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Clinical Trial Results:
A randomized, double-blind, placebo controlled study of canakinumab in patients with Hereditary Periodic Fevers (TRAPS, HIDS, or crFMF), with subsequent randomized withdrawal/dosing frequency reduction and open-label long-term treatment epochs

Summary
EudraCT number	2013-004291-35
Trial protocol	IT ES IE DE BE HU NL GR
Global end of trial date	04 Jul 2017

Results information
Results version number	v1(current)
This version publication date	23 Dec 2017
First version publication date	23 Dec 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

CACZ885N2301

ISRCTN number

-

US NCT number

NCT02059291

WHO universal trial number (UTN)

-

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000060-PIP04-14 EMEA-000060-PIP05-14

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

04 Jul 2017

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

04 Jul 2017

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective of the randomized treatment epoch and of the overall study was to demonstrate that canakinumab treatment at a dose of 150 mg (or 2 mg/kg in patients weighing ≤ 40 kg) sc q4w is superior to placebo in achieving a clinically meaningful reduction of disease activity, defined as resolution of the index flare at Day 15 and no new disease flares over 16 weeks of treatment.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

27 Jun 2014

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 14

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

France: 11

Country: Number of subjects enrolled

Germany: 19

Country: Number of subjects enrolled

United Kingdom: 17

Country: Number of subjects enrolled

Hungary: 6

Country: Number of subjects enrolled

Ireland: 2

Country: Number of subjects enrolled

Israel: 17

Country: Number of subjects enrolled

Italy: 30

Country: Number of subjects enrolled

Japan: 11

Country: Number of subjects enrolled

Netherlands: 17

Country: Number of subjects enrolled

Russian Federation: 6

Country: Number of subjects enrolled

Spain: 21

Country: Number of subjects enrolled

Switzerland: 5

Country: Number of subjects enrolled

Turkey: 20

Country: Number of subjects enrolled

United States: 2

Worldwide total number of subjects

203

EEA total number of subjects

137

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

2

Children (2-11 years)

67

Adolescents (12-17 years)

45

Adults (18-64 years)

86

From 65 to 84 years

3

85 years and over

0

Subject disposition

Top of page

Recruitment details

This study consists of 4 study epochs. A total of 203 participants ((181randomized + 4 non-randomized open-label participants who entered in Epoch 2 (E2)) + (18 TRAPS roll-over participants from ACZ885D2203 (NCT01242813) and ACZ885D2207M who entered in Epoch 3 (E3))) have been enrolled into this study.

Screening details

Of the 181 E2 randomized patients 41 were re-randomized to canakinumab or placebo, and 126 patients were not re-randomized and switched to open-label (OL) treatment in E3. 2 re-randomized and 6 OL patients discontinued E3. 178 patients from E2 and E3 received OL treatment in E4.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Epoch 2 crFMF: 150 mg

Arm 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.

Arm type

Experimental

Investigational medicinal product name

Canakinumab

Investigational medicinal product code

ACZ885

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

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.

Epoch 2: crCMF: placebo

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Canakinumab

Investigational medicinal product code

ACZ885

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

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.

Epoch 2: HIDS/MKD: 150 mg

Arm 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.

Arm type

Experimental

Investigational medicinal product name

Canakinumab

Investigational medicinal product code

ACZ885

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

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.

Epoch 2: HIDS/MKD: placebo

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Canakinumab

Investigational medicinal product code

ACZ885

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

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.

Epoch 2: TRAPS: 150 mg

Arm 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

Arm type

Experimental

Investigational medicinal product name

Canakinumab

Investigational medicinal product code

ACZ885

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

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

Epoch 2: TRAPS: placebo

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Canakinumab

Investigational medicinal product code

ACZ885

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

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.

Epoch 2: Non-randomized open label treatment - crFMF

Arm description

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 .

Arm type

Experimental

Investigational medicinal product name

Canakinumab

Investigational medicinal product code

ACZ885

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

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

Epoch 2: Non-randomized open label HIDS/MKD

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Canakinumab

Investigational medicinal product code

ACZ885

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

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.

Epoch 2 (Epoch 3) - non-randomized open label TRAPS

Arm description

Open-label treatment in Epoch 3 was initiated for TRAPS patients who rolled over from CACZ885D2203 or CACZ885D2207M.

Arm type

Experimental

Investigational medicinal product name

Canakinumab

Investigational medicinal product code

ACZ885

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Open-label treatment in Epoch 3 was initiated for TRAPS patients who rolled over from CACZ885D2203 or CACZ885D2207M.

Number of subjects in period 1	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
Started	31	32	37	35	22	24	2	2	18
Completed	31	31	36	33	22	22	2	1	16
Not completed	0	1	1	2	0	2	0	1	2
Consent withdrawn by subject	-	1	-	-	-	1	-	-	1
Adverse event, non-fatal	-	-	1	1	-	-	-	1	1
Lack of efficacy	-	-	-	1	-	1	-	-	-

Baseline characteristics

Top of page

Reporting group title

Epoch 2 crFMF: 150 mg

Reporting 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.

Reporting group title

Epoch 2: crCMF: placebo

Reporting group description

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

Reporting group title

Epoch 2: HIDS/MKD: 150 mg

Reporting 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.

Reporting group title

Epoch 2: HIDS/MKD: placebo

Reporting group description

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.

Reporting group title

Epoch 2: TRAPS: 150 mg

Reporting 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

Reporting group title

Epoch 2: TRAPS: placebo

Reporting group description

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.

Reporting group title

Epoch 2: Non-randomized open label treatment - crFMF

Reporting group description

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 .

Reporting group title

Epoch 2: Non-randomized open label HIDS/MKD

Reporting group description

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.

Reporting group title

Epoch 2 (Epoch 3) - non-randomized open label TRAPS

Reporting group description

Open-label treatment in Epoch 3 was initiated for TRAPS patients who rolled over from CACZ885D2203 or CACZ885D2207M.

Reporting group values	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
Number of subjects	31	32	37	35	22	24	2	2	18	203
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	2	0	2
Children (2-11 years)	9	4	18	19	9	8	0	0	0	67
Adolescents (12-17 years)	5	11	9	7	5	5	0	0	2	44
Adults (18-64 years)	17	16	10	9	7	11	2	0	15	87
From 65-84 years	0	1	0	0	1	0	0	0	1	3
85 years and over	0	0	0	0	0	0	0	0	0	0
Gender, Male/Female
Units: Subjects
Female	14	15	24	19	10	13	2	0	7	104
Male	17	17	13	16	12	11	0	2	11	99
Race
Units: Subjects
Asian	0	1	0	1	2	4	2	1	0	11
White	27	27	34	31	20	18	0	1	16	174
Other	4	4	3	3	0	2	0	0	2	18

End points

Top of page

Reporting group title

Epoch 2 crFMF: 150 mg

Reporting 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.

Reporting group title

Epoch 2: crCMF: placebo

Reporting group description

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

Reporting group title

Epoch 2: HIDS/MKD: 150 mg

Reporting 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.

Reporting group title

Epoch 2: HIDS/MKD: placebo

Reporting group description

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.

Reporting group title

Epoch 2: TRAPS: 150 mg

Reporting 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

Reporting group title

Epoch 2: TRAPS: placebo

Reporting group description

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.

Reporting group title

Epoch 2: Non-randomized open label treatment - crFMF

Reporting group description

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 .

Reporting group title

Epoch 2: Non-randomized open label HIDS/MKD

Reporting group description

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.

Reporting group title

Epoch 2 (Epoch 3) - non-randomized open label TRAPS

Reporting group description

Open-label treatment in Epoch 3 was initiated for TRAPS patients who rolled over from CACZ885D2203 or CACZ885D2207M.

Primary: Percentage of participants with resolution of initial flare and absence of new flares up to the end of the randomized treatment epoch (16 weeks)

Top of page

End point 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) ^[1]

End point 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.

End point type

Primary

End point timeframe

16 weeks

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistics do not apply to all arms.

End point values	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
Number of subjects analysed	31	32	37	35	22	24
Units: Percentage of participants
number (not applicable)	61.29	6.25	35.14	5.71	45.45	8.33

Resolution of initial flare/absence of new flares

Comparison groups

Epoch 2 crFMF: 150 mg v Epoch 2: crCMF: placebo

Number of subjects included in analysis

63

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Fisher's exact test

Confidence interval

Resolution of initial flare/absence of new flares

Comparison groups

Epoch 2: TRAPS: 150 mg v Epoch 2: TRAPS: placebo

Number of subjects included in analysis

46

Analysis specification

Pre-specified

Analysis type

P-value

= 0.005

Method

Fisher's exact test

Confidence interval

Resolution of initial flare/absence of new flares

Comparison groups

Epoch 2: HIDS/MKD: 150 mg v Epoch 2: HIDS/MKD: placebo

Number of subjects included in analysis

72

Analysis specification

Pre-specified

Analysis type

P-value

= 0.002

Method

Fisher's exact test

Confidence interval

Secondary: Percentage of participants who achieve Physician's global assessment < 2

Top of page

End point title

Percentage of participants who achieve Physician's global assessment < 2 ^[2]

End point 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.

End point type

Secondary

End point timeframe

16 weeks

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistics do not apply to all arms.

End point values	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
Number of subjects analysed	31	32	37	35	22	24
Units: Percentage of participants
number (not applicable)	64.52	9.38	45.95	5.71	45.45	4.17

Participnats who achieve PGA < 2

Comparison groups

Epoch 2 crFMF: 150 mg v Epoch 2: crCMF: placebo

Number of subjects included in analysis

63

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

16.96

Confidence interval

level

95%

sides

2-sided

lower limit

4.15

upper limit

69.21

Participnats who achieve PGA < 2

Comparison groups

Epoch 2: HIDS/MKD: 150 mg v Epoch 2: HIDS/MKD: placebo

Number of subjects included in analysis

72

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0006

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

13.63

Confidence interval

level

95%

sides

2-sided

lower limit

2.83

upper limit

65.59

Participnats who achieve PGA < 2

Comparison groups

Epoch 2: TRAPS: 150 mg v Epoch 2: TRAPS: placebo

Number of subjects included in analysis

46

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0028

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

23.79

Confidence interval

level

95%

sides

2-sided

lower limit

2.52

upper limit

224.86

Secondary: Percentage of participants with the serologic remission

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End point title

Percentage of participants with the serologic remission ^[3]

End point description

Serologic remission was defined as C-reactive protein <= 10 mg/L.

End point type

Secondary

End point timeframe

16 weeks

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistics do not apply to all arms.

End point values	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
Number of subjects analysed	31	32	37	35	22	24
Units: Percentage of participants
number (not applicable)	67.74	6.25	40.54	5.71	36.36	8.33

Participants with the serologic remission

Comparison groups

Epoch 2 crFMF: 150 mg v Epoch 2: crCMF: placebo

Number of subjects included in analysis

63

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

29.78

Confidence interval

level

95%

sides

2-sided

lower limit

5.86

upper limit

151.31

Participants with the serologic remission

Comparison groups

Epoch 2: HIDS/MKD: 150 mg v Epoch 2: HIDS/MKD: placebo

Number of subjects included in analysis

72

Analysis specification

Pre-specified

Analysis type

P-value

= 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

12.71

Confidence interval

level

95%

sides

2-sided

lower limit

2.53

upper limit

63.89

Participants with the serologic remission

Comparison groups

Epoch 2: TRAPS: 150 mg v Epoch 2: TRAPS: placebo

Number of subjects included in analysis

46

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0149

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

6.64

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

36.57

Secondary: Percentage of participants with normalized Serum Amyloid A (SAA) level

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End point title

Percentage of participants with normalized Serum Amyloid A (SAA) level ^[4]

End point description

Normalized SAA was defined as SAA <= 10 mg/L.

End point type

Secondary

End point timeframe

16 weeks

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistics do not apply to all arms.

End point values	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
Number of subjects analysed	31	32	37	35	22	24
Units: Percentage of participants
number (not applicable)	25.81	0.00	13.51	2.86	27.27	0.00

Participants with normalized SAA level

Comparison groups

Epoch 2 crFMF: 150 mg v Epoch 2: crCMF: placebo

Number of subjects included in analysis

63

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0286

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

17.46

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

332.92

Participants with normalized SAA level

Comparison groups

Epoch 2: HIDS/MKD: 150 mg v Epoch 2: HIDS/MKD: placebo

Number of subjects included in analysis

72

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0778

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

5.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

51.97

Participants with normalized SAA level

Comparison groups

Epoch 2: TRAPS: 150 mg v Epoch 2: TRAPS: placebo

Number of subjects included in analysis

46

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0235

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

16.69

Confidence interval

level

95%

sides

2-sided

lower limit

1.04

upper limit

268.5

Secondary: Percentage of participants of canakinumab responders from epoch 2 who maintained a clinically meaningful response (absence of new flares) (40 weeks)

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End point title

Percentage of participants of canakinumab responders from epoch 2 who maintained a clinically meaningful response (absence of new flares) (40 weeks) ^[5]

End point description

A responder was defined as a participant who had no flare between week 16 and week 40.

End point type

Secondary

End point timeframe

40 weeks

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistics do not apply to all arms.

End point values	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
Number of subjects analysed	9	10	6	7	4	5
Units: Percentage of participants
number (not applicable)	77.8	30.0	50.0	14.3	75.0	40.0

Absence of new flares from weeks 16 to 40

Comparison groups

Epoch 2 crFMF: 150 mg v Epoch 2: crCMF: placebo

Number of subjects included in analysis

19

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0513

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

8.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

113.44

Absence of new flares from weeks 16 to 40

Comparison groups

Epoch 2: HIDS/MKD: 150 mg v Epoch 2: HIDS/MKD: placebo

Number of subjects included in analysis

13

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2168

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

6

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

366.24

Absence of new flares from weeks 16 to 40

Comparison groups

Epoch 2: TRAPS: 150 mg v Epoch 2: TRAPS: placebo

Number of subjects included in analysis

9

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3571

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

4.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

313.49

Adverse events

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Timeframe for reporting adverse events

Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Non-randomized open@label group at the@beginging of epoch 2

Reporting group description

Non-randomized open@label group at the@beginging of epoch 2

Reporting group title

Roll over subjects

Reporting group description

Roll over subjects

Reporting group title

Randomized at the@beginning of epoch 2

Reporting group description

Randomized at the@beginning of epoch 2

Reporting group title

Any ACZ group

Reporting group description

Any ACZ group

Serious adverse events	Non-randomized open@label group at the@beginging of epoch 2	Roll over subjects	Randomized at the@beginning of epoch 2	Any ACZ group
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 4 (75.00%)	1 / 18 (5.56%)	47 / 181 (25.97%)	47 / 193 (24.35%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
General disorders and administration site conditions
Hyperpyrexia
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Polyserositis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	7 / 181 (3.87%)	8 / 193 (4.15%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 7	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal stenosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord polyp
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intentional self-injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Schizophrenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Scar
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Familial mediterranean fever
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	4 / 181 (2.21%)	4 / 193 (2.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 7	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyper IgD syndrome
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	4 / 181 (2.21%)	5 / 193 (2.59%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 6	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour necrosis factor receptor-associated periodic syndrome
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	4 / 181 (2.21%)	3 / 193 (1.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure congestive
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Seizure
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	2 / 181 (1.10%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	1 / 181 (0.55%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileal ulcer
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	2 / 181 (1.10%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	2 / 181 (1.10%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Granulomatous liver disease
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Drug eruption
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Granulomatous rosacea
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyoderma gangrenosum
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Thyroiditis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Acute sinusitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	2 / 181 (1.10%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Conjunctivitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes virus infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infectious colitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Orchitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic abscess
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngotonsillitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	5 / 181 (2.76%)	5 / 193 (2.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 6	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vulval abscess
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	2 / 181 (1.10%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obesity
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Non-randomized open@label group at the@beginging of epoch 2	Roll over subjects	Randomized at the@beginning of epoch 2	Any ACZ group
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 4 (100.00%)	18 / 18 (100.00%)	176 / 181 (97.24%)	188 / 193 (97.41%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pyogenic granuloma
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	1	0	0	1
Vascular disorders
Hypertension
subjects affected / exposed	0 / 4 (0.00%)	2 / 18 (11.11%)	1 / 181 (0.55%)	3 / 193 (1.55%)
occurrences all number	0	2	1	3
Hypotension
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	11 / 181 (6.08%)	12 / 193 (6.22%)
occurrences all number	0	1	17	18
Fatigue
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	12 / 181 (6.63%)	11 / 193 (5.70%)
occurrences all number	0	0	13	12
Influenza like illness
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	12 / 181 (6.63%)	10 / 193 (5.18%)
occurrences all number	0	0	15	12
Injection site reaction
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	28 / 181 (15.47%)	28 / 193 (14.51%)
occurrences all number	0	1	78	78
Malaise
subjects affected / exposed	1 / 4 (25.00%)	1 / 18 (5.56%)	5 / 181 (2.76%)	7 / 193 (3.63%)
occurrences all number	1	1	7	9
Non-cardiac chest pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	14 / 181 (7.73%)	14 / 193 (7.25%)
occurrences all number	0	0	16	16
Pyrexia
subjects affected / exposed	1 / 4 (25.00%)	5 / 18 (27.78%)	71 / 181 (39.23%)	74 / 193 (38.34%)
occurrences all number	14	6	276	282
Reproductive system and breast disorders
Breast mass
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Polycystic ovaries
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	1 / 181 (0.55%)	2 / 193 (1.04%)
occurrences all number	0	1	1	2
Vaginal haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 4 (0.00%)	3 / 18 (16.67%)	38 / 181 (20.99%)	40 / 193 (20.73%)
occurrences all number	0	3	62	62
Epistaxis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	11 / 181 (6.08%)	11 / 193 (5.70%)
occurrences all number	0	0	15	15
Oropharyngeal pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	40 / 181 (22.10%)	39 / 193 (20.21%)
occurrences all number	0	1	60	59
Pleuritic pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Pneumonitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Rhinitis allergic
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	3 / 181 (1.66%)	4 / 193 (2.07%)
occurrences all number	0	2	3	5
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 4 (25.00%)	1 / 18 (5.56%)	3 / 181 (1.66%)	5 / 193 (2.59%)
occurrences all number	4	1	3	8
Aspartate aminotransferase increased
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	2 / 193 (1.04%)
occurrences all number	1	0	1	2
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	5 / 181 (2.76%)	6 / 193 (3.11%)
occurrences all number	0	1	6	7
C-reactive protein increased
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	2 / 181 (1.10%)	3 / 193 (1.55%)
occurrences all number	2	0	2	4
Eosinophil count increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Glomerular filtration rate decreased
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Neutrophil count decreased
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	2 / 193 (1.04%)
occurrences all number	1	0	1	2
Neutrophil count increased
subjects affected / exposed	1 / 4 (25.00%)	1 / 18 (5.56%)	2 / 181 (1.10%)	3 / 193 (1.55%)
occurrences all number	1	1	2	3
Serum amyloid A protein increased
subjects affected / exposed	1 / 4 (25.00%)	3 / 18 (16.67%)	6 / 181 (3.31%)	9 / 193 (4.66%)
occurrences all number	5	3	9	15
White blood cell count increased
subjects affected / exposed	1 / 4 (25.00%)	1 / 18 (5.56%)	2 / 181 (1.10%)	3 / 193 (1.55%)
occurrences all number	1	1	2	3
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	2 / 181 (1.10%)	3 / 193 (1.55%)
occurrences all number	0	1	2	3
Skin abrasion
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	1 / 181 (0.55%)	2 / 193 (1.04%)
occurrences all number	0	1	1	2
Thermal burn
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	2 / 181 (1.10%)	2 / 193 (1.04%)
occurrences all number	0	2	2	3
Wound
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	2	0	2
Congenital, familial and genetic disorders
Familial mediterranean fever
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	29 / 181 (16.02%)	25 / 193 (12.95%)
occurrences all number	2	0	92	79
Hyper IgD syndrome
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	21 / 181 (11.60%)	21 / 193 (10.88%)
occurrences all number	2	0	82	80
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Tachycardia
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	2 / 181 (1.10%)	3 / 193 (1.55%)
occurrences all number	0	1	2	3
Nervous system disorders
Headache
subjects affected / exposed	1 / 4 (25.00%)	2 / 18 (11.11%)	64 / 181 (35.36%)	62 / 193 (32.12%)
occurrences all number	7	6	130	136
Somnolence
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	1	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	8 / 181 (4.42%)	8 / 193 (4.15%)
occurrences all number	0	1	9	8
Lymphadenopathy
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	27 / 181 (14.92%)	27 / 193 (13.99%)
occurrences all number	0	0	41	39
Neutropenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	11 / 181 (6.08%)	10 / 193 (5.18%)
occurrences all number	0	0	13	12
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	13 / 181 (7.18%)	13 / 193 (6.74%)
occurrences all number	0	0	19	19
Eye disorders
Eye allergy
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	1	0	0	1
Eye pain
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	4 / 181 (2.21%)	5 / 193 (2.59%)
occurrences all number	1	0	5	6
Scleritis
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	4	0	0	4
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 4 (0.00%)	3 / 18 (16.67%)	2 / 181 (1.10%)	4 / 193 (2.07%)
occurrences all number	0	3	2	4
Abdominal pain
subjects affected / exposed	0 / 4 (0.00%)	4 / 18 (22.22%)	59 / 181 (32.60%)	61 / 193 (31.61%)
occurrences all number	0	5	91	89
Abdominal pain upper
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	28 / 181 (15.47%)	27 / 193 (13.99%)
occurrences all number	0	1	45	44
Aphthous ulcer
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	18 / 181 (9.94%)	19 / 193 (9.84%)
occurrences all number	6	0	33	39
Constipation
subjects affected / exposed	1 / 4 (25.00%)	1 / 18 (5.56%)	12 / 181 (6.63%)	13 / 193 (6.74%)
occurrences all number	1	1	13	14
Dental caries
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	3 / 181 (1.66%)	4 / 193 (2.07%)
occurrences all number	1	0	3	4
Diarrhoea
subjects affected / exposed	2 / 4 (50.00%)	4 / 18 (22.22%)	45 / 181 (24.86%)	49 / 193 (25.39%)
occurrences all number	7	4	71	78
Dyspepsia
subjects affected / exposed	0 / 4 (0.00%)	2 / 18 (11.11%)	5 / 181 (2.76%)	7 / 193 (3.63%)
occurrences all number	0	2	5	7
Gastric dilatation
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Gastritis
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	5 / 181 (2.76%)	6 / 193 (3.11%)
occurrences all number	1	0	7	8
Haemorrhoids
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	2 / 193 (1.04%)
occurrences all number	1	0	2	3
Nausea
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	17 / 181 (9.39%)	18 / 193 (9.33%)
occurrences all number	1	0	21	22
Proctitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Stomatitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	3 / 181 (1.66%)	4 / 193 (2.07%)
occurrences all number	7	0	4	11
Teething
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	1	0	0	1
Toothache
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	7 / 181 (3.87%)	8 / 193 (4.15%)
occurrences all number	0	1	7	8
Vomiting
subjects affected / exposed	1 / 4 (25.00%)	1 / 18 (5.56%)	27 / 181 (14.92%)	26 / 193 (13.47%)
occurrences all number	1	1	37	36
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	2 / 193 (1.04%)
occurrences all number	1	0	1	2
Drug eruption
subjects affected / exposed	2 / 4 (50.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	2 / 193 (1.04%)
occurrences all number	2	0	0	2
Eczema
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	10 / 181 (5.52%)	11 / 193 (5.70%)
occurrences all number	1	0	11	12
Keloid scar
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	1	0	0	1
Pain of skin
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	1	0	0	1
Pyoderma gangrenosum
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	1	0	0	1
Rash
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	19 / 181 (10.50%)	16 / 193 (8.29%)
occurrences all number	0	0	24	21
Rash pruritic
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	2 / 193 (1.04%)
occurrences all number	1	0	1	2
Skin ulcer
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	1	0	0	1
Urticaria
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	9 / 181 (4.97%)	9 / 193 (4.66%)
occurrences all number	2	0	11	12
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 4 (25.00%)	5 / 18 (27.78%)	39 / 181 (21.55%)	42 / 193 (21.76%)
occurrences all number	1	10	60	68
Arthritis
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	2 / 181 (1.10%)	3 / 193 (1.55%)
occurrences all number	0	1	2	3
Back pain
subjects affected / exposed	1 / 4 (25.00%)	2 / 18 (11.11%)	29 / 181 (16.02%)	32 / 193 (16.58%)
occurrences all number	1	3	38	42
Intervertebral disc disorder
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Musculoskeletal chest pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	1 / 181 (0.55%)	2 / 193 (1.04%)
occurrences all number	0	1	1	2
Musculoskeletal pain
subjects affected / exposed	0 / 4 (0.00%)	2 / 18 (11.11%)	17 / 181 (9.39%)	16 / 193 (8.29%)
occurrences all number	0	2	18	17
Myalgia
subjects affected / exposed	0 / 4 (0.00%)	3 / 18 (16.67%)	19 / 181 (10.50%)	21 / 193 (10.88%)
occurrences all number	0	4	27	30
Pain in extremity
subjects affected / exposed	1 / 4 (25.00%)	3 / 18 (16.67%)	23 / 181 (12.71%)	25 / 193 (12.95%)
occurrences all number	1	3	35	37
Spinal pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	2 / 181 (1.10%)	3 / 193 (1.55%)
occurrences all number	0	1	2	3
Tendon pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Tenosynovitis stenosans
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	0	1	0	1
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 4 (50.00%)	1 / 18 (5.56%)	13 / 181 (7.18%)	16 / 193 (8.29%)
occurrences all number	4	1	15	20
Conjunctivitis
subjects affected / exposed	2 / 4 (50.00%)	1 / 18 (5.56%)	8 / 181 (4.42%)	11 / 193 (5.70%)
occurrences all number	4	1	9	14
Cystitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	3 / 181 (1.66%)	4 / 193 (2.07%)
occurrences all number	0	1	5	6
Ear infection
subjects affected / exposed	1 / 4 (25.00%)	1 / 18 (5.56%)	10 / 181 (5.52%)	12 / 193 (6.22%)
occurrences all number	2	2	11	15
Gastroenteritis
subjects affected / exposed	2 / 4 (50.00%)	1 / 18 (5.56%)	24 / 181 (13.26%)	27 / 193 (13.99%)
occurrences all number	2	1	30	33
Influenza
subjects affected / exposed	1 / 4 (25.00%)	2 / 18 (11.11%)	31 / 181 (17.13%)	33 / 193 (17.10%)
occurrences all number	1	2	51	52
Lower respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	5 / 181 (2.76%)	6 / 193 (3.11%)
occurrences all number	0	1	7	8
Nasopharyngitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	8 / 181 (4.42%)	8 / 193 (4.15%)
occurrences all number	3	0	18	20
Oral herpes
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	12 / 181 (6.63%)	11 / 193 (5.70%)
occurrences all number	0	2	18	18
Otitis media
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	13 / 181 (7.18%)	13 / 193 (6.74%)
occurrences all number	0	0	16	16
Pharyngitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	16 / 181 (8.84%)	16 / 193 (8.29%)
occurrences all number	0	0	19	19
Pilonidal cyst
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	1 / 181 (0.55%)	2 / 193 (1.04%)
occurrences all number	0	1	1	2
Respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	11 / 181 (6.08%)	12 / 193 (6.22%)
occurrences all number	0	1	25	25
Rhinitis
subjects affected / exposed	1 / 4 (25.00%)	2 / 18 (11.11%)	25 / 181 (13.81%)	28 / 193 (14.51%)
occurrences all number	1	4	47	51
Sialoadenitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	1	0	0	1
Sinusitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	7 / 181 (3.87%)	8 / 193 (4.15%)
occurrences all number	0	1	7	8
Tonsillitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	15 / 181 (8.29%)	16 / 193 (8.29%)
occurrences all number	0	1	18	19
Tonsillitis bacterial
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	1	0	0	1
Tracheitis
subjects affected / exposed	0 / 4 (0.00%)	2 / 18 (11.11%)	0 / 181 (0.00%)	2 / 193 (1.04%)
occurrences all number	0	2	0	2
Upper respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	3 / 18 (16.67%)	47 / 181 (25.97%)	49 / 193 (25.39%)
occurrences all number	0	3	81	80
Urinary tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 18 (0.00%)	16 / 181 (8.84%)	15 / 193 (7.77%)
occurrences all number	0	0	19	18
Viral infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 18 (5.56%)	15 / 181 (8.29%)	16 / 193 (8.29%)
occurrences all number	0	1	31	32
Viral tonsillitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	2 / 193 (1.04%)
occurrences all number	2	0	1	3
Viral upper respiratory tract infection
subjects affected / exposed	1 / 4 (25.00%)	5 / 18 (27.78%)	38 / 181 (20.99%)	44 / 193 (22.80%)
occurrences all number	1	11	82	94
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	1 / 181 (0.55%)	2 / 193 (1.04%)
occurrences all number	1	0	1	2
Hypocalcaemia
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	1	0	0	1
Hypophosphataemia
subjects affected / exposed	1 / 4 (25.00%)	0 / 18 (0.00%)	0 / 181 (0.00%)	1 / 193 (0.52%)
occurrences all number	1	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

15 Jul 2014

Changed pregnancy and assessments of fertility section to reference the use of effective contraception in accordance with locally approved prescribing information

22 Oct 2014

Updated exploratory objectives to reflect the request from the Paediatric Committee at the European Medicines Agency to include patients > 28 days but < 2 years of age in addition to patients ≥ 2 years of age; Clarified how patients in the randomized and non-randomized groups were managed: study entry time and treatment was harmonized between the patients who were > 28 days but < 2 years of age and Japanese crFMF patients with non-exon 10 mutations; clarified the definition of the resolution of index flare; and clarified the blinded escape criteria

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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