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

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.

Time frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, and 76

Population: FAS-OLE: all participants enrolled into the OLE, grouped according to the treatment assigned (omalizumab or placebo) at randomization of the previous studies. Participants who were not enrolled in the OLE study, their parent study data were not included in the analyses. All participants in the FAS received at least one dose of study drug.

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.

Time frame: Baseline, Weeks 4, 8, 16, 24, 36, 52, 64, and 76

Population: Full Analysis Set (FAS) of the open label extension (OLE): all participants enrolled into the OLE, grouped according to the treatment assigned (omalizumab or placebo) at randomization of the previous studies. Participants who were not enrolled in the OLE study, their parent study data were not included in the analyses. All participants in the FAS received at least one dose of study drug.

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.

Time frame: From Start to End (Weeks 24 to 52) of OLE Study

Population: All safety analyses were based on the subset of the full analysis set of the OLE study (FAS-OLE), who received at least one dose of omalizumab in the OLE study (Safety-OLE), grouped according to the treatment received (omalizumab or placebo) in the parent studies. One participant randomized to the placebo arm in a parent study accidently received 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.

Time frame: From Start to End (Weeks 24 to 76) of OLE Study

Population: All safety analyses were based on the subset of the full analysis set of the OLE study (FAS-OLE), who received at least one dose of omalizumab in the OLE study (Safety-OLE), grouped according to the treatment received (omalizumab or placebo) in the parent studies. One participant randomized to the placebo arm in a parent study accidently received omalizumab.

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.

Time frame: Baseline, Weeks 16, 24, 36, 52, 64, and 76

Population: FAS-OLE: all participants enrolled into the OLE, grouped according to the treatment assigned (omalizumab or placebo) at randomization of the previous studies. Participants who were not enrolled in the OLE study, their parent study data were not included in the analyses. All participants in the FAS received at least one dose of study drug. Only participants with comorbid asthma were included in the analysis.

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.

Time frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, and 76

Population: FAS-OLE: all participants enrolled into the OLE, grouped according to the treatment assigned (omalizumab or placebo) at randomization of the previous studies. Participants who were not enrolled in the OLE study, their parent study data were not included in the analyses. All participants in the FAS received at least one dose of study drug.

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.

Time frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, and 76

Population: FAS-OLE: all participants enrolled into the OLE, grouped according to the treatment assigned (omalizumab or placebo) at randomization of the previous studies. Participants who were not enrolled in the OLE study, their parent study data were not included in the analyses. All participants in the FAS received at least one dose of study drug.

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.

Time frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, and 76

Population: FAS-OLE: all participants enrolled into the OLE, grouped according to the treatment assigned (omalizumab or placebo) at randomization of the previous studies. Participants who were not enrolled in the OLE study, their parent study data were not included in the analyses. All participants in the FAS received at least one dose of study drug.

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.

Time frame: Baseline, Weeks 16, 24, 36, 52, 64, and 76

Population: FAS-OLE: all participants enrolled into the OLE, grouped according to the treatment assigned (omalizumab or placebo) at randomization of the previous studies. Participants who were not enrolled in the OLE study, their parent study data were not included in the analyses. All participants in the FAS received at least one dose of study drug.

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.

Time frame: Baseline, Weeks 4, 8, 16, 24, 36, 52, 64, and 76

Population: FAS-OLE: all participants enrolled into the OLE, grouped according to the treatment assigned (omalizumab or placebo) at randomization of the previous studies. Participants who were not enrolled in the OLE study, their parent study data were not included in the analyses. All participants in the FAS received at least one dose of study drug.

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.

Time frame: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, and 76

Population: FAS-OLE: all participants enrolled into the OLE, grouped according to the treatment assigned (omalizumab or placebo) at randomization of the previous studies. Participants who were not enrolled in the OLE study, their parent study data were not included in the analyses. All participants in the FAS received at least one dose of study drug.

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.

Time frame: Baseline, Weeks 8, 16, 24, 36, 52, 64, and 76

Population: FAS-OLE: all participants enrolled into the OLE, grouped according to the treatment assigned (omalizumab or placebo) at randomization of the previous studies. Participants who were not enrolled in the OLE study, their parent study data were not included in the analyses. All participants in the FAS received at least one dose of study drug.

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.

Time frame: Predose at Weeks 36, 52, 64, and 76

Population: The pharmacokinetic evaluable analysis set (PKAS) consisted of participants who received study drug in the form of their per-protocol dose according to baseline total IgE and body weight in the dosing table. Participants receiving the wrong dose or frequency of the treatment assigned (placebo or omalizumab) or the wrong treatment assigned were excluded from this population.

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.

Time frame: Baseline, Weeks 16, 24, 36, 52, 64 and 76

Population: FAS-OLE: all participants enrolled into the OLE, grouped according to the treatment assigned (omalizumab or placebo) at randomization of the previous studies. Participants who were not enrolled in the OLE study, their parent study data were not included in the analyses. All participants in the FAS received at least one dose of study drug.

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.

Time frame: Baseline, Weeks 36, 52, 64, and 76

Population: All safety analyses were based on the subset of the full analysis set of the OLE study (FAS-OLE), who received at least one dose of omalizumab in the OLE study (Safety-OLE), grouped according to the treatment received (omalizumab or placebo) in the parent studies.

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)

Time frame: Predose at Weeks 36, 52, 64, and 76

Population: The pharmacokinetic evaluable analysis set (PKAS) consisted of participants who received study drug in the form of their per-protocol dose according to baseline total IgE and body weight in the dosing table. Participants receiving the wrong dose or frequency of the treatment assigned (placebo or omalizumab) or the wrong treatment assigned were excluded from this population.

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.

Time frame: Predose at Weeks 36, 52, 64, and 76

Population: The pharmacokinetic evaluable analysis set (PKAS) consisted of participants who received study drug in the form of their per-protocol dose according to baseline total IgE and body weight in the dosing table. Participants receiving the wrong dose or frequency of the treatment assigned (placebo or omalizumab) or the wrong treatment assigned were excluded from this population.