Study, to investigate, if Tadalafil, a Phosphodiesterase-5 inhibitor, is benficial for the treatment of pulmonary hypertension due to left heart failure.

Phase 1

• Conditions: Combined post- and pre-capillary pulmonary hypertension and heart failure with preserved ejection fraction; MedDRA version: 20.0Level: LLTClassification code 10077732Term: Pulmonary hypertension WHO functional class IISystem Organ Class: 100000004855; MedDRA version: 20.0Level: LLTClassification code 10024106Term: Left heart failureSystem Organ Class: 100000004849; Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

• Registration Number: EUCTR2017-003688-37-DE
• Lead Sponsor: Philipps-Universität Marburg

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2018-05-02
• Last Update Posted: 25 April 2022

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 372

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

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) <70% of the predicted value or a forced expiratory volume in 1 second (FEV1) <50% of the predicted value
11.Comorbidities that according to the investigator will limit the life expectancy independently from the disease under study (Life expectancy < 1 year)
12.Transient ischaemic attack or stroke within 3 months prior to screening
13.Body mass index =50 kg/m2 at screening
14.Previous treatment with phosphodiesterase-5 inhibitors for pulmonary hypertension
15.Liver cirrhosis Child-Pugh class C
16.Liver dysfunction as indicated by serum bilirubin levels >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 < 90/50 mmHg at screening
20.Uncontrolled hypertension, i.e. RR >180/110 mmHg
21.Resting heart rate <48/min and >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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified