A Randomised, Double-blind, Placebo-controlled, Parallel Group, Multicentre, Phase III Study to Evaluate the Efficacy and Safety of Tezepelumab in Adult Participants with Moderate to Very Severe Chronic Obstructive Pulmonary Disease (EMBARK)

AstraZeneca AB17 个研究点分布在 1 个国家目标入组 990 人开始时间: 2025年5月19日最近更新: 2025年8月5日

试验速览

阶段: 3 期
状态: 尚未招募
发起方: AstraZeneca AB
入组人数: 990
试验地点: 17
主要终点: To compare the effect of tezepelumab with placebo on moderate or severe COPD exacerbations in participants with moderate to very severe COPD

研究概览研究设计入排标准结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

Treatment options for COPD remain largely limited toBDs and/or ICS (Calderon et al 2023). Despite adequate treatment with optimisedmaintenance inhaled therapy, approximately 30 to 40% of patients continue tohave moderate or severe exacerbations (Müllerová et al 2017). Additionaltherapies such as azithromycin, and the phosphodiesterase-4 inhibitor,roflumilast, are underutilised due to side effects (GOLD 2024). Hence, there isstill an unmet medical need in the growing population of COPD patients whocontinue to have exacerbations despite current COPD therapies.

Overall,tezepelumab420 mg Q4W was well tolerated in patients with COPD, and no new safety concernswere identified compared to its known safety profile from asthma studies.

Althoughthe 210 mg Q4W dose regimen was not studied in COPD, a higher dose of 420 mgwas shown to be well tolerated in the COPD patient population. In addition, the210 mg dose has also been shown to be well tolerated and efficacious inpatients with severe asthma. There are no Important Identified Risks fortezepelumab. Although no causal relationship to tezepelumab has beenestablished during the development of tezepelumab in asthma, the following areidentified as Important Potential Risks: serious infections,serious cardiac events and malignancies, and Potential Risk: serioushypersensitivity reactions, all of which can be managed through medicalpractices. AZ will continue to manage any risks through a collection of datafrom clinical studies, post-marketing data, and routine pharmacovigilance andrisk minimisation activities, as appropriate

研究设计

研究类型: Interventional
分配方式: Stratified block randomization
盲法: Participant and Investigator Blinded

入排标准

年龄范围: 40.00 Year(s) 至 80.00 Year(s)（—）
性别: All

入选标准

•Age 1Adult participants 40 to 80 years of age at the time of signing the informed consent. 2Documented physician-diagnosed COPD for at least 12 months before Visit
•3A post-BD FEV1/FVC less than 0.70 and a post-BD FEV1 greater than or equal to 20% and less than or equal to 70% of the predicted normal value during screening. 4Documented regular dose of triple (ICS+LABA+LAMA) or dual (LABA+LAMA, ICS+LABA, ICS+LAMA) inhaled therapy for at least 3 consecutive months before Visit
•5Documented history reater than or equal to 2 moderate1 or reater than or equal to 1 severe2 COPD exacerbations within 12 months before Visit
•At least 1 of the 2 moderate exacerbations must have been treated with SCS. 6EOS greater than or equal to 150 cells per microliter during the screening period. 7CAT total score reater than or equal to 15 at Visit
•8Current or former smokers (with smoking cessation reater than or equal to 6 months before Visit 1) have a history of at least 10 pack-years of tobacco smoking (1 pack year = 20 cigarettes smoked per day for 1 year). 9Body weight reater than or equal to 40 kg at Visit
•10Participants not of childbearing potential are defined as participants who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomisation without an alternative medical cause. The following age-specific requirements apply.
•Women less than 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and FSH levels in the postmenopausal range.
•Women reater than or equal to 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment PoCBP must use one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of company 1% per year when used consistently and correctly. PoCBP who are sexually active with a non- sterilised partner must agree to use one highly effective method of birth control as definedbelow, from screening throughout the study and until at least 16 weeks after the final dose of IP. Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception. Female condom and male condom should not be used together.
•Highly effective birth control methods include: Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the participant (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments) [(periodic abstinence eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to study intervention, and withdrawal are not acceptable methods of contraception], a vasectomised partner, Implanon, bilateral tubal occlusion, intrauterine device/levonorgestrel intrauterine system, Depo-Provera™ injections, oral contraceptive associated with inhibition of ovulation, and Evra Patch, Xulane, or NuvaRing. Informed Consent 11Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. 12Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, or analysis. 13Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports the Genomic Initiative. Inclusion Criteria Re-confirmation Before Randomisation reater than or equal to 70% compliance with participant s maintenance COPD therapy within 2 weeks immediately before Visit 2.

排除标准

•Participants are excluded from the study if any of the following criteria apply: Medical Conditions 1.Clinically important pulmonary disease other than COPD (eg, active lung infection, clinically significant bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency and primary ciliary dyskinesia) or another diagnosed pulmonary or systemic disease that is associated with elevated peripheral EOS (eg, allergic bronchopulmonary aspergillosis/mycosis, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome).
•2.Radiological findings suggestive of a respiratory disease other than COPD that is significantly contributing to the participant s respiratory symptoms.
•Radiological findings of pulmonary nodules suspicious for lung cancer, as per applicable guidance, (eg, ACR Lung-RADS v2022, (Christensen et al 2024)) without appropriate follow up before Visit
•3.Radiological findings suggestive of acute infection.
•4.Current physician diagnosed asthma according to the Global Initiative for Asthma (GINA 2024 and onwards versions) guidelines or other accepted guidelines, past physician diagnosed asthma including paediatric asthma, or asthma-COPD overlap syndrome.
•5.Any unstable disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, immune, psychiatric, or major physical/or cognitive impairment that is not stable in the opinion of the investigator or the sponsor and/or could: a.Affect the safety of the participant throughout the study b.Influence the findings of the study or their interpretation c.Impede the participant s ability to complete the entire duration of the study and/or comply with the study visit schedule and procedures.
•6.Unstable cardiovascular disorder (including but not limited to ischemic heart disease, arrhythmia, cardiomyopathy, severe right and/or left heart failure (NYHA class IV)), renal failure, uncontrolled hypertension, as defined by the Investigator, or any other relevant cardiovascular disorder or ECG abnormality that in the Investigator s judgment may put the participant at risk or negatively affect the outcome of the study.
•7.Acute upper or lower respiratory infection requiring antibiotics or systemic antiviral medication within 2 weeks before Visit 1 (based on the last day of antibiotic/antiviral treatment, whichever occurred later).
•Lower respiratory infection requiring hospitalisation less than 4 weeks before Visit 1 (based on the date of discharge from hospital).
•8.COPD exacerbation treated with SCS and/or antibiotics within 2 weeks before Visit 1 (based on the last dose of corticosteroids or antibiotics, whichever occurred later), or/and requiring hospitalisation for COPD within 4 weeks before Visit 1 (based on the date of discharge from hospital).
•9.A helminth parasitic infection within 6 months before Visit 1 that has not been treated with, or has failed to respond to, the SoC therapy, or diagnosed during the screening period.
•10.Immunodeficiency disorder including a positive HIV test before Visit 1 or during the screening period.
•11.Tuberculosis requiring treatment within the 12 months before Visit
•12.Anaphylaxis or documented immune complex disease (Type III hypersensitivity reactions) following any biologic therapy.
•13.Chronic alcohol or drug abuse within 12 months before Visit 1 or during screening, which may compromise the interpretation of the study data as judged by investigator.
•14.Major surgery within 8 weeks before Visit 1 or planned surgical procedures requiring general anaesthesia or hospitalisation for greater than 1 day during the study.
•15.Malignancy, current or past (within 5 years before Visit 1), except for basal cell carcinoma, localised squamous cell carcinoma of the skin, or in situ carcinoma of the cervix provided when a curative therapy was completed at least 12 months before Visit
•Prior Concomitant Therapy 16.Past or planned partial or total lung volume reduction (single lobe or segmentectomy is acceptable).
•Surgical or endoscopic (eg, valves) lung volume reduction within 6 months before Visit 1 or a planned procedure.
•17.Treatment with systemic immunosuppressive/immunomodulating medications including maintenance use of SCS within the last 12 weeks or 5 half-lives before Visit 1 or during the screening for other reasons than COPD exacerbation.
•Expected need for chronic use during the study for any reason.
•18.LTOT with signs and/or symptoms of cor pulmonale and/or right ventricular failure, or LTOT greater than 4.0 litres/minute (L/min) at rest or an oxyhaemoglobin saturation less than 89% despite LTOT.
•19.Use, or need for chronic use, of any non-invasive positive pressure ventilation device.
•Stable use of non-invasive ventilation for the treatment of Obstructive Sleep Apnoea is permitted.
•20.Treatment with maintenance allergen-specific immunotherapy initiated less than 30 days before Visit
•22.Treatment with any marketed respiratory biologic or investigational biologic within 4 months or 5 half-lives before randomisation, whichever is longer.
•Note: Treatment with marketed ocular biologics is allowed.
•Other marketed biologics that are not likely to interfere with the safety assessment and/or efficacy of tezepelumab might be allowed upon a prior AZ study physician/delegate approval.
•23.Receipt of immunoglobulin or blood products within 30 days before randomisation.
•24.Receipt of live attenuated vaccines 30 days before first IP administration.
•25.Receipt of any COVID-19 vaccine within 28 days before first IP administration.
•27.Concurrent enrolment in another IP-related interventional clinical trial.
•28.Previous receipt of tezepelumab.
•A participant randomised to the placebo arm in previous tezepelumab studies may be allowed to participate following agreement with AZ study physician/delegate.
•29.Involvement in the planning and/or conduct of the study (applies to AZ staff and/or site staff), or participants employed by or relatives of the employees of the site or sponsor.
•Diagnostic Assessments 30.Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening, which, in the opinion of the Investigator, may put the participant at risk, because of his/her participation in the study, or may influence the results of the study, or the participant s ability to complete the entire duration of the study.
•31.Evidence of active liver disease, including jaundice or AST, ALT, or ALP greater than twice the ULN (laboratory results during screening and/or before first dose).
•32.Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C.
•Participants with a history of hepatitis B vaccination without history of hepatitis B are allowed to enrol.
•Genetic Research Exclusion Criteria 33.Non-leukocyte-depleted whole blood transfusion within 120 days of genetic sample collection.
•34.Previous allogenic bone marrow transplant.
•36.Taking part in, or are scheduled for, an intensive (active) COPD rehabilitation programme (however participants who are in the maintenance phase of a rehabilitation programme are eligible to take part).
•37.Inability to follow the study procedures or restrictions, in the opinion of the investigator (eg, use of ePRO device or app, unacceptable inhaler techniques, and spirometry techniques according to the ATS/ERS 2019 guidelines (Graham et al 2019)).
•38.Donation of blood, plasma, or platelets within the past 90 days before randomisation.
•Lifestyle Considerations Meals and Dietary Restrictions •Avoid eating a large meal for at least 2 hours before a spirometry.
••Avoid eating or drinking for 1 hour before a FeNO.
•Alcohol, Tobacco, E-cigarette, and Vaping •Chronic alcohol or drug abuse is not allowed within 12 months before Visit 1 and throughout the study.
••Current tobacco smokers should not smoke on the day of any lung function and FeNO assessments (before it is performed).
••Use of e-cigarettes, vaping of any products (eg, nicotine, THC), heated tobacco products (eg, Intelligent Quotient of Smoking), and use of marijuana are discouraged during the study.
•Activity Avoid engaging in strenuous exercise for at least 30 minutes prior to any lung function assessment, ECG, and blood collection.
另有 2 项未显示

结局指标

主要结局

To compare the effect of tezepelumab with placebo on moderate or severe COPD exacerbations in participants with moderate to very severe COPD

时间窗: Annualised rate of moderate or severe COPD exacerbations up to 76 weeks

次要结局

To compare the effect of tezepelumab with placebo on pre-BD lung function in participants with moderate to very severe COPD(Change from baseline in pre-BD FEV1 at Week 52)
To compare the effect of tezepelumab with placebo on HRQL in participants with moderate to very severe COPD(Change from baseline in the SGRQ total score over 52 weeks)
To compare the effect of tezepelumab with placebo on moderate or severe COPD exacerbations in participants with moderate to very severe COPD and screening EOS greater than or equal to 300 cells per microlite(Annualised rate of moderate or severe COPD exacerbations up to 76 weeks among participants with screening EOS greater than or equal to 300 cells per microlite)
To compare the effect of tezepelumab with placebo on severe COPD exacerbation(Annualised rate of severe COPD exacerbations up to 76 weeks)
To compare the effect of tezepelumab with placebo on HRQLin participants with moderate to very severe COPD(Participants achieving a clinically meaningful improvement from baseline in SGRQ total score (4-point score decrease over) 52 weeks)
To compare the effect of tezepelumab with placebo on COPD health status in participants with moderate to very severe COPD(Change from baseline in the CAT total score over 52 weeks)
To compare the effect of tezepelumab with placebo on time to first moderate to severe COPD exacerbation(Time to first moderate to severe COPD exacerbation up to 76 weeks)
To compare the effect of tezepelumab with placebo on time to first severe COPD exacerbation(Time to first severe COPD exacerbation up to 76 weeks)
To explore the effect of tezepelumab on post-BD lung function(Change from baseline in post-BD FEV1 at Week 52)
To assess the PK and immunogenicity of tezepelumab in participants with moderate to very severe COPD(PK: Serum trough concentrations)

研究者

发起方

AstraZeneca AB

申办方类型

Pharmaceutical industry-Global

研究点 (17)

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