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

NCT02559791 | Completed Phase 2

• 1 other identifier: RES-38072
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Severe Persistent Asthma; Eosinophilic Bronchitis

Keywords

Reslizumab; Eosinophils; Asthma; Airway inflammation; Prednisone

Outcome Measures

Primary Outcomes (2)

• Sputum eosinophil percentage

  Change in sputum eosinophil %

  Measured before the placebo phase (week 2), after 2 infusions of placebo (week 10), and after 4 infusions (week 26) of reslizumab 3mg/kg

• Blood eosinophil absolute number

  Change in 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

Secondary Outcomes (4)

• 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

• 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

• 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

• Number of eosinophilic exacerbations

  During the placebo phase (2 months/weeks 2-10) and during the Reslizumab phase (weeks 10-26) 4 months)

Study Arms (1)

Study participants

EXPERIMENTAL

All study participants will receive 2 monthly doses of placebo followed by 4 monthly doses of IV reslizumab 3mg/kg

Biological: Reslizumab; Drug: Placebo

Interventions

Reslizumab BIOLOGICAL

Reslizumab 3ml/kg once monthly for 4 months

Also known as: Anti Il 5 monoclonal antibody

Study participants

Placebo DRUG

Matching placebo once monthly for 2 months

Also known as: 0.9% normal saline

Study participants

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed consent Prior to the beginning of the study, patients must be willing and fully capable to provide written informed consent.
• 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.
• 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
• Sputum eosinophils ≥3% and blood eosinophil ≥300/µL on visit 1 (screening visit).
• Age between 18 and 75 years.
• 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.
• 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.

You may not qualify if:

• Currently receiving another monoclonal antibody
• Currently receiving other investigational drug or immunosuppressive medication
• Known hypersensitivity to Reslizumab product or any of its excipients.
• Intolerance, hypersensitivity, insensitivity or neutralizing antibody to mepolizumab.
• Malignancy within the last 2 years
• 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.
• Current pregnancy or lactation
• Current smoker or ex-smoker with a smoking history greater than 20 pack years.

Sponsors & Collaborators

• McMaster University: lead
• Teva Pharmaceuticals USA: collaborator
• St. Joseph's Healthcare Hamilton: collaborator

Study Sites (1)

Firestone Institute for Respiratory Health, St. Joseph's Healthcare

Hamilton, Ontario, L8N 4A6, Canada

Location

Related Publications (19)

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• Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemiere C, Pizzichini E, Cartier A, Hussack P, Goldsmith CH, Laviolette M, Parameswaran K, Hargreave FE. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006 Mar;27(3):483-94. doi: 10.1183/09031936.06.00137704.

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• Zhang J, Kuvelkar R, Murgolo NJ, Taremi SS, Chou CC, Wang P, Billah MM, Egan RW. Mapping and characterization of the epitope(s) of Sch 55700, a humanized mAb, that inhibits human IL-5. Int Immunol. 1999 Dec;11(12):1935-44. doi: 10.1093/intimm/11.12.1935.

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• Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord ID. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009 Mar 5;360(10):973-84. doi: 10.1056/NEJMoa0808991.

  PMID: 19264686 BACKGROUND

• Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012 Aug 18;380(9842):651-9. doi: 10.1016/S0140-6736(12)60988-X.

  PMID: 22901886 BACKGROUND

• Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW, Chanez P; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014 Sep 25;371(13):1198-207. doi: 10.1056/NEJMoa1403290. Epub 2014 Sep 8.

  PMID: 25199059 BACKGROUND

• Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, Wilkins HJ, Henkel T, Nair P; Res-5-0010 Study Group. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011 Nov 15;184(10):1125-32. doi: 10.1164/rccm.201103-0396OC. Epub 2011 Aug 18.

  PMID: 21852542 BACKGROUND

• Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, Ortega HG, Pavord ID; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014 Sep 25;371(13):1189-97. doi: 10.1056/NEJMoa1403291. Epub 2014 Sep 8.

  PMID: 25199060 BACKGROUND

• Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, Hargreave FE, O'Byrne PM. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009 Mar 5;360(10):985-93. doi: 10.1056/NEJMoa0805435.

  PMID: 19264687 BACKGROUND

• Nair P. Anti-interleukin-5 monoclonal antibody to treat severe eosinophilic asthma. N Engl J Med. 2014 Sep 25;371(13):1249-51. doi: 10.1056/NEJMe1408614. Epub 2014 Sep 8. No abstract available.

  PMID: 25197762 BACKGROUND

• McKenzie AN. Type-2 innate lymphoid cells in asthma and allergy. Ann Am Thorac Soc. 2014 Dec;11 Suppl 5(Suppl 5):S263-70. doi: 10.1513/AnnalsATS.201403-097AW.

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• Hogan SP, Rosenberg HF, Moqbel R, Phipps S, Foster PS, Lacy P, Kay AB, Rothenberg ME. Eosinophils: biological properties and role in health and disease. Clin Exp Allergy. 2008 May;38(5):709-50. doi: 10.1111/j.1365-2222.2008.02958.x. Epub 2008 Apr 1.

  PMID: 18384431 BACKGROUND

• Smith SG, Chen R, Kjarsgaard M, Huang C, Oliveria JP, O'Byrne PM, Gauvreau GM, Boulet LP, Lemiere C, Martin J, Nair P, Sehmi R. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016 Jan;137(1):75-86.e8. doi: 10.1016/j.jaci.2015.05.037. Epub 2015 Jul 17.

  PMID: 26194544 BACKGROUND

• Kabata H, Moro K, Fukunaga K, Suzuki Y, Miyata J, Masaki K, Betsuyaku T, Koyasu S, Asano K. Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation. Nat Commun. 2013;4:2675. doi: 10.1038/ncomms3675.

  PMID: 24157859 BACKGROUND

• Mukherjee M, Aleman Paramo F, Kjarsgaard M, Salter B, Nair G, LaVigne N, Radford K, Sehmi R, Nair P. Weight-adjusted Intravenous Reslizumab in Severe Asthma with Inadequate Response to Fixed-Dose Subcutaneous Mepolizumab. Am J Respir Crit Care Med. 2018 Jan 1;197(1):38-46. doi: 10.1164/rccm.201707-1323OC.

  PMID: 28915080 DERIVED

Related Links

• Global Initiative for Asthma. GINA report, global strategy for asthma management and prevention. Report 2015.

MeSH Terms

Conditions

Asthma

Interventions

reslizumab; Saline Solution

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Parameswaran Nair, MD, PhD

  McMaster University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 22, 2015
• First Posted: September 24, 2015
• Study Start: October 1, 2015
• Primary Completion: April 1, 2017
• Study Completion: August 1, 2017
• Last Updated: April 4, 2018

Record last verified: 2017-04

Locations

CA (1)