PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

Association of circulating angiogenesis inhibitors and asymmetric dimethyl arginine with coronary plaque burden.

BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for the development and severity of coronary artery disease (CHD) and endothelial dysfunction. There is an increase in the circulating angiogenesis inhibitors endostatin (END), thrombospondin-2 (TSP), angiopoietin-2 (ANG) and the nitric oxide (NO) inhibitor asymmetric dimethyl arginine (ADMA) in CKD patients. The aim of this study was to evaluate associations of the serum level of these factors and of the related angiogenesis inhibitor, endoglin (ENG), with burden of coronary atherosclerosis. METHODS: One hundred twenty-two patients undergoing coronary angiography were recruited from the cardiac catheterization lab at a single center. The total burden of coronary plaque (mm(2)) and the presence of coronary collaterals were quantified using quantitative coronary angiography (QCA). Serum levels of angiogenesis inhibitors were measured by ELISA (ENG, END, and ANG), Luminex assay (TSP), or HLPC (ADMA), respectively. Associations with plaque burden and coronary collateral supply were analyzed in multi-variable linear and logistic regression models. RESULTS: There was no significant association found between levels of circulating ADMA, ENG, END, ANG, or TSP and coronary plaque burden or collateral formation. CONCLUSIONS: Our findings suggest that associations of circulating END, ENG, TSP, and ANG with cardiovascular mortality are unlikely to be mediated via direct effects on coronary plaque formation or by inhibition of collateral formation. Whether associations of these factors with mortality are mediated via local concentrations, myocardial tissue, or intra-plaque expression of these factors or by an effect on plaque vulnerability merits additional investigation.

Increased concentration of circulating angiogenesis and nitric oxide inhibitors induces endothelial to mesenchymal transition and myocardial fibrosis in patients with chronic kidney disease.

BACKGROUND: Sudden cardiovascular death is increased in chronic kidney disease (CKD). Experimental CKD models suggest that angiogenesis and nitric oxide (NO) inhibitors induce myocardial fibrosis and microvascular dropout thereby facilitating arrhythmogenesis. We undertook this study to characterize associations of CKD with human myocardial pathology, NO-related circulating angiogenesis inhibitors, and endothelial cell behavior. METHODS: We compared heart (n=54) and serum (n=162) samples from individuals with and without CKD, and assessed effects of serum on human coronary artery endothelial cells (HCAECs) in vitro. Left ventricular fibrosis and capillary density were quantified in post-mortem samples. Endothelial to mesenchymal transition (EndMT) was assessed by immunostaining of post-mortem samples and RNA expression in heart tissue obtained during cardiac surgery. Circulating asymmetric dimethylarginine (ADMA), endostatin (END), angiopoietin-2 (ANG), and thrombospondin-2 (TSP) were measured, and the effect of these factors and of subject serum on proliferation, apoptosis, and EndMT of HCAEC was analyzed. RESULTS: Cardiac fibrosis increased 12% and 77% in stage 3-4 CKD and ESRD and microvascular density decreased 12% and 16% vs. preserved renal function. EndMT-derived fibroblast proportion was 17% higher in stage 3-4 CKD and ESRD (P trend = 0.02). ADMA, ANG, TSP, and END concentrations increased in CKD. Both individual factors and CKD serum increased HCAEC apoptosis (P=0.02), decreased proliferation (P=0.03), and induced EndMT. CONCLUSIONS: CKD is associated with an increase in circulating angiogenesis and NO inhibitors, which impact proliferation and apoptosis of cardiac endothelial cells and promote EndMT, leading to cardiac fibrosis and capillary rarefaction. These processes may play key roles in CKD-associated CV disease.

Circulating endoglin concentration is not elevated in chronic kidney disease.

BACKGROUND: Soluble endoglin, a TGF-ß receptor, plays a key role in cardiovascular physiology. Whether circulating concentrations of soluble endoglin are elevated in CKD or underlie the high risk of cardiovascular death associated with chronic kidney disease (CKD) is unknown. METHODS: Individuals with and without CKD were recruited at a single center. Estimated glomerular filtration rate (eGFR) was estimated using the modified MDRD study equation and the serum creatinine at the time of recruitment, and patients were assigned to specific CKD stage according to usual guidelines. Serum endoglin concentration was measured by ELISA and univariate and multivariable regression was used to analyze the association between eGFR or CKD stage and the concentration of soluble endoglin. RESULTS: Serum endoglin was measured in 216 patients including 118 with stage 3 or higher CKD and 9 individuals with end stage renal disease (ESRD). Serum endoglin concentration did not vary significantly with CKD stage (increase of 0.16 ng/mL per 1 stage increase in CKD, P = 0.09) or eGFR (decrease -0.06 ng/mL per 10 mL/min/1.73 m(2) increase in GFR, P = 0.12), and was not higher in individuals with ESRD than in individuals with preserved renal function (4.2±1.1 and 4.3±1.2 ng/mL, respectively). Endoglin concentration was also not significantly associated with urinary albumin excretion. CONCLUSIONS: Renal function is not associated with the circulating concentration of soluble endoglin. Elevations in soluble endoglin concentration are unlikely to contribute to the progression of CKD or the predisposition of individuals with CKD to develop cardiovascular disease.