Efficacy of Reslizumab Dose Escalation in Patients With Severe Asthma

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

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

Study Overview

• Status: Completed
• Conditions: Asthma; Eosinophilic
• Intervention / Treatment: Biological: Reslizumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • Firestone Institute of Respiratory Health, St Joseph's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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

2. 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
3. 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
4. Ability to provide informed consent

Exclusion Criteria:

1. Current smokers, ex-smokers with greater than 20 pack-year history or ex-smokers who have smoked within the past 6 months
2. 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
3. Currently treated with another biologic agent (excluding denosumab for osteoporosis)
4. Use of anti-IL-5 (other than reslizumab) or anti-IgE mAb use within the past one month
5. Use of a systemic immunosuppressive or immunomodulatory agent within 6 months prior to study entry
6. Suspected of abusing drugs or alcohol
7. Pregnancy or lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Reslizumab 3 mg/kg; All patients will initially receive reslizumab 3 mg/kg for at least 16 weeks.	Biological: Reslizumab; Reslizumab 3,4, or 5 mg/kg IV q4 weeks
Active Comparator: Reslizumab 4 mg/kg; 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; Reslizumab 3,4, or 5 mg/kg IV q4 weeks
Active Comparator: Reslizumab 5 mg/kg; 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; Reslizumab 3,4, or 5 mg/kg IV q4 weeks

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: Teva Canada
• Investigators: Principal Investigator: Parameswaran Nair, MD, PhD, McMaster University

Publications and helpful links

General Publications

• Mukherjee M, Lim HF, Thomas S, Miller D, Kjarsgaard M, Tan B, Sehmi R, Khalidi N, Nair P. Airway autoimmune responses in severe eosinophilic asthma following low-dose Mepolizumab therapy. Allergy Asthma Clin Immunol. 2017 Jan 6;13:2. doi: 10.1186/s13223-016-0174-5. eCollection 2017.
• Mukherjee M, Forero DF, Tran S, Boulay ME, Bertrand M, Bhalla A, Cherukat J, Al-Hayyan H, Ayoub A, Revill SD, Javkar T, Radford K, Kjarsgaard M, Huang C, Dvorkin-Gheva A, Ask K, Olivenstein R, Dendukuri N, Lemiere C, Boulet LP, Martin JG, Nair P. Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena. Eur Respir J. 2020 Oct 8;56(4):2000117. doi: 10.1183/13993003.00117-2020. Print 2020 Oct.
• Mukherjee M, Bulir DC, Radford K, Kjarsgaard M, Huang CM, Jacobsen EA, Ochkur SI, Catuneanu A, Lamothe-Kipnes H, Mahony J, Lee JJ, Lacy P, Nair PK. Sputum autoantibodies in patients with severe eosinophilic asthma. J Allergy Clin Immunol. 2018 Apr;141(4):1269-1279. doi: 10.1016/j.jaci.2017.06.033. Epub 2017 Jul 24.
• Passarell J, Jaworowicz D, Ludwig E, Rabinovich-Guilatt L, Cox DS, Levi M, Garin M, Fiedler-Kelly J, Bond M. Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Modeling of Weight-Based Intravenous Reslizumab Dosing. J Clin Pharmacol. 2020 Aug;60(8):1039-1050. doi: 10.1002/jcph.1609. Epub 2020 Apr 25.

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2021
• Primary Completion (Actual): January 9, 2024
• Study Completion (Actual): January 9, 2024

Study Registration Dates

• First Submitted: January 8, 2021
• First Submitted That Met QC Criteria: January 12, 2021
• First Posted (Actual): January 14, 2021

Study Record Updates

• Last Update Posted (Actual): January 25, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Asthma; Reslizumab; Eosinophilic bronchitis
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Hematologic Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Leukocyte Disorders; Eosinophilia; Hypereosinophilic Syndrome; Asthma; Pulmonary Eosinophilia; Anti-Asthmatic Agents; Respiratory System Agents; Reslizumab
• Other Study ID Numbers: RES-2020-20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No