Unmet needs in rheumatoid arthritis

Until the pathophysiology/etiology of rheumatoid arthritis (RA) is better understood, treatment strategies must focus on disease management. Early diagnosis and treatment with disease-modifying antirheumatic drugs (DMARDs) are necessary to reduce early joint damage, functional loss, and mortality. Several clinical trials have now clearly shown that administering appropriate DMARDs early yields better therapeutic outcomes. However, RA is a heterogeneous disease in which responses to treatment vary considerably for any given patient. Thus, choosing which patients receive combination DMARDs, and which combinations, remains one of our major challenges in treating RA patients. In many well controlled clinical trials methotrexate and other DMARDs, including the tumor necrosis factor-alpha inhibitors, have shown considerable efficacy in controlling the inflammatory process, but many patients continue to have active disease. Optimizing clinical response requires the use of a full spectrum of clinical agents with different therapeutic targets. Newer therapies, such as rituximab, that specifically target B cells have emerged as viable treatment options for patients with RA.     

The assessment and management of insomnia: an update

Insomnia poses significant challenges to public health. It is a common condition associated with marked impairment in function and quality of life, psychiatric and physical morbidity, and accidents. As such, it is important that effective treatment is provided in clinical practice. To this end, this paper reviews critical aspects of the assessment of insomnia and the available treatment options. These options include both non‐medication treatments, most notably cognitive behavioral therapy for insomnia, and a variety of pharmacologic therapies such as benzodiazepines, “z‐drugs”, melatonin receptor agonists, selective histamine H1 antagonists, orexin antagonists, antidepressants, antipsychotics, anticonvulsants, and non‐selective antihistamines. A review of the available research indicates that rigorous double‐blind, randomized, controlled trials are lacking for some of the most commonly administered insomnia therapies. However, there are an array of interventions which have been demonstrated to have therapeutic effects in insomnia in trials with the above features, and whose risk/benefit profiles have been well characterized. These interventions can form the basis for systematic, evidence‐based treatment of insomnia in clinical practice. We review this evidence base and highlight areas where more studies are needed, with the aim of providing a resource for improving the clinical management of the many patients with insomnia.     

International Society for Cell & Gene Therapy Stem Cell Engineering Committee: Cellular therapies for the treatment of graft-versus-host-disease after hematopoietic stem cell transplant

Background aimsAllogeneic hematopoietic stem cell transplant is a curative approach for many malignant and non-malignant hematologic conditions. Despite advances in its prevention and treatment, the morbidity and mortality related to graft-versus-host disease (GVHD) remains. The mechanisms by which currently used pharmacologic agents impair the activation and proliferation of potentially alloreactive T cells reveal pathways essential for the detrimental activities of these cell populations. Importantly, these same pathways can be important in mediating the graft-versus-leukemia effect in recipients transplanted for malignant disease. This knowledge informs potential roles for cellular therapies such as mesenchymal stromal cells and regulatory T cells in preventing or treating GVHD. This article reviews the current state of adoptive cellular therapies focused on GVHD treatment.MethodsWe conducted a search for scientific literature in PubMed® and ongoing clinical trials in clinicaltrial.gov with the keywords “Graft-versus-Host Disease (GVHD),” “Cellular Therapies,” “Regulatory T cells (Tregs),” “Mesenchymal Stromal (Stem) Cells (MSCs),” “Natural Killer (NK) Cells,” “Myeloid-derived suppressor cells (MDSCs),” and “Regulatory B-Cells (B-regs).” All the published and available clinical studies were included.ResultsAlthough most of the existing clinical data focus on cellular therapies for GVHD prevention, there are observational and interventional clinical studies that explore the potential for cellular therapies to be safe modalities for GVHD treatment while maintaining the graft-versus-leukemia effect in the context of malignant diseases. However, there are multiple challenges that limit the broader use of these approaches in the clinical scenario.ConclusionsThere are many ongoing clinical trials to date with the promise to expand our actual knowledge on the role of cellular therapies for GVHD treatment in an attempt to improve GVHD-related outcomes in the near future.     

Debate: Do all patients with heart failure require automatic implantable defibrillators for the prevention of sudden death?

Surrogate outcomes are frequently used in cardiovascular disease research. A concern is that changes in surrogate markers may not reflect changes in disease outcomes. Two recent clinical trials (Heart and Estrogen/Progestin Replacement Study [HERS], and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]) underscore this problem since their results contradicted what was expected based on the surrogate outcomes. The current regulatory policy to allow new therapies to be introduced onto the market based solely on surrogate outcomes may need to be reviewed.     

Biomarkers in rare neuromuscular diseases

Neuromuscular diseases (NMDs) comprise a range of rare disorders that include both hereditary peripheral neuropathies and myopathies. The heterogeneity and rarity of neuromuscular disorders are challenges for researchers seeking to develop effective diagnosis and treatment strategies. In particular, clinical trials of new therapies are made more difficult due to lack of reliable and monitorable clinical outcome measures. Biomarkers could be a way to speed up research in this field, shedding light on the pathophysiological mechanisms behind such diseases and providing invaluable tools for monitoring their progression, prognosis and response to drug treatment. Furthermore, biomarkers could represent a surrogate endpoint for clinical trials, enabling better stratification of patient cohorts through more accurate diagnosis and prognosis prediction.     

Carotid intimal-media thickness as a surrogate for cardiovascular disease events in trials of HMG-CoA reductase inhibitors

BACKGROUND: Surrogate measures for cardiovascular disease events have the potential to increase greatly the efficiency of clinical trials. A leading candidate for such a surrogate is the progression of intima-media thickness (IMT) of the carotid artery; much experience has been gained with this endpoint in trials of HMG-CoA reductase inhibitors (statins). METHODS AND RESULTS: We examine two separate systems of criteria that have been proposed to define surrogate endpoints, based on clinical and statistical arguments. We use published results and a formal meta-analysis to evaluate whether progression of carotid IMT meets these criteria for HMG-CoA reductase inhibitors (statins).IMT meets clinical-based criteria to serve as a surrogate endpoint for cardiovascular events in statin trials, based on relative efficiency, linkage to endpoints, and congruency of effects. Results from a meta-analysis and post-trial follow-up from a single published study suggest that IMT meets established statistical criteria by accounting for intervention effects in regression models. CONCLUSION: Carotid IMT progression meets accepted definitions of a surrogate for cardiovascular disease endpoints in statin trials. This does not, however, establish that it may serve universally as a surrogate marker in trials of other agents.     

Mesenchymal stem cell therapy in retinal and optic nerve diseases: An update of clinical trials

Retinal and optic nerve diseases are degenerative ocular pathologies which lead to irreversible visual loss. Since the advanced therapies availability, cell-based therapies offer a new all-encompassing approach. Advances in the knowledge of neuroprotection, immunomodulation and regenerative properties of mesenchymal stem cells(MSCs) have been obtained by several preclinical studies of various neurodegenerative diseases. It has provided the opportunity to perform the translation of this knowledge to prospective treatment approaches for clinical practice. Since 2008, several first steps projecting new treatment approaches, have been taken regarding the use of cell therapy in patients with neurodegenerative pathologies of optic nerve and retina. Most of the clinical trials using MSCs are in Ⅰ/Ⅱ phase, recruiting patients or ongoing, and they have as main objective the safety assessment of MSCs using various routes of administration. However, it is important to recognize that, there is still a long way to go to reach clinical trials phase Ⅲ-Ⅳ. Hence, it is necessary to continue preclinical and clinical studies to improve this new therapeutic tool. This paper reviews the latest progress of MSCs in human clinical trials for retinal and optic nerve diseases.     

Endpoints in the design of clinical trials for primary sclerosing cholangitis

Primary sclerosing cholangitis is an enigmatic disease affecting the bile ducts, eventually leading to liver failure necessitating liver transplantation in many cases. There is currently no therapy that has proven to halt disease progression. One of the reasons for this is the lack of proper endpoints to measure the effect of medical intervention on the course of the disease. Relevant clinical endpoints such as death or liver transplantation occur too infrequently in this orphan disease to be used as endpoints in phase 2 or 3 trials. It is therefore of utmost importance to identify appropriate surrogate endpoints that are reasonably likely to measure true clinical benefit. This article will discuss a number of surrogate endpoints that are likely candidates to serve this role. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.     

Processing laboratory considerations for multi-center cellular therapy clinical trials: a report from the Consortium for Pediatric Cellular Immunotherapy

``Cellular therapies first emerged as specialized therapies only available at a few “boutique” centers worldwide. To ensure broad access to these investigational therapies—regardless of geography, demographics and other factors—more and more academic clinical trials are becoming multi-center. Such trials are typically performed with a centralized manufacturing facility receiving the starting material and shipping the final product, either fresh or cryopreserved, to the patient's institution for infusion. As these academic multi-center trials increase in number, it is critical to have procedures and training programs in place to allow these sites that are remote from the production facility to successfully participate in these trials and satisfy regulatory compliance and patient safety best practices. Based on the collective experience of the Consortium for Pediatric Cellular Immunotherapy, the authors summarize the challenges encountered by institutions in shipping and receiving the starting material and final product as well as preparing the final product for infusion. The authors also discuss best practices implemented by each of the consortia institutions to overcome these challenges.     

Current status and perspectives of regulatory T cell-based therapy

The CD4⁺FOXP3⁺ regulatory T (Treg) cells are essential for maintaining immune homeostasis in healthy individuals. Results from clinical trials of Treg cell-based therapies in patients with graft versus host disease (GVHD), type 1 diabetes (T1D), liver transplantation, and kidney transplantation have demonstrated that adoptive transfer of Treg cells is emerging as a promising strategy to promote immune tolerance. Here we provide an overview of recent progresses and current challenges of Treg cell-based therapies. We summarize the completed and ongoing clinical trials with human Treg cells. Notably, a few of the chimeric antigen receptor (CAR)-Treg cell therapies are currently undergoing clinical trials. Meanwhile, we describe the new strategies for engineering Treg cells used in preclinical studies. Finally, we envision that the use of novel synthetic receptors, metabolic regulators, combined therapies, and in vivo generated antigen-specific or engineered Treg cells through the delivery of modified mRNA and CRISPR-based gene editing will further promote the advances of next-generation Treg cell therapies.     

Value or desirability of hemorheological-hemostatic parameter changes as endpoints in blood lipid-regulating trials.

High levels of plasma lipids have been recognized as a major risk factor in the development and progression of atherosclerosis, and to influence hemorheological factors that may predispose to thrombotic complications. Lipid-lowering interventions have been associated with a significant reduction of morbidity and mortality. Several mechanisms have been postulated for the observed clinical effect. Serum lipid-regulating therapies may reduce cardiovascular risk not only by altering the arterial wall, improving disturbed endothelial function, atherogenesis and plaque stability, but also through their antithrombogenic effects and influence on blood flow properties associated with hyperlipidemia. In this article, we will review the recent literature and discuss the value of hemorheological-hemostatic findings as surrogate endpoints for clinical trials in dyslipidemic patients.     

On assessing surrogacy in a single trial setting using a semicompeting risks paradigm

Summary .  There has been a recent emphasis on the identification of biomarkers and other biologic measures that may be potentially used as surrogate endpoints in clinical trials. We focus on the setting of data from a single clinical trial. In this article, we consider a framework in which the surrogate must occur before the true endpoint. This suggests viewing the surrogate and true endpoints as semicompeting risks data; this approach is new to the literature on surrogate endpoints and leads to an asymmetrical treatment of the surrogate and true endpoints. However, such a data structure also conceptually complicates many of the previously considered measures of surrogacy in the literature. We propose novel estimation and inferential procedures for the relative effect and adjusted association quantities proposed by Buyse and Molenberghs (1998, Biometrics 54, 1014–1029). The proposed methodology is illustrated with application to simulated data, as well as to data from a leukemia study.     

Neural regeneration therapies for Alzheimer's and Parkinson's disease-related disorders

Neurodegenerative diseases are devastating mental illnesses without a cure. Alzheimer's disease (AD) characterized by memory loss, multiple cognitive impairments, and changes in personality and behavior. Although tremendous progress has made in understanding the basic biology in disease processes in AD and PD, we still do not have early detectable biomarkers for these diseases. Just in the United States alone, federal and nonfederal funding agencies have spent billions of dollars on clinical trials aimed at finding drugs, but we still do not have a drug or an agent that can slow the AD or PD disease process. One primary reason for this disappointing result may be that the clinical trials enroll patients with AD or PD at advances stages. Although many drugs and agents are tested preclinical and are promising, in human clinical trials, they are mostly ineffective in slowing disease progression. One therapy that has been promising is ‘stem cell therapy’ based on cell culture and pre-clinical studies. In the few clinical studies that have investigated therapies in clinical trials with AD and PD patients at stage I. The therapies, such as stem cell transplantation – appear to delay the symptoms in AD and PD. The purpose of this article is to describe clinical trials using 1) stem cell transplantation methods in AD and PD mouse models and 2) regenerative medicine in AD and PD mouse models, and 3) the current status of investigating preclinical stem cell transplantation in patients with AD and PD.     

Targeted therapy of human immunodeficiency virus-related disease.

Since the discovery of human immunodeficiency virus (HIV) as a pathogenic retrovirus linked to acquired immunodeficiency syndrome (AIDS), a number of potentially useful strategies for antiretroviral therapy of AIDS and its related diseases have emerged. One such strategy involves use of the broad family of 2',3'-dideoxynucleosides, to which 3'-azido-2',3'-dideoxythymidine (AZT) belongs. AZT has been shown to reduce the replication of HIV in vivo and to confer significant clinical benefits in patients in both early and advanced stages of infection. Other members of the family, 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI), and 2',3'-didehydro-2',3'-dideoxythymidine (d4T), have also been reported to be active against HIV in short-term clinical trials. The armamentarium of antiretroviral agents is rapidly growing. Various nonnucleoside agents have recently been identified to be active against HIV in vitro. HIV-1 protease inhibitors are notable as possible new therapies for HIV-1-related diseases. However, we have faced several new challenges in the antiretroviral therapy in AIDS. These include long-term drug-related toxicities; emergence of drug-resistant HIV variants; and development of various cancers, particularly as effective therapies prolong survival. Progress in understanding structure-activity relations and clinical effectiveness will continue with dideoxynucleoside analogs. However, it seems certain that a variety of nonnucleoside analogs affecting multiple steps in viral replication will become available before long, and combination therapies using multiple antiretroviral drugs will be available. Such therapies will exert major effects against the moribidity and mortality caused by HIV.     

AACE/ACE Disease State Clinical Review: Medical Management of Cushing Disease

ObjectiveTo review available medical therapies for patients with Cushing disease and to provide a roadmap for their use in clinical practice.MethodsPubMed searches were performed to identify all of the available published data on medical management of Cushing disease.ResultsMedical therapy is usually not the firstline treatment for patients with Cushing disease but may be used to improve clinical manifestations of Cushing disease in patients who are not suitable candidates for surgery, following unsuccessful surgery or recurrence, or as a “bridge therapy” in those who have undergone radiotherapy. Medical therapy may also be used in preoperative preparation of patients with severe disease. Current available medical options for patients with Cushing disease include centrally acting agents, steroidogenesis inhibitors, and a glucocorticoid receptor antagonists. At present, there are no head-to-head studies comparing the efficacy, tolerability, and safety of different U.S. Food and Drug Administration (FDA)- and non-FDA-approved drugs in patients with Cushing disease. With the initiation of new studies and the completion of ongoing clinical trials, the number of FDA-approved drugs for medical treatment of Cushing disease is expected to increase.ConclusionMedical therapy has an important adjunctive role in the management of patients with Cushing disease. The decision to initiate medical treatment depends on many factors, including patient characteristics and preference. Long-term studies are needed to better define the clinical efficacy, safety, and tolerability of medical treatment of Cushing disease, including the role of combination therapies. (Endocr Pract. 2014;20:746-757)     

Immunotherapy for advanced prostate cancer

The absence of curative therapies for advanced or recurrent forms of prostate cancer mandates continued development of novel, more effective treatment regimens. Due to recent advances in basic and translational research, therapeutic vaccines and monoclonal antibody-based therapies are steadily gaining ground as promising treatment modalities against prostate cancer. Several immunotherapeutic products have recently been investigated in later-phase trials and have reported evidence for clinical benefit while maintaining an excellent quality of life for participants. The cumulative clinical results available to date indicate that immune-based therapies will likely play a role in the treatment of patients with prostate and other malignancies. The objective of this article is to increase awareness of contemporary immunologic therapies and clinical trials of new biologic reagents against prostate cancer. We also seek to encourage urologists to actively participate in clinical trials and evaluate the potential of immunotherapeutic drugs for impacting standards of care.     

Impact of early personal‐history characteristics on the Pace of Aging: implications for clinical trials of therapies to slow aging and extend healthspan

Therapies to extend healthspan are poised to move from laboratory animal models to human clinical trials. Translation from mouse to human will entail challenges, among them the multifactorial heterogeneity of human aging. To inform clinical trials about this heterogeneity, we report how humans’ pace of biological aging relates to personal‐history characteristics. Because geroprotective therapies must be delivered by midlife to prevent age‐related disease onset, we studied young‐adult members of the Dunedin Study 1972–73 birth cohort (n = 954). Cohort members’ Pace of Aging was measured as coordinated decline in the integrity of multiple organ systems, by quantifying rate of decline across repeated measurements of 18 biomarkers assayed when cohort members were ages 26, 32, and 38 years. The childhood personal‐history characteristics studied were known predictors of age‐related disease and mortality, and were measured prospectively during childhood. Personal‐history characteristics of familial longevity, childhood social class, adverse childhood experiences, and childhood health, intelligence, and self‐control all predicted differences in cohort members’ adulthood Pace of Aging. Accumulation of more personal‐history risks predicted faster Pace of Aging. Because trials of anti‐aging therapies will need to ascertain personal histories retrospectively, we replicated results using cohort members’ retrospective personal‐history reports made in adulthood. Because many trials recruit participants from clinical settings, we replicated results in the cohort subset who had recent health system contact according to electronic medical records. Quick, inexpensive measures of trial participants’ early personal histories can enable clinical trials to study who volunteers for trials, who adheres to treatment, and who responds to anti‐aging therapies.     

Properties of a nonparametric test for early comparison of treatments in clinical trials in the presence of surrogate endpoints

A nonparametric test is derived for comparing treatments with respect to the final endpoint in clinical trials in which the final endpoint has been observed for a random subset of patients, but results are available for a surrogate endpoint for a larger sample of patients. The test is an adaptation of the Wilcoxon-Mann-Whitney two-sample test, with an adjustment that involves a comparison of the ranks of the surrogate endpoints between patients with and without final endpoints. The validity of the test depends on the assumption that the patients with final endpoints represent a random sample of the patients registered in the study. This assumption is viable in trials in which the final endpoint is evaluated at a "landmark" timepoint in the patients' natural history. A small sample simulation study demonstrates that the test has a size that is close to the nominal value for all configurations evaluated. When compared with the conventional test based only on the final endpoints, the new test delivers substantial increases in power only when the surrogate endpoint is highly correlated with the true endpoint. Our research indicates that, in the absence of modeling assumptions, auxiliary information derived from surrogate endpoints can provide significant additional information only under special circumstances.