Trial Title:
Cardioprotective Empagliflozin for Cancer Patients Receiving Doxorubicin
NCT ID:
NCT06103279
Condition:
Cancer
Conditions: Official terms:
Cardiomyopathies
Empagliflozin
Conditions: Keywords:
Empagliflozin
Doxorubicin OR Adriamycin
Cardiomyopathy OR Cardiotoxicity
Study type:
Interventional
Study phase:
Phase 2/Phase 3
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
The work is a prospective, randomized, controlled study. A total of 40 cancer patients
who will receive DOX-based chemotherapy will be enrolled in the study
These patients will be randomly assigned to either Group I or Group II (each group
contains 20 patients) Group I: will receive the standard chemotherapy protocol (DOX-based
chemotherapy) only.
Group II: will receive the standard chemotherapy protocol (DOX-based chemotherapy) plus
Empagliflozin.
Primary purpose:
Prevention
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Empagliflozin 10 MG
Description:
1 tablet once daily of (EMPAGLIMAX® 10 mg) continuously starting from 1 week before
starting doxorubicin till the end of last Dox-based chemotherapy dose according to the
given chemotherapy protocol
Arm group label:
Empa Arm
Summary:
Doxorubicin induced cardiomyopathy is the most common and serious side effect associated
with doxorubicin treatment in cancer patients receiving doxorubicin. Studies have been
shown that Empagliflozin can reduce cardiovascular mortality and hospitalization for
heart failure in patients with heart failure with or without diabetes and current
clinical trials indicate that SGLT2 inhibitors protect against heart failure outcomes and
can reduce cardiac remodeling even in patients without diabetes. Empagliflozin had
beneficial effects on the outcome of the cardiomyopathy and also has anti-tumor activity
in animal studies, but clinical studies are still lacking. We are going to investigate
the cardioprotective effect of Empagliflozin against doxorubicin induced cardiomyopathy.
Objective:
- Evaluate the prophylactic effect of using Empagliflozin "a selective inhibitor of
the sodium glucose co-transporter 2 (SGLT2)" against doxorubicin induced
cardiotoxicity in patients receiving doxorubicin-based chemotherapy.
- Monitor the safety of adding empagliflozin to doxorubicin-based chemotherapy.
Detailed description:
In cancer therapy, several cytotoxic drugs may cause cardiotoxicity which is associated
with poor short- and long-term outcome. Anthracyclines (ANT) are natural products with
topoisomerase-interacting activity. These compounds are broadly utilized in the treatment
of lymphoma, sarcoma, breast cancer, and pediatric leukemia. ANT has long been
demonstrated to improve survival in cancer patients. However, despite its broad
effectiveness, ANT therapy is associated with irreversible dilated cardiomyopathy (CMP).
Toxic effect may occur at any stage of ANT treatment. and it seems that females are
affected more often than males. The incidence increases from 5% in patients receiving
doses up to 400 mg/m2 to 48% in patients receiving more than 700 mg/m2 of doxorubicin
(DOX). Although the risk of cardiac dysfunction is proportional to the cumulative ANT
exposure, a substantial number of patients still develop severe cardiotoxicity at doses
well below 550 mg/m2. In a study on the early detection and prediction of cardiotoxicity,
27.6% of patients developed chemotherapy-related cardiotoxicity. Another study found that
DOX in doses of less than 300 mg/m2 could induce cardiotoxicity. Strategies that might
prevent chemotherapy-induced CMP are receiving increased attention from oncologists and
cardiologists. It is also well known that most doxorubicin-induced cardiotoxicity occurs
within the first year (mainly within 6-months after chemotherapy). Acute toxicity is a
reversible adverse effect that develops during or within days of ANT infusion, and its
incidence has been significantly reduced by slowing the ANT infusion rates. Congestive
heart failure due to chronic cardiotoxicity is the most common type of ANT damage, is
irreversible, and peaks at 1-3 months but can occur even years after therapy. Free
radical formation is generally accepted as the main mechanism. cardiomyocytes have poor
antioxidant defense systems, and free oxygen radicals can damage various targets in the
cell. This may result in impairment of cardiac contractility and the development of CMP.
Compared with other more common forms of CMP, myocardial damage has been accompanied by a
grave prognosis, has a 2-year mortality rate of up to 6 %, and seems to be refractory to
therapy. The various approaches that can be employed in clinical practice include dosage
restriction; encapsulating ANT in liposomes to reduce myocardial uptake; and simultaneous
administration with iron chelator dexrazoxane to reduce the free iron-catalyzed reactive
oxygen formation and the alteration of ANT configuration.
Nonetheless, ANT-induced heart failure has morbidity and mortality sequelae. The second
evident problem of using DOX as a chemotherapeutic agent is the acquired tumor resistance
against it "Multidrug resistance (MDR)". DOX drug resistance is developed as a result of
increased expression of the ATP-dependent efflux pump ABCB1 (MDR1), which encodes the
membrane drug transporter P-glycoprotein.
Empagliflozin (EMPA) exerts an antidiabetic effect by reducing glucose reabsorption from
the renal proximal tubules using sodium-glucose cotransporter-2 (SGLT-2) inhibition.
Dissecting the exact molecular mechanism of SGLT2 inhibitors is therefore hampered by the
diabetic scenario. Moreover, current clinical trials indicate that SGLT2 inhibitors
protect against heart failure outcomes even in patients without diabetes. Beyond its
antidiabetic effects, it has been shown to reduce all-cause death, cardiovascular death,
and hospitalizations due to heart failure in diabetic patients compared to placebo in the
EMPA-REG OUTCOME clinical study. As well, EMPORER reduced clinical trial revealed EMPA
reduced cardiovascular mortality and hospitalization for heart failure in patients with
heart failure with or without diabetes. The SGLT2 inhibitors canagliflozin,
dapagliflozin, empagliflozin, ertugliflozin and sotagliflozin were studied in patients
with established CV disease in the EMPAREG OUTCOME and VERTIS-CV trials, with established
CV disease or CV risk factors in the CANVAS and DECLARE-TIMI 58 trials, and with CKD and
CV risk in the SCORED trial, respectively. EMPA and canagliflozin reduced the primary
composite endpoint of major CV adverse events, including CV death or nonfatal MI or
non-fatal stroke, and HF hospitalizations in EMPA-REG OUTCOME and CANVAS, respectively.
EMPA also reduced all-cause death or CV death alone. The effects on the primary endpoint
were driven by the reduction in HF-related events. Many different chemical agents have
been examined to prevent ANT-induced CMP and some of them showed promising results.
Recent animal studies and experimental observations showed that EMPA prevented the
development of CMP, free radical release, and apoptosis in cardiomyocytes due to
chemotherapeutics including; DOX. These cardiovascular outcome trials of SGLT2 inhibitors
have led to numerous speculations and studies related to their potential protective
mechanisms in patients with heart failure. Some of the proposed mechanisms are
hemodynamic-related, including natriuresis, osmotic diuresis, blood pressure-lowering,
and LV remodeling. Other mechanisms are related to more systemic effects, including the
regulation of myocardial energetics, inhibition of sodium-hydrogen exchange, adipokines
and myokines, uric acid homeostasis, elevation in erythropoietin levels, increases in
endothelial progenitor cells, protection from DOX, and the regulation of autophagy.
Despite this, little is currently known about the molecular mechanisms underlying the
cardiac protection provided by SGLT2 inhibitors. According to ESC guidelines in Aug.2021,
Dapagliflozin or EMPA is recommended for patients with chronic Heart failure with reduced
ejection fraction (HFrEF) with or without diabetes to reduce the risk of HF
hospitalization and death.
Evidence Class Ia Level Ab. The sodium-glucose co-transporter 2 (SGLT2) inhibitors
dapagliflozin and EMPA added to therapy with ACE-I/ARNI/betablocker/MRA reduced the risk
of CV death and worsening HF in patients with HFrEF. Unless contraindicated or not
tolerated, dapagliflozin or EMPA are recommended for all patients with HFrEF already
treated with an ACE-I/ARNI (angiotensin-converting enzyme inhibitor/ angiotensin receptor
neprilysin inhibitor), a beta-blocker, and an MRA (mineralocorticoid receptor
antagonist), regardless of whether they have diabetes or not. The SGLT2 inhibitor, EMPA,
protects the heart from DOX associated CMP in mice, by acting through a novel Beclin
1-toll-like receptor (TLR) 9-sirtuin-(SIRT) 3 axis. EMPA increases the abundance of
mitochondrial SIRT3. Also; it enhances the activation of TLR9 to bind with Beclin 1,
triggering communication to the autophagic, immune system, and Inflammatory machinery.
Further studies also showed that EMPA can protect DOX-induced heart failure in mice. This
evidence clearly indicates that SGLT2 inhibitors have direct cardiac protection
mechanisms other than glucose modulation. EMPA attenuates the cardiotoxic effects exerted
by DOX on LV function and remodeling in nondiabetic mice, independently of glycemic
control. EMPA prevents the reduction in cardiac systolic function induced by a
cardiotoxic ANT in a model of non-diabetic mice. The protective impact of EMPA on
systolic function was also associated with better systolic and diastolic blood pressures
in mice treated with EMPA compared to those treated with DOX alone. Finally, histological
examination showed a lower degree of myocardial fibrosis in mice treated with EMPA. Also
the protective effect of EMPA against DOX cardiotoxicity can be explained by several
mechanisms including;
1. EMPA upregulates mitochondrial PGC-1α, thereby increasing mitochondrial biogenesis
and protecting mitochondria.
2. EMPA prevents cardiomyocyte apoptosis by reducing sarcoplasmic reticulum
degeneration in a significant manner.
4- Prevents the deterioration of left ventricular systolic functions in echocardiography.
5- EMPA markedly attenuates DOX -induced prolongation of the QT and QTc intervals on the
ECG through decreasing the amount of cytosolic calcium and decreasing late sodium channel
activation in this way can shorten QT interval. 6- Oh et al. showed EMPA improved
fractional shortening (FS) but not ejection fraction (EF) in MRI and reduced perivascular
and interstitial fibrosis in histologic examination in DOX-induced chronic
cardiotoxicity. 7- Protective effects of EMPA on cardiomyocytes originate from an
increase in beta-hydroxybutyrate (βoh) (as an antioxidant) level. 8- Decrease in preload
and afterload due to natriuresis or the antioxidant effect provided by the elevated
levels of antioxidant βoh. EMPA exerts anti-inflammatory and cardioprotective effects in
DOXO-induced cardiotoxicity as EMPA inhibits the activity of SGLT-2 thereby reducing
intracellular glucose and sodium in cardiomyocytes, resulting in the inhibition of iROS,
lipid peroxidation and NLRP3/MyD88-related pathways; the inhibition of NLRP3 and NF-kB
reduces the pro-inflammatory cytokine storm in cardiomyocytes exposed to DOXO. Finally,
EMPA has shown antitumor activity in different murine cancer models The
anti-hyperglycemic drug, EMPA, was recently indicated to have in vitro anticancer
potential together with its previously reported cardioprotective properties related to
calmodulin inhibition.
- Recently, it was indicated that EMPA has an in vitro anticancer potential against
both breast cancer cell lines MCF-7 and lung cancer cell lines (A549.21).
- EMPA has shown cardioprotective properties due to its role as an inhibitor of
calmodulin.
- Calmodulin is a calcium-binding protein which is regulating many of the
intracellular actions of calcium. It is proposed that calmodulin is responsible for
the regulation of cellular proliferation and that its function may be altered in
malignancy.
- Mustroph et al. proposed that EMP reduces Ca2+/calmodulin-dependent kinase (CaMKII)
activity in isolated murine ventricular myocytes. Also, the diastolic function of
heart failure was improved in a nondiabetic rodent model by using EMPA.
- Also; calmodulin antagonists are cytotoxic and can restore the sensitivity of
resistant cells to drugs such as DOX and vincristine. Consequently, calmodulin has
been suggested as an emerging target for anticancer therapeutic intervention.
The aim of this study is to:
- Evaluate the prophylactic effect of using Empagliflozin "a selective inhibitor of
the sodium glucose co-transporter 2 (SGLT2)" against doxorubicin induced
cardiotoxicity in patients receiving doxorubicin-based chemotherapy.
- Monitor the safety of adding empagliflozin to doxorubicin-based chemotherapy.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Chemo-naive patients with a first diagnosis of cancer and indication for first-line
therapy with doxorubicin-based chemotherapy.
2. Patients intended to receive at least 4 cycles of doxorubicin or greater.
3. No previous cardiac conditions (including ischemic heart disease and clinically
important congenital or acquired valvular and myocardial diseases) and taking no
cardiac-related drugs.
4. An echocardiographic LVEF value ≥55%.
5. Normal hepatic and renal function (bilirubin ≤1.5 mg/dL, creatinine ≤2.0 mg/dL).
6. ECOG performance grade 0, 1 or 2.
Exclusion Criteria:
1. Hypersensitivity / Allergy to Empagliflozin.
2. Any condition that contraindicates chemotherapy (i.e., pregnancy, lactation).
3. New-onset cardiac symptoms or presence of congestive heart failure symptoms or
established (dilated, restrictive or hypertrophic) cardiomyopathy, coronary heart
disease, moderate or severe aortic and/or mitral valve disease or atrial
fibrillation detected by baseline echocardiography.
4. Systemic hypertension, acute coronary syndrome or cardiac surgery within the last 3
months.
5. Patients with known history or current treatment with cardiotoxic agents.
6. Receiving radiation on the left side of body.
7. History of rheumatic fever
8. Alcohol abuse.
9. Current participation in any other clinical investigation.
10. End-stage renal disease or patients on dialysis.
11. Patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.
12. Glomerular Filtration Rate <30ml/Kg/min.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Start date:
November 2023
Completion date:
August 2024
Lead sponsor:
Agency:
Ain Shams University
Agency class:
Other
Source:
Ain Shams University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06103279
