Pulmonary Arterial Hypertension
Conditions
Brief summary
Randomized, triple-masked, parallel arm clinical trial of empagliflozin versus placebo in pulmonary arterial hypertension (PAH) participants on stable approved PAH-targeted medical therapy.
Detailed description
The central hypothesis is that treatment with empagliflozin will improve right ventricular (RV) function and other key outcomes in patients with PAH. To test this hypothesis, the EmPATH team will conduct a multicenter Phase 2 clinical trial of empagliflozin to improve right ventricular (RV) function in pulmonary arterial hypertension (PAH). Participants will be randomized in a 1:1 ratio into two arms: empagliflozin 10 mg or matching placebo orally daily for 6 months. Randomization will be stratified by enrollment site and blocked with randomly varying block sizes. The analysis plan includes no formal interim analysis of treatment efficacy or futility.
Interventions
DRUGEmpagliflozin 10 MG
10 mg tablet once daily
DRUGPlacebo
matching tablet once daily
Sponsors
Gustavo A Heresi, MD, MS
The Cleveland Clinic
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* In order to be eligible to participate in this study, an individual must meet all the following criteria: 1. Provision of signed and dated informed consent form 2. Ability and stated willingness to comply with all study procedures and availability for the duration of the study 3. Ability to read and write in English 4. Male or female, aged 18 years or older, with group 1 PAH, idiopathic, heritable, associated with drugs and toxins, associated with connective tissue disease and with congenital heart disease (simple repaired or unrepaired defects) according to the current guidelines and adjudicated by the local PI 5. PAH confirmed by right heart catheterization in the last 5 years 6. RV dysfunction defined as FAC ≤ 40.0% on echocardiography performed during the screening visit. In PVDOMICS, FAC has a strong correlation with CMR RV ejection fraction; group 1 PAH patients with an FAC ≤ 40% (mean 27.0 ± 8.0%) had a mean RV ejection fraction of 35.5 ± 11.3% CMR RV ejection fraction ≤ 54% classifies PAH as intermediate (37-54%) or high (\<37%) risk under current guidelines. However, to ensure we recruit patients with significantly impaired RV function, patients with RV FAC between 35.0-40.0% on the screening echocardiogram will have to meet at least one of the following additional criteria: a) TAPSE/sPAP ratio \< 0.31 mm/mmHg; b) elevated right atrial pressure defined as inferior vena cava (IVC) \> 2.1 cm in diameter and the IVC does not collapse with sniff/respiration; c) RV enlargement defined as RV basal diameter ≥ 4.1 cm; d) RV free wall longitudinal strain ≥ -22%; e) Interventricular septal flattening; and f) RV outflow tract mid or late systolic notching. 7. On FDA-approved PAH-targeted therapy (any combination including infused prostacyclin analogues and sotatercept) with stable doses for at least 8 weeks or 24 weeks for sotatercept prior to the screening visit and no clinical plans to change this therapy. 8. Diuretic doses stable for at least 4 weeks prior to screening. After screening, diuretic doses may be changed as directed by the site PIs and/or the treating physician. 9. Ability to take oral medication and willingness to adhere to the study drug regimen. 10. For females of reproductive potential: use of highly effective contraception for at least 4 weeks prior to screening and agreement to use such a method during study participation and for an additional 2 weeks after the end of study drug administration 11. Able to have baseline and week 24 CMR according to Imaging Core criteria, as adjudicated by the Site PI
Exclusion criteria
* An individual who meets any of the following criteria will be excluded from participation in this study: 1. Current use of insulin, insulin secretagogues (sulfonylureas and meglitinides), lithium or an SGLT2 inhibitor 2. Use of an SGLT2 inhibitor within the past 3 months prior to screening 3. Prior documented inability to tolerate an SGLT2 inhibitor 4. Volume depletion, as ascertained by the site PI, at screening or baseline 5. History of diabetic ketoacidosis or type 1 diabetes mellitus 6. Chronic alcohol or drug abuse 7. More than one bacterial or yeast genitourinary tract infection in the year prior to enrollment 8. Estimated glomerular filtration rate under 30 mL/minute/1.73m2 or on renal replacement therapy 9. Pregnancy or lactation 10. Known allergy or hypersensitivity to empagliflozin or another SGLT-2 inhibitor 11. Currently taking or has taken another investigational drug within the past 4 weeks 12. Enrollment in another randomized intervention trial. (Participants participating in observational trials will not be excluded). 13. Decompensated right heart failure, as adjudicated by the site PI. 14. Screening HbA1c \>10% with symptoms such as polyuria and polydipsia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in RV ejection fraction measured by CMR | 24 weeks | RV ejection fraction measured by CMR before and after treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fractional Area Change (FAC) measured by echocardiography | 24 weeks | Fractional Area Change (FAC) measured by echocardiography before and after treatment |
| Change in the 6-minute walk distance (6MWD) | 24 weeks | 6-minute walk distance (6MWD) before and after treatment |
| Change in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels | 24 weeks | NT-proBNP before and after treatment |
| Time to clinical worsening | 24 weeks | Composite endpoint defined as the occurrence of death, listing for lung or heart-lung transplantation, initiation of an additional PAH-targeted medication or increase in the prostacyclin dose by ≥10% due to PAH clinical worsening judged by the treating PAH clinician, atrial septostomy, hospitalization ≥ 24 hours for worsening of PAH, or functional deterioration defined by both a worsened NYHA functional class and a decrease in 6-minute walk distance by ≥15% from baseline. |
| Change in Multicomponent improvement | 24 weeks | Percentage of participants meeting all three of the following criteria at the end of the study: any improvement in NYHA class or maintenance of class I-II, increase in 6-minute walk distance by at least 30 meters, decrease in NT-proBNP by at least 30%. |
| Change in French risk score | 24 weeks | Proportion of participants meeting all three low-risk criteria at the end of the study: NYHA class I or II, 6-minute walk distance \> 440 meters, and NT-proBNP \< 300 pg/ml at Week 24 versus baseline. |
| Change in health-related quality of life (HRQOL) | 24 weeks | Change in health-related quality of life (HRQOL) using participant reported outcome: the Medical Outcomes Survey Short Form-36 (SF-36) instrument Physical Health Composite (PHC) score. |
Countries
United States
Contacts
CONTACTGustavo Heresi, MD
CONTACTErica Corrao, MS
PRINCIPAL_INVESTIGATORGustavo Heresi, MD
The Cleveland Clinic
Outcome results
None listed