Introduction and Objective Pulmonary capillary endothelial transient receptor potential vanilloid 4 (TRPV4) channel plays a critical role in mediating the development of cardiogenic pulmonary edema. GSK2798745 is a first-in-class, highly potent, selective, orally active TRPV4 channel blocker being evaluated in a first-time-in-humans study (NCT02119260). Methods GSK2798745 was administered in a randomized, placebo-controlled study design to healthy volunteers in three separate cohorts as single escalating doses, with and without food, and as once-daily repeat doses for up to 14 days, respectively. Two cohorts of subjects with mild to moderate heart failure were also administered GSK2798745 once daily for up to 7 days. Safety, tolerability, and systemic exposure data were collected. Results No significant safety issues or serious adverse events were observed with GSK2798745 in healthy volunteers and patients with heart failure. GSK2798745 systemic exposure data demonstrated linear pharmacokinetics up to 12.5 mg, less than twofold accumulation with once-daily dosing, and a systemic half-life of ~ 13 h. There was a slight increase in GSK2798745 exposure [14% increase in area under the plasma concentration-time curve (AUC) and 9% increase in maximum observed plasma concentration (C max)] after administration with a high-fat meal. Conclusions GSK2798745 was well-tolerated in healthy volunteers and patients with stable heart failure. The safety and exposure data obtained in this study allow further evaluation of the drug in long-term clinical studies in heart failure as well as other indications.
Adjudication has not been shown to improve the ability to determine treatment effects. Thus, adjudication may be overly complex and overused in many large simple trials. The appropriate role of central adjudication - which trials, which outcomes, what methods - deserves scrutiny and further study.
Introduction
Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation.
Methods
The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers.
Results
GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ−induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs.
Conclusion
Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population.
Trial registration
NCT02723786.
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