The Effect of Benralizumab on Structural and Lung Function Changes in Patients with Severe Asthma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Astrazeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

11 Nov 2019 → ongoing

Decision date (initial)

2024-03-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2023-506614-40-00

EudraCT number

2018-003391-13

ClinicalTrials.gov

NCT03953300

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacodynamic

To evaluate the effect of benralizumab on submucosal eosinophils in endobronchial biopsies as measured by major basic protein (MBP) staining.
To evaluate the effect of treatment with benralizumab on airway wall dimensions as measured by quantitative computed tomography (QCT) imaging.

Secondary objectives 10

1. The effect of benralizumab on eosinophils in endobronchial biopsies as measured by MBP staining
2. The effect of benralizumab on small airway obstruction as measured by QCT
3. The effect of benralizumab on computational fluid dynamics by QCT
4. The effect of benralizumab on mucus plugging as measured by QCT
5. The effect of benralizumab on large airway remodeling as measured by histology and immunohistochemistry (IHC)
6. The effect of benralizumab on small airway obstruction as measured by airwave oscillometry (AO)
7. The effect of benralizumab on change in lung function as measured by pre-bronchodilator (BD) and post-BD whole body plethysmography (WBP)
8. The effect of benralizumab on airway function as measured by spirometry
9. The effect of benralizumab on basophil numbers in endobronchial biopsies as measured by IHC
10. The short-term (anti-inflammatory) effect of benralizumab on changes in the primary and secondary endpoints measured by QCT, AO, WBP, and spirometry

Conditions and MedDRA coding

Severe eosinophilic asthma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Able to understand and give written informed consent and has signed a written informed consent form (ICF) approved by the Investigator's Institutional Review Board (IRB)/Ethics Committee (EC), prior to conducting any study related procedures (including withholding of any asthma medications required for procedures)
2. Male or female aged 18 through 70 years at the time of Visit 1
3. History of physician-diagnosed asthma requiring continuous treatment with medium- or high-dose ICS (>250μg fluticasone propionate dry powder formulation equivalents total daily dose) plus LABA with or without additional controller medication for at least 12 months prior to Visit 1
4. Documented current treatment with high-dose ICS plus LABA for at least 3 months prior to Visit 1 with or without additional asthma maintenance medication. If the participant is taking ICS plus LABA, the ICS and LABA can be parts of a combination product or given by separate inhalers. -For ICS plus LABA combination preparations, highest-strength maintenance doses approved in the given country will meet this criterion. -If the ICS and LABA are given by separate inhalers, then the participant must be on a high daily ICS dose during the last 3 months prior to Visit 1(see Appendix D for high daily ICS doses by formulation).
5. Morning pre-BD FEV1 ≥ 50 to < 80% of PNV and ≥ 1 L at Visit 2, or morning pre-BD FEV1 ≥ 50 to < 90% of PNV, if documented historical pre-BD FEV1 value (within 12 months prior to screening visit) was < 80% of PNV. One retest is allowed
6. A blood eosinophil count meeting any of 3 criteria below: - ≥ 300 cells/μL during screening at Visit 1 or Visit 2, OR - ≥ 220 to < 300 cells/μL during screening at Visit 1 or Visit 2 and documented eosinophil count of ≥ 300 cells/μL in the past 12 months, OR - ≥ 150 to < 300 cells/μL during screening at Visit 1 or Visit 2 PLUS one of the following: Presence of nasal polyps, or Pre-BD FVC < 65% predicted at Visit 2
7. Weight of ≥40 kg
8. Negative serum pregnancy test for female participants of childbearing potential at Visit 1
9. Negative urine pregnancy test in female participants of childbearing potential prior to randomization and administration of IP
10. Women are authorized to participate if they meet the following criteria: Female participants who cannot bear children as evidenced by: Women ""not of childbearing potential"" are defined as women who are either permanently sterilized (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 randomization without an alternative medical cause. The following age-specific requirements apply - Women <50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range. Until FSH is documented to be within menopausal range treat the participant as WOCBP - Women ≥50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment. If criteria not met, participant should be regarded as having child bearing potential. Female participant capable of having children and both of the following conditions are met: - Have a negative urine pregnancy test prior to administration of the IP and - Must agree to use a highly effective method of birth control (confirmed by the investigator) from randomization throughout the study duration and within 12 weeks after last dose of IP. Highly effective methods ( those that can achieve a failure rate of less than 1% per year when used consistently and correctly) ) include: -Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation- oral, intravaginal, or transdermal -Progestogen-only hormonal contraception associated with inhibition of ovulation- oral, injectable, or implantable -Intrauterine device (IUD) -Intrauterine hormone-releasing system (IUS) -Bilateral tubal occlusion -Sexual abstinence, ie. refraining from heterosexual intercourse (The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant) -Vasectomized sexual partner provided that partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has received medical assessment of the surgical success
11. Acceptable inhaler technique, as judged by the investigator.
12. ACQ-6 >1.5
13. Compliance with inhaled asthma maintenance medication >70% (calculated in the period from Visit 2 to Visit 3). The screening/run-in period may be extended to accommodate this criterion
14. Fewer than 12 exacerbations within the 6 months prior to Visit 3

Exclusion criteria 30

1. Clinically important pulmonary disease other than asthma or participants who have ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts.
2. Life-threatening asthma, defined as episodes requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episodes within the 12 months prior to Visit 1.
3. In participants undergoing bronchoscopy, a history of allergies or adverse drug reactions to medications used for pre-bronchoscopy procedures.
4. Any disorders that is not stable in the opinion of the investigator and could affect the safety of the participant during the study, influence the findings of the studies or their interpretations, or impede the participant's ability to complete the entire duration of the study.
5. Current smokers. Ex-smokers must not have smoked for a minimum of 12 months and should not have a smoking history >15 pack-years at Visit 1. Participants who use e-cigarettes or smoke marijuana will also be excluded from the study.
6. Alcohol or drug abuse (past or present) or any conditions associated with poor compliance.
7. Participants who are scheduled to be admitted to hospital or undergo inpatient surgery during the study.
8. History of anaphylaxis to any biologic therapy.
9. Known history of allergy or reaction to any component of the IP formulation
10. History of cancer: - Participants who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the participant curative therapy was completed at least 12 months prior to the date informed consent is obtained - Participants who have had other malignancies are eligible provided that the participant curative therapy was completed at least 5 years prior to the date informed consent is obtained
11. A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to standard of care therapy
12. A history of known immunodeficiency disorder including a positive human immunodeficiency virus test.
13. Current active liver disease, except for chronic stable hepatitis B and C, or other stable chronic liver disease are acceptable if participant otherwise meets eligibility criteria.
14. In participants undergoing bronchoscopy, any medical condition that requires chronic treatment with chronic anti-coagulation, chronic aspirin, or anti-platelet therapy.
15. In participants undergoing bronchoscopy, use of anticoagulants within 4 weeks prior to randomization into the study.
16. In participants undergoing bronchoscopy, use of non-steroidal antiinflammatory drugs within 72 hours before or aspirin within 7 days of randomization
17. Use of chronic (i.e. >4 weeks) immunosuppressive medication within 3 months prior to the date informed consent is obtained.
18. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
19. Receipt of any marketed or investigational biologic for the treatment of asthma within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer.
20. Previously received benralizumab. Participants that participated in other studies with benralizumab but have been confirmed to have received placebo are eligible.
21. Receipt of live attenuated vaccines 30 days prior to the date of randomization. Receipt of inactive/killed vaccinations is allowed provided they are not administered within 1 week before/after any IP administration.
22. Change to allergen immunotherapy or new allergen immunotherapy within 30 days prior to the date of informed consent and anticipated changes in immunotherapy during the study.
23. Receipt of bronchial thermoplasty in the last 24 months prior to Visit 1.
24. Participation in an interventional clinical study during the past 3 months or participants previously randomized into this study. If it is documented that the participant was known to be on placebo treatment of a completed study, then a 3-month period is not required.
25. Receipt of any investigational non-biologic within 30 days or 5 halflives prior to the date informed consent is obtained, whichever is longer.
26. Any clinically significant abnormal findings, which in the opinion of the Investigator, may put the particpant at risk, or may influence the results of the study, or the participant's ability to complete the entire duration of the study.
27. Alanine aminotransferase or aspartate aminotransferase level ≥3 times the upper limit of normal, confirmed by repeated testing during the screening period.
28. Currently pregnant, breastfeeding or lactating women.
29. Blood draws of 100 mL or more within 45 days prior to enrolment in the study.
30. Radiological findings suggestive of a respiratory disease other than asthma that is contributing to the participant's respiratory symptoms.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The change, expressed as a percentage from baseline to end of treatment (EOT) in eosinophil numbers, expressed as number/mm2 in submucosa.
2. The change, expressed as a percentage, from baseline to EOT in airway WA% as the overall median for airway generations 3 and 4 combined. Supportive measure: Change, expressed as a percentage, from baseline to EOT in airway lumen area (LA), airway wall area (WA) and airway wall thickness (WT).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Astrazeneca AB

Sponsor organisation

Astrazeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

2 EU/EEA countries · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

3 submissions — initial application plus substantial / non-substantial modifications