Trial Outcomes & Findings for Efficacy and Safety of Tezepelumab in Participants With Severe Chronic Rhinosinusitis With Nasal Polyposis (NCT NCT04851964)

A total of 416 participants were randomized, 6 of which were removed from analyses due to GCP issues, before study unblinding. The remaining 410 were randomized to either the treatment arm (204 participants) or placebo (206 participants) arms of the double-blind treatment period. Two participants were randomized but not dosed (one was withdrawal by subject, one did not meet inclusion/exclusion criteria). Therefore, 203 participants started in the treatment arm and 205 in the placebo arm.

All patients completed a 5-week run-in period during which inclusion/exclusion criteria were assessed, medical history was recorded, nasal endoscopy and biopsy and CT scan were performed, and patient-reported outcomes (PROs) and clinical laboratory tests were performed.

Efficacy and Safety of Tezepelumab in Participants With Severe Chronic Rhinosinusitis With Nasal Polyposis

The total nasal polyp score (NPS) is the sum of the right and left nostril scores (maximum of 8), as evaluated by nasal endoscopy. Higher scores indicate greater symptom severity. The left and right score will be based on a central read with a scale from 0 to 4. Each nasal endoscopy is evaluated by two independent physician reviewers.

The NCS is captured by one item in the NPSD (nasal polyps symptom diary) asking participants to rate the severity of their worst NC over the past 24 hours using the following response options: 0 - None; 1 - Mild; 2 - Moderate; 3 - Severe. Baseline will be the mean of daily responses from Day -13 to Day 0. Bi-weekly (14-day) mean NCS will be calculated if at least 8 days in each 14-day period has evaluable data; otherwise the bi-weekly mean is set to missing.

Participant reported sense of smell will be evaluated as part of the NPSD. Loss of smell is captured by the DSS item (difficulty with sense of smell) in the NPSD asking participants to rate the severity of their worst difficulty with sense of smell over the past 24 hours using the following response options: 0 - None; 1 - Mild; 2 - Moderate; 3 - Severe. Baseline will be the mean of daily responses to the from Day -13 to Day 0. Bi-weekly (14-day) mean loss of smell will be calculated if at least 8 days in each 14-day period has evaluable data; otherwise the bi-weekly mean is set to missing.

SinoNasal Outcome Test 22 scores are participant-reported and assess physical problems, functional limitations and emotional consequences of SinoNasal conditions. Patient-reported symptom severity and symptom impact over the past 2 weeks are captured via a 6-point scale (0-No Problem to 5-Problem as bad as it can be). The total score is the sum of item scores and has a range from 0 to 110 (higher scores indicate poorer outcomes).

The Lund-Mackay score scoring system is used to provide a quantitative assessment of nasal sinuses on sinus CT scans. Based on the sinus CT images, the five sinuses (maxillary, anterior ethmoid, posterior ethmoid, sphenoid and frontal) on each site are score by central radiologist as follows: (0-Normal; 1-Partial Opacification; 2-Total Opacification). The osteomeatal complex is scored for right and left sides (0 - Not occluded; 2- Occluded). The total score ranges from 0 to 24 (higher scores indicate poorer outcomes).

Surgery is defined as any procedure involving instruments resulting in incision and removal of tissue (e.g., polypectomy, endoscopic sinus surgery). Rescue treatment of NP is defined as requiring treatment with systemic corticosteroids (SCS) for at least 3 consecutive days (a single depo-injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids). Time to first NP surgery decision or SCS for NP = (date of the first NP surgery decision or start date of first SCS for NP use - date of randomisation)+1. Kaplan Meier estimates of percentage of participants with events and 95% confidence interval are provided for each treatment group.

Surgery is defined as any procedure involving instruments resulting in incision and removal of tissue (e.g., polypectomy, endoscopic sinus surgery). Time to first NP surgery decision = (date of the first NP surgery decision - date of randomisation)+1. Kaplan Meier estimates of percentage of participants with events and 95% confidence interval are provided for each treatment group.

Systemic corticosteroids (SCS) for nasal polyposis (NP) is defined as requiring at least 3 consecutive days (a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of SCS) for NP. Time to first SCS for NP = (start date of first SCS for NP use - date of randomisation)+1. Kaplan Meier estimates of percentage of participants with events and 95% confidence interval are provided for each treatment group.

The participant completed the nasal polyposis symptom diary each morning throughout the study. The participant was asked to consider their experience with nasal polyposis/nasal polyps over the past 24 hours when responding to each question. Participants were asked to report their experience with nasal polyposis symptoms (nasal blockage, nasal congestion, runny nose, postnasal drip (mucus drainage down the throat), headache, facial pain, facial pressure, difficulty with sense of smell). Participants reported the severity of each symptom and symptom impact at its worst using a 4-point verbal rating scale (0-None to 3-Severe). A total symptom score (range from 0 to 24) was calculated by taking the sum of the 8 equally weighted symptom items. Higher scores indicate greater symptom severity.

For participants with comorbid asthma and aspirin exacerbated respiratory disease (AERD)/nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NSAID-ERD), difference in change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) in the tezepelumab arm as compared to placebo at Week 52. FEV1 is defined as the volume of air exhaled from the lungs in the first second of forced expiration.

The total nasal polyp score (NPS) is the sum of the right and left nostril scores (maximum of 8), as evaluated by nasal endoscopy. Higher scores indicate greater symptom severity. The left and right score will be based on a central read with a scale from 0 to 4. Each nasal endoscopy is evaluated by two independent physician reviewers.

The Nasal Polyp Score is the sum of the right and left nostril scores (maximum 8), as evaluated by nasal endoscopy. A participant with ≥1 point reduction in NPS at Week 52 in the absence of SCS for NP, biologic for NP, or NP surgery at or prior to that time point was defined as a responder, otherwise the participant was defined as a non-responder.

The Nasal Polyp Score is the sum of the right and left nostril scores (maximum 8), as evaluated by nasal endoscopy. A participant with ≥2 point reduction in NPS at Week 52 in the absence of SCS for NP, biologic for NP, or NP surgery at or prior to that time point was defined as a responder, otherwise the participant was defined as a non-responder.

The NCS is captured by one item in the NPSD (nasal polyps symptom diary) asking participants to rate the severity of their worst NC over the past 24 hours using the following response options: 0 - None; 1 - Mild; 2 - Moderate; 3 - Severe. Baseline will be the mean of daily responses from Day -13 to Day 0. Bi-weekly (14-day) mean NCS will be calculated if at least 8 days in each 14-day period has evaluable data; otherwise the bi-weekly mean is set to missing.

The University of Pennsylvania Smell Identification Test is a quantitative test of olfactory function which uses microencapsulated odorants that are released by scratching standardized odour-impregnated test booklets. Scores are based on number of correctly identified odours (score range 0-40, lower scores indicate poorer outcomes).

The Modified Lund-Mackay score scoring system was used to provide a semi-quantitative assessment of nasal sinuses on sinus CT scans. Based on the sinus CT images, the five sinuses (maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal) on each side were scored. Each sinus on each side was scored based on the percentage of opacification from mucosal thickening according to matrix: (score 0 for 0% Opacification; score 1 for 1-25% Opacification; score 2 for 26-50% Opacification; score 3 for 51-75% Opacification; score 4 for 76-99% Opacification; score 5 for 100% Opacification). The range of total Modified Lund Mackay score is from 0 to 50. Higher scores indicate greater symptom severity.

Quantitative assessment of sinus CT image data were used to derive an objective measure of sinus disease burden called sinus severity score. The sinus severity score is defined as: (sinus mucosal volume)/(sinus mucosal volume + sinus air volume)×100%. The range of sinus severity score is 0 to 100. Higher scores indicate greater symptom severity.

The number of courses of SCS for NP per year was analysed using a negative binomial model. The response variable was the number of courses of SCS for NP received by a participant over the planned treatment period. The model included treatment group, baseline co-morbid asthma/AERD/NSAID-ERD status, prior NP surgery status, and region as factors. The logarithm of the time at risk (in years) was used as an offset variable, to adjust different follow-up times. Time during a course was not included in the calculation of time at risk.

The participant will complete an 11-item nasal polyposis symptom diary each morning throughout the screening, treatment and follow-up periods. The participant is asked to consider their experience with nasal polyposis/nasal polyps over the past 24 hours when responding to each question. Participants are asked to report their experience with nasal polyposis symptoms (nasal blockage, nasal congestion, runny nose, postnasal drip (mucus drainage down the throat), headache, facial pain, facial pressure, and difficulty with sense of smell) and symptom impacts (difficulty with sleeping due to nasal symptoms and difficulty with daily activities due to nasal symptoms). Participants report the severity of each symptom and symptom impact at its worst using a 4-point verbal rating scale (0-None to 3-Severe).

Nasal peak inspiratory flow evaluation represents a physiologic measure of the air flow through both nasal cavities during forced inspiration expressed in liters per minute.

The Asthma Control Questionnaire is an assessment of asthma symptoms (nighttime waking, symptoms on waking, activity limitation, shortness of breath, wheezing, and short acting beta-agonist use). Participants are asked to recall their level of asthma control during the previous week by responding to one bronchodilator use question and 5 symptom questions. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled).

Serum concentrations of tezepelumab through Week 64. Logarithm transformation was used when calculating geometric mean of serum concentrations. The results were transformed back to original scale.

Anti-drug antibodies (ADA) responses at baseline and post-baseline. ADA prevalence was defined as patients who are ADA positive at any time including baseline. Persistently positive was defined as having at least two post-baseline ADA positive measurements (with ≥16 weeks between first and last positive) or an ADA positive result at the last available post-baseline assessment. Transiently positive was defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Treatment boosted ADA was defined as baseline positive ADA titre that was boosted to a 4-fold or higher-level following treatment. Treatment emergent ADA (ADA incidence) was defined as the sum of treatment induced ADA and treatment boosted ADA.

Anti-drug antibodies (ADA) responses at baseline and post-baseline. ADA prevalence was defined as patients who are ADA positive at any time including baseline. Persistently positive was defined as having at least two post-baseline ADA positive measurements (with ≥16 weeks between first and last positive) or an ADA positive result at the last available post-baseline assessment. Transiently positive was defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Treatment boosted ADA was defined as baseline positive ADA titre that was boosted to a 4-fold or higher-level following treatment. Treatment emergent ADA (ADA incidence) was defined as the sum of treatment induced ADA and treatment boosted ADA.