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Digoxin for Congenital Erythrocytosis Due to Up-Regulated Hypoxia Sensing

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ClinicalTrials.gov Identifier: NCT03433833
Recruitment Status : Not yet recruiting
First Posted : February 15, 2018
Last Update Posted : September 27, 2019
Sponsor:
Information provided by (Responsible Party):
Victor Gordeuk, University of Illinois at Chicago

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.

Condition or disease Intervention/treatment Phase
Polycythemia; Familial Erythrocytosis; Familial VHL Gene Mutation HIF-2alpha Erythrocytosis PHD2 Erythrocytosis Chuvash Erythrocyotsis Drug: Digoxin Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Study of Digoxin for Congenital Erythrocytosis Due to Up-Regulated Hypoxia Sensing
Estimated Study Start Date : September 1, 2020
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Digoxin

Arm Intervention/treatment
Experimental: Intervention
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
Digoxin oral route once daily for 24 weeks.
Other Name: No other interventions




Primary Outcome Measures :
  1. Hemoglobin concentration [ Time Frame: 24 weeks ]
    Change of 1.5 g/dL or more


Secondary Outcome Measures :
  1. Serum EPO concentration [ Time Frame: 24 weeks ]
    Change in log Epo concentration of 15% or more

  2. Plasma concentration of PAI-1 (plasminogen activator inhibitor 1) [ Time Frame: 24 weeks ]
    Change compared to baseline

  3. Granulocyte mRNA (messenger ribonucleic acid) expression of F3 as determined by RT-PCR (reverse transcription polymerase chain reaction) [ Time Frame: 24 weeks ]
    Change compared to baseline

  4. Tricuspid regurgitation velocity determine by echocardiogram [ Time Frame: 24 weeks ]
    Change compared to baseline



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03433833


Contacts
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Contact: Victor R Gordeuk, MD 312-996-5680 vgordeuk@uic.edu

Sponsors and Collaborators
University of Illinois at Chicago
Investigators
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Principal Investigator: Victor R Gordeuk, MD University of Illinois at Chicago

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Responsible Party: Victor Gordeuk, Professor of Medicine, University of Illinois at Chicago
ClinicalTrials.gov Identifier: NCT03433833     History of Changes
Other Study ID Numbers: 2019-0064
First Posted: February 15, 2018    Key Record Dates
Last Update Posted: September 27, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: The research data will be shared with the co-investigators and the referring physicians.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Polycythemia
Hypoxia
Signs and Symptoms, Respiratory
Signs and Symptoms
Hematologic Diseases
Digoxin
Anti-Arrhythmia Agents
Cardiotonic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs