| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced systolic chronic heart failure NYHA class III-IV and EF ≤ 40% or NYHA class II and EF ≤ 30% |
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| E.1.1.1 | Medical condition in easily understood language |
| Advanced systolic chronic heart failure |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008908 |
| E.1.2 | Term | Chronic heart failure |
| E.1.2 | System Organ Class | 100000004849 |
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| 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 |
| To demonstrate in a large and simple clinical trial-approach that digitoxin (target serum concentrations preferably 8 - 18 ng/ml (10.5 – 23.6 nmol/l)) on top of standard of care is superior in reducing a composite of all-cause mortality and hospitalization for worsening heart failure (whichever occurs first) in patients with advanced systolic chronic heart failure (NYHA class III-IV and EF ≤ 40% or NYHA class II and ≤ 30%) to a greater extent compared to standard care plus placebo. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study 1:
Title: The effect of digitoxin on atrial and ventricular arrhythmia
Version of synopsis of sub-study: 1.5, 16.07.2020
Objective: The purpose of this sub-study is to investigate the hypothesis that digitoxin therapy has no influence on the occurrence of atrial tachyarrhythmia (AT) or ventricular tachyarrhythmia (VT)
Sub-study 2:
Title: DIGIT-HF Sub-study: The effect of digitoxin on endothelial function in heart failure with reduced ejection fraction
Version of synopsis of sub-study: Vs 1.4, 16.07.2020
Objectives:
1. Investigation whether digitoxin has an influence on endothelial function.
2. To investigate potential relationships between demographic and clinical factors and biomarkers of endothelial function in patients with chronic heart failure.
Sub-study 3:
Title: Effect of digitoxin on stress capacity
Version of synopsis of sub-study: Vs 2.0, 16.07.2020
Objectives:
primary: Demonstration that digitoxin improves cardiopulmonary performance in severely heart failure patients
secondary: Investigation of the influence of digitoxin on hemodynamics in patients receiving regular right heart catheterisation (RHK) as part of an evaluation in severe heart failure.
Sub-study 4:
Titel: Effect of digitoxin on cardiac function and remodeling
Version of synopsis of sub-study: Vs 2.0, 16.07.2020
Objectives:
Primary: Proof that digitoxin positively affects left ventricular remodeling, i.e. reducing the end-systolic LV index
Secondary: Investigation of the influence of digitoxin on left ventricular function and right heart function |
Substudie 1:
Titel: Effekt von Digitoxin auf die atriale und ventrikuläre Arrhythmielast
Version der Synopse der Substudie: Vs 1.5, 16.07.2020
Studienziel:
Es soll in dieser Substudie die Hypothese untersucht werden, dass eine Therapie mit Digitoxin keinen Einfluss auf das Auftreten von atrialen Tachyarrhythmien (AT) oder ventrikulären Tachyarrhythmien (VT) hat
Substudie 2:
Titel: Die Wirkung von Digitoxin auf die Endothelfunktion bei Herzinsuffizienz mit verringerter Ejektionsfraktion
Version der Synopse der Substudie: Vs 1.4, 16.07.2020
Studienziele:
1.Untersuchung, ob Digitoxin einen Einfluss auf die Endothelfunktion hat.
2. Untersuchung potenzieller Beziehungen zwischen demographischen und klinischen Faktoren und Biomarker zur Endothelfunktion bei Patienten mit chronischer Herzinsuffizienz
Substudie 3:
Titel: Effekt von Digitoxin auf die Belastungskapazität
Version der Synopse der Substudie: Vs 2.0, 16.07.2020
Studienziele:
1. Nachweis, dass Digitoxin die kardiopulmonale Leistungsfähigkeit von schwer herzinsuffizienten Patienten verbessert
2. Untersuchung des Einflusses von Digitoxin auf die Hämodynamik bei denjenigen Patienten, die im Rahmen einer Evaluierung bei schwerer Herzinsuffizienz regulär Rechtsherzkatheteruntersuchungen (RHK) erhalten
Substudie 4:
Titel: Effekt von Digitoxin auf kardiale Funktion und Remodeling
Version der Synopse der Substudie: Vs 2.0, 16.07.2020
Studienziele:
Primär: Nachweis, dass Digitoxin das linksventrikuläre Remodeling positiv beeinflusst, d.h. den endsystolischen LV-Index reduziert
Sekundär: Untersuchung des Einflusses von Digitoxin auf die linksventrikuläre Funktion sowie die Rechtsherzfunktion
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| E.3 | Principal inclusion criteria |
1. Signed written informed consent and willingness to comply with treatment and follow-up
2. Male or female patients age ≥ 18 years at day of inclusion
3. Patients capable of understanding the investigational nature, potential risks and benefits of the clinical trial
4. Patients with chronic heart failure NYHA class III-IV and a ventricular ejection fraction of EF ≤ 40%* or patients with heart failure NYHA class II and EF ≤ 30 %*
* determined at screening by echocardiography or cardiac magnetic resonance tomography or within 8 weeks prior to study inclusion by left-ventricular angiography, echocardiography, radionuclide ventriculography, cardiac magnetic resonance tomography
AND
an evidence based heart failure therapy at least for six months upon discretion of the treating physician
5. Women without childbearing potential defined as one or more of following:
• Women at least 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral oophorectomy with or without hysterectomy at the day of inclusion
• Women ≥ 50 years of age at the day of inclusion who have been postmenopausal since at least 1 year
• Women < 50 years and in postmenopausal state ≥ 1 year with serum FSH > 40 IU/l (proved by a second laboratory assessment after 4 weeks)
OR
Women of childbearing potential who have a negative hCG pregnancy test and agree to meet one of the following criteria from the time of screening/baseline, during the study and for a period of 40 days following the last administration of study medication:
• Correct use of reliable contraception methods. This includes hormonal contraceptive (oral contraceptives, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release) or an intrauterine device (IUD/IUS) or a barrier method of contraception such as condom or occlusive cap (diaphragm or cervical/vault caps) with spermicide (foam/gel/film/cream/suppository)
• True abstinence (periodic abstinence and withdrawal are not acceptable methods of contraception)
• Sexual relationship only with female partners and/or sterile male partners
OR
Men
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| E.4 | Principal exclusion criteria |
1. Recent (< 2 months ago): myocardial infarction, coronary revascularization, surgery or catheter intervention for valvular heart disease, acute coronary syndrome, stroke or cerebral ischemia, start of heart failure device therapy potentially improving left ventricular ejection fraction or heart failure symptoms (e.g. cardiac resynchronization therapy (CRT), cardiac contractility modulation (CCM), baroreflex-activation therapy (BAT))
2. Scheduled surgery or catheter intervention for valvular heart disease, scheduled coronary revascularization or scheduled heart failure device therapy potentially improving left ventricular ejection fraction or heart failure symptoms (e.g. cardiac resynchronization therapy (CRT), cardiac contractility modulation (CCM), baroreflex-activation therapy (BAT))
3. Active myocarditis
4. Complex congenital heart disease; this does not include: mild-moderate valve disease, uncomplicated shunts (isolated patent foramen ovale, small atrial or ventricular septum defects without associated lesions), repaired secundum or sinus venosus atrial septal defects or ventricular septal defects without residua, previously ligated or occluded ductus arteriosus
5. High-urgency listing for heart transplantation or scheduled therapy with left ventricular assist device (LVAD)
6. Heart rate < 60 b.p.m. (except if functional CRT in place)
7. SA-/AV-block > I°, sick sinus syndrome or carotis sinus syndrome (except if pace-maker protected)
8. Proven or suspected accessory, atrio-ventricular pathways (e.g. WPW-syndrome)
9. History of symptomatic or sustained (≥ 30 s) ventricular arrhythmia unless a cardioverter/defibrillator implanted
10. Current ventricular tachycardia or fibrillation (this means patients presenting with a running ventricular tachycardia or fibrillation. If ventricular arrhythmias are terminated and a cardioverter/defibrillator is implanted inclusion is allowed according to point 9.)
11. Hypertrophic obstructive cardiomyopathy (idiopathic subaortic stenosis)
12. Cor pulmonale
13. Constrictive pericarditis
14. Thoracic aortic aneurysm (defined as diameter ≥ 45 mm)
15. Concomitant severe liver and renal disease
16. Persistent hypokalaemia (< 3.2 mM)
17. Hypercalcemia or hypomagnesemia, if clinically suspected and verified by laboratory testing (e. g. hyperpara-thyroidism, neoplasia induced hypercalcemia, signs of neuromuscular hyperexcitability)
18. Present (within 6 weeks before baseline/day 0 visit) and continuous treatment with Amiodarone (Single or short-term (up to 3 days), not continuous administration of amiodarone immediately before or during study treatment are acceptable)
19. Scheduled direct current cardioversion (DCC) in the next 24 h (e. g. patients not on cardiac glycosides with new onset of atrial fibrillation. Patients already included and on treatment with IMP can continue IMP and study when scheduled for DCC)
20. Presence of both treatment with cardiac glycosides and atrial fibrillation
21. Simultaneous intravenous treatment with calcium salts
22. Evidence of cardiac glycosides intolerance or known hypersensitivity to any component of investigational medicinal products
23. Suspected intoxication with cardiac glycosides
24. Unlikely compliance with protocol requirements
25. Pregnant and lactating women
26. Use of other investigational drugs or devices at the time of enrollment, or within 30 days prior to enrollment or 5 half-lives for investigational drugs, whichever is longer
27. Life expectancy < 12 month (e.g. due to active cancer)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Composite endpoint of all-cause mortality and hospital admission for worsening heart failure (whatever occurs first)
Admission for worsening heart failure is defined by presence of the following points together:
1.) Worsening of heart failure based on clinical judgment (presence of heart failure symptoms) by the treating physician.
2.) hospital stay overnight
3.) i.v.-treatment with diuretics or vasoactive substances (e. g. nitroglycerine) or inotropes (e. g. dobutamine)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| week 6, week 12, month 6 and thereafter every 6 months until end of IMP treatment at termination visit |
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| E.5.2 | Secondary end point(s) |
Key secondary endpoints:
All-cause mortality, hospital admission for worsening heart failure, (recurrent) hospital admission for worsening heart failure
Ohter secondary endpoints:
Cardiovascular mortality, death from heart failure, any non-cardiovascular death, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, any cardiovascular hospitalization, hospital admission for any cause, implantation of a cardioverter-defibrillator, implantation of a cardiac-resynchronisation device, implantation of a pacemaker, sudden cardiac death, change in functional capacity assessed by NYHA class.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| week 6, week 12, month 6 and thereafter every 6 months until end of IMP treatment at termination visit |
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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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | 44 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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