Clinical trial NCT06570473: Feasibility Trial for a Right Ventricular Failure Platform Trial
Official title: Feasibility Trial for the Canadian Right Ventricular AdaptiVE (CRAVE) Platform for Therapies Targeting Right Ventricular Failure
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Pulmonary Hypertension
Right Ventricular Dysfunction
Right Heart Failure
Keywords: Pulmonary Hypertension
Right Ventricular Dysfunction
Right Heart Failure
Empagliflozin
Ranolazine
Lead sponsor: University of Alberta
Sponsor class: OTHER
Collaborators: name: Canadian Heart Function Alliance
name: Accelerating Clinical Trial (ACT) Consortium
name: Ottawa Heart Institute Research Corporation
name: Team PHenomenal Hope
First posted: 2024-08-26
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: The proportion of eligible participants approached that consent
timeFrame: 16 weeks
measure: The proportion of participants who consent that are randomized
timeFrame: 16 weeks
measure: Average enrolment rate of participants per centre per month
timeFrame: 16 weeks
measure: Loss of follow up or death
timeFrame: 16 weeks
measure: Ability to capture data for secondary outcomes
timeFrame: 16 weeks
Secondary outcomes:
measure: RV function
timeFrame: 16 weeks
measure: Natriuretic peptides
timeFrame: 16 weeks
measure: Hemodynamics
timeFrame: 16 weeks
measure: Exercise capacity measured virtually
timeFrame: 16 weeks
measure: Exercise capacity measured in-person
timeFrame: 16 weeks
measure: NYHA functional class
timeFrame: 16 weeks
measure: EmPHasis-10
timeFrame: 16 weeks
measure: KCCQ-12
timeFrame: 16 weeks
measure: EQ-5D-5L
timeFrame: 16 weeks
measure: Clinical event outcomes
timeFrame: 16 weeks
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: The University of British Columbia
state: British Columbia
city: London
country: Canada
facility: London Health Sciences Centre - University Hospital
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
Study officials:
affiliation: University of Alberta
name: Jason Weatherald, MD,MSc,FRCPC
role: PRINCIPAL_INVESTIGATOR
References: