Heart Failure With Preserved Ejection Fraction (HFPEF)
Conditions
Keywords
Mangafodipir, HFpEF, CMR, Heart Failure, Heart Disease, Manganese-enhanced magnetic resonance imaging (MEMRI)
Brief summary
More than half of heart failure patients have preserved ejection fraction (HFpEF), a condition caused by increased wall stiffness that impairs proper heart filling. Two types of cardiac fibrosis, replacement fibrosis and interstitial fibrosis, contribute to this stiffening. In addition, altered calcium handling in the cardiomyocytes is relevant. The currently available contrast agents in Magnetic Resonace Imaging (MRI) primarily detect cell loss caused by replacement fibrosis, and measurements of the extracellular volume provide clues about the status of interstitial fibrosis. However, the planned trial aims to utilise mangafodipir trisodium to measure cellular function independent of the impact of fibrosis. This information could be vital for accurate diagnosis, selection and monitoring of therapy. In addition, manganese-enhanced magnetic resonance imaging (MEMRI) may be used as an alternative to examinations with gadolinium-based contrast agents in the future.
Detailed description
The trial is an open-label, single centre, Phase 2A, Proof-of-Concept (PoC) trial in adult male and female patients without randomisation. Overall, up to 42 participants will be enrolled in this trial: * A run-in phase will include up to 6 participants (healthy volunteers and HFpEF patients regardless of aetiology (HCM, CA). * The main phase of the trial will include 12 HFpEF with HCM, 12 HFpEF with CA and 12 healthy volunteers. During a run-in phase up to 6 participants will be enrolled to standardise the trial procedures, especially mangafodipir-enhanced imaging. The number and sequence of trial visits will be the same for participants of the run-in and the main phase. All enrolled participants will undergo gadolinium-enhanced imaging at Visit 2. A gadolinium-based contrast agent (authorised AMP) will be injected i.v. and T1 mapping and Extracellular Volume (ECV) measurement will be done for approximately 60 minutes. Mangafodipir-enhanced mapping will be done at Visit 3. After baseline T2 mapping, mangafodipir trisodium injection (IMP) will be administered i.v. and T1 mapping, Saturation Recovery T1 weighted imaging for measurement of the uptake rate, and T2 mapping, will be done for approximately 90 minutes. Clinical safety data will be collected throughout the trial; the participants will be followed up by a phone call 24+6 hours after Visit 3 for evaluation of late-appearing AEs. The analyses of the images will be done by an investigator of the study team, blinded to the clinical data.
Interventions
DRUGGadoteric acid
A gadolinium-based contrast agent (authorised auxiliary medicinal product (AMP)) will be injected i.v. at a dose of 0.2 mmol Gd/kg bw and T1 mapping and ECV measurement will be done.
DRUGMangafodipir trisodium injection
Mangafodipir trisodium injection (IMP) will be administered i.v. at a dose of 5 µmol/kg bw and T1 mapping, Saturation Recovery T1 weighted imaging for measurement of the uptake rate, and T2 mapping, will be done.
Sponsors
IC TARGETS AS
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
Yes
Inclusion criteria
1. Participants who have given their signed declaration of consent and data protection declaration. 2. Males and females (postmenopausal or surgically sterile females) aged ≥ 18 years and ≤ 90 years 3. HFpEF (= LVEF \> 50%) with NYHA (New York Heart Association) class I, II and III and objective evidence of cardial structural and/or functional abnormalities consistent with the presence of left ventricular (LV) diastolic dysfunction/raised LV filling pressures, including raised natriuretic peptides. 4. Patients with HCM or CA (according to current guidelines) 5. Kidney functions eGFR (Estimated Glomerular Filtration Rate) \> 30 mL/min/1.73 m2 6. Healthy volunteers (cohort specific criteria): adults with no known pre-existing medical conditions.
Exclusion criteria
1. Tachycardia (heart rate \> 100, R-R interval \< 600 ms) 2. NYHA IV 3. Previous coronary artery disease requiring intervention, including history of myocardial infarction including septal reduction therapies 4. Severely reduced renal function, defined as eGFR \< 30 mL/min/1.73 m2 5. Severely reduced liver function (Child-Pugh class C), especially severe obstructive hepatobiliary disease 6. Phaeochromocytoma 7. Advanced cancer (with short/medium term prognosis) 8. History of chest radiation therapy 9. Diabetic patients 10. Severe valvular disease 11. Previous heart surgery 12. Left ventricular assist device (LVAD) 13. Severe pulmonary disease 14. Hypersensitivity to any medicinal products containing gadolinium 15. Hypersensitivity to the active substance of the IMP or to any of the excipients 16. Contraindications to MRI, including implanted cardiac devices/pacemakers 17. Participants not able to follow instructions necessary to conduct the MRI 18. Women of childbearing potential 19. Participation in other clinical studies with investigational drugs either concurrently or within the last 30 days 20. Previous participation in this clinical trial 21. History of ongoing drug abuse or alcoholism 22. Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, scope, and possible impact of the trial 23. Investigator site staff and sponsor directly involved in the conduct of the study and their family members.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To quantify the manganese uptake rate after administration of mangafodipir trisodium in all segments of the left ventricular wall. | Images to be captured during the trial MRI examinations (up to 60 to 90 minutes after the drug administration); image evaluations shall be executed remotely. | Determination of the manganese uptake rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Comparison of manganese uptake rate constant in healthy volunteers, HFpEF with HCM or CA. | Images to be captured during the trial MRI examinations (up to 60 to 90 minutes after the drug administration); image evaluations shall be executed remotely. | Difference in the uptake rate constant between healthy volunteers, HFpEF with HCM or CA. |
| To assess the safety of mangafodipir trisodium injection based on AEs. | From AMP administration at Visit 2 to the end of the Follow-up period (1 day after Vist 3). | Frequency and severity of adverse events (AE). |
| To assess the safety of mangafodipir trisodium injection based on injection site AEs. | From AMP administration at Visit 2 to the end of the Follow-up period (1 day after Vist 3). | Frequency of injection site AEs. |
| To assess the safety of mangafodipir trisodium injection based on vital signs. | From AMP administration at Visit 2 to the end of the Follow-up period (1 day after Vist 3). | Significant changes in vital signs. |
| To assess the safety of mangafodipir trisodium injection based on ECG. | From AMP administration at Visit 2 to the end of the Follow-up period (1 day after Vist 3). | Significant changes in ECG. |
Countries
Norway
Outcome results
None listed