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

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)

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.

This is a phase-3 multicentre, double-blind, parallel-group placebo-controlled, randomised study.

The study will comprise of:

1. Screening/Run-in period of 4 to 6 weeks,
2. 52-week double-blind Treatment period,
3. 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 104-week open-label Treatment period prior to the 12-week post-treatment Follow-up period.

Inclusion Criteria:

1. 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.

2. 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.

3. Documented physician diagnosis of severe asthma confirmed and evaluated for at least 6 months prior to Visit 1.

4. 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.

5. 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.

6. Supportive evidence of asthma as documented by one of the following:

   1. Post-BD (albuterol/salbutamol) responsiveness of FEV1 ≥ 10% during Screening (15 to 30 min after administration of 4 puffs of albuterol/salbutamol with a maximum of 12 puffs of reliever medication only if tolerated by the participant) at either Visit 1 or Visit 2.

      If (a) is not achieved at Visit 1 or Visit 2, historical documentation by any of the below prior to Visit 1:

   2. Post-BD responsiveness of FEV1 ≥ 10%.

   3. Positive methacholine challenge defined as provocative concentration (PC20) of ≤ 16 mg/mL.

   4. PEF average daily diurnal variability > 13% over a 2-week period.

   5. Variability of FEV1 ≥ 12% between any two clinical visits.

   6. Positive exercise challenge test (defined as a fall in FEV1 of > 12%).

   7. FeNO ≥ 20 ppb despite confirmed ICS maintenance therapy.

7. 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.

8. Pre-BD FEV1 >50% and ≤ 95%PN OR FEV1/forced vital capacity (FVC) ratio ≤ 0.85 at either Visit 1 or Visit 2.

9. Evidence of uncontrolled asthma, with at least 1 of the below criteria:

   1. 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.
   2. 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.
   3. Sleep awakening due to asthma symptoms requiring use of reliever medication at least once during the Screening/Run-in period.
   4. Asthma symptoms 3 or more days per week in at least 1 week during the Screening/Run-in period.

10. Body weight ≥ 16 kg at Visit 1 (Screening) and Visit 3 (Randomisation).

Exclusion Criteria:

1. History of vocal cord dysfunction, cystic fibrosis, primary ciliary dyskinesia, or chronic rhinosinusitis with nasal polyposis.
2. 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.
3. 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.
4. Change in ICS dose within 1 month prior to Visit 1.
5. History of a life-threatening asthma exacerbation resulting in a hypoxic seizure or requiring intubation.