Tadalafil for Severe Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease

Prior treatment

• Exacerbation of the COPD requiring hospitalization in the last 8 weeks before screening,
• Patients listed for lung transplantation at the time of inclusion,
• Concomitant use of potent CYP3A4 inhibitors or inducers, soluble guanylate cyclase stimulator (riociguat), other PDE5 inhibitors or nitrates or doxazosin
• Pulmonary or upper respiratory infection requiring antibiotics, or pulmonary embolism in the last 4 weeks before screening
• Participation in a respiratory rehabilitation program within the 4 weeks prior to screening or scheduled during the study period
• Right heart failure necessitating catecholamine support within the 4 weeks prior to screening.

Other illness

• Patients with a medical disorder, condition, or history of such that would impair the patient's ability to participate or complete this study in the opinion of the investigator,
• Patients with underlying medical disorders and anticipated life expectancy below 12 months (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 clinical classification of PH),
• Other respiratory diseases: interstitial lung disease, sarcoidosis, lymphangioleiomyomatosis, histiocytosis, or untreated severe sleep apnea disorders,
• 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 of priapism

Lab values

• Systolic left ventricular dysfunction with left ventricular ejection fraction \<40% on echocardiography,
• Pregnant women, or breast-feeding women, or women with childbearing potential not using a combination of condoms and a safe and highly effective contraception method (hormonal contraception with implants or oral contraceptives, or intrauterine devices) and one month after the end of the study, WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal \[defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level \> 35 mIU/mL\],
• 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

Other

• 6-minutes walk distance \< 50 m or patients unable to perform the 6-minutes walk test,
• COPD with mild (\> 80% predicted value) or severe (FEV1 \<30% predicted value) airflow limitation,
• Patient on AME (state medical aid),
• Participation in another clinical trial during the preceding 3 months and during the study,
• Patient under guardianship or curatorship
  • Non-inclusion criteria related to treatment by tadalafil:

• 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 persistent airflow limitation defined by post-bronchodilatator Forced expiratory volume in 1 second (FEV1) / forced vital capacity (FVC): FEV1/FVC \< 0.70,
• Naive patients from PDE5i (sildenafil, tadalafil) PH treatments and who did not receive 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 be supplied sufficiently before study entry. The amount of supplemental oxygen and the delivery 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 to participate in the study for the entire period,
• Patients must have given their written informed consent to participate in the study after having received adequate previous information and prior to any study-specific procedures,
• Affiliation to a social security regime,