Empagliflozin + Ranolazine for Right Ventricular Dysfunction

(CRAVE Trial)

Recruiting at 4 trial locations

Overseen By Courtney Gubbels, BA

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Alberta

Must be taking: Loop diuretics, mineralocorticoid antagonists

Must not be taking: CYP 3A4 inhibitors, antiarrhythmics

Disqualifiers: Low eGFR, Pregnancy, Transplantation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new methods to assist individuals with right ventricular dysfunction and pulmonary hypertension, where the heart struggles to pump blood efficiently due to high lung blood pressure. Researchers are testing two medications: empagliflozin (an SGLT2 inhibitor) and ranolazine (used for chronic angina) to determine if they enhance heart function more effectively than standard treatments alone. Participants will receive either one of these medications plus their usual care or just their usual care. Ideal candidates for this trial are those with right-sided heart problems who are already on medications like loop diuretics. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you do not take certain medications, such as strong inhibitors or inducers of Cytochrome P450 3A4, certain antiarrhythmics, and others. If you are on these medications, you may need to stop them to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that empagliflozin is safe. It did not significantly affect blood pressure in patients and reduced the risk of death from heart problems or hospitalization for heart failure. This indicates it is generally well-tolerated by individuals with heart issues.

Ranolazine has also proven safe for individuals with pulmonary arterial hypertension. In one study, 90% of patients tolerated it well, though some required a lower dose.

Both treatments have FDA approval for other uses, providing extra reassurance about their safety. However, since this study is in an early stage, it continues to evaluate how people respond to these drugs for this specific purpose. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about empagliflozin and ranolazine for right ventricular dysfunction because of their unique mechanisms of action. Empagliflozin, typically used for diabetes, works by helping the body eliminate excess glucose through urine, which may also reduce heart stress and improve heart function. Ranolazine, on the other hand, helps improve blood flow to the heart by altering the heart's energy metabolism, potentially enhancing its efficiency. Unlike the standard treatments that primarily focus on symptoms, these drugs target underlying metabolic and functional issues, offering a fresh approach to managing heart conditions.

What evidence suggests that this trial's treatments could be effective for right ventricular dysfunction?

This trial will compare the effects of empagliflozin and ranolazine on right ventricular dysfunction. Research has shown that empagliflozin, which participants in one arm of this trial may receive, can aid heart failure by reducing stress on the heart's right side, potentially improving heart function. While some studies found no overall effect on the right side of the heart, others showed it could lower the risk of hospital visits for heart failure, suggesting potential benefits for heart health.

Ranolazine, which participants in another arm of this trial may receive, may also support the right side of the heart by improving energy use. Some studies found it reduces heart muscle thickness and improves symptoms in people with pulmonary arterial hypertension, a type of high blood pressure affecting the lungs and heart. Overall, both treatments seem promising for addressing right-side heart issues, but more research is needed to fully understand their benefits. ^{1 3 6 7 8}

Who Is on the Research Team?

Jason Weatherald, MD,MSc,FRCPC

Principal Investigator

University of Alberta

Are You a Good Fit for This Trial?

This trial is for adults over 18 with pulmonary hypertension and right ventricular dysfunction who can follow the study procedures. They must have certain types of pulmonary hypertension, symptoms matching NYHA Functional Class II-IV, specific heart function measurements on tests, and be on certain heart medications for at least 4 weeks.

Inclusion Criteria

Able to provide informed consent

Able to comply with all study procedures

Access to an iOS or android smart phone or tablet

Exclusion Criteria

LVEF < 50%

Pregnancy or lactation

Participants requiring augmentation of diuretics or otherwise not meeting definition for clinical stability

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either empagliflozin, ranolazine, or standard of care for right ventricular failure

16 weeks

Regular visits for monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Empagliflozin
• Ranolazine

Trial Overview The CRAVE feasibility trial is testing whether it's possible to do a bigger study on two drugs: Empagliflozin or Ranolazine plus standard care versus just standard care in people with pulmonary hypertension and right ventricular dysfunction. It's a small test run with 30 participants.

How Is the Trial Designed?

Group I: Ranolazine Experimental Treatment 1 Intervention

Participants in the ranolazine arm will receive ranolazine 500 mg by mouth twice daily, which will be increased to 1000 mg twice daily after 2 weeks (unless concurrently using moderate CYP 3A4 inhibitors, then dose is limited to 500 mg twice daily) and will receive standard of care.

Group II: Empagliflozin Experimental Treatment 1 Intervention

Participants in the empagliflozin arm will receive 10 mg by mouth once daily and standard of care.

Group III: Standard of Care Active Control 1 Intervention

Participants in this group will receive standard of care.

Who Is Running the Clinical Trial?

University of Alberta

Lead Sponsor

Trials

957

Recruited

437,000+

Team PHenomenal Hope

Collaborator

Trials

1

Recruited

30+

Canadian Heart Function Alliance

Collaborator

Trials

2

Recruited

1,400+

Accelerating Clinical Trial (ACT) Consortium

Collaborator

Trials

1

Recruited

30+

Ottawa Heart Institute Research Corporation

Collaborator

Trials

200

Recruited

95,800+

Accelerating Clinical Trials Consortium

Collaborator

Published Research Related to This Trial

Empagliflozin (EMPA) significantly reduced the induction of ventricular fibrillation (VF) in an ex-vivo model of ischemia-reperfusion, with only 16.7% of EMPA-treated hearts experiencing VF compared to 60% in control hearts.

EMPA improved cardiac contractility, as shown by a higher left ventricular developed pressure (LVDP) and enhanced calcium cycling, indicating its potential to protect heart function during ischemic events through mechanisms that do not involve sodium-glucose co-transporter-2 (SGLT2).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-arrhythmic and inotropic effects of empagliflozin following myocardial ischemia. Azam, MA., Chakraborty, P., Si, D., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12163198/

Empagliflozin and Right-Sided Heart Failure - PubMed Central From a hemodynamic perspective, empagliflozin reduces both preload and afterload, thereby lowering RV wall stress and improving cardiac ...

2. medrxiv.org medrxiv.org/content/10.1101/2025.05.30.25328686v1.full-text

Effects of Empagliflozin on Right Ventricular Function in ... Conclusions Empagliflozin exerted no overall effect on RV function in stable HFrEF patients, but significantly improved RVFWS in patients in the ...

3. ahajournals.org ahajournals.org/doi/10.1161/CIRCULATIONAHA.124.069217

Effect of Empagliflozin on Heart Failure Outcomes After ... Empagliflozin reduced the risk of first and total heart failure (HF) hospitalizations by 23% and 33%, respectively, in patients with left ...

4. frontiersin.org frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1302265/full

Effects of empagliflozin on right ventricular adaptation to ... - Empagliflozin treatment caused a mild reduction in RV end-systolic pressure. - Empagliflozin treatment did not alter systolic function (Ees) or ventricular- ...

5. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2818219

Empagliflozin vs Dapagliflozin in Patients With Heart Failure Patients who started using empagliflozin were less likely to experience the primary outcome of composite of all-cause mortality or hospitalization compared ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa2022190

Cardiovascular and Renal Outcomes with Empagliflozin in ... Those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2666602222000714

Safety and effects of SGLT-2 inhibitor use among LVAD ... Several major trials have recently shown SGLT-2 inhibitors (SGLT2i) confer a reduced risk of adverse cardiovascular (CV) events in patients with heart failure.

8. jacc.org jacc.org/doi/10.1016/j.jacc.2024.03.405

Left Ventricular Function, Congestion, and Effect of ... Empagliflozin reduced the risk for first (HR: 0.77; 95% CI: 0.60-0.98) and total (RR: 0.67; 95% CI: 0.50-0.89) HF hospitalizations, irrespective of LVEF or ...