An Extension Study of Omalizumab in Participants With Chronic Rhinosinusitis With Nasal Polyps

Study Overview
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Brief Summary
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The overall purpose of this study is to evaluate the safety, efficacy, and durability of response of omalizumab in an open-label setting in adult participants with chronic rhinosinusitis with nasal polyps who completed the double-blind, placebo-controlled, Phase III studies GA39688 (NCT03280550) or GA39855 (NCT03280537). Participants will be eligible for enrollment in the study at, or within 28 days after, the Week 24 visit of Studies GA39688/GA39855. After enrollment into this open-label extension (OLE) study, participants will receive 28 weeks of dosing of omalizumab before entering a 24-week off-treatment observation phase of the study. Baseline in this OLE study is defined as the last pre-treatment measurement prior to randomization in Studies GA39688/GA39855 (i.e., baseline of Studies GA39688/GA39855). The data that will be reported from baseline to Week 24 inclusive will come from Studies GA39688/GA39855.

Official Title
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Open-Label Extension Study of Omalizumab in Patients With Chronic Rhinosinusitis With Nasal Polyps

Conditions
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Nasal Polyps, Chronic Rhinosinusitis

Intervention / Treatment
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* Drug: Omalizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to comply with the study protocol, in the investigator's judgment Participation in Study GA39688 or GA39855, including completion of endoscopy and other assessments at Week 24, without discontinuation of study drug Completion of eDiary daily assessments for at least 4 out of 7 days in the week prior to the Week 24 visit of Study GA39688 or GA39855 For women of childbearing potential: agreement to remain abstinent or use acceptable contraceptive methods during the treatment period and for 60 days after the last dose of study drug Exclusion Criteria: Anaphylaxis/hypersensitivity related to study drug in Study GA39688 or GA39855 Serious adverse events related to study drug in Study GA39688 or GA39855 that the investigator or Sponsor determines may jeopardize the patient's safety if he or she continues in the study Uncontrolled epistaxis within Study GA39688 or GA39855 Pregnant or breastfeeding, or intending to become pregnant during the study or within 60 days after the last dose of omalizumab Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Study GA39688 Omalizumab<br>Participants who received omalizumab once every 2 weeks (Q2W) or once every 4 weeks (Q4W) in Study GA39688 will continue to receive omalizumab at Week 24 at the same dosing schedule. | Drug: Omalizumab<br>* Omalizumab will be administered as a subcutaneous (SC) injection Q2W or Q4W.<br>* Other names: Xolair;|
| Experimental: Cohort A: Study GA39688 Placebo<br>Participants who received placebo Q2W or Q4W in Study GA39688 will start receiving omalizumab Q2W or Q4W at Week 24 at the same dosing schedule. | Drug: Omalizumab<br>* Omalizumab will be administered as a subcutaneous (SC) injection Q2W or Q4W.<br>* Other names: Xolair;Drug: Placebo<br>* Participants will not be receiving placebo in this OLE study. Participants who were randomized to the placebo arms for 24 weeks in studies GA39688/GA39855 and then enter this OLE study will receive omalizumab, but they will be placed in separate analysis cohorts.<br>|
| Experimental: Cohort B: Study GA39855 Omalizumab<br>Participants who received omalizumab Q2W or Q4W in Study GA39855 will continue to receive omalizumab at Week 24 at the same dosing schedule. | Drug: Omalizumab<br>* Omalizumab will be administered as a subcutaneous (SC) injection Q2W or Q4W.<br>* Other names: Xolair;|
| Experimental: Cohort B: Study GA39855 Placebo<br>Participants who received placebo Q2W or Q4W in Study GA39855 will start receiving omalizumab Q2W or Q4W at Week 24 at the same dosing schedule. | Drug: Omalizumab<br>* Omalizumab will be administered as a subcutaneous (SC) injection Q2W or Q4W.<br>* Other names: Xolair;Drug: Placebo<br>* Participants will not be receiving placebo in this OLE study. Participants who were randomized to the placebo arms for 24 weeks in studies GA39688/GA39855 and then enter this OLE study will receive omalizumab, but they will be placed in separate analysis cohorts.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Nasal Polyp Score (NPS) | Total NPS ranges from 0 to 8 (sum of 0-4 for left and right nasal passage scores per the following criteria), with a lower score indicating smaller-sized nasal polyps: 0 = No polyps; 1 = Small polyps in the middle meatus not reaching below the inferior border of the middle turbinate; 2 = Polyps reaching below the lower border of the middle turbinate (modified to accommodate those with a middle turbinectomy, such that polyp must have reached the top of the inferior turbinate.); 3 = Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate; and 4 = Large polyps causing complete obstruction of the inferior nasal cavity. Two blinded primary independent expert readers reviewed every post-screening recorded video endoscopy for a given participant to determine total NPS. A third reader chose one of the two scores to be used for analysis in cases where there was any discrepancy in total NPS assigned between the two primary readers. | Baseline, Weeks 4, 8, 16, 24, 36, 52, 64, and 76 | 
| Change From Baseline in Average Daily Nasal Congestion Score (NCS) | The Nasal Congestion Score (NCS) was assessed daily by the participant via an electronic diary as the response to the following question: Is your nose blocked? The four available response options were scored from 0 (no symptoms) to 3 (severe symptoms): 0 = Not at all; 1 = Mild; 2 = Moderate; and 3 = Severe. For each study day, a score was calculated using an average of the prior 7 days among the available days within the pre-specified window (For Week 24: Study Days 155 to 186), excluding the study day itself, if a value had been recorded by the participant on at least 4 of the prior 7 days; otherwise, the 7-day prior average for that study day was to be considered missing. One calculated (non-missing) 7-day prior average was selected for analysis according to the study day with nearest proximity to Week 24 (Study Day 168), with the earlier selected in the case of a tie. Baseline was defined as the (non-missing) 7-day interval ending on the latest day prior to randomization. | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, and 76 | 
| Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | A serious adverse event was defined as any adverse event that met any of the following criteria: was fatal; was life-threatening; required or prolonged inpatient hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the study drug; or, was a significant medical event in the investigator's judgment. Multiple occurrences of the same serious adverse event in one individual were counted once. | From Start to End (Weeks 24 to 52) of OLE Study | 
| Percentage of Participants With Adverse Events Leading to Discontinuation of Omalizumab | A serious adverse event was defined as any adverse event that met any of the following criteria: was fatal; was life-threatening; required or prolonged inpatient hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the study drug; or, was a significant medical event in the investigator's judgment. Multiple occurrences of the same serious adverse event in one individual were counted once. | From Start to End (Weeks 24 to 76) of OLE Study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Average Daily Total Nasal Symptom Score (TNSS) | The Total Nasal Symptom Score (TNSS) was defined as the sum of the four individual scores for Nasal Congestion Score, Anterior Rhinorrhea Score, Posterior Rhinorrhea Score, and Sense of Smell Score, ranging from 0 (no symptoms) to 12 (most severe symptoms), assessed daily by the participant via an electronic diary. For each study day, a score was calculated using an average of the prior 7 days among the available days within the pre-specified window (For Week 24: Study Days 155 to 186), excluding the study day itself, if a value had been recorded by the participant on at least 4 of the prior 7 days; otherwise, the 7-day prior average for that study day was to be considered missing. One calculated (non-missing) 7-day prior average was selected for analysis according to the study day with nearest proximity to Week 24 (Study Day 168), with the earlier selected in the case of a tie. Baseline was defined as the (non-missing) 7-day interval ending on the latest day prior to randomization. | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, and 76 | 
| Change From Baseline in Loss of Sense of Smell Score | The Sense of Smell Score was assessed daily by the participant via an electronic diary as the response to the following question: Is your sense of smell reduced? The four available response options were scored from 0 (no symptoms) to 3 (severe symptoms): 0 = Not at all; 1 = Mild; 2 = Moderate; and 3 = Severe. For each study day, a score was calculated using an average of the prior 7 days among the available days within the pre-specified window (For Week 24: Study Days 155 to 186), excluding the study day itself, if a value had been recorded by the participant on at least 4 of the prior 7 days; otherwise, the 7-day prior average for that study day was to be considered missing. One calculated (non-missing) 7-day prior average was selected for analysis according to the study day with nearest proximity to Week 24 (Study Day 168), with the earlier selected in the case of a tie. Baseline was defined as the (non-missing) 7-day interval ending on the latest day prior to randomization. | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, and 76 | 
| Change From Baseline in Average Daily Posterior Rhinorrhea Score | The Posterior Rhinorrhea Score was assessed daily by the participant via an electronic diary as the response to the following question: Do you feel dripping at the back of the nose? The four available response options were scored from 0 (no symptoms) to 3 (severe symptoms): 0=Not at all; 1=Mild; 2=Moderate; and 3=Severe. For each study day, a score was calculated using an average of the prior 7 days among available days within a pre-specified window (For Week 24: Study Days 155 to 186), excluding the study day itself, if a value had been recorded by the participant on at least 4 of the prior 7 days, otherwise the 7-day prior average for that study day was to be considered missing. One calculated (non-missing) 7-day prior average was selected for analysis according to the study day with nearest proximity to Week 24 (Study Day 168), with the earlier selected in the case of a tie. Baseline was defined as the (non-missing) 7-day interval ending on the latest day prior to randomization. | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, and 76 | 
| Change From Baseline in Average Daily Anterior Rhinorrhea Score | The Anterior Rhinorrhea Score was assessed daily by the participant via an electronic diary as the response to the following question: Do you have a runny nose? The four available response options were scored from 0 (no symptoms) to 3 (severe symptoms): 0=Not at all; 1=Mild; 2=Moderate; and 3=Severe. For each study day, a score was calculated using an average of the prior 7 days among available days within a pre-specified window (For Week 24: Study Days 155 to 186), excluding the study day itself, if a value had been recorded by the participant on at least 4 of the prior 7 days, otherwise the 7-day prior average for that study day was to be considered missing. One calculated (non-missing) 7-day prior average was selected for analysis according to the study day with nearest proximity to Week 24 (Study Day 168), with the earlier selected in the case of a tie. Baseline was defined as the (non-missing) 7-day interval ending on the latest day prior to randomization. | Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, and 76 | 
| Change From Baseline in Health-Related Quality of Life (HRQoL) as Assessed by the Total Sino-Nasal Outcome Test (SNOT)-22 Score | The SNOT-22 Questionnaire, a disease specific HRQoL measure, comprises a list of 22 symptoms and social or emotional consequences of the nasal disorder. Every participant was asked to rate how severe each problem had been for them over the past 2 weeks on a scale from 0 (no problem at all) to 5 (problem as bad as it can be). The total score is the sum of the scores for all 22 items, ranging from 0 to 110, with a lower score indicating less disease and better HRQoL. A negative score indicates a decrease (or improvement) from the baseline score. | Baseline, Weeks 4, 8, 16, 24, 36, 52, 64, and 76 | 
| Change From Baseline in European Quality of Life 5-Dimension 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) Score | The EQ-5D-5L contains a visual analog score (VAS), providing a global assessment of health. The EQ-VAS questionnaire is a self-reported questionnaire that measures health state. The VAS is a 100 mm scale from worst (0 mm) to best (100 mm) health the participant can imagine. | Baseline, Weeks 16, 24, 36, 52, 64, and 76 | 
| Percentage of Participants Reporting No Problem in the European Quality of Life 5-Dimension 5-Level Questionnaire (EQ-5D-5L) Subdomains | The EQ-5D-5L contains five domains: Mobility, Self-Care, Usual activity, Pain/Discomfort, and Anxiety/Depression, providing a global assessment of health. Each item is rated by the participant on a five-point scale indicating the followings: Level 1 - no problem; Level 2 - slight problems; Level 3 - moderate problems; Level 4 - severe problems; Level 5 - extreme problems. | Baseline, Weeks 16, 24, 36, 52, 64 and 76 | 
| Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Score (in Participants With Comorbid Asthma Only) | The AQLQ is a 32-item participant-reported measure of asthma-related quality of life (QoL) with a total score (the mean of all 32 responses) ranging from 1 (severely impaired) to 7 (not impaired at all); a higher score indicates a better QoL. An increase of at least 0.5 points in the AQLQ score was considered the minimal important difference for improvement in QoL. | Baseline, Weeks 16, 24, 36, 52, 64, and 76 | 
| Change From Baseline in Sense of Smell, as Assessed by The University of Pennsylvania Smell Identification Test (UPSIT) Score | The UPSIT is a 40-question instrument that measures an individual's ability to detect odors and ranges from 0 to 40, with a higher score indicating a better sense of smell. It is a self-administered scratch-and-sniff test provided in booklets that have 40 microencapsulated odorants, each with a multiple-choice option for the response. The number of correct responses is summed to provide a total score. | Baseline, Weeks 8, 16, 24, 36, 52, 64, and 76 | 
| Percentage of Participants With a Clinically Significant Change From Baseline in Laboratory Values | Investigators will assess the participants' clinical laboratory values (e.g., serum chemistry, hematology evaluations including complete blood count [CBC] with differential and platelet counts, and urinalysis values) at timepoints throughout this OLE study relative to the participants' values at baseline from studies GA39688/GA39855 and parameters with clinically significant changes from baseline will be reported. | Baseline, Weeks 36, 52, 64, and 76 | 
| Minimum Serum Concentrations (Ctrough) of Omalizumab at Specified Timepoints | Serum concentrations of omalizumab were quantified using an enzyme-linked immunoabsorbent assay (ELISA) with a lower limit of quantification (LLOQ) of 28.0 nanograms per millilitre (ng/mL). According to the analysis plan, values below the lower limit of quantification (BLQ) were set to 14 ng/mL (i.e. half of LLOQ value). We confirm that all 121 and 123 participants contributed data to the PK outcome measure. The reason why the numbers of participants analyzed per row are different from the overall number of participants is mainly because some PK concentrations at those time points are below LLOQ. Other reasons include: (1) Five participants received accidental dose of Omalizumab at the OLE Week52 thus are excluded for PK sample results for OLE Week64 and OLE Week76, and (2) One participant received omalizumab as concomitant medication in the follow-up period and is excluded from PK sample results for OLE Week76. | Predose at Weeks 36, 52, 64, and 76 | 
| Serum Concentration of Total Immunoglobulin E (IgE) | Serum concentrations of total immunoglobulin E (IgE) were measured throughout the study, as target engagement biomarkers of omalizumab, using validated quantitative immunoassays with lower limits of quantification of 2 International Units per millilitre (IU/mL), and upper limits of quantification (ULQ) of 5000 IU/mL. | Predose at Weeks 36, 52, 64, and 76 | 
| Serum Concentration of Free IgE | Serum concentrations of free IgE were measured throughout the study, as target engagement biomarkers of omalizumab, using validated quantitative immunoassays with LLOQ of 0.83 IU/mL, and ULQ of 62.5 IU/mL. The free IgE assay had limited range to measure circulating levels of free IgE in the presence of complexes of omalizumab-IgE. Results above ULQ were set to 62.5 IU/mL. If results for 1/3 or fewer of the participants were greater than the ULQ, then all summary statistics were reported. If the results for more than 1/3 of participants were greater than the ULQ, then only the median, interquartile range and minimum were calculated, and the mean, standard deviation, and maximum were non-reportable.The following are available for median and interquartile ranges (IQR; IQ1-IQ3): Placebo: OLE Week 64 median 55.4 (IQR 33.3 - 62.5), OLE Week 76 median 62.5 (IQR 31.1 - 62.5). Omalizumab: OLE Week 64 median 55.8 (IQR 37.5 - 62.5), OLE Week 76 median 62.5 (IQR 47.9 - 62.5) | Predose at Weeks 36, 52, 64, and 76 |