Lessons from Randomised Clinical Trials for Triiodothyronine Treatment of Hypothyroidism: Have They Achieved Their Objectives?

Randomised controlled trials are deemed to be the strongest class of evidence in evidence-based medicine. Failure of trials to prove superiority of T3/T4 combination therapy over standard LT4 monotherapy has greatly influenced guidelines, while not resolving the ongoing debate. Novel studies have recently produced more evidence from the examination of homeostatic equilibria in humans and experimental treatment protocols in animals. This has exacerbated a serious disagreement with evidence from the clinical trials. We contrasted the weight of statistical evidence against strong physiological counterarguments. Revisiting this controversy, we identify areas of improvement for trial design related to validation and sensitivity of QoL instruments, patient selection, statistical power, collider stratification bias, and response heterogeneity to treatment. Given the high individuality expressed by thyroid hormones, their interrelationships, and shifted comfort zones, the response to LT4 treatment produces a statistical amalgamation bias (Simpson’s paradox), which has a key influence on interpretation. In addition to drug efficacy, as tested by RCTs, efficiency in clinical practice and safety profiles requires reevaluation. Accordingly, results from RCTs remain ambiguous and should therefore not prevail over physiologically based counterarguments. In giving more weight to other forms of valid evidence which contradict key assumptions of historic trials, current treatment options should remain open and rely on personalised biochemical treatment targets. Optimal treatment choices should be guided by strict requirements of organizations such as the FDA, demanding treatment effects to be estimated under actual conditions of use. Various improvements in design and analysis are recommended for future randomised controlled T3/T4 combination trials.

Download Full-text

Stem Cells in Clinical Trials for Pelvic Floor Disorders: a Systematic Literature Review

Reproductive Sciences ◽

10.1007/s43032-021-00745-6 ◽

2021 ◽

Author(s):

Stefano Manodoro ◽

Matteo Frigerio ◽

Marta Barba ◽

Sara Bosio ◽

Luigi Antonio de Vitis ◽

...

Keyword(s):

Clinical Trials ◽

Stem Cell ◽

Pelvic Floor ◽

Pelvic Floor Disorders ◽

Treatment Options ◽

Current Treatment ◽

Cochrane Library ◽

Safe Procedure ◽

Alternative Treatment Strategy ◽

Beneficial Impact

AbstractPelvic floor disorders (PFDs) include a series of conditions that can be poorly tolerated, negatively affecting the quality of life. Current treatment options show unsatisfactory results and new ones are therefore needed. Stem cell (SC) therapy might be an alternative treatment strategy. This systematic review aims to define the state of art of SC therapy for PFDs in clinical trials, by systematically reviewing the available evidence. A systematic search strategy was conducted up to November 7, 2020, in PubMed, Scopus, Cochrane Library, and ISI Web of Science. Preclinical studies on animal models were not considered. Studies were included when the patients were affected by any PFDs and cells were isolated, cultured, and characterized as SC. The study protocol was registered in PROSPERO (CRD42020216551). A total of 11 prospective clinical studies were included in the final assessment, specifically 7 single-arm studies dealing with SC therapy for stress urinary incontinence and 4 with anal incontinence. Among the latter, there were two prospective, single-arm studies and two randomized controlled trials. No papers concerning the use of SC for prolapse repair were retrieved. Due to the great heterogeneity, data pooling was not possible. Stem cell injection resulted in a safe procedure, with few mild adverse side effects, mostly related to harvesting sites. However, a clear beneficial impact of SC treatment for the treatment of pelvic floor disorders could not be demonstrated. Further larger targeted studies with control arms are needed before any conclusions can be made.

Download Full-text

Immigration Brings New Pathology with No Standardized Treatment Protocol

Journal of the American Podiatric Medical Association ◽

10.7547/17-058 ◽

2018 ◽

Vol 108 (6) ◽

pp. 517-522

Author(s):

Tara L. Harrington ◽

Denten Eldredge ◽

Erica K. Benson

Keyword(s):

Opportunistic Infections ◽

Treatment Options ◽

Treatment Protocol ◽

Current Treatment ◽

Foot And Ankle ◽

Treatment Protocols ◽

Clinical Presentations ◽

Standardized Treatment ◽

Madura Foot ◽

Antimicrobial Interventions

Madura foot is an uncommon invasive soft-tissue infection that foot and ankle specialists encounter. We present two rare cases of Phialemonium and Phaeoacremonium fungi infections of the foot diagnosed in northern California to inform physicians on the presentation and current treatment options for this unique pathology. The two cases presented outline the clinical presentations, diagnostic data, and surgical and antimicrobial interventions. There is a concentration on the antimicrobial options depending on which of the over 20 species is encountered. The pertinent literature and supporting data are reviewed to create an outline for discussion of treatment protocols when faced with these emerging opportunistic infections.

Download Full-text

The design, analysis and application of mouse clinical trials in oncology drug development

10.1101/425256 ◽

2018 ◽

Author(s):

Sheng Guo ◽

Xiaoqian Jiang ◽

Binchen Mao ◽

Qi-Xiang Li

Keyword(s):

Clinical Trials ◽

Drug Development ◽

Statistical Power ◽

Objective Response ◽

Drug Efficacy ◽

Design Analysis ◽

Frailty Models ◽

Oncology Drug ◽

Power Curves ◽

Oncology Drug Development

AbstractMouse clinical trials (MCTs) are becoming widely used in pre-clinical oncology drug development. In this study, we provide some general guidelines on the design, analysis and application of MCTs. We first established empirical quantitative relationships between mouse number and measurement accuracy for both categorical and continuous efficacy endpoints, and showed that more mice are needed to achieve given accuracy for syngeneic models than for PDXs and CDXs. There is considerable disagreement between categorical methods on calling drug responses as objective response, indicating limitations of such approaches. We then introduced linear mixed models, or LMMs, to describe MCTs as clustered longitudinal studies, which explicitly model growth and drug response heterogeneities across mouse models and among mice within a mouse model. Several case studies were used to demonstrate the advantages of LMMs in discovering biomarkers and exploring a drug’s mechanism of action. We also introduced the additive frailty models to perform survival analysis on MCTs, which more accurately estimate hazard ratios by modeling the clustered population structures in MCTs. We performed computational simulations for LMMs and frailty models to generate statistical power curves, and showed that statistical power is close for designs with similar total number of mice at given drug efficacy. Finally, we explained how MCTs can explain discrepant results in clinical trials, hence, MCTs are more than preclinical versions of clinical trials but possess their unique values. Results in the report will make MCTs a better tool for oncology drug development.

Download Full-text

Hemicraniectomy – An Overview of Current Status and Future Considerations

European Neurological Review ◽

10.17925/enr.2009.04.02.112 ◽

2009 ◽

Vol 4 (2) ◽

pp. 112

Author(s):

Hagen B Huttner ◽

Stefan Schwab ◽

◽

Keyword(s):

Brain Infarction ◽

Treatment Options ◽

Current Treatment ◽

Artery Occlusion ◽

Current Status ◽

Basilar Artery Occlusion ◽

Middle Cerebral Artery Infarction ◽

Open Questions ◽

Ischaemic Brain ◽

Randomised Controlled

Space-occupying so-called ‘malignant’ middle cerebral artery infarction is – besides acute basilar artery occlusion – the most devastating form of ischaemic stroke. Until recently, there was no proven treatment. In 2007, results from randomised controlled trials were published providing evidence for the benefit of early hemicraniectomy with respect to mortality after three months. This article focuses on current treatment options for malignant ischaemic brain infarction, especially hemicraniectomy. Moreover, major unsolved problems and open questions regarding the disease are discussed, and a perspective is given on future clinical studies in this field.

Download Full-text

Filling the Gap: Neural Stem Cells as A Promising Therapy for Spinal Cord Injury

Pharmaceuticals ◽

10.3390/ph12020065 ◽

2019 ◽

Vol 12 (2) ◽

pp. 65 ◽

Cited By ~ 20

Author(s):

Inês M. Pereira ◽

Ana Marote ◽

António J. Salgado ◽

Nuno A. Silva

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Clinical Trials ◽

Neural Stem Cells ◽

Treatment Options ◽

Experimental Studies ◽

Current Treatment ◽

Surgical Interventions ◽

Cord Injury

Spinal cord injury (SCI) can lead to severe motor, sensory and social impairments having a huge impact on patients’ lives. The complex and time-dependent SCI pathophysiology has been hampering the development of novel and effective therapies. Current treatment options include surgical interventions, to stabilize and decompress the spinal cord, and rehabilitative care, without providing a cure for these patients. Novel therapies have been developed targeting different stages during trauma. Among them, cell-based therapies hold great potential for tissue regeneration after injury. Neural stem cells (NSCs), which are multipotent cells with inherent differentiation capabilities committed to the neuronal lineage, are especially relevant to promote and reestablish the damaged neuronal spinal tracts. Several studies demonstrate the regenerative effects of NSCs in SCI after transplantation by providing neurotrophic support and restoring synaptic connectivity. Therefore, human clinical trials have already been launched to assess safety in SCI patients. Here, we review NSC-based experimental studies in a SCI context and how are they currently being translated into human clinical trials.

Download Full-text

Once-Daily Nevirapine XR

Journal of the International Association of Physicians in AIDS Care ◽

10.1177/1545109712456427 ◽

2012 ◽

Vol 11 (6) ◽

pp. 369-373 ◽

Cited By ~ 2

Author(s):

Laveeza Bhatti ◽

Jay Gladstein

Keyword(s):

Clinical Trials ◽

Serum Lipids ◽

Treatment Guidelines ◽

Treatment Options ◽

Transcriptase Inhibitor ◽

Current Treatment ◽

Additional Treatment ◽

Controlled Clinical Trials ◽

Once Daily ◽

Randomized Controlled Clinical Trials

Nevirapine (NVP) was the first nonnucleoside reverse transcriptase inhibitor (NNRTI) approved by the US Food and Drug Administration (FDA) in 1996, for the treatment of HIV infection. Current treatment guidelines include NVP as a component of a recommended alternative NNRTI regimen, which may be the preferred regimen for patients with established cardiovascular risk factors since NVP has minimal untoward effects on serum lipids. Two randomized and controlled clinical trials established the noninferior virologic efficacy of twice-daily NVP versus ritonavir-boosted atazanavir (ATV/r), a protease inhibitor with limited effects on serum lipids, each drug on a background regimen of once-daily (QD) tenofovir (TDF)/emtricitabine (FTC). An extended-release (XR) formulation of NVP was developed since QD dosing and reduced pill burdens have been shown to improve regimen adherence. This formulation (Viramune XR 400 mg) was recently FDA approved based on the results of 2 randomized, controlled clinical trials. The XR formulation will provide additional treatment options for patients who may benefit from NVP-based regimens.

Download Full-text

Breast cancer with brain metastases: current treatment options

Problems in oncology ◽

10.37469/0507-3758-2021-67-5-614-623 ◽

2021 ◽

Vol 67 (5) ◽

pp. 614-623

Author(s):

Sergei Banov ◽

Sergei Gutorov ◽

Irina Koliadina ◽

Aleksandr Smolin ◽

Evgenii Kriukov ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Brain Metastases ◽

Scientific Literature ◽

Systemic Treatment ◽

Treatment Options ◽

Current Treatment ◽

Extracranial Metastases ◽

Constant Improvement ◽

Systemic Therapies

Breast cancer is the main cause of brain metastases in women. The incidence of brain metastases in breast cancer continues to increase, which is mainly associated with improved systemic therapy, which ensures the control of extracranial metastases and an increase in survival. The management brain metastases of breast cancer remain a challenge, despite the constant improvement of local and systemic therapies. This review of the scientific literature presents the latest data from clinical trials of local and systemic treatment of patients with brain metastatic of breast cancer.

Download Full-text

Using numerical modeling and simulation to assess the ethical burden in clinical trials and how it relates to the proportion of responders in a trial sample

PLoS ONE ◽

10.1371/journal.pone.0258093 ◽

2021 ◽

Vol 16 (10) ◽

pp. e0258093

Author(s):

Jean-Pierre Boissel ◽

David Pérol ◽

Hervé Décousus ◽

Ingrid Klingmann ◽

Marc Hommel

Keyword(s):

Clinical Trials ◽

Statistical Power ◽

Controlled Trial ◽

False Negative ◽

Experimental Treatment ◽

Chi Square ◽

Randomized Controlled Clinical Trials ◽

Numerical Modeling And Simulation ◽

Event Rates ◽

Trial Participants

In order to propose a more precise definition and explore how to reduce ethical losses in randomized controlled clinical trials (RCTs), we set out to identify trial participants who do not contribute to demonstrating that the treatment in the experimental arm is superior to that in the control arm. RCTs emerged mid-last century as the gold standard for assessing efficacy, becoming the cornerstone of the value of new therapies, yet their ethical grounds are a matter of debate. We introduce the concept of unnecessary participants in RCTs, the sum of non-informative participants and non-responders. The non-informative participants are considered not informative with respect to the efficacy measured in the trial in contrast to responders who carry all the information required to conclude on the treatment’s efficacy. The non-responders present the event whether or not they are treated with the experimental treatment. The unnecessary participants carry the burden of having to participate in a clinical trial without benefiting from it, which might include experiencing side effects. Thus, these unnecessary participants carry the ethical loss that is inherent to the RCT methodology. On the contrary, responders to the experimental treatment bear its entire efficacy in the RCT. Starting from the proportions observed in a real placebo-controlled trial from the literature, we carried out simulations of RCTs progressively increasing the proportion of responders up to 100%. We show that the number of unnecessary participants decreases steadily until the RCT’s ethical loss reaches a minimum. In parallel, the trial sample size decreases (presumably its cost as well), although the trial’s statistical power increases as shown by the increase of the chi-square comparing the event rates between the two arms. Thus, we expect that increasing the proportion of responders in RCTs would contribute to making them more ethically acceptable, with less false negative outcomes.

Download Full-text

Ethical Justification of Involving Human Volunteers in Phase 1 Trials

Bangladesh Journal of Bioethics ◽

10.3329/bioethics.v8i2.34476 ◽

2017 ◽

Vol 8 (2) ◽

pp. 19-22

Author(s):

Zoheb Rafique

Keyword(s):

Clinical Trials ◽

Standard Treatment ◽

Phase 1 ◽

Treatment Options ◽

Experimental Treatment ◽

Human Beings ◽

Ethical Justification ◽

Phase 1 Trials ◽

Medical Benefit ◽

Human Volunteers

Tremendous development in recent medical science and the consequent discoveries resulting in successful prevention and also cure of different diseases are shared by clinical research involving the human volunteers. Preceding the trials in the human subjects, and to ensure safety, the proposed drug and other interventions are either tested in animals (vivo) or in laboratory (vitro) to evaluate initial safe starting dose for the human beings and to key out the benchmarks for the clinical monitoring for the potential unfavorable effects. These pre human trials might not necessarily protect against the untoward effects in the human beings as happened in the case of thalidomide tragedy, which caused disability and killed thousands of babies born to the mothers, those who took this medicine. Use of healthy human volunteers in the preliminary experiments or phase I clinical trials either reduces or excludes risks of subsequent undesirable effects in the future trails (1). Phase-1 trials are conducted in order to test the safety, reactions and immunogenicity of vaccines in volunteers. Novel treatments for the cancer are first tested in phase 1 trials enrolling the patients with advanced disease, who have exhausted the standard treatment options. Phase-1 oncology trials are the pivot point in the translation of new cancer therapies from bench to bedside. Nevertheless, these trials remain ethically controversial. The controversy stems from the fact that, classically, phase-1 oncology clinical trials involve first-in-human testing of experimental treatment candidates in patients with a terminal diagnosis, who typically have exhausted standard treatment options. Commentators on the ethics of phase-1 clinical trials make diametrically opposed claims about the prospect of direct medical benefit from participation in these trials-benefits that can be attributed to receiving the experimental treatment intervention. One camp of benefit skeptics, inhabited mainly by bioethicists, characterizes this form of research as lacking any reasonable prospect of direct medical benefit. They see an ethical cloud hovering over phase-1 trials, because the vast majority of patients volunteer for phase-1 trials out of a motivation to receive medical benefit. In the view of these skeptics, such patients therefore harbor a therapeutic misconception about research participation. This misconception calls into question the validity of informed consent and thereby undercuts the ethical basis of these trials (2). In this paper, I will discuss the ethical justification of the participation of human volunteers in phase-1 trials.

Download Full-text

Clinical Trials in Schizophrenia with Results for the Real World

CNS Spectrums ◽

10.1017/s1092852900026638 ◽

2006 ◽

Vol 11 (S7) ◽

pp. 9-13 ◽

Cited By ~ 7

Author(s):

Diana O. Perkins

Keyword(s):

Clinical Trials ◽

Clinical Practice ◽

Real World ◽

Clinical Decision Making ◽

Treatment Options ◽

Healthcare Providers ◽

Clinical Decision ◽

Clinical Practices ◽

Treatment Protocols ◽

The Real

AbstractMost clinical data for antipsychotics come from studies designed to test the efficacy and safety of the drugs under ideal conditions, in limited subgroups of patients. In contrast, practical clinical trials (PCTs) are designed to test the effectiveness of different treatment options under conditions that more accurately reflect actual clinical practice. Consequently, PCTs are able to provide information that can be utilized by healthcare providers and other decision makers. Characteristics of PCTs include a clinically relevant question, a representative sample of patients and practice settings, sufficient power to identify modest relevant effects, randomization to protect against bias, uncertainty regarding the outcome of treatment, assessment and treatment protocols that enact best clinical practices, simple and relevant outcomes, and limited subject and investigator burden. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program is an example of a PCT. The CATIE study illustrates how PCTs, when properly designed, might be helpful in informing clinical decision making. Because the CATIE study was designed to reflect the effectiveness of antipsychotics under naturalistic clinical conditions, its results should have particular applicability to the arena of clinical practice. This article provides a discussion of the differences between efficacy and effectiveness studies. In assessing the practical utility of results from the CATIE study, much can be learned on how to shape future studies of effectiveness so as to better generate data that are applicable to the “real world.”

Download Full-text