Clinical Trial Details
— Status: Withdrawn
Administrative data
NCT number |
NCT03433833 |
Other study ID # |
2019-0064 |
Secondary ID |
|
Status |
Withdrawn |
Phase |
Phase 1
|
First received |
|
Last updated |
|
Start date |
December 1, 2022 |
Est. completion date |
December 31, 2024 |
Study information
Verified date |
June 2023 |
Source |
University of Illinois at Chicago |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial 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.
Description:
The study will investigate 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/or 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, and likely HIF-2.
VHL mutations- 15 known patients in the US, 55 in Western Europe, 150 in Chuvashia, in Ischia
and 11 in India.4 Chuvash erythrocytosis (CE), endemic in the Chuvash Republic of Russia and
the Italian island of Ischia, is due to homozygosity for a missense mutation of VHL (VHL
c.598C>T; VHL R200W). VHL R200W impairs interactions of VHL with HIF-α subunits, reducing
their ubiquitin-mediated destruction. HIF-1 and HIF-2 heterodimers increase, leading to
increased expression of their target genes, including erythropoietin (EPO). In addition, CE
erythroid progenitors are hypersensitive to EPO, the explanation of which is not known. In
pilot studies this hypersensitivity is inhibited by digoxin. CE patients are prone to develop
thrombosis and early mortality that is independent of the increase in hematocrit. This
phenotype is different from the dominantly inherited VHL tumor predisposition syndrome
mutations that in combination with acquired somatic mutations result in tumorigenesis. Other
homozygous and compound heterozygous VHL mutations that cause erythrocytosis but not tumors
have been described.
EGLN1 (Egl-9 family hypoxia inducible factor 1) mutations- 5 patients in the US. and 21 in
Europe. PHD2 (encoded by the EGLN1 gene) is, along with VHL, a principal negative regulator
of HIFs. It targets HIF-α subunits for degradation. The first loss-of-function mutation of
PHD2 (PHD2 P317R) was identified in a family in which heterozygotes had mild or borderline
erythrocytosis. Since then, 25 additional patients with unexplained erythrocytosis who are
heterozygote carriers of different PHD2 mutations have been reported. Almost all patients
with PHD2-associated erythrocytosis have normal EPO levels.
EPAS1 mutations- 20 known patients in the US and approximately 100 in Europe. Affected
patients have heterozygous missense mutations in the coding sequence of the EPAS1 gene
encoding HIF-2α that result in gain-of function of HIF-2 and elevated EPO levels. There is
heterogeneity in these gain-of-function EPAS1 mutations, but their existence supports the
critical role of HIF-2 in controlling the expression of renal EPO.
Digoxin as an agent to inhibit HIFs. Digoxin, a common and readily available FDA-approved
drug for treatment of congestive heart failure, was found to inhibit HIF-dependent gene
transcription by ~90% at a concentration of 0.4 μM; it also inhibits HIF-1α protein
translation and blocks HIF-1 activity in vivo. Doses of digoxin that prevent and treat murine
hypoxic pulmonary hypertension partially protect from hypoxia-induced erythrocytosis. These
doses lead to plasma digoxin levels in mice that are at or below the therapeutic range for
humans. In unpublished data, therapeutic doses of digoxin diminished exaggerated
erythropoiesis in vitro in a CE subject.
The study hypothesizes 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 upregulated
hypoxic responses. The proposed study is conducted under IND138480 and is approved by the
FDA.
Aim 1. Determine if digoxin is safe and will decrease EPO, hemoglobin concentration and
pulmonary pressure in patients with congenital erythrocytosis due to up-regulated hypoxia
sensing.
Aim 2. Determine if digoxin will decrease purified blood cell lineage transcription and
reduce plasma levels of the products of pro-thrombotic genes up-regulated by the hypoxic
response, including IL1B (interleukin-1 beta), THBS1 (thrombospondin), EGR1 (early growth
response 1), NLRP3 (NLR family pyrin domain containing 3), SERPINE1 (serpin family E member
1), and F3 (tissue factor).
Aim 3. In a corollary study, determine if in vivo achievable digoxin concentrations abrogate
in vitro erythroid progenitor EPO hypersensitivity of mutations other than VHL R200W, and if
HIF-2α inhibitors (already in clinical trials) abrogate erythroid progenitor EPO
hypersensitivity alone or in combination with digoxin.
In summary, this proposal provides an unprecedented opportunity to identify inexpensive
therapy for rare forms of erythrocytosis due to up-regulated hypoxia sensing for which there
is now no safe, effective therapy. As such, this proposal fully coincides with the goals of
the FDA's Orphan Products Program. The research will also help define the role of hypoxia in
common maladies of mankind including chronic mountain sickness, obstructive sleep apnea, deep
vein thrombosis, cancer associated thrombosis and pulmonary hypertension.