Efficacy of Reslizumab Dose Escalation in Patients With Severe Asthma

Study Overview
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Brief Summary
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Dose escalation of reslizumab can ameliorate sputum eosinophilia in severe asthmatics who have persistent sputum eosinophilia despite treatment with reslizumab at the standard dose.

Detailed Description
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Monoclonal antibody therapies targeting the interleukin-5 (IL-5) pathway, critical for maintaining eosinophil homeostasis, have been developed as adjunct therapy for severe asthma with an eosinophilic phenotype. Reslizumab/Cinqair is an approved/marketed product administered monthly by intravenous to severe eosinophilic asthmatics at 3mg/kg. However some patients do exhibit sputum eosinophilia at this dosage. We are investigating whether those that receive 3mg/kg that have persistent sputum eosinophils would benefit at a higher dose of 4mg/kg and those that still exhibit sputum eosinophils at this elevated dose would show improvement at 5mg/kg. The overall aim of this study is to determine whether dose escalation of reslizumab can ameliorate sputum eosinophilia in severe asthmatics who have persistent sputum eosinophilia despite treatment with reslizumab at the standard dose.

Official Title
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Efficacy of Reslizumab Dose Escalation in Patients With Severe Asthma and Persistent Sputum Eosinophilia Despite Standard Dose Therapy

Conditions
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Asthma; Eosinophilic

Intervention / Treatment
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* Biological: Reslizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Asthma confirmed within the past 2 years by: a. A ≥12% improvement in forced expiratory volume in 1 second (FEV1) after use of a beta agonist, or a methacholine challenge test showing a ≥20% reduction in FEV1 after a concentration of ≤8 mg/mL of methacholine Blood eosinophils ≥400 cells/µL and/or sputum eosinophils ≥3% (or presence of moderate-to-many free eosinophil granules) at the time of study enrollment Treated with an inhaled corticosteroid at a dose of ≥1500 µg of fluticasone propionate (or equivalent) and a long-acting beta agonist with or without oral corticosteroids Ability to provide informed consent Exclusion Criteria: Current smokers, ex-smokers with greater than 20 pack-year history or ex-smokers who have smoked within the past 6 months Any comorbidity that the investigator believes is a contraindication including but not limited to any respiratory (e.g., chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis, pulmonary fibrosis), cardiovascular (e.g., congestive cardiac failure, pulmonary hypertension), hematological, gastrointestinal, immunological, musculoskeletal, infectious, or neoplastic disease Currently treated with another biologic agent (excluding denosumab for osteoporosis) Use of anti-IL-5 (other than reslizumab) or anti-IgE mAb use within the past one month Use of a systemic immunosuppressive or immunomodulatory agent within 6 months prior to study entry Suspected of abusing drugs or alcohol Pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Patients will initially all receive 3 mg/kg of reslizumab. After 16 weeks of treatment, those patients that have uncontrolled sputum eosinophilia will be escalated to 4 mg/kg; the remaining patients will continue on 3 mg/kg. After a further 16 weeks of therapy, those that still have uncontrolled sputum eosinophilia will receive 5 mg/kg; the remaining patients will continue on the dose they were receiving (i.e., either 3 or 4 mg/kg).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Reslizumab 3 mg/kg<br>All patients will initially receive reslizumab 3 mg/kg for at least 16 weeks. | Biological: Reslizumab<br>* Reslizumab 3,4, or 5 mg/kg IV q4 weeks<br>|
| Active Comparator: Reslizumab 4 mg/kg<br>Patients who have uncontrolled sputum eosinophilia at 16 weeks will receive an increased dose of 4 mg/kg for the next 16 weeks. The patients with controlled eosinophilia will continue to receive 3 mg/kg. | Biological: Reslizumab<br>* Reslizumab 3,4, or 5 mg/kg IV q4 weeks<br>|
| Active Comparator: Reslizumab 5 mg/kg<br>Patients who have uncontrolled sputum eosinophilia who were previously receiving reslizumab at 4 mg/kg at 32 weeks will receive an increased dose of 5 mg/kg for the next 16 weeks. The patients remaining patients will continue on the dose they were receiving (i.e., either 3 mg/kg or 4 mg/kg). | Biological: Reslizumab<br>* Reslizumab 3,4, or 5 mg/kg IV q4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Sputum eosinophilia | Absolute difference between the mean sputum eosinophil percent | At baseline and at the end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Proportion of patients with sputum eosinophils ≤3% | Number of patients with sputum eosinophils ≤3% | At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks | 
| Change in Blood eosinophil count | Absolute blood eosinophil count | At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks | 
| Change in ACQ5 score | Mean of 5-question Asthma Control Questionnaire | At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks | 
| Change in FEV1 | Forced expired volume in 1 second measured in litres | At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks | 
| Change in Number of asthma exacerbations | Number of asthma event that are defined as exacerbation (requiring increase in corticosteroids) | At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks | 
| Change in Type of asthma exacerbations (as determined by quantitative sputum cytometry) | Type of exacerbation shown by: neutrophilic, eosinophilic or mixed neutrophilic/eosinophilic bronchitis | At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks | 
| Change in Proportion of patients requiring daily oral corticosteroid therapy | Number of patients that require daily oral corticosteroids | At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks | 
| Change in Cumulative systemic corticosteroid dose | The total daily dose of oral corticosteroids | At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Eosinophilic bronchitis, Reslizumab