Feasibility Trial for a Right Ventricular Failure Platform Trial (CRAVE)

Feasibility Trial for the Canadian Right Ventricular AdaptiVE (CRAVE) Platform for Therapies Targeting Right Ventricular Failure

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.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Hypertension; Right Ventricular Dysfunction; Right Heart Failure
• Intervention / Treatment: Drug: Empagliflozin; Drug: Ranolazine

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 Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jason Weatherald, MD,MSc,FRCPC; Phone Number: 780-492-9937; Email: weathera@ualberta.ca
• Study Contact Backup: Name: Courtney Gubbels, BA; Phone Number: 780-492-1113; Email: courtney.gubbels@ualberta.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • Not yet recruiting
      • University of Calgary
    • Edmonton, Alberta, Canada, T6G 2G3
      • Recruiting
      • University of Alberta
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Not yet recruiting
      • The University of British Columbia
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • Not yet recruiting
      • London Health Sciences Centre - University Hospital
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Not yet recruiting
      • The Ottawa Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empagliflozin; Participants in the empagliflozin arm will receive 10 mg by mouth once daily and standard of care.	Drug: Empagliflozin; Tablet; Other Names: Jardiance
Experimental: 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.	Drug: Ranolazine; Tablet; Other Names: Corzyna
No Intervention: Standard of Care; Participants in this group will receive standard of care.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Alberta
• Collaborators: Ottawa Heart Institute Research Corporation; Canadian Heart Function Alliance; Accelerating Clinical Trials Consortium; Team PHenomenal Hope
• Investigators: Principal Investigator: Jason Weatherald, MD,MSc,FRCPC, University of Alberta

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2025
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: August 21, 2024
• First Submitted That Met QC Criteria: August 22, 2024
• First Posted (Actual): August 26, 2024

Study Record Updates

• Last Update Posted (Estimated): September 18, 2025
• Last Update Submitted That Met QC Criteria: September 16, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Empagliflozin; Ranolazine; Right Heart Failure; Right Ventricular Dysfunction
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Respiratory Tract Diseases; Lung Diseases; Ventricular Dysfunction; Hypertension; Heart Failure; Hypertension, Pulmonary; Ventricular Dysfunction, Right; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Anilides; Amides; Aniline Compounds; Amines; Acetanilides; Piperazines; Ranolazine; empagliflozin
• Other Study ID Numbers: CRAVE-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no plan to share individual participant data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes