| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe corticosteroid-dependent asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Asthma is a condition that causes swelling (inflammation) of the air ways. The inflammation makes them extra-sensitive which brings on the asthma symptoms. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| 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 levels of serum periostin in a population of patients with severe OCS-dependent asthma at Baseline
• To examine the stability of serum periostin levels and individual patient phenotypes in relation to sputum eosinophils ( as defined by % eosinophils), blood eosinophil count, FeNO (ppb), lung function ( FEV1), and Asthma Control Questionnaire (ACQ-7)
• To examine the changes in serum periostin levels in a study population with uncontrolled asthma that receives 7 days of high-dose OCS treatment and relate these changes to blood eosinophils, FeNO, lung function, AQLQ12+, and ACQ-7 |
|
| E.2.2 | Secondary objectives of the trial |
•To examine the change from Baseline in other biomarkers related to IL-13 biology, e.g. chemokine ligand (CCL)-13, CCL-17, CCL-18, IgE, FeNO, and eosinophils
• To examine the change from Baseline in serum IL-17A in patients with severe OCS-dependent asthma
•To examine sputum differential cell counts in patients with severe OCS-dependent asthma
•To examine sputum and whole blood gene expression for response to corticosteroid signalling, IL-13 and periostin biology, and putative inflammatory pathways in severe steroid-dependent asthma
•To examine genetic determinants that may predict response to glucocorticoids and clinical features of uncontrolled asthma, and to understand the relationship between heritable factors and the response to OCS therapy used in the treatment of uncontrolled asthma |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. For patients considered to be minors according to national legislation in each country, the written consent of the parent or legal guardian must be obtained, as well as the assent of the minor according to his or her capacity to understand the information provided. Patients within the specified age range who are not legally considered to be minors according to national legislation must consent in their own right. Patients enrolled as minors who attain legal adulthood during the course of the study must consent in their own right at that time
2. Ability and willingness to comply with the study procedures
3. Age ≥12 to ≤75 years at the time of informed consent
4. Severe asthma (as defined by GINA step 5 classification of asthma severity) after a detailed systematic assessment (the BTS UK Difficult Asthma Network assessment model [Heaney et al 2010] or equivalent) and follow-up by an asthma specialist for at least six months
5. History of asthma treatment with high doses of ICS (≥1500 μg beclomethasone dipropionate daily, or equivalent) and LABAs, with or without an additional controller, for at least six months before Screening
6. Chronic treatment with maintenance OCS for at least six months before the time of informed consent with treatment during the last 28 days being within the following ranges:
• ±2.5 mg/day daily dose equivalent for patients within the range of 10 to 20 mg/day (range 5 to 20 mg for adolescents)
• ±5 mg/day daily dose equivalent for patients within the range of
21 to 40 mg/day
7. Baseline OCS dose as follows:
• Adults: 10 to 40 mg/day
• Adolescents: 5 to 40 mg/day daily dose equivalent
8. Compliance with OCS therapy will be based on prior detectable levels of serum prednisolone, cortisol suppression, or observation of Cushingoid appearance consistent with regular systemic steroid use
9. Prior assessment within the six months before the time of informed consent is obtained according to the assessment model of the BTS UK Difficult Asthma Network or equivalent to ensure a diagnosis of refractory asthma (Heaney et al 2010) with OCS dependence on minimal effective or maximum tolerated dose, defined as follows:
• Patient has ‘uncontrolled’ asthma and has detectable serum prednisolone or undetectable cortisol. ‘Uncontrolled’ asthma is defined by any of the following:
• ACQ-7 >1.25 or
•Persistent blood eosinophil count (>0.4 x 109/mL) or
• Persistent sputum eosinophilia (>3%) or
• Recurrent exacerbations requiring a boost in steroid dose
Note: Patients that do not meet the ‘uncontrolled’ asthma criteria listed previously will be defined as ‘controlled’
• Patient has ‘controlled’ asthma and has documented evidence of previous failed OCS down-titration
Note: For patients who are controlled with no documented evidence of failed OCS down-titration, OCS dose optimisation will take place within the context of the BTS (or equivalent) standardised protocols before considering the patient for Screening (considered standard of care for optimisation daily steroid use). During this process, the OCS dose will be reduced at weekly intervals in predefined steps until either of the following criteria for OCS down-titration failure is met:
• Forced expiratory volume in 1 second (FEV1) <80% of the patient’s personal best value while on the current OCS dose, or
• Increase in 24-hour asthma symptoms, night time awakenings, or
SABA use
10. Chest x-ray or computed tomography (CT) scan obtained within the
12 months before the time of informed consent or chest x-ray during the screening period confirming the absence of other significant lung disease (at the discretion of the investigator. For example a degree of co-morbid bronchiectasis is common in this population and would not exclude them.
Severe forms of co-morbid diseases such as emphysema and clinically significant bronchiectasis should be excluded. All cases of doubt should be discussed with the medical monitor)
11. Documented history of bronchodilator reversibility response of ≥12% and
≥200 mL within the past 12 months before the time of informed consent, as demonstrated by any of the following:
• Documented airflow obstruction (FEV1/forced vital capacity [FVC] <70%), where FEV1 has varied by ≥12% either spontaneously or in response to
OCS therapy, or
• A decrease of 20% in FEV1 (PC20) in response to methacholine or histamine challenge at <8 mg/mL, indicating the presence of airway hyperresponsiveness, or
• Change in FEV1 by ≥12% and ≥200 mL after acute reversibility testing with
400 μg salbutamol via metered dose inhaler (via spacer) or 2.5 to 5 mg nebulised salbutamol. (This assessment can be undertaken during the screening period if an assessment has not been performed within the
12 months before the time of informed consent).
|
|
| E.4 | Principal exclusion criteria |
1. Baseline FEV1 ≤39% of predicted
2. Asthma exacerbation (as described in Section 4.2.6.5) within 28 days before the time of informed consent or during Screening
3. Major episode of infection requiring any of the following:
• Admission to hospital for ≥24 hours within the 28 days before the time of informed consent or during Screening
• Treatment with intravenous antibiotics within the 28 days before the time of informed consent or during Screening
• Treatment with oral antibiotics within the 14 days before the time of informed consent or during Screening
4. Active parasitic infection or Listeria monocytogenes infection within the 6 months before the time of informed consent
5. For adults: Active tuberculosis (TB) requiring treatment within the 12 months before the time of informed consent (patients are also required to have no recurrence of symptoms in the 12 months following completion of TB treatment), or For adolescents: History of active TB requiring treatment
6. Known history of severe clinically significant immunodeficiency, including, but not limited to, human immunodeficiency virus infection and/or currently receiving or have historically received intravenous Ig for treatment for immunodeficiency
Note: Immunodeficiency encompasses a wide spectrum of human conditions and/or diseases. A relative IgG deficiency that is thought, but not proven, to be a feature of severe asthma would not be exclusionary for the study. All cases of doubt should be discussed with the medical monitor
7. Evidence of acute or chronic hepatitis or known liver cirrhosis
8. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) and/or total bilirubin elevation ≥2.0 x the upper limit of normal (ULN)
9. Diagnosis or history of malignancy, or current investigation for possible malignancy
10. Other clinically significant medical disease that is uncontrolled despite treatment or that is likely, in the opinion of the investigator, to require a change in therapy or affect the ability to participate in the study
11. History of alcohol, drug, or chemical abuse that would impair or risk the patient’s full participation in the study, in the opinion of the investigator
12. Current smoker or former smoker with a smoking history of >15 pack-years. A current smoker is defined as someone who has smoked one or more cigarettes per day (or marijuana or pipe or cigar) for ≥30 days within the 24 months before the time of informed consent and for whom cotinine testing is positive.
A former smoker is defined as someone who has smoked one or more cigarettes per day (or marijuana or pipe or cigar) for ≥30 days in his or her lifetime (as long as the 30-day total did not include the 24 months before the time of informed consent) and for whom cotinine testing is negative.
A pack-year is defined as the average number of packs per day times the number of years of smoking.
13. Current use of an immunomodulatory/immunosuppressive therapy or past use within three months or five drug half-lives (whichever is longer) before the time of informed consent
14. Use of a biologic therapy (including omalizumab) at any time during the 4 months before the time of informed consent
15. History of anaphylaxis with omalizumab treatment or history of anaphylaxis to any therapeutic biological agent
16. Use of zileuton or roflumilast at any time during the two months before the time of informed consent
17. Initiation of or change in allergen immunotherapy within three months before the time of informed consent
18. Treatment with an investigational agent within 30 days of informed consent or 5 half-lives of the investigational agent, whichever is longer
19. Receipt of a live/attenuated vaccine within the 28 days before the time of informed consent, or anticipation of the receipt of live/attenuated vaccine throughout the study
20. Female patients of reproductive potential who are not willing to use a highly effective method of contraception (e.g. contraceptive pill or transdermal patch, spermicide and barrier [condoms], intrauterine device, implants for contraception, injections for contraception [with prolonged release], hormonal vaginal device, sterilisation, surgical tubal ligation, hysterectomy, or true abstinence [in adolescent patients only]) for the duration of the study
21. Female patients who are pregnant or lactating
22. Body mass index (BMI) (mass [kg]/height [m]2) >38 kg/m2
23. Body weight <40 kg
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objectives for this study are as follows:
•To evaluate the levels of serum periostin in a population of patients with severe OCS-dependent asthma at Baseline
•To examine the stability of serum periostin levels and individual patient phenotypes in relation to sputum eosinophils ( as defined by % eosinophils), blood eosinophil count, FeNO (ppb), lung function ( FEV1), and Asthma Control Questionnaire (ACQ-7)
•To examine the changes in serum periostin levels in a study population with uncontrolled asthma that receives 7 days of high-dose OCS treatment and relate these changes to blood eosinophils, FeNO, lung function, AQLQ12+, and ACQ-7 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Serum periostin: Screening, Baseline, Visit 2 (day 8), Visit 3 (day 39), Visit 4 (day67), Visit 5 (day 95)
•Blood eosinophil count: Screening, Baseline, Visit 2 (day 8), Visit 3 (day 39), Visit 4 (day67), Visit 5 (day 95)
•FeNO (ppb): Baseline, Visit 2 (day 8), Visit 3 (day 39), Visit 4 (day67), Visit 5 (day 95)
•Lung function ( FEV1), and Asthma Control Questionnaire (ACQ-7): Screening, Baseline, Visit 2 (day 8), Visit 3 (day 39), Visit 4 (day67), Visit 5 (day 95)
|
|
| E.5.2 | Secondary end point(s) |
The aggregate data is directed at addressing the potential to understand biomarkers in this population and specifically the biomarkers that may help more specific phenotyping to allow targeted therapies to be tested in this population.
The exploratory objectives for this study are as follows:
•To examine the change from Baseline in other biomarkers related to IL-13 biology, e.g. chemokine ligand (CCL)-13, CCL-17, CCL-18, IgE, FeNO, and eosinophils
• To examine the change from Baseline in serum IL-17A in
patients with severe OCS-dependent asthma
•To examine sputum differential cell counts in patients with severe
OCS-dependent asthma
• To examine sputum and whole blood gene expression for response to corticosteroid signalling, IL-13 and periostin biology, and putative inflammatory pathways in severe steroid-dependent asthma
•To examine genetic determinants that may predict response to
glucocorticoids and clinical features of uncontrolled asthma, and to
understand the relationship between heritable factors and the response to OCS therapy used in the treatment of uncontrolled asthma.
• DNA sampling is optional |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening, Baseline, Visit 2 (day 8), Visit 3 (day 39), Visit 4 (day67), Visit 5 (day 95)
|
|
| 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 | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
The aggregate data is directed at addressing the potential to understand biomarkers in this population and specifically the biomarkers that may help more specific phenotyping to allow targeted therapies to be tested in this population.
This study will help collect the data necessary to understand how a change in prednisolone requirement could be effectively measured in this patient setting.
|
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| 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 | 11 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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