Phase 1 Study of Digoxin for Congenital Erythrocytosis Due to Up-Regulated Hypoxia Sensing

2019-0064

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.

2022-12-01

2024-12-31

2024-12-31

Withdrawn

Early phase I

Inclusion criteria. To be eligible to participate, an individual must meet all of the following criteria: * Have mutation of VHL (von Hippel Lindau), EGLN1 (encoding prolyl hydroxylase 2 \[PHD2\]) or EPAS1 (encoding HIF-2α) that has been associated with congenital erythrocytosis with upregulated hypoxia sensing. * Have an up-regulated hypoxic response defined by a hemoglobin concentration of greater than 15.5 g/dL in women and 17.5 g/dL in men in association with a serum EPO concentration that is increased above the reference range or that is in the reference range but above the expected level given the presence of erythrocytosis, i.e. above the lower quartile of the range. * Male or female, aged 18 years and older. * For females of reproductive potential: use of highly effective contraception for 1 month prior to screening and agreement to use such a method during study participation and for an additional two weeks after the end of digoxin administration. Exclusion criteria. An individual who meets any of the following criteria will be excluded from participation: * Diagnosis of polycythemia vera or high oxygen affinity hemoglobinopathy. * End stage renal disease: estimated GFR \<15 mL/min/1.73 m2 or receiving hemodialysis or peritoneal dialysis. * Electrolyte imbalance: potassium \<3.5 mEq/L, magnesium \<1.8 mg/dL, or calcium \>10.7 mg/dL. * Hyperthyroidism (TSH \<0.3 U/ml and T4 \>12 μg/dL) or hypothyroidism (TSH \> 6 U/ml). * Myocarditis. * History of hypersensitivity, arrhythmia or severe gastrointestinal side effects related to digoxin. * Presence or history of any of the following conditions: first or second-degree AV block, Wolff-Parkinson-White Syndrome, other cardiac conduction abnormalities, or heart failure with preserved left ventricular systolic function including restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, acute cor pulmonale and idiopathic hypertrophic subaortic stenosis. * Peripheral arterial disease or ischemic heart disease * Pregnancy

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2023-06-13