A Study in Asthma Patients to Evaluate Efficacy, Safety and Tolerability of 14 Days Once Daily Inhaled Interferon Beta-1a After the Onset of Symptoms of an Upper Respiratory Tract Infection

Study Overview
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Brief Summary
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A study to investigate if inhaled Interferon beta-1a is safe and tolerated, and can prevent or reduce the severity of asthma attacks when administered to asthma patients at the onset of symptoms of common cold or influenza

Detailed Description
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The study will consist of a Pre-Treatment Phase followed by a Treatment Phase. Patients are screened and enter the Pre-Treatment phase where they remain until they develop symptoms of a common cold or the flu. During this Pre-Treatment Phase patients will be asked daily if they think they have a common cold or the flu. When the patient answers yes to the question that he/she is coming down with a common cold or the flu, arrangements are made to evaluate the patient at the study site and, if eligible, enters the Treatment Phase. Baseline assessments are performed and the patient is randomized 1:1 to receive 24 μg (metered dose) inhaled Interferon beta-1a or placebo once daily for 14 days (delivered by the I-neb® device [Philips Respironics]). Treatment should start as soon as possible but no later than 48 hours after the onset of the first of the common cold or flu symptoms. Patients will be assessed with regards to exacerbations and changes in respiratory symptoms and reliever medication use at home using an ePRO device. Lung function will be measured both at home by the patients and at the study site. There will be five clinical visits during the Treatment Phase and two visits after the end of treatment; efficacy and safety will be monitored until 2-3 weeks after end of treatment when a final follow-up visit will take place. The study population will comprise adult asthmatic patients on a maintenance treatment of medium to high dose inhaled corticosteroids and a second controller medication (eg, long- acting β2 agonist), with a documented history of at least two severe exacerbations within the last 24 months, of which at least one has occurred during the last 12 months, and it is suspected by the patient that these aforementioned exacerbations were triggered by an upper respiratory tract infection (ie, related to symptoms of a common cold or the flu).

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel Group, Multi-centre Phase IIa Study in Asthma Patients Comparing the Efficacy and Safety of Once Daily Inhaled Interferon Beta-1a to Placebo, Administered for 14 Days After the Onset of Symptoms of an Upper Respiratory Tract Infection for the Prevention of Severe Exacerbations

Conditions
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Asthma

Intervention / Treatment
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* Drug: Interferon beta-1a Nebuliser solution 48 μg/mL
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For inclusion in the study patients should fulfil the following criteria: Provision of signed and dated written informed consent prior to any study specific procedures Male or female aged 18 and above at the time of enrolment 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 Appendix G), and a second controller medication as recommended in the GINA guidelines (ie, LABA, leukotriene receptor antagonist or sustained release theophylline). 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 oral corticosteroids (OCS), theophylline, tiotropium, or leukotriene receptor antagonists. The maintenance treatment must have been kept at the same or at a higher level these last 12 months. 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 decrease 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 Must answer Yes to the question Does a cold or flu make your asthma worse? 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 common 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 common cold or flu Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception. Negative pregnancy test (urine) for female patients of childbearing potential 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 Ability to read and write and use the electronic devices, including demonstrating an acceptable technique when using the ePRO device, home spirometer and the I-neb Exclusion Criteria: Patients should not enter the study if any of the following exclusion criteria are fulfilled: Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and staff at third party vendors or staff at the study sites) Previous randomization to treatment in the present study Any condition, including findings in the medical history or in the pre-study assessments that, in the opinion of the Investigator, constitutes a risk or a contraindication for the participation of the patient in the study or that could interfere with the study objectives, conduct or evaluation 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 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 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 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 Abnormal vital signs, after at least 10 minutes supine rest, defined as any of the following: In patients < 60 years old, systolic blood pressure <90 mmHg or ≥150 mmHg 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 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, may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology (particularly in the protocol defined primary lead) or left ventricular hypertrophy Prolonged QTcF >450 ms (for both gender) or shortened QTcF <340 ms or family history of long QT syndrome PR(PQ) interval shortening <120ms (PR<120 ms but >110 ms is acceptable if there is no evidence of ventricular pre-excitation). PR(PQ) interval prolongation (>240ms), intermittent second or third degree AV block, or AV dissociation QRS duration >120ms including persistent or intermittent bundle branch block Patients with implantable cardiac defibrillator (ICD) or a permanent pacemaker and patients with symptomatic ventricular and / or atrial tachyarrhythmias 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 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 History of hypersensitivity to natural or recombinant Interferon beta-1a or to any of the drug preparation excipients 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 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 History of epilepsy or seizures after the age of 5 years, other than febrile childhood seizure(s) History of drug or alcohol abuse within 12 months prior to enrolment Patients who have hepatic serum enzyme levels ≥2.5 times the normal range Positive test for serum hepatitis B surface antigen, hepatitis C antibody, or HIV Patients with a smoking history of ≥20 pack-years (1 pack year = 20 cigarettes smoked per day for one year) Female who is breast-feeding, pregnant (verified by urine dipstick pregnancy test) or intends to become pregnant during the study Patients who are unable to demonstrate an acceptable spirometry technique Patients that have previously been included in studies evaluating the investigational medicinal product

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (matching)<br>Placebo, once daily inhalation for 14 days | Drug: Placebo<br>* Placebo solution for once daily inhalation for 14 days<br>|
| Experimental: Interferon beta-1a<br>Interferon beta-1a, 24 μg (metered dose) once daily inhalation for 14 days | Drug: Interferon beta-1a Nebuliser solution 48 μg/mL<br>* Interferon beta-1a, 0,5 ml (24 μg, metered dose) once daily inhalation for 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With a Severe Asthma Exacerbation During 14 Days of Treatment | Evaluation of the efficacy of inhaled AZD9412 compared to placebo in preventing severe exacerbations during the 14 day treatment phase following the onset of an URTI in asthmatic patients. A severe exacerbation was defined as worsening 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 3 consecutive days and/or an unscheduled visit or emergency room visit due to asthma symptoms that required at least 1 dose of systemic corticosteroids and/or an in-patient hospitalisation due to asthma requiring at least 1 dose of systemic corticosteroids. The number of patients with severe asthma exacerbations with onset during the treatment phase is presented for each treatment group. | Day 1 - 14 of the treatment phase. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Severe Asthma Exacerbations Within 7 and 30 Days Following Randomisation | Evaluation of the efficacy of inhaled AZD9412 compared to placebo in preventing severe exacerbations within 7 and 30 days after the start of treatment (Day 1). A severe exacerbation was defined as worsening 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 3 consecutive days and/or an unscheduled visit or emergency room visit due to asthma symptoms that required at least 1 dose of systemic corticosteroids and/or an in-patient hospitalisation due to asthma requiring at least 1 dose of systemic corticosteroids. The numbers of patients with severe asthma exacerbations with onset during Days 1 - 7 and Days 1 - 30 are presented for each treatment group. | Day 1 of treatment phase up to 30 days post-randomisation. | 
| Proportion of Patients With Moderate Asthma Exacerbation Within 7, 14 and 30 Days Following Randomisation | Evaluation of the efficacy of inhaled AZD9412 compared to placebo in preventing moderate exacerbations within 7, 14 and 30 days after the start of treatment (Day 1). A moderate exacerbation was defined as a temporary increase in maintenance therapy in order to prevent a severe event supported by a sustained (2 or more days) worsening in at least one key control metric, including asthma score, rescue use, night time awakening or morning peak expiratory flow. The numbers of patients with moderate exacerbations with onset during Days 1 - 7, Days 1 - 14 and Days 1 - 30 are presented for each treatment group. With respect to the Day 1-7 analysis, the model did not converge so the analysis could not be performed. | Day 1 of treatment phase up to 30 days post-randomisation. | 
| Time to First Severe Asthma Exacerbation During 30 Days Following Randomisation | The time to first event was calculated as start date of events - date of randomisation + 1. Patients with no observed event were censored at the date of their last visit, or for lost-to-follow-up patients, at the last time point after which an event could not be assessed. The median time to first exacerbation was not calculated in either treatment group due to low numbers of events. | From Day 1 of treatment phase up to 30 days post-randomisation. | 
| Time to First Moderate Asthma Exacerbation During 30 Days Following Randomisation | The time to first event was calculated as start date of events - date of randomisation + 1. Patients with no observed event were censored at the date of their last visit, or for lost-to-follow-up patients, at the last time point after which an event could not be assessed. The median time to first exacerbation was not calculated in either treatment group due to low numbers of events. | From Day 1 of treatment phase up to 30 days post-randomisation. | 
| Duration of Moderate or Severe Exacerbations | The duration of each individual moderate or severe exacerbation was calculated as: Cessation date of exacerbation - Start date of exacerbation + 1. The start date of a severe exacerbation was defined as the start date of systemic corticosteroids or increase of systemic corticosteroids or emergency room visit or hospital admission, whichever occurred first. The stop date was defined as the last day of systemic corticosteroids/increase of systemic corticosteroids or hospital discharge, whichever occurred last. The start date of a moderate exacerbation was defined as the first day of increase in temporary maintenance therapy. The stop date was defined as the last day of this treatment. The mean duration of moderate or severe exacerbations is presented for each treatment group. | Day 1 of treatment phase up to 30 days post-randomisation. | 
| Change in Asthma Control From Baseline up to 30 Days as Measured by the Asthma Control Questionnaire (ACQ-6) | The ACQ-6 consists of 6 questions to assess asthma control, each question measured on a 7-point scale scored from 0 (totally controlled) to 6 (severely uncontrolled). The ACQ-6 total score is computed as the un-weighted mean of the responses to the 6 questions. Baseline assessments were taken as the last non-missing assessment prior to randomisation. The change from baseline at Visit 4 (Day 7 +/- 1), at Visit 6 (Day 14 +/- 1) and at Visit 8 (Day 30) is presented for the total score and for each of the 6 questions. | From baseline up to 30 days after start of treatment phase. | 
| AUC for Change in Daytime and Night-time Asthma Symptom Score From Baseline up to 30 Days | Asthma symptoms during night-time and daytime were recorded by the patient each morning and evening in the Asthma Daily Diary on a daily basis. Symptoms were recorded using a scale of 0 to 3 where 0 indicates no asthma symptoms up to an absolute score of 3. Baseline assessments were taken as the last non-missing assessment prior to randomisation. The total daily asthma symptom score was calculated by taking the sum of the night-time and daytime asthma scores recorded each day. The outcome variable is the area under the curve (AUC) for change from baseline in day-time, night-time and total daily asthma symptom scores over Days 1-14, Days 1-7, Days 8-14 and Days 15-30. | From baseline up to 30 days after start of treatment phase. | 
| Change in the Proportion of Night-time Awakening Using the ePRO Questionnaire From Baseline up to 30 Days | Night-time awakenings due to asthma symptoms were recorded by the patient in the Asthma Daily Diary each morning by answering the question whether he/she woke up during the night due to asthma symptoms with a 'yes' or 'no' response. Biweekly means were calculated as the percentages of times the subject answered 'yes' over a period of 14 sequential days. Biweekly means are presented for the periods over Days 2-15 and Days 16-30. | From baseline up to 30 days after start of treatment phase. | 
| Change in Health-related Quality of Life as Measured by the Asthma Quality of Life Questionnaire (AQLQ[S]) From Baseline up to 30 Days | The AQLQ(S) was used to assess health-related quality of life and consisted of 32 questions. Patients were asked to score each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The questions were allocated to 4 domains assessing: activity limitation, symptoms, emotional function, and environmental stimuli The overall score was calculated as the mean of the responses to all questions. The mean change in overall score from baseline at Visit 6 (Day 14+/-1) and Visit 8 (Day 30) are presented. | From baseline up to 30 days after start of treatment phase. | 
| AUC for Change in Daytime and Night-time Reliever Medication Use From Baseline up to 14 Days | Patients recorded the number of reliever medication inhalations taken twice daily in the Asthma Daily Diary. The number of inhalations taken between the morning and evening lung function assessments were recorded in the evening. The number of inhalations taken between the evening and morning lung function assessments were recorded in the morning. Baseline assessments were taken as the last non-missing assessment prior to randomisation. The AUC for change from baseline over Days 1-14 (inclusive of Days 1 and 14) is presented. | From baseline up to Day 14 of treatment phase. | 
| AUC for Change in the Morning Peak Expiratory Flow (PEF) From Baseline to up to 30 Days | Patients measured morning PEF at home and recorded the results using the ePRO device. Baseline assessments were taken as the last non-missing assessment prior to randomisation. The mean AUC for change from baseline is presented for the periods Days 1-14, 1-7, 8-14 and 15-30. | From baseline up to 30 days after start of treatment phase. | 
| AUC for Change in the Morning Forced Expiratory Volume in 1 Second (FEV1) From Baseline up to 30 Days | Patients measured morning FEV1 at home and recorded the results using the ePRO device. Baseline assessments were taken as the last non-missing assessment prior to randomisation. The mean AUC for change from baseline is presented for the periods Days 1-14, 1-7, 8-14 and 15-30. | From baseline up to 30 days after start of treatment phase. | 
| AUC for Change in the Evening PEF From Baseline to up to 30 Days | Patients measured evening PEF at home and recorded the results using the ePRO device. Baseline assessments were taken as the last non-missing assessment prior to randomisation. The mean AUC for change from baseline is presented for the periods Days 1-14, 1-7, 8-14 and 15-30. | From baseline up to 30 days after start of treatment phase. | 
| AUC for Change in the Evening FEV1 From Baseline up to 30 Days | Patients measured evening FEV1 at home and recorded the results using the ePRO device. Baseline assessments were taken as the last non-missing assessment prior to randomisation. The mean AUC for change from baseline is presented for the periods Days 1-14, 1-7, 8-14 and 15-30. | From baseline up to 30 days after start of treatment phase. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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safety, asthma, Upper Respiratory Tract Infection, exacerbation, Interferon, efficacy, prevention