Empagliflozin in Pulmonary Arterial Hypertension (Emphower PoC)

Feasibility Study of Empagliflozin As Treatment for Idiopathic Pulmonary Arterial Hypertension

The aim of the study is to determine whether conducting a randomized placebo-controlled clinical trial is feasible, safe for the patient and whether the treatment is well tolerated in patients with idiopathic pulmonary arterial hypertension.

Study Overview

• Status: Completed
• Conditions: Idiopathic Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Empagliflozin 10 MG

Detailed Description

This study is designed as a prospective, single-center, phase IIa, single-arm, open-label, interventional proof-of-concept trial in patients diagnosed with idiopathic pulmonary arterial hypertension (IPAH) who are currently on stable therapy. Patients will be administered a once-daily oral dose of 10 mg empagliflozin for a duration of 12 weeks along with standard treatment. The primary objective of this study is to assess safety and tolerability of empagliflozin and to assess whether a potential future randomized, double-blind, placebo-controlled study is feasible.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Noord Holland
    • Amsterdam, Noord Holland, Netherlands, 1081 HV
      • Amsterdam UMC, location VUmc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years
2. Diagnosis of idiopathic PAH

3. Documented diagnostic right heart catheterization (RHC) at any time prior to screening confirming diagnosis of WHO diagnostic pulmonary hypertension Group I: PAH with subtype idiopathic PAH. The documented RHC shows all of the following criteria:

   1. mPAP > 20 mmHg at rest
   2. Pulmonary artery wedge pressure (PAWP) or left ventricular end-diastolic pressure (LVEDP) ≤ 15 mmHg at rest
   3. PVR ≥ 240 dyn·sec/cm5 (3 Wood units) at rest
4. Symptomatic pulmonary hypertension classified as World Health Organization (WHO) functional class (FC) II, III or IV
5. PAH therapy is at stable (per investigator) dose levels of standard of care (SoC) therapies for at least 90 days prior screening. SoC therapy refers to a therapy consisting of at least 1 agent from a list including: an endothelin-receptor antagonist (ERA), a phosphodiesterase 5 (PDE5) inhibitor, a soluble guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist (SC/inhaled/PO).

Exclusion Criteria:

1. Any subject who received any investigational medication within 1 month prior to the start of this study or who is scheduled to receive another investigational drug during the course of this study. Patients participating in a purely observational trial will not be excluded

2. Females of childbearing potential, defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 months), unable or unwillingly to either:

   1. Use highly effective methods of birth control according to the International Conference on harmonisation of pharmaceuticals for human use (ICH) that result in a low failure rate of less than 1% per year when used consistently and correctly 43. Highly effective methods include hormonal contraception (for example, birth control pills, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation (having your tubes tied); or a partner with a vasectomy who has completed follow-up to confirm a successful procedure
   2. Have a negative pregnancy tests as verified by the investigator prior to starting study therapy and agrees to have an extra pregnancy test 8 weeks after start of the study
3. Contraindication for CMR imaging as defined in the protocol of the Amsterdam UMC "Kwaliteitsdocument Cardiale MRI (Versie 1)". The list of contra-indications includes: claustrophobia, ferromagnetic implants, implanted cardioverter defibrillator (ICD) or pacemaker (except for the MR conditional) and ball-in-cage mechanic heart valve.
4. Impaired renal function, defined as eGFR < 30 mL/min/1.73 m2 (CKD-EPI) or requiring dialysis
5. History of chronic severe (Child Pugh classification score >10, Appendix 1) or active liver disease defined as serums transaminases >5 x upper limit of normal (ULN) or bilirubin > 1.5 x ULN
6. History of ketoacidosis
7. Known allergy, intolerance or hypersensitivity to empagliflozin or other SGLT-2 inhibitors
8. Use of lithium compounds and being unable or unwillingly to increase the monitoring frequency of lithium levels
9. Current or scheduled use of the following Uridine glucuronosyltransferase (UGT) inducers: phenytoin, rifampicin, carbamazepine, lamotrigine, ritonavir, efavirenz, tipranavir, phenobarbital, testosterone propionate and nelfinavir.
10. Current or prior use of a SGLT-2 inhibitor
11. Heart transplant recipient or listed for heart transplant
12. Chronic pulmonary disease requiring home oxygen or steroid maintenance therapy
13. Symptomatic hypotension and/or a systolic blood pressure (SBP) < 90 mmHg at screening
14. Gastrointestinal (GI) surgery or GI disorder that could interfere with absorption of trial medication in the investigator's opinion
15. Presence of any other disease than pulmonary arterial hypertension with a life expectancy of <1 year in the investigator's opinion
16. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
17. History of severe (previously required or prolonged patient hospitalization, resulted in persistent or marked disability/incapacity) or recurrent (≥2 infections in six months or ≥3 infections in one year) genital infections.
18. History of severe hypoglycaemia (<40 - 30 mg/dL = <2.2 - 1.7 mmol/L), previous hospitalisation for hypoglycaemia or seizures attributed to hypoglycaemia
19. Active solid or haematological malignancy, with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 squamous cell carcinomas of the skin
20. History or suspicion of inability to cooperate adequately
21. Any condition that, in the investigator's opinion, makes them an unreliable trial subject or unlikely to complete the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empagliflozin	Drug: Empagliflozin 10 MG; 10 mg once daily empagliflozin oral tablets for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Tolerability: the number of patients who have to prematurely discontinue treatment due to intolerability or adverse events.	12 weeks
Feasibility: time needed to include all patients and number of patients needed to screen.	12 weeks
Safety: the number of adverse events (AEs), severe adverse events (SAEs), adverse event of special interest (AESI) and suspected unexpected serious adverse reactions (SUSARs).	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Right ventricle ejection fraction (RVEF) measured using MRI	RVEF is calculated using the RVESV, RVEDV	12 weeks
Right ventricle mass measured using MRI		12 weeks
Left ventricle ejection fraction (LVEF) measured using MRI	LVEF is calculated using the LVESV, LVEDV	12 weeks
Stroke volume (SV) measured using MRI	SV is calculated using the LVESV, LVEDV	12 weeks
Tricuspid annular plane systolic excursion (TAPSE) measured using transthoracic ultrasound		12 weeks
Estimated sPAP measured using transthoracic ultrasound		12 weeks
Right ventricle fractional area change (RVFAC) measured using transthoracic ultrasound		12 weeks
Blood biomarkers	Endpoints: Expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and bone morphogenetic protein receptor II (BMPR2) in peripheral blood mononuclear cells (PMBC)	12 weeks
Blood safety biomarkers	Fasting glucose, N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP) and creatinine in blood.	12 weeks
Urine safety biomarkers	Ketones, nitrites, leukocytes and glucose in urine test strip (dipstick).	12 weeks
Functional class	World Health Organization Function Classification of Pulmonary Hypertension. Outcome: Class I, Class II, Class III or Class IV	12 weeks
Six-Minute Walk Distance	Six-minute walk distance (6MWD) will be measured by the 6-minute walk test (6MWT). The test should preferably be conducted on a straight 30 metre track. The patient is instructed to walk as far as possible for six minutes. One lap is demonstrated. The patient is told that slowing down can be necessary, and after pausing are encouraged to start walking as soon as possible.	12 weeks
Quality of life measured with use of the EMPHASIS-10 questionnaire	The emPHasis-10 is a short questionnaire for assessing Health-related quality of life in pulmonary arterial hypertension. The questionnaire comprises 10 items that are formatted as a semantic six-point differential scale and results in a score out of 50 where a higher score represents a higher symptom burden.	12 weeks
Quality of life measured with use of the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire	The CAMPHOR questionnaire contains 65 items in total. The measure consists of three different scales: a symptom scale assessing energy, breathlessness and mood (25-items; low score indicating minimal symptoms); activity limitations scale with a 3-point rating system (15-items; range 0 to 30, lower score indicating minimal activity limitation); and a QoL scale (25-items; lower score indicating better QoL). It is negatively weighted; a higher score indicates worse QoL and greater functional limitation.	12 weeks

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: Harm Jan Bogaard, Prof. dr., Amsterdam UMC, location VUmc

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2023
• Primary Completion (Actual): November 1, 2024
• Study Completion (Actual): November 1, 2024

Study Registration Dates

• First Submitted: July 28, 2022
• First Submitted That Met QC Criteria: August 4, 2022
• First Posted (Actual): August 9, 2022

Study Record Updates

• Last Update Posted (Estimated): November 20, 2024
• Last Update Submitted That Met QC Criteria: November 17, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Empagliflozin
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Hypertension; Familial Primary Pulmonary Hypertension; Sodium-Glucose Transporter 2 Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Empagliflozin
• Other Study ID Numbers: 81866; 2022-002400-20 (EudraCT Number); 2022-501512-33-00 (Other Identifier: Clinical Trials Information System (CTIS) EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: On reasonable request
• IPD Sharing Time Frame: Six months after study completion
• IPD Sharing Access Criteria: data can be obtained on request by email
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

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