Search

Increasing adverse outcomes in patients with chronic kidney disease reflect growth of patients with early-stage chronic kidney disease and their increasing per population rates of these outcomes. Progression of chronic kidney disease, more than current level of kidney function, is the primary driver of adverse chronic kidney disease-related outcomes. Racial/ethnic minorities progress faster to end-stage kidney disease with greater risk for adverse outcomes. Diabetes and hypertension cause two-thirds of end-stage kidney disease, for which primary medical care integrated with healthy eating and increased physical activity (healthy moving) slows chronic kidney disease progression. Patients with early-stage chronic kidney disease are appropriately managed by primary care practices but most lack infrastructure to facilitate this integration that reduces adverse chronic kidney disease-related outcomes. Individuals of low socioeconomic status are at greater chronic kidney disease risk, and flexible regulatory options in Medicaid can fund infrastructure to facilitate healthy eating and healthy moving integration with primary medical care. This integration promises to reduce chronic kidney disease-related adverse outcomes, disproportionately in racial/ethnic minorities, and thereby reduce chronic kidney disease-related health disparities.

Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain.In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18-50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017-001588-19] and SPIRIT 2 [2017-001632-19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication.638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3-56·0]; p0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2-53·5]; p0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5-28·2]; p0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9-32·8]; p0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was -0·70% versus 0·21% in SPIRIT 1 and -0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was -2·0% in SPIRIT 1 and -1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo.Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment.Myovant Sciences.

Background Epidemiological studies demonstrate an association between kidney stones and risk of chronic kidney disease (CKD) and CKD progression. Metabolic acidosis, as a consequence of CKD, results in a reduced urine pH which promotes the formation of some types of kidney stones and inhibits the formation of others. While metabolic acidosis is a risk factor for CKD progression, the association of serum bicarbonate with risk of incident kidney stones is not well understood. Methods We used an Integrated Claims-Clinical dataset of US patients to generate a cohort of patients with non-dialysis-dependent CKD with two serum bicarbonate values of 12 to Results A total of 142 884 patients qualified for the study cohort. Patients with metabolic acidosis experienced post–index date kidney stones at greater frequency than patients with normal serum bicarbonate at the index date (12.0% vs 9.5%, P Conclusions Metabolic acidosis was associated with a higher incidence of kidney stones and shorter time to incident stone formation in patients with CKD. Future studies may investigate the role of correcting metabolic acidosis to prevent stone formation.

Background The risk of adverse geriatric outcomes such as falls and fractures is high among patients with chronic kidney disease (CKD). Metabolic acidosis is associated with protein catabolism and bone loss in experimental animal and human studies. We sought to quantify the independent association of metabolic acidosis with adverse muscle, bone and functional outcomes in a large US community-based cohort. Methods The Optum's de-identified Integrated Claims-Clinical dataset of US patients (2007–2017) was used to generate a cohort of patients with nondialysis-dependent CKD who had estimated glomerular filtration rate >10 to Results A total of 51 558 patients qualified for the study, with a median [Interquartile Range (IQR)] follow-up time of 4.2 (2.5–5.8) years. Over a ≤10-year period, for each 1 mmol/L increase in serum bicarbonate, the hazard ratios (adjusted for age, sex, race, estimated glomerular filtration rate, serum albumin, hemoglobin, diabetes and cardiovascular comorbidities) for failure to thrive, protein-calorie malnutrition and fall or fracture were 0.91 [95% confidence interval (CI): 0.90–0.92], 0.91 (95% CI: 0.90–0.92) and 0.95 (95% CI: 0.95–0.96), all P < 0.001, respectively. Conclusions The presence and severity of metabolic acidosis was a significant, independent risk factor for failure to thrive, protein-calorie malnutrition and fall or fracture in this large community cohort of patients with stage 3–5 CKD.

Introduction: Metabolic acidosis is associated with chronic kidney disease (CKD) progression and mortality, but the association of race/ethnicity with incident metabolic acidosis and/or its adverse outcomes in patients with CKD is unknown. Methods: We used deidentified medical records data (2007–2019) to generate a cohort of 136,067 patients with nondialysis-dependent CKD stages 3–5 and ≥2 years’ postindex data or death within 2 years. We grouped participants into those with and without metabolic acidosis (serum bicarbonate 12 to Results: Metabolic acidosis incidence was higher for Asian, Black, and Hispanic versus non-Hispanic White individuals (p values for adjusted hazard ratios [HR] all p < 0.0001), for metabolic acidosis versus normal serum bicarbonate. Discussion/Conclusion: The higher incidence of metabolic acidosis observed in Asian, Black, and Hispanic individuals was mitigated by residing in higher education zip codes. Once established, metabolic acidosis was independently associated with DD40 in patients with CKD in all racial/ethnic groups examined.

INTRODUCTION: Low serum bicarbonate at a single point in time is associated with accelerated kidney decline in patients with chronic kidney disease (CKD). We modeled how changes in serum bicarbonate over time affect incidence of adverse kidney outcomes. METHODS: We analyzed data from Optum’s deidentified Integrated Claims-Clinical data set of US patients (2007–2019) with ≥1 year of prior medical record data, CKD stages G3 to G5, and metabolic acidosis (i.e., index serum bicarbonate 12 to

Given current evidence, clinical guidelines consider obesity (body mass index [BMI] ≥ 30), but not overweight (BMI 25–29.9), to be a risk factor for all-cause mortality. Two prominent meta-analyses in general populations have estimated associations of different BMI categories with all-cause mortality; these meta-analyses reported modest associations in opposite directions for the overweight category. Another meta-analysis suggested that in older adults, being overweight is associated with modestly reduced mortality. Given that primary care physicians (PCPs) frequently advise patients on BMI, we used matched clinical vignettes to assess PCPs’ perceptions of the direction and strength of the overweight-mortality association (n=192). We found that a large majority of PCPs (90%) perceive that being overweight increases all-cause mortality risk, contrasting with findings of clinical guidelines’ authors. PCPs typically estimate a strength of association that substantially exceeds current empirical estimates.

Background: Frailty is common in patients with chronic kidney disease (CKD), as is its physical component, phenotypic frailty, and each contributes to CKD-related disability and are associated with increased mortality. Chronic kidney disease has been described as a model of premature aging and its phenotypic frailty shares features with that which has been better characterized for aging. Summary: Decreased skeletal muscle function contributes to the phenotypic frailty of CKD and aging and potentially remediable metabolic derangements appear to mediate both. Key Messages: Metabolic derangements of skeletal muscle dysfunction shared by CKD-related and aging-related phenotypic frailty offer potential research avenues to help identify additional preventive and treatment strategies. Those derangements distinctive for CKD provide potential treatment targets for the kidney care community to enhance the quality and quantity of life for patients with CKD.

Background Management of chronic kidney disease (CKD) requires the management of risk factors, such as hypertension and albuminuria, that affect CKD progression. Identification of additional modifiable risk factors is necessary to develop new treatment strategies for CKD. We sought to quantify the association of metabolic acidosis with CKD progression and mortality in a large U.S. community-based cohort. Methods In this longitudinal, retrospective cohort study we identified non-dialysis-dependent patients with stage 3‒5 CKD from Optum’s de-identified integrated electronic health records. We selected cohorts of patients with confirmed metabolic acidosis or normal serum bicarbonate levels based on 2 consecutive serum bicarbonate values: 12 to Results A total of 51,558 patients qualified for the study. The unadjusted 2-year incidence of adverse renal and fatal outcomes was significantly worse among patients in the metabolic acidosis group vs. those who had normal serum bicarbonate levels: 48 % vs. 17 % for DD40, 10 % vs. 4 % for ≥ 40 % decline in eGFR, 20 % vs. 6 % for renal replacement therapy, and 31 % vs. 10 % for all-cause mortality (all P P P Conclusions In this large community cohort of patients with stage 3‒5 CKD, the presence of metabolic acidosis was a significant, independent risk factor for the composite adverse outcome of CKD progression, renal replacement therapy, and all-cause mortality (DD40).

Background Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation. Methods This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies. Results No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin. Conclusions Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy. Clinical trial registry name and registration number Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.

Summary Background Metabolic acidosis, a complication of chronic kidney disease, causes protein catabolism and bone demineralisation and is associated with adverse kidney outcomes and mortality. Veverimer, a non-absorbed, counterion-free, polymeric drug candidate selectively binds and removes hydrochloric acid from the gastrointestinal lumen. Methods We did a multicentre, randomised, blinded, placebo-controlled, 40-week extension of a 12-week parent study at 29 sites (hospitals and specialty clinics) in seven countries (Bulgaria, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA). Eligible patients were those with chronic kidney disease (estimated glomerular filtration rate 20–40 mL/min per 1·73 m2) and metabolic acidosis (serum bicarbonate 12–20 mmol/L), who had completed the 12-week parent study, for which they were randomly assigned (4:3) to veverimer (6 g/day) or placebo as oral suspensions in water with food. Participants in the extension continued with the same treatment assignment as in the parent study. The primary endpoint was safety; the four secondary endpoints assessed the long-term effects of veverimer on serum bicarbonate concentration and physical functioning. The safety analysis set was defined as all patients who received any amount of study drug. This trial is registered at ClinicalTrials.gov, number NCT03390842, and has now completed. Findings Participants entered the study between Dec 20, 2017, and May 4, 2018. Of the 217 patients randomly assigned to treatment in the parent study (124 to veverimer and 93 to placebo), 196 patients (114 veverimer and 82 placebo) continued on their blinded randomised treatment assignment into this 40-week extension study. Compared with placebo, fewer patients on veverimer discontinued treatment prematurely (3% vs 10%, respectively), and no patients on veverimer discontinued because of an adverse event. Serious adverse events occurred in 2% of veverimer-treated patients and in 5% of placebo patients (two of whom died). Renal system adverse events were reported in 8% and 15% in the veverimer and placebo groups, respectively. More patients on veverimer than placebo had an increase in bicarbonate (≥4 mmol/L or normalisation) at week 52 (63% vs 38%, p=0·0015) and higher bicarbonate concentrations were observed with veverimer than placebo at all timepoints starting at week 1 (p Interpretation In patients with chronic kidney disease and metabolic acidosis, veverimer safely and effectively corrected metabolic acidosis and improved subjective and objective measures of physical function. Funding Tricida.

Background Metabolic acidosis is a complication of chronic kidney disease (CKD) that increases risk of CKD progression, and causes bone demineralization and muscle protein catabolism. Patients with diabetes are prone to metabolic acidosis and functional limitations that decrease quality of life. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. This post hoc subgroup analysis evaluated effects of veverimer on metabolic acidosis and physical function among patients with diabetes. Methods This was a Phase 3, multicenter, randomized, blinded, placebo-controlled trial in 196 patients with CKD (estimated glomerular filtration rate 20–40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. Results At Week 52, veverimer-treated patients with diabetes (n = 70), had a significantly greater increase in mean serum bicarbonate than the placebo group (n = 57) (4.4 versus 2.9 mmol/L, P Conclusions Few interventions for patients with diabetes and CKD have successfully improved quality of life or physical functioning. Our study demonstrated that veverimer effectively treated metabolic acidosis in patients with diabetes and CKD, and significantly improved how these patients felt and functioned.

Background and Aims Veverimer, an investigational, novel, orally-administered, non-absorbed polymer that binds gastrointestinal hydrochloric acid and results in an increase in serum bicarbonate, is being developed as a treatment for metabolic acidosis in patients with chronic kidney disease (CKD). Metabolic acidosis is a complication of CKD that has deleterious effects on kidney function, bone (demineralization), and muscle (protein catabolism).1 Albuminuria and metabolic acidosis are independently associated with CKD progression and treatment of each may reduce the risk of kidney failure.2,3 We sought to assess (post-hoc) if albuminuria impacts the ability of veverimer to increase serum bicarbonate level and improve physical functioning. Method TRCA-301E is a multicenter, Phase 3, randomized, blinded, placebo-controlled trial in 196 patients with CKD (eGFR 20 - 40 ml/min/1.73 m2) and metabolic acidosis (serum bicarbonate 12 - 20 mEq/L) who were treated for up to 1 year with veverimer (previously TRC101) or placebo, with dose titration targeted to achieve a normal serum bicarbonate. 4 The randomization was performed in a ratio of 4:3 (veverimer:placebo). Results We previously reported4 that, compared with placebo, veverimer significantly increased serum bicarbonate and significantly improved physical function as reported on the Kidney Disease and Quality of Life-Physical Function Domain (KDQOL-PFD) (e.g., walking several blocks, climbing stairs) and as measured objectively using the 5-times repeated chair stand test with a safety profile that was similar to placebo. Baseline characteristics of the subgroups of patients by baseline urine albumin to creatinine ratio (UACR) ≤ 300 vs. >300 mg/g are shown in the Table. Neither albuminuria (log UACR) as a continuous covariate nor the presence of UACR > 300 mg/g had an effect on the efficacy of veverimer treatment in correction of acidosis or improvement of physical function (interaction p-values >0.4). In patients with UACR > 300 mg/g, at Week 52, serum bicarbonate increased by 4.1 (0.5) mEq/L on veverimer (p = 0.047 vs. placebo) and a significantly higher percentage (vs. placebo) had a ≥ 4 mEq/L increase or normalization of serum bicarbonate (59% vs. 30%, p = 0.014). Patient-reported limitations of physical function (KDQOL-PFD) improved in the veverimer vs. placebo group (+10.4 vs. +1.2 seconds, respectively, p = 0.034). Objective physical performance on the chair stand test at Week 52 also improved in the veverimer group vs. placebo (p < 0.001). In patients with UACR ≤ 300 mg/g, at Week 52, serum bicarbonate increased by 5.2 (0.5) mEq/L on veverimer (p = 0.003 vs. placebo) and a numerically higher percentage (vs. placebo) had a ≥ 4 mEq/L increase or normalization of serum bicarbonate (65% vs. 45%, p = 0.063). KDQOL-PFD improved in the veverimer vs. placebo group (+12.5 vs. -2.8 seconds, respectively, p = 0.001). The chair stand test at Week 52 also improved in the veverimer group vs. placebo (p = 0.002). Conclusion The drug candidate veverimer effectively treated metabolic acidosis and improved the ability to repeatedly stand from a seated position and physical function related to daily activities independent of albuminuria, and therefore independent of the kidney injury reflected by albuminuria.

Background and Aims Lupus nephritis (LN) is a leading cause of morbidity and mortality in systemic lupus erythematosus (SLE) patients. T cells are believed to play a central role in the pathogenesis of both SLE and LN. CD6 is a co-stimulatory receptor, predominantly expressed on T cells, that binds to activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen presenting cells and various epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T cell activation, proliferation, differentiation and trafficking, and is central to immune mediated inflammation. Itolizumab (EQ001) is a humanized IgG1 monoclonal antibody that binds CD6, blocks the interaction between CD6 and ALCAM, and inhibits both the activation and trafficking of T cells. Inhibiting the CD6-ALCAM pathway with itolizumab potentially represents a promising therapeutic approach for the treatment of LN. The aim of this study is to assess the safety and tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of subcutaneously administered itolizumab in patients with SLE with and without active proliferative lupus nephritis (apLN). Method This cohort-based dose escalation study includes two types of patients: The Type A cohort will enroll ∼24 patients with SLE without apLN (all treated with itolizumab) and the Type B cohort will randomize in a blinded manner ∼36 patients (3:1, itolizumab:placebo) with biopsy-proven ISN/RPS class III or IV (+ V) apLN who have had inadequate response to induction and/or post-induction maintenance treatment, exhibiting urine protein to creatinine ratio [UPCR] ≥1 g/g and active serology. Within both the Type A and Type B cohorts, up to 4 dose groups will be tested (Figure). Background treatments for SLE or LN are allowed. Following 4 weeks of treatment in a new higher dose Type A cohort and recommendation by an independent safety data review committee (DRC), the dose studied in the Type A cohort may then be studied in a Type B Cohort for a 12-week treatment duration (Figure). The primary endpoint is the safety and tolerability of itolizumab. Efficacy endpoints (in the Type B cohorts) include UPCR, estimated glomerular filtration rate, prednisone dose requirements, renal response, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), FACIT Fatigue Scale, serologic markers, and other patient reported outcomes. In Type A cohort patients, clinical responses and pharmacologic activity will be assessed based on changes in serologic markers, SLEDAI-2K, FACIT Fatigue Scale. Pharmacodynamic markers, including markers that may allow future risk stratification, urinary ALCAM and CD6, will be examined in both cohort types. Results The study is ongoing. Six patients have been enrolled in Type A Cohort 1 (0.4 mg/kg dose) and completed both treatment and 4 weeks of post-treatment follow-up. The mean age was 59.5 (12.9) years, 100% were female; 67% were Hispanic/Latino; and 50% were White, and 50% were Black. Duration of SLE ranged from 3 years to 31 years. Concomitant medications for lupus included prednisone (83%, dose range 2.5 mg – 10 mg), methotrexate (33%), and anti-malarials (33%). Baseline SLEDAI-2K (mean 7.5 [2.2]) was based on findings of alopecia (83%); arthritis (67%); mucosal ulcers and rash (50% each); fever, increased dsDNA, and low complement (17% each). There were no adverse events. Additional data from this ongoing study will be presented. Conclusion Itolizumab, a monoclonal antibody blocking the CD6-ALCAM pathway, is a novel experimental treatment for LN. This is the first trial of itolizumab in patients with SLE and apLN. Data from the first cohort of patients suggest that the drug is safe and well-tolerated at a dose of 0.4 mg/kg over a 4-week treatment period. Additional cohorts of patients with SLE and apLN are currently being enrolled.

As with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor–induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of andexanet alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of andexanet alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of andexanet alfa administration, compared with placebo, were observed when andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).

Phosphate is one of the vital macronutrient required for the plant growth and development. Phosphorus (P) bioavailability in the plant can be supplemented by the phosphate-solubilizing fungi (PSF) in the soil. Most of the PSF belongs to the genus Aspergillus, Penicillium, and Fusarium. Few researchers have developed different strategies for the efficient phosphate solubilization which further directly used by the plant for its growth and development. Researcher’s findings suggest that PSF is effective in plant growth promotion which occurs adjacent to the plant root system and provides the basic availability of phosphorus (P) to the plant. PSF have plant growth promoting properties such as phytohormones production and phosphate solubilization, which enhanced plant growth and yield and also used in phytoremediation of different chemicals.

Rationale & Objective Metabolic acidosis related to chronic kidney disease (CKD) is associated with an accelerated decline in glomerular filtration rate (GFR) and the development of end-stage kidney disease. Whether metabolic acidosis is associated with cardiovascular (CV) events in patients with CKD is unclear. Study Design Retrospective cohort study. Setting & Participants The Optum De-identified Electronic Health Records Dataset, 2007–2017, was used to generate a cohort of patients with non-dialysis-dependent CKD who had at least 3 estimated GFR < 60 mL/min/1.73 m2. Patients with metabolic acidosis (serum bicarbonate 12 to, Graphical abstract

Background and objectives Metabolic acidosis is common in patients with CKD and has significant adverse effects on kidney, muscle, and bone. We tested the efficacy and safety of TRC101, a novel, sodium-free, nonabsorbed hydrochloric acid binder, to increase serum bicarbonate in patients with CKD and metabolic acidosis. Design, setting, participants, & measurements One hundred thirty-five patients were enrolled in this randomized, double-blind, placebo-controlled, multicenter, in-unit study (designated the TRCA-101 Study). Patients had a mean baseline eGFR of 35 ml/min per 1.73 m 2 , a mean baseline serum bicarbonate of 17.7 mEq/L, and comorbidities, including hypertension (93%), diabetes (70%), and heart failure (21%). Patients ate a controlled diet and were treated for 14 days with placebo or one of four TRC101 dosing regimens (1.5, 3, or 4.5 g twice daily or 6 g once daily). After treatment, patients were discharged and followed for 7–14 days. Results All TRC101 treatment groups had a mean within-group increase in serum bicarbonate of ≥1.3 mEq/L ( P P Conclusions TRC101 safely and significantly increased the level of serum bicarbonate in patients with metabolic acidosis and CKD.

Veverimer is a polymer being developed as a potential treatment for metabolic acidosis in patients with chronic kidney disease. Veverimer selectively binds and removes hydrochloric acid from the gastrointestinal tract, resulting in an increase in serum bicarbonate. Veverimer is not systemically absorbed, so potential drug-drug interactions (DDIs) are limited to effects on the absorption of other oral drugs through binding to veverimer in the gastrointestinal tract or increases in gastric pH caused by veverimer binding to hydrochloric acid. In in vitro binding experiments using a panel of 16 test drugs, no positively charged, neutral or zwitterionic drugs bound to veverimer. Three negatively charged drugs (furosemide, aspirin, ethacrynic acid) bound to veverimer; however, this binding was reduced or eliminated in the presence of normal physiological concentrations (100-170 mM) of chloride. Veverimer increased gastric pH in vivo by 1.5-3 pH units. This pH elevation peaked within 1 hour and had returned to baseline after 1.5-3 hours. Omeprazole did not alter the effect of veverimer on gastric pH. The clinical relevance of in vitro binding and the transient increase in gastric pH was evaluated in human DDI studies using two drugs with the most binding to veverimer (furosemide, aspirin) and two additional drugs with pH-dependent solubility effecting absorption (dabigatran, warfarin). None of the four drugs showed clinically meaningful DDI with veverimer in human studies. Based on the physicochemical characteristics of veverimer and results from in vitro and human studies, veverimer is unlikely to have significant DDIs. Significance Statement Patients with chronic kidney disease, who are usually on many drugs, are vulnerable to drug-drug interactions (DDIs). The potential for DDIs with veverimer was evaluated based on the known site of action and physicochemical structure of the polymer, which restricts the compound to the gastrointestinal tract. Based on the findings from in vitro and human studies, we conclude that veverimer is unlikely to have clinically significant DDIs.

Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant.Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported.Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).

Summary Background Patients with advanced chronic kidney disease lose the capacity to fully excrete endogenous acid, resulting in chronic metabolic acidosis that increases the risk of disease progression and causes muscle catabolism and bone resorption. Veverimer, a non-absorbed, counterion-free, polymeric drug, selectively binds and removes hydrochloric acid from the gastrointestinal lumen, unlike current oral sodium bicarbonate therapy for metabolic acidosis that only neutralises accumulated acid. We assessed the efficacy and safety of veverimer as a treatment for metabolic acidosis in patients with chronic kidney disease. Methods We did a multicentre, parallel, randomised, double-blind, placebo-controlled study at 37 sites (hospitals and specialty clinics) in Bulgaria, Croatia, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA. Eligible participants were patients aged 18–85 years with non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate of 20–40 mL/min per 1·73 m2) and metabolic acidosis (serum bicarbonate concentration of 12–20 mmol/L). Patients were randomly assigned (4:3) to veverimer 6 g/day or placebo for 12 weeks while they consumed their typical diet. Both drugs were taken as oral suspensions in water with lunch. Randomisation was done by study site personnel with a computer-generated randomisation code with balanced permuted blocks (block size of seven) and stratified by baseline bicarbonate (≤18 mmol/L vs >18 mmol/L). Patients and investigators were masked to treatment allocation; however, because the appearance of placebo differed from veverimer, a non-masked site staff member who had no other role in the study dispensed, prepared, and supervised dosing of the study drugs. The composite primary efficacy endpoint was the difference (veverimer–placebo) in the proportion of patients achieving at week 12 either an increase of 4 mmol/L or more from baseline in serum bicarbonate concentration or serum bicarbonate in the normal range of 22–29 mmol/L, assessed in the modified intention-to-treat population (all patients with a baseline and at least one post-baseline serum bicarbonate value). Patients fasted for at least 4 h (consuming only water) before measurements of bicarbonate. Safety was assessed in all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, number NCT03317444. Findings Between Sept 26, 2017, and Feb 9, 2018, we randomly assigned 124 participants to veverimer and 93 to placebo. The composite primary endpoint was met by 71 (59%) of 120 patients in the veverimer group versus 20 (22%) of 89 patients in the placebo group (a difference of 37%, 95% CI 23–49; p Interpretation Veverimer effectively and safely corrected metabolic acidosis. Longer-term studies are warranted to assess the effects of veverimer on physical functioning and to assess other deleterious consequences of metabolic acidosis including progression of chronic kidney disease and bone health. Funding Tricida.

Introduction: Andexanet alfa (AnXa) is a recombinant modified fXa molecule that acts as a specific antidote for fXa inhibitors. We report clinical results in healthy subjects anticoagulated with apixaban (apix), rivaroxaban (riva), edoxaban (edox), or enoxaparin (enox), demonstrating rapid and sustained reversal of anticoagulation following administration of AnXa. Methods: These were Phase 2/3 randomized, double-blind, placebo-controlled studies in healthy subjects. In Phase 2, about153 subjects age18 - 45 were given one of the fXa inhibitors (apix 5 mg BID, riva 20 mg QD, edox 60 mg QD or enox 40 mg QD) for 6 days. AnXa or placebo (3:1 randomization) was given IV on Day 6, 3hrs after the last inhibitor dose (∼inhibitor Cmax). Safety was followed through Day 48. A range of AnXa doses (bolus or bolus+infusion) was evaluated by correction of biomarkers (anti-fXa activity, free inhibitor concentrations and thrombin generation (TG)). In Phase 3 (ANNEXA™), older subjects age 50 to 75 were dosed with apix (5 mg BID) or riva (20 mg QD) for 4 days. ANNEXA™-A had 63 subjects treated with apix. AnXa (400 mg bolus; 400 mg bolus plus 4 mg/min x 2hr infusion) or placebo (3:1 randomization) was given on Day 4, 3 hrs after the last apix dose. ANNEXA™-R had 82 subjects treated with riva. AnXa (800 mg bolus; 800 mg bolus plus 8 mg/min x 2hr infusion) or placebo (2:1) was given on Day 4, 4 hrs after the last riva dose. Safety was followed through Day 43. Results: About 298 healthy subjects were enrolled in the studies. AnXa demonstrated rapid and sustained reversal of both direct and indirect fXa inhibitors as measured by correction of biomarkers. The ANNEXA™ studies confirmed findings from Phase 2, and met all primary (reversal of anti-fXa) and secondary endpoints (reduction of free inhibitor concentration and restoration of TG) with high statistical significance. AnXa was well-tolerated with no serious adverse events, thrombotic events, or antibodies to fX or fXa reported. Conclusion: AnXa treatment results in rapid and sustained reversal of anticoagulation of fXa inhibitors. A Phase 3b/4 confirmatory study (ANNEXA-4) in patients with acute major bleeds is ongoing.

The advent o f women entrepreneurship in our country is a recent phenom enon. Women entrepreneurs have to be aware of the opportunities available to them and their creative talent and abilities should be put to maximum use. The changing economic situations have made m ore and more w omen to take up jobs and ensure a definite source o f incom e for them. Women entrepreneurs are defined as a group o f w om en who initiate, organise and operate a business enterprise. The Governm ent o f India (1988) defines w om en enterprises as follows: “Enterprise owned and controlled by a w om an entrepreneur with a m inim um financial interest o f 51 per cent o f the capital and giving at least 50 per cent employment to w om en.” It has been rightly stated by Pandit Jawaharlal Nehru, “In order to awaken the people it is the w om en who have to be awakened. Once she is on the move, the fam ily moves, the village m oves and the nation m oves.”

UNLABELLED Despite successful therapies for chronic hypertension, hospital admissions for hypertensive emergency more than tripled between 1983 and 1992. OBJECTIVE To examine the safety and efficacy of fenoldopam, the first antihypertensive with selective and specific action on vascular dopamine (DA1) receptors, in a clinical trial involving emergency department patients with true hypertensive emergencies. METHODS Patients with a sustained diastolic blood pressure (DBP) of > or =120 mm Hg and evidence of target organ compromise were randomized in a double-blinded manner to one of four fixed doses of intravenous fenoldopam (0.01, 0.03, 0.1, or 0.3 microg/kg/min) for 24 hours. The primary endpoint was the magnitude of DBP reduction in each of the three higher-dose groups after four hours of fenoldopam treatment compared with the lowest-dose group. RESULTS One hundred seven participants from 21 centers were enrolled, and 94 patients received fenoldopam. Evidence of acute target-organ damage included new renal dysfunction or hematuria (50%), acute congestive heart failure or myocardial ischemia (48%), and papilledema or grade III-IV hypertensive retinopathy (34%). The DBP decreased in a dose-dependent fashion, with significant differences between the 0.1- and 0.3-microg/kg/min groups compared with the lowest-dose group. Treatment was well tolerated, and there were no deaths or serious adverse events during follow-up, up to 48 hours. All patients were successfully transitioned to oral or transdermal antihypertensives with maintenance of blood pressure control. CONCLUSIONS Fenoldopam safely and effectively lowers blood pressure in a dose-dependent manner in patients with hypertensive emergencies. Observations supporting potential risk factors for hypertensive emergency are discussed.

A randomized, controlled clinical trial demonstrated that intravenous (IV) fenoldopam did not prevent further deterioration in renal function after contrast administration in patients with chronic renal insufficiency. This lack of effect may have been a consequence of the inability to administer an effective renal dose of IV fenoldopam. This study sought to determine whether compared with IV administration, selective intrarenal (IR) fenoldopam would increase local concentration, leading to a higher glomerular filtration rate (GFR), and, because of first-pass renal elimination, result in lower systemic drug levels and less decrease in systemic blood pressure (BP). A randomized, controlled, open-label, partial crossover design trial was conducted in which 33 patients who underwent coronary angiography were randomized in a 1:2 ratio to control or fenoldopam (initially IV, then crossed over to IR through a bifurcated renal infusion catheter). Compared with IV fenoldopam, IR administration was associated with a significantly higher GFR (73.7 +/- 3.1 vs 62.6 +/- 2.5 ml/min, p = 0.0007) and renal plasma flow (537.2 +/- 34.0 vs 494.0 +/- 35.5 ml/min, p0.01), lower fenoldopam plasma levels (3.3 +/- 0.3 vs 4.8 +/- 0.3 ng/ml, p0.0001), and greater nadir systolic BP (125.5 +/- 3.6 vs 117.4 +/- 2.8 mm Hg, p0.0001). Two hours after drug discontinuation after contrast administration, GFRs in the patients who received IR fenoldopam remained higher than in controls (+15.0 ml/min [+25%] vs -8.0 ml/min [-14.0%], p0.05). In conclusion, this pilot trial demonstrates that the IR infusion of fenoldopam is safe and practical, producing greater renal effect and less reduction of BP than IV infusion. It would be appropriate to restudy this renal vasodilator for the prevention of contrast nephropathy, using selective IR delivery.

Background Radiocontrast nephropathy (RCN) is a common source of acute renal failure in hospitalized patients and is associated with increased morbidity and mortality rates. Fenoldopam mesylate is a dopamine A1 receptor agonist that augments renal plasma flow (RPF) in patients with normotensive and hypertensive conditions. To determine whether fenoldopam mesylate attenuates reductions in RPF after contrast infusion, we conducted a double-blind, randomized, placebo-controlled pilot trial of fenoldopam mesylate in patients who underwent contrast angiography. Methods Fifty-one patients with chronic renal insufficiency (creatinine level, 2.0-5.0 mg/dL) who were undergoing contrast angiography were screened, and 45 patients were randomized to receive normal saline solution (1/2 NS) or 1/2 NS plus fenoldopam mesylate at 0.1 μg/kg/min at lease 1 hour before infusion with contrast dye. Serum creatinine level was measured at baseline and at 24, 48, and 72 hours after angiography. The primary endpoint was change in RPF 1 hour after contrast infusion. The secondary endpoint was incidence of RCN, defined as a 0.5 mg/dL or a 25% rise in serum creatinine level at 48 hours. Results RPF at 1 hour after angiography was 15.8% above baseline in the fenoldopam mesylate group compared with 33.2% below baseline in the 1/2 NS group (P

We evaluated the ability of fenoldopam, a newly available renal vasodilator, to prevent radiocontrast nephropathy in high-risk patients undergoing interventional diagnostic and therapeutic angiographic procedures. We reviewed the results from 46 consecutive procedures in patients with serum creatinine ≥ 1.5 mg/dL if diabetic and ≥ 1.7 mg/dL if nondiabetic. We compared our results to a previously published cohort of similarly at-risk patients. The incidence of radiocontrast nephropathy, defined as an increase in serum creatinine of ≥ 25% at 48 hr following the procedure, was 13% in the group treated with fenoldopam, compared to an expected 38%. The percentage change in serum creatinine at 48 hr was +16% vs. +118%, respectively, in the two groups. In this preliminary experience, the use of fenoldopam in high-risk patients appears to minimize the likelihood of radioncontrast nephropathy. Cathet Cardiovasc Intervent 2001;53:341–345. © 2001 Wiley-Liss, Inc.

Z ICONOTIDE is the first in a new pharmacological class of analgesics that selectively target neuron-specific (N-type), voltage-gated calcium channels. Formerly known as SNX-111 (Elan Pharmaceuticals, South San Francisco, CA), ziconotide is the synthetic form of a peptide, ~-conopeptide-MVIIA, derived from the venom of fish-hunting marine snails. By selectively antagonizing N-type channels, intraspinally administered ziconotide produces potent analgesia in animals by mechanisms that appear to include interruption of primary afferent transmission (Fig 1) as well as reversal of the pathological hypersensitivity in spinal cord circuitry known as central sensitization. 1 Controlled clinical trials have demonstrated the analgesic efficacy of ziconotide in both acute and chronic pain, including pain refractory to opioids. z-4 Furthermore, unlike analgesics that bind to opioid receptors, ziconotide does not produce abuse, dependence, or tolerance, 5 nor does it cause respiratory depression 3 or bowel dysfunction. 5 Ziconotide is currently awaiting clearance by the Food and Drug Administration for the management of pain. This article reviews the mechanism of action of ziconotide, its pharmacological profile, and its efficacy and safety in con~olled clinical trials.

OBJECTIVE Acute renal failure, frequently a consequence of renal vasoconstriction and subsequent renal ischemia, is a common problem for which no proven preventive or therapeutic agents exist. Fenoldopam is a new, selective, dopamine-1 receptor agonist that causes both systemic and renal arteriolar vasodilation. In hypertensive patients, fenoldopam rapidly decreases blood pressure, increases renal blood flow, and maintains or improves the glomerular filtration rate. We sought to determine a dose of fenoldopam that increases renal blood flow without inducing hypotension in normotensive patients and to explore the role of volume status (sodium replete vs. deplete) in these effects. DESIGN Randomized, double-blind, placebo-controlled, cross-over study. SETTING Clinical research unit. PATIENTS Fourteen normal male volunteers. INTERVENTIONS Renal plasma flow (para-aminohippurate clearance) and glomerular filtration rate (inulin clearance) were measured during three fixed, escalating doses of fenoldopam (0.03, 0.1, and 0.3 Lg/kg/min) on both a high-sodium and a low-sodium diet. MEASUREMENTS AND MAIN RESULTS Fenoldopam significantly increased renal plasma flow in a dose-dependent manner compared with placebo: 670 + 148 vs. 576 + 85 mUmin at 0.03 iLg/kg/min; 777 + 172 vs. 579 + 80 mUmin at 0.1 tig/kg/min; and 784 + 170 vs. 592 + 165 mUmin at 0.3 ilg/kg/min (p < .05 fenoldopam vs. placebo at all three doses). Glomerular filtration rate was maintained. At the lowest dose (i.e., 0.03 ILg/kg/min), significant renal blood flow increases occurred without changes in systemic blood pressure or heart rate. At 0.1 and 0.3 Lgl/kg/ min, systolic blood pressure did not change, but diastolic blood pressure was slightly lower in the fenoldopam group than in the placebo group: 62.5 + 6.4 vs. 63.6 + 2.6 mm Hg, respectively, at 0.3 tg/kg/min (p < .05). None of the effects of fenoldopam were altered by volume status. CONCLUSIONS Fenoldopam increased renal blood flow in a dose-dependent manner compared with placebo, and, at the lowest dose, significantly increased renal blood flow occurred without changes in systemic blood pressure or heart rate. These findings will be useful in designing future studies exploring the role of fenoldopam in preventing or treating renal failure in patients who are not hypertensive.

We present two case reports of renal polyomavirus infection leading to renal allograft dysfunction, review the literature of this entity, and discuss the role of specific immunosupressives. Histologically, the virus caused an interstitial infiltrate composed of plasma cells and lymphocytes, interstitial fibrosis, and tubular atrophy. Viral inclusions were seen within tubular cells on light microscopy. Electron microscopy showed viral particles of 40 to 50 nm in a characteristic paracrystalline array. Both patients had been on FK-506-based immunosuppression. In both patients, the virus appeared to clear histologically and renal function stabilized when the patients were converted to cyclosporine-based immunosuppression. Contrary to prior reports, our patients have not lost their grafts and continue to have stable, albeit reduced, graft function at 2.5 years and 4.5 years following the initial diagnosis of renal polyomavirus infection.

Renal transplantation using infant donors is associated with significantly less graft survival (GS) and increased morbidity, especially from very young and small donors. We report our results using specific strategies to determine which age and size donor require en bloc renal transplant reconstruction and associated immunologic protocols for optimization of subsequent GS. Forty cadaveric pediatric en bloc renal transplants were performed. Mean donor age was 23.6±18.4 months with subgroups: 2-12 months, n=14; 13-24 months, n=19; and 25-60 months, n=7. Mean donor weight was 14.4±4.5 kg. All kidneys were placed in primary, nonsensitized (peak PRA = 7.9±5.6%) adult (41.6±16 years) recipients. Low weight was preferred (62.4±12.8 kg). Mean cold ischemia time was 26.9±8.6 hr. Immunosuppression consisted of quadruple immunosuppression (QI) with OKT3 induction. All patients had ureteral stents placed intraoperatively. Mean follow-up was 16.9 months. Actuarial GS at 12, 24, and 33 months were 100% (n=13), 85% (n=20), and 71% (n=7), respectively. Total GS was 35/40=88%. All grafts functioned immediately and there were no technical losses. Biopsy proven rejections occurred in 12 (30%) patients, developing at 16-167 days postoperatively (mean = 50.3 days). Mean serum creatinine at one week and 1, 6, 12, and 18 months were 2.1±2.0, 1.5±0.8, 1.3±0.5, 1.1±0.4, and 0.9±0.4 mg/dl, respectively. Functional isotopic renography, as well as sonographic monitoring reflected rapid initial and continued growth in these kidneys. Mean BP at 12 and 24 months postoperatively were 145/83±18/13 and 122/ 76±20/10 mmHg, respectively, with no significant pro-teinuria noted. Excellent results with minimal complications utilizing very small and young infant donors can be achieved with QI immunosuppression, and selection of low immune reactive and noncomplicated adult recipients. Additionally, maximal renal dosing by minimizing recipient weight may prevent future hyperfiltration damage.

Background Direct factor Xa inhibitors [fXaI] have superior anticoagulant efficacy and/or safety relative to warfarin and LMWH but are limited by lack of a specific antidote to reverse anticoagulation during episodes of serious bleeding or before surgery. PRT064445 [PRT] is a modified, human recombinant fXa that is catalytically inactive but retains high-affinity binding to direct fXaI and heparin- antithrombin III complexes. It competes with native fXa for fXaI drugs, thus reversing direct and indirect fXaI-mediated anticoagulation. Methods In this phase I, first-in-man double-blind study, 32 healthy volunteers were randomized (6:2) within dosing cohorts to a single IV bolus of PRT (30 mg, 90 mg, 300 mg, or 600 mg) or placebo and followed for 28 days. Anti-fXa activity was assayed in vitro by adding exogenous rivaroxaban (50 ng/mL) to subject plasma samples. Results The terminal t1/2 was ~6 hours. AUC and Cmax increased disproportionately relative to dose. In the presence of PRT, thrombin generation and anti-fXa activity of rivaroxaban ( Figure ) were reversed in a dose-dependent manner. There were no thrombotic AEs or deaths. There was 1 serious AE (pneumonia) and 3 non-serious infusion-related reactions without anaphylaxis [90 mg (2) and placebo (1)]. One unplanned pregnancy occurred ~10 days post-treatment, followed shortly by a spontaneous abortion. Prothrombin fragment 1 + 2, thrombin-antithrombin complex, and D-dimer transiently increased with dose; other coagulation parameters including PT, aPTT, ACT and platelet activity were unchanged. Conclusions PRT is a promising universal antidote for fXaI. A Phase 2 trial evaluating PRT reversal of several fXaI is ongoing.