Dapagliflozin in Pulmonary Arterial Hypertension

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to investigate the effects of dapagliflozin on exercise capacity and hemodynamics in patients with pulmonary arterial hypertension

Detailed Description
-----------------
The objective of this study is to evaluate the effects of oral dapagliflozin (Forxiga®) treatment versus placebo in clinically stable patients with pulmonary arterial hypertension or CTEPH on background vasodilator combination therapy on cardio-pulmonary exercise capacity, pulmonary vascular hemodynamics, RV function and metabolomic profile of the pulmonary vascular endothelium.

Official Title
-----------------
Effects of DAPAgliflozin on Cardiopulmonary Exercise Capacity and Hemodynamics in Pulmonary Arterial Hypertension: A Double Blind Randomized Trial. (DAPAH-trial)

Conditions
-----------------
Pulmonary Arterial Hypertension, Chronic Thromboembolic Pulmonary Hypertension

Intervention / Treatment
-----------------
* Drug: Dapagliflozin 10 MG [Farxiga]
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A diagnosis of PAH group 4 or group 1 in any of the following subtypes: Idiopathic PAH (iPAH) Heritable PAH (hPAH) Connective tissue disease associated PAH (aPAH) Associated with congenital heart disease (aPAH) In case of PH in group 4, no further invasive treatment including pulmonary endarterectomy or pulmonary balloon angioplasty must be planned at time of inclusion. Symptomatic PAH in WHO functional class II-III as assessed by the screening clinician. Clinically stable patients on pulmonary vasodilator treatment with PDE5i, ERA, PA/IPA alone or in combination without considerations from the treating physician team towards treatment escalation and a treatment duration of at least four weeks. Clinical stability defined as stable symptoms without progression as assessed by treating clinician and without the need for unplanned hospital admissions due to worsening PAH within three months of screening. Fertile women (< 50 years of age) must use safe contraceptives (Intra uterine device or hormonal contraception) for the duration of the study and have a negative pregnancy test Able to understand the written patient information in Danish and give informed consent. Age ≥ 18 years Ability to perform cardio pulmonary exercise test Exclusion Criteria: Known allergy to the study medication Treatment with an SGLT2i within 6 months prior to baseline Type 1 or type 2 diabetes Impaired renal function with an eGFR < 30 mL/min/m2 within four weeks of screening Severe liver dysfunction (Child-Pugh class c) Listed for lung transplantation at the time of screening Planned initiation of iv prostacyclin therapy/ IPA or current dose escalation planned Planned pulmonary endarterectomy or pulmonary balloon angioplasty. LVEF < 50% Diagnosis of PAH group 2, 3 or 5

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dapagliflozin 10 mg once daily<br>Dapagliflozin 10 mg (Farxiga 10 mg) given once daily for three months | Drug: Dapagliflozin 10 MG [Farxiga]<br>* Dapagliflozin 10 mg given once daily for three months<br>|
| Placebo Comparator: Matching placebo<br>Placebo given once daily for three months | Drug: Placebo<br>* Matching placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in VO2 max from baseline to follow up |  | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6 minutes walking distance |  | 3 months | 
| Change in VE/VCO2 |  | 3 months | 
| Change in pulmonary vascular resistance |  | 3 months | 
| Change in mean pulmonary artery pressure |  | 3 months | 
| Change in Cardiac index |  | 3 months | 
| Change in central venous pressure |  | 3 months | 
| Change in transpulmonary gradient |  | 3 months | 
| Change in pulmonary arterial compliance |  | 3 months | 
| Change in right ventricular size on 3D echocardiography |  | 3 months | 
| Change in right ventricular free wall strain |  | 3 months | 
| Change in right ventricular free wall strain-work (free wall strain/ pulmonary artery pressure) |  | 3 months | 
| Change in NTproBNP |  | 3 months | 
| Change in EQ-5D-5L questionnaire |  | 3 months | 
| Change in metabolomic pattern on central venous blood |  | 3 months |