Tadalafil for Severe Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease

Inclusion Criteria:

• Patients ≥ 18 and <85 years at inclusion,

• Dyspnea WHO functional class II to IV,

• Severe precapillary pulmonary hypertension defined by :

• a mean pulmonary artery pressure (mPAP) >20

• associated with normal pulmonary artery wedge pressure (PawP ≤15 mmHg)

• and pulmonary vascular resistance (PVR) >5 WU

• COPD diagnosed according to current international recommendation with persistentairflow limitation defined by post-bronchodilatator Forced expiratory volume in 1second (FEV1) / forced vital capacity (FVC): FEV1/FVC < 0.70,

• Naive patients from PDE5i (sildenafil, tadalafil) PH treatments and who did notreceive other specific PH treatment in the last 3 months (bosentan, ambrisentan,macitentan, riociguat, epoprostenol, treprostinil, iloprost),

• Treatments for COPD need to be stable for at least 1 month before screening visit,

• Patients who fulfill criteria for a supplemental long-term oxygen therapy need to besupplied sufficiently before study entry. The amount of supplemental oxygen and thedelivery method need to be stable for at least 1 month before screening visit,

• Patients who are able to understand and follow instructions and who are able toparticipate in the study for the entire period,

• Patients must have given their written informed consent to participate in the studyafter having received adequate previous information and prior to any study-specificprocedures,

• Affiliation to a social security regime,

Exclusion Criteria:

• Patients with a medical disorder, condition, or history of such that would impairthe patient's ability to participate or complete this study in the opinion of theinvestigator,

• Patients with underlying medical disorders and anticipated life expectancy below 12months (eg active cancer disease with localized and/or metastasized tumor mass),

• PH not due to chronic respiratory diseases (group 1, 2, 4 or 5 of the clinicalclassification of PH),

• Other respiratory diseases: interstitial lung disease, sarcoidosis,lymphangioleiomyomatosis, histiocytosis, or untreated severe sleep apnea disorders,

• 6-minutes walk distance < 50 m or patients unable to perform the 6-minutes walktest,

• Exacerbation of the COPD requiring hospitalization in the last 8 weeks beforescreening,

• COPD with mild (> 80% predicted value) or severe (FEV1 <30% predicted value) airflowlimitation,

• Patients listed for lung transplantation at the time of inclusion,

• Systolic left ventricular dysfunction with left ventricular ejection fraction <40%on echocardiography,

• Patient on AME (state medical aid),

• Participation in another clinical trial during the preceding 3 months and during thestudy,

• Pregnant women, or breast-feeding women, or women with childbearing potential notusing a combination of condoms and a safe and highly effective contraception method (hormonal contraception with implants or oral contraceptives, or intrauterinedevices) and one month after the end of the study, WOCBP include any woman who hasexperienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is notpostmenopausal [defined as amenorrhea ≥ 12 consecutive months; or women on hormonereplacement therapy (HRT) with documented serum follicle stimulating hormone (FSH)level > 35 mIU/mL],

• Patient under guardianship or curatorship

Non-inclusion criteria related to treatment by tadalafil:

• Contraindication to tadalafil:

• Severe renal failure (creatinine clearance < 30 mL/min/1,73 m2)

• Severe liver cirrhosis Child-Plugh C

• Severe systemic hypotension <90/50

• Recent myocardial infarction <90 days

• Medical history of anterior ischemic optic neuropathy

• Hypersensitivity to tadalafil or any of the excipients

• Concomitant use of potent CYP3A4 inhibitors or inducers, soluble guanylate cyclasestimulator (riociguat), other PDE5 inhibitors or nitrates or doxazosin

• Cardiovascular diseases:

• Clinically significant aortic and mitral valve disease

• Pericardial constriction

• Restrictive or congestive cardiomyopathy

• Significant left ventricular dysfunction

• Life-threatening arrhythmias

• Symptomatic coronary artery disease

• Uncontrolled hypertension.

• Angulation of the penis, cavernosal fibrosis, Peyronie's disease or history ofpriapism

• Pulmonary or upper respiratory infection requiring antibiotics, or pulmonaryembolism in the last 4 weeks before screening

• Participation in a respiratory rehabilitation program within the 4 weeks prior toscreening or scheduled during the study period

• Right heart failure necessitating catecholamine support within the 4 weeks prior toscreening.