Feasibility Trial for a Right Ventricular Failure Platform Trial

Phase 2

Recruiting

• Conditions: Pulmonary Hypertension; Right Ventricular Dysfunction; Right Heart Failure
• Interventions: Drug: Empagliflozin; Drug: Ranolazine

• Registration Number: NCT06570473
• Lead Sponsor: University of Alberta

Brief Summary

The primary objective of the CRAVE feasibility trial is to assess the feasibility of conducting a larger CRAVE platform trial by performing a randomized trial of 30 participants with pulmonary hypertension and right ventricular dysfunction, comparing empagliflozin or ranolazine plus standard of care to standard of care alone.

Detailed Description

This study is an investigator-initiated, open label, prospective, multi-centre, phase 2, randomized control trial. This CRAVE feasibility trial will seek to establish the feasibility of a larger platform trial for testing multiple interventions in various domains to improve right ventricular function. In this feasibility trial, 30 participants with pulmonary hypertension and right heart failure with be randomized 1:1:1 to empagliflozin 10 mg daily + standard of care, ranolazine twice daily + standard of care, or standard of care alone. Participant outcomes (medical records review) will be followed for 16 weeks after randomization.

Study Timeline

• Study First Submitted: 2024-08-21
• Study First Submitted QC: 2024-08-22
• Study First Posted: 2024-08-26
• Study Start: 2025-02-12
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-24
• Last Update Posted: 2025-03-27
• Primary Completion: 2025-08
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

1. Age ≥ 18 years.

2. Able to provide informed consent.

3. Able to comply with all study procedures.

4. History of RV dysfunction or RHF secondary to any of:

   a. Group 1 PH, pulmonary arterial hypertension b. Group 2 PH, left heart disease with normal left ventricular ejection fraction (LVEF) > 50% and a previous RHC demonstrating combined pre and post-capillary PH, defined as: i. mPAP >20 mmHg ii. PAWP > 15 mmHg iii. PVR> 2 WU c. Group 3 PH d. Group 4 PH, chronic thromboembolic PH that is either persistent after pulmonary endarterectomy or inoperable due to distal disease.

5. Symptomatic with current NYHA Functional Class II-IV

6. Biomarker and 2D echocardiogram evidence of RV dysfunction within 3 months:

   1. NT-proBNP >300 ng/L and qualitative evidence of at least 'mild' RV dysfunction on echocardiography OR NT-proBNP<300 ng/L and qualitative evidence of at least moderate RV dysfunction and/or dilatation on 2D echocardiogram AND
   2. A quantitative 2D echocardiogram with evidence of RV dysfunction defined as having both of the following:

   i. TAPSE ≤18 mm ii. RV dilatation (RV diameter > 42 mm at the base).

7. Receiving loop diuretics or mineralocorticoid receptor antagonists for at least 4 weeks.

8. Access to an iOS or android smart phone or tablet.

Exclusion Criteria

1. Estimated glomerular filtration rate (eGFR) <30 ml/min.

2. LVEF < 50%

3. Normal RV size and function

4. Severe aortic or mitral valvular disease

5. Moderate or severe hepatic dysfunction (Child-Pugh Class B or C)

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

7. Pregnancy or lactation

8. Unable to provide consent and comply with follow-up visits

9. Listed for lung, heart or heart/lung transplantation

10. Myocardial infarction or acute coronary syndrome within 90 days of screening

11. Enrolled in another interventional trial

12. Planned cardiac or thoracic surgical intervention in the next 6 months.

13. Known hypersensitivity to empagliflozin or ranolazine.

14. Concurrent treatment with:

    • strong inhibitors of Cytochrome P450 3A4 (CYP 3A4), (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, nelfinavir, ritonavir, indinavir, saquinavir and grapefruit juice)
    • class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide) or class III antiarrhythmics (e.g., sotalol, ibutilide, amiodarone, dronedarone)
    • inducers of CYP 3A4 (e.g., rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort)

15. Congenital long QT syndrome or a QTc interval >500 ms

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Empagliflozin	Empagliflozin	Participants in the empagliflozin arm will receive 10 mg by mouth once daily and standard of care.
Ranolazine	Ranolazine	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.

Primary Outcome Measures

Name	Time	Method
Average enrolment rate of participants per centre per month	16 weeks	(target ≥1 participant per centre/month)
The proportion of eligible participants approached that consent	16 weeks	(target ≥30%)
The proportion of participants who consent that are randomized	16 weeks	(target ≥90%)
Loss of follow up or death	16 weeks	Loss of follow up (target at 16 weeks ≤5%)
Ability to capture data for secondary outcomes	16 weeks	(target ≥90% completion)

Secondary Outcome Measures

Name	Time	Method
Natriuretic peptides	16 weeks	(N-terminal pro-B-type natriuretic peptide \[NT-proBNP\])
Clinical event outcomes	16 weeks	number of clinical events that occur
Exercise capacity measured virtually	16 weeks	6-minute walk distance (6MWD) assessed using the novel Walk.Talk.Track. mobile app
Exercise capacity measured in-person	16 weeks	assessed using in-person 6-minute walk distance (6MWD)
NYHA functional class	16 weeks	(New York Heart Association Functional Classification for heart failure)
EmPHasis-10	16 weeks	questionnaire used during clinical assessments to determine how pulmonary hypertension affects someone's life
RV function	16 weeks	assessed using echocardiogram
Hemodynamics	16 weeks	assessed using right heart catheterization (RHC)
KCCQ-12	16 weeks	questionnaire for assessing health-related quality of life in chronic heart failure
EQ-5D-5L	16 weeks	questionnaire provides a simple descriptive profile of a respondent's health state

Trial Locations

Locations (5)

University of Calgary; 🇨🇦 Calgary, Alberta, Canada

University of Alberta; 🇨🇦 Edmonton, Alberta, Canada

The University of British Columbia; 🇨🇦 Vancouver, British Columbia, Canada

London Health Sciences Centre - University Hospital; 🇨🇦 London, Ontario, Canada

The Ottawa Hospital; 🇨🇦 Ottawa, Ontario, Canada