Combined post- and pre-capillary pulmonary hypertension and heart failure with preserved ejection fraction MedDRA version: 20.0 Level: LLT Classification code 10077732 Term: Pulmonary hypertension WHO functional class II System Organ Class: 100000004855 MedDRA version: 20.0 Level: LLT Classification code 10024106 Term: Left heart failure System Organ Class: 100000004849
Conditions
Interventions
Trade Name: Tadafil, 20mg
Product Name: Tadalafil, 20mg
Pharmaceutical Form: Tablet
INN or Proposed INN: Tadalafil
CAS Number: 171596-29-5
Concentration unit: mg/g milligram(s)/gram
Concentration type
Sponsors
Philipps-Universität Marburg
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed written informed consent form 2. Capability and willingness to comply with study procedures 3. Adult patients = 18 years with a diagnosis of heart failure with preserved ejection fraction and combined post- and pre- capillary pulmonary hypertension assessed by right heart catheterization during the past 12 months 4. Diagnosis of HFpEF according to the 2016 heart failure guidelines of the European Society of Cardiology assessed at screening: - History and/or clinical signs of heart failure - Left ventricular ejection fraction =50% - Elevated levels of BNP or NT-proBNP (i.e., =75 pg/,ml or = 250 pg/ml, respectively) - At least one of the following criteria, (i) relevant structural heart disease (left ventricular hypertrophy, i.e. left ventricular septal thickness or posterior wall thickness = 1.1 cm, and/or left atrial enlargement i.e. left atrial volume >58 ml in males or >52 ml in females or left atrial volume index =28 ml/m2, or LA area >20 cm2, or LA diameter >4.0 cm in males or >3.8 cm in females), (ii) echocardiographic signs of diastolic dysfunction 5. Hemodynamic criteria: - Pulmonary arterial wedge pressure (PAWP) or left ventricular enddiastolic pressure (LVEDP) >15 mmHg, and - Mean pulmonary artery pressure (PAPm) =25 mmHg, and - Pulmonary vascular resistance (PVR) > 3 WU (240 dyn·s·cm-5) 6. NYHA functional class III or IV, or functional class II with at least one heart failure-associated hospitalization during the past 12 months 7. Patients on optimized doses of diuretics resulting in the absence of clinically relevant fluid retention 8. Ability to perform the 6MWT. Patients with comorbidities affecting the patient's ability to perform the 6MWT but otherwise eligible can be enrolled into the study. These patients will be marked in the CRF and will be excluded from the 6MWT analysis. 9. Patients with renal function impairment can be enrolled as long as they do not require renal replacement therapy. 10. Patients receiving supplemental oxygen therapy may be included as long as they achieve a resting oxygen saturation =92% with an oxygen flow rate = 4L/min. 11. Negative serum/urine pregnancy test in women of childbearing potential 12. Patients with reproductive potential must agree to maintain highly effective methods of contraception by practicing abstinence or by using at least two methods of birth control from the date of consent through the individual end of the study. If abstinence could not be practiced, a combination of hormonal contraceptive (oral, injectable, or implants) and a barrier method (condom, diaphragm with a vaginal spermicidal agent) has to be used Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 186 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 186
Exclusion criteria
Exclusion criteria: 1. Decompensated heart failure at screening Patients with decompensated heart failure cannot be included, but can be re-assessed after recompensation 2. Symptomatic coronary heart disease, including percutaneous coronary intervention within the past 3 months or coronary artery bypass surgery within the past 6 months 3. Myocardial infarction during the previous 90 days. 4. Primary restrictive cardiomyopathy or hypertrophic obstructive cardiomyopathy 5. Constrictive pericarditis 6. Uncontrolled, severe (life-threatening) arrhythmias 7. Hemodynamically relevant aortic or mitral valve disease 8. Severe aortic valve regurgitation or moderate or severe aortic valve stenosis 9. Severe mitral regurgitation or moderate or severe mitral stenosis 10. Severe restrictive or obstructive lung disease indicated by a total lung capacity (TLC) 3 ULN 17. Patients with a non-arteritic anterior ischemic optic neuropathy (NAION) 18. Hypersensitivity to the active substance (tadalafil) or one the ingredients (see current SmPC) 19. Systemic hypotension with blood pressure 180/110 mmHg 21. Resting heart rate 115/min 22. Treatment with nitrates, NO donors or soluble guanylate cyclase stimulators (e.g. riociguat), endothelin receptor antagonists or prostacyclin analogues or prostacyclin receptor agonists within 3 months prior to study entry or during study 23. Concomitant therapy with doxazosine 24. Concomitant therapy with strong cytochrome P450 inhibitors, such as ketoconazole or itraconazole or P450 inducer, such as Rifampicin 25. Concomitant therapy with any PDE5 inhibitor to treat erectile dysfunction 26. Breastfeeding 27. Participation in another clinical study with other investigational drugs within 30 days prior to randomization
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate that treatment with the phosphodiesterase-5 inhibitor tadalafil at a target dose of 40 mg reduces the combined outcome measure of heart failure-related hospitalization and all-cause mortality in patients with combined post- and pre-capillary pulmonary hypertension associated with heart failure with preserved ejection fraction ;Secondary Objective: Secondary objectives:To assess: 1.Cumulative number of primary composite events of cardiovascular (CV) death and total (first and recurrent) HF hospitalizations 2.Satisfactory clinical response defined as absence of death or cardiac hospitalizations (adjudicated) and improvement compared to baseline in either NYHA functional class (FC), 6-minute walking distance (by at least 10%) or both 2.Time from randomization to clinical worsening 3. EFS in subgroups of patients with a) DPG =7 mmHg, b) PAC 30 m from baseline versus proportion of patients with clinical worsening (as defined above) 5.Changes -6-minute walking distance -NYHA functional class -serum NT-proBNP -serum bilirubin -GFR -quality of life (QoL) 11.Health economics 12. safety assessment ;Primary end point(s): Primary efficacy endpoint: Event-free survival (EFS) ;Timepoint(s) of evaluation of this end point: Time to event is defined as time from randomization to first HF-associated hospitalization (adjudicated) or death from any cause (whatever occurs first). Survivors without HF-associated hospitalization will be censored on the last date they were known to be alive. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): See secondary objectives ;Timepoint(s) of evaluation of this end point: after 24 weeks and inidividual study termination | — |
Countries
Germany
Contacts
Public ContactSusanne Harnisch
Kooridinierungszentrum für Klinische Studien Marburg
Outcome results
None listed