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Study of Efficacy and Safety of Canakinumab in Patients With Hereditary Periodic Fevers

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: NCT02059291
Recruitment Status : Completed
First Posted : February 11, 2014
Results First Posted : March 17, 2017
Last Update Posted : May 17, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Hereditary Periodic Fevers
Interventions Drug: Canakinumab
Drug: Placebo
Enrollment 203
Recruitment Details This study consists of 4 study epochs. A total of 203 participants ((181randomized + 4 non-randomized open-label participants in Epoch 2) + (18 TRAPS rollover participants from ACZ885D2203 (NCT01242813) and ACZ885D2207M in Epoch 3)) have been enrolled into this study.
Pre-assignment Details 126 patients, randomized in Epoch 2, were not re-randomized in Epoch 3. These patients were switched to open-label (OL) treatment. Six patients discontinued OL treatment (1 due to physician decision, 1 due to subject/guardian decision, 3 due to lack of efficacy and 1 due to an adverse event).
Arm/Group Title Epoch 2: crFMF: 150 mg Epoch 2: crCMF: Placebo Epoch 2: HIDS/MKD: 150 mg Epoch 2: HIDS/MKD: Placebo Epoch 2: TRAPS: 150 mg Epoch 2: TRAPS: Placebo Epoch 2: Non-randomized Open Label Treatment - crFMF Epoch 2: Non-randomized Open Label HIDS/MKD Epoch 2 (Epoch 3) - Non-randomized Open Label TRAPS Epoch 3: crFMF Re-randomized From Epoch 2 - 150 mg Epoch 3: crFMF Re-randomized From Epoch 2 - Placebo Epoch 3: HIDs/MKD Re-randomized From Epoch 2 - 150 mg Epoch 3: HIDS/MKD Re-randomized From Epoch 2 - Placebo Epoch 3: TRAPS Re-randomized From Epoch 2 - 150 mg Epoch 3: TRAPS Re-randomized From Epoch 2 - Placebo Epoch 3: crFMF, HIDS/MKD, TRAPS - Not Re-randomized Epoch 4: crFMF - Open Label Cumulative Dose <2700 mg Epoch 4: crFMF - Open Label Cumulative Dose 2700 mg - <5400 mg Epoch 4: crFMF - Open Label Cumulative Dose >=5400 mg Epoch 4: HIDS/MKD - Open Label Cumulative Dose <2700 mg Epoch 4: HIDS/MKD - OL Cumulative Dose 2700 - <=5400 mg Epoch 4: HIDS/MKD - Open Label Cumulative Dose >=5400 mg Epoch 4: TRAPS - Open Label Cumulative Dose < 2700 mg Epoch 4: TRAPS - Open Label Cumulative Dose 2700 - <5400 mg Epoch 4: TRAPS - Open Label Cumulative Dose >=5400 mg
Hide Arm/Group Description During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.

During epoch 2, participants received matching placebo to canakinumab 150 mg Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab.

150mg, participants were uptitrated to open-label canakinumab 300 mg

 During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration. During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg. During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between Day 8 and 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.

Canakinumab-naïve Japanese patients with non-exon 10 mutations received open-label canakinumab 150 mg (or 2 mg/kg for patients weighing

≤ 40 kg) q4w .

Participants in the 28 days to less than 2 years old cohort who received open-label canakinumab 150 mg (or 2mg/kg for patients weighing

≤ 40 kg) q4w.

 Open-label treatment in Epoch 3 was initiated for TRAPS patients who rolled over from CACZ885D2203 or CACZ885D2207M. Canakinumab responders who were initially randomized to canakinumab 150 mg q4w and did not re-flare in Epoch 2 were re-randomized at the start of Epoch 3 to canakinumab 150 mg q8w for 24 weeks. Canakinumab responders who were initially randomized to canakinumab 150 mg q4w and did not re-flare in Epoch 2 were re-randomized at the start of Epoch 3 to placebo for 24 weeks. Canakinumab responders who were initially randomized to canakinumab 150 mg q4w and did not re-flare in Epoch 2 were re-randomized at the start of Epoch 3 to canakinumab 150 mg q8w for 24 weeks. Canakinumab responders who were initially randomized to canakinumab 150 mg q4w and did not re-flare in Epoch 2 were re-randomized at the start of Epoch 3 to placebo for 24 weeks. Canakinumab responders who were initially randomized to canakinumab 150 mg q4w and did not re-flare in Epoch 2 were re-randomized at the start of Epoch 3 to canakinumab 150 mg q8w for 24 weeks. Canakinumab responders who were initially randomized to canakinumab 150 mg q4w and did not re-flare in Epoch 2 were re-randomized at the start of Epoch 3 to placebo for 24 weeks. All Epoch 2 non-responders were switched to canakinumab q8w at the start of Epoch 3 for 24 weeks, During epoch 4, participants received open label treatment according to the dose regimen administered in epoch 3. Cumulative dose received was less than 2700 mg. During epoch 4, participants received open label treatment according to the dose regimen administered in epoch 3. Cumulative dose received was >= 2700 mg and < 5400 mg. During epoch 4, participants received open label treatment according to the dose regimen administered in epoch 3. Cumulative dose received was > 5400 mg. During epoch 4, participants received open label treatment according to the dose regimen administered in epoch 3. Cumulative dose received was less than 2700 mg. During epoch 4, participants received open label treatment according to the dose regimen administered in epoch 3. Cumulative dose received was >= 2700 mg and < 5400 mg. During epoch 4, participants received open label treatment according to the dose regimen administered in epoch 3. Cumulative dose received was > 5400 mg. During epoch 4, participants received open label treatment according to the dose regimen administered in epoch 3. Cumulative dose received was less than 2700 mg. During epoch 4, participants received open label treatment according to the dose regimen administered in epoch 3. Cumulative dose received was >= 2700 mg and < 5400 mg. During epoch 4, participants received open label treatment according to the dose regimen administered in epoch 3. Cumulative dose received was > 5400 mg.
Period Title: Epoch 2
Started 31 32 37 35 22 24 2 2 18 [1] 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Completed 31 31 36 33 22 22 2 1 16 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Not Completed 0 1 1 2 0 2 0 1 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Reason Not Completed
Lack of Efficacy             0             0             0             1             0             1             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0
Adverse Event             0             0             1             1             0             0             0             1             1             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0
Withdrawal by Subject             0             1             0             0             0             1             0             0             1             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0
[1]
This Epoch 3 group is shown in Epoch 2 to account for the 203 patients enrolled in the study.
Period Title: Epoch 3
Started 0 0 0 0 0 0 2 1 0 [1] 9 10 6 7 4 5 126 0 0 0 0 0 0 0 0 0
Completed 0 0 0 0 0 0 2 1 0 9 10 6 7 3 5 120 0 0 0 0 0 0 0 0 0
Not Completed 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 6 0 0 0 0 0 0 0 0 0
Reason Not Completed
Physician Decision             0             0             0             0             0             0             0             0             0             0             0             0             0             1             0             1             0             0             0             0             0             0             0             0             0
Adverse Event             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             1             0             0             0             0             0             0             0             0             0
Lack of Efficacy             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             3             0             0             0             0             0             0             0             0             0
Withdrawal by Subject             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             1             0             0             0             0             0             0             0             0             0
[1]
Presented in Epoch 2.
Period Title: Epoch 4
Started 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 43 14 2 18 34 14 31 22 0
Completed 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 41 14 2 18 33 14 30 21 0
Not Completed 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0 0 1 0 1 1 0
Reason Not Completed
Adverse Event             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             1             0             0             0             0             0             1             0             0
Pregnancy             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             1             0             0             0             0             0             0             0             0
Withdrawal by Subject             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             1             0             0             0             0
Lack of Efficacy             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             1             0
Arm/Group Title Epoch 2: crFMF: 150 mg Epoch 2: crCMF: Placebo Epoch 2: HIDS/MKD: 150 mg Epoch 2: HIDS/MKD: Placebo Epoch 2: TRAPS: 150 mg Epoch 2: TRAPS: Placebo Epoch 2: Non-randomized Open Label Treatment - crFMF Epoch 2: Non-randomized Open Label HIDS/MKD Epoch 2 (Epoch 3) - Non-randomized Open Label TRAPS Total
Hide Arm/Group Description During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.

During epoch 2, participants received matching placebo to canakinumab 150 mg Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab.

150mg, participants were uptitrated to open-label canakinumab 300 mg

 During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration. During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg. During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between Day 8 and 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.

Canakinumab-naïve Japanese patients with non-exon 10 mutations received open-label canakinumab 150 mg (or 2 mg/kg for patients weighing

≤ 40 kg) q4w

Participants in the 28 days to less than 2 years old cohort who received open-label canakinumab 150 mg (or 2mg/kg for patients weighing

≤ 40 kg) q4w.

 Open-label treatment in Epoch 3 was initiated for TRAPS patients who rolled over from CACZ885D2203 or CACZ885D2207M. Total of all reporting groups
Overall Number of Baseline Participants 31 32 37 35 22 24 2 2 18 203
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
 Number Analyzed 31 participants 32 participants 37 participants 35 participants 22 participants 24 participants 2 participants 2 participants 18 participants 203 participants
crFMF cohort - randomized
18.0
(2 to 60)
18.0
(4 to 69)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
18
(2 to 69)
HIDS/MKD cohort - randomized
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
12.0
(2 to 43)
9.0
(3 to 47)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
11.0
(2 to 47)
TRAPS cohort - randomized
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
13.5
(3 to 76)
16.5
(2 to 57)
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
15.5
(2 to 76)
crFMF - non-randomized
NA [4] 
(NA to NA)
NA [4] 
(NA to NA)
NA [4] 
(NA to NA)
NA [4] 
(NA to NA)
NA [4] 
(NA to NA)
NA [4] 
(NA to NA)
24.5
(20 to 29)
NA [4] 
(NA to NA)
NA [4] 
(NA to NA)
24.5
(20 to 29)
HIDS/MKD - non-randomized
NA [5] 
(NA to NA)
NA [5] 
(NA to NA)
NA [5] 
(NA to NA)
NA [5] 
(NA to NA)
NA [5] 
(NA to NA)
NA [5] 
(NA to NA)
NA [5] 
(NA to NA)
1.0
(1 to 1)
NA [5] 
(NA to NA)
1.0
(1 to 1)
roll-over TRAPS - non-randomized
NA [6] 
(NA to NA)
NA [6] 
(NA to NA)
NA [6] 
(NA to NA)
NA [6] 
(NA to NA)
NA [6] 
(NA to NA)
NA [6] 
(NA to NA)
NA [6] 
(NA to NA)
NA [6] 
(NA to NA)
42.5
(15 to 81)
42.5
(15 to 81)
[1]
This row reflects crFMF cohort - randomized data only.
[2]
This row reflect HIDS/MKD cohort - randomized data only.
[3]
This row reflect TRAPS cohort - randomized data only.
[4]
This row reflects crFMF non-randomized data only.
[5]
This row reflects HIDS/MIK non-randomized data only.
[6]
This row reflects roll-over TRAPS non-randomized data only.
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 31 participants 32 participants 37 participants 35 participants 22 participants 24 participants 2 participants 2 participants 18 participants 203 participants
Female
14
  45.2%
15
  46.9%
24
  64.9%
19
  54.3%
10
  45.5%
13
  54.2%
2
 100.0%
0
   0.0%
7
  38.9%
104
  51.2%
Male
17
  54.8%
17
  53.1%
13
  35.1%
16
  45.7%
12
  54.5%
11
  45.8%
0
   0.0%
2
 100.0%
11
  61.1%
99
  48.8%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 31 participants 32 participants 37 participants 35 participants 22 participants 24 participants 2 participants 2 participants 18 participants 203 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
1
   3.1%
0
   0.0%
1
   2.9%
2
   9.1%
4
  16.7%
2
 100.0%
1
  50.0%
0
   0.0%
11
   5.4%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
White
27
  87.1%
27
  84.4%
34
  91.9%
31
  88.6%
20
  90.9%
18
  75.0%
0
   0.0%
1
  50.0%
16
  88.9%
174
  85.7%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
4
  12.9%
4
  12.5%
3
   8.1%
3
   8.6%
0
   0.0%
2
   8.3%
0
   0.0%
0
   0.0%
2
  11.1%
18
   8.9%
1.Primary Outcome
Title Percentage of Participants With Resolution of Initial Flare and Absence of New Flares up to the End of the Randomized Treatment Epoch (16 Weeks)
Hide Description Resolution of the initial disease flare is defined as: Physician's Global Assessment of Disease activity (PGA) <2 and C-reactive protein (CRP) within normal range (<= 10 mg/L) or reduction by at least 70% from baseline. The PGA was evaluated by the investigator based on a 5-point scale: 0 = None (no) disease associated with clinical signs and symptoms; 1 = minimal disease associated signs and symptoms; 2 = mild disease associated signs and symptoms; 3 = moderate disease associated signs and symptoms; and 5 = severe disease associated signs and symptoms.
Time Frame 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS), which consisted of all randomized participants in the randomized treatment epoch who received at least one dose of study drug in Epoch 2, was analyzed.
Arm/Group Title Epoch 2: crFMF: 150 mg Epoch 2: crCMF: Placebo Epoch 2: HIDS/MKD: 150 mg Epoch 2: HIDS/MKD: Placebo Epoch 2: TRAPS: 150 mg Epoch 2: TRAPS: Placebo
Hide Arm/Group Description:
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.

During epoch 2, participants received matching placebo to canakinumab 150 mg Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab.

150mg, participants were uptitrated to open-label canakinumab 300 mg
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.
During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration
During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between Day 8 and 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
Overall Number of Participants Analyzed 31 32 37 35 22 24
Measure Type: Number
Unit of Measure: Percentage of participants
61.29 6.25 35.14 5.71 45.45 8.33
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Epoch 2: crFMF: 150 mg, Epoch 2: crCMF: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher's exact test
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Epoch 2: HIDS/MKD: 150 mg, Epoch 2: HIDS/MKD: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0020
Comments [Not Specified]
Method Fisher's exact test
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Epoch 2: TRAPS: 150 mg, Epoch 2: TRAPS: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0050
Comments [Not Specified]
Method Fisher's exact test
Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Participants Who Achieve Physician's Global Assessment (PGA) < 2
Hide Description The PGA was evaluated by the investigator based on a 5-point scale: 0 = None (no) disease associated with clinical signs and symptoms; 1 = minimal disease associated signs and symptoms; 2 = mild disease associated signs and symptoms; 3 = moderate disease associated signs and symptoms; and 5 = severe disease associated signs and symptoms.
Time Frame 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS), which consisted of all randomized participants in the randomized treatment epoch who received at least one dose of study drug in Epoch 2, was analyzed.
Arm/Group Title Epoch 2: crFMF: 150 mg Epoch 2: crCMF: Placebo Epoch 2: HIDS/MKD: 150 mg Epoch 2: HIDS/MKD: Placebo Epoch 2: TRAPS: 150 mg Epoch 2: TRAPS: Placebo
Hide Arm/Group Description:
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.

During epoch 2, participants received matching placebo to canakinumab 150 mg Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab.

150mg, participants were uptitrated to open-label canakinumab 300 mg
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.
During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration
During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between Day 8 and 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
Overall Number of Participants Analyzed 31 32 37 35 22 24
Measure Type: Number
Unit of Measure: Percentage of participants
64.52 9.38 45.95 5.71 45.45 4.17
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Epoch 2: crFMF: 150 mg, Epoch 2: crCMF: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 16.96
Confidence Interval (2-Sided) 95%
4.15 to 69.21
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Epoch 2: HIDS/MKD: 150 mg, Epoch 2: HIDS/MKD: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0006
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 13.63
Confidence Interval (2-Sided) 95%
2.83 to 65.59
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Epoch 2: TRAPS: 150 mg, Epoch 2: TRAPS: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0028
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 23.79
Confidence Interval (2-Sided) 95%
2.52 to 224.86
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Participants With the Serologic Remission
Hide Description Serologic remission was defined as C-reactive protein <= 10 mg/L.
Time Frame 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS), which consisted of all randomized participants in the randomized treatment epoch who received at least one dose of study drug in Epoch 2, was analyzed.
Arm/Group Title Epoch 2: crFMF: 150 mg Epoch 2: crCMF: Placebo Epoch 2: HIDS/MKD: 150 mg Epoch 2: HIDS/MKD: Placebo Epoch 2: TRAPS: 150 mg Epoch 2: TRAPS: Placebo
Hide Arm/Group Description:
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.

During epoch 2, participants received matching placebo to canakinumab 150 mg Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab.

150mg, participants were uptitrated to open-label canakinumab 300 mg
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.
During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration
During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between Day 8 and 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
Overall Number of Participants Analyzed 31 32 37 35 22 24
Measure Type: Number
Unit of Measure: Percentage of participants
67.74 6.25 40.54 5.71 36.36 8.33
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Epoch 2: crFMF: 150 mg, Epoch 2: crCMF: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 29.78
Confidence Interval (2-Sided) 95%
5.86 to 151.31
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Epoch 2: HIDS/MKD: 150 mg, Epoch 2: HIDS/MKD: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0010
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 12.71
Confidence Interval (2-Sided) 95%
2.53 to 63.89
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Epoch 2: TRAPS: 150 mg, Epoch 2: TRAPS: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0149
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 6.64
Confidence Interval (2-Sided) 95%
1.20 to 36.57
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Participants With Normalized Serum Amyloid A (SAA) Level
Hide Description Normalized SAA was defined as SAA <= 10 mg/L.
Time Frame 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS), which consisted of all randomized participants in the randomized treatment epoch who received at least one dose of study drug in Epoch 2, was analyzed.
Arm/Group Title Epoch 2: crFMF: 150 mg Epoch 2: crCMF: Placebo Epoch 2: HIDS/MKD: 150 mg Epoch 2: HIDS/MKD: Placebo Epoch 2: TRAPS: 150 mg Epoch 2: TRAPS: Placebo
Hide Arm/Group Description:
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.

During epoch 2, participants received matching placebo to canakinumab 150 mg Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab.

150mg, participants were uptitrated to open-label canakinumab 300 mg
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.
During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration
During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between Day 8 and 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
Overall Number of Participants Analyzed 31 32 37 35 22 24
Measure Type: Number
Unit of Measure: Percentage of participants
25.81 0.00 13.51 2.86 27.27 0.00
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Epoch 2: crFMF: 150 mg, Epoch 2: crCMF: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0286
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 17.46
Confidence Interval (2-Sided) 95%
0.92 to 332.92
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Epoch 2: HIDS/MKD: 150 mg, Epoch 2: HIDS/MKD: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0778
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 5.26
Confidence Interval (2-Sided) 95%
0.53 to 51.97
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Epoch 2: TRAPS: 150 mg, Epoch 2: TRAPS: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0235
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 16.69
Confidence Interval (2-Sided) 95%
1.04 to 268.50
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percentage of Participants of Canakinumab Responders From Epoch 2 Who Maintained a Clinically Meaningful Response (Absence of New Flares) (40 Weeks)
Hide Description A responder was defined as a participant who had no flare between week 16 and week 40.
Time Frame 40 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The re-randomized set was analyzed.
Arm/Group Title Epoch 2: crFMF: 150 mg Epoch 2: crCMF: Placebo Epoch 2: HIDS/MKD: 150 mg Epoch 2: HIDS/MKD: Placebo Epoch 2: TRAPS: 150 mg Epoch 2: TRAPS: Placebo
Hide Arm/Group Description:
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.

During epoch 2, participants received matching placebo to canakinumab 150 mg Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab.

150mg, participants were uptitrated to open-label canakinumab 300 mg
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration.
During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration
During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between Day 8 and 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
Overall Number of Participants Analyzed 9 10 6 7 4 5
Measure Type: Number
Unit of Measure: Percentage of participants
77.8 30.0 50.0 14.3 75.0 40.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Epoch 2: crFMF: 150 mg, Epoch 2: crCMF: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0513
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 8.17
Confidence Interval (2-Sided) 95%
0.75 to 113.44
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Epoch 2: HIDS/MKD: 150 mg, Epoch 2: HIDS/MKD: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2168
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 6.00
Confidence Interval (2-Sided) 95%
0.27 to 366.24
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Epoch 2: TRAPS: 150 mg, Epoch 2: TRAPS: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3571
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.50
Confidence Interval (2-Sided) 95%
0.15 to 313.49
Estimation Comments [Not Specified]
Time Frame up to week 112
Adverse Event Reporting Description

Cohort groups were analyzed according to the occurrence of events corresponding to treatments given during epochs 2, 3 and 4.

'No medication' events cover events that occurred during epoch 4 when no treatment was given.
 
Arm/Group Title Non-randomized Open Label crFMF, HIDS/MKD Patients Non-randomized Open Label TRAPS Patients Randomized ACZ and Placebo TRAPS Patients - Placebo Events Randomized ACZ and Placebo TRAPS Pts - No Medication Events Randomized ACZ and Placebo TRAPS Patients - ACZ Events Randomized ACZ and Placebo HIDS/MKD Pts - Placebo Events Randomized ACZ and Placebo HIDS/MKD Pts - No Medication Events Randomized ACZ and Placebo HIDS/MKD Patients - ACZ Events Randomized ACZ and Placebo crFMF Patients - Placebo Events Randomized ACZ and Placebo crFMF Pts - No Medication Events Randomized ACZ and Placebo crFMF Patients - ACZ Events Any ACZ TRAPS Patients - Placebo Events Any ACZ TRAPS Patients - no Medication Events Any ACZ TRAPS Patients - ACZ Events Any ACZ HIDS/MKD Patients - Placebo Events Any ACZ HIDS/MKD Patients - No Medication Events Any ACZ HIDS/MKD Patients - ACZ Events Any ACZ crFMF Patients - Placebo Events Any ACZ crFMF Patients - No Medication Events Any ACZ crFMF Patients - ACZ Events
Hide Arm/Group Description

Canakinumab-naïve Japanese patients with non-exon 10 mutations with cr-FMF who received open-label canakinumab 150 mg (or 2 mg/kg for patients weighing ≤ 40 kg) q4w; and patients in the 28 days to less than 2 years old cohort with HIDS/MKD who received open-label canakinumab 150 mg (or 2mg/kg for patients weighing

≤ 40 kg) q4w

 Open-label treatment in Epoch 3 was initiated for TRAPS patients who rolled over from CACZ885D2203 or CACZ885D2207M Patients who received ACZ885 and/or placebo during epoch 2 and/or epoch 3. Patients who received ACZ885 and/or placebo during epoch 2 and/or epoch 3 . Patients who received ACZ885 and/or placebo during epoch 2 and/or epoch 3 Patients who received ACZ885 and/or placebo during epoch 2 and/or epoch 3 Patients who received ACZ885 and/or placebo during epoch 2 and/or epoch 3 Patients who received ACZ885 and/or placebo during epoch 2 and/or epoch 3 Patients who received ACZ885 and/or placebo during epoch 2 and/or epoch 3 Patients who received ACZ885 and/or placebo during epoch 2 and/or epoch 3 Patients who received ACZ885 and/or placebo during epoch 2 and/or epoch 3 Patients who received ACZ885 during epoch 2 and/or epoch 3 Patients who received ACZ885 during epoch 2 and/or epoch 3 Patients who received ACZ885 during epoch 2 and/or epoch 3 Patients who received ACZ885 during epoch 2 and/or epoch 3 Patients who received ACZ885 during epoch 2 and/or epoch 3 Patients who received ACZ885 during epoch 2 and/or epoch 3 Patients who received ACZ885 during epoch 2 and/or epoch 3 Patients who received ACZ885 during epoch 2 and/or epoch 3 Patients who received ACZ885 during epoch 2 and/or epoch 3
All-Cause Mortality
Non-randomized Open Label crFMF, HIDS/MKD Patients Non-randomized Open Label TRAPS Patients Randomized ACZ and Placebo TRAPS Patients - Placebo Events Randomized ACZ and Placebo TRAPS Pts - No Medication Events Randomized ACZ and Placebo TRAPS Patients - ACZ Events Randomized ACZ and Placebo HIDS/MKD Pts - Placebo Events Randomized ACZ and Placebo HIDS/MKD Pts - No Medication Events Randomized ACZ and Placebo HIDS/MKD Patients - ACZ Events Randomized ACZ and Placebo crFMF Patients - Placebo Events Randomized ACZ and Placebo crFMF Pts - No Medication Events Randomized ACZ and Placebo crFMF Patients - ACZ Events Any ACZ TRAPS Patients - Placebo Events Any ACZ TRAPS Patients - no Medication Events Any ACZ TRAPS Patients - ACZ Events Any ACZ HIDS/MKD Patients - Placebo Events Any ACZ HIDS/MKD Patients - No Medication Events Any ACZ HIDS/MKD Patients - ACZ Events Any ACZ crFMF Patients - Placebo Events Any ACZ crFMF Patients - No Medication Events Any ACZ crFMF Patients - ACZ Events
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 (%) 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   0/4 (0.00%)   0/18 (0.00%)   0/46 (0.00%)   0/46 (0.00%)   0/46 (0.00%)   0/72 (0.00%)   0/72 (0.00%)   0/72 (0.00%)   0/63 (0.00%)   0/63 (0.00%)   0/63 (0.00%)   0/61 (0.00%)   0/61 (0.00%)   0/61 (0.00%)   0/71 (0.00%)   0/71 (0.00%)   0/71 (0.00%)   0/61 (0.00%)   0/61 (0.00%)   0/61 (0.00%) 
Hide Serious Adverse Events
Non-randomized Open Label crFMF, HIDS/MKD Patients Non-randomized Open Label TRAPS Patients Randomized ACZ and Placebo TRAPS Patients - Placebo Events Randomized ACZ and Placebo TRAPS Pts - No Medication Events Randomized ACZ and Placebo TRAPS Patients - ACZ Events Randomized ACZ and Placebo HIDS/MKD Pts - Placebo Events Randomized ACZ and Placebo HIDS/MKD Pts - No Medication Events Randomized ACZ and Placebo HIDS/MKD Patients - ACZ Events Randomized ACZ and Placebo crFMF Patients - Placebo Events Randomized ACZ and Placebo crFMF Pts - No Medication Events Randomized ACZ and Placebo crFMF Patients - ACZ Events Any ACZ TRAPS Patients - Placebo Events Any ACZ TRAPS Patients - no Medication Events Any ACZ TRAPS Patients - ACZ Events Any ACZ HIDS/MKD Patients - Placebo Events Any ACZ HIDS/MKD Patients - No Medication Events Any ACZ HIDS/MKD Patients - ACZ Events Any ACZ crFMF Patients - Placebo Events Any ACZ crFMF Patients - No Medication Events Any ACZ crFMF Patients - ACZ Events
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 (%) 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   3/4 (75.00%)   1/18 (5.56%)   1/46 (2.17%)   0/46 (0.00%)   8/46 (17.39%)   6/72 (8.33%)   1/72 (1.39%)   16/72 (22.22%)   5/63 (7.94%)   0/63 (0.00%)   16/63 (25.40%)   0/61 (0.00%)   0/61 (0.00%)   9/61 (14.75%)   3/71 (4.23%)   1/71 (1.41%)   18/71 (25.35%)   3/61 (4.92%)   0/61 (0.00%)   17/61 (27.87%) 
Blood and lymphatic system disorders                                         
Anaemia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Lymphadenopathy † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Neutropenia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/72 (1.39%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Pancytopenia † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Cardiac disorders                                         
Cardiac failure congestive † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Pericarditis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Congenital, familial and genetic disorders                                         
Familial mediterranean fever † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  3/63 (4.76%)  0/63 (0.00%)  2/63 (3.17%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  2/61 (3.28%)  0/61 (0.00%)  2/61 (3.28%) 
Hyper IgD syndrome † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/72 (1.39%)  0/72 (0.00%)  3/72 (4.17%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/71 (1.41%)  0/71 (0.00%)  4/71 (5.63%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Tumour necrosis factor receptor-associated periodic syndrome † 1  0/4 (0.00%)  0/18 (0.00%)  1/46 (2.17%)  0/46 (0.00%)  3/46 (6.52%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Endocrine disorders                                         
Thyroiditis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Gastrointestinal disorders                                         
Abdominal pain † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/72 (1.39%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Ascites † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Constipation † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Diarrhoea † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Dysphagia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Ileal ulcer † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Inguinal hernia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/63 (1.59%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/61 (1.64%)  0/61 (0.00%)  0/61 (0.00%) 
Umbilical hernia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/63 (1.59%)  0/63 (0.00%)  2/63 (3.17%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/61 (1.64%)  0/61 (0.00%)  2/61 (3.28%) 
Vomiting † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
General disorders                                         
Hyperpyrexia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Polyserositis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Pyrexia † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  3/46 (6.52%)  0/72 (0.00%)  0/72 (0.00%)  2/72 (2.78%)  1/63 (1.59%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  4/61 (6.56%)  0/71 (0.00%)  0/71 (0.00%)  2/71 (2.82%)  1/61 (1.64%)  0/61 (0.00%)  1/61 (1.64%) 
Hepatobiliary disorders                                         
Bile duct stone † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Granulomatous liver disease † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Hepatic cirrhosis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Hepatic failure † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Immune system disorders                                         
Drug hypersensitivity † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Infections and infestations                                         
Acute sinusitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Anal abscess † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Appendicitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Atypical pneumonia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/63 (1.59%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Bronchitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Cellulitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  2/63 (3.17%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%) 
Conjunctivitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Diarrhoea infectious † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/72 (1.39%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/71 (1.41%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Gastroenteritis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Gastroenteritis rotavirus † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Herpes virus infection † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Infectious colitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Influenza † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Laryngitis † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Orchitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Pelvic abscess † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Peritonitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Pharyngitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Pharyngotonsillitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Pneumonia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/72 (1.39%)  0/72 (0.00%)  4/72 (5.56%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/71 (1.41%)  0/71 (0.00%)  4/71 (5.63%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Pyelonephritis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Septic shock † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Tonsillitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Urinary tract infection † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Vulval abscess † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Injury, poisoning and procedural complications                                         
Scar † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Metabolism and nutrition disorders                                         
Dehydration † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Hypercalcaemia † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Hypokalaemia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Obesity † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Musculoskeletal and connective tissue disorders                                         
Arthralgia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Bursitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Nervous system disorders                                         
Seizure † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/72 (1.39%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Psychiatric disorders                                         
Depression † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Intentional self-injury † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Schizophrenia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Suicidal ideation † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Suicide attempt † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Renal and urinary disorders                                         
Acute kidney injury † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Respiratory, thoracic and mediastinal disorders                                         
Cough † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/63 (1.59%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Laryngeal stenosis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Oropharyngeal pain † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Pleurisy † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Vocal cord polyp † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Skin and subcutaneous tissue disorders                                         
Drug eruption † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Granulomatous rosacea † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Pyoderma gangrenosum † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
1
Term from vocabulary, MedDRA (20.0)
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Non-randomized Open Label crFMF, HIDS/MKD Patients Non-randomized Open Label TRAPS Patients Randomized ACZ and Placebo TRAPS Patients - Placebo Events Randomized ACZ and Placebo TRAPS Pts - No Medication Events Randomized ACZ and Placebo TRAPS Patients - ACZ Events Randomized ACZ and Placebo HIDS/MKD Pts - Placebo Events Randomized ACZ and Placebo HIDS/MKD Pts - No Medication Events Randomized ACZ and Placebo HIDS/MKD Patients - ACZ Events Randomized ACZ and Placebo crFMF Patients - Placebo Events Randomized ACZ and Placebo crFMF Pts - No Medication Events Randomized ACZ and Placebo crFMF Patients - ACZ Events Any ACZ TRAPS Patients - Placebo Events Any ACZ TRAPS Patients - no Medication Events Any ACZ TRAPS Patients - ACZ Events Any ACZ HIDS/MKD Patients - Placebo Events Any ACZ HIDS/MKD Patients - No Medication Events Any ACZ HIDS/MKD Patients - ACZ Events Any ACZ crFMF Patients - Placebo Events Any ACZ crFMF Patients - No Medication Events Any ACZ crFMF Patients - ACZ Events
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 (%) 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   4/4 (100.00%)   18/18 (100.00%)   14/46 (30.43%)   1/46 (2.17%)   43/46 (93.48%)   25/72 (34.72%)   1/72 (1.39%)   68/72 (94.44%)   29/63 (46.03%)   2/63 (3.17%)   54/63 (85.71%)   4/61 (6.56%)   1/61 (1.64%)   61/61 (100.00%)   7/71 (9.86%)   1/71 (1.41%)   70/71 (98.59%)   10/61 (16.39%)   2/61 (3.28%)   56/61 (91.80%) 
Blood and lymphatic system disorders                                         
Anaemia † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/72 (1.39%)  0/72 (0.00%)  4/72 (5.56%)  1/63 (1.59%)  0/63 (0.00%)  3/63 (4.76%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  4/71 (5.63%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%) 
Lymphadenopathy † 1  0/4 (0.00%)  0/18 (0.00%)  1/46 (2.17%)  0/46 (0.00%)  4/46 (8.70%)  1/72 (1.39%)  0/72 (0.00%)  18/72 (25.00%)  0/63 (0.00%)  0/63 (0.00%)  5/63 (7.94%)  0/61 (0.00%)  0/61 (0.00%)  4/61 (6.56%)  0/71 (0.00%)  0/71 (0.00%)  18/71 (25.35%)  0/61 (0.00%)  0/61 (0.00%)  5/61 (8.20%) 
Neutropenia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  3/46 (6.52%)  1/72 (1.39%)  0/72 (0.00%)  4/72 (5.56%)  0/63 (0.00%)  0/63 (0.00%)  3/63 (4.76%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%)  0/71 (0.00%)  0/71 (0.00%)  4/71 (5.63%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%) 
Cardiac disorders                                         
Atrial fibrillation † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Tachycardia † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  2/63 (3.17%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%) 
Congenital, familial and genetic disorders                                         
Familial mediterranean fever † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  15/63 (23.81%)  2/63 (3.17%)  19/63 (30.16%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  5/61 (8.20%)  2/61 (3.28%)  20/61 (32.79%) 
Hyper IgD syndrome † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  5/72 (6.94%)  1/72 (1.39%)  19/72 (26.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/71 (1.41%)  1/71 (1.41%)  20/71 (28.17%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Tumour necrosis factor receptor-associated periodic syndrome † 1  0/4 (0.00%)  0/18 (0.00%)  2/46 (4.35%)  0/46 (0.00%)  6/46 (13.04%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  6/61 (9.84%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Ear and labyrinth disorders                                         
Ear pain † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  2/46 (4.35%)  0/72 (0.00%)  0/72 (0.00%)  10/72 (13.89%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%)  0/71 (0.00%)  0/71 (0.00%)  10/71 (14.08%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Endocrine disorders                                         
Hyperthyroidism † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Eye disorders                                         
Eye allergy † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Eye pain † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  2/46 (4.35%)  0/72 (0.00%)  0/72 (0.00%)  2/72 (2.78%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%)  0/71 (0.00%)  0/71 (0.00%)  3/71 (4.23%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Scleritis † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Gastrointestinal disorders                                         
Abdominal discomfort † 1  0/4 (0.00%)  3/18 (16.67%)  1/46 (2.17%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  4/61 (6.56%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Abdominal pain † 1  0/4 (0.00%)  4/18 (22.22%)  2/46 (4.35%)  0/46 (0.00%)  14/46 (30.43%)  3/72 (4.17%)  0/72 (0.00%)  25/72 (34.72%)  4/63 (6.35%)  0/63 (0.00%)  16/63 (25.40%)  1/61 (1.64%)  0/61 (0.00%)  18/61 (29.51%)  1/71 (1.41%)  0/71 (0.00%)  25/71 (35.21%)  1/61 (1.64%)  0/61 (0.00%)  16/61 (26.23%) 
Abdominal pain upper † 1  0/4 (0.00%)  1/18 (5.56%)  1/46 (2.17%)  1/46 (2.17%)  5/46 (10.87%)  1/72 (1.39%)  0/72 (0.00%)  14/72 (19.44%)  0/63 (0.00%)  0/63 (0.00%)  6/63 (9.52%)  0/61 (0.00%)  1/61 (1.64%)  6/61 (9.84%)  0/71 (0.00%)  0/71 (0.00%)  14/71 (19.72%)  0/61 (0.00%)  0/61 (0.00%)  6/61 (9.84%) 
Aphthous ulcer † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  16/72 (22.22%)  0/63 (0.00%)  0/63 (0.00%)  2/63 (3.17%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  17/71 (23.94%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%) 
Constipation † 1  1/4 (25.00%)  1/18 (5.56%)  1/46 (2.17%)  0/46 (0.00%)  2/46 (4.35%)  0/72 (0.00%)  0/72 (0.00%)  5/72 (6.94%)  0/63 (0.00%)  0/63 (0.00%)  4/63 (6.35%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%)  0/71 (0.00%)  0/71 (0.00%)  5/71 (7.04%)  0/61 (0.00%)  0/61 (0.00%)  5/61 (8.20%) 
Dental caries † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  2/72 (2.78%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  2/71 (2.82%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%) 
Diarrhoea † 1  2/4 (50.00%)  4/18 (22.22%)  1/46 (2.17%)  1/46 (2.17%)  8/46 (17.39%)  2/72 (2.78%)  0/72 (0.00%)  22/72 (30.56%)  1/63 (1.59%)  0/63 (0.00%)  12/63 (19.05%)  0/61 (0.00%)  1/61 (1.64%)  12/61 (19.67%)  0/71 (0.00%)  0/71 (0.00%)  23/71 (32.39%)  0/61 (0.00%)  0/61 (0.00%)  13/61 (21.31%) 
Dyspepsia † 1  0/4 (0.00%)  2/18 (11.11%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  2/72 (2.78%)  0/63 (0.00%)  0/63 (0.00%)  2/63 (3.17%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%)  0/71 (0.00%)  0/71 (0.00%)  2/71 (2.82%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%) 
Gastric dilatation † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Gastritis † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  3/46 (6.52%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%) 
Haemorrhoids † 1  1/4 (25.00%)  0/18 (0.00%)  1/46 (2.17%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/61 (1.64%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Mouth ulceration † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  1/72 (1.39%)  0/72 (0.00%)  4/72 (5.56%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  4/71 (5.63%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Nausea † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  4/46 (8.70%)  0/72 (0.00%)  0/72 (0.00%)  8/72 (11.11%)  0/63 (0.00%)  0/63 (0.00%)  5/63 (7.94%)  0/61 (0.00%)  0/61 (0.00%)  4/61 (6.56%)  0/71 (0.00%)  0/71 (0.00%)  8/71 (11.27%)  0/61 (0.00%)  0/61 (0.00%)  6/61 (9.84%) 
Proctitis † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Stomatitis † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  2/72 (2.78%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  2/71 (2.82%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Teething † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Toothache † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  2/46 (4.35%)  0/72 (0.00%)  0/72 (0.00%)  2/72 (2.78%)  1/63 (1.59%)  0/63 (0.00%)  2/63 (3.17%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%)  0/71 (0.00%)  0/71 (0.00%)  2/71 (2.82%)  1/61 (1.64%)  0/61 (0.00%)  2/61 (3.28%) 
Vomiting † 1  1/4 (25.00%)  1/18 (5.56%)  1/46 (2.17%)  0/46 (0.00%)  6/46 (13.04%)  2/72 (2.78%)  0/72 (0.00%)  12/72 (16.67%)  1/63 (1.59%)  0/63 (0.00%)  5/63 (7.94%)  0/61 (0.00%)  0/61 (0.00%)  7/61 (11.48%)  1/71 (1.41%)  0/71 (0.00%)  12/71 (16.90%)  0/61 (0.00%)  0/61 (0.00%)  6/61 (9.84%) 
General disorders                                         
Asthenia † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  3/46 (6.52%)  0/72 (0.00%)  0/72 (0.00%)  6/72 (8.33%)  0/63 (0.00%)  0/63 (0.00%)  2/63 (3.17%)  0/61 (0.00%)  0/61 (0.00%)  4/61 (6.56%)  0/71 (0.00%)  0/71 (0.00%)  6/71 (8.45%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%) 
Fatigue † 1  0/4 (0.00%)  0/18 (0.00%)  1/46 (2.17%)  0/46 (0.00%)  3/46 (6.52%)  0/72 (0.00%)  0/72 (0.00%)  6/72 (8.33%)  1/63 (1.59%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%)  0/71 (0.00%)  0/71 (0.00%)  6/71 (8.45%)  1/61 (1.64%)  0/61 (0.00%)  1/61 (1.64%) 
Influenza like illness † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  2/46 (4.35%)  0/72 (0.00%)  0/72 (0.00%)  2/72 (2.78%)  3/63 (4.76%)  0/63 (0.00%)  6/63 (9.52%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%)  0/71 (0.00%)  0/71 (0.00%)  2/71 (2.82%)  0/61 (0.00%)  0/61 (0.00%)  6/61 (9.84%) 
Injection site reaction † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  7/46 (15.22%)  1/72 (1.39%)  0/72 (0.00%)  9/72 (12.50%)  0/63 (0.00%)  0/63 (0.00%)  11/63 (17.46%)  0/61 (0.00%)  0/61 (0.00%)  8/61 (13.11%)  0/71 (0.00%)  0/71 (0.00%)  9/71 (12.68%)  0/61 (0.00%)  0/61 (0.00%)  11/61 (18.03%) 
Malaise † 1  1/4 (25.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  4/72 (5.56%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%)  0/71 (0.00%)  0/71 (0.00%)  4/71 (5.63%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Non-cardiac chest pain † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  4/46 (8.70%)  0/72 (0.00%)  0/72 (0.00%)  3/72 (4.17%)  0/63 (0.00%)  0/63 (0.00%)  7/63 (11.11%)  0/61 (0.00%)  0/61 (0.00%)  4/61 (6.56%)  0/71 (0.00%)  0/71 (0.00%)  3/71 (4.23%)  0/61 (0.00%)  0/61 (0.00%)  7/61 (11.48%) 
Pyrexia † 1  1/4 (25.00%)  5/18 (27.78%)  1/46 (2.17%)  1/46 (2.17%)  14/46 (30.43%)  11/72 (15.28%)  0/72 (0.00%)  39/72 (54.17%)  3/63 (4.76%)  0/63 (0.00%)  13/63 (20.63%)  0/61 (0.00%)  1/61 (1.64%)  19/61 (31.15%)  4/71 (5.63%)  0/71 (0.00%)  40/71 (56.34%)  2/61 (3.28%)  0/61 (0.00%)  13/61 (21.31%) 
Infections and infestations                                         
Bronchitis † 1  2/4 (50.00%)  1/18 (5.56%)  1/46 (2.17%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  10/72 (13.89%)  0/63 (0.00%)  1/63 (1.59%)  0/63 (0.00%)  1/61 (1.64%)  0/61 (0.00%)  2/61 (3.28%)  0/71 (0.00%)  0/71 (0.00%)  11/71 (15.49%)  0/61 (0.00%)  1/61 (1.64%)  1/61 (1.64%) 
Conjunctivitis † 1  2/4 (50.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  4/46 (8.70%)  0/72 (0.00%)  0/72 (0.00%)  2/72 (2.78%)  1/63 (1.59%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  5/61 (8.20%)  0/71 (0.00%)  0/71 (0.00%)  3/71 (4.23%)  1/61 (1.64%)  0/61 (0.00%)  2/61 (3.28%) 
Cystitis † 1  0/4 (0.00%)  1/18 (5.56%)  1/46 (2.17%)  1/46 (2.17%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  2/72 (2.78%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  1/61 (1.64%)  1/61 (1.64%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  2/71 (2.82%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Ear infection † 1  1/4 (25.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  7/72 (9.72%)  0/63 (0.00%)  0/63 (0.00%)  2/63 (3.17%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%)  0/71 (0.00%)  0/71 (0.00%)  8/71 (11.27%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%) 
Gastroenteritis † 1  2/4 (50.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  5/46 (10.87%)  0/72 (0.00%)  1/72 (1.39%)  10/72 (13.89%)  1/63 (1.59%)  0/63 (0.00%)  8/63 (12.70%)  0/61 (0.00%)  0/61 (0.00%)  6/61 (9.84%)  0/71 (0.00%)  1/71 (1.41%)  11/71 (15.49%)  1/61 (1.64%)  0/61 (0.00%)  9/61 (14.75%) 
Influenza † 1  1/4 (25.00%)  2/18 (11.11%)  1/46 (2.17%)  0/46 (0.00%)  5/46 (10.87%)  0/72 (0.00%)  0/72 (0.00%)  14/72 (19.44%)  1/63 (1.59%)  0/63 (0.00%)  10/63 (15.87%)  1/61 (1.64%)  0/61 (0.00%)  7/61 (11.48%)  0/71 (0.00%)  0/71 (0.00%)  14/71 (19.72%)  0/61 (0.00%)  0/61 (0.00%)  11/61 (18.03%) 
Lower respiratory tract infection † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  2/72 (2.78%)  0/63 (0.00%)  0/63 (0.00%)  2/63 (3.17%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%)  0/71 (0.00%)  0/71 (0.00%)  2/71 (2.82%)  0/61 (0.00%)  0/61 (0.00%)  2/61 (3.28%) 
Nasopharyngitis † 1  1/4 (25.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/72 (1.39%)  0/72 (0.00%)  4/72 (5.56%)  0/63 (0.00%)  0/63 (0.00%)  3/63 (4.76%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  5/71 (7.04%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%) 
Oral herpes † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  4/46 (8.70%)  0/72 (0.00%)  0/72 (0.00%)  3/72 (4.17%)  2/63 (3.17%)  0/63 (0.00%)  3/63 (4.76%)  0/61 (0.00%)  0/61 (0.00%)  5/61 (8.20%)  0/71 (0.00%)  0/71 (0.00%)  3/71 (4.23%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%) 
Otitis media † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  4/46 (8.70%)  0/72 (0.00%)  0/72 (0.00%)  9/72 (12.50%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  4/61 (6.56%)  0/71 (0.00%)  0/71 (0.00%)  9/71 (12.68%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Otitis media acute † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  5/72 (6.94%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  5/71 (7.04%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Paronychia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  4/72 (5.56%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  4/71 (5.63%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Pharyngitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  7/72 (9.72%)  0/63 (0.00%)  0/63 (0.00%)  8/63 (12.70%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  7/71 (9.86%)  0/61 (0.00%)  0/61 (0.00%)  8/61 (13.11%) 
Pharyngotonsillitis † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  5/72 (6.94%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  0/71 (0.00%)  0/71 (0.00%)  5/71 (7.04%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%) 
Pilonidal cyst † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  0/72 (0.00%)  0/72 (0.00%)  1/72 (1.39%)  0/63 (0.00%)  0/63 (0.00%)  0/63 (0.00%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  1/71 (1.41%)  0/61 (0.00%)  0/61 (0.00%)  0/61 (0.00%) 
Pneumonia † 1  0/4 (0.00%)  0/18 (0.00%)  0/46 (0.00%)  0/46 (0.00%)  1/46 (2.17%)  0/72 (0.00%)  0/72 (0.00%)  4/72 (5.56%)  0/63 (0.00%)  0/63 (0.00%)  3/63 (4.76%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)  0/71 (0.00%)  0/71 (0.00%)  4/71 (5.63%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%) 
Respiratory tract infection † 1  0/4 (0.00%)  1/18 (5.56%)  0/46 (0.00%)  0/46 (0.00%)  2/46 (4.35%)  1/72 (1.39%)  0/72 (0.00%)  8/72 (11.11%)  0/63 (0.00%)  0/63 (0.00%)  1/63 (1.59%)  0/61 (0.00%)  0/61 (0.00%)  3/61 (4.92%)  0/71 (0.00%)  0/71 (0.00%)  8/71 (11.27%)  0/61 (0.00%)  0/61 (0.00%)  1/61 (1.64%)