The UKM is the keystone for conducting such studies.