E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with heart failure with preserved ejection fraction (HFpEF) and iron deficiency (ID) with and without anaemia |
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E.1.1.1 | Medical condition in easily understood language |
Patients with heart failure with preserved ejection fraction (HFpEF) and iron deficiency (ID) with and without anaemia |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary efficacy endpoint: The primary endpoint is the difference in exercise capacity from baseline to visit 5 as assessed by the 6-minute walking test after initiation of therapy (FCM or placebo/saline) in patients with HFpEF and ID
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E.2.2 | Secondary objectives of the trial |
Secondary endpoints: Secondary endpoints include the difference in 6-minute-walking distance (in meters) from baseline to visits 3, 4, 6 and 7 respectively; PGA assessment at visit 3, 4, 5, 6, and 7; change in NYHA functional class from baseline to visit 3, 4, 5, 6, and 7, respectively. Further, improvement of Quality of Life from baseline as well as kidney function and inflammatory parameters will be assessed.Further assessments include differences in plasma levels of blood parameters of kidney function and inflammation, and differences in quality of life from baseline to respective assessment time point as well as the rate of recurrent events of HF hospitalization and death.
Tertiary endpoints (efficacy): Tertiary endpoints are resource use and costs associated with the treatment with IV FCM compared to placebo/saline.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient is willing to participate and provides written informed consent; 2. Age ≥18 years; 3. Clinical diagnosis of heart failure with preserved ejection fraction (HFpEF) with LVEF ≥45% at screening or within 6 months prior to planned randomisation (assessed by echocardiography or MRI); 4. Ambulatory for at least 7 days with NYHA class II or III at time of randomisation (the screening visit can take place at the end of a hospitalisation); 5. Treated with a diuretic; 6. Presence of atrial fibrillation (AF) at screening or randomisation is allowed in 2 out of 4 patients (calculated per centre); 7. At screening or randomisation, presence of one of the following criteria: a) hospitalisation with a diagnosis of HF within 12 months prior to planned randomisation; OR b) raised plasma levels of natriuretic peptides in a patient with sinus rhythm (i.e. in patients without AF: NT-proBNP >300 pg/mL or BNP >100 pg/mL or MR-proANP >120 pmol/L; in patients with AF: NT-proBNP >600 pg/mL or BNP >200 pg/mL or MR-proANP >250 pmol/l) 8. Evidence of diastolic dysfunction at screening or randomisation, defined as: a) E/E’ >13; OR b) LA width ≥38 mm; OR c) LA length ≥50 mm; OR d) LA area ≥20 cm2; OR e) LA volume ≥55 ml; OR f) left atrial volume index >28 mL/m2; 9. Haemoglobin >9.0 g/dL and ≤14.0 g/dL (at screening); 10. ID with ferritin <100 ng/mL or ferritin 100-299 plus TSAT <20% (at screening); 11. 6-minute-walking distance at baseline <450 m (average of the last 2 documented tests within 8 weeks prior to planned randomisation that also need to be within 20% of each other).
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E.4 | Principal exclusion criteria |
1. Unable to sign informed consent 2. Any prior echocardiography measurement of LVEF <40%; 3. Clinical signs and symptoms of infection including fever >38°C; 4. SARS-CoV-2 infection 5. Use of IV iron, erythropoietin or blood transfusions within the previous 60 days; 6. Use of concurrent immunosuppressive therapy; 7. History of acquired iron overload or haemochromatosis (or a first relative with haemochromatosis); 8. Known hypersensitivity to FCM or any other IV iron product; 9. Known bleeding or haemolytic anemia; 10. Presence of any condition that precludes exercise testing, such as decompensated HF, significant musculoskeletal disease, unstable angina pectoris, obstructive cardiomyopathy, severe uncorrected valvular disease, or uncontrolled bradyarrhythmias or tachy-arrhythmias; 11. Probable alternative diagnoses that in the opinion of the investigator could account for the patient’s HF symptoms such as severe obesity, primary pulmonary hypertension, or chronic obstructive pulmonary disease (COPD); hence, patients with the following are excluded: a) Severe COPD, i.e. with known FEV1 <50%, requiring home oxygen therapy, or on chronic oral steroid therapy; b) body mass index ≥40.0 kg/m2; 12. Presence of uncontrolled atrial fibrillation with resting heart rate >110/min; 13. Presence of uncontrolled hypertension with blood pressure >160/100 mm Hg; 14. Renal replacement therapy; 15. Concurrent therapy with an erythropoiesis stimulating agent; 16. Known active malignancy; 17. Known HIV or active hepatitis infection; 18. Pregnancy; 19. Patients, who may be dependent on the sponsor, the investigator or the trial sites, have to exclude from the trial; 20. Lack of willingness to storage and disclosure of pseudonymous disease data in the context of the clinical trial; 21. Participation in another clinical trial within previous 30 days and/or anticipated participation in another trial during this study; 22. Inability to fully comprehend and/or perform study procedures in the investigator’s opinion; 23. Persons staying at an institution due to order by a national body or a court of law (in accordance with the German Arzneimittelgesetz §40, Abs. 1, S. 3, Nr. 4); |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint: The primary endpoint is the difference in exercise capacity from baseline to visit 5 as assessed by the 6-minute walking test after initiation of therapy (FCM or placebo/saline) in patients with HFpEF and ID
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary endpoints include the difference in 6-minute-walking distance (in meters) from baseline to visits 3, 4, 6 and 7 respectively; Secondary endpoints: Secondary endpoints include the difference in 6-minute-walking distance (in meters) from baseline to visits 3, 4, 6 and 7 respectively; PGA assessment at visit 3, 4, 5, 6, and 7; change in NYHA functional class from baseline to visit 3, 4, 5, 6, and 7, respectively. Further, improvement of Quality of Life from baseline as well as kidney function and inflammatory parameters will be assessed.Further assessments include differences in plasma levels of blood parameters of kidney function and inflammation, and differences in quality of life from baseline to respective assessment time point as well as the rate of recurrent events of HF hospitalization and death.
Tertiary endpoints (efficacy): Tertiary endpoints are resource use and costs associated with the treatment with IV FCM compared to placebo/saline.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Change in 6min-walking distance to weeks 3, 4, 6 and 7 respectively, adjusted for baseline; - Change in PGA assessment at visit 3, 4, 5, 6, and 7; - Change in NYHA functional class to visit 3, 4, 5, 6, and 7, respectively, adjusted for baseline;
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 67 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 28 |