Digoxin for Congenital Erythrocytosis Due to Up-Regulated Hypoxia Sensing

NCT03433833 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: 2019-0064
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Polycythemia; Familial; Erythrocytosis; Familial; VHL Gene Mutation; HIF-2alpha Erythrocytosis; PHD2 Erythrocytosis; Chuvash Erythrocytosis

Outcome Measures

Primary Outcomes (1)

• Hemoglobin concentration

  Change of 1.5 g/dL or more

  24 weeks

Secondary Outcomes (4)

• Serum EPO concentration

  24 weeks

• Plasma concentration of PAI-1 (plasminogen activator inhibitor 1)

  24 weeks

• Granulocyte mRNA (messenger ribonucleic acid) expression of F3 as determined by RT-PCR (reverse transcription polymerase chain reaction)

  24 weeks

• Tricuspid regurgitation velocity determine by echocardiogram

  24 weeks

Study Arms (1)

Intervention

EXPERIMENTAL

Patients will be given digoxin orally daily for 24 weeks. The initial dose will be selected with the goal of achieving a serum digoxin concentration of 0.5-0.9 ng/ml, a dose range recommended for heart failure patients. A dose of 0.0625, 0.125 or 0.25 mg daily will be selected based on a normogram.

Drug: Digoxin

Interventions

Digoxin DRUG

Digoxin oral route once daily for 24 weeks.

Also known as: No other interventions

Intervention

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Illinois at Chicago: lead

MeSH Terms

Conditions

Polycythemia, primary familial and congenital

Interventions

Digoxin

Intervention Hierarchy (Ancestors)

Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates

Study Officials

• Victor R Gordeuk, MD

  University of Illinois at Chicago

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: February 8, 2018
• First Posted: February 15, 2018
• Study Start: November 10, 2019
• Primary Completion: April 16, 2024
• Study Completion: December 31, 2024
• Last Updated: September 20, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share