| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe eosinophilic asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068462 |
| E.1.2 | Term | Eosinophilic asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068462 |
| E.1.2 | Term | Eosinophilic asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- 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 |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate:
- the effect of benralizumab on eosinophils in endobronchial biopsies as measured by MBP staining
- the effect of benralizumab on small airway obstruction as measured by QCT
- the effect of benralizumab on computational fluid dynamics by QCT
- the effect of benralizumab on mucus plugging as measured by QCT
- the effect of benralizumab on large airway remodeling as measured by histology and immunohistochemistry (IHC)
- the effect of benralizumab on small airway obstruction as measured by airwave oscillometry (AO)
- the effect of benralizumab on change in lung function as measured by pre-bronchodilator (BD) and post-BD whole body plethysmography (WBP)
- the effect of benralizumab on airway function as measured by spirometry
- the effect of benralizumab on basophil numbers in endobronchial biopsies as measured by IHC
- the short-term (anti-inflammatory) effect of benralizumab on changes in the primary and secondary endpoints measured by QCT, AO, WBP, and spirometry |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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. |
|
| E.4 | Principal exclusion criteria |
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 anti-inflammatory 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 half-lives 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. The change, expressed as a percentage, from baseline to EOT in eosinophil numbers, expressed as number/mm2 in:
- Epithelium
- Epithelium and submucosa
2. Absolute change from baseline to EOT in:
- Air trapping expressed as percentage of the lung with expiratory density less than -856 Hounsfield Units (HU), and as expiratory-to-inspiratory ratio of mean lung density on computed tomography (CT) scans
- Air trapping/small airway obstruction derived from regional matching of the inspiratory/expiratory CT scans
3. Change, expressed as a percentage, from baseline to EOT in:
- Airway lumen volume
- Airway resistance
4. Absolute change from baseline to EOT in mucus score.
5. Change, expressed as a percentage, from baseline to EOT in endobronchial biopsies on:
- Airway epithelial cell integrity
- RBM thickening
- Vascularization of the sub-mucosa
- Airway smooth muscle mass percentage
- Mucus glands, goblet cells and mucin 5AC,oligomeric mucus/gel-forming (MUC5AC)
6. Absolute change from baseline to EOT in R5-R20 (peripheral airway resistance defined as the difference in resistance between 5 Hz [R5, total respiratory system resistance] and 20 Hz [R20, central resistance]) and area under the reactance curve (AX).
7. Absolute change from baseline to EOT in pre-BD whole body plethysmography (WBP), post-BD WBP, and change from pre-BD WBP to post-BD WBP: Residual volume (RV), Total lung capacity (TLC), Inspiratory capacity (IC), RV/TLC ratio, Functional residual capacity (FRC) and Vital capacity (VC).
8. Change, expressed as a percentage, from baseline to EOT in post-BD forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and FEV1/FVC
9. Change, expressed as a percentage, from baseline to EOT in basophil number (number/mm2) in endobronchial biopsies
10. Change from baseline to Week 8 in the primary and secondary variables measured by quantitative computed tomography (QCT), airwave oscillometry (AO), whole body plethysmography (WBP), and spirometry |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For secondary endpoints from 1. to 8. - EOT
For secondary endpoint 10. - Week 8 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United Kingdom |
| United States |
| Denmark |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as the last expected visit/contact of the last participant undergoing the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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