Digoxin for Congenital Erythrocytosis Due to Up-Regulated Hypoxia Sensing
Status:
Not yet recruiting
Trial end date:
2023-12-31
Target enrollment:
Participant gender:
Summary
The investigators will study digoxin to inhibit the hypoxic response in congenital
erythrocytosis due to germ line mutations that result in up-regulated hypoxia sensing. These
forms of congenital erythrocytosis, characterized by augmented levels of hypoxia inducible
factor (HIF)-1 and HIF-2, are due to mutations of VHL (von Hippel Lindau), EGLN1 (encoding
prolyl hydroxylase 2 [PHD2]) and EPAS1 (endothelial PAS domain-containing protein 1)
(encoding HIF-2α). In addition to a high hematocrit, patients have thrombotic complications
and early mortality that are not improved by phlebotomy therapy. There is no effective
therapy. Digoxin, long used to treat congestive heart failure, is a potent inhibitor of the
master hypoxia-inducible transcription factor, HIF-1. The study hypothesis is that
pharmacologic doses and levels of digoxin will decrease hemoglobin and hematocrit, decrease
need for phlebotomy, decrease the propensity to thrombosis and decrease pulmonary pressure in
patients with erythrocytosis due to up-regulated hypoxic responses. The clinical trial
consists of 24 weeks of digoxin therapy in patients with hypoxic response-related
erythrocytosis. The complete blood count, safety, symptoms of headache and lack of energy,
echocardiogram, physical performance, and plasma products and blood cell expression of
HIF-1-regulated genes are the outcome variables.