A Study to Investigate the Efficacy and Safety of Tezepelumab Compared With Placebo in Children 5 to < 12 Years Old With Severe Asthma

Study Overview
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Brief Summary
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To assess the efficacy and safety of tezepelumab in pediatric participants with severe uncontrolled asthma on medium to high-dose inhaled corticosteroids (ICS) and at least one additional asthma controller medication with or without oral corticosteroids.

Detailed Description
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This is a phase-3 multicentre, double-blind, parallel-group placebo-controlled, randomised study. The study will comprise of: Screening/Run-in period of 4 to 6 weeks, 52-week double-blind Treatment period, Post-treatment Follow-up period of 12 weeks. Participants will be randomised 2:1 to receive either tezepelumab or placebo administered by (SC) Subcutaneous injections for 52 weeks (double-blind Treatment period). There will then be a 12-week off-treatment Follow-up period for participants who do not continue in the optional open-label Active Treatment Extension period. An optional open-label Active Treatment Extension will allow all eligible participants the opportunity to receive active treatment with tezepelumab. The Active Treatment Extension period of the study will start following the 52-week double-blind Treatment period and will consist of a 24-week open-label Treatment period prior to the 12-week post-treatment Follow-up period.

Official Title
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A Multicentre, Randomised, Double-Blind, Parallel-Group Placebo-Controlled, Phase 3, Efficacy and Safety Study of Tezepelumab in 5 to < 12 Year Old Children With Severe Uncontrolled Asthma (HORIZON)

Conditions
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Asthma

Intervention / Treatment
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* Biological: Tezepelumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent from (ICF) at least one parent/caregiver (as per local guidelines) and accompanying informed assent from the participant (where the participant is able to provide assent) prior to admission to the study. Participants must be 5 to < 12 years of age, at the time of signing the assent form (as applicable per local guidelines) and their caregivers signing the ICF and at Visit 3. Documented physician diagnosis of severe asthma for at least 6 months prior to Visit 1. Documented physician-prescribed treatment with a total daily dose of either medium or high dose, for at least 3 months with stable dose ≥ 1 month prior to Visit 1. Documented treatment with at least one additional maintenance asthma controller medication is required according to local guidelines and standard of care; (long-acting beta agonist, leukotriene receptor antagonist, long-acting muscarinic antagonist) for at least 3 months with stable dose ≥ 1 month prior to Visit 1. Evidence of asthma as documented by one of the following: Documented historical BD responsiveness of FEV1 ≥ 10% in the previous 12 months prior to Visit 1 OR Documented historical methacholine challenge result of ≤ 16 mg/mL in the previous 12 months prior to Visit 1 OR Post-BD (albuterol/salbutamol) responsiveness of FEV1 ≥ 10% during Screening (15 to 30 min after administration of 4 puffs of albuterol/salbutamol) at either Visit 1 or Visit 2. History of at least 2 severe asthma exacerbation events OR 1 severe asthma exacerbation event resulting in hospitalisation within 12 months prior to Visit 1. Pre-BD FEV-1 >50% and ≤ 95%PN OR FEV1/forced vital capacity (FVC) ratio ≤ 0.8 at either Visit 1 or Visit 2. Evidence of uncontrolled asthma, with at least 1 of the below criteria: ACQ-IA score ≥ 1.5 at least once during Screening/Run-in, including Visit 3 (prior to Randomisation) for participants ≥ 6 years old at Screening Use of reliever medication, other than as a preventive for exercise induced bronchospasm, on 3 or more days per week for at least 1 week during the Screening/Run-in period Sleep awakening due to asthma symptoms requiring use of reliever medication at least once during the Screening/Run-in period Asthma symptoms 3 or more days per week in at least 1 week during the Screening/Run-in period Body weight ≥ 16 kg at Visit 1 (Screening) and Visit 3 (Randomisation). Exclusion Criteria: History of cystic fibrosis, primary ciliary dyskinesia, or chronic rhinosinusitis with nasal polyposis. History of any clinically significant disease or disorder other than asthma which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant's ability to participate in the study. History of a clinically significant deterioration in asthma or asthma exacerbation including those requiring use of systemic corticosteroids or increase in the maintenance dose of oral corticosteroids within 30 days prior to Visit 1. Change in ICS dose within 1 month prior to Visit 1. History of a life-threatening asthma exacerbation resulting in a hypoxic seizure or requiring intubation or mechanical ventilation.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 11 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized in a 2:1 ratio to either tezepelumab or matching placebo both administered subcutaneously
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tezepelumab<br>Participants will be receiving tezepelumab subcutaneous injection | Biological: Tezepelumab<br>* Participants will be receiving subcutaneous injection of tezepelumab<br>* Other names: MEDI9929 and AMG157;|
| Placebo Comparator: Placebo<br>Participants will be receiving placebo through a subcutaneous injection | Other: Placebo<br>* Participants will be receiving subcutaneous injection of matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized asthma exacerbation rate (AAER) | To assess the effect of tezepelumab on severe asthma exacerbations in children 5 to < 12 years old with severe uncontrolled asthma compared with placebo. | From Baseline to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in pre-bronchodilator (pre-BD) forced expiratory volume in 1 second (FEV1) percent predicted normal (PN) | To assess the effect of tezepelumab on pulmonary function (FEV1) in children with severe uncontrolled asthma compared with placebo. Pre-bronchodilator FEV1% PN will be determined by spirometry at the clinic visit. | From Baseline to Week 52 | 
| AAER associated with allergic asthma | AAER will be assessed in association with both allergic asthma (defined by a positive perennial allergen using serum specific IgE [FEIA]). | From Baseline to Week 52 | 
| Time to first severe asthma exacerbation | Time to first severe asthma exacerbation will be assessed. | From Baseline to Week 52 | 
| Proportion of participants with ≥ 1 severe asthma exacerbation | Proportion of participants with ≥ 1 severe asthma exacerbation will be assessed. | From Baseline to Week 52 | 
| AAER associated with ER visit or hospitalisation | AAER will be assessed in association with ER visits or hospitalisations. | From Baseline to Week 52 | 
| Cumulative asthma exacerbation days | The cumulative asthma exacerbation days from baseline to week 52 will be assessed | From Baseline to Week 52 | 
| Change from baseline in Paediatric Asthma Quality of Life Questionnaire (PAQLQ-IA) total score | Change from baseline of PAQLQ-IA total score will be assessed. The PAQLQ was developed to measure the functional problems (physical, emotional, and social) that are most troublesome to children with asthma. The PAQLQ-IA has 23 questions in 3 domains (symptoms, activity limitation, and emotional function). Participants are asked to think about how they have been during the previous week and respond to each question on a 7-point scale (1 = extremely bothered to 7 = not bothered at all or 1 = all of the time to 7 = none of the time). There are 2 coloured cards (green and blue), which list sets of response options appropriate to different questions. The appropriate card should be used by the participant during completion of each question and then taken back when it is no longer required. The overall PAQLQ-IA score is the mean of all 23 responses and the individual domain scores are the means of the items in those domains. | From Baseline to Week 52 | 
| Change from baseline in weekly mean daily Paediatric Asthma Symptom Observer (PASO) score | Change from baseline in PASO score will be assessed. The PASO questionnaire will be completed by the caregiver each day from the evening of Treatment period. Caregivers in this study will complete 4 items from the morning assessment capturing night-time asthma symptoms, rescue medication use, night-time awakenings, and maintenance asthma medication use. The evening assessment will capture daytime asthma symptoms, rescue medication use, activity limitation and change in asthma. | From Baseline to Week 52 | 
| Change from baseline in Asthma Control Questionnaire - Interviewer Administered (ACQ-IA) score | Change from baseline in ACQ-IA score will be assessed. The ACQ-IA will only be completed for participants ≥ 6 years old at Screening. The ACQ-IA is administered by trained individuals according to standardised instructions to help the child understand concepts like symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, and wheezing) and use of SABA during the past week using a 7-point scale. The ACQ-IA score is calculated by taking the mean of the 6 equally weighted items and ranges from 0 (well controlled) to 6 (extremely poorly controlled). The estimated minimal clinically important difference is 0.5 | From Baseline to Week 52 | 
| Change from baseline in weekly mean rescue medication use | Change from baseline in weekly mean rescue medication use will be assessed. | From Baseline to Week 52 | 
| Change from baseline in weekly mean number of night-time awakenings | Change from baseline in weekly mean number of night-time awakenings will be assessed. | From Baseline to Week 52 | 
| Change from baseline in blood eosinophil count | Change from baseline in blood eosinophil count will be assessed. | From Baseline to Week 52 | 
| Change from baseline in fractional exhaled nitric oxide (FeNO) | Change from baseline in FeNO will be assessed. | From Baseline to Week 52 | 
| Change from baseline in total serum IgE | Change from baseline in total serum IgE will be assessed. | From Baseline to Week 52 | 
| Change from baseline in pre-bronchodilator (pre-BD) peak expiratory flow (PEF) | The effect of tezepelumab on pulmonary function compared with placebo will be assessed using spirometry. | From Baseline to Week 52 | 
| Number of asthma--related healthcare resource utilization (HRU) | Mean number and type of Asthma specific HRU (eg, unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications) will be assessed. | From Baseline to Week 52 | 
| Number of participant/caregiver health-related absences | Mean number of participant/caregiver health-related absences from work/school due to asthma will be assessed. | From Baseline to Week 52 | 
| Serum concentrations of tezepelumab | To evaluate the pharmacokinetics of tezepelumab. | At Baseline, Week 4, Week 24, and Week 52 | 
| Incidence of anti-drug antibodies (ADAs) | To evaluate the immunogenicity of tezepelumab. | At Baseline, and from time of first dose at Week 0 to end of study at week 64 | 
| Incidence of neutralising antibodies (nAbs) | To evaluate the immunogenicity of tezepelumab. | At Baseline, and from time of first dose at Week 0 to end of study at week 64 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Uncontrolled Asthma, Severe Uncontrolled Asthma, Human monoclonal antibody (IgG2λ) cytokine