Reports Of Clinical Trials Research Articles

Sharing data: a requirement for expanding precision oncology

Identification of somatic genomic variants in tumor DNA to identify matched targeted agents (MTAs—drugs that are supposed to target the abnormal encoded proteins) is nowadays accessible to patients from several companies and may be funded by Health Insurances. A lot of cancer centers have developed institutional precision profiling programs. Beyond the fact that using molecular profiling is feasible in the clinic, what is the optimal goal of this genomic medicine? The level of outcome improvement in studies investigating the impact of MTAs on a broad variety of advanced cancers (pathology-agnostic therapies) have proven to be limited. Reports of precision medicine clinical trials [including the prospective randomized SHIVA trial (1)] demonstrated minimal impact of MTAs on large population of patients with advanced cancers (even though the molecular profile of each patient’s tumor was established with a specific mandatory biopsy) (2).

An Updated Review of Randomized Clinical Trials Testing the Improvement of Cognitive Function of Ginkgo biloba Extract in Healthy People and Alzheimer's Patients.

Alzheimer’s disease (AD) is a common neurodegenerative disease, mainly manifested by cognitive dysfunction. It seriously reduces the quality of life, and there is no ideal treatment strategy in clinical practice. Clinical studies on the treatment of AD with Ginkgo biloba L. leaf extract (EGb) have been reported since 1980s, and many clinical studies have been carried out during the following 30 years. However, the benefits of EGb on the treatment of AD are still controversial. In this review, we collected the clinical trial reports of EGb on cognitive function from Pubmed, Elsevier, Europe PMC, and other database since the 1980s. Through analysis and comparison, we consider that EGb may be able to improve the cognitive function in patients who suffered from mild dementia during long-term administration (more than 24 weeks) and appropriate dosage (240 mg per day). The main evidences and existing problems of the negative and positive experimental results were summarized.

Evaluating the re-identification risk of a clinical study report anonymized under EMA Policy 0070 and Health Canada Regulations

BackgroundRegulatory agencies, such as the European Medicines Agency and Health Canada, are requiring the public sharing of clinical trial reports that are used to make drug approval decisions. Both agencies have provided guidance for the quantitative anonymization of these clinical reports before they are shared. There is limited empirical information on the effectiveness of this approach in protecting patient privacy for clinical trial data.MethodsIn this paper we empirically test the hypothesis that when these guidelines are implemented in practice, they provide adequate privacy protection to patients. An anonymized clinical study report for a trial on a non-steroidal anti-inflammatory drug that is sold as a prescription eye drop was subjected to re-identification. The target was 500 patients in the USA. Only suspected matches to real identities were reported.ResultsSix suspected matches with low confidence scores were identified. Each suspected match took 24.2 h of effort. Social media and death records provided the most useful information for getting the suspected matches.ConclusionsThese results suggest that the anonymization guidance from these agencies can provide adequate privacy protection for patients, and the modes of attack can inform further refinements of the methodologies they recommend in their guidance for manufacturers.

Candida Endocarditis: A Review of the Pathogenesis, Morphology, Risk Factors, and Management of an Emerging and Serious Condition.

Infective endocarditis is a significant healthcare burden due to the associated high mortality and complications. Endocarditis caused by both Candida albicans (C. albicans) and non-Candida albicans Candida (NCAC) species has been associated with a substantial rise in in-hospital morbidity and mortality. We used the Pubmed database to identify 47 out of 101 articles that had met our inclusion and exclusion criteria. We had put in place a broad inclusion criterion with no age or gender restrictions. These 47 articles included abstracts, 11 review articles, 13 case reports, 10 research articles, 1 clinical trial report, 1 meta-analysis, and other research articles. And they comprehensively cover the pathogenesis, risk factors, and management of infections caused by C. albicans and NCAC species in the past 26 years. The articles we scanned provided us with information on different associations in correlation to multiple types of Candida species. Here, we discuss the association between Candida and endocarditis, a major cause of morbidity and mortality in both C. albicans and NCAC. We also present our understanding regarding this interesting association and attempt to address some of the recurring questions.

Physical drug delivery enhancement for aged skin, UV damaged skin and skin cancer: Translation and commercialization.

This review analyses physical drug delivery enhancement technologies with a focus on improving UV damaged skin, actinic keratoses and non-melanoma skin cancer treatment. In recent years, physical drug delivery enhancement has been shown to enhance cosmeceutical and skin cancer treatment efficacy, but there are pros and cons to each approach which we discuss in detail. Mechanisms of action, clinical efficacy, experimental design, outcomes in academic publications, clinical trial reports and patents are explored to evaluate each technology with a critical, translation focused lens. We conclude that the commercial success of cosmeceutical applications, e.g. microneedles, will drive further innovation in this arena that will impact how actinic keratoses and non-melanoma skin cancers are clinically managed.

Recent update on crosslinked polyethylene in total hip arthroplasty.

More than two decades after their clinical introduction, crosslinked polyethylenes (XLPE) have been widely adopted. Though concerns were initially raised regarding oxidation and brittleness, on a large scale, the first generation of XLPE continues to be highly effective 15 years after the surgery, even in a young and active population. Remelted XLPE might display lower wear rates than annealed XLPE. Second generation XLPEs, not only including sequentially irradiated and annealed but also associated with antioxidants, demonstrate encouraging short- to mid-term results. Registry data support clinical trial reports. Even in less favorable settings (lipped liners, dual mobility cups, revision surgery, hip resurfacing) results are promising. However, failures (fractures) have already been described. Therefore, a high level of surveillance remains crucial.

Trialstreamer: Mapping and Browsing Medical Evidence in Real-Time.

We introduce Trialstreamer, a living database of clinical trial reports. Here we mainly describe the evidence extraction component; this extracts from biomedical abstracts key pieces of information that clinicians need when appraising the literature, and also the relations between these. Specifically, the system extracts descriptions of trial participants, the treatments compared in each arm (the interventions), and which outcomes were measured. The system then attempts to infer which interventions were reported to work best by determining their relationship with identified trial outcome measures. In addition to summarizing individual trials, these extracted data elements allow automatic synthesis of results across many trials on the same topic. We apply the system at scale to all reports of randomized controlled trials indexed in MEDLINE, powering the automatic generation of evidence maps, which provide a global view of the efficacy of different interventions combining data from all relevant clinical trials on a topic. We make all code and models freely available alongside a demonstration of the web interface.

Progress in treating inherited retinal diseases: Early subretinal gene therapy clinical trials and candidates for future initiatives.

Due to improved phenotyping and genetic characterization, the field of 'incurable' and 'blinding' inherited retinal diseases (IRDs) has moved substantially forward. Decades of ascertainment of IRD patient data from Philadelphia and Toronto centers illustrate the progress from Mendelian genetic types to molecular diagnoses. Molecular genetics have been used not only to clarify diagnoses and to direct counseling but also to enable the first clinical trials of gene-based treatment in these diseases. An overview of the recent reports of gene augmentation clinical trials by subretinal injections is used to reflect on the reasons why there has been limited success in this early venture into therapy. These first-in human experiences have taught that there is a need for advancing the techniques of delivery of the gene products - not only for refining further subretinal trials, but also for evaluating intravitreal delivery. Candidate IRDs for intravitreal gene delivery are then suggested to illustrate some of the disorders that may be amenable to improvement of remaining central vision with the least photoreceptor trauma. A more detailed understanding of the human IRDs to be considered for therapy and the calculated potential for efficacy should be among the routine prerequisites for initiating a clinical trial.

Topical CBD for the Management of Acute and Chronic Pain: A Brief Review and Report of an Open-Label Dose-Ranging Clinical Trial

Topical CBD for the Management of Acute and Chronic Pain: A Brief Review and Report of an Open-Label Dose-Ranging Clinical Trial

Japanese Dermatological Association Guidelines: Outlines of guidelines for cutaneous melanoma 2019.

With consideration of the ongoing developments in treatment options for cutaneous melanoma, the Japanese Skin Cancer Society published the first guidelines for cutaneous melanoma in 2007 and later revised them in 2015. Here, we report on an English version of the 2019 Japanese Melanoma Guidelines. In this latest edition, all processes were carried out according to the Grading of Recommendations, Assessment, Development and Evaluation system. A comprehensive published work search, systematic review and determination of recommendations in each clinical question were performed by a multidisciplinary expert panel consisting of dermatologists, a plastic and reconstructive surgeon, and a radiation oncologist. The advent of novel agents, such as immune checkpoint inhibitors and molecular-targeted agents, has drastically changed the nature of treatment for adjuvant and advanced-stage diseases among melanoma patients worldwide. Additionally, recent reports of clinical trials regarding surgical procedures and a better understanding of molecular biology and tumor immunology in clinical types of melanoma have had an impact on clinical practise. Based on these viewpoints, eight relevant clinical questions were raised in this report that aim to help clinicians select the appropriate therapeutic approach.

Blinatumomab and Venetoclax for Minimal Residual Disease Relapse in Acute Lymphoblastic Leukemia

Introduction: The 5-year relative survival in patients aged 15-24 years old is around 57% (Blood 2019; 134: 407-410), with a median survival after relapse of 10 months. No uniform consensus about rescue treatment is available, but those who achieve a complete remission can undergo to an allogeneic transplant if feasible. The use of intense rescue chemotherapy is associated with systemic toxicities and risk of serious infections that can delay an allogeneic transplant. Objective: We describe the combination of two ALL targeted therapies, combining bispecific T-cell engager (BiTE) against CD 19 (Blinatumomab) and selective inhibitor of the B-cell lymphoma 2 (Bcl-2) regulator protein, an antiapoptotic protein (Venetoclax). This combination was developed based in their mechanism of action that offers synergetic effects against ALL cells and the reports of ongoing clinical trials using Venetoclax combinations for ALL, but no with Blinatumomab. Patients and methods: Patients with B cell precursors ALL in minimal residual disease relapse by flow cytometry. Rescue treatment with Blinatumomab and Venetoclax before allogeneic transplant. Results: Two patients treated with LAFAMI-LLA-2002 Protocol (Blood 2009; 114: 4104 and Hematologia 2016; 17: 5137), adapted to young adults with high dose methotrexate at 5 gr/m2 every four months in the maintenance phase, had MDR positivity by FC in the surveillance phase, with normal CBC. One male with 22 years old at the time of relapse, after 60 months of surveillance with 1.9 % of malignant lymphoblasts. One female with 21 years old at the time of relapse, after 25 months of surveillance with 0.2 % of malignant lymphoblasts. Both relapses were confirmed with an additional MRD one week after. Extension studies were performed, including PET-CT, to determinate other affected sites and were negative. Treatment administrated was Blinatumomab at 9 mcg/day continuous IV infusion on days 1-7 and 28 mcg/day on days 8-14 with Venetoclax in a ramp-up phase for 5 weeks. Both patients were in negative MRD after the complete Blinatumomab and continue with Venetoclax while a donor was available. No side effects were observed during and after the treatment. Both patients had a compatible sibling and underwent for allogeneic transplant. At the moment of this report the patients have 11 months and 18 months after transplant with EMR negative and complete donor cells from the bone marrow, with no secondary effects. Conclusion: This is a novel combination with no reports of its use before our communication. Targeted therapies in low leukemic burden is a feasible treatment with no side effects and rapid control of the relapse, allowing the patients to reach an allogeneic transplant as soon as possible avoiding substantial toxicity and risk of infections. No infusion related reaction or cytokine release syndrome were observed due low leukemic burden. More patients need to be included to this combination to demonstrate reproducibility, optimizing time and costs. OffLabel Disclosure: Blinatumomab and Venetoclax combination for acute lymphoblastic leukemia relapse

Reporting and methodological quality of clinical trials on exercise therapy for Parkinson's disease

BackgroundExercise therapy is becoming extremely relevant as a new efficacious intervention in multiple medical fields. Although several clinical trials have reported benefits of exercise therapy for Parkinson's disease (PD), recommendations and prescriptions for its use in clinical practice remain limited. ObjectivesTo evaluate the methodological quality and publication rate of clinical trials on exercise therapy for PD. MethodsWe analyzed all clinical trials assessing exercise therapy for PD registered in the WHO International Clinical Trials Registry Platform and the ClinicalTrials.gov registries, from 2000 to 2017. We evaluated the methodological quality of trials using the Cochrane Risk of Bias criteria. ResultsA total of 236 clinical trials were identified. Only 70 (29.7%) trials reported their findings, and 61 (25.8%) had results published in scientific journals. Most trials had an unclear risk of bias concerning incomplete and selective outcome reporting and lacked data on the randomization process, allocation concealment, blinding of participants and personnel, and outcomes assessors. Aerobic capacity was the most frequent type of exercise intervention. ConclusionsAlthough a large number of trials on exercise are registered in international portals, the quality of reporting remains suboptimal and only a quarter of trials have their results published in scientific journals. These two factors, in addition to the heterogeneity of the interventions tested and the unsatisfactory reported methodological quality of most trials, compromise the interpretation of study results. Therefore, higher quality clinical trials reports are needed to establish exercise as part of the PD armamentarium.

ICON 2019—International Scientific Tendinopathy Symposium Consensus: There are nine core health-related domains for tendinopathy (CORE DOMAINS): Delphi study of healthcare professionals and patients

BackgroundThe absence of any agreed-upon tendon health-related domains hampers advances in clinical tendinopathy research. This void means that researchers report a very wide range of outcome measures inconsistently. As a...

342O - Response of nivolumab monotherapy in 124 Japanese patients with advanced melanoma: Interim analysis of prospective observational study (CREATIVE study)

BackgroundAnti-PD-1 antibody nivolumab has been approved for advanced melanoma in Japan. Although there have been clinical trial reports on nivolumab treatment for advanced melanoma, real-world data on the efficacy of nivolumab in an Asian patient cohort is still lacking. The aim of this study is to obtain real-world data on the efficacy of nivolumab in Japanese patients with advanced melanoma. MethodsThis prospective observational study was performed on unresectable or metastatic melanoma patients who were treated with nivolumab. Primary endpoints were response rate (RR), and overall survival (OS). The secondary endpoints were progression-free survival (PFS) and the immune-related adverse events (irAEs) ratio. ResultsIn total, 124 patients from 22 institutions in Japan were enrolled between Dec. 2015 and Dec. 2017. Mucosal melanoma (34%) was the most frequent subtype in this study, followed by acral lentiginous melanoma (20%), nodular melanoma (15%), superficial spreading melanoma (13%). We observed complete response (CR) in 2 (2%), partial response (PR) in 21 (17%), stable disease (SD) in 27 (22%), and progressive disease (PD) in 59 patients (47.6%) (objective RR: 19%). Use of nivolumab as first-line treatment showed a tendency toward higher response than when used as second-line treatment (objective RR, 23% vs 11%, P = 0.12). IrAEs comprised skin reactions and endocrine-related adverse effects. The median PFS in patients with skin reactions (or skin-related irAEs) was 8.61 months compared to 2.14 months without skin-related irAEs, and 8.99 months (p < 0.001) with endocrine function suppression compared to 2.14 months in the absence of endocrine-related irAEs. ConclusionsThe results of this interim analysis showed a lower RR than that reported in recent phase 2 trials conducted in Japan. The differences in the proportions of melanoma subtypes, with a higher proportion of mucosal and acral melanoma, and use of nivolumab as second-line treatment will probably lead to a lower RR to nivolumab in Japan. As the results of this study showed that the occurrence of irAEs had a significant impact on therapeutic efficiency, it is critical to take appropriate measures to manage the occurrence of irAEs. Legal entity responsible for the studyThe authors. FundingThis study was sponsored by Public Health Research Foundation under the funding support from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb K.K. DisclosureN. Yamazaki: Honoraria (self), Honoraria (institution), Non-remunerated activity/ies: ONO Phamaceuticals; Honoraria (self), Honoraria (institution), Non-remunerated activity/ies: Bristol-Myers Squibb; Honoraria (self), Honoraria (institution), Non-remunerated activity/ies: Novartis Pharma K.K.; Honoraria (self), Honoraria (institution), Non-remunerated activity/ies: MSD K.K.; Honoraria (self), Honoraria (institution): Merck Serono Co., Ltd.; Honoraria (self): Takeda Pharmaceutical Co., Ltd. K. Namikawa: Honoraria (institution): Public Health Research Foundation; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Merck Sharp & Dohme. T. Takenouchi: Advisory / Consultancy: Ono Pharmaceutical Co., Ltd.; Advisory / Consultancy: MSD KK; Advisory / Consultancy: Chugai Pharmaceutical Co., LTD.; Advisory / Consultancy: Novartis Pharma KK. Y. Nakamura: Honoraria (self): ONO pharmaceuticals; Honoraria (self): MSD; Honoraria (self): Bristol Myers-Squibb; Honoraria (self): Novartis Pharma K.K.; Honoraria (self): Taisho Toyama Pharma; Honoraria (self): Maruho; Honoraria (self): Taiho Pharma. S. Kitano: Honoraria (self): AstraZeneca; Honoraria (self): Chugai; Honoraria (self): Pfizer; Honoraria (self): Sanofi; Honoraria (self): Nippon Kayaku; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Meiji Seika Pharma; Honoraria (self): Taiho. T. Fujita: Honoraria (self): Public Health Research Foundation; Advisory / Consultancy: ONO PHARMACEUTICAL CO., LTD; Advisory / Consultancy: Bristol-Myers Squibb Company. T. Yamanaka: Honoraria (self), Honoraria (institution): Takeda; Honoraria (self), Honoraria (institution): Taiho; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Chugai. Y. Kawakami: Advisory / Consultancy: Public Health Research Foundation; Advisory / Consultancy: Ono Pharmaceutical Co., LTD; Advisory / Consultancy: Bristol-Myers Squibb Company. All other authors have declared no conflicts of interest.

Forum on Augmentative and Alternative Communication in Acute Care.

This forum provides some insights into the process of initiating a clinical service to enhance patient- provider communication. It also provides a report of a large-scale clinical trial that introduced augmentative and alternative communication (AAC) tools in an acute-care setting.

A Single Arm Trial in Treatment of CKD Patients with Sodium Copper Chlorophyllin Formulation

In a prospective, single arm study of 34 Chronic Kidney Disease (CKD) patients in a trial of 90 days wherein patients got standard-of-care treatment and liquid composition containing Sodium Copper Chlorophyllin, the Investigational Product (IP), as add-on treatment for first 60 days and patients were ‘off’ the IP for last 30 days. Significant reduction in serum creatinine, Blood Urea and Uric acid level and significant improvement in estimated Glomerular Filtration Rate (eGFR), and Health related criteria for quality of life were observed in 60 days’ period of administration. eGFR remained significantly higher on 90th day than 0 day despite withdrawal of IP after 60 days. These observations suggest partial/limited reversal of lost kidney function as a lingering effect of the IP. Both these are first observations opening up new avenues for improving life of CKD patients. This is first clinical trial report of an orally consumed product that decreases serum creatinine and also actually improved health related quality of life within 60 days and a surprising evidence that suggests significant degree of restoration of kidney function in the progressively degenerative disease CKD. This clinical trial opens opportunities for managing CKD that were never available so far.

Vaccines for preventing rotavirus diarrhoea: vaccines in use.

Vaccines for preventing rotavirus diarrhoea: vaccines in use.

Advances of adeno-associated virus applied in gene therapy to hemophilia from bench work to the clinical use.

Hemophilia A and B are diseases caused by a single gene deficiency and are thus suitable for gene therapy. In recent clinical research, adeno-associated virus (AAV) was employed by several teams in the treatment of hemophilia A and B, and the outcomes were encouraging. In this review, we summarized the most recent research on the mechanism and application of AAV in the treatment of hemophilia, trying to analyze the advantages of AAV gene therapy and the main challenges in its clinical use. We also summarized the clinical trials involving hemophilia, especially those employing AAV gene therapy to treat hemophilia A and B, some of which have already been completed and some that are still ongoing. From the reports of the completed clinical trials, we tried to determine the correlations among AAV dose, AAV serotype, immune response, and gene expression time. Finally, taking into account the most recent studies investigating AAV capsid modification, transgene optimization, and AAV chaperones, we summarized the direction of basic research and clinical applications of AAV in the future.

An investigation into the impact and implications of published papers from retracted research: systematic search of affected literature

ObjectiveAnalyses of the impact of a body of clinical trial reports subject to research misconduct have been few. Our objective was to examine the impact on clinically relevant research of...

Towards Comprehensive Clinical Trial Reporting: The Value of Unpublished Data to Inform Therapeutic Decision-Making in Metastatic Renal Cell Carcinoma.

Towards Comprehensive Clinical Trial Reporting: The Value of Unpublished Data to Inform Therapeutic Decision-Making in Metastatic Renal Cell Carcinoma.