| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe Eosinophilic Asthma |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 100000004855 |
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| 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 assess the inflammatory and physiological characteristics of an asthma exacerbation whilst on treatment with benralizumab for severe eosinophilic asthma. |
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| E.2.2 | Secondary objectives of the trial |
• To measure patient outcomes after 4, 16, 24, and 56 weeks of treatment with benralizumab, and assess their associations with baseline patient characteristics, in a real-world setting.
• To study biomarkers of response.
• To determine if improvement in early clinical response indicators at 4, 16 and 24 weeks on treatment can predict a successful response to benralizumab at one year [50% reduction of high dose oral corticosteroid courses and/or dose of maintenance steroids at the end of 56 weeks on treatment].
• To assess the reduction in oral corticosteroid courses and/or dose of maintenance oral steroids at the end of 56 weeks of treatment with benralizumab.
• To assess early changes in biomarkers following benralizumab at 4 weeks [link with IMI 3TR project]
• To compare the gut and lung microbiome at baseline and after 4 weeks of benralizumab therapy [link with IMI project]
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Severe Asthma Questionnaire (SAQ) Sub-study: Further validation of a scale to measure quality of life in patients with severe asthma.
The sub-study aims to validate a new asthma quality of life scale, the Severe Asthma Questionnaire (SAQ) by 1. providing data from factor analysis of the SAQ, 2. examining the correlations between the SAQ with five other questionnaires used in outcome research (ACQ, AQLQ, SGRQ, EQ-5D-5L, WPAI:Asthma) and 3. comparing the extent to which all six questionnaires discriminate between patients with different profiles.
Breathomics Sub-study (Manchester and Leicester only): Pilot study investigating early and late changes in breath biomarkers on benralizumab. Aims: 1. to investigate stability in breath biomarkers before starting treatment with benralizumab. 2. to investigate changes in breath biomarkers after one, four and 12 months of treatment with benralizumab related to changes in key clinical endpoints measured at month 12 versus baseline (a. systemic steroid use, b. annual exacerbation frequency, c. blood eosinophils, d. sputum eosinophils, e. asthma control, f. asthma quality of life, g. FeNO) |
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| E.3 | Principal inclusion criteria |
- Age ≥ 18 and ≤ 80 years at Visit 1
- able and willing to provide written informed consent and to comply with the study protocol including being able to attend for assessment during a symptomatic deterioration.
- severe asthma confirmed after assessment by an asthma specialist, requiring treatment with high dose inhaled corticosteroids(ICS)as per BTS criteria (≥ 1000 fluticasone propionate equivalent) and ≥1 additional drug for asthma (e.g. long acting beta2 agonist (LABA)/leukotriene receptor antagonist (e.g. theophylline / long acting muscarinic antagonist) at screening [participants may be included with a lower dose of current ICS at the discretion of the investigator if previous high ICS dose had led to side effects]
- adherent with background asthma medication in the opinion of the investigator
- assessed and treatment optimised for any significant asthma-related co-morbidities
- considered suitable by an asthma specialist for treatment with a monoclonal antibody to block the Interleukin-5 pathway as per local practice. Participants will have [a] recorded blood eosinophil count ≥0.3 x 109/L within the past year along with a history of either ≥ 4 asthma exacerbations requiring high dose oral corticosteroids* and/or maintenance systemic corticosteroids equivalent to prednisolone ≥5 mg/day for 6 months or longer
OR
[b]recorded blood eosinophil count ≥0.4 x 109/L within the past year along with a history of ≥3 asthma exacerbations requiring high dose oral corticosteroids*
*Exacerbations of asthma in the past year will be defined as worsening of asthma symptoms leading to treatment with prednisolone ≥30 mg oral corticosteroids for ≥3 days or an increase ≥ 10mg in oral corticosteroids for at least 3 days for patients on maintenance oral steroids]
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| E.4 | Principal exclusion criteria |
-acute exacerbation requiring high dose oral corticosteroids in the 2 weeks prior to Visit 1 or during the screening period. Such patients would be re-assessed after 2 weeks.
- other clinically significant medical disease or uncontrolled concomitant disease that is likely, in the opinion of the investigator, to require a change in therapy or impact the ability to participate in the study.
- history of current alcohol, drug, or chemical abuse or past abuse that would impair or risk the patient's full participation in the study, in the opinion of the investigator
- female patients who are pregnant or lactating or planning a family
- active lung disease other than asthma [note: controlled obstructive sleep apnoea (OSA), minor bronchiectasis, asbestos pleural plaques or old (inactive) TB scars are not exclusion criteria). Patients where an asthma-COPD overlap is suspected by the investigator are not eligible for inclusion.
- current smoker (history of smoking including e-cigarettes in the past 3 months)prior to Visit 1
- Treatment with any of the following prior to Visit 1 or during the study: any biologic medicine for asthma or an immunomodulating biologic agent for other conditions in the 3 months prior to Visit 1; regular use of systemic(oral/IM) corticosteroids except for the indication of asthma; an investigational agent within 30 days of visit 1 (or five half-lives of the investigational agent, whichever is longer); administration of live attenuated vaccines 30 days prior to Visit 1. Other types of approved vaccine are allowed; regular use of systemic (oral/IM) corticosteroids except for the indication of asthma or adrenal insufficiency [note: patients taking systemic steroid replacement primarily for adrenal insufficiency can be included provided they meet exacerbation inclusion criteria], ; other ongoing immunosuppressive / immunomodulating therapy (e..g. methotrexate, cyclosporine, azathioprine) other than oral corticosteroids for asthma.
- Bronchial thermoplasty conducted within 6 months of Visit 1.
- history of known immunodeficiency disorder including a previous positive HIV test
- Active or suspected Helminth infectionpatients with helminth infections must be excluded until the infection has been treated.
- known hypersensitivity to benralizumab (the active substance) or any of the excipients (Histidine, Histidine hydrochloride monohydrate, Trehalose dihydrate, Polysorbate 20, water for injections)
- women of childbearing potential who are not willing to use highly effective contraception during treatment with benralizumab and for 16 weeks after the last dose. WoCBP will be required to undergo a urine pregnancy test prior to on-siteadministration of each benralizumab injection.Pregnancy testing will be in accordance with standard care requirements for participants converted to local NHS benralizumab supply arrangements.
13. Current malignancy, or history of malignancy, except for:
a) Patients who have had non-melanoma skin cancers or in situ carcinoma of the cervix – these patients are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to the date informed consent is obtained
12.b) Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent is obtained.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The main aim of the study is to assess the inflammatory and physiological characteristics of an asthma exacerbation whilst on treatment with benralizumab for severe eosinophilic asthma.
Key exploratory outcomes will be blood eosinophil counts, fall in lung function, exhaled Nitric Oxide change in asthma symptom scores and number of patients progressing to rescue oral corticosteroids during a clinical deterioration whilst on benralizumab. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Exacerbation events at any time whilst on treatment with benralizumab |
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| E.5.2 | Secondary end point(s) |
• To measure patient outcomes after 16, 24, and 56 weeks of treatment with benralizumab, and assess their associations with baseline patient characteristics, in a real-world setting.
• To study biomarkers of response.
• To determine if improvement in early clinical response indicators at 16 and 24 weeks on treatment can predict a successful response to benralizumab at one year [50% reduction of high dose oral corticosteroid courses and/or dose of maintenance steroids at the end of 56 weeks on treatment].
• To assess the reduction in oral corticosteroid courses and/or dose of maintenance oral steroids at the end of 56 weeks of treatment with benralizumab.
- Early changes at 4 weeks compared to baseline
• Blood eosinophil counts
• Sputum eosinophils
• Blood neutrophil counts
• Exhaled nitric oxide
• Nasosorption eosinophil markers
• ACQ-6, SGRQ, mini-ACLQ
• FEV1
• Stool microbiome compared to lung microbiome and biomarkers in blood and sputum [measured within the 3TR IMI Programme]
• Oral Wash microbiome
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 4, 16, 24 and 56 weeks after initiation of treatment. |
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| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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