Effect of Mepolizumab in Severe Bilateral Nasal Polyps

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03085797
• Collaborator: CRF health (Other), Bristol-Myers Squibb (Industry)
• Enrollment: 414
• Locations: 101
• Arms: 2
• Actual Duration (Months): 30.6
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Nasal Polyps	Drug: Mepolizumab; Drug: Placebo; Drug: Mometasone furoate	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 414 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A 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 - SYNAPSE (StudY in NAsal Polyps Patients to Assess the Safety and Efficacy of Mepolizumab)
• Actual Study Start Date: May 25, 2017
• Actual Primary Completion Date: Dec 11, 2019
• Actual Study Completion Date: Dec 11, 2019

Arms and Interventions

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; 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.; 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.; 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).

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Total Endoscopic Nasal Polyps Score at Week 52 [Baseline (Day 1) and Week 52]

   Independent reviewers, blinded to treatment, reviewed image recordings of nasal endoscopies to determine total endoscopic NP score based on NP size. The right and left nostrils were scored from 0 to 4 (0 = No polyps; 1 = Small polyps in the middle meatus not reaching below the inferior border of the middle concha; 2 = Polyps reaching below the lower border of the middle turbinate; 3 = Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle concha; and 4 = Large polyps causing complete obstruction/congestion of the inferior meatus). The total score is the sum of the right and left nostril scores and ranges from 0 to 8, higher scores indicate greater disease severity. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis. Baseline was defined as Day 1 value. Change from Baseline = Post-baseline value minus Baseline value.

2. Change From Baseline in Nasal Obstruction Visual Analog Scale (VAS) Score During the 4 Weeks Prior to Week 52 [Baseline and Weeks 49 to 52]

   Participants rated individual (nasal obstruction, nasal discharge, mucus in the throat, loss of smell, facial pain) and overall symptoms on a visual analog scale (VAS) using an electronic diary (eDiary). Captured scores ranged between 0 (none) and 100 (as bad as you can imagine), final scores derived from the electronically captured scores by dividing by 10. The final nasal obstruction VAS score ranged between 0 and 10, with higher scores indicating greater disease severity. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis. The average of daily scores in 4-weekly intervals were calculated and data is presented for Weeks 49-52. Baseline was defined as the average score from the 7 days of eDiary data collected prior to Day 1. Change from Baseline = Post-baseline value minus Baseline value.

Secondary Outcome Measures

1. Percentage of Participants With Nasal Surgery Over Time [Weeks 8, 16, 24, 32, 40, 48 and 52]

   The percentage of participants with nasal surgery over time (by Weeks 8, 16, 24, 32, 40, 48 and 52) was derived from Kaplan-Meier time-to-event analyses for the event 'first nasal surgery'. Nasal surgery was defined as any procedure involving instruments resulting in incision and removal of tissue (polypectomy) in the nasal cavity. Time to first nasal surgery was defined as (Date of first nasal surgery - Date of first dose of study treatment) + 1. Percentage of participants with nasal surgery over time (by Weeks 8, 16, 24, 32, 40, 48 and 52) and corresponding 95% CI have been presented, calculated using the Kaplan-Meier method. Analysis included surgeries occurring up to Week 52, reported on-treatment and those reported after early discontinuation from IP by participants who remained in the study.

2. Change From Baseline in Overall VAS Score During the 4 Weeks Prior to Week 52 [Baseline and Weeks 49 to 52]

   Participants rated individual (nasal obstruction, nasal discharge, mucus in the throat, loss of smell, facial pain) and overall symptoms on a visual analog scale using an eDiary. Captured scores ranged between 0 (none) and 100 (as bad as you can imagine), final scores derived from the electronically captured scores by dividing by 10. The final overall VAS score ranged between 0 and 10, with higher scores indicating greater disease severity. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis. The average of daily scores in 4-weekly intervals were calculated and data is presented for Weeks 49-52. Baseline was defined as the average score from the 7 days of eDiary data collected prior to Day 1. Change from Baseline = Post-baseline value minus Baseline value.

3. Change From Baseline in Sino-nasal Outcome Test (SNOT)-22 Total Score at Week 52 [Baseline (Day 1) and Week 52]

   The SNOT-22 is a 22-item self-reported questionnaire developed to measure symptoms and impacts related to chronic rhinosinusitis. The 22 questions are self-completed by participants based on their recall of their symptoms over the previous 2 weeks using a 6-point rating scale (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"). Scores for each question are summed to derive the total score. The SNOT-22 total score ranges from 0 to 110, with higher scores representing worse quality of life. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis. Baseline was defined as Day 1 value. Change from Baseline = Post-baseline value minus Baseline value.

4. Percentage of Participants Requiring at Least One Course of Systemic Steroids for Nasal Polyps up to Week 52 [Up to Week 52]

   The number of courses of systemic steroids received by participants were recorded. For the purpose of this study, a course of systemic corticosteroid separated by less than 7 days was considered as a continuation of the same course. Percentage of participants requiring at least one course of systemic steroids for nasal polyps up to Week 52 is presented. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis.

5. Change From Baseline in the Composite VAS Score (Combining VAS Scores for Nasal Obstruction, Nasal Discharge, Mucus in the Throat and Loss of Smell) During the 4 Weeks Prior to Week 52 [Baseline and Weeks 49 to 52]

   Participants rated individual (nasal obstruction, nasal discharge, mucus in the throat, loss of smell, facial pain) and overall symptoms on a visual analog scale using an eDiary. Captured scores ranged between 0 (none) and 100 (as bad as you can imagine), final scores derived from electronically captured scores by dividing by 10. The composite VAS score was calculated as average of individual scores of nasal obstruction, nasal discharge, mucus in the throat and loss of smell and ranged between 0 and 10, with higher scores indicating greater disease severity. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis. The average of daily scores in 4-weekly intervals were calculated and data is presented for Weeks 49-52. Baseline was defined as the average score from the 7 days of eDiary data collected prior to Day 1. Change from Baseline = Post-baseline value minus Baseline value.

6. Change From Baseline in Individual VAS Symptom Score: Loss of Smell During the 4 Weeks Prior to Week 52 [Baseline and Weeks 49 to 52]

   Participants rated individual (nasal obstruction, nasal discharge, mucus in the throat, loss of smell, facial pain) and overall symptoms on a visual analog scale using an eDiary. Captured scores ranged between 0 (none) and 100 (as bad as you can imagine), final scores derived from the electronically captured scores by dividing by 10. The final loss of smell VAS score ranged between 0 and 10, with higher scores indicating greater disease severity. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis. The average of daily scores in 4-weekly intervals were calculated and data is presented for Weeks 49-52. Baseline was defined as the average score from the 7 days of eDiary data collected prior to Day 1. Change from Baseline = Post-baseline value minus Baseline value.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

• 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

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Birmingham	Alabama	United States	35209
2	GSK Investigational Site	Riverside	California	United States	92506
3	GSK Investigational Site	Roseville	California	United States	95661
4	GSK Investigational Site	San Diego	California	United States	92103
5	GSK Investigational Site	Colorado Springs	Colorado	United States	80907
6	GSK Investigational Site	Lake Mary	Florida	United States	32746
7	GSK Investigational Site	Boise	Idaho	United States	83706
8	GSK Investigational Site	Chicago	Illinois	United States	60657
9	GSK Investigational Site	Des Moines	Iowa	United States	50312
10	GSK Investigational Site	West Des Moines	Iowa	United States	50265
11	GSK Investigational Site	Louisville	Kentucky	United States	40205
12	GSK Investigational Site	Marrero	Louisiana	United States	70072
13	GSK Investigational Site	White Marsh	Maryland	United States	21162
14	GSK Investigational Site	Columbia	Missouri	United States	65201
15	GSK Investigational Site	Saint Louis	Missouri	United States	63141
16	GSK Investigational Site	Piscataway	New Jersey	United States	08854
17	GSK Investigational Site	New York	New York	United States	10016
18	GSK Investigational Site	Matthews	North Carolina	United States	28105
19	GSK Investigational Site	Raleigh	North Carolina	United States	27607
20	GSK Investigational Site	Winston-Salem	North Carolina	United States	27103
21	GSK Investigational Site	Oklahoma City	Oklahoma	United States	73120
22	GSK Investigational Site	Medford	Oregon	United States	97504
23	GSK Investigational Site	Bethlehem	Pennsylvania	United States	18017
24	GSK Investigational Site	Pittsburgh	Pennsylvania	United States	15213
25	GSK Investigational Site	Charleston	South Carolina	United States	29425
26	GSK Investigational Site	Orangeburg	South Carolina	United States	29118
27	GSK Investigational Site	Dallas	Texas	United States	75235
28	GSK Investigational Site	McKinney	Texas	United States	75070
29	GSK Investigational Site	San Antonio	Texas	United States	78258
30	GSK Investigational Site	North Logan	Utah	United States	84341
31	GSK Investigational Site	Salt Lake City	Utah	United States	84102
32	GSK Investigational Site	Lynchburg	Virginia	United States	24501
33	GSK Investigational Site	Norfolk	Virginia	United States	23507
34	GSK Investigational Site	Richmond	Virginia	United States	23235
35	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1414AIF
36	GSK Investigational Site	Florida	Buenos Aires	Argentina	1602
37	GSK Investigational Site	La Plata	Buenos Aires	Argentina	1900
38	GSK Investigational Site	Mar del Plata	Buenos Aires	Argentina	7600
39	GSK Investigational Site	Rosario	Santa Fe	Argentina	S2000DBS
40	GSK Investigational Site	Ciudad Autonoma de Buenos Aires		Argentina	C1425BEN
41	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1121ABE
42	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1426ABP
43	GSK Investigational Site	Mendoza		Argentina	5500
44	GSK Investigational Site	Mendoza		Argentina	M5500CCG
45	GSK Investigational Site	San Miguel de Tucumán		Argentina	4000
46	GSK Investigational Site	Darlinghurst	New South Wales	Australia	2010
47	GSK Investigational Site	Westmead	New South Wales	Australia	2145
48	GSK Investigational Site	Clayton	Victoria	Australia	3169
49	GSK Investigational Site	Melbourne	Victoria	Australia	3004
50	GSK Investigational Site	Murdoch	Western Australia	Australia	6150
51	GSK Investigational Site	Vancouver	British Columbia	Canada	V5Z 1M9
52	GSK Investigational Site	Hamilton	Ontario	Canada	L8L 2X2
53	GSK Investigational Site	London	Ontario	Canada	N6A 4V2
54	GSK Investigational Site	Ottawa	Ontario	Canada	K1G 6C6
55	GSK Investigational Site	Montreal	Quebec	Canada	H2X 1P1
56	GSK Investigational Site	Montreal	Quebec	Canada	H3G 1L5
57	GSK Investigational Site	Saskatoon	Saskatchewan	Canada	S7K 1N4
58	GSK Investigational Site	Québec		Canada	G1S 4L8
59	GSK Investigational Site	Tuebingen	Baden-Wuerttemberg	Germany	72076
60	GSK Investigational Site	Muenchen	Bayern	Germany	81377
61	GSK Investigational Site	Muenchen	Bayern	Germany	81675
62	GSK Investigational Site	Wiesbaden	Hessen	Germany	65183
63	GSK Investigational Site	Duesseldorf	Nordrhein-Westfalen	Germany	40225
64	GSK Investigational Site	Muenster	Nordrhein-Westfalen	Germany	48149
65	GSK Investigational Site	Dresden	Sachsen	Germany	01139
66	GSK Investigational Site	Dresden	Sachsen	Germany	01307
67	GSK Investigational Site	Luebeck	Schleswig-Holstein	Germany	23538
68	GSK Investigational Site	Berlin		Germany	13353
69	GSK Investigational Site	Incheon		Korea, Republic of	21565
70	GSK Investigational Site	Seongnam-si Gyeonggi-do		Korea, Republic of	463-707
71	GSK Investigational Site	Seoul		Korea, Republic of	03722
72	GSK Investigational Site	Seoul		Korea, Republic of	06351
73	GSK Investigational Site	Seoul		Korea, Republic of	06591
74	GSK Investigational Site	Amsterdam		Netherlands	1105 AZ
75	GSK Investigational Site	Brasov		Romania	500091
76	GSK Investigational Site	Brasov		Romania	500283
77	GSK Investigational Site	Bucuresti		Romania	014452
78	GSK Investigational Site	Cluj Napoca		Romania	400015
79	GSK Investigational Site	Targu Mures		Romania	540098
80	GSK Investigational Site	Moscow		Russian Federation	119991
81	GSK Investigational Site	Moscow		Russian Federation	123095
82	GSK Investigational Site	Moscow		Russian Federation	123182
83	GSK Investigational Site	Moscow		Russian Federation	127473
84	GSK Investigational Site	Moscow		Russian Federation	142190
85	GSK Investigational Site	Saint-Peterburgh		Russian Federation	197022
86	GSK Investigational Site	Saint-Petersburg		Russian Federation	190013
87	GSK Investigational Site	St. Petersburg		Russian Federation	194356
88	GSK Investigational Site	Yaroslavl		Russian Federation	150003
89	GSK Investigational Site	Göteborg		Sweden	SE-413 45
90	GSK Investigational Site	Helsingborg		Sweden	SE-251 87
91	GSK Investigational Site	Lund		Sweden	SE-221 85
92	GSK Investigational Site	Stockholm		Sweden	SE-114 86
93	GSK Investigational Site	Stockholm		Sweden	SE-171 76
94	GSK Investigational Site	Darlington	Durham	United Kingdom	DL3 6HX
95	GSK Investigational Site	Liverpool	Merseyside	United Kingdom	L9 7AL
96	GSK Investigational Site	London		United Kingdom	SE1 9RT
97	GSK Investigational Site	London		United Kingdom	SW3 6HP
98	GSK Investigational Site	London		United Kingdom	WC1X 8DA
99	GSK Investigational Site	Manchester		United Kingdom	M23 9QZ
100	GSK Investigational Site	Newcastle upon Tyne		United Kingdom	NE7 7DN
101	GSK Investigational Site	Rotherham		United Kingdom	S60 2UD

Sponsors and Collaborators

• GlaxoSmithKline
• CRF health
• Bristol-Myers Squibb

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Feb 13, 2020
• Statistical Analysis Plan - Feb 20, 2020

More Information

Publications

• Han JK, Bachert C, Fokkens W, Desrosiers M, Wagenmann M, Lee SE, Smith SG, Martin N, Mayer B, Yancey SW, Sousa AR, Chan R, Hopkins C; SYNAPSE study investigators. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2021 Oct;9(10):1141-1153. doi: 10.1016/S2213-2600(21)00097-7. Epub 2021 Apr 16.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT03085797
• Other Study ID Numbers: 205687; 2016-004255-70
• First Posted: Mar 21, 2017
• Last Update Posted: Aug 3, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by GlaxoSmithKline: SB240563; Nasal Polyps; Mepolizumab; Phase 3; Parallel group; Efficacy
• Additional relevant MeSH terms: Nasal Polyps; Polyps; Mometasone Furoate

Study Results

Participant Flow

Recruitment Details	Participants (par.) were enrolled across 11 countries (Germany, Netherlands, Romania, Sweden, United Kingdom, United States, Argentina, Australia, Canada, Republic of Korea and Russian Federation).
Pre-assignment Detail	A total of 414 participants were enrolled and randomized in the study, of which only 407 participants received study treatment and were included in the Intent-to-Treat Population (defined as all randomized participants who took at least 1 dose of study treatment). Seven participants did not receive study treatment as they were randomized in error.

Arm/Group Title	Placebo	Mepolizumab 100 mg SC
Arm/Group Description	Participants were randomized to receive up to 13 subcutaneous (SC) doses of mepolizumab matching placebo every 4 weeks to Week 52 (Wk 52) on top of standard of care (SoC) for nasal polyps (NP) which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.	Participants were randomized to receive up to 13 SC doses of mepolizumab 100 milligrams per milliliter (mg/mL) every 4 weeks to Week 52 on top of SoC for nasal polyps which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.
Period Title: Treatment Period (TP) (52 Weeks)
STARTED	201	206
Completed Investigational Product (IP)	167	183
Not Completed IP	34	23
Withdrew IP Due to: Adverse Event	4	4
Withdrew IP Due to: Lack of Efficacy	11	5
Withdrew IP Due to: Protocol Deviation	1	0
Withdrew IP Due to: Stopping Criteria	1	1
Withdrew IP Due to: Physician Decision	2	1
Withdrew IP Due to: Withdrawal by Par.	15	12
COMPLETED	184	189
NOT COMPLETED	17	17
Period Title: Treatment Period (TP) (52 Weeks)
STARTED	65	69
COMPLETED	65	68
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Placebo	Mepolizumab 100 mg SC	Total
Arm/Group Description	Participants were randomized to receive up to 13 subcutaneous (SC) doses of mepolizumab matching placebo every 4 weeks to Week 52 (Wk 52) on top of standard of care (SoC) for nasal polyps (NP) which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.	Participants were randomized to receive up to 13 SC doses of mepolizumab 100 milligrams per milliliter (mg/mL) every 4 weeks to Week 52 on top of SoC for nasal polyps which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.	Total of all reporting groups
Overall Participants	201	206	407
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	48.9 (12.46)	48.6 (13.55)	48.8 (13.01)
Sex: Female, Male (Count of Participants)
Female	76 37.8%	67 32.5%	143 35.1%
Male	125 62.2%	139 67.5%	264 64.9%
Race/Ethnicity, Customized (Count of Participants)
Asian-Central/South Asian Heritage (H.)	1 0.5%	2 1%	3 0.7%
Asian-Japanese H./East Asian H./SouthEast Asian H.	8 4%	7 3.4%	15 3.7%
Black or African American (AA)	4 2%	5 2.4%	9 2.2%
White	187 93%	192 93.2%	379 93.1%
AA/African H. and American Indian or Alaska Native	1 0.5%	0 0%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Total Endoscopic Nasal Polyps Score at Week 52
Description	Independent reviewers, blinded to treatment, reviewed image recordings of nasal endoscopies to determine total endoscopic NP score based on NP size. The right and left nostrils were scored from 0 to 4 (0 = No polyps; 1 = Small polyps in the middle meatus not reaching below the inferior border of the middle concha; 2 = Polyps reaching below the lower border of the middle turbinate; 3 = Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle concha; and 4 = Large polyps causing complete obstruction/congestion of the inferior meatus). The total score is the sum of the right and left nostril scores and ranges from 0 to 8, higher scores indicate greater disease severity. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis. Baseline was defined as Day 1 value. Change from Baseline = Post-baseline value minus Baseline value.
Time Frame	Baseline (Day 1) and Week 52

Outcome Measure Data

Analysis Population Description

ITT Population which included all randomized participants who took at least 1 dose of study treatment.

Arm/Group Title	Placebo	Mepolizumab 100 mg SC
Arm/Group Description	Participants were randomized to receive up to 13 subcutaneous (SC) doses of mepolizumab matching placebo every 4 weeks to Week 52 (Wk 52) on top of standard of care (SoC) for nasal polyps (NP) which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.	Participants were randomized to receive up to 13 SC doses of mepolizumab 100 milligrams per milliliter (mg/mL) every 4 weeks to Week 52 on top of SoC for nasal polyps which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.
Measure Participants	201	206
Median (Full Range) [Scores on a scale]	0.0	-1.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 100 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-Value was based on Wilcoxon rank-sum test.
	Method	Wilcoxon rank-sum test
	Comments
Method of Estimation	Estimation Parameter	Difference in Medians
	Estimated Value	-0.73
	Confidence Interval	(2-Sided) 95%; -1.11 to -0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Quantile regression with covariates: treatment,region,Baseline score,Baseline eosinophilcount(BEC). Par. with nasal surgery prior to Wk52/withdrew early with no nasal surgery assigned their worst observed score prior to nasal surgery/study withdrawal

2. Primary Outcome

Title	Change From Baseline in Nasal Obstruction Visual Analog Scale (VAS) Score During the 4 Weeks Prior to Week 52
Description	Participants rated individual (nasal obstruction, nasal discharge, mucus in the throat, loss of smell, facial pain) and overall symptoms on a visual analog scale (VAS) using an electronic diary (eDiary). Captured scores ranged between 0 (none) and 100 (as bad as you can imagine), final scores derived from the electronically captured scores by dividing by 10. The final nasal obstruction VAS score ranged between 0 and 10, with higher scores indicating greater disease severity. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis. The average of daily scores in 4-weekly intervals were calculated and data is presented for Weeks 49-52. Baseline was defined as the average score from the 7 days of eDiary data collected prior to Day 1. Change from Baseline = Post-baseline value minus Baseline value.
Time Frame	Baseline and Weeks 49 to 52

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo	Mepolizumab 100 mg SC
Arm/Group Description	Participants were randomized to receive up to 13 subcutaneous (SC) doses of mepolizumab matching placebo every 4 weeks to Week 52 (Wk 52) on top of standard of care (SoC) for nasal polyps (NP) which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.	Participants were randomized to receive up to 13 SC doses of mepolizumab 100 milligrams per milliliter (mg/mL) every 4 weeks to Week 52 on top of SoC for nasal polyps which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.
Measure Participants	201	206
Median (Full Range) [Scores on a scale]	-0.82	-4.41

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 100 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-Value was based on Wilcoxon rank-sum test.
	Method	Wilcoxon rank-sum test
	Comments
Method of Estimation	Estimation Parameter	Difference in Medians
	Estimated Value	-3.14
	Confidence Interval	(2-Sided) 95%; -4.09 to -2.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Quantile regression with covariates: treatment, region, Baseline score, Baseline BEC. Par. with nasal surgery prior to Wks 49-52/withdrew early with no nasal surgery assigned their worst observed 4-wk mean prior to nasal surgery/study withdrawal.

3. Secondary Outcome

Title	Percentage of Participants With Nasal Surgery Over Time
Description	The percentage of participants with nasal surgery over time (by Weeks 8, 16, 24, 32, 40, 48 and 52) was derived from Kaplan-Meier time-to-event analyses for the event 'first nasal surgery'. Nasal surgery was defined as any procedure involving instruments resulting in incision and removal of tissue (polypectomy) in the nasal cavity. Time to first nasal surgery was defined as (Date of first nasal surgery - Date of first dose of study treatment) + 1. Percentage of participants with nasal surgery over time (by Weeks 8, 16, 24, 32, 40, 48 and 52) and corresponding 95% CI have been presented, calculated using the Kaplan-Meier method. Analysis included surgeries occurring up to Week 52, reported on-treatment and those reported after early discontinuation from IP by participants who remained in the study.
Time Frame	Weeks 8, 16, 24, 32, 40, 48 and 52

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo	Mepolizumab 100 mg SC
Arm/Group Description	Participants were randomized to receive up to 13 subcutaneous (SC) doses of mepolizumab matching placebo every 4 weeks to Week 52 (Wk 52) on top of standard of care (SoC) for nasal polyps (NP) which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.	Participants were randomized to receive up to 13 SC doses of mepolizumab 100 milligrams per milliliter (mg/mL) every 4 weeks to Week 52 on top of SoC for nasal polyps which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.
Measure Participants	201	206
Week 8	1.0 0.5%	0.5 0.2%
Week 16	3.5 1.7%	1.0 0.5%
Week 24	9.1 4.5%	4.0 1.9%
Week 32	14.2 7.1%	6.0 2.9%
Week 40	18.9 9.4%	7.6 3.7%
Week 48	22.0 10.9%	9.2 4.5%
Week 52	23.6 11.7%	9.2 4.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 100 mg SC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-Value was based on Cox Proportional Hazards Model.
	Method	Cox Proportional Hazards Model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (Mepolizumab/Placebo)
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95%; 0.25 to 0.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis using a Cox Proportional Hazards Model with covariates of treatment, geographic region, Baseline total endoscopic score (centrally read), Baseline nasal obstruction VAS, Baseline BEC, number of previous surgeries (1, 2, >2 as ordinal).

4. Secondary Outcome

Title	Change From Baseline in Overall VAS Score During the 4 Weeks Prior to Week 52
Description	Participants rated individual (nasal obstruction, nasal discharge, mucus in the throat, loss of smell, facial pain) and overall symptoms on a visual analog scale using an eDiary. Captured scores ranged between 0 (none) and 100 (as bad as you can imagine), final scores derived from the electronically captured scores by dividing by 10. The final overall VAS score ranged between 0 and 10, with higher scores indicating greater disease severity. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis. The average of daily scores in 4-weekly intervals were calculated and data is presented for Weeks 49-52. Baseline was defined as the average score from the 7 days of eDiary data collected prior to Day 1. Change from Baseline = Post-baseline value minus Baseline value.
Time Frame	Baseline and Weeks 49 to 52

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo	Mepolizumab 100 mg SC
Arm/Group Description	Participants were randomized to receive up to 13 subcutaneous (SC) doses of mepolizumab matching placebo every 4 weeks to Week 52 (Wk 52) on top of standard of care (SoC) for nasal polyps (NP) which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.	Participants were randomized to receive up to 13 SC doses of mepolizumab 100 milligrams per milliliter (mg/mL) every 4 weeks to Week 52 on top of SoC for nasal polyps which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.
Measure Participants	201	206
Median (Full Range) [Scores on a scale]	-0.90	-4.48

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 100 mg SC
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-Value was based on Wilcoxon rank-sum test and is adjusted for multiplicity.
	Method	Wilcoxon rank-sum test
	Comments
Method of Estimation	Estimation Parameter	Difference in Medians
	Estimated Value	-3.18
	Confidence Interval	(2-Sided) 95%; -4.10 to -2.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Quantile regression with covariates: treatment, region, Baseline score, Baseline BEC. Par. with nasal surgery prior to Wks 49-52/withdrew early with no nasal surgery assigned their worst observed 4-wk mean prior to nasal surgery/study withdrawal.

5. Secondary Outcome

Title	Change From Baseline in Sino-nasal Outcome Test (SNOT)-22 Total Score at Week 52
Description	The SNOT-22 is a 22-item self-reported questionnaire developed to measure symptoms and impacts related to chronic rhinosinusitis. The 22 questions are self-completed by participants based on their recall of their symptoms over the previous 2 weeks using a 6-point rating scale (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"). Scores for each question are summed to derive the total score. The SNOT-22 total score ranges from 0 to 110, with higher scores representing worse quality of life. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis. Baseline was defined as Day 1 value. Change from Baseline = Post-baseline value minus Baseline value.
Time Frame	Baseline (Day 1) and Week 52

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified data point were analyzed.

Arm/Group Title	Placebo	Mepolizumab 100 mg SC
Arm/Group Description	Participants were randomized to receive up to 13 subcutaneous (SC) doses of mepolizumab matching placebo every 4 weeks to Week 52 (Wk 52) on top of standard of care (SoC) for nasal polyps (NP) which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.	Participants were randomized to receive up to 13 SC doses of mepolizumab 100 milligrams per milliliter (mg/mL) every 4 weeks to Week 52 on top of SoC for nasal polyps which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.
Measure Participants	198	205
Median (Full Range) [Scores on a scale]	-14.0	-30.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 100 mg SC
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-Value was based on Wilcoxon rank-sum test and is adjusted for multiplicity.
	Method	Wilcoxon rank-sum test
	Comments
Method of Estimation	Estimation Parameter	Difference in Medians
	Estimated Value	-16.49
	Confidence Interval	(2-Sided) 95%; -23.57 to -9.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Quantile regression with covariates: treatment, region, Baseline score, Baseline BEC. Par. with nasal surgery prior to Wk 52/withdrew early with no nasal surgery assigned their worst observed score prior to nasal surgery/study withdrawal.

6. Secondary Outcome

Title	Percentage of Participants Requiring at Least One Course of Systemic Steroids for Nasal Polyps up to Week 52
Description	The number of courses of systemic steroids received by participants were recorded. For the purpose of this study, a course of systemic corticosteroid separated by less than 7 days was considered as a continuation of the same course. Percentage of participants requiring at least one course of systemic steroids for nasal polyps up to Week 52 is presented. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo	Mepolizumab 100 mg SC
Arm/Group Description	Participants were randomized to receive up to 13 subcutaneous (SC) doses of mepolizumab matching placebo every 4 weeks to Week 52 (Wk 52) on top of standard of care (SoC) for nasal polyps (NP) which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.	Participants were randomized to receive up to 13 SC doses of mepolizumab 100 milligrams per milliliter (mg/mL) every 4 weeks to Week 52 on top of SoC for nasal polyps which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.
Measure Participants	201	206
Number [Percentage of participants]	37 18.4%	25 12.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 100 mg SC
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments	p-Value was based on logistic regression model and is adjusted for multiplicity.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; 0.36 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Covariates: treatment group, geographic region, number of oral corticosteroids courses for NP in last 12 months(0,1,>1 as ordinal), Baseline total endoscopic score(centrally read),Baseline nasal obstruction VAS score,log(e) Baseline eosinophil count.

7. Secondary Outcome

Title	Change From Baseline in the Composite VAS Score (Combining VAS Scores for Nasal Obstruction, Nasal Discharge, Mucus in the Throat and Loss of Smell) During the 4 Weeks Prior to Week 52
Description	Participants rated individual (nasal obstruction, nasal discharge, mucus in the throat, loss of smell, facial pain) and overall symptoms on a visual analog scale using an eDiary. Captured scores ranged between 0 (none) and 100 (as bad as you can imagine), final scores derived from electronically captured scores by dividing by 10. The composite VAS score was calculated as average of individual scores of nasal obstruction, nasal discharge, mucus in the throat and loss of smell and ranged between 0 and 10, with higher scores indicating greater disease severity. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis. The average of daily scores in 4-weekly intervals were calculated and data is presented for Weeks 49-52. Baseline was defined as the average score from the 7 days of eDiary data collected prior to Day 1. Change from Baseline = Post-baseline value minus Baseline value.
Time Frame	Baseline and Weeks 49 to 52

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo	Mepolizumab 100 mg SC
Arm/Group Description	Participants were randomized to receive up to 13 subcutaneous (SC) doses of mepolizumab matching placebo every 4 weeks to Week 52 (Wk 52) on top of standard of care (SoC) for nasal polyps (NP) which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.	Participants were randomized to receive up to 13 SC doses of mepolizumab 100 milligrams per milliliter (mg/mL) every 4 weeks to Week 52 on top of SoC for nasal polyps which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.
Measure Participants	201	206
Median (Full Range) [Scores on a scale]	-0.89	-3.96

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 100 mg SC
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments	p-Value was based on Wilcoxon rank-sum test and is adjusted for multiplicity.
	Method	Wilcoxon rank-sum test
	Comments
Method of Estimation	Estimation Parameter	Difference in Medians
	Estimated Value	-2.68
	Confidence Interval	(2-Sided) 95%; -3.44 to -1.91
	Parameter Dispersion	Type: Value:
	Estimation Comments	Quantile regression with covariates: treatment, region, Baseline score, Baseline BEC. Par. with nasal surgery prior to Wks 49-52/withdrew early with no nasal surgery assigned their worst observed 4-wk mean prior to nasal surgery/study withdrawal.

8. Secondary Outcome

Title	Change From Baseline in Individual VAS Symptom Score: Loss of Smell During the 4 Weeks Prior to Week 52
Description	Participants rated individual (nasal obstruction, nasal discharge, mucus in the throat, loss of smell, facial pain) and overall symptoms on a visual analog scale using an eDiary. Captured scores ranged between 0 (none) and 100 (as bad as you can imagine), final scores derived from the electronically captured scores by dividing by 10. The final loss of smell VAS score ranged between 0 and 10, with higher scores indicating greater disease severity. Data up to Week 52, including from participants who remained in the study after early discontinuation from IP, were included in analysis. The average of daily scores in 4-weekly intervals were calculated and data is presented for Weeks 49-52. Baseline was defined as the average score from the 7 days of eDiary data collected prior to Day 1. Change from Baseline = Post-baseline value minus Baseline value.
Time Frame	Baseline and Weeks 49 to 52

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Placebo	Mepolizumab 100 mg SC
Arm/Group Description	Participants were randomized to receive up to 13 subcutaneous (SC) doses of mepolizumab matching placebo every 4 weeks to Week 52 (Wk 52) on top of standard of care (SoC) for nasal polyps (NP) which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.	Participants were randomized to receive up to 13 SC doses of mepolizumab 100 milligrams per milliliter (mg/mL) every 4 weeks to Week 52 on top of SoC for nasal polyps which included daily mometasone furorate nasal spray. By design, some randomized participants were eligible to enter a further 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment.
Measure Participants	201	206
Median (Full Range) [Scores on a scale]	0.00	-0.53

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Mepolizumab 100 mg SC
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments	p-Value was based on Wilcoxon rank-sum test and is adjusted for multiplicity.
	Method	Wilcoxon rank-sum test
	Comments
Method of Estimation	Estimation Parameter	Difference in Medians
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.65 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Quantile regression with covariates: treatment, region, Baseline score, Baseline BEC. Par. with nasal surgery prior to Wks 49-52/withdrew early with no nasal surgery assigned their worst observed 4-wk mean prior to nasal surgery/study withdrawal.

Adverse Events

Time Frame	Non-serious adverse events (AEs) and serious AEs were collected from start of study treatment (Day 1) up to Week 52 for treatment period and up to 6 months during no-treatment follow-up period after Week 52 visit
Adverse Event Reporting Description	Non-serious AEs and serious AEs were collected for Safety Population which consisted of all randomized participants who took at least one dose of study treatment. Adverse events are presented treatment-wise and period-wise.
Arm/Group Title	Placebo (Treatment Period)		Mepolizumab 100 mg SC (Treatment Period)		Placebo (Follow-up)		Mepolizumab 100 mg SC (Follow-up)
Arm/Group Description	Participants were randomized to receive up to 13 SC doses of mepolizumab matching placebo every 4 weeks to Week 52 on top of SoC for nasal polyps which included daily mometasone furorate nasal spray.		Participants were randomized to receive up to 13 SC doses of mepolizumab 100 mg/mL every 4 weeks to Week 52 on top of SoC for nasal polyps which included daily mometasone furorate nasal spray.		Participants entered in a 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment. Participants received mepolizumab matching placebo during treatment period.		Participants entered in a 6-month no-treatment follow-up period to assess maintenance of response after cessation of treatment. Participants received mepolizumab 100 mg/mL during treatment period.
All Cause Mortality
	Placebo (Treatment Period)		Mepolizumab 100 mg SC (Treatment Period)		Placebo (Follow-up)		Mepolizumab 100 mg SC (Follow-up)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/201 (0%)		0/206 (0%)		1/65 (1.5%)		0/69 (0%)
Serious Adverse Events
	Placebo (Treatment Period)		Mepolizumab 100 mg SC (Treatment Period)		Placebo (Follow-up)		Mepolizumab 100 mg SC (Follow-up)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/201 (7%)		12/206 (5.8%)		4/65 (6.2%)		2/69 (2.9%)
Blood and lymphatic system disorders
Anaemia	0/201 (0%)	0	2/206 (1%)	2	1/65 (1.5%)	1	0/69 (0%)	0
Cardiac disorders
Angina pectoris	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Cardiac failure congestive	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Coronary artery stenosis	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Mitral valve incompetence	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Myocardial infarction	0/201 (0%)	0	1/206 (0.5%)	1	1/65 (1.5%)	1	0/69 (0%)	0
Myocardial ischaemia	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Gastrointestinal disorders
Anal polyp	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Gastritis erosive	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Hiatus hernia	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Pancreatitis acute	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Duodenal ulcer	0/201 (0%)	0	0/206 (0%)	0	1/65 (1.5%)	1	0/69 (0%)	0
Hepatobiliary disorders
Cholecystitis acute	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Cholelithiasis	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Infections and infestations
Pneumonia	1/201 (0.5%)	1	1/206 (0.5%)	1	0/65 (0%)	0	1/69 (1.4%)	1
Acute sinusitis	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Cellulitis	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Influenza	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Periorbital cellulitis	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/201 (0%)	0	2/206 (1%)	3	0/65 (0%)	0	0/69 (0%)	0
Procedural complication	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Rib fracture	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Road traffic accident	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Metabolism and nutrition disorders
Type 2 diabetes mellitus	0/201 (0%)	0	2/206 (1%)	2	0/65 (0%)	0	0/69 (0%)	0
Musculoskeletal and connective tissue disorders
Foot deformity	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Intervertebral disc disorder	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Osteoarthritis	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Back pain	0/201 (0%)	0	0/206 (0%)	0	0/65 (0%)	0	1/69 (1.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign vulval neoplasm	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Rectal adenoma	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Nervous system disorders
Facial paralysis	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Migraine with aura	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Syncope	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Transient ischaemic attack	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion missed	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Renal and urinary disorders
Focal segmental glomerulosclerosis	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Nephrolithiasis	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Nephrotic syndrome	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Reproductive system and breast disorders
Prostatitis	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Uterine polyp	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	1/201 (0.5%)	1	0/206 (0%)	0	1/65 (1.5%)	1	0/69 (0%)	0
Pleural effusion	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Pulmonary oedema	0/201 (0%)	0	1/206 (0.5%)	1	0/65 (0%)	0	0/69 (0%)	0
Pulmonary embolism	0/201 (0%)	0	0/206 (0%)	0	1/65 (1.5%)	1	0/69 (0%)	0
Skin and subcutaneous tissue disorders
Urticaria	0/201 (0%)	0	0/206 (0%)	0	1/65 (1.5%)	1	0/69 (0%)	0
Vascular disorders
Hypertensive crisis	1/201 (0.5%)	1	0/206 (0%)	0	0/65 (0%)	0	0/69 (0%)	0
Deep vein thrombosis	0/201 (0%)	0	0/206 (0%)	0	1/65 (1.5%)	1	0/69 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo (Treatment Period)		Mepolizumab 100 mg SC (Treatment Period)		Placebo (Follow-up)		Mepolizumab 100 mg SC (Follow-up)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	141/201 (70.1%)		139/206 (67.5%)		13/65 (20%)		14/69 (20.3%)
Blood and lymphatic system disorders
Anaemia	0/201 (0%)	0	0/206 (0%)	0	2/65 (3.1%)	3	0/69 (0%)	0
Ear and labyrinth disorders
Ear pain	8/201 (4%)	14	4/206 (1.9%)	5	2/65 (3.1%)	2	0/69 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	5/201 (2.5%)	5	7/206 (3.4%)	11	0/65 (0%)	0	0/69 (0%)	0
Infections and infestations
Nasopharyngitis	46/201 (22.9%)	64	52/206 (25.2%)	83	4/65 (6.2%)	6	6/69 (8.7%)	8
Sinusitis	22/201 (10.9%)	29	10/206 (4.9%)	12	0/65 (0%)	0	3/69 (4.3%)	3
Acute sinusitis	13/201 (6.5%)	18	13/206 (6.3%)	17	0/65 (0%)	0	0/69 (0%)	0
Upper respiratory tract infection	14/201 (7%)	18	12/206 (5.8%)	20	0/65 (0%)	0	0/69 (0%)	0
Bronchitis	13/201 (6.5%)	16	10/206 (4.9%)	10	0/65 (0%)	0	0/69 (0%)	0
Influenza	8/201 (4%)	10	7/206 (3.4%)	7	0/65 (0%)	0	0/69 (0%)	0
Otitis media	10/201 (5%)	12	5/206 (2.4%)	5	0/65 (0%)	0	0/69 (0%)	0
Rhinitis	8/201 (4%)	10	5/206 (2.4%)	5	0/65 (0%)	0	0/69 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	14/201 (7%)	16	15/206 (7.3%)	24	0/65 (0%)	0	0/69 (0%)	0
Arthralgia	5/201 (2.5%)	6	13/206 (6.3%)	14	0/65 (0%)	0	0/69 (0%)	0
Nervous system disorders
Headache	44/201 (21.9%)	141	37/206 (18%)	114	5/65 (7.7%)	14	5/69 (7.2%)	8
Respiratory, thoracic and mediastinal disorders
Epistaxis	18/201 (9%)	20	17/206 (8.3%)	24	0/65 (0%)	0	0/69 (0%)	0
Oropharyngeal pain	10/201 (5%)	11	16/206 (7.8%)	19	0/65 (0%)	0	0/69 (0%)	0
Nasal polyps	16/201 (8%)	28	8/206 (3.9%)	11	1/65 (1.5%)	1	3/69 (4.3%)	3
Asthma	17/201 (8.5%)	20	4/206 (1.9%)	31	0/65 (0%)	0	0/69 (0%)	0
Cough	13/201 (6.5%)	15	7/206 (3.4%)	9	2/65 (3.1%)	3	2/69 (2.9%)	2
Nasal congestion	6/201 (3%)	9	7/206 (3.4%)	12	0/65 (0%)	0	0/69 (0%)	0
Rhinorrhoea	0/201 (0%)	0	0/206 (0%)	0	2/65 (3.1%)	3	2/69 (2.9%)	2
Vascular disorders
Hypertension	9/201 (4.5%)	11	8/206 (3.9%)	11	0/65 (0%)	0	0/69 (0%)	0

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.