Mepolizumab in Nasal Polyposis

Assessment of the nasal polyposis condition was performed after six months of dosing to determine the situation indicative of a reduction in the need for surgery. The components used to determine the need for surgery were endoscopic polyp (ENP) scores and a severity of condition as measured by a visual analogue scale (VAS). Surgery was still deemed required for a participant with an ENP score of >=3, or an ENP score of 2 and a VAS symptom score of >7. The number of participants with reduced need for polyp surgery are presented as missing data set to non-responders (NR) and missing data last observation carry forward (LOCF). LOCF is defined as missing responses at Week 25 imputed with the last non-missing post-dose observation for that participant.

Each nostril was assessed for polyps and graded at Weeks 1, 2, 5, 9, 13, 17, 21, and 25. The right and left nostrils were scored from 0 to 4, where, 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 ENP score was recorded for both the right and the left nostril. The higher of the two scores was derived and used for the analysis. The ENP score ranges from 0 to 4, with a higher score indicating a larger polyp.

Assessment of the nasal polyposis condition was performed after 6 months of dosing to determine the situation indicative of a reduction in the need for surgery. The components used to determine the need for surgery were endoscopic polyp scores and a severity of condition as measured by a VAS. Surgery was required for participants with ENP scores of >=3, or ENP scores of 2 and a VAS symptom score of >7.

SBP and DBP were measured at Baseline (Week 1) and at Weeks 2, 5, 9, 13, 17, 21, and 25. Baseline is defined as the Week 1 pre-dose assessment. Change from Baseline is defined as the difference between the post-dose post-Baseline visit value and the Baseline value.

Pulse rate was measured at Baseline (Week 1) and at Weeks 2, 5, 9, 13, 17, 21, and 25. Baseline is defined as the Week 1 pre-dose assessment. Change from Baseline is defined as the difference between the post-dose post-Baseline visit value and the Baseline value.

A single safety 12-lead ECG was performed using a standard 12-lead ECG machine at Weeks 1, 2, 5, 9, 13, 17, 21, and 25. Any abnormal clinically significant (CS) and not clinically significant (NCS) findings were identified. ECG abnormaility with respect to CS and NCS findings were judged by the investigator or appropriately qualified designee. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

BUN, glucose fasting, chloride, sodium, potassium, carbon dioxide (CO2), and calcium were assessed at Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose).

ALT, AST, ALP, and GGT were assessed at Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose).

Albumin and protein were assessed at Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose).

Total bilirubin (TB) and direct bilirubin (DB), creatinine, and uric acid were assessed at Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose).

Platelet count, WBC count, basophils, eosinophils, lymphocytes, monocytes, and neutrophils were assessed at Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose).

Hemoglobin and MCHC were assessed at Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose).

RBC count and RC were assessed at Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose).

MCH was assessed at Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose).

MCV was assessed at Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose).

Reticulocyte count was assessed at Week 1 pre-dose, Week 2, Week 5 pre-dose, Week 9 pre-dose, Week 13 pre-dose, Week 17 pre-dose, Week 21 pre-dose, and Week 25 (4 Weeks post last dose).

Specific gravity, power of hydrogen (pH), glucose, protein, blood, and ketones were assessed at Weeks (Wk) 1, 2, 5, 9, 13, 17, 21, and 25. Results for all urinalysis parameters were assessed for clinical relevance by physician. Clinically relevant positive results are presented. Clinically relevant positive results are defined as those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is an important medical event that jeopardizes the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, or is associated with liver injury and impaired liver function.

FEV1 is defined as the volume of air forcefully expelled from the lungs in one second. FEV1 measurements were taken by spirometry at each clinic visit. FEV1 was calculated as the maximum of three readings taken at each time point for each participant. Spirometry data is plotted and analyzed using a repeated measures model to calculate treatment difference, confidence intervals and p-values.

FVC is defined as the maximum amount of air that can forcibly be blown out after a maximum inspiration. FVC was calculated as the maximum of three readings taken at each time point for each participant. Spirometry data are plotted and analyzed using a repeated measures model to calculate treatment difference, confidence intervals and p-values.

PEFR is defined as the maximum airflowrate generated during a forced expiration beginning with the lungs fully inflated. PEFR was calculated as the maximum of three readings taken at each time point for each participant. Spirometry data is plotted and analyzed using a repeated measures model to calculate treatment difference, confidence intervals and p-values.

Participants were asked to indicate on a VAS (0 to 10 centimeters) the severity of nasal polyposis and its four symptoms (one VAS for each symptom): rhinorrhea; mucus in the throat; nasal blockage; loss of smell. The left-hand side of the scale (0) represents "not troublesome," and the right hand side of the scale (10) represents "worst possible troublesome." Hence the score ranges between 0 to 10, with higher scores indicating greater severity.

Participants used a portable hand-held inspiratory flow meter to measure and record PNIF in the morning prior to taking the study medication. Three measurements were taken, and the largest measurement was recorded in the electronic diary. PNIF data is plotted and analyzed using a repeated measures model to calculate treatment difference, confidence intervals and p-values.

Sniffin'Sticks were used to assess each participant's sense of smell (olfaction). Olfaction testing results were recorded for both the right and left nostrils The worst nostril score (number of correct answers for the worst nostril) and the mean nostril score (mean number of correct answers across both nostrils) were recorded. Scores range from 0 to 12 (high score indicating normal olfactory sensation). Olfaction data are plotted and analyzed using a repeated measures model to calculate treatment difference, confidence intervals and p-values.

SNOT-22 questionnaire is a modification of the SNOT-20 and contains the questions (ques) related to smell and nasal obstruction. Each ques is graded with a numerical score for each response (resp); scores range from 0 for "no symptoms" to 5 for "as bad as things could be." Scores for each of the ques is summed to derive the total score for that par. at that visit. If the par. did not complete any ques at a visit, then he/she were not to have any missing values imputed, and his/her total score for that visit was set to missing. If a par. had some missing scores (but no more than 50% missing at that visit), then scores for the missing resp were imputed as the mean of the non-missing resp for that par. at that visit. The SNOT-22 total score ranges from 0 to 110, with higher scores representing a worse quality of life. Questionnaire data analysis was done using an ANCOVA to obtain the LS-means, treatment difference and confidence interval at Week 25, adjusting for Week 1 Baseline scores.

The EQ-5D is a standardized, 2-part questionnaire used to measure health outcomes. The first part contains descriptions of the following five components: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses to each of the five domains are measured on a 3-point scale (1-no problems, 2-some problems, and 3-severe problems). An index for the descriptive scores was derived using the general European weights, obtained for each of the countries in this study. Index scores were derived for each participant at each time point by taking sum of weights. Index score ranges from -0.718 to 1, with lower scores indicating poor health. ANCOVA model with treatment, Baseline (Week 1 scores) and country as factors was used to calculate treatment difference and confidence intervals at Week 25.

The EQ-5D is a standardized, 2-part questionnaire used to measure health outcomes. The second part of the questionnaire is a VAS question, requiring the participant to self rate his/her health score on a scale of 0 (worst imaginable health state) to 100 (best imaginable health state). ANCOVA model with treatment, Baseline (Week 1 scores) and country as factors was used to calculate treatment difference and confidence intervals at Week 25.

Blood samples were collected for the assessment of systemic clearance at Weeks 1, 2, 5, 9, 13, and 25. Systemic Clearance (CL) is estimated using a population-Pharmacokinetic model incorporating all available data points from all participants. Individual values were estimated from the model as post-hoc values after incorporating between-participant variability.

Volume of distribution at steady-state was derived from pharmacokinetic parameter estimates of a population pharmacokinetic model. Blood samples were collected for analysis of volume of distribution at Weeks 1, 2, 5, 9, 13, and 25. All available concentrations at all available datapoints from all participants were incorporated into the model. Individual values were estimated from the model as post-hoc values after incorporating between-participant variability.

Clearance is the volume of plasma that would contain the amount of drug excreted per day. Blood samples were collected for the assessment of bodyweight-adjusted clearance at Weeks 1, 2, 5, 9, 13, and 25. Clearance was estimated using a population-pharmacokinetic model incorporating all available data points from all participants. Individual values were estimated from the model as post-hoc values after incorporating between-participant variability.

Steady-state volume of distribution is the blood and tissue volume into which a drug is distributed and the relative binding of drug to protein in these spaces. Blood samples were collected for the assessment of steady-state volume of distribution at Weeks 1, 2, 5, 9, 13, and 25. Steady-state volume of distribution was estimated using a population-pharmacokinetic model incorporating all available data points from all participants. Individual values were estimated from the model as post-hoc values after incorporating between-participant variability.

Blood samples were collected for the assessment of Cmax, Cav(0-inf), and Cmax SS at Weeks 1, 2, 5, 9, 13, and 25. These parameters were estimated using a population-pharmacokinetic model incorporating all available data points from all participants. Individual values were estimated from the model as post-hoc values after incorporating between-participant variability.

Blood samples were scheduled to be collected for the assessment of AUC(0-inf) at Weeks 1, 2, 5, 9, 13, and 25 AUC[0-inf] is derived from individual systemic clearance estimates using the expression AUC[0-inf] = Dose/CL. Hence all data are incorporated into the estimation of CL and by implication AUC[0-inf].

Half-life (Alpha) is the rate of decline in plasma concentrations due to the process of drug redistribution from the central to the peripheral compartment and half-life (Beta ) is the rate of decline due to the process of drug elimination due to metabolism. Blood samples were collected for the assessment of half-life (Alpha) and half-life (Beta) at Weeks 1, 2, 5, 9, 13, and 25. Half-life was estimated using a population-pharmacokinetic model incorporating all available data points from all participants. Individual values were estimated from the model as post-hoc values after incorporating between-participant variability.

Blood samples were collected for the assessment of PK/PD model derived Baseline at Weeks 1, 2, 5, 9, 13, 17, 21 and 25. An exploratory Emax direct response model was fitted to serial blood eosinophil count data (including placebo) using model-predicted mepolizumab concentrations (with zero imputed for placebo treated participants). All available blood eosinophil count data were incorporated into the model. Individual values were estimated from the model as post-hoc values after incorporating between-participant variability.

A residual is the difference between the observed and predicted values. Blood samples were collected for the assessment of PK/PD model derived CV(Baseline), CV(Emax), and residual at Weeks 1, 2, 5, 9, 13, 17, 21 and 25. An exploratory Emax direct response model was fitted to serial blood eosinophil count data (including placebo) using model-predicted mepolizumab concentrations (with zero imputed for placebo treated subjects). All available datapoints were incorporated into the model. Individual values are estimated from the model as post-hoc values after incorporating between-participant variability.

Blood samples were collected for the assessment of PK/PD model derived EC50 at Weeks 1, 2, 5, 9, 13, 17, 21 and 25. An exploratory Emax direct response model was fitted to serial blood eosinophil count data (including placebo) using model-predicted mepolizumab concentrations (with zero imputed for placebo treated participants). All available datapoints were incorporated into the model. Individual values are estimated from the model as post-hoc values after incorporating between-partcipant variability.

Blood samples were collected for the assessment of Maximum Inhibition at Weeks 1, 2, 5, 9, 13, 17, 21 and 25. An exploratory Emax direct response model was fitted to serial blood eosinophil count data (including placebo) using model-predicted mepolizumab concentrations (with zero imputed for placebo treated participants). All available datapoints were incorporated into the model. Individual values are estimated from the model as post-hoc values after incorporating between-participant variability.

Blood samples were collected at Week 1 pre-dose, Week 5 pre-dose, Week 13 pre-dose and Week 25 (4 weeks post last dose) for anti-mepolizumab antibody testing using a validated electrochemiluminescent (ECL) immunoassay. The assay involved screening, confirmation and titration steps. If serum samples tested positive in the screening assay, they were considered 'potentially positive' and were further analyzed for the specificity using the confirmation assay. Samples that confirmed positive in the confirmation assay were reported as 'positive'.