Adaptive Design: A Review of the Technical, Statistical, and Regulatory Aspects of Implementation in a Clinical Trial

Background: In an adaptive trial, the researcher may have the option of responding to interim safety and efficacy data in a number of ways, including narrowing the study focus or increasing the number of subjects, balancing treatment allocation or different forms of randomization based on responses of subjects prior to treatment. This research aims at compiling the technical, statistical, and regulatory implications of the employment of adaptive design in a clinical trial. Methods: Review of adaptive design clinical trials in Medline, PubMed, EU Clinical Trials Register, and ClinicalTrials.gov. Phase I and seamless phase I/II trials were excluded. We selected variables extracted from trials that included basic study characteristics, adaptive design features, size and use of independent data-monitoring committees (DMCs), and blinded interim analysis. Results: The research retrieved 336 results, from which 78 were selected for analysis. Sixty-seven were published articles, and 11 were guidelines, papers, and regulatory bills. The most prevalent type of adaptation was the seamless phase II/III design 23.1%, followed by adaptive dose progression 19.2%, pick the winner / drop the loser 16.7%, sample size re-estimation 10.3%, change in the study objective 9.0%, adaptive sequential design 9.0%, adaptive randomization 6.4%, biomarker adaptive design 3.8%, and endpoint adaptation 2.6%. Discussion: It is possible to infer that the use of Adaptive Design is an ethical and scientific advantage when properly planned and applied, since it increases the flexibility of the trial, shortens the overall clinical investigation time of a drug, and reduces the risk of patient exposure to adverse effects related to the experimental drug. Its greater methodologic and analytic complexity requires an adequate statistical methodology. Conclusions: The application of “adaptive clinical designs” for phase II/III studies appear to have been limited to trials with a small number of study centers, with smaller extensions of time and to experimental drugs with more immediate clinical effects that are amenable to risk/benefit decisions based on interim analyses. According to the reviewed studies, simple adaptive trial designs—such as early study terminations due to futility and sample size re-estimation—are becoming widely adopted throughout the pharmaceutical industry, especially in phase II and III studies. The pharmaceutical industry and contract research organizations (CROs) are implementing simple adaptations more frequently and the more complex adaptations—biomarker adaptive design, endpoint adaptation—are more sporadic.info:eu-repo/semantics/publishedVersio

The Morphology, Physiology and Pathophysiology of Coronary Microcirculation

The heart is one of the most demanding organs of the human body. The high nutrient and oxygen demands need to be met through an adequate vascularization of the myocardium. In fact, the myocardium vascular supply is achieved through an extensive vascular network that includes larger arteries, also known as coronary arteries, smaller arteries (arterioles) and capillaries. This set of arterioles and capillaries is known as microcirculation. Coronary artery disease is usually associated with larger epicardial coronary arteries. However, several studies have shown an important role of coronary microvascular dysfunction. This review aimed to explore the (a) morphology, with particular interest on the anatomical and histological aspects; (b) physiology, providing an insight on the several endothelium-dependent and endothelium-independent regulatory mechanisms; and (c) pathophysiology of the cardiac microcirculation, with a special focus on the changes in the regulatory mechanisms, on the atherogenesis and on the correlation to the systemic cardiovascular disease

Plaquetas, serotonina e enxaqueca

Tese de doutoramento em Farmácia (Farmacologia) apresentada à Fac. de Farmácia da Univ. de CoimbraA fisiopatologia da enxaqueca continua por esclarecer e tem sido objecto de investigação permanente. Nos últimos anos surgiram novas teorias que não satisfazem plenamente o elevado número de questões que se colocam para explicar as suas várias formas clínicas. O objectivo deste trabalho foi o de avaliar, sob o ponto de vista farmacológico e bioquímico, algumas das alterações na enxaqueca, particularmente no diz respeito às alterações plaquetares. Assim, procurámos estabelecer os valores de serotonina sérica em indivíduos normais e a variação dos seus níveis durante as crises de enxaqueca com e sem aura e no intervalo das crises. Caracterizámos os receptores 5-HT2 das plaquetas e comparámos o número de locais de ligação existentes nos indivíduos normais com os de enxaqueca (com e sem aura), no intervalo das crises. Estudámos a captação de serotonina em indivíduos normais, comparando-a com a de indivíduos com enxaqueca com e sem aura, no intervalo das crises, relacionando os resultados obtidos com a libertação de serotonina nas mesmas populações. Foi ainda nosso objectivo estudar a participação da monoami-noxidase plaquetar na fisiopatologia da enxaqueca, determinando a actividade nesta enzima no intervalo das crises. Finalmente, procurámos estabelecer uma relação entre as alterações plaquetares verificadas e uma possível anormalidade da membrana das plaquetas, determinando a fluidez das membranas das plaquetas o que sugeriu uma modificação permanente nas propriedades da membrana das plaquetas traduzida por diminuição da fluidez

Histomorphometric analysis of the human internal thoracic artery and relationship with cardiovascular risk factors.

In this study, we aimed at performing a histomorphometric analysis of human left internal thoracic artery (ITA) samples as well as at correlating the histomorphometric findings with the clinical profile, including risk factors and medication. Distal segments of ITA were obtained from 54 patients undergoing coronary artery bypass grafting. Histological observation was performed in paraffin-embedded transverse sections of ITA through four staining protocols: hematoxylin-eosin, van Gieson, Masson's trichrome and von Kossa. Morphometric analysis included the intimal width (IW), medial width (MW) and intima/media ratio (IMR). No overt atherosclerotic lesions were observed. Mild calcifications were observed across the vascular wall layers in almost all samples. Multivariable linear regression analysis showed associations between IW and IMR and the following clinical variables: age, gender, kidney function expressed as eGFR and myocardial infarction history. Age (odds ratio = 1.16, P = 0.004), female gender (odds ratio = 11.34, P = 0.011), eGFR (odds ratio = 1.03, P = 0.059) and myocardial infarction history (odds ratio = 4.81, P = 0.040) were identified as the main clinical predictors for intimal hyperplasia. Preatherosclerotic lesions in ITA samples from patients undergoing coronary revascularization were associated not only with classical cardiovascular risk factors such as age and gender, but also with other clinical variables, namely kidney function and myocardial infarction history

Vascular effects of Fragaria vesca L. in human arteries

Fragaria vesca L. (wild strawberry) is traditionally used for its anti-inflammatory activity and for gastrointestinal, cardiovascular and urinary disorders. A previous study with the rat aorta showed that its leaves extract elicits endothelium-dependent vasorelaxation. Our aim was to investigate the clinical application of Fragaria vesca in vascular disease, by assessing the vascular effects of an infusion and hydroalcoholic extract in internal thoracic arteries from patients with coronary artery disease. The extracts elicited no effects on basal vascular tone and did not induce any vasorelaxation. At low concentration (0.02 mg/mL), the infusion potentiated the noradrenaline-induced contraction, while the other concentrations did not elicit significant changes in efficacy or potency. Differences between our findings and the previous report on rat aorta may result from methodological differences, e.g. vascular bed, method of extraction and extract composition. The clinical applicability of extracts of Fragaria vesca in patients with cardiovascular disease remains to be fully validated

Vascular Effects of Polyphenols from <i>Agrimonia eupatoria</i> L. and Role of Isoquercitrin in Its Vasorelaxant Potential in Human Arteries

Agrimonia eupatoria L. has been traditionally used for the treatment of inflammatory diseases but also as a hypotensive. To our knowledge, only one study has previously suggested an improvement in vascular endothelial function in diabetic conditions, as the underlying mechanisms and responsible compounds are unknown. In this study, we aimed to assess the direct vascular effects of Agrimonia eupatoria L. in human arteries. The infusion elicited a mild increase in basal vascular tone and a significant potentiation of the adrenergic contraction of 49.18% at 0.02 mg/mL, suggesting the presence of compounds with mild vasoconstrictor activity. In contrast, the ethyl acetate fraction inhibited adrenergic contraction by 80.65% at 2 mg/mL and elicited no effect on basal vascular tone. A potent concentration-dependent vasorelaxation was observed for both the infusion and the ethyl acetate fraction (maximal relaxation above 76% and 47%, respectively). Inhibition of nitric oxide synthase and cyclooxygenase elicited significant decreases in the vasorelaxation to the infusion, as, for the ethyl acetate fraction, only the cyclooxygenase pathway appeared to be involved. Isoquercitrin elicited a vasoactivity consistent with the ethyl acetate fraction, suggesting this is a major component responsible for the vasorelaxant properties of A. eupatoria. Further research is warranted to fully evaluate its vasoprotective properties with therapeutic potential in several conditions, e.g., atherosclerosis

Vascular effects of <i>Fragaria vesca</i> L. in human arteries

Fragaria vesca L. (wild strawberry) is traditionally used for its anti-inflammatory activity and for gastrointestinal, cardiovascular and urinary disorders. A previous study with the rat aorta showed that its leaves extract elicits endothelium-dependent vasorelaxation. Our aim was to investigate the clinical application of Fragaria vesca in vascular disease, by assessing the vascular effects of an infusion and hydroalcoholic extract in internal thoracic arteries from patients with coronary artery disease. The extracts elicited no effects on basal vascular tone and did not induce any vasorelaxation. At low concentration (0.02 mg/mL), the infusion potentiated the noradrenaline-induced contraction, while the other concentrations did not elicit significant changes in efficacy or potency. Differences between our findings and the previous report on rat aorta may result from methodological differences, e.g. vascular bed, method of extraction and extract composition. The clinical applicability of extracts of Fragaria vesca in patients with cardiovascular disease remains to be fully validated.</p

Chemistry and pharmacology of the kazakh crataegus almaatensis pojark: An asian herbal medicine

Crataegus almaatensis, an endemic ornamental plant in Kazakhstan is used in popular medicine due to its cardiotonic properties. The most studied species of the same genus are commonly found in Europe, which shows the importance of having the Kazakh species validated via its chemical and pharmacological studies. High-speed countercurrent chromatography (HSCCC) operated under optimized conditions enabled an isolation of the three main compounds from the aqueous phase of the leaves ethanol extract, further identified by nuclear magnetic resonance (NMR), as quercetin 3-O-rhamnoside (quercitrin) (4.02% of the crude extract-CECa); quercetin 3-O-?-galactoside (hyperoside) (1.82% of CECa); kaempferol 3-O-?-L-rhamnoside (afzelin) (0.94% of CECa). The CECa, the aqueous phase of the crude extract (APCa) together with the isolates were evaluated for their vascular (vascular reactivity in human internal mammary artery-HIMA), anti-nociceptive (formalin-induced liking response and hot plate) and anti-inflammatory (subcutaneous air-pouch model-SAP) activities. CECa at the concentrations of 0.014 and 0.14 mg/mL significantly increased the maximum contractility response of HIMA to noradrenaline. The APCa CR curve (0.007?0.7 mg/mL) showed an intrinsic relaxation effect of the HIMA. APCa at the dose of 100 mg/kg i.p. significantly decreased the total leukocyte count and the IL-1? release in the SAP wash