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

Overview

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.

Interventions

• Drug Empagliflozin
  Tablet
• Drug Ranolazine
  Tablet

Primary outcome measures

• The proportion of eligible participants approached that consent [Time frame: 16 weeks]
• The proportion of participants who consent that are randomized [Time frame: 16 weeks]
• Average enrolment rate of participants per centre per month [Time frame: 16 weeks]
• Loss of follow up or death [Time frame: 16 weeks]
• Ability to capture data for secondary outcomes [Time frame: 16 weeks]

Secondary outcome measures (10)

• RV function [Time frame: 16 weeks]
• Natriuretic peptides [Time frame: 16 weeks]
• Hemodynamics [Time frame: 16 weeks]
• Exercise capacity measured virtually [Time frame: 16 weeks]
• Exercise capacity measured in-person [Time frame: 16 weeks]
• NYHA functional class [Time frame: 16 weeks]
• EmPHasis-10 [Time frame: 16 weeks]
• KCCQ-12 [Time frame: 16 weeks]
• EQ-5D-5L [Time frame: 16 weeks]
• Clinical event outcomes [Time frame: 16 weeks]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years.
• Able to provide informed consent.
• Able to comply with all study procedures.
• 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.

• Symptomatic with current NYHA Functional Class II-IV
• Biomarker and 2D echocardiogram evidence of RV dysfunction within 3 months:

• 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
• 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).

• Receiving loop diuretics or mineralocorticoid receptor antagonists for at least 4 weeks.
• Access to an iOS or android smart phone or tablet.

Exclusion criteria

• Estimated glomerular filtration rate (eGFR) <30 ml/min.
• LVEF < 50%
• Normal RV size and function
• Severe aortic or mitral valvular disease
• Moderate or severe hepatic dysfunction (Child-Pugh Class B or C)
• Participants requiring augmentation of diuretics or otherwise not meeting definition for clinical stability
• Pregnancy or lactation
• Unable to provide consent and comply with follow-up visits
• Listed for lung, heart or heart/lung transplantation
• Myocardial infarction or acute coronary syndrome within 90 days of screening
• Enrolled in another interventional trial
• Planned cardiac or thoracic surgical intervention in the next 6 months.
• Known hypersensitivity to empagliflozin or ranolazine.
• 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)
• Congenital long QT syndrome or a QTc interval >500 ms

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 5 centers

• University of Calgary — Calgary
• University of Alberta — Edmonton
• The University of British Columbia — Vancouver
• London Health Sciences Centre - University Hospital — London
• The Ottawa Hospital — Ottawa

Identifiers

NCT: NCT06570473 · CRAVE-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗