ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 14 of 29 for:    LY2439821

A Phase 3 Study in Participants With Moderate to Severe Psoriasis (UNCOVER-1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01474512
Recruitment Status : Active, not recruiting
First Posted : November 18, 2011
Results First Posted : May 27, 2016
Last Update Posted : November 28, 2018
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Psoriasis
Interventions Drug: 80 mg Ixekizumab Dosing Regimens 1, 2, and 3
Drug: Placebo
Enrollment 1296
Recruitment Details  
Pre-assignment Details Participants who received Ixekizumab (ixe) and classified as responder (Resp, sPGA 0/1) in Induction (IND) were re-randomized to receive 80 mg ixe Q4W, Q12W or placebo (PBO) in Maintenance (MAIN) [Primary Population (Pop)]. Non-responders (Non-Resp, sPGA >1) in IND received 80 mg ixe Q4W, PBO Resp received PBO in MAIN (Secondary Pop).
Arm/Group Title Placebo- Induction Period Ixe Q4W - Induction Period Ixe Q2W - Induction Period Ixe/Placebo- Maintenance Period Primary Pop Ixe/Ixe Q12W - Maintenance Period Primary Pop Ixe/Ixe Q4W - Maintenance Period Primary Pop Placebo Resp/Placebo - Maintenance Period Secondary Pop Placebo Non-Resp/Ixe Q4W - Maintenance Period Secondary Pop Ixe Q4W Non-Resp/Ixe Q4W- Maintenance Period Secondary Pop Q2W Non-Resp/Q4W - Maintenance Period Secondary Pop
Hide Arm/Group Description Placebo was administered as 2 subcutaneous (SC) injections every 2 weeks (Q2W) up to Week 10. 160 milligrams (mg) ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection every 4 weeks (Q4W). Placebo was administered as 1 SC injection at Weeks 2, 6, and 10. 160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W at Weeks 4, 6, 8, and 10. Participants who received 80 mg ixe Q2W or Q4W in Induction Period (Weeks 0 to 10) and classified as responders were administered placebo as 2 SC injections at Week 12 followed by placebo as 1 SC injection Q4W up to and including Week 56. Participants who received 80 mg ixe Q2W or Q4W in Induction Period (Weeks 0 to 10) and classified as responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection every 12 weeks (Q12W) up to and including Week 56. Participants who received 80 mg ixe Q2W or Q4W in Induction Period (Weeks 0 to 10) and classified as responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56. Participants who received Placebo during the Induction Period (Weeks 0 to 10) and classified as responders and were administered placebo as 2 SC injections at Week 12 followed by placebo as 1 SC injection Q4W up to and including Week 56. Participants who received placebo in Induction Period (Weeks 0 to 10) and classified as non-responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56. Participants who received 80 mg ixe Q4W in Induction Period (Weeks 0 to 10) and classified as non-responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56. Participants who received 80 mg ixe Q2W in Induction Period (Weeks 0 to 10) and classified as non-responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56.
Period Title: Induction Period
Started 431 432 433 0 0 0 0 0 0 0
Received Study Drug 431 432 433 0 0 0 0 0 0 0
Completed 407 408 415 0 0 0 0 0 0 0
Not Completed 24 24 18 0 0 0 0 0 0 0
Reason Not Completed
Adverse Event             6             10             10             0             0             0             0             0             0             0
Lack of Efficacy             7             1             0             0             0             0             0             0             0             0
Withdrawal by Subject             6             6             5             0             0             0             0             0             0             0
Protocol Violation             3             6             0             0             0             0             0             0             0             0
Sponsor Decision             1             1             1             0             0             0             0             0             0             0
Lost to Follow-up             1             0             2             0             0             0             0             0             0             0
Period Title: Maintenance Period
Started 0 0 0 226 227 [1] 229 16 391 78 62
Received Study Drug 0 0 0 226 227 229 16 391 78 62
Completed 0 0 0 24 108 177 6 350 62 44
Not Completed 0 0 0 202 119 52 10 41 16 18
Reason Not Completed
Relapsed (sPGA ≥3)             0             0             0             186             111             39             9             0             0             0
Adverse Event             0             0             0             4             2             7             0             19             1             3
Withdrawal by Subject             0             0             0             6             2             3             1             6             3             1
Lost to Follow-up             0             0             0             3             3             0             0             2             1             1
Death             0             0             0             0             0             2             0             0             0             0
Investigator Decision             0             0             0             0             0             1             0             2             0             0
Clinical Relapse             0             0             0             1             0             0             0             0             0             0
Lack of Efficacy             0             0             0             1             0             0             0             11             11             12
Protocol Violation             0             0             0             1             0             0             0             1             0             1
Treated but Discontinued in Induction             0             0             0             0             1             0             0             0             0             0
[1]
One participant withdrew end of Induction but re-randomized and treated with maintenance dose ixe.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W Total
Hide Arm/Group Description Placebo administered as 2 SC injections Q2W up to Week 10. 160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W. 160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W up to Week 10. Total of all reporting groups
Overall Number of Baseline Participants 431 432 433 1296
Hide Baseline Analysis Population Description
All randomized participants who received at least 1 dose of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
46.4  (13.40) 45.6  (12.95) 45.1  (12.40) 45.7  (12.93)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
Female
128
  29.7%
143
  33.1%
142
  32.8%
413
  31.9%
Male
303
  70.3%
289
  66.9%
291
  67.2%
883
  68.1%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
Canada 77 69 66 212
Romania 8 3 2 13
Hungary 23 17 26 66
United States 146 156 159 461
Japan 13 12 8 33
Denmark 4 4 8 16
Poland 43 41 55 139
Italy 3 2 1 6
United Kingdom 7 7 7 21
Australia 19 15 8 42
Germany 88 106 93 287
Static Physician Global Assessment (sPGA)   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
sPGA=3 204 197 231 632
sPGA=4, 5 227 235 202 664
[1]
Measure Description: The sPGA is the physician's determination of the participant's Ps lesions overall at a given time point. Lesions were categorized by descriptions for induration, erythema, and scaling. Participants Ps were assessed as 0 (clear), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe), or 5 (very severe).
Psoriasis Area and Severity Index (PASI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
20.32  (8.641) 20.03  (7.304) 20.09  (7.992) 20.15  (7.992)
[1]
Measure Description: PASI combines body surface involvement in 4 regions (head, trunk, arms, and legs), percent area of skin involved was estimated from 0 (0%) to 6 (90%-100%) and severity was estimated by clinical signs of erythema, induration and scaling with a scores range from 0 (no involvement) to 4 (severe involvement). Each area is scored separately and the scores then combined for final PASI, calculated as: sum of severity parameters for each region*area score*weighing factor [head (0.1), upper limbs (0.2), trunk (0.3), lower limbs (0.4)]. Scores range from 0 (no Ps) to 72 (the most severe disease).
Itch Numeric Rating Scale (NRS)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
7.0  (2.58) 7.0  (2.50) 7.2  (2.39) 7.1  (2.49)
[1]
Measure Description: The Itch NRS is a participant-administered, 11-point horizontal scale anchored at 0 (no itch) and 10 (worst itch imaginable). Overall severity of a participant's itching from psoriasis (Ps) is indicated by circling the number that best describes the worst level of itching in the past 24 hours.
Dermatology-Specific Quality of Life Index (DLQI) Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
12.8  (7.11) 13.2  (7.02) 13.4  (7.02) 13.1  (7.05)
[1]
Measure Description: DLQI is a participant-administered, 10-question, validated, quality-of-life questionnaire that covers 6 domains, including symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. Response categories include 0 (not at all), 1 (a little), 2 (a lot), and 3 (very much) and unanswered ("not relevant") responses were scored as "0." Total scores range from 0 to 30, with higher score indicating greater quality of life is impairment.
Nail Psoriasis Severity Index (NAPSI) (n=283, 281, 283)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
26.9  (20.492) 24.12  (18.243) 24.64  (18.916) 24.95  (19.238)
[1]
Measure Description: The NAPSI is a numeric, reproducible, objective tool to evaluate the severity of fingernail bed Ps and fingernail matrix Ps. Each fingernail is given a score for fingernail bed Ps and fingernail matrix Ps, each with scores of 0 (none) to 4 (Ps in all 4 quadrants) depending on the features of each fingernail bed and fingernail matrix Ps.The NAPSI score of a fingernail is the sum of scores in fingernail bed and fingernail matrix from each quadrant (maximum of 8). The sum of all fingernails equals the total NAPSI score with a range from 0 to 80. Higher scores indicated more severe psoriasis.
Percent of Body Surface Area (BSA) involvement of Ps   [1] 
Mean (Standard Deviation)
Unit of measure:  Percent of body surface
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
27.4  (17.77) 27.4  (16.20) 28.2  (17.83) 27.7  (17.27)
[1]
Measure Description: BSA is a physician rating of the percentage of involvement of Ps for each participant. BSA is assessed on a continuous scale from 0% (no involvement) to 100% (full involvement), where 1% corresponds to the size of the participants hand (includes the palm, fingers and thumb).
Psoriasis Scalp Severity Index (PSSI) (n=393, 413, 393)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
21.8  (15.70) 19.9  (14.83) 21.1  (14.69) 20.9  (15.08)
[1]
Measure Description: The PSSI is a physician assessment of erythema, induration and desquamation and percent of scalp that is covered with a scores range from 0 (none) to 4 (very severe). The composite score is derived from the sum of scores for erythema, induration, and desquamation multiplied by the score recorded for the extent of the scalp area involved, 1 (<10%) to 6 (90%-100%) with a total scores range from 0 to 72, with lower scores indicating less severity.
Quick Inventory of Depressive Symptomatology-Self Reported 16 Items (QIDS-SR16) (n=430, 431, 431)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
4.7  (4.34) 5.0  (4.34) 4.5  (4.09) 4.8  (4.26)
[1]
Measure Description: QIDS-SR16 is a participant-administered, 16-item instrument to assess the existence and severity of depression symptoms. A participant is asked to consider each statement as it relates to the way they have felt for the past 7 days and rate each on a 4-point scale: 0 (best) to 3 (worst). The sum of the 16 items corresponding to 9 depression domains (sad mood, concentration, self-criticism, suicidal ideation, interest, energy, sleep disturbance, change in appetite/weight, and psychomotor agitation/retardation) to give a total scores range from 0 to 27, higher scores indicate greater severity.
Work Productivity Activity Impairment Questionnaire-Psoriasis (WPAI-PSO)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
Absenteeism (n=281, 287, 290) 4.5  (17.07) 4.0  (16.26) 5.7  (19.41) 4.7  (17.63)
Activity Impairment (n=431, 429, 432) 31.3  (29.29) 34.7  (28.83) 34.2  (28.99) 33.4  (29.05)
Presenteeism (297, 301, 299) 22.2  (25.85) 25.2  (27.22) 22.6  (26.46) 23.3  (26.53)
Work Productively Loss (n=279, 284, 288) 24.6  (27.90) 27.0  (27.90) 24.9  (28.77) 25.5  (28.18)
[1]
Measure Description: WPAI-PSO is a self-administered, 6-item instrument used to assess the impact of Ps on productivity impairment within the past 7 days. WPAI-PSO has 4 domains: absenteeism, presenteeism (reduced productivity at work), an overall work impairment score and impairment in daily activities performed outside work. Four scores are derived as percentages: absenteeism, presenteeism (reduced productivity while at work), overall work impairment (absenteeism and presenteeism), and impairment in activities performed outside of work. Percentage = each score * 100. Greater scores indicate greater impairment.
Medical Outcomes Study 36-Item Short Form (SF36) Physical component (PCS) and Mental Component (MCS)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
PCS (n=428, 428, 432) 46.92  (9.769) 47.34  (9.169) 46.58  (9.146) 46.95  (9.363)
MCS (n=428, 428, 432) 48.77  (11.182) 47.46  (11.655) 47.94  (11.535) 48.05  (11.463)
[1]
Measure Description: The SF-36 is a self-reported instrument that measures the participant's health status during the previous 7 days. It comprises 36-items covering 8 domains: physical functioning, role physical, role emotional, bodily pain, vitality, social functioning, mental health, and general health. Items are answered on Likert scales of varying lengths. The 8 domains are regrouped in the PCS and MCS scores. Scores range from 0 to 100, with higher scores indicating better levels of function and/or better health.
Patient's Global Assessment of Disease Severity (PatGA) (n=431, 430, 430)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 431 participants 432 participants 433 participants 1296 participants
4.1  (0.95) 4.1  (0.88) 4.1  (0.94) 4.1  (0.92)
[1]
Measure Description: The PatGA is a single-item self-reported instrument asking the participant to rate severity of their psoriasis "today" by circling a number on a 0 to 5 numeric rating scale from 0 (Clear = no psoriasis) to 5 (Severe = the worst their psoriasis has ever been).
1.Primary Outcome
Title Percentage of Participants With Static Physician Global Assessment (sPGA) of 0 or 1 (Efficacy of Ixekizumab in Participants With Moderate to Severe Plaque Ps Measure: sPGA)
Hide Description The sPGA is the physician's determination of the participant's Ps lesions overall at a given time point. Lesions were categorized by descriptions for induration, erythema, and scaling. Participants Ps were assessed as 0 (clear), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe), or 5 (very severe). An sPGA responder was defined as having a post-baseline sPGA score of "0" or "1" with at least a 2-point improvement from baseline.
Time Frame Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) Population: all randomized participants analyzed according to the treatment to which they were assigned. Participants who did not meet the clinical response criteria or had missing data at Week 12 were considered non-responders for Non-Responder Imputation (NRI) analysis.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 431 432 433
Measure Type: Number
Unit of Measure: percentage of participants
3.2 76.4 81.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
2.Primary Outcome
Title Percentage of Participants Achieving ≥75% Improvement in Ps Area and Severity Index (PASI75) (Efficacy of Ixekizumab in Participants With Moderate to Severe Plaque Psoriasis Measure: PASI)
Hide Description The PASI combines the extent of body surface involvement in 4 anatomical regions (head, trunk, arms, and legs). For each region the percent area of skin involved was estimated from 0 (0%) to 6 (90%-100%) and severity was estimated by clinical signs of erythema, induration and scaling with a scores range from 0 (no involvement) to 4 (severe involvement). Each area is scored separately and the scores then combined for the final PASI. Final PASI calculated as: sum of severity parameters for each region * area score * weighing factor [head (0.1), upper limbs (0.2), trunk (0.3), lower limbs (0.4)]. Overall scores range from 0 (no Ps) to 72 (the most severe disease). Participants achieving PASI75 were defined as having an improvement of ≥75% in the PASI score compared to baseline.
Time Frame Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they were assigned. Participants who did not meet the clinical response criteria or had missing data at Week 12 were considered non-responders for NRI analysis.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 431 432 433
Measure Type: Number
Unit of Measure: percentage of participants
3.9 82.6 89.1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
3.Secondary Outcome
Title Percentage of Participants Achieving an sPGA of 0 (Efficacy of Ixekizumab in Participants With Moderate to Severe Plaque Ps Measure: sPGA)
Hide Description The sPGA is the physician's determination of the participant's Ps lesions overall at a given time point. Lesions were categorized by descriptions for induration, erythema, and scaling. Participants Ps were assessed as 0 (clear), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe), or 5 (very severe).
Time Frame Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned. Participants who did not meet the clinical response criteria or had missing data at Week 12 were considered non-responders for NRI analysis.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 431 432 433
Measure Type: Number
Unit of Measure: percentage of participants
0.0 34.5 37.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Fisher Exact
Comments Due to the zero count in placebo group, p-values from Logistic Regression were not obtainable, therefore the p-value is from Fisher's exact test.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Fisher Exact
Comments Due to the zero count in placebo group, p-values from Logistic Regression were not obtainable, therefore the p-value is from Fisher's exact test.
4.Secondary Outcome
Title Percentage of Participants Achieving PASI 90% (PASI90) or 100% (PASI100) (Efficacy of Ixekizumab in Participants With Moderate to Severe Plaque Ps Measure: PASI)
Hide Description The PASI combines the extent of body surface involvement in 4 anatomical regions (head, trunk, arms, and legs). For each region the percent area of skin involved was estimated from 0 (0%) to 6 (90%-100%) and severity was estimated by clinical signs of erythema, induration and scaling with a scores range from 0 (no involvement) to 4 (severe involvement). Each area is scored by itself and the scores were then combined for the final PASI. Final PASI calculated as: sum of severity parameters for each region * area score * weighing factor [head (0.1), upper limbs (0.2), trunk (0.3), lower limbs (0.4)]. Overall scores range from 0 (no Ps) to 72 (the most severe disease). Participants achieving PASI90 or PASI100 were defined as having an improvement of ≥90% or of 100% respectively in PASI scores compared to baseline.
Time Frame Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned. Participants who did not meet the clinical response criteria or had missing data at Week 12 were considered non-responders for NRI analysis.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 431 432 433
Measure Type: Number
Unit of Measure: percentage of participants
PASI90 0.5 64.6 70.9
PASI100 0.0 33.6 35.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-value is for PASI90.
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-value is for PASI90.
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-value is for PASI100.
Method Fisher Exact
Comments Due to the zero count in placebo group, p-values from Logistic Regression were not obtainable; therefore the p-value is from Fisher's exact test.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-value is for PASI100.
Method Fisher Exact
Comments Due to the zero count in placebo group, p-values from Logistic Regression were not obtainable; therefore the p-value is from Fisher's exact test.
5.Secondary Outcome
Title Percentage of Participants Maintaining sPGA 0 or 1 After Re-Randomization at Start of Maintenance Dosing Period
Hide Description The sPGA is the physician's determination of the participant's Ps lesions overall at a given time point. Lesions were categorized by descriptions for induration, erythema, and scaling. Participants Ps were assessed as 0 (clear), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe), or 5 (very severe).
Time Frame Week 60
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Maintenance Period Primary Population (MPPP): all randomized participants from Period 2 who achieved sPGA (0, 1), were re-randomized at Week 12 and who received at least 1 dose of study treatment Period 3 period. Participants did not meet the clinical response criteria or had missing data at Week 12 were considered non-responders for NRI analysis.
Arm/Group Title Ixe/Placebo Ixe/Q12W Ixe/Q4W
Hide Arm/Group Description:
Participants who received ixe (Q2W or Q4W) in Induction Period who were re-randomized at Week 12 and administered placebo as 2 SC injections at Week 12 followed by placebo as 1 SC injection Q4W up to and including Week 56 (Maintenance Period).
Participants who received ixe (Q2W or Q4W) in Induction Period who were re-randomized at Week 12 and were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q12W up to and including Week 56 (Maintenance Period).
Participants who received ixe (Q2W or Q4W) in Induction Period who were re-randomized at Week 12 and were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56 (Maintenance Period).
Overall Number of Participants Analyzed 226 227 229
Measure Type: Number
Unit of Measure: percentage of participants
7.5 37.4 72.9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ixe/Placebo, Ixe/Q12W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments Logistic Regression analysis included treatment and baseline weight category as factors.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ixe/Placebo, Ixe/Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments Logistic Regression analysis included treatment and baseline weight category as factors.
6.Secondary Outcome
Title Percentage of Participants With Itch Numeric Rating Scale (Itch NRS) Score ≥4 Point Reduction From Baseline
Hide Description The Itch NRS is a participant-administered, 11-point horizontal scale anchored at 0 (no itch) and 10 (worst itch imaginable). Overall severity of a participant's itching from Ps is indicated by circling the number that best describes the worst level of itching in the past 24 hours.
Time Frame Baseline, Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned; and had an Itch NRS score ≥4 at baseline. Participants who did not meet the clinical response criteria or had missing data at Week 12 were considered non-responders for NRI analysis.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 374 379 391
Measure Type: Number
Unit of Measure: percentage of participants
15.5 80.5 85.9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
7.Secondary Outcome
Title Change From Baseline in Dermatology-Specific Quality of Life Index (DLQI) Score
Hide Description DLQI is a participant-administered, 10-question, validated, quality-of-life questionnaire that covers 6 domains, including symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. Response categories include 0 (not at all), 1 (a little), 2 (a lot), and 3 (very much) and unanswered ("not relevant") responses were scored as "0." Total scores range from 0 to 30, with higher score indicating greater quality of life is impairment. A 5-point change from baseline is considered clinically relevant. Least squares (LS) mean change from baseline was calculated using mixed model repeated measures (MMRM).
Time Frame Baseline, Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned; and who had at least 1 post-baseline DLQI measurement.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 421 421 427
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.0  (0.27) -10.7  (0.27) -11.1  (0.26)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments LS mean and P-value were calculated using MMRM with baseline score as a covariate, treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, visit and treatment-by-visit interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments LS mean and P-value were calculated using MMRM with baseline score as a covariate, treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, visit and treatment-by-visit interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline in Nail Psoriasis Severity Index (NAPSI)
Hide Description The NAPSI is a numeric, reproducible, objective tool for evaluation of fingernail Ps. This scale is used to evaluate the severity of fingernail bed Ps and fingernail matrix Ps by area of involvement in the fingernail unit. The fingernail is divided with imaginary horizontal and longitudinal lines into quadrants. Each fingernail is given a score for fingernail bed Ps 0 (none) to 4 (Ps in 4 quadrants of the fingernail) and fingernail matrix Ps 0 (none) to 4 (Ps in 4 quadrants of the matrix), depending on the presence (score of 1) or absence (score of 0) of any of the features of fingernail bed or matrix Ps in each quadrant. The NAPSI score of a fingernail is the sum of scores in fingernail bed and fingernail matrix from each quadrant (maximum of 8). Each fingernail is evaluated, then the sum of all fingernails equals the total NAPSI score with a range from 0 to 80 with higher scores indicating more severe psoriasis. LS mean change from baseline was calculated using MMRM.
Time Frame Baseline, Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned; and had fingernail Ps at baseline.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 280 276 279
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
2.17  (0.672) -7.19  (0.671) -7.24  (0.657)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments LS mean and P-value were calculated using MMRM with baseline score as a covariate, treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, visit and treatment-by-visit interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments LS mean and P-value were calculated using MMRM with baseline score as a covariate, treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, visit and treatment-by-visit interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
9.Secondary Outcome
Title Percent of Body Surface Area (BSA) Involvement of Ps
Hide Description BSA is a physician rating of the percentage of involvement of Ps for each participant. BSA is assessed on a continuous scale from 0% (no involvement) to 100% (full involvement), where 1% corresponds to the size of the participants hand (includes the palm, fingers and thumb). Total BSA is the sum of handprints from the affected areas. LS mean change from baseline was calculated using MMRM.
Time Frame Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned; and had at least 1 post-baseline BSA measurement.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 426 425 428
Least Squares Mean (Standard Error)
Unit of Measure: percentage of body surface
1.3  (0.67) -21.4  (0.67) -22.4  (0.66)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments LS mean and P-value were calculated using MMRM with baseline score as a covariate, treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, visit and treatment-by-visit interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments LS mean and P-value were calculated using MMRM with baseline score as a covariate, treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, visit and treatment-by-visit interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
10.Secondary Outcome
Title Change From Baseline in Psoriasis Scalp Severity Index (PSSI)
Hide Description The PSSI is a physician assessment of erythema, induration and desquamation and percent of scalp that is covered with a scores range from 0 (none) to 4 (very severe). The composite score is derived from the sum of scores for erythema, induration, and desquamation multiplied by the score recorded for the extent of the scalp area involved, 1 (<10%) to 6 (90%-100%) with a total scores range from 0 to 72, with lower scores indicating less severity. LS mean change from baseline was calculated using MMRM.
Time Frame Baseline, Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned; and had scalp Ps at baseline.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 393 413 393
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.8  (0.53) -18.3  (0.52) -19.2  (0.52)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments LS mean and P-value were calculated using MMRM with baseline score as a covariate, treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, visit and treatment-by-visit interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments LS mean and P-value were calculated using MMRM with baseline score as a covariate, treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, visit and treatment-by-visit interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
11.Secondary Outcome
Title Change From Baseline in All Scores of the Work Productivity Activity Impairment Questionnaire-Psoriasis (WPAI-PSO) (Quality of Life and Outcome Assessments. Measures: Participant Reported Outcomes [PRO])
Hide Description WPAI-PSO is a participant administered, 6-item instrument used to assess the impact of Ps on the productivity impairment within the past 7 days. WPAI-PSO has 4 domains: absenteeism, presenteeism (reduced productivity while at work), an overall work impairment score, and impairment in daily activities performed outside of work. Four scores are derived as percentages: absenteeism, presenteeism (reduced productivity while at work), overall work impairment (absenteeism and presenteeism), and impairment in activities performed outside of work. Percentage is calculated as: each score * 100 with greater scores indicating greater impairment. LS mean change from baseline was calculated using analysis of covariance (ANCOVA).
Time Frame Baseline, Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned, and had results at specified time points, last observation carried forward (LOCF).
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 420 417 427
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Absenteeism (253, 250, 255) 0.2  (0.88) -3.5  (0.87) -2.6  (0.84)
Activity Impairment (420, 417, 427) 0.8  (1.18) -24.5  (1.18) -25.2  (1.15)
Presenteeism (275, 273, 278) 0.5  (1.30) -18.8  (1.28) -18.3  (1.24)
Work Productivity Loss (250, 246, 252) -0.8  (1.40) -20.6  (1.38) -19.8  (1.33)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The LS Mean and p-values were calculated using an ANCOVA model and included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline WPAI value.
Method ANCOVA
Comments P-value is for Absenteeism.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments The LS Mean and p-values were calculated using an ANCOVA model and included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline WPAI value.
Method ANCOVA
Comments P-value is for absenteeism.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The LS Mean and p-values were calculated using an ANCOVA model and included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline WPAI value.
Method ANCOVA
Comments P-value is for activity impairment.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The LS Mean and p-values were calculated using an ANCOVA model and included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline WPAI value.
Method ANCOVA
Comments P-value is for activity impairment.
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The LS Mean and p-values were calculated using an ANCOVA model and included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline WPAI value.
Method ANCOVA
Comments P-value is for presenteeism.
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The LS Mean and p-values were calculated using an ANCOVA model and included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline WPAI value.
Method ANCOVA
Comments P-value is for presenteeism.
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The LS Mean and p-values were calculated using an ANCOVA model and included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline WPAI value.
Method ANCOVA
Comments P-value is for work productively loss.
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The LS Mean and p-values were calculated using an ANCOVA model and included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline WPAI value.
Method ANCOVA
Comments P-value is for work productively loss.
12.Secondary Outcome
Title Change From Baseline in Quick Inventory of Depressive Symptomatology-Self Reported 16 Items (QIDS-SR16)
Hide Description QIDS-SR16 is a participant-administered, 16-item instrument intended to assess the existence and severity of symptoms of depression. A participant is asked to consider each statement as it relates to the way they have felt for the past 7 days and rate each on a 4-point scale: 0 (best) to 3 (worst). The sum of the 16 items corresponding to 9 depression domains [sad mood, concentration, self-criticism, suicidal ideation, interest, energy/fatigue, sleep disturbance (initial, middle and late insomnia or hypersomnia), decrease/increase in appetite/weight, and psychomotor agitation/retardation] to give a single total scores range from 0 to 27, with higher scores indicating greater symptom severity. LS mean change from baseline was calculated using ANCOVA.
Time Frame Baseline, Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned, and had results at the specified time points, LOCF.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 421 417 423
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.1  (0.17) -1.0  (0.17) -1.3  (0.17)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments LS Mean and p-values were calculated using an ANCOVA model that included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline QIDS value in the model.
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments LS Mean and p-values were calculated using an ANCOVA model that included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline QIDS value in the model.
Method ANCOVA
Comments [Not Specified]
13.Secondary Outcome
Title Change From Baseline in Medical Outcomes Study 36-item Short Form Health Survey (SF-36) and Physical Component Summary (PCS) and Mental Component Summary (MCS)
Hide Description The SF-36 is a self-reported instrument that measures the participant's health status during the previous 7 days. It comprises 36-items covering 8 domains: physical functioning, role physical, role emotional, bodily pain, vitality, social functioning, mental health, and general health. Items are answered on Likert scales of varying lengths. The 8 domains are regrouped in the PCS and MCS scores. Scores range from 0 to 100, with higher scores indicating better levels of function and/or better health. LS mean change from baseline was calculated using ANCOVA.
Time Frame Baseline, Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned; and with results at the specified time points, LOCF.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 418 415 427
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
PCS -0.1747  (0.4012) 4.3081  (0.3990) 4.3159  (0.3878)
MCS 0.8729  (0.4638) 3.7386  (0.4633) 4.1293  (0.4480)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The LS Mean and p-values were calculated using an ANCOVA model and included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline SF-36 value in the model.
Method ANCOVA
Comments P-value is for PCS.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The LS Mean and p-values were calculated using an ANCOVA model and included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline SF-36 value in the model.
Method ANCOVA
Comments P-value is for PCS.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The LS Mean and p-values were calculated using an ANCOVA model and included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline SF-36 value in the model.
Method ANCOVA
Comments P-value is for MCS.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The LS Mean and p-values were calculated using an ANCOVA model and included treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, and baseline SF-36 value in the model.
Method ANCOVA
Comments P-value is for MCS.
14.Secondary Outcome
Title Change From Baseline in Patient's Global Assessment of Disease Severity (PatGA)
Hide Description The PatGA is a single-item self-reported instrument asking the participant to rate the severity of their psoriasis "today" by circling a number on the numeric rating scale from 0 (Clear = no psoriasis) to 5 (Severe = the worst their psoriasis has ever been). LS mean change from baseline calculated using MMRM.
Time Frame Baseline, Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned; and with at least 1 post-baseline PatGA measurement.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 424 425 427
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.2  (0.06) -3.1  (0.06) -3.2  (0.06)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments LS mean and P-value were calculated using MMRM with baseline score as a covariate, treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, visit and treatment-by-visit interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments LS mean and P-value were calculated using MMRM with baseline score as a covariate, treatment, geographic region, previous non-biologic systemic therapy, baseline weight category, visit and treatment-by-visit interaction as fixed effects.
Method Mixed Models Analysis
Comments [Not Specified]
15.Secondary Outcome
Title Percentage of Participants Achieving Palmoplantar PASI (PPASI) of ≥50% (PPASI50), ≥75% (PPASI75), or 100% (PPASI100) Improvement
Hide Description The Palmoplantar PASI is a composite score derived from the sum of scores for erythema, induration, and desquamation [scores range from 0 (none) to 4 (very severe) for each] multiplied by the score for the extent of palm and sole area involvement [scores range from 0 (0%) to 6 (90 to100%)], with a total scores range from 0 to 72. Participants achieving PPASI50, PPASI75 or PASI100 were defined as having an improvement of at least 50%, 90%, or of 100%, respectively, in the PPASI scores compared to baseline.
Time Frame Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned; and who had palmoplantar Ps at baseline.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 133 131 140
Measure Type: Number
Unit of Measure: percentage of participants
PPASI50 35.3 84.0 82.9
PPASI75 26.3 74.8 77.1
PPASI100 20.3 65.6 70.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-value is for PPASI50.
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-value is for PPASI50.
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-value is for PPASI75
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-value is for PPASI75
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q4W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-value is for PPASI100
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Placebo, Ixe Q2W
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments P-value if for PPASI100.
Method Regression, Logistic
Comments Logistic Regression analysis included treatment, geographic region, previous non-biologic systemic therapy and baseline weight category as factors.
16.Secondary Outcome
Title Pharmacokinetics (PK): Trough Concentration at Steady State (Ctrough ss)
Hide Description [Not Specified]
Time Frame Weeks 12 and 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants analyzed according to the treatment to which they are assigned; and who had Ctrough ss results at specified time points where the concentration met the definition of being a trough concentration.
Arm/Group Title Ixe Q2W - Induction Period Ixe Q4W - Induction Period Ixe Q4W - Maintenance Period Ixe Q12W - Maintenance Period
Hide Arm/Group Description:
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
80 mg ixe administered as 1 SC injection Q4W from Week 12 up to Week 60
80 mg ixe administered as 1 SC injection Q12W from Week 12 up to Week 60
Overall Number of Participants Analyzed 192 215 223 60
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: micrograms/milliliter (µg/mL)
Week 12
7.73
(79%)
2.94
(89%)
NA [1] 
(NA%)
NA [1] 
(NA%)
Week 24
NA [2] 
(NA%)
NA [2] 
(NA%)
2.36
(111%)
0.281
(175%)
[1]
No Induction Period results available.
[2]
No Maintenance Period results available.
17.Secondary Outcome
Title Percentage of Participants With Anti-ixekizumab Antibodies
Hide Description Percentage of participants with treatment-emergent positive anti-ixekizumab antibodies was summarized by treatment group. Percentage was calculated based on the number of evaluable participants and was calculated by number of participants with treatment-emergent positive anti-ixekizumab antibodies / number of evaluable participants * 100%.
Time Frame Baseline through Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least 1 dose of study drug and had evaluable data.
Arm/Group Title Placebo Ixe Q4W Ixe Q2W
Hide Arm/Group Description:
Placebo was administered as 2 SC injections Q2W (Weeks 2, 4, 6, 8, and 10).
160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W (Weeks 4 and 8).
160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W (Weeks 2, 4, 6, 8, and 10).
Overall Number of Participants Analyzed 431 432 433
Measure Type: Number
Unit of Measure: percentage of participants
0.5 12.5 10.3
Time Frame [Not Specified]
Adverse Event Reporting Description Primary Pop defined as: participants who received ixe or PBO and classified as Resp in IND and were re-randomized to ixe 80 mg Q4W, Q12W or PBO in MAIN. Secondary Pop defined as: participants who received ixe and classified as Non-Resp in IND and participants who received PBO in IND who were Resp and continued on PBO in MAIN.
 
Arm/Group Title Placebo - Induction Period Ixe Q4W - Induction Period Ixe Q2W - Induction Period Ixe/Placebo- Maintenance Period Primary Pop Ixe/Ixe Q12W - Maintenance Period Primary Pop Ixe/Ixe Q4W - Maintenance Period Primary Pop Placebo Resp/Placebo - Maintenance Period Secondary Pop Placebo Non-Resp/Ixe Q4W - Maintenance Period Secondary Pop Ixe Q4W Non-Resp/Ixe Q4W - Maintenance Period Secondary Pop Q2W Non-Resp/Q4W - Maintenance Period Secondary Pop Ixe Q4W - Maintenance Period Relapse Pop
Hide Arm/Group Description Placebo was administered as 2 SC injections Q2W up to Week 10. 160 mg ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W. Placebo was administered as 1 SC injection at Weeks 2, 6, and 10. 160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W up to Weeks 4, 6, 8 and 10. Participants who received 80 mg ixe Q2W or Q4W in Induction Period (Weeks 0 to 10) and classified as responders were administered placebo as 2 SC injections at Week 12 followed by placebo as 1 SC injection Q4W up to and including Week 56. Participants who received 80 mg ixe Q2W or Q4W in Induction Period (Weeks 0 to 10) and classified as responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q12W up to and including Week 56. Participants who received 80 mg ixe Q2W or Q4W in Induction Period (Weeks 0 to 10) and classified as responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56. Participants who received Placebo during the Induction Period (Weeks 0 to 10) and classified as responders and were administered placebo as 2 SC injections at Week 12 followed by placebo as 1 SC injection Q4W up to and including Week 56. Participants who received placebo in Induction Period (Weeks 0 to 10) and classified as non-responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56. Participants who received 80 mg ixe Q4W in Induction Period (Weeks 0 to 10) and classified as non-responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56. Participants who received 80 mg ixe Q2W in Induction Period (Weeks 0 to 10) and classified as non-responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56. Participants who relapsed (loss of response, sPGA ≥3 during Maintenance Period) were administered 80 mg ixe as 1 SC injection Q4W up to and including Week 56.
All-Cause Mortality
Placebo - Induction Period Ixe Q4W - Induction Period Ixe Q2W - Induction Period Ixe/Placebo- Maintenance Period Primary Pop Ixe/Ixe Q12W - Maintenance Period Primary Pop Ixe/Ixe Q4W - Maintenance Period Primary Pop Placebo Resp/Placebo - Maintenance Period Secondary Pop Placebo Non-Resp/Ixe Q4W - Maintenance Period Secondary Pop Ixe Q4W Non-Resp/Ixe Q4W - Maintenance Period Secondary Pop Q2W Non-Resp/Q4W - Maintenance Period Secondary Pop Ixe Q4W - Maintenance Period Relapse Pop
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo - Induction Period Ixe Q4W - Induction Period Ixe Q2W - Induction Period Ixe/Placebo- Maintenance Period Primary Pop Ixe/Ixe Q12W - Maintenance Period Primary Pop Ixe/Ixe Q4W - Maintenance Period Primary Pop Placebo Resp/Placebo - Maintenance Period Secondary Pop Placebo Non-Resp/Ixe Q4W - Maintenance Period Secondary Pop Ixe Q4W Non-Resp/Ixe Q4W - Maintenance Period Secondary Pop Q2W Non-Resp/Q4W - Maintenance Period Secondary Pop Ixe Q4W - Maintenance Period Relapse Pop
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/431 (1.16%)      12/432 (2.78%)      6/433 (1.39%)      7/226 (3.10%)      9/227 (3.96%)      15/229 (6.55%)      0/16 (0.00%)      24/391 (6.14%)      6/78 (7.69%)      3/62 (4.84%)      10/345 (2.90%)    
Cardiac disorders                       
Acute myocardial infarction  1  0/431 (0.00%)  0 1/432 (0.23%)  1 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Angina pectoris  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 3/391 (0.77%)  4 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Arteriospasm coronary  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 1/62 (1.61%)  2 0/345 (0.00%)  0
Atrial fibrillation  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Atrioventricular block first degree  1  0/431 (0.00%)  0 1/432 (0.23%)  1 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Bradycardia  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 1/226 (0.44%)  1 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Coronary artery disease  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Coronary artery occlusion  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 1/227 (0.44%)  1 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Coronary artery stenosis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 1/227 (0.44%)  1 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Mitral valve incompetence  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 1/78 (1.28%)  1 0/62 (0.00%)  0 0/345 (0.00%)  0
Myocardial infarction  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Stress cardiomyopathy  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Supraventricular tachycardia  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Congenital, familial and genetic disorders                       
Congenital ectopic pancreas  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Ear and labyrinth disorders                       
Tinnitus  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 1/62 (1.61%)  1 0/345 (0.00%)  0
Eye disorders                       
Retinal detachment  1  0/431 (0.00%)  0 1/432 (0.23%)  1 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Gastrointestinal disorders                       
Abdominal pain upper  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 1/78 (1.28%)  1 0/62 (0.00%)  0 0/345 (0.00%)  0
Anal fistula  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Colitis ischaemic  1  0/431 (0.00%)  0 1/432 (0.23%)  1 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Crohn's disease  1  0/431 (0.00%)  0 1/432 (0.23%)  2 0/433 (0.00%)  0 1/226 (0.44%)  1 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Enteritis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Gastric ulcer  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 1/62 (1.61%)  1 0/345 (0.00%)  0
Gastrointestinal haemorrhage  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 1/78 (1.28%)  1 0/62 (0.00%)  0 0/345 (0.00%)  0
Gastrooesophageal reflux disease  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 1/78 (1.28%)  1 0/62 (0.00%)  0 0/345 (0.00%)  0
Inguinal hernia  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Pancreatitis relapsing  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Upper gastrointestinal haemorrhage  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 1/226 (0.44%)  1 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
General disorders                       
Death  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Fatigue  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Non-cardiac chest pain  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Hepatobiliary disorders                       
Cholecystitis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 1/433 (0.23%)  1 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Cholelithiasis  1  1/431 (0.23%)  1 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Immune system disorders                       
Drug hypersensitivity  1  0/431 (0.00%)  0 0/432 (0.00%)  0 1/433 (0.23%)  1 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Infections and infestations                       
Abscess  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  2 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Appendicitis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 1/433 (0.23%)  4 0/226 (0.00%)  0 1/227 (0.44%)  1 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Bronchopneumonia  1  0/431 (0.00%)  0 1/432 (0.23%)  1 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Cellulitis  1  0/431 (0.00%)  0 2/432 (0.46%)  2 1/433 (0.23%)  1 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 2/391 (0.51%)  2 1/78 (1.28%)  1 0/62 (0.00%)  0 0/345 (0.00%)  0
Chronic tonsillitis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Clostridium difficile colitis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Clostridium difficile sepsis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Device related infection  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Gastroenteritis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Infectious mononucleosis  1  1/431 (0.23%)  1 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Peritonitis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 1/433 (0.23%)  1 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Pilonidal cyst  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 1/226 (0.44%)  2 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Pneumonia  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 1/226 (0.44%)  1 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Postoperative wound infection  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Rectal abscess  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Sinusitis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Staphylococcal infection  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Staphylococcal osteomyelitis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Subcutaneous abscess  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Tonsillitis  1  0/431 (0.00%)  0 1/432 (0.23%)  1 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Injury, poisoning and procedural complications                       
Alcohol poisoning  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Bone contusion  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Fall  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 1/226 (0.44%)  1 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Humerus fracture  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 1/226 (0.44%)  1 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Road traffic accident  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Spinal compression fracture  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Upper limb fracture  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Wrist fracture  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Metabolism and nutrition disorders                       
Type 2 diabetes mellitus  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 1/227 (0.44%)  1 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Musculoskeletal and connective tissue disorders                       
Intervertebral disc degeneration  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Intervertebral disc protrusion  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 1/227 (0.44%)  1 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Musculoskeletal chest pain  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Osteoarthritis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Rotator cuff syndrome  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Synovitis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                       
B-cell lymphoma  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 1/78 (1.28%)  1 0/62 (0.00%)  0 0/345 (0.00%)  0
Colon cancer  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Hypopharyngeal cancer  1  1/431 (0.23%)  1 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Invasive ductal breast carcinoma  1  0/431 (0.00%)  0 1/432 (0.23%)  1 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Squamous cell carcinoma of lung  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Nervous system disorders                       
Carotid artery stenosis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 1/226 (0.44%)  1 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Encephalopathy  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 1/227 (0.44%)  2 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Epilepsy  1  0/431 (0.00%)  0 1/432 (0.23%)  1 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Ischaemic stroke  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Lumbar radiculopathy  1  0/431 (0.00%)  0 0/432 (0.00%)  0 1/433 (0.23%)  1 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Meralgia paraesthetica  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 1/78 (1.28%)  1 0/62 (0.00%)  0 0/345 (0.00%)  0
Multiple sclerosis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 1/227 (0.44%)  2 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Parkinson's disease  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 1/226 (0.44%)  1 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Psychiatric disorders                       
Mood swings  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Renal and urinary disorders                       
Glomerulonephritis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Nephrolithiasis  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 1/227 (0.44%)  1 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Renal colic  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 1/345 (0.29%)  1
Renal failure acute  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                       
Asthma  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 1/229 (0.44%)  1 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Chronic obstructive pulmonary disease  1  1/431 (0.23%)  2 1/432 (0.23%)  1 0/433 (0.00%)  0 1/226 (0.44%)  1 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Pleurisy  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 1/226 (0.44%)  1 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Pulmonary embolism  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 1/227 (0.44%)  1 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Skin and subcutaneous tissue disorders                       
Dermatitis contact  1  0/431 (0.00%)  0 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 1/391 (0.26%)  1 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Drug eruption  1  1/431 (0.23%)  1 0/432 (0.00%)  0 0/433 (0.00%)  0 0/226 (0.00%)  0 0/227 (0.00%)  0 0/229 (0.00%)  0 0/16 (0.00%)  0 0/391 (0.00%)  0 0/78 (0.00%)  0 0/62 (0.00%)  0 0/345 (0.00%)  0
Psoriasis  1  0/431 (0.00%)  0 0/432 (0.00%)  0