| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 evaluate the efficacy of inhaled Interferon beta-1a compared to placebo in preventing severe exacerbations during the 14 days of treatment following onset of an upper respiratory tract infection in asthmatic patients, on top of their regular asthma maintenance treatment. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the preventive or attenuating effect of inhaled Interferon beta-1a compared to placebo on deterioration of secondary efficacy endpoints during and after upper respiratory tract infection. Analysed variables will include:
- Occurrence of severe exacerbations with onset during day 1-30 after start of treatment
- Occurrence of moderate exacerbations with onset during day 1-30 after start of treatment
- Time to severe exacerbation
- Time to moderate exacerbation
- Change from treatment baseline in Patient reported outcomes
- (a) Asthma control as measured by ACQ-6
- (b) Day-time and night-time asthma symptom score and night-time awakenings as determined by area under the curve (AUC) over day 1-14
- (c) Health-related quality of life as measured by AQLQ(S)
- Day-time and night-time reliever medication use as determined by AUC over day 1-14 as change from the treatment baseline level
- Lung function, ie morning and evening PEF and FEV1 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For inclusion in the study patients should fulfil the following criteria:
1.Provision of signed and dated written informed consent prior to any study specific procedures
2.Male or female aged 18 and above at the time of screening
3.History of physician-diagnosed asthma requiring treatment with medium-to-high dose ICS (>250 μg fluticasone dry powder formulation equivalents total daily dose, as defined in GINA 2014; see CSP App. G) and a second controller medication as recommended in the GINA guidelines (ie, LABA or leukotriene receptor antagonist). The medium or high dose ICS plus LABA can be any combination inhaler or 2 separate inhalers. Patients must have taken ICS (>250 μg fluticasone or the equivalent daily) plus second controller medication for at least 12 months prior to the date the informed consent is obtained, with or without another controller such as OCS, theophylline, tiotropium, or leukotriene receptor antagonists. The maintenance treatment must have been kept at the same or at ahigher level these last months.
4.Proof of post-bronchodilator reversibility in FEV1 of ≥12% and ≥200 mL (Pellegrino et al 2005) documented within 5 years prior to Visit 1, or proof of a positive response to a methacholine or histamine challenge (a decrease in FEV1 by 20% [PC20] at ≤8 mg/mL) performed according to ATS/ERS guidelines (American Thoracic Society 2000) or proof of positive response to mannitol challenge (a descrease in FEV1 by 15%[PD15] at <=635 mg)(Anderson et al 2009) documented within 5 years prior to Visit 1. If historical documentation is not available, reversibility or proof of a positive response to a methacholine, histamine or mannitol challenge must be demonstrated and documented at Visit 1
5.Must answer “Yes” to the question “Does a cold or flu make your asthma worse?”
6.To have had at least two documented severe asthma exacerbations within the last
24 months that were suspected by the patient to have been caused by a cold or flu and
To have had at least one documented severe asthma exacerbation within the last
12 months that was suspected by the patient to have been caused by a cold or flu
A severe asthma exacerbation is defined as worsening of asthma symptoms and:
-Use of systemic corticosteroids (or a temporary increase of at least 2-fold in a stable oral corticosteroid background dose) for at least three days and/or
- An unscheduled visit or emergency room visit due to asthma symptoms that requires at least one dose of systemic corticosteroids and/or
- An in-patient hospitalization due to asthma requiring at least one dose of systemic corticosteroids
The below defines what is acceptable to document exacerbations in this study
- Discharge summaries from a hospital, emergency department, or an urgent care facility indicating that a subject was hospitalized/treated with systemic steroids for an asthma exacerbation.
- Signed and dated notes from a referring physician, including information regarding diagnosis and treatment of an exacerbation with systemic steroids.
-Patients can provide evidence of prescriptions for systemic steroids used during an exacerbation.
-A documented conversation between the treating/referral physician or nurse/nurse practitioner certifying that a patient was treated for an exacerbation with steroids at their clinic or under their supervision. The dates (month/year)
of the exacerbations and verbal confirmation that appropriate prescriptions
were provided is necessary. This option should be used only if reasonable attempts to procure patient records have been unsuccessful.
A combination of the above is acceptable to document the two required exacerbations. However, it is necessary for the Investigator to document how they obtained confirmation of the patient’s asthma exacerbations. It is the Investigator’s responsibility to ensure patient eligibility into the clinical study.
7.Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception
8.Negative pregnancy test (urine) for female patients of childbearing potential
9. Motivation (in the Investigator’s opinion) to complete all study visits, the ability to communicate well with the Investigator and be capable of understanding the nature of the research and its treatment including its risks and benefits
10. Ability to read and write and use the electronic devices, including demonstrating an acceptable techniques when using the ePRO device, home spirometer and the I-neb
For participation in the optional genetic research:
10.Provision of signed and dated written informed consent for optional genetic research. If a patient declines to participate in the optional exploratory genetic research there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study |
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| E.4 | Principal exclusion criteria |
Patients should not enter if any exclusion criteria are fulfilled:
1.Involvement in planning and/or conduct of the study(applies to both AZ staff and staff at third party vendors or staff at the study sites)
2.Previous randomization to treatment in present study
3.Any condition, including findings in the medical history or in the pre-study assessm. that, in the opinion of the Investigator constitutes a risk or a contraindication for the participation of the pat in the study
4.Lung disease other than asthma (eg, chronic obstructive pulmonary disease, cystic fibrosis, allergic bronchopulmonary aspergillosis, active tuberculosis). patients with CT or chest X-ray findings indicating bronchiectasis which in the opinion of the Investigator are not clinically significant may be enrolled at the discretion of the Investigator.
5.Patients with ≥4 severe exacerbations during the last 12 months that the patient suspected were triggered by something else than an upper respiratory tract infection
6.Current participation in another clinical trial or participation in a clinical trial where the patient has received a dose of a test product (IMP) within 12 weeks prior to
entry into the study for small molecules and within 12 months prior to entry into the study for biologicals, or 5 times the half-life (whichever is the longest) of the biologic or small molecule IMP.
7.Patients who currently have, or have had within the past 3 months, any significant underlying medical condition(s) that could impact interpretation of results eg, infections, haematological disease, malignancy, renal, hepatic, coronary heart disease or other cardiovascular disease, including arrhythmias, endocrinological or gastrointestinal disease
8.Abnormal vital signs, after at least 10 minutes supine rest, defined as any of the following:
-In patients<60 years old, systolic blood pressure <90mmHG or >=150mmHg
-In patients >= 60 years old, systolic blood pressure <90 mmHg or ≥160 mmHg
-Diastolic blood pressure <50 mmHg or ≥100 mmHg
-HR <45 or >95 beats per minute
9.Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and any abnormalities in the 12-lead ECG that, as considered by the Investigator,
10.Prolonged QTcF >450 ms (for both gender) or shortened QTcF <340 ms or family history of long QT syndrome
11.PR(PQ) interval shortening <120ms (PR<120 ms but >110 ms is acceptable if there is no evidence of ventricular pre-excitation).
12.PR(PQ) interval prolongation (>240ms), intermittent second or third degree AV
block, or AV dissociation
13.QRS duration >120ms including persistent or intermittent bundle branch block
14.Patients with implantable cardiac defibrillator (ICD) or a permanent pacemaker and patients with symptomatic ventricular and / or atrial tachyarrhythmias
15.Patients with unstable angina pectoris or stable angina pectoris classified higher than Canadian Cardiovascular Society (CSS) class II or a myocardial infarction or stroke within 6 months
16.History of hospitalization within 12 months caused by heart failure or a diagnosis of heart failure higher than New York Heart Association (NYHA) class II
17.History of hypersensitivity to natural or recombinant Interferon beta-1a or to any of the drug preparation excipients
18.Received any marketed biologic agent (eg, omalizumab) within 12 months or
5 times the half-life (whichever is the longer) of the agent prior to enrolment
19.Significant history of depressive disorder or suicidal ideation. Specifically; individuals with current severe depression (ie, a low mood, which pervades all aspects of life and an inability to experience pleasure in activities that formerly were enjoyed); individuals with a past history of depression that required
hospitalization or referral to psychiatric services in the past 5 years; individuals who
currently feel suicidal or have attempted suicide in the past
20.History of epilepsy or seizures after age 5 years, other than febrile childhood seizure(s)
21.History of drug or alcohol abuse within 12 months prior to screening enrolment
22.Patients who have hepatic serum enzyme levels ≥2.5 times the normal range
23.Positive test for serum hepatitis B surface antigen, hepatitis C antibody, or HIV
24.Patients with a smoking history of ≥20 pack-years (1 pack year = 20 cigarettes smoked per day for 1 year)
25.Female who is breast-feeding, pregnant (verified by urine dipstick pregnancy test)
or intends to become pregnant during the study
26.Patients who are unable to demonstrate an acceptable spirometry technique
27.Patients that have previously been included in studies evaluating the investigational medicinal product
For participation in the optional genetic research. Any of the following is regarded as a criterion for exclusion from the genetic research:
28.Previous bone marrow transplant
29.Non-leukocyte depleted whole blood transfusion within 120 days of the date of the
PGx sample collection |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Number of severe exacerbations (during 14 days of treatment)
Duration of severe exacerbation
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During the 14 days of treatment |
|
| E.5.2 | Secondary end point(s) |
Number of moderate exacerbations (during 14 days of treatment)
Number of severe exacerbations (during day 1-30 after start of treatment)
Number of moderate exacerbations (during day 1-30 after start of treatment)
Time to sever exacerbation
Time to exacerbation (moderate or severee)
Change from treatment baseline in Patient reported outcomes in the following variables:
- Asthma control as measured by ACQ-6
- Day-time and night-time asthma symptom score and night-time awakenings as determined by area under the curve (AUC) over day 1-14
- Health-related quality of life as measured by AQLQ(S)
Day-time and night-time reliever medication use as determined by AUC over day 1-14 as change from the treatment baseline level
Lung function ie, PEF, FEV1
Morning and evening peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1) measured daily at home, as determined by AUC over day 1-14 as change from the baseline level
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the 14 days of treatment and for some up to 30 days after start of treatment |
|
| 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) | 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 | 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
| Argentina |
| Australia |
| Colombia |
| France |
| Korea, Democratic People's Republic of |
| Spain |
| United Kingdom |
|
| 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 | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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