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Empagliflozin in Pulmonary Arterial Hypertension (Emphower PoC)

Primary Purpose

Idiopathic Pulmonary Arterial Hypertension

Status
Recruiting
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Empagliflozin 10 MG
Sponsored by
Amsterdam UMC, location VUmc
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Idiopathic Pulmonary Arterial Hypertension focused on measuring Empagliflozin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Amsterdam UMC, location VumcRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Empagliflozin

Arm Description

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Right ventricle ejection fraction (RVEF) measured using MRI
RVEF is calculated using the RVESV, RVEDV
Right ventricle mass measured using MRI
Left ventricle ejection fraction (LVEF) measured using MRI
LVEF is calculated using the LVESV, LVEDV
Stroke volume (SV) measured using MRI
SV is calculated using the LVESV, LVEDV
Tricuspid annular plane systolic excursion (TAPSE) measured using transthoracic ultrasound
Estimated sPAP measured using transthoracic ultrasound
Right ventricle fractional area change (RVFAC) measured using transthoracic ultrasound
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)
Blood safety biomarkers
Fasting glucose, N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP) and creatinine in blood.
Urine safety biomarkers
Ketones, nitrites, leukocytes and glucose in urine test strip (dipstick).
Functional class
World Health Organization Function Classification of Pulmonary Hypertension. Outcome: Class I, Class II, Class III or Class IV
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.
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.
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.

Full Information

First Posted
July 28, 2022
Last Updated
July 26, 2023
Sponsor
Amsterdam UMC, location VUmc
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1. Study Identification

Unique Protocol Identification Number
NCT05493371
Brief Title
Empagliflozin in Pulmonary Arterial Hypertension
Acronym
Emphower PoC
Official Title
Feasibility Study of Empagliflozin as Treatment for Idiopathic Pulmonary Arterial Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2023 (Actual)
Primary Completion Date
November 1, 2024 (Anticipated)
Study Completion Date
November 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Amsterdam UMC, location VUmc

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Idiopathic Pulmonary Arterial Hypertension
Keywords
Empagliflozin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
prospective single-center, phase IIa, single arm, open label, interventional proof-of-concept study
Masking
None (Open Label)
Allocation
N/A
Enrollment
8 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Empagliflozin
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Empagliflozin 10 MG
Intervention Description
10 mg once daily empagliflozin oral tablets for 12 weeks
Primary Outcome Measure Information:
Title
Tolerability: the number of patients who have to prematurely discontinue treatment due to intolerability or adverse events.
Time Frame
12 weeks
Title
Feasibility: time needed to include all patients and number of patients needed to screen.
Time Frame
12 weeks
Title
Safety: the number of adverse events (AEs), severe adverse events (SAEs), adverse event of special interest (AESI) and suspected unexpected serious adverse reactions (SUSARs).
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Right ventricle ejection fraction (RVEF) measured using MRI
Description
RVEF is calculated using the RVESV, RVEDV
Time Frame
12 weeks
Title
Right ventricle mass measured using MRI
Time Frame
12 weeks
Title
Left ventricle ejection fraction (LVEF) measured using MRI
Description
LVEF is calculated using the LVESV, LVEDV
Time Frame
12 weeks
Title
Stroke volume (SV) measured using MRI
Description
SV is calculated using the LVESV, LVEDV
Time Frame
12 weeks
Title
Tricuspid annular plane systolic excursion (TAPSE) measured using transthoracic ultrasound
Time Frame
12 weeks
Title
Estimated sPAP measured using transthoracic ultrasound
Time Frame
12 weeks
Title
Right ventricle fractional area change (RVFAC) measured using transthoracic ultrasound
Time Frame
12 weeks
Title
Blood biomarkers
Description
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)
Time Frame
12 weeks
Title
Blood safety biomarkers
Description
Fasting glucose, N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP) and creatinine in blood.
Time Frame
12 weeks
Title
Urine safety biomarkers
Description
Ketones, nitrites, leukocytes and glucose in urine test strip (dipstick).
Time Frame
12 weeks
Title
Functional class
Description
World Health Organization Function Classification of Pulmonary Hypertension. Outcome: Class I, Class II, Class III or Class IV
Time Frame
12 weeks
Title
Six-Minute Walk Distance
Description
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.
Time Frame
12 weeks
Title
Quality of life measured with use of the EMPHASIS-10 questionnaire
Description
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.
Time Frame
12 weeks
Title
Quality of life measured with use of the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire
Description
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.
Time Frame
12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥ 18 years Diagnosis of idiopathic PAH 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: mPAP > 20 mmHg at rest Pulmonary artery wedge pressure (PAWP) or left ventricular end-diastolic pressure (LVEDP) ≤ 15 mmHg at rest PVR ≥ 240 dyn·sec/cm5 (3 Wood units) at rest Symptomatic pulmonary hypertension classified as World Health Organization (WHO) functional class (FC) II, III or IV 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: 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 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: 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 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 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. Impaired renal function, defined as eGFR < 30 mL/min/1.73 m2 (CKD-EPI) or requiring dialysis 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 History of ketoacidosis Known allergy, intolerance or hypersensitivity to empagliflozin or other SGLT-2 inhibitors Use of lithium compounds and being unable or unwillingly to increase the monitoring frequency of lithium levels Current or scheduled use of the following Uridine glucuronosyltransferase (UGT) inducers: phenytoin, rifampicin, carbamazepine, lamotrigine, ritonavir, efavirenz, tipranavir, phenobarbital, testosterone propionate and nelfinavir. Current or prior use of a SGLT-2 inhibitor Heart transplant recipient or listed for heart transplant Chronic pulmonary disease requiring home oxygen or steroid maintenance therapy Symptomatic hypotension and/or a systolic blood pressure (SBP) < 90 mmHg at screening Gastrointestinal (GI) surgery or GI disorder that could interfere with absorption of trial medication in the investigator's opinion Presence of any other disease than pulmonary arterial hypertension with a life expectancy of <1 year in the investigator's opinion Women who are pregnant, nursing, or who plan to become pregnant while in the trial 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. History of severe hypoglycaemia (<40 - 30 mg/dL = <2.2 - 1.7 mmol/L), previous hospitalisation for hypoglycaemia or seizures attributed to hypoglycaemia 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 History or suspicion of inability to cooperate adequately Any condition that, in the investigator's opinion, makes them an unreliable trial subject or unlikely to complete the trial
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Harm Jan Bogaard, Prof. dr.
Phone
+31204444782
Email
hj.bogaard@amsterdamumc.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Erik Duijvelaar, MD
Phone
+31204442322
Email
e.duijvelaar@amsterdamumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Harm Jan Bogaard, Prof. dr.
Organizational Affiliation
Amsterdam UMC, location VUmc
Official's Role
Principal Investigator
Facility Information:
Facility Name
Amsterdam UMC, location Vumc
City
Amsterdam
State/Province
Noord Holland
ZIP/Postal Code
1081 HV
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Harm Jan Bogaard, Prof. dr.

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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

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Empagliflozin in Pulmonary Arterial Hypertension

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