Anti-Interleukin-5 (IL5) Monoclonal Antibody (MAb) in Prednisone-dependent Eosinophilic Asthma

Phase 2

Completed

• Conditions: Severe Persistent Asthma; Eosinophilic Bronchitis
• Interventions: Biological: Reslizumab; Drug: Placebo

• Registration Number: NCT02559791
• Lead Sponsor: McMaster University

Brief Summary

The steroid sparing effect of anti interleukin (IL-5) monoclonal antibody has been proven, but the effectiveness of subcutaneous (SC) compared to intravenous (IV) administration of these drugs to suppress airway eosinophilia is still under debate. As part of a previous study, 100mg of mepolizumab were administered subcutaneously to a group of subjects with prednisone-dependent eosinophilic asthma. Despite this intervention, 50% of the subjects (15 patients participated in this study) had persistently elevated sputum eosinophil counts. The same 15 patients will be invited to participate in the current study, and if they provide their informed consent, will receive 2 monthly doses of placebo, followed by 4 monthly doses of IV reslizumab. The primary outcomes are blood and sputum eosinophils, and the secondary outcomes include sputum and blood Innate lymphoid cell-2 (ILC2) cells, cluster of differentiation 4 (CD4+) cells, cluster of differentiation-8 (CD8+) cells, cluster of differentiation-34 (CD34+), Eosinophil-Basophil cluster cells (Eo/B progenitor cells), forced expired volume in 1 second (FEV1), asthma control questionnaire (ACQ) and number of eosinophilic exacerbations. Measurements of the outcomes will be done before placebo, after placebo and after IV reslizumab. This study design will determine whether IV reslizumab is effective in suppressing airway eosinophilia in prednisone-dependent patients.

Detailed Description

Study design

Blinded placebo-controlled sequential clinical trial of 4 monthly doses of intravenously administered reslizumab.

The study will include two periods:

Period 1: After establishing the minimum dose of prednisone to observe sputum eosinophils ≥3% and blood eosinophils ≥300/µL, all subjects will receive 2 infusions (once monthly) of matching placebo.

Period 2: All subjects will then receive 4 infusions (once monthly) of reslizumab 3mg/kg.

Methods

15 patients (all of whom had sputum eosinophils ≥3% and blood eosinophils ≥300/µL) who were previously treated with S/C100 mg mepolizumab for at least 6 months, with the last dose at least 4 months before entering the study, will be invited to participate in the study.

Since discontinuing mepolizumab, these patients would have been re-established on their maintenance dose of daily prednisone + high doses of inhaled corticosteroids (ICS) and long acting beta agonist (LABA).

Baseline measurements of blood and sputum eosinophils, spirometry, symptoms (ACQ), and immune cells in blood and sputum (ILC2 cells, CD4 + cells, CD8+ cells, CD34+ Eo/B progenitor cells) will be enumerated by flow cytometry, and measures of local autoimmunity, using our established protocols at the start of Period 1 (baseline measurement).

They will then receive 2 infusions of placebo at monthly intervals, and measurements will be repeated at the end of Period 1 (post-placebo measurement).

The subjects will then receive by 4 infusions of 3 mg/kg reslizumab at monthly intervals. At the end of the 4 months, these measurements will be repeated (post-reslizumab measurement).

Study Timeline

• Study First Submitted: 2015-09-22
• Study First Submitted QC: 2015-09-23
• Study First Posted: 2015-09-24
• Study Start: 2015-10
• Status Verified: 2017-04
• Primary Completion: 2017-04
• Study Completion: 2017-08
• Last Update Submitted: 2018-04-03
• Last Update Posted: 2018-04-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

1. Informed consent Prior to the beginning of the study, patients must be willing and fully capable to provide written informed consent.

2. Prednisone-dependent eosinophilic asthma

   • Documented evidence of asthma: FEV1 reversibility of 12% and 200 ml after 200-400 micrograms of SABA. Or Methacholine challenge test <8mg/ml.
   • Documented history of persistent eosinophilia (sputum eosinophils ≥3% and/or blood eosinophils ≥300/µL) despite maintenance treatment with systemic glucocorticoids (5 to 35 mg per day of prednisone or its equivalent) before entering the study.

3. Previous treatment with 100 mg mepolizumab administered subcutaneously for at least 6 months, with the last dose at least 4 months before entering the study

4. Sputum eosinophils ≥3% and blood eosinophil ≥300/µL on visit 1 (screening visit).

5. Age between 18 and 75 years.

6. Male or eligible female subjects:

   To be eligible for entry into the study, females of childbearing potential (premenopausal women who are not permanently sterilized by means of hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) must commit to consistent and correct use of a highly effective method of birth control (true sexual abstinence, a vasectomized sexual partner, Implanon, female tubal occlusion, Intrauterine device (IUD), Depo provera injections, oral contraceptive pills or Nuvaring) for the duration of the trial and for 3 months after the last study drug administration. A serum pregnancy test is required of all females at the initial Baseline Visit (Visit 1). In addition, a urine pregnancy test will be performed for all females prior to enrollment, during each scheduled study visit prior to the injection of investigational product, and during the Follow-up Visit.

7. Male subjects who are sexually active must agree to use a double barrier method of contraception (condom with spermicide) from the first dose of study drug and for 3 months after the last dose of study drug.

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Exclusion Criteria

1. Currently receiving another monoclonal antibody
2. Currently receiving other investigational drug or immunosuppressive medication
3. Known hypersensitivity to Reslizumab product or any of its excipients.
4. Intolerance, hypersensitivity, insensitivity or neutralizing antibody to mepolizumab.
5. Malignancy within the last 2 years
6. Any co-morbidity that the investigator believes is a contraindication. This includes but is not limited to any respiratory (eg. COPD, pulmonary fibrosis, EGPA, ABPA), cardiovascular, gastrointestinal, hematological, neurological, immunological, musculoskeletal, renal, infectious, neoplastic or inflammatory condition that may place the safety of the subject at risk during the duration of the study, influence the results of the study or their interpretation, or prevent the patient from completing the entire duration of the study.
7. Current pregnancy or lactation
8. Current smoker or ex-smoker with a smoking history greater than 20 pack years.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Study participants	Reslizumab	All study participants will receive 2 monthly doses of placebo followed by 4 monthly doses of IV reslizumab 3mg/kg
Study participants	Placebo	All study participants will receive 2 monthly doses of placebo followed by 4 monthly doses of IV reslizumab 3mg/kg

Primary Outcome Measures

Name	Time	Method
Sputum eosinophil percentage	Measured before the placebo phase (week 2), after 2 infusions of placebo (week 10), and after 4 infusions (week 26) of reslizumab 3mg/kg	Change in sputum eosinophil %
Blood eosinophil absolute number	Measured before the placebo phase (week 2), after 2 infusions of placebo (week 10), and after 4 infusions/4 months (week 26) of reslizumab 3mg/kg	Change in blood eosinophil absolute number

Secondary Outcome Measures

Name	Time	Method
Number of eosinophilic exacerbations	During the placebo phase (2 months/weeks 2-10) and during the Reslizumab phase (weeks 10-26) 4 months)
Sputum and blood blood Innate lymphoid cell-2 (ILC2) cells, cluster of differentiation 4 (CD4+) cells, cluster of differentiation-8 (CD8+) cells, cluster of differentiation-34 (CD34+), Eosinophil-Basophil cluster cells (Eo/B progenitor cells),	Measured before the placebo phase (week 2), after 2 infusions of placebo (week 10), and after 4 infusions (week 26)of reslizumab 3mg/kg	Change in absolute number of both sputum and blood blood Innate lymphoid cell-2 (ILC2) cells. Change in absolute number of different T-lymphocyte populations in cluster of differentiation 4 (CD4+) cells, cluster of differentiation-8 (CD8+) cells, cluster of differentiation-34 (CD34+) and Eosinophil-Basophil cluster cells (Eo/B progenitor cells),
Forced Expiratory Volume in 1 second (FEV1)	Measured before the placebo phase (week 2), after 2 infusions of placebo (week 10), and after 4 infusions (week 26) of reslizumab 3mg/kg	Change in Forced Expiratory Volume in 1 second (FEV1)
Asthma Control Questionnaire (ACQ)	Measured before the placebo phase (week 2), after 2 infusions of placebo (week 10), and after 4 infusions (week 26) of reslizumab 3mg/kg	Change in ACQ

Trial Locations

Locations (1)

Firestone Institute for Respiratory Health, St. Joseph's Healthcare; 🇨🇦 Hamilton, Ontario, Canada