Using Tadalafil to Treat Severe Pulmonary Hypertension in COPD Patients

Efficacy of Phosphodiesterase Type 5 Inhibitors in Severe Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease

This study tests if the medication Tadalafil can help people with severe pulmonary hypertension caused by COPD feel better and improve their ability to exercise.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 200 (estimated)
• Ages: 18 Years to 85 Years
• Sex: All
• Sponsor: Assistance Publique - Hôpitaux de Paris (Academic / other)
• Locations: 1 site (Le Kremlin-Bicêtre, France)
• Trial ID: NCT05844462 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the efficacy and safety of Tadalafil, an oral phosphodiesterase type 5 inhibitor, in patients suffering from severe pulmonary hypertension due to chronic obstructive pulmonary disease (COPD). It is a randomized, double-blind study where participants will be assigned to receive either Tadalafil or a placebo for 16 weeks. The study aims to assess improvements in symptoms, exercise capacity, and overall clinical outcomes in this patient population. The trial addresses a significant gap in understanding the benefit-risk ratio of PDE5 inhibitors in severe pulmonary hypertension associated with COPD.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 to 85 with severe pulmonary hypertension and COPD, experiencing significant dyspnea.

Not a fit: Patients who have previously received PDE5 inhibitors or other specific pulmonary hypertension treatments in the last three months may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve the quality of life and clinical outcomes for patients with severe pulmonary hypertension due to COPD.

How similar studies have performed: Previous studies have suggested potential benefits of PDE5 inhibitors in COPD patients, but this specific approach is novel and aims to provide more definitive evidence.

Eligibility criteria

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 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,

Exclusion Criteria:

* 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,
* 6-minutes walk distance \< 50 m or patients unable to perform the 6-minutes walk test,
* Exacerbation of the COPD requiring hospitalization in the last 8 weeks before screening,
* COPD with mild (\> 80% predicted value) or severe (FEV1 \<30% predicted value) airflow limitation,
* 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 the study,
* 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 \[defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level \> 35 mIU/mL\],
* 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 cyclase stimulator (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 of priapism
* 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.

Where this trial is running

Le Kremlin-Bicêtre, France

• Kremlin Bicêtre — Le Kremlin-Bicêtre, France, France (Recruiting)

Study contacts

• Study coordinator: David Pr MONTANI, PU-PH

Conditions Pulmonary Hypertension; Chronic Obstructive Pulmonary Disease