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Tadalafil for Severe Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease (ERASE PH-COPD)

Primary Purpose

Pulmonary Hypertension, Chronic Obstructive Pulmonary Disease

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Tadalafil
Placebo
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Hypertension

Eligibility Criteria

19 Years - 79 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients >18 and <80 years at inclusion, Dyspnea WHO functional class II to IV, Severe precapillary pulmonary hypertension defined by : a mean pulmonary artery pressure (mPAP) >35 mmHg or mPAP ≥25 mmHg with a cardiac index < 2.5 L/min/m² associated with normal pulmonary artery wedge pressure (PawP ≤15 mmHg) and pulmonary vascular resistance (PVR) >3 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 specific PH treatments (bosentan, ambrisentan, macitentan, sildenafil, tadalafil, 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 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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    Experimental arm

    Control arm

    Arm Description

    Oral Tadalafil 40 mg or Tadalafil 20 mg [(mild or moderate chronic renal failure or liver cirrhosis (Child-Pugh A or B)].

    Oral Placebo 40 mg or Placebo 20 mg [(mild or moderate chronic renal failure or liver cirrhosis (Child-Pugh A or B)].

    Outcomes

    Primary Outcome Measures

    6 minute Walk
    The distance cover in meter during a 6-minute walk at week 16 post-randomization for patients treated with tadalafil compared to placebo

    Secondary Outcome Measures

    Full Information

    First Posted
    April 25, 2023
    Last Updated
    May 25, 2023
    Sponsor
    Assistance Publique - Hôpitaux de Paris
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05844462
    Brief Title
    Tadalafil for Severe Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease
    Acronym
    ERASE PH-COPD
    Official Title
    Efficacy of Phosphodiesterase Type 5 Inhibitors in Severe Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    May 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    September 2023 (Anticipated)
    Primary Completion Date
    September 2025 (Anticipated)
    Study Completion Date
    September 2026 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Assistance Publique - Hôpitaux de Paris

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    ERASE PH-COPD is a randomized double-blind study, with 2 parallel groups. Patients with severe pulmonary hypertension due to chronic obstructive pulmonary disease, will be randomly assigned to receive Tadalafil orally or placebo.
    Detailed Description
    Pulmonary hypertension (PH) is a frequent complication of chronic parenchymal lung diseases particularly in chronic obstructive pulmonary disease (COPD) and represents one of the major cause of all causes of PH. When present, PH contributes to more severe symptoms; exercise intolerance and can lead to right heart failure, which portends a worse prognosis and an increased mortality. Mechanisms of severe PH in chronic respiratory diseases are complex and include rarefaction of vascular bed, endothelial dysfunction and exaggerated pulmonary arterial remodeling. In patients with idiopathic pulmonary arterial hypertension (PAH), targeted medical therapies, including oral phosphodiesterase type 5 inhibitors (PDE5i), improve endothelial cell dysfunction, have vasodilatory and anti-proliferative effects on the pulmonary vasculature, reduce the right ventricular afterload and improve symptoms, exercise capacity, and clinical outcomes in randomized trials. Several studies suggested a potential effect of PDE5i in COPD on dyspnea, exertional capacity and quality of life. However, these results were based on including small number of patients with heterogenous severity of lung disease and usually without complete hemodynamic evaluation. Data are lacking regarding the benefit/risk ratio of these treatments in the context of severe PH due to COPD. The main objective to this randomized controlled trial (16 weeks) is to evaluate the efficacy and safety of an oral PDE5i, tadalafil, in patients with severe PH due to COPD.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Pulmonary Hypertension, Chronic Obstructive Pulmonary Disease

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantCare ProviderInvestigator
    Allocation
    Randomized
    Enrollment
    200 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Experimental arm
    Arm Type
    Experimental
    Arm Description
    Oral Tadalafil 40 mg or Tadalafil 20 mg [(mild or moderate chronic renal failure or liver cirrhosis (Child-Pugh A or B)].
    Arm Title
    Control arm
    Arm Type
    Placebo Comparator
    Arm Description
    Oral Placebo 40 mg or Placebo 20 mg [(mild or moderate chronic renal failure or liver cirrhosis (Child-Pugh A or B)].
    Intervention Type
    Drug
    Intervention Name(s)
    Tadalafil
    Other Intervention Name(s)
    Talmanco
    Intervention Description
    Oral Tadalafil
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    Oral Placebo
    Primary Outcome Measure Information:
    Title
    6 minute Walk
    Description
    The distance cover in meter during a 6-minute walk at week 16 post-randomization for patients treated with tadalafil compared to placebo
    Time Frame
    16 weeks

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    19 Years
    Maximum Age & Unit of Time
    79 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Patients >18 and <80 years at inclusion, Dyspnea WHO functional class II to IV, Severe precapillary pulmonary hypertension defined by : a mean pulmonary artery pressure (mPAP) >35 mmHg or mPAP ≥25 mmHg with a cardiac index < 2.5 L/min/m² associated with normal pulmonary artery wedge pressure (PawP ≤15 mmHg) and pulmonary vascular resistance (PVR) >3 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 specific PH treatments (bosentan, ambrisentan, macitentan, sildenafil, tadalafil, 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 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
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    David Pr MONTANI, PU-PH
    Phone
    01 45 21 78 85
    Ext
    +33
    Email
    david.montani@aphp.fr

    12. IPD Sharing Statement

    Learn more about this trial

    Tadalafil for Severe Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease

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