scholarly journals New approaches for testing non-inferiority for three-arm trials with Poisson distributed outcomes

Biostatistics ◽  
2020 ◽  
Author(s):  
Samiran Ghosh ◽  
Erina Paul ◽  
Shrabanti Chowdhury ◽  
Ram C. Tiwari
Keyword(s):  
Treatment Options ◽  
Sample Size Calculation ◽  
Experimental Treatment ◽  
Therapeutic Area ◽  
Cardiovascular Research ◽  
Reference Treatment ◽  
Ethical Reason ◽  
Bayesian Procedures ◽  
Interesting Connection ◽  
Efficacious Treatment

Summary With the availability of limited resources, innovation for improved statistical method for the design and analysis of randomized controlled trials (RCTs) is of paramount importance for newer and better treatment discovery for any therapeutic area. Although clinical efficacy is almost always the primary evaluating criteria to measure any beneficial effect of a treatment, there are several important other factors (e.g., side effects, cost burden, less debilitating, less intensive, etc.), which can permit some less efficacious treatment options favorable to a subgroup of patients. This leads to non-inferiority (NI) testing. The objective of NI trial is to show that an experimental treatment is not worse than an active reference treatment by more than a pre-specified margin. Traditional NI trials do not include a placebo arm for ethical reason; however, this necessitates stringent and often unverifiable assumptions. On the other hand, three-arm NI trials consisting of placebo, reference, and experimental treatment, can simultaneously test the superiority of the reference over placebo and NI of experimental treatment over the reference. In this article, we proposed both novel Frequentist and Bayesian procedures for testing NI in the three-arm trial with Poisson distributed count outcome. RCTs with count data as the primary outcome are quite common in various disease areas such as lesion count in cancer trials, relapses in multiple sclerosis, dermatology, neurology, cardiovascular research, adverse event count, etc. We first propose an improved Frequentist approach, which is then followed by it’s Bayesian version. Bayesian methods have natural advantage in any active-control trials, including NI trial when substantial historical information is available for placebo and established reference treatment. In addition, we discuss sample size calculation and draw an interesting connection between the two paradigms.

scholarly journals Medication of Hydroxychloroquine, Remdesivir and Convalescent Plasma during the COVID-19 Pandemic in Germany—An Ethical Analysis

2021 ◽  
Vol 18 (11) ◽  
pp. 5685
Author(s):  
Katja Voit ◽  
Cristian Timmermann ◽  
Florian Steger
Keyword(s):  
Early Stage ◽  
Treatment Options ◽  
Drug Distribution ◽  
Experimental Treatment ◽  
Ethical Analysis ◽  
Ethical Principles ◽  
Ethical Challenges ◽  
Ethical Guidelines ◽  
Negative Effects ◽  
Experimental Drug

This paper aims to analyze the ethical challenges in experimental drug use during the early stage of the COVID-19 pandemic, using Germany as a case study. In Germany uniform ethical guidelines were available early on nationwide, which was considered as desirable by other states to reduce uncertainties and convey a message of unity. The purpose of this ethical analysis is to assist the preparation of future guidelines on the use of medicines during public health emergencies. The use of hydroxychloroquine, remdesivir and COVID-19 convalescent plasma in clinical settings was analyzed from the perspective of the ethical principles of beneficence, non-maleficence, justice and autonomy. We observed that drug safety and drug distribution during the pandemic affects all four ethical principles. We therefore recommend to establish ethical guidelines (i) to discuss experimental treatment options with patients from all population groups who are in urgent need, (ii) to facilitate the recording of patient reactions to drugs in off-label use, (iii) to expand inclusion criteria for clinical studies to avoid missing potentially negative effects on excluded groups, and (iv) to maintain sufficient access to repurposed drugs for patients with prior conditions.

scholarly journals Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1548
Author(s):  
Mustafa N. Mithaiwala ◽  
Danielle Santana-Coelho ◽  
Grace A. Porter ◽  
Jason C. O’Connor
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Kynurenine Pathway ◽  
Economic Problem ◽  
Cns Disease ◽  
Therapeutic Implications ◽  
Efficacious Treatment ◽  
The Central Nervous System ◽  
Significant Health

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

Relevance of Aromatase Inhibitors in Breast Cancer Treatment

2021 ◽  
Vol 21 ◽  
Author(s):  
Ankita Sood ◽  
Damanpreet Kaur Lang ◽  
Rajwinder Kaur ◽  
Balraj Saini ◽  
Sandeep Arora
Keyword(s):  
Breast Cancer ◽  
Aromatase Inhibitors ◽  
Breast Tissue ◽  
Positive Impact ◽  
Treatment Options ◽  
Living Standards ◽  
Efficacious Treatment ◽  
Clinical Resistance ◽  
Steroidal Aromatase Inhibitors ◽  
Near Future

: Efficacious treatment for breast cancer is still a challenge despite the presence of various treatment options. Aromatase enzyme present in the breast tissue is responsible for estrogen formation from androgens. Aromatase inhibitors manifest remarkably ameliorated therapeutic efficacy as compared to the current therapeutic options available and exhibit a better safety profile as compared to the other drugs. Clinical resistance to aromatase inhibitors is perceived as a lack of growth inhibition by aromatase inhibitors treatment and cancer therapy becomes ineffective in causing a decrease in the size of the tumor. Naturally extracted aromatase inhibitors have a huge positive impact on vitality and living standards. This review article highlights the particulars about the currently approved steroidal and non-steroidal aromatase inhibitors for clinical use, adverse effects associated with their use and approach to tackling the problem, various strategies to overcome aromatase inhibitors resistance, information on the synthesis of various peculiar aromatase inhibitors which can prove as highly efficient and potent drugs in the near future and the drugs of natural and semi-synthetic origin which can demonstrate to be more efficient, potent and less-toxic than conventional therapy.

The right to choose treatment-without-treatment: respecting civil rights or an unprecedented manifestation of ‘reverse stigma’?

2018 ◽  
Vol 31 (1) ◽  
pp. 56-58
Author(s):  
Konstantinos N Fountoulakis ◽  
Kyriakos Souliotis
Keyword(s):  
Health Care ◽  
Civil Rights ◽  
Social Services ◽  
Treatment Options ◽  
Health Minister ◽  
Proper Treatment ◽  
Free Treatment ◽  
Efficacious Treatment ◽  
The Right ◽  
First Time

AbstractRecently the Norwegian Health Minister ordered the creation of medication-free treatment wards as a result of the lobbying by patients’ groups and activists. The idea behind this is that patients should have the right to choose their treatment, but for the first time, with this arrangement, the user/patient does not choose between treatment options; he literally determines by himself what efficacious treatment is. In our opinion this is another step towards a ‘reverse stigma’ which denies patients the right to be considered as such and eventually kicks them out of the health care system, deprives them of the right for proper treatment and care and instead puts them at the jurisdiction of the much cheaper and ineffective social services.

scholarly journals Treatment of inoperable hepatocellular carcinoma with immunotherapy

2019 ◽  
Vol 12 (7) ◽  
pp. e229744 ◽  
Author(s):  
Sean P Tighe ◽  
Umair Iqbal ◽  
Christopher T Fernandes ◽  
Aijaz Ahmed
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Presentation ◽  
Treatment Options ◽  
Linkage To Care ◽  
Experimental Treatment ◽  
Hepatitis C Virus Infection ◽  
Chronic Liver Diseases ◽  
The Third ◽  
The Usa ◽  
High Risk Populations

In the USA, mortality associated with hepatocellular carcinoma (HCC) continues to rise. Globally, HCC is the third most common cause of cancer-related death. In early stages of HCC, hepatic resection or liver transplantation are the preferred treatment options with a high probability of recurrence-free postoperative course. However, ineffective screening of chronic liver diseases in high-risk populations, poor linkage to care and suboptimal HCC surveillance has led to increasing rates of late-stage HCC at clinical presentation or diagnosis amenable only to palliative and experimental treatment options. Our case is a 66-year-old man with chronic hepatitis C virus infection complicated by cirrhosis and inoperable HCC which was non-responsive to selective intrahepatic trans-arterial chemoembolisation by interventional radiology. Therefore, he was treated with nivolumab immunotherapy and demonstrated normalisation of previously elevated alpha-fetoprotein levels suggestive of at least a partial response to immunotherapy. No adverse events related to nivolumab immunotherapy were encountered.

scholarly journals Cost-effectiveness analysis (CEA) of IMRT plus C12 boost vs IMRT only in adenoid cystic carcinoma (ACC) of the head and neck

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
A D Jensen ◽  
Jürgen Debus
Keyword(s):  
Cost Effectiveness ◽  
Local Control ◽  
Recurrent Disease ◽  
Treatment Options ◽  
Combined Treatment ◽  
Intensity Modulated Radiotherapy ◽  
Experimental Treatment ◽  
Clinical Results ◽  
Particle Therapy ◽  
Combination Regimen

Abstract Background Particle therapy provides steep dose gradients to facilitate dose escalation in challenging anatomical sites which has been shown not only to improve local control but also overall survival in patients with ACC. Cost-effectiveness of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost vs IMRT alone was performed in order to objectivise and substantiate more widespread use of this technology in ACC. Methods Patients with pathologically confirmed ACC received a combination regimen of IMRT plus C12 boost. Patients presenting outside C12 treatment slots received IMRT only. Clinical results were published; economic analysis on patient-level data was carried out from a healthcare purchaser’s perspective based on costs of healthcare utilization. Cost histories were generated from resource use recorded in individual patient charts and adjusted for censoring using the Lin I method. Cost-effectiveness was measured as incremental cost-effectiveness ratio (ICER). Sensitivity analysis was performed regarding potentially differing management of recurrent disease. Results The experimental treatment increased overall costs by € 18,076 (€13,416 – €22,922) at a mean survival benefit of 0.86 years. Despite improved local control, following costs were also increased in the experimental treatment. The ICER was estimated to 26,863 €/LY. After accounting for different management of recurrent disease in the two cohorts, the ICER was calculated to 20,638 €/LY. Conclusion The combined treatment (IMRT+C12 boost) substantially increased initial and overall treatment cost. In view of limited treatment options in ACC, costs may be acceptable though. Investigations into quality of life measures may support further decisions in the future.

Mayo Clinic Infectious Diseases Board Review

2012 ◽  
Keyword(s):  
Virus Infection ◽  
Infectious Diseases ◽  
Treatment Options ◽  
Influenza Virus Infection ◽  
H1n1 Influenza ◽  
General Internists ◽  
Efficacious Treatment ◽  
Immunodeficiency Virus ◽  
History Of ◽  
Board Review

While infections have always played an important role in the history of mankind, advances in science and technology as well as rapid globalization have resulted in an unprecedented wave of new and old infections thrust into the limelight. The recent pandemic of H1N1 influenza virus infection demonstrates the recurrent theme of emerging and reemerging pathogens that continue to impact public health and patient care areas. Drug resistance among various organisms (not limited to bacteria) has unfortunately become the expectation and, not infrequently, we have been left with few or no efficacious treatment options, an experience not witnessed in more than 7 decades. Human immunodeficiency virus infection continues to challenge our abilities to provide the desired level of care in most areas of the world. Novel syndromes of infection continue to be defined as newer forms of immunosuppression and the development of unique medical devices become standard practice in all areas of medicine and surgery. For trainees and practitioners in the field of infectious diseases today, these factors mandate intense study to establish an expertise in the field that is required to provide best practices now and beyond. This board review will be pivotal in that education. This book is designed and intended primarily for infectious diseases trainees and practitioners preparing for the infectious disease subspecialty examination of the American Board of Internal Medicine. We believe that this book will also be useful to infectious diseases practitioners as well as general internists and other clinicians who desire a comprehensive but practical overview of contemporary infectious diseases topics.

scholarly journals Does cranberry extract reduce antibiotic use for symptoms of acute uncomplicated urinary tract infections (CUTI)? Protocol for a feasibility study

Trials ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Oghenekome Gbinigie ◽  
Julie Allen ◽  
Anne-Marie Boylan ◽  
Alastair Hay ◽  
Carl Heneghan ◽  
...  
Keyword(s):  
Primary Care ◽  
Urinary Tract ◽  
Feasibility Study ◽  
Urinary Tract Infections ◽  
Treatment Options ◽  
Sample Size Calculation ◽  
Antibiotic Use ◽  
Primary Objective ◽  
Feasibility Trial ◽  
Tract Infections

Abstract Background Consultations in primary care for symptoms of urinary tract infections (UTIs) are common and patients are frequently treated with antibiotics. Given increasing antimicrobial resistance, there has been interest in non-antibiotic treatment options for common infections. One such option is the use of cranberry extract to treat symptoms attributable to UTIs. Methods A target of 45 women consulting in primary care, with symptoms suggestive of an uncomplicated UTI for whom the practitioner would normally prescribe antibiotics, will be randomised to receive one of three treatment approaches: (1) immediate prescription for antibiotics; (2) immediate prescription for antibiotics plus a 7-day course of cranberry capsules and (3) cranberry capsules plus a delayed prescription for antibiotics to be used in case their symptoms do not get better, or get worse. Follow-up will be by daily rating of symptoms and recording of treatments used for 2 weeks in an online symptom diary. Interviews will be conducted with around 10–15 study participants, as well as with around 10–15 women who have experienced a UTI but have not been approached to take part in the study. Both groups will be asked about their experience of having a UTI, their thoughts on non-antibiotic treatments for UTIs and their thoughts on, or experience of, the feasibility trial. The primary objective is to assess the feasibility of undertaking a full trial in primary care of the effectiveness of cranberry extract to reduce antibiotic use for symptoms of acute uncomplicated UTI. The secondary objective is to conduct a preliminary assessment of the extent to which cranberry might reduce antibiotic use and symptom burden. Discussion This feasibility study with embedded interviews will inform the planning and sample size calculation of an adequately powered trial to definitively determine whether cranberry helps to alleviate the symptoms of acute uncomplicated UTIs in women and whether it can safely reduce antibiotic use. Trial registration ISRCTN registry, ID: 10399299. Registered on 24 January 2019.

scholarly journals Noninferior Antibiotics: When Is “Not Bad” “Good Enough”?

2016 ◽  
Vol 3 (3) ◽  
Author(s):  
Mark J. DiNubile
Keyword(s):  
Nursing Home ◽  
Clinical Practice ◽  
Antimicrobial Agents ◽  
Treatment Options ◽  
Chronically Ill ◽  
Multidrug Resistant ◽  
Everyday Clinical Practice ◽  
Novel Treatment ◽  
Efficacious Treatment

Abstract Novel treatment options are urgently needed for patients with serious multidrug-resistant infections seen increasingly in routine everyday clinical practice, both in the hospital and nursing home as well as in the clinic and office setting. Unfortunately, the problem is no longer confined to chronically ill, repeatedly hospitalized patients. This essay explores the role of noninferiorly studies in addressing the pressing need for new antimicrobial agents to combat the emerging “superbugs”, calling attention to the nuances of interpreting their sometimes less-than-straightforward results. The overriding aim is not to find better antibiotics for routinely treatable infections but to identify safe and efficacious treatment options where none presently exist.

Right to Experimental Treatment: FDA New Drug Approval, Constitutional Rights, and the Public's Health

2009 ◽  
Vol 37 (2) ◽  
pp. 269-279 ◽  
Author(s):  
Elizabeth Weeks Leonard
Keyword(s):  
Treatment Options ◽  
Terminally Ill ◽  
Experimental Treatment ◽  
Drug Approval ◽  
New Drugs ◽  
Constitutional Rights ◽  
Court Of Appeals ◽  
Fda Approval ◽  
Life Saving ◽  
Constitutional Right

Do terminally ill patients who have exhausted all other available, government-approved treatment options have a constitutional right to experimental treatment that may prolong their lives? On May 2, 2006, a divided panel of the U.S. Court of Appeals for the District of Columbia, in a startling opinion, Abigail Alliance for Better Access to Developmental Drugs v. Von Eschenbach, held “Yes.” The plaintiffs, Abigail Alliance for Better Access to Developmental Drugs (Abigail Alliance) and Washington Legal Foundation, sought to enjoin the Food and Drug Administration (FDA) from refusing to allow the sale of investigational new drugs that had not yet received FDA approval. The terminally ill plaintiffs contended that they quite literally could not wait that long for the drugs. With no other treatment options available, the plaintiffs urged the court to recognize a fundamental, constitutional right to take potentially life-saving or life-prolonging drugs, even though the treatment had not been fully tested through human trials for safety and effectiveness and could not be legally marketed to the public.

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