Clinical trial NCT04710134: Efficacy of Reslizumab Dose Escalation in Patients With Severe Asthma
Official title: Efficacy of Reslizumab Dose Escalation in Patients With Severe Asthma and Persistent Sputum Eosinophilia Despite Standard Dose Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Asthma; Eosinophilic
Keywords: Asthma
Eosinophilic bronchitis
Reslizumab
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: Teva Canada
First posted: 2021-01-14
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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).
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Sputum eosinophilia
timeFrame: At baseline and at the end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks.
Secondary outcomes:
measure: Change in Proportion of patients with sputum eosinophils ≤3%
timeFrame: At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks
measure: Change in Blood eosinophil count
timeFrame: At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks
measure: Change in ACQ5 score
timeFrame: At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks
measure: Change in FEV1
timeFrame: At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks
measure: Change in Number of asthma exacerbations
timeFrame: At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks
measure: Change in Type of asthma exacerbations (as determined by quantitative sputum cytometry)
timeFrame: At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks
measure: Change in Proportion of patients requiring daily oral corticosteroid therapy
timeFrame: At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks
measure: Change in Cumulative systemic corticosteroid dose
timeFrame: At the start and end of each of three dosing periods (every 16 weeks) for total study duration of 48 weeks
Other outcomes:
Locations:
city: Hamilton
country: Canada
facility: Firestone Institute of Respiratory Health, St Joseph's Hospital
state: Ontario
Study officials:
affiliation: McMaster University
name: Parameswaran Nair, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.