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We propose a pilot clinical trial lasting 12 weeks of digoxin 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 blood cell expression of hypoxia inducible factor-1-regulated genes are the outcome variables. The enrolled patients will receive standard of care at the provider's and institutional preference. The patients will be studied at baseline, at two and four weeks and then at four-week intervals during treatment with digoxin.
(c) Criteria for patient selection and for exclusion of patients and estimate of number of patients to be studied.
1. Diagnosis of congenital polycythemia due to an up-regulated hypoxic response, such as Chuvash polycythemia, other VHL mutations, EGLN1 (PHD2) mutations and EPAS1 (HIF-2α) gain-of-function mutations.
2. Age of 18 years or older
1. End stage renal disease
2. History of hypersensitivity, arrhythmia or severe gastrointestinal side effects related to digoxin therapy.
3. First or second-degree AV block.
4. Wolff-Parkinson-White Syndrome.
5. Heart failure with preserved left ventricular systolic function: restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, acute cor pulmonale, idiopathic hypertrophic subaortic stenosis.
Number of patients to be studied: 25
(d) Design of the study. This is a phase 1 study in which all subjects will receive open-label digoxin. Comparisons will be made of the longitudinal observations made during therapy with digoxin over 12 weeks compared to the baseline measurements, medical history and health related quality of life.
(e) Digoxin dosage and duration of individual patient exposure to the drug.
Dose of digoxin. Study subjects will be given a standard dose of digoxin by mouth daily for 12 weeks and will be evaluated at 4-week intervals. The initial dose will be selected based on the normogram in the figure below, with the goal of achieving a serum digoxin concentration of 0.8-2.0 ng/ml.1 A similar nomogram method to dose digoxin can be used to achieve a target level 0.5-0.9 ng/ml,2 a dose range recommended for heart failure patients.3 However, we wish to maximize the inhibition of HIF-1 in congenital polycythemia patients without heart failure, and therefore a level of 0.8-2 ng/ml is acceptable and reasonable.
Serum digoxin concentration. Serum digoxin levels will be performed at 2, 4, 8 and 12 weeks. The digoxin trough serum concentrations will be obtained immediately prior to administration of the daily dose. The target trough serum digoxin concentration will be 0.8 to 2.0 ng/ml. The dose will be decreased according to a linear relationship between the digoxin dose and the trough levels if the serum concentration is >0.2 ng/ml and it will be increased if the concentration is less than 0.8 ng/ml and there are no signs of toxicity.
Monitoring for digoxin toxicity. The digoxin serum concentration will be measured sooner if subjects report possible digoxin toxicity such as new onset of anorexia, nausea, vomiting, confusion, or palpitations.
Potential drug interactions. Additional serum digoxin levels will be obtained if potentially interacting drugs are initiated. Drugs that increase digoxin levels include potassium-depleting diuretics, calcium, quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, alprazolam, spironolactone, erythromycin, clarithromycin, other macrolide antibiotics, tetracycline, propantheline and diphenoxylate. Drugs that decrease digoxin levels include antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine, certain anticancer drugs, metoclopramide, rifampin and thyroid.
(f) Observations and measurements
1. Hemoglobin, hematocrit and red blood cell count measured at baseline and every four weeks.
2. Safety profile of digoxin.
1. Symptoms of headache and lack of energy
2. Plasma concentrations of the products of HIF targeted genes after 12 weeks of digoxin therapy compared to baseline.
3. QT-RT PCR of platelet, granulocyte and reticulocyte RNA of HIF-regulated genes at baseline, after two weeks of digoxin therapy, and at completion of the trial.
4. TRV and tricuspid pressure gradient after 12 weeks of digoxin therapy compared to baseline as measured by echocardiography.
5. Six-minute walk (6MW) distance after 12 weeks of digoxin therapy compared to baseline.
6. NT-pro BNP after 12 weeks of digoxin therapy compared to baseline.
7. Phlebotomy requirements during treatment with digoxin compared to the 12 weeks prior to initiation of therapy.
Study visits. The study visits are summarized in Table 1.
Baseline studies before starting digoxin therapy:
1. Completion of questionnaire with focus on symptoms related to erythrocytosis or pulmonary hypertension. The questionnaire will also include a recording of all prior phlebotomy sessions over the last 12 months.
2. Physical examination with recording of weight, height, BMI, SBP, DBP, MAP, pulse pressure, pulse rate, oxygen saturation as measured by pulse oximetry, liver size, spleen size and any peripheral edema.
4. Complete blood count, reticulocytes, fasting blood sugar, hemoglobin A1C, serum electrolytes, creatinine, BUN, liver function tests, iron, TIBC, ferritin, C-reactive protein, NT-proBNP.
5. Storing plasma at -70 degrees C for measurement of concentrations of products of HIF-regulated genes including endothelin-1, erythropoietin, hepcidin, plasminogen activator inhibitor-1, protein S, thrombospondin-1, transferrin, transferrin receptor
6. Isolation of RNA from platelets, granulocytes and reticulocytes for quantitative RT-PCR (qRT-PCR) of HIF-regulated genes
7. Echocardiogram with measurement of TRV and tricuspid pressure gradient
8. Six-minute walk test
Studies at 2 weeks:
1. History, physical examination, blood tests.
3. Serum digoxin concentration
4. Storing plasma at -70 degrees C for measurement of concentrations of products of HIF-regulated genes
5. Isolation of RNA from platelets, granulocytes and reticulocytes for qRT-PCR of HIF-regulated genes
Studies at 4 weeks and 8 weeks:
1. Baseline evaluations 1 to 5 will be repeated
2. Serum digoxin concentration will be measured.
Studies at 12 weeks:
1. All of the studies performed at baseline will be repeated: evaluations 1 to 8.
2. Serum digoxin concentration will be measured.
3. Digoxin therapy will be discontinue
Studies at 16 weeks:
History, physical examination, complete blooc count and other blood tests, electrocardiogram
Table 1. Summary of study visits and tests or procedures at each visit. Study procedure or test Base-line Week 2 Week 4 Week 8 Week 12 Week16 Digoxin started X X X ended Health questionnaire with focus on symptoms related to erythrocytosis or pulmonary hypertension. Baseline questionnaire will inquire about phlebotomy over the preceding 12 months, and subsequent questionnaires will ask for dates of phlebotomy since the last assessment. X X X X X X Physical examination to focus on weight, height, BMI, SBP, DBP, MAP, pulse pressure, pulse rate, oxygen saturation as measured by pulse oximetry, liver size, spleen size and any peripheral edema X X X X X X Electrocardiogram X X X X X X Serum digoxin concentration X X X X X Complete blood count, reticulocytes, fasting blood sugar, hemoglobin A1C, serum electrolytes, creatinine, BUN, liver function tests, iron, TIBC, ferritin, C-reactive protein, NT-proBNP. X X X X X X Store plasma at -70 degrees C for measurement of products of HIF-regulated genes including endothelin-1, erythropoietin, hepcidin, plasminogen activator inhibitor-1, protein S, thrombospondin-1, transferrin, transferrin receptor X X X X X Isolation of RNA from platelets, granulocytes and reticulocytes for qRT-PCR of HIF-regulated genes X X X Echocardiogram with measurement of TRV and tricuspid pressure gradient X X Six-minute walk test X X
Plasma and serum measurements of the products of HIF-regulated genes:
We will perform ELISA to measure plasma or serum levels of HIF-responsive proteins including but not limited to vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGF-R1), endothelin-1, and erythropoietin.
qRT PCR of HIF-regulated genes: The effect of digoxin on HIF-regulated gene expression will be profiled separately for platelets, granulocytes and reticulocytes. Expression levels of the HIF-regulated genes and endogenous control genes will be measured by qRT PCR, with baseline, 2 weeks and 12 weeks samples obtained after initiation of digoxin therapy.
1. Hemoglobin, hematocrit, red blood cell count, NT-proBNP, weight, BMI, SBP, DBP, MAP, pulse pressure, pulse rate and oxygen saturation as measured by pulse oximetry will be compared at baseline and weeks 4, 8 and 12 using repeated measures ANOVA.
2. TRV, TPG, 6MW distance, phlebotomy requirements and plasma concentrations of the products of HIF-regulated genes will be compared between baseline and 12 weeks with the paired t test.
3. Transcriptome. HIF-regulated gene expression levels will be normalized against each endogenous control for each cell type and relative gene expression levels at 2 and 12 weeks will be assessed by comparing to baseline with paired t-test. Normalized gene expression levels across time will be analyzed using multilevel modeling, including growth curve modeling, to assess the expression changes over time, with age and gender being controlled.
(g) Clinical procedures, laboratory tests, and other measures to monitor the effects of the drug in human subjects and to minimize risk.
Clinical procedures and laboratory tests. The clinical procedures and laboratory tests are summarized in Table 1.
Data Safety and Monitoring Board. Investigators Gordeuk and Prchal will serve as the Data and Safety Monitoring Board. They will have weekly teleconferences to review the safety reports of each subject involved in the study.
Interim Analysis. There will be a formal interim analysis of the results at the end of each year of the study. The project manager/data coordinator and the biostatistician will work together to provide a comprehensive report for the DSMB.
Adverse events. Patients will be monitored for potential side effects and toxicity of digoxin. Investigators should refer to the Safety Information section of the current Prescribing Information for digoxin for the expected side effects of digoxin. As with any agent, there is always the potential for unexpected adverse events (AEs). Therapeutic monitoring will be performed in a manner consistent with the local clinical standard of care. All concomitant medications will be recorded. Patients will be carefully monitored for AEs. This monitoring also includes clinical laboratory tests. Adverse events will be assessed in terms of their seriousness, intensity, and relationship to the study drug. AEs will be collected from the time of enrollment until the study visit at 30±2 days following discontinuation of the study drug.
Not yet recruiting
University of Illinois at Chicago
Published on BioPortfolio: 2018-02-21T19:15:13-0500
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