Randomized phase 2 trial of regadenoson for treatment of acute vaso-occlusive crises in sickle cell disease

Abstract

Adenosine A2A receptor (A2AR) agonists have been shown to decrease tissue inflammation induced by hypoxia/reoxygenation in mice with sickle cell disease (SCD). The key mediator of the A2AR agonist's anti-inflammatory effects is a minor lymphocyte subset, invariant natural killer T (iNKT) cells. We tested the hypothesis that administration of an A2AR agonist in patients with SCD would decrease iNKT cell activation and dampen the severity of vaso-occlusive (VO) crises. In a phase 2, randomized, placebo-controlled trial, we administered a 48-hour infusion of the A2AR agonist regadenoson (1.44 μg/kg per hour) to patients with SCD during VO crises to produce a plasma concentration of ∼5 nM, a concentration known from prior studies to suppress iNKT cell activation in SCD. The primary outcome measure was a >30% reduction in the percentage of activated iNKT cells. Ninety-two patients with SCD were randomized to receive a 48-hour infusion of regadenoson or placebo, in addition to standard-of-care treatment, during hospital admission for a VO crisis and had analyzable iNKT cell samples. The proportion of subjects who demonstrated a reduction of >30% in activated iNKT cells was not significantly different between the regadenoson and placebo arms (43% vs 23%; P = .07). There were also no differences between regadenoson and placebo groups in length of hospital stay, mean total opioid use, or pain scores. These data demonstrate that a low-dose infusion of regadenoson intended to reduce the activity of iNKT cells is not sufficient to produce a statistically significant reduction in such activation or in measures of clinical efficacy. This trial was registered at www.clinicaltrials.gov as #NCT01788631.

Conflict of interest statement

Conflict-of-interest disclosure: J.J.F. declares past or current research support from NKT Therapeutics, Astellas Pharma, and Prolong Pharmaceuticals. D.G.N. declares past or current research support from NKT Therapeutics and Astellas Pharma. The remaining authors declare no competing financial interests.

Figures

Graphical abstract

Figure 1.

Subject flow through the study.

Figure 2.

Baseline vs end-of-infusion p65-phospho NF-κB iNKT cell activation. Points below the black line represent patients who achieved the primary outcome measure of a p65-phospho-NF-κB iNKT cell activation at 48 hours that was a >30% reduction from baseline. Subjects in the regadenoson and placebo arms are represented by red and white circles, respectively.