A study to learn how well tezepelumab works and how safe it is in adults with chronic obstructive pulmonary disease (COPD)
Scientific Title of Study
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)
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
D5241C00006 Protocol Version 1.0 dated 02 Dec 2024
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Srikanth Krishnamurthy
Designation
Consultant Pulmonologist
Affiliation
Hindusthan Hospital
Address
Department of Pulmonology, Room # 136, 522/3, 523/3 Nava India Road, Udaiyampalayam
Coimbatore TAMIL NADU 641028 India
Phone
9894257706
Fax
Email
drsrikanthcbe@gmail.com
Details of Contact Person Scientific Query
Name
Tapankumar M Shah
Designation
Senior Director – Site Management and Monitoring, Biopharmaceuticals R& D
Affiliation
AstraZeneca Pharma India Ltd.
Address
Site Management and Monitoring
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road, Bangalore - 560045
Bangalore KARNATAKA 560045 India
Phone
9535104975
Fax
Email
tapankumar.shah@astrazeneca.com
Details of Contact Person Public Query
Name
Tapankumar M Shah
Designation
Senior Director – Site Management and Monitoring, Biopharmaceuticals R& D
Affiliation
AstraZeneca Pharma India Ltd.
Address
Site Management and Monitoring
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road, Bangalore - 560045
KARNATAKA 560045 India
Phone
9535104975
Fax
Email
tapankumar.shah@astrazeneca.com
Source of Monetary or Material Support
AstraZeneca AB, 151 85 Södertälje, Sweden
Primary Sponsor
Name
AstraZeneca AB
Address
151 85 Södertälje, Sweden
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
AstraZeneca Pharma India Ltd
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road, Bangalore - 560045,
Karnataka, India
Countries of Recruitment
Brazil Canada Chile Czech Republic Denmark Germany India Italy Malaysia Mexico Philippines Poland Republic of Korea Slovakia Spain United Kingdom United States of America China
Professor and Head, Department of Pulmonary Medicine, Ansari Nagar, PIN- 110029
New Delhi DELHI
9810048204
anantmohan@yahoo.com
Dr Srikant Kashinath Malegaonkar
All India Institute of Medical Sciences, Nagpur
Assistant Professor, Department of Pulmonary Medicine, Plot No.02, Sector 20, MIHAN, PIN - 441108
Nagpur MAHARASHTRA
9582273519
kmsrikant@gmail.com
Dr Arun Chowdary Kotaru
Artemis Hospital
Consultant, Department of Pulmonary Medicine, Sector - 51, PIN - 122001
Gurgaon HARYANA
8411099001
arun.chowdary@artemishospitals.com
Dr Praveen Valsalan
Aster Medcity
Lead Consultant Pulmonologist, Department of Pulmonary Medicine,South Chittoor P.O, Cheranelloor, PIN - 682027
Ernakulam KERALA
9496072264
drpraveen.valsalan@asterhospital.in
Dr Samadarshi Datta
B P Poddar Hospital and Medical Research Ltd
Consultant Pulmonologist, Department of Pulmonary Medicine, 71/1, Humayun Kabir Sarani, Block G, New Alipore, PIN - 700053
Kolkata WEST BENGAL
91 9830253734
samadoc@gmail.com
Dr Rahul Kumar Rathore
Charak Hospital and Research Centre
Consultant Pulmonologist, Department of Pulmonary Medicine, Hardoi Road, Dubagga, PIN - 226003
Lucknow UTTAR PRADESH
7408441522
drrahulkgmu85@gmail.com
Dr Vivek Gupta
Criticare Hospital and Research Institute
Dhanshree Complex, Near Hotel Hardeo, Sitabuldi, PIN– 440012 Nagpur MAHARASHTRA
9373115548
vivekurvashi@yahoo.co.in
Dr Arti Dhawal Shah
Dhiraj Hospital, Smt. B.K Shah Medical Institute & Research Centre (affiliated to Sumandeep Vidyapee
Professor & Head, Department of Pulmonary Medicine, At & PO. Piparia, Ta. Waghodia, PIN - 391760
Vadodara GUJARAT
9925047880
hod_pul_medicine@sumandeepvidyapeethdu.edu.in
Dr Sachinkumar Dole
Dr DY Patil Medical College, Hospital and Research Centre
Professor, Department of Pulmonary Medicine, Sant Tukaram Nagar, Pimpri, PIN - 411018
Pune MAHARASHTRA
9637104972
sachindole85@gmail.com
Dr Kamran Choudhary
ESIC Medical College and Hospital
Assistant Professor, Department of Pulmonary Medicine, Clinical Trial Unit, MRU (Multidisciplinary Research Unit), Basement, NH-3, NIT, PIN-121001
Faridabad HARYANA
9871022476
kamran851@hotmail.com
Dr Srikanth Krishnamurthy
Hindusthan Hospital
Consultant Pulmonologist, Department of Pulmonary Medicine, 522/3, 523/3 Nava India Road, Udaiyampalayam, PIN - 641028
Coimbatore TAMIL NADU
9894257706
drsrikanthcbe@gmail.com
Dr Jyothi Hattiholi
KLES Dr Prabhakar Kore Hospital & Medical Research Centre
Cosultant Pulmonologist, Department of Pulmonary, Nehrunagar, PIN- 590010,
Belgaum KARNATAKA
7022799910
pulmojyoti@gmail.com
Dr Velkumar Gopal
Meenakshi Super Specialty Hospital
Senior Consultant & HOD, Department of Pulmonary, Lake Area, Melur Road, PIN - 625107
Madurai TAMIL NADU
9894082302
gvk.tbrd@gmail.com
Dr C Prashanth
Princess Krishnajammanni Tuberculosis and Chest Diseases Hospital (P.K.T B and C.D Hospital)
Professor and HOD, Department of Pulmonary Medicine, Mysore Medical College and Research Institute, Mysore, KRS Road, Kumbarakoppal, Gokulam, PIN- 570002
Mysore KARNATAKA
7022247227
drprashanthg2019@gmail.com
Dr Sujal Patel
Shalby Hospital
Consultant Pulmonologist, Department of Pulmonary Medicine, Naroda, Haridarshan Cross road, Naroda-Kathawada road, Naroda, PIN- 382330
Ahmadabad GUJARAT
9687639215
sujpatel2@gmail.com
Dr Jagdish Kumar Rawat
Shri Guru Ram Rai Institute of Medical & Health Sciences and Shri Mahant Indiresh Hospital
HOD & Professor, Department of Pulmonary Medicine,Patel Nagar, Dehradun, Uttarakhand - 248001
Dehradun UTTARANCHAL
9639212630
drjagdishrawat@yahoo.com
Dr Rohit Kumar
Vardhman Mahavir Medical College & Safdarjung Hospital (VMMC & SJH)
Associate Professor & HOD, Department of Pulmonary Medicine, Near AIIMS Hospital, Ansari Nagar West, PIN- 110029
New Delhi DELHI
9911218081
dr.rohitkumar@mail.com
Dr Pratibha Gogia
Venkateshwar Hospital, Delhi
Sector 18 A, Dwarka, PON – 110075 New Delhi DELHI
9891170363
pratibha.gogia@venkatshwarhospitals.com
Dr Jitendra Girdharlal Kotadiya
Zydus Hospitals & Healthcare Research Pvt. Ltd.
Consultant Pulmonologist, Department of Pulmonary, Zydus Hospital Road, S G Highway, Thaltej, APIN - 380054
Ahmadabad GUJARAT
Age
1 Adult participants 40 to 80 years of age at the time of signing the informed consent.
2 Documented physician-diagnosed COPD for at least 12 months before Visit 1.
3 A 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.
4 Documented 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 1.
5 Documented history reater than or equal to 2 moderate1 or reater than or equal to 1 severe2 COPD exacerbations within 12 months before Visit 1. At least 1 of the 2 moderate exacerbations must have been treated with SCS.
6 EOS greater than or equal to 150 cells per microliter during the screening period.
7 CAT total score reater than or equal to 15 at Visit 1.
8 Current 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).
9 Body weight reater than or equal to 40 kg at Visit 1.
10 Participants 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
11 Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
12 Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, or analysis.
13 Provision 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.
ExclusionCriteria
Details
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 2.
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 2.
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 1.
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 1.
21. Maintenance treatment with macrolides or other antibiotics for COPD if the duration of the treatment is less than 6 consecutive months before Visit 1.
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.
Prior/Concurrent Clinical Study Experience
26. Sensitivity to any component of the study intervention formulation or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation.
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.
Other Exclusions
35. Pregnant (confirmed with positive pregnancy test), breastfeeding, or lactating participants.
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).
• Former tobacco smokers should be encouraged not to smoke during the study.
• 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.
Other Restrictions
Abstain from donating blood or plasma from the time of informed consent to 14 weeks (5.5 half-lives) after last dose of IP.
PoCBP must follow the contraception requirements outlined in Inclusion Criterion 11
Method of Generating Random Sequence
Stratified block randomization
Method of Concealment
Centralized
Blinding/Masking
Participant and Investigator Blinded
Primary Outcome
Outcome
TimePoints
To compare the effect of tezepelumab with placebo on moderate or severe COPD exacerbations in participants with moderate to very severe COPD
Annualised rate of moderate or severe COPD exacerbations up to 76 weeks
Secondary Outcome
Outcome
TimePoints
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
•Participants achieving a clinically meaningful improvement from baseline in CAT total score (2-point score decrease) 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
Immunogenicity: Incidence of anti-drug antibodies and neutralising antibodies
Target Sample Size
Total Sample Size="990" Sample Size from India="100" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
Treatment options for COPD remain largely limited to
BDs and/or ICS (Calderon et al 2023). Despite adequate treatment with optimised
maintenance inhaled therapy, approximately 30 to 40% of patients continue to
have moderate or severe exacerbations (Müllerová et al 2017). Additional
therapies such as azithromycin, and the phosphodiesterase-4 inhibitor,
roflumilast, are underutilised due to side effects (GOLD 2024). Hence, there is
still an unmet medical need in the growing population of COPD patients who
continue to have exacerbations despite current COPD therapies.
Overall,
tezepelumab
420 mg Q4W was well tolerated in patients with COPD, and no new safety concerns
were identified compared to its known safety profile from asthma studies.
Although
the 210 mg Q4W dose regimen was not studied in COPD, a higher dose of 420 mg
was shown to be well tolerated in the COPD patient population. In addition, the
210 mg dose has also been shown to be well tolerated and efficacious in
patients with severe asthma. There are no Important Identified Risks for
tezepelumab. Although no causal relationship to tezepelumab has been
established during the development of tezepelumab in asthma, the following are
identified as Important Potential Risks: serious infections,
serious cardiac events and malignancies, and Potential Risk: serious
hypersensitivity reactions, all of which can be managed through medical
practices. AZ will continue to manage any risks through a collection of data
from clinical studies, post-marketing data, and routine pharmacovigilance and
risk minimisation activities, as appropriate