Effect of Mepolizumab in Severe Bilateral Nasal Polyps

ID: NCT03085797
Status: Recruiting
Phase: Phase 3
Start Date: May 25, 2017
First Submitted: March 15, 2017
Last Updated: February 22, 2018
Results: N/A
Organization: GlaxoSmithKline
Sponsors & Collaborators: GlaxoSmithKline, CRF health, Bristol-Myers Squibb
Location: Argentina, Australia, Canada, Germany, Korea, Republic of, Netherlands, Romania, Russian Federation, Sweden, United Kingdom, United States
Conditions: Polyps, Nasal
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Study Description

Brief Summary

Nasal polyps (NP) has long been known as chronic inflammatory disease of the nasal mucosa. This disease is characterized by the presence of polyps in the upper nasal cavity, originating from within the ostiomeatal complex. The presence of polyps can cause long-term symptoms such as prominent nasal obstruction, post-nasal drip, loss of smell, and discharge.

Mepolizumab (SB240563) is an Immunoglobulin G 1 [IgG1], kappa humanized monoclonal antibody (mAB) that blocks human interleukin-5 (hIL-5) from binding to the interleukin-5 (IL-5) receptor complex expressed on the eosinophil cell surface and thus inhibits signaling. Neutralization of IL-5 with mepolizumab has been shown to reduce blood, sputum and tissue eosinophils and hence is assumed to be a treatment option in a number of eosinophilic diseases including NP.

The aim of this randomized, double-blind, parallel group, phase 3 (PhIII) study is to assess the clinical efficacy and safety of 100 milligram (mg) subcutaneous (SC) mepolizumab as an add on to maintenance treatment in adults with severe bilateral NP. The study will include a 4-week run in period followed by randomization to a 52-week treatment period. Participants will receive mepolizumab 100 mg or placebo SC by the investigator or delegate via a pre-filled safety syringe every 4 weeks for 52 weeks. Throughout the entire study period (run in + treatment period + follow up), participants will receive a standard of care (SoC) for NP which consists of daily mometasone furorate (MF) nasal spray, and if required, saline nasal douching, occasional short courses of high dose oral corticosteroids (OCS) and/or antibiotics. The treatment period will consist of thirteen, 4-weekly doses of mepolizumab or placebo. In addition, up to the first 200 randomized participants will be followed up every other month for up to a further 6 months after the Visit 15 (7 months post last dose) in order to assess maintenance of response and to validate a physiological model derived from the previous Phase 2 study. Approximately 400 participants will be randomized (200 participants per treatment arm) in to the study. Total duration of the study will be 76 weeks for first 200 randomized participants and 52 weeks for remainder of participants who are not participating in the 6 months no treatment follow up.

Detailed Description

Condition or disease Intervention/treatment Phase

Polyps, Nasal

Drug: Mepolizumab
Other Names
Drug: Placebo
Other Names
Drug: Mometasone furoate
Other Names
Phase 3

Tracking Information

First Submitted DateMarch 15, 2017
Last Update Posted DateFebruary 22, 2018
Actual Start DateMay 25, 2017
Anticipated Completion DateAugust 02, 2019
Actual Primary Completion DateAugust 02, 2019
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Change from Baseline in total endoscopic NP score at Week 52 [Time Frame: Baseline and Week 52]

    Each nostril was assessed for polyps and graded at Week 0, 4, 8, 12, 16, 20, 24, 28, 32, 36 and 52. The grading was based on NP size and recorded as the sum of the right and left nostril scores. Total score ranges from 0 to 8; higher scores indicate worse status. Individual score ranges from 0 (no polyps) to 4 (large polyps causing almost complete congestion/ obstruction of the inferior meatus).

  • Change from Baseline in mean nasal obstruction visual analogue scale (VAS) score during the 4 weeks prior to Week 52 [Time Frame: Baseline and up to Week 52]

    VAS is an instrument that measures a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. The participant will be asked to indicate on a VAS (0 to 100 units on an electronic device which corresponds to 0 to 10 score) the severity of 5 nasal polyposis symptoms, one VAS for each symptom (1. nasal obstruction; 2. nasal discharge; 3. mucus in the throat; 4. loss of smell; 5. facial pain) and overall VAS symptoms score. The left hand side of the scale (0) represents "None" and the right hand side of the scale (100) represents "As bad as you can imagine". VAS will be collected daily in morning from screening up to Week 52.

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • Time to first nasal surgery up to Week 52 [Time Frame: Up to Week 52]

    NP surgery is defined as any procedure involving instruments resulting in incision and removal of tissue (polypectomy) or dilatation of the air passages (e.g. balloon sinuplasty) in the nasal cavity. Time to first nasal surgery up to Week 52 will be assessed.

  • Change from Baseline in mean overall VAS symptom score during the 4 weeks prior to Week 52 [Time Frame: Baseline and up to Week 52]

    The mean VAS score over the last 7 days before Visit 2 (Week 0) will be used to determine the Baseline value. The participant will be asked to indicate on a VAS (0 to 100 units on an electronic device which corresponds to 0 to 10 score) the severity of 5 nasal polyposis symptoms, one VAS for each symptom (1. nasal obstruction; 2. nasal discharge; 3. mucus in the throat; 4. loss of smell; 5. facial pain) and overall VAS symptoms score. The left hand side of the scale (0) represents "None" and the right hand side of the scale (100) represents "As bad as you can imagine". VAS will be collected daily in morning from screening up to Week 52.

  • Change from Baseline in sino-nasal outcome test (SNOT)-22 total score at Week 52 [Time Frame: Baseline and Week 52]

    The SNOT-22 is a health related quality of life questionnaire and has been shown to be a reliable outcome measure for successful septal surgery and in chronic rhinosinusitis (CRS) management. It is also a tool to evaluate outcomes in nasal polyposis. Participants will be asked to rate the severity of their condition on each of the 22 items over the previous 2 weeks using a 6-point rating scale of 0-5 including: 0 = Not present/no problem; 1 = Very mild problem; 2 = Mild or slight problem; 3 = Moderate problem; 4 = Severe problem; 5 = Problem as "bad as it can be". The theoretical total score range for the SNOT-22 is 0-110, where lower scores imply less severe symptoms and higher scores representing a worse quality of life. The SNOT-22 questionnaire will be completed by participants at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36 and 52.

  • Number of mgs per year of prednisolone-equivalent OCS dose up to Week 52 [Time Frame: Up to Week 52]

    The number of courses of systemic steroids and OCS as well as the dose and duration of the courses will be recorded. The dose for a course of OCS will be according to the participants SoC for OCS use for its NP condition. A course of systemic corticosteroid is considered continuous if treatment is separated by less than 7 days. Various doses of intravenous and oral steroids will be converted to prednisolone-equivalent OCS.

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleEffect of Mepolizumab in Severe Bilateral Nasal Polyps
Official TitleA Randomised, Double-blind, Parallel Group PhIII Study to Assess the Clinical Efficacy and Safety of 100 mg SC Mepolizumab as an Add on to Maintenance Treatment in Adults With Severe Bilateral Nasal Polyps
Brief Summary

Nasal polyps (NP) has long been known as chronic inflammatory disease of the nasal mucosa. This disease is characterized by the presence of polyps in the upper nasal cavity, originating from within the ostiomeatal complex. The presence of polyps can cause long-term symptoms such as prominent nasal obstruction, post-nasal drip, loss of smell, and discharge.

Mepolizumab (SB240563) is an Immunoglobulin G 1 [IgG1], kappa humanized monoclonal antibody (mAB) that blocks human interleukin-5 (hIL-5) from binding to the interleukin-5 (IL-5) receptor complex expressed on the eosinophil cell surface and thus inhibits signaling. Neutralization of IL-5 with mepolizumab has been shown to reduce blood, sputum and tissue eosinophils and hence is assumed to be a treatment option in a number of eosinophilic diseases including NP.

The aim of this randomized, double-blind, parallel group, phase 3 (PhIII) study is to assess the clinical efficacy and safety of 100 milligram (mg) subcutaneous (SC) mepolizumab as an add on to maintenance treatment in adults with severe bilateral NP. The study will include a 4-week run in period followed by randomization to a 52-week treatment period. Participants will receive mepolizumab 100 mg or placebo SC by the investigator or delegate via a pre-filled safety syringe every 4 weeks for 52 weeks. Throughout the entire study period (run in + treatment period + follow up), participants will receive a standard of care (SoC) for NP which consists of daily mometasone furorate (MF) nasal spray, and if required, saline nasal douching, occasional short courses of high dose oral corticosteroids (OCS) and/or antibiotics. The treatment period will consist of thirteen, 4-weekly doses of mepolizumab or placebo. In addition, up to the first 200 randomized participants will be followed up every other month for up to a further 6 months after the Visit 15 (7 months post last dose) in order to assess maintenance of response and to validate a physiological model derived from the previous Phase 2 study. Approximately 400 participants will be randomized (200 participants per treatment arm) in to the study. Total duration of the study will be 76 weeks for first 200 randomized participants and 52 weeks for remainder of participants who are not participating in the 6 months no treatment follow up.

Detailed Description

Study TypeInterventional
Study PhasePhase 3
Estimated Enrollment
400
Allocation
Randomized
Interventional Model
Parallel Assignment
Masking
Triple
Primary Purpose
Treatment
Conditions
Polyps, Nasal
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: Mepolizumab

Mepolizumab injection 100 mg/millilitre (mL) is a clear to opalescent, colorless to pale yellow to pale brown sterile solution for SC injection in a single-use, safety syringe.

Other Names
Drug: Placebo

Placebo is a clear to opalescent, colorless sterile solution for SC injection in a single-use, safety syringe.

Other Names
Drug: Mometasone furoate

All participants will receive mometasone furoate usually 400 micrograms (mcg), 2 actuations (50 mcg/actuation) in each nostril twice daily. Intolerant participants will use 200g (2 actuations [50 g/actuation] in each nostril once daily).

Other Names
Study Groups/Cohorts
Mepolizumab 100 mg SC + MF
Participants will receive total thirteen doses of 100 mg SC of mepolizumab in thigh, abdomen or upper arm every 4 weeks for 52 weeks on top of SoC which includes daily nasal spray of mometasone furoate.

Placebo SC + MF
Participants will receive total thirteen doses of SC matching placebo in thigh, abdomen or upper arm every 4 weeks for 52 weeks on top of SoC which includes daily nasal spray of mometasone furoate.

Study Arms
Experimental Mepolizumab 100 mg SC + MF
Participants will receive total thirteen doses of 100 mg SC of mepolizumab in thigh, abdomen or upper arm every 4 weeks for 52 weeks on top of SoC which includes daily nasal spray of mometasone furoate.
Drug : Mepolizumab
Mepolizumab injection 100 mg/millilitre (mL) is a clear to opalescent, colorless to pale yellow to pale brown sterile solution for SC injection in a single-use, safety syringe.

Experimental Mepolizumab 100 mg SC + MF
Participants will receive total thirteen doses of 100 mg SC of mepolizumab in thigh, abdomen or upper arm every 4 weeks for 52 weeks on top of SoC which includes daily nasal spray of mometasone furoate.
Drug : Mometasone furoate
All participants will receive mometasone furoate usually 400 micrograms (mcg), 2 actuations (50 mcg/actuation) in each nostril twice daily. Intolerant participants will use 200g (2 actuations [50 g/actuation] in each nostril once daily).

Placebo Comparator Placebo SC + MF
Participants will receive total thirteen doses of SC matching placebo in thigh, abdomen or upper arm every 4 weeks for 52 weeks on top of SoC which includes daily nasal spray of mometasone furoate.
Drug : Mometasone furoate
All participants will receive mometasone furoate usually 400 micrograms (mcg), 2 actuations (50 mcg/actuation) in each nostril twice daily. Intolerant participants will use 200g (2 actuations [50 g/actuation] in each nostril once daily).

Placebo Comparator Placebo SC + MF
Participants will receive total thirteen doses of SC matching placebo in thigh, abdomen or upper arm every 4 weeks for 52 weeks on top of SoC which includes daily nasal spray of mometasone furoate.
Drug : Placebo
Placebo is a clear to opalescent, colorless sterile solution for SC injection in a single-use, safety syringe.

Arm Intervention/Treatment
Experimental Mepolizumab 100 mg SC + MF
Participants will receive total thirteen doses of 100 mg SC of mepolizumab in thigh, abdomen or upper arm every 4 weeks for 52 weeks on top of SoC which includes daily nasal spray of mometasone furoate.
Drug : Mepolizumab
Experimental Mepolizumab 100 mg SC + MF
Participants will receive total thirteen doses of 100 mg SC of mepolizumab in thigh, abdomen or upper arm every 4 weeks for 52 weeks on top of SoC which includes daily nasal spray of mometasone furoate.
Drug : Mometasone furoate
Placebo Comparator Placebo SC + MF
Participants will receive total thirteen doses of SC matching placebo in thigh, abdomen or upper arm every 4 weeks for 52 weeks on top of SoC which includes daily nasal spray of mometasone furoate.
Drug : Mometasone furoate
Placebo Comparator Placebo SC + MF
Participants will receive total thirteen doses of SC matching placebo in thigh, abdomen or upper arm every 4 weeks for 52 weeks on top of SoC which includes daily nasal spray of mometasone furoate.
Drug : Placebo

Recruitment Information

Recruitment Status:Recruiting
Enrollment400
Completion DateAugust 02, 2019
Eligibility Criteria: Inclusion Criteria
- 18 years of age and older inclusive, at the time of signing the informed consent.
- Body weight greater or equal to 40 kilogram (kg).
- Male or female participants (with appropriate contraceptive methods) to be eligible for entry into the study. To be eligible for entry into the study, woman of childbearing potential (WOCBP) must commit to consistent and correct use of an acceptable method of birth control from the time of consent, for the duration of the trial, and for 105 days after last study drug administration.
- Participants who have had at least one previous surgery in the previous 10 years for the removal of NP. NP Surgery is defined as any procedure involving instruments with resulting incision (cutting open) and removal of polyp tissue from the nasal cavity (polypectomy). For the purpose of inclusion into this study, any procedure involving instrumentation in the nasal cavity resulting in dilatation of the nasal passage such as balloon sinuplasty, insertion of coated stents or direct injection of steroids or other medication without any removal of NP tissue is not accepted.
- Participants with bilateral NP as diagnosed by endoscopy or computed tomography (CT) scan.
- Presence of at least two of the following symptoms one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip) and either nasal discharge (anterior/posterior nasal drip); facial pain/pressure; reduction or loss of smell for at least 12 weeks prior to screening.
- Participants with severe NP symptoms defined as an obstruction VAS symptom score of >5.
- Severity consistent with a need for surgery as described by:
1. Participants with an overall VAS symptom score >7,
2. Participants with an endoscopic bilateral NP score of at least 5 out of a maximum score of 8 (with a minimum score of 2 in each nasal cavity).
- Treatment with intranasal corticosteroids (INCS) for at least 8 weeks prior to screening.
- Capable of giving signed informed consent
Exclusion Criteria
- As a result of medical interview, physical examination, or screening investigation, the physician responsible considers the participant unfit for the study.
- Cystic fibrosis
- Eosinophilic granulomatosis with polyangiitis (also known as churg strauss syndrome), young's, kartagener's or dyskinetic ciliary syndromes.
- Antrochoanal polyps
- Nasal septal deviation occluding one nostril
- Acute sinusitis or upper respiratory track infection (URTI) at screening or in 2 weeks prior to screening
- Ongoing rhinitis medicamentosa (rebound or chemical induced rhinitis)
- Participants who have had an asthma exacerbation requiring admission to hospital within 4 weeks of Screening.
- Participants who have undergone any intranasal and/or sinus surgery (for example polypectomy, balloon dilatation or nasal stent insertion) within 6 months prior Visit 1.
- Participants where NP surgery is contraindicated in the opinion of the Investigator.
- Participants with a known medical history of human immunodeficiency virus (HIV) infection.
- Participants with a known, pre-existing parasitic infestation within 6 months prior to Visit 1.
- Participants who are currently receiving, or have received within 3 months (or 5 half lives - whatever is the longest) prior to first mepolizumab dose, chemotherapy, radiotherapy or investigational medications/therapies.
- Participants with a history of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK medical monitor, contraindicates their participation. Aspirin-sensitive participants are acceptable.
- Participants with a history of allergic reaction to anti-IL-5 or other monoclonal antibody therapy.
- Participants on a waiting list for NP surgery while at screening
- Participants that have taken part in previous mepolizumab, reslizumab, dupilumab or benralizumab studies.
- Use of systemic corticosteroids (including oral corticosteroids) or corticosteroid nasal solution (intranasal corticosteroid is accepted) within 4 weeks prior to Screening or planned use of such medications during the double-blind period.
- INCS dose changes within 1 month prior to screening.
- Treatments with biological or immunosuppressive treatment (other than omalizumab) treatment within 5 terminal phase half lives of Visit 1.
- Omalizumab treatment in the 130 days prior to Visit 1.
- Commencement of leukotriene antagonist treatment less than 30 days prior to Visit 1.
- Allergen immunotherapy within the previous 3 months.
- Women who are pregnant or lactating or are planning on becoming pregnant during the study.
- Participants who currently smoke or have smoked in the last 6 months.
- Any participant who is considered unlikely to survive the duration of the study period or has any rapidly progressing disease or immediate life-threatening illness (e.g. cancer). In addition, any participant who has any other condition (e.g. neurological condition) that is likely to affect respiratory function should not be included in the study.
- Participants who have known, pre-existing, clinically significant endocrine, autoimmune, cardiovascular, metabolic, neurological, renal, gastrointestinal, hepatic, hematological or any other system abnormalities that are uncontrolled with standard treatment.
- Immunocompromized, other than that explained by the use of corticosteroids taken as therapy.
- A current malignancy or previous history of cancer in remission for less than 12 months prior to Screening. Participants with successfully treated basal cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ, with no evidence of recurrence may participate in the study.
- Current active liver or biliary disease (with the exception of gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment).
- Corrected QT interval (QTc) >450 milliseconds (msec) or QTc >480 msec in participants with bundle branch block at visit 1.
- A known or suspected history of alcohol or drug abuse within 2 years prior to Screening (Visit 1) that in the opinion of the investigator would prevent the participant from completing the study procedures.
- An investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study.
- In the opinion of the investigator, any participant who is unable to read and/or would not be able to complete a questionnaire.
GenderAll
Age18 Years to N/A
Accepts Healthy VolunteersNo
Contacts
Listed Location Countries
Argentina
Australia
Canada
Germany
Korea, Republic of
Netherlands
Romania
Russian Federation
Sweden
United Kingdom
United States

Administrative Information

NCT Number:NCT03085797
Other Study ID Numbers
205687
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
GlaxoSmithKline
Collaborators
CRF health
Bristol-Myers Squibb
Investigators
Study Director
GSK Clinical Trials
GlaxoSmithKline