Ensayos clínicos

Inclusion Criteria: 

Participants with a physician diagnosis of COPD who meet the following criteria: 

• Current or former smokers with a smoking history of ≥ 10 pack-years.
• Moderate-to-severe COPD (post-bronchodilator FEV1/ forced vital capacity [FVC] ≤ 70% and post-bronchodilator FEV1 % predicted > 30% and ≤ 70%). 
• Medical Research Council (MRC) Dyspnea Scale grade ≥ 2. 
• Patient-reported history of signs and symptoms of chronic bronchitis (chronic productive cough) for 3 months in the year up to screening in the absence of other known causes of chronic cough. 
• Documented history of high exacerbation risk defined as exacerbation history of ≥ 2 moderate* or ≥ 1 severe** within the year prior to inclusion. At least one exacerbation should have occurred while the patient was taking ICS/LAMA/LABA (or LAMA/LABA if ICS is contradicted).
  • *Moderate exacerbations are recorded by the investigator and defined as AECOPD that require either systemic corticosteroids (intramuscular (IM), intravenous, or oral) and/or antibiotics. One of the two required moderate exacerbations has to require the use of systemic corticosteroids.
  • **Severe exacerbations are recorded by the investigator and defined as AECOPD requiring hospitalization or observation > 24 hours in emergency department/urgent care facility.
• Background triple therapy (ICS + LABA + LAMA) for 3 months prior to randomization with a stable dose of medication for ≥ 1 month prior to Visit 1: (Double therapy: LABA + LAMA allowed if ICS is contraindicated).
• Evidence of Type 2 inflammation: Patients with blood eosinophils ≥ 300 cells/microliter at Visit 1.
• Body mass index (BMI) ≥ 16 kg/m^2.
• Male or female.
• Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
  • Not a woman of childbearing potential (WOCBP); OR
  • A WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 12 weeks after the last dose of study intervention.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria: 

• COPD diagnosis for less than 12 months prior to randomization.
• A patient with current diagnosis of asthma or history of asthma according to the 2018 Global Initiative for Asthma (GINA) guidelines or other accepted guidelines.
• Significant pulmonary disease other than COPD (e.g., lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome, etc.) or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts.
• Cor pulmonale, evidence of right cardiac failure.
• Treatment with oxygen of more than 12 hours per day.
• Hypercapnia requiring BiPAP.
• Acute exacerbation of COPD (AECOPD, as defined above in I 02) within 4 weeks prior to or during the screening period.
• Respiratory tract infection within 4 weeks prior to screening, or during the screening period.
• History of, or planned pneumonectomy or lung volume reduction surgery. Patients who are participating in the acute phase of a pulmonary rehabilitation program; i.e., who started rehabilitation < 4 weeks prior to screening.
  • Note: patients in the maintenance phase of a rehabilitation program can be included.
• Diagnosis of α-1 anti-trypsin deficiency.
• Inability to follow the procedures of the study (e.g., due to language problems, psychological disorders) or unable to read, understand and fill out a questionnaire or use an e-Diary without any help.
• Anti-immunoglobulin E (IgE) therapy (omalizumab) within 130 days prior to Visit 1 or any other biologic therapy (including anti-IL5 mAb) or immunosuppressant to treat inflammatory disease or autoimmune disease (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.) as well as other diseases within 2 months or 5 half-lives prior to Visit 1, whichever is longer.
• Exposure to another investigative drug (small molecules as well as monoclonal antibodies) within a time period prior to Visit 1 that is less than 6 months. The minimum interval since exposure to any other (non-antibody) investigative study medication is 30 days prior to Visit 1.
• History of systemic hypersensitivity or anaphylaxis to any biologic therapy, including any excipients.
• Patients receiving medication or therapy that are prohibited as concomitant therapy.
• Patient is the Investigator, or any Sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the study.
• Clinically significant abnormal electrocardiogram (ECG) at randomization that may affect the conduct of the study in the judgment of the investigator, prolonged QTc interval [male > 450 msec, female > 470 msec, Fredericia correction].
• A patient with a history of clinically significant renal, hepatic, cardiovascular, metabolic, neurologic, hematologic, ophthalmologic, respiratory (other than COPD), gastrointestinal, cerebrovascular disease/condition, substance and/or alcohol abuse disorder, active or prior history of malignancy or active malignancy, including lymphoproliferative diseases (except successfully-treated carcinoma in-situ of the cervix, non-metastatic squamous cell or basal cell carcinoma of the skin) within 5 years prior to baseline, or history of or current other significant medical illness or disorder which, in the judgment of the investigator.
• Active tuberculosis or non-tuberculous mycobacterial infection, latent untreated tuberculosis or a history of incompletely treated tuberculosis will be excluded from the study unless it is well documented by a specialist that the patient has been adequately treated and can now start treatment with a biologic agent, in the medical judgment of the investigator and/or infectious disease specialist. Tuberculosis testing will be performed on a country-by-country basis, according to local guidelines if required by regulatory authorities or ethics boards.
• Acute myocardial infarction < 6 months from screening visit.
• TIA or stroke < 6 months from screening visit.
• Hospitalization for any CV or cerebrovascular event < 6 months from screening visit.
• Heart failure NYHA Class III or IV.
• Patients on cardiac medications not on a stable dose during the last 6 months; e.g., antiarrythmics, antihypertensives, and antidiuretics, etc. Dose modification of cholesterol-modifying agents and anticoagulants is allowed.
• Cardiac arrhythmias including paroxysmal (e.g., intermittent) atrial fibrillation are excluded.
• Patients with persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months and controlled with a rate control strategy (i.e., selective beta blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) and stable appropriate level of anticoagulation for at least 6 months may be considered for inclusion.
• Unstable ischemic heart disease or other relevant cardiovascular disorder such as pulmonary embolism, deep vein thrombosis within ≤ 6 months from enrollment that in Investigator's judgment may put the patient at risk or negatively affect the study outcome.
• Patients who are < 80% compliant with controller therapy during screening.
• Previous use of dupilumab.
• Females who are lactating, breastfeeding or who are pregnant.
• Women of childbearing potential (pre-menopausal female biologically capable of becoming pregnant) who:
  • Do not have a confirmed negative serum beta-hCG test at Visit 1 or negative urine pregnancy test at Visit 2;
  • Who are not willing to use one of the acceptable forms of effective contraception for the duration of the study;
  • Postmenopausal women (defined as at least 12 consecutive months without menses) are not required to use additional contraception.
• Diagnosed active parasitic infection (helminthes), suspected or high risk of parasitic infection, unless clinical and (if necessary) laboratory assessments have ruled out active infection before randomization.
• History of HIV infection or positive HIV 1/2 serology at Visit 1.
• Known or suspected history of immunosuppression, including history of invasive opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, penumocystosis, aspergillosis), despite infection resolution; or unusually frequent, recurrent or prolonged infections, per investigator’s judgment.
• Evidence of acute or chronic infection requiring treatment with antibacterials, antivirals, antifungals, antiparasitics, or antiprotozoals within 4 weeks before Visit 1, significant viral infections within 4 weeks before Visit 1 that may not have received antiviral treatment (e.g., influenza receiving only symptomatic treatment).
• Live, attenuated vaccinations within 4 weeks prior to Visit 1 or planned live, attenuated vaccinations during the study.
• Patients with active autoimmune disease or patients using immunosuppressive therapy for autoimmune disease (e.g., inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.).
• Patients with any of the following result at screening:
  • Positive (or indeterminate) HBsAg;
  • Positive IgM HBc Ab; or
  • Positive total HBc Ab confirmed by positive HBV DNA; or
  • Positive HCV Ab confirmed by positive HCV RNA.
• Clinically significant laboratory tests at screening/randomization (Visit 1):
  • Alanine transaminase (ALT) > 3 times upper limit of normal range (ULN);
  • Hemoglobin < 10g /100 mL for male and < 9g/ 100 mL for female;
  • Platelets < 100 000/mm^3;
  • Creatinine ≥ 150 μmol/L.
• Patients on macrolide (e.g., azithromycin) therapy, unless on stable therapy for >12 months.
• Patient who has withdrawn consent before enrollment/randomization.
• Despite screening of the patient, enrollment/randomization is stopped at the study level.