Study protocol of a phase 2, randomised, placebo-controlled, double-blind, adaptive, parallel group clinical study to evaluate the efficacy and safety of recombinant alpha-1-microglobulin in subjects at high risk for acute kidney injury following open-chest cardiac surgery (AKITA trial).

INTRODUCTION: Acute kidney injury (AKI) is a common complication after cardiac surgery (CS) and is associated with adverse short-term and long-term outcomes. Alpha-1-microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme binding and mitochondrial-protective mechanisms. RMC-035 is a modified, more soluble, variant of A1M and has been proposed as a novel targeted therapeutic protein to prevent CS-associated AKI (CS-AKI). RMC-035 was considered safe and generally well tolerated when evaluated in four clinical phase 1 studies. METHODS AND ANALYSIS: This is a phase 2, randomised, double-blind, adaptive design, parallel group clinical study that evaluates RMC-035 compared with placebo in approximately 268 cardiac surgical patients at high risk for CS-AKI. RMC-035 is administered as an intravenous infusion. In total, five doses will be given. Dosing is based on presurgery estimated glomerular filtration rate (eGFR), and will be either 1.3 or 0.65 mg/kg.The primary study objective is to evaluate whether RMC-035 reduces the incidence of postoperative AKI, and key secondary objectives are to evaluate whether RMC-035 improves postoperative renal function compared with placebo. A blinded interim analysis with potential sample size reassessment is planned once 134 randomised subjects have completed dosing. An independent data monitoring committee will evaluate safety and efficacy data at prespecified intervals throughout the trial. The study is a global multicentre study at approximately 30 sites. ETHICS AND DISSEMINATION: The trial was approved by the joint ethics committee of the physician chamber Westfalen-Lippe and the University of Münster (code '2021-778 f-A') and subsequently approved by the responsible ethics committees/relevant institutional review boards for the participating sites. The study is conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT05126303.

The impact of acute kidney injury by serum creatinine or urine output criteria on major adverse kidney events in cardiac surgery patients.

OBJECTIVES: Oliguria after cardiac surgery remains of uncertain clinical significance. Therefore, we investigated the relationship of acute kidney injury severity across urine output and creatinine domains with the risk for major adverse kidney events at 180 days. We aimed to determine the impact of acute kidney injury after cardiac surgery. METHODS: In a retrospective multicenter study, we investigated the relationship of acute kidney injury severity across urine output and creatinine categories with the risk for major adverse kidney events at 180 days-the composite of death, dialysis, and persistent renal dysfunction-using a large database of patients undergoing cardiac surgery at 1 of 5 hospitals within the regional medical system. We analyzed electronic records from 6637 patients treated between 2008 and 2014, of whom 5389 (81.2%) developed any acute kidney injury within 72 hours of surgery. We stratified patients by levels of urine output or serum creatinine according to Kidney Disease Improving Global Outcomes criteria for acute kidney injury. RESULTS: Major adverse kidney events at 180 days increased from 4.5% for no acute kidney injury to 61.3% for stage 3 acute kidney injury (P < .001). Death or dialysis by day 180 was 2.4% for those with no acute kidney injury and 46.7% for those with acute kidney injury stage 3 (P < .001). Isolated oliguria was common (42.6%), and isolated azotemia was rare (6.1%). Even stage 1 acute kidney injury by oliguria alone was associated with an increased risk of major adverse kidney events at 180 days (odds ratio, 1.76; 1.20-2.57; P = .004), mainly driven by persistent renal dysfunction (odds ratio, 2.01; 1.26-3.18; P = .003). CONCLUSIONS: Acute kidney injury is common in patients undergoing cardiac surgery, and even milder forms of acute kidney injury, including isolated stage 1 oliguria, are associated with adverse long-term consequences.

Vascular Adhesion Protein-1 Is Associated With Acute Kidney Injury in High-Risk Patients After Cardiac Surgery.

BACKGROUND: Acute kidney injury is a common complication after cardiac surgery, with a high impact on morbidity and mortality. Vascular adhesion protein-1 is involved in inflammation, which, in turn, is part of the development of acute kidney injury after cardiac surgery. METHODS: In this ancillary study to the RENal effects of Remote Ischemic Preconditioning in cardiac surgery trial, we investigated whether vascular adhesion protein-1 might be associated with the development of acute kidney injury in high-risk patients after cardiac surgery. In total, 114 patients were included in this data set. Acute kidney injury was defined by the Kidney Disease: Improving Global Outcomes criteria serum creatinine and/or urine output. Vascular adhesion protein-1 concentrations were measured at baseline (before surgery), 4 hours, and 12 hours after cardiopulmonary bypass. RESULTS: Vascular adhesion protein-1 levels at 12 hours were significantly higher in patients with acute kidney injury (no acute kidney injury, 271 ng/mL [Q1, Q3, 179, 364 ng/mL] versus acute kidney injury, 384 ng/mL [Q1, Q3, 311, 478 ng/mL]; P < .001). Moreover, patients developing acute kidney injury had higher differences in vascular adhesion protein-1 levels between 12 hours and baseline (P < .001) and between 12 and 4 hours (P < .001) after cardiopulmonary bypass. At a cut point difference value of 99 ng/mL (95% CI, 63-133) between 12 hours and baseline, patients with differences >99 ng/mL showed a higher occurrence rate of acute kidney injury (acute kidney injury, 78.6% versus no acute kidney injury, 31.5%; P < .001). Receiver-operating characteristic curve analyses demonstrated best performance for vascular adhesion protein-1 levels at 12 hours for acute kidney injury within 72 hours after surgery, especially in the subgroup of patients with chronic kidney disease (area under the receiver-operating characteristic curve, 0.78; P < .001). CONCLUSIONS: Vascular adhesion protein-1 is elevated in patients developing acute kidney injury assuming that vascular adhesion protein-1 plays a crucial role in the development of acute kidney injury in high-risk patients after cardiac surgery.

Primary outcomes of the VIDI study: phase 2, double-masked, randomized, active-controlled study of ASP8232 for diabetic macular edema.

BACKGROUND: ASP8232 is a potent and specific small molecule vascular adhesion protein-1 (VAP-1) inhibitor. This study evaluated the effect of ASP8232 on excess retinal thickness when given alone or in combination with ranibizumab in patients with center-involved diabetic macular edema (CI-DME). METHODS: This was a phase 2a, placebo and sham-injection controlled, double-masked, randomized, parallel-group clinical trial. Participants were patients with CI-DME and central subfield thickness (CST) ≥ 375 µm in the study eye as assessed by spectral domain optical coherence tomography. Eligible patients were randomized to (1) daily oral ASP8232 40 mg monotherapy; (2) combination therapy of daily oral ASP8232 40 mg and monthly intravitreal ranibizumab 0.3 mg; or (3) monthly intravitreal ranibizumab 0.3 mg monotherapy. The treatment period was 12 weeks. CST and best corrected visual acuity (BCVA) were assessed at baseline and at Weeks 2, 4, 8, 12, 16 and 24. The primary outcome was the mean percent change from baseline in excess CST at Week 12. Secondary outcomes were BCVA, safety and tolerability, and pharmacokinetic and pharmacodynamic characteristics of ASP8232. RESULTS: After 12 weeks, the mean (95% confidence interval) percent change in excess CST was 11.4% (- 15.0%, 37.8%) in the ASP8232 group, - 61.7% (- 86.1%, - 37.2%) in the ASP8232/ranibizumab group, and - 75.3% (- 94.8%, - 55.8%) in the ranibizumab group. The change from baseline in the two ranibizumab arms was statistically significant (P < 0.001) as was the difference between the ranibizumab groups and the ASP8232 group (P < 0.001). Mean (SD) increase in BCVA score from baseline was 3.1 (7.3) in the ASP8232 group, 5.2 (7.1) in the ASP8232/ranibizumab group, and 8.2 (9.5) in the ranibizumab group. The increase from baseline in BCVA score was statistically and clinically significant in the ranibizumab group compared with the ASP8232 group (P = 0.015). ASP8232 resulted in near complete inhibition of plasma VAP-1 activity whilst ranibizumab had no effect. CONCLUSIONS: Near complete inhibition of plasma VAP-1 activity with ASP8232 had no effect on CST in patients with CI-DME. Furthermore, combination therapy did not provide additional benefit to treatment with ranibizumab alone, which significantly reduced CST and improved BCVA.Trial registration clinicaltrials.gov; NCT02302079. Registered on November 26, 2014.

Efficacy of a novel inhibitor of vascular adhesion protein-1 in reducing albuminuria in patients with diabetic kidney disease (ALBUM): a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Many patients with diabetic kidney disease have residual albuminuria and are at risk of disease progression. The ALBUM trial investigated the efficacy of a novel, orally active inhibitor of vascular adhesion protein-1, ASP8232, compared with placebo for reducing albuminuria in individuals with type 2 diabetes and chronic kidney disease. METHODS: In this randomised, double-blind, placebo-controlled phase 2 trial, we randomly assigned individuals (aged 18-85 years) from 64 clinical sites in nine European countries to receive ASP8232 40 mg or placebo orally once daily for 12 weeks using a web-based randomisation schedule (block size 4), stratified by country. Eligible patients had a urinary albumin-to-creatinine ratio (UACR) of 200-3000 mg/g, an estimated glomerular filtration rate of at least 25 mL/min per 1·73 m2 but lower than 75 mL/min per 1·73 m2, HbA1c less than 11·0% (97 mmol/mol), and stable treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antidiabetic medication for 3 months or more. The primary endpoint was mean change from baseline to week 12 in log-transformed first morning void UACR, which was assessed in all patients who received at least one dose of study drug and had at least one post-baseline UACR measurement (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. Participants and investigators were masked to treatment allocation. This trial is registered with ClinicalTrials.gov, number NCT02358096. FINDINGS: 125 participants were randomly assigned to receive ASP8232 (n=64) or placebo (n=61), of whom 120 (60 in each group) were included in the full analysis set; all participants were assessed for safety endpoints. At 12 weeks, UACR decreased by 17·7% (95% CI 5·0 to 28·6) in the ASP8232 group and increased by 2·3% (-11·4 to 18·1) in the placebo group; the placebo-adjusted difference between groups was -19·5% (95% CI -34·0 to -1·8; p=0·033). 39 (61%) patients in the ASP8232 group and 34 (56%) patients in the placebo group had a treatment-emergent adverse event, of which 16 in the ASP8232 group and four in the placebo group were drug-related. The most frequently reported adverse events that were possibly drug-related in the ASP8232 group were renal impairment (five patients) and decreased eGFR (three patients); in the placebo group, no single drug-related treatment-emergent adverse event was reported by more than one participant. INTERPRETATION: ASP8232 is effective in reducing albuminuria in patients with diabetic kidney disease and is safe and well tolerated. These findings warrant further research to ascertain the effect of ASP8232 on delaying progression of diabetic kidney disease. FUNDING: Astellas.

Darexaban (YM150) versus enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a randomised phase IIb dose confirmation study (ONYX-3).

This double-blind, double-dummy, randomised, phase IIb study (NCT00902928) evaluated different dosing regimens of darexaban compared with enoxaparin (randomised 1:1:1:1:1 to 15 mg twice daily [bid], 30 mg once daily [qd], 30 mg bid or 60 mg qd or enoxaparin 40 mg qd) in patients undergoing elective total hip arthroplasty. Patients, investigators, pharmacists and sponsor were all blinded to treatment allocation. Darexaban administration started 6-10 hours (h) post-surgery. Enoxaparin 40 mg qd administration started 12 ± 2 h before surgery. Treatment continued for 35 days. Bilateral venography was performed on Day 10 ± 2. The primary efficacy outcome was total VTEs (composite of proximal/distal deep-vein thrombosis, pulmonary embolism) or death, at Day 12. Total VTE rates were similar across all groups. There was no apparent difference in efficacy between once- and twice-daily darexaban (odds ratio [OR] 1.00; 95% confidence interval [CI] 0.71-1.42; p=0.988), or total daily dose (30 mg/day vs 60 mg/day; OR 0.81; 95% CI 0.57-1.15; p=0.244). There was no significant difference in major and/or clinically relevant non-major bleeding between darexaban qd or bid, or between total daily doses of 30 mg or 60 mg, and also for any dosing regimen of darexaban vs enoxaparin. Darexaban was well tolerated, without signs of liver toxicity. In conclusion, darexaban, administered qd or bid, and at total daily doses of 30 mg or 60 mg, appears to be effective for VTE prevention and was well tolerated. Data suggest no significant differences between a once- or twice-daily dosing regimen.

RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome.

AIMS: To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS). METHODS: In a 26-week, multi-centre, double-blind, randomized, parallel-group study, 1279 patients with recent high-risk non-ST-segment or ST-segment elevation ACS received one of six darexaban regimens: 5 mg b.i.d., 10 mg o.d., 15 mg b.i.d., 30 mg o.d., 30 mg b.i.d., or 60 mg o.d. or placebo, on top of dual antiplatelet treatment. Primary outcome was incidence of major or clinically relevant non-major bleeding events. The main efficacy outcome was a composite of death, stroke, myocardial infarction, systemic thromboembolism, and severe recurrent ischaemia. RESULTS: Bleeding rates were numerically higher in all darexaban arms vs. placebo (pooled HR: 2.275; 95% CI: 1.13-4.60, P = 0.022). Using placebo as reference (bleeding rate 3.1%), there was a dose-response relationship (P = 0.009) for increased bleeding with increasing darexaban dose (6.2, 6.5, and 9.3% for 10, 30, and 60 mg daily, respectively), which was statistically significant for 30 mg b.i.d. (P = 0.002). There was no decrease (indeed a numerical increase in the 30 and 60 mg dose arms) in efficacy event rates with darexaban, but the study was underpowered for efficacy. Darexaban showed good tolerability without signs of liver toxicity. CONCLUSIONS: Darexaban when added to dual antiplatelet therapy after ACS produces an expected dose-related two- to four-fold increase in bleeding, with no other safety concerns but no signal of efficacy. Establishing the potential of low-dose darexaban in preventing major cardiac events after ACS requires a large phase III trial. ClinicalTrials.gov Identifier: NCT00994292.