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

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT02059291
Collaborator
(none)
203
Enrollment
65
Locations
6
Arms
36.2
Actual Duration (Months)
3.1
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is to determine whether canakinumab is able to induce and maintain a clinically meaningful reduction of disease activity in participants with Hereditary Periodic Fevers (HPF) compared to placebo.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

This study consists of 3 randomized cohorts (one per condition of colchicine resistant/intolerant Familial Mediterranean Fever (crFMF), Hyper Immunoglobulin D Syndrome (also known as mevalonate kinase deficiency (HIDS/MKD), and Tumor Necrosis Factor Receptor

Associated Periodic Syndrome (TRAPS), and 4 study epochs:

  1. Epoch 1: a screening epoch to assess participant's eligibility;

  2. Epoch 2: a randomized treatment epoch of 16 weeks where participants are randomized to canakinumab 150 mg every 4 weeks (q4w) or to placebo to obtain efficacy and safety data in a double-blind placebo controlled parallel-arm setting. This epoch contained 2 possible escape options :

  3. early blinded escape option for non responders from Day 8 to Day 28 with here an add-on dose of 150mg canakinumab followed by blinded uptitration at the next scheduled visit (Day 29)

  4. late unblinded escape option for non responders from Day 29 to Day 112; with open-label uptitration

  5. Epoch 3: a randomized withdrawal epoch of 24 weeks where canakinumab responders from the randomized treatment epoch were re-randomized to canakinumab 150mg q8w or placebo to assess the potential for canakinumab to maintain clinical efficacy at a reduced dosing frequency;

  6. Epoch 4: an open-label treatment epoch of 72 weeks to collect long-term

Study Design

Study Type:
Interventional
Actual Enrollment :
203 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Jun 27, 2014
Actual Primary Completion Date :
Jul 4, 2017
Actual Study Completion Date :
Jul 4, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: crFMF: 150 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.

Drug: Canakinumab
Canakinumab solution for subcutaneous injection in vial which contained 150mg/mL canakinumab in 1 mL solution.
Other Names:
  • ACZ885

    		•
    Placebo Comparator: crCMF: placebo

    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.

    Drug: Placebo
    Matching placebo to canakinumab solution for subcutaneous injection
    Experimental: HIDS/MKD: 150 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.

    Drug: Canakinumab
    Canakinumab solution for subcutaneous injection in vial which contained 150mg/mL canakinumab in 1 mL solution.
    Other Names:
  • ACZ885

    		•
    Placebo Comparator: HIDS/MKD: placebo

    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.

    Drug: Placebo
    Matching placebo to canakinumab solution for subcutaneous injection
    Experimental: TRAPS: 150 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

    Drug: Canakinumab
    Canakinumab solution for subcutaneous injection in vial which contained 150mg/mL canakinumab in 1 mL solution.
    Other Names:
  • ACZ885

    		•
    Placebo Comparator: TRAPS: placebo

    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.

    Drug: Placebo
    Matching placebo to canakinumab solution for subcutaneous injection

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants With Resolution of Initial Flare and Absence of New Flares up to the End of the Randomized Treatment Epoch (16 Weeks) [16 weeks]

      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.

    Secondary Outcome Measures

    1. Percentage of Participants Who Achieve Physician's Global Assessment (PGA) < 2 [16 weeks]

      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.

    2. Percentage of Participants With the Serologic Remission [16 weeks]

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

    3. Percentage of Participants With Normalized Serum Amyloid A (SAA) Level [16 weeks]

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

    4. Percentage of Participants of Canakinumab Responders From Epoch 2 Who Maintained a Clinically Meaningful Response (Absence of New Flares) (40 Weeks) [40 weeks]

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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    1 Month and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    Inclusion Criteria: - Patient's written informed consent (or parent's written informed consent in case of pediatric patient) at screening - Male and female patients at least 2 years of age at the time of the screening visit. Male and female patients >28 days but <2 years eligible for open label treatment only. - Confirmed diagnosis and active flare at randomization - CRP >10mg/L at randomization

    Exclusion Criteria: - Use of the following therapies (within varying protocol defined timeframes): Corticosteroids, anakinra, canakinumab, rilonacept, tocilizumab, TNF inhibitors, abatacept, tofacitinib, rituximab, leflunomide, thalidomide, cyclosporine, intravenous immunoglobulin, 6-Merceptopurine, azathioprine, cyclophosphamide, or chlorambucil, any other investigational biologics - History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in - situ cervical cancer), treated or untreated - Significant medical diseases, including but not limited to the following: a. History of organ transplantation b. Elevated liver enzymes ≥3x ULN d. Increase in total bilirubin e. Serious hepatic disorder (Child-Pugh scores B or C) f. Chronic Kidney Disease g. Thyroid disease h. Diagnosis of active peptic ulcer disease i. Coagulopathy j. Significant CNS effects including vertigo and dizziness - Any conditions or significant medical problems which immunecompromise the patient and/or places the patient at unacceptable risk for immunomodulatory therapy - Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 months following the last dose

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Novartis Investigative Site Los Angeles California United States 90027
    2 Novartis Investigative Site Ann Arbor Michigan United States 48109
    3 Novartis Investigative Site Cleveland Ohio United States 44195
    4 Novartis Investigative Site Edegem Antwerpen Belgium 2650
    5 Novartis Investigative Site Bruxelles Belgium 1200
    6 Novartis Investigative Site Hasselt Belgium 3500
    7 Novartis Investigative Site Leuven Belgium 3000
    8 Novartis Investigative Site Liege Belgium 4000
    9 Novartis Investigative Site Calgary Alberta Canada T3B 6A8
    10 Novartis Investigative Site Vancouver British Columbia Canada V6H 3V4
    11 Novartis Investigative Site Bron Cedex France 69677
    12 Novartis Investigative Site Le Kremlin Bicetre France 94275
    13 Novartis Investigative Site Nimes Cedex France 30029
    14 Novartis Investigative Site Paris France 75015
    15 Novartis Investigative Site Berlin Germany 10117
    16 Novartis Investigative Site Berlin Germany 13353
    17 Novartis Investigative Site Essen Germany 45147
    18 Novartis Investigative Site Germering Germany 82110
    19 Novartis Investigative Site Hamburg Germany 20246
    20 Novartis Investigative Site Hamburg Germany 22081
    21 Novartis Investigative Site Muenchen Germany 80337
    22 Novartis Investigative Site Saint Augustin Germany 53757
    23 Novartis Investigative Site Tübingen Germany 72076
    24 Novartis Investigative Site Budapest Hungary 1023
    25 Novartis Investigative Site Budapest Hungary 1094
    26 Novartis Investigative Site Galway Ireland
    27 Novartis Investigative Site Haifa Israel 3339419
    28 Novartis Investigative Site Haifa Israel 3525408
    29 Novartis Investigative Site Jerusalem Israel 9103102
    30 Novartis Investigative Site Petach-Tikva Israel 49202
    31 Novartis Investigative Site Ramat Gan Israel 5266202
    32 Novartis Investigative Site Sciacca AG Italy 92019
    33 Novartis Investigative Site Brescia BS Italy 25123
    34 Novartis Investigative Site Firenze FI Italy 50139
    35 Novartis Investigative Site Genova GE Italy 16147
    36 Novartis Investigative Site Messina ME Italy 98125
    37 Novartis Investigative Site Pavia PV Italy 27100
    38 Novartis Investigative Site Roma RM Italy 00165
    39 Novartis Investigative Site Trieste TS Italy 34137
    40 Novartis Investigative Site Napoli Italy 80131
    41 Novartis Investigative Site Roma Italy 00168
    42 Novartis Investigative Site Fukuoka city Fukuoka Japan 812-8582
    43 Novartis Investigative Site Yokohama-city Kanagawa Japan 236-0004
    44 Novartis Investigative Site Sakyo-ku Kyoto Japan 606 8507
    45 Novartis Investigative Site Niigata Japan 951-8520
    46 Novartis Investigative Site Nijmegen Netherlands 6500 HB
    47 Novartis Investigative Site Utrecht Netherlands 3508 GA
    48 Novartis Investigative Site Moscow Russian Federation 115522
    49 Novartis Investigative Site Moscow Russian Federation 117198
    50 Novartis Investigative Site Moscow Russian Federation 119991
    51 Novartis Investigative Site Rostov on Don Russian Federation 344022
    52 Novartis Investigative Site Saint-Petersburg Russian Federation 194100
    53 Novartis Investigative Site Esplugues de Llobregat Barcelona Spain 08950
    54 Novartis Investigative Site Barcelona Catalunya Spain 08035
    55 Novartis Investigative Site Valencia Comunidad Valenciana Spain 46026
    56 Novartis Investigative Site El Palmar Murcia Spain 30120
    57 Novartis Investigative Site Madrid Spain 28034
    58 Novartis Investigative Site Madrid Spain 28046
    59 Novartis Investigative Site Lausanne Switzerland 1011
    60 Novartis Investigative Site Istanbul TUR Turkey 34098
    61 Novartis Investigative Site Ankara Turkey 06100
    62 Novartis Investigative Site Istanbul Turkey 34093
    63 Novartis Investigative Site Leeds United Kingdom LS9 7TF
    64 Novartis Investigative Site London United Kingdom NW3 2QG
    65 Novartis Investigative Site London United Kingdom WC1N 1EH

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT02059291
    Other Study ID Numbers:
    • CACZ885N2301
    First Posted:
    Feb 11, 2014
    Last Update Posted:
    May 17, 2018
    Last Verified:
    Apr 1, 2018
    Keywords provided by Novartis Pharmaceuticals
    Canakinumab, interleukin-1, Hereditary Periodic Fevers, auto-inflammatory diseases
    Additional relevant MeSH terms:
    Familial Mediterranean Fever
    Hereditary Autoinflammatory Diseases
    Amyloidosis
    Fever

    Study Results

    Participant Flow

    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 Detail 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
    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 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
    Period Title: Epoch 2
    STARTED 0 0 0 0 0 0 2 1 0 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
    Period Title: Epoch 2
    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

    Baseline Characteristics

    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
    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 Participants 31 32 37 35 22 24 2 2 18 203
    Age (Years) [Median (Full Range) ]
    crFMF cohort - randomized
    18.0
    (15.02)
    18.0
    (13.38)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    NA
    NA
    18
    (14.10)
    HIDS/MKD cohort - randomized
    NA
    (NA)
    NA
    (NA)
    12.0
    (8.49)
    9.0
    (11.64)
    NA
    (NA)
    NA
    (NA)
    NA
    NA
    NA
    11.0
    (10.08)
    TRAPS cohort - randomized
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    13.5
    (19.22)
    16.5
    (18.25)
    NA
    NA
    NA
    15.5
    (18.55)
    crFMF - non-randomized
    NA
    NA
    NA
    NA
    NA
    NA
    24.5
    NA
    NA
    24.5
    HIDS/MKD - non-randomized
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    1.0
    NA
    1.0
    roll-over TRAPS - non-randomized
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    42.5
    42.5
    Sex: Female, Male (Count of Participants)
    Female
    14
    45.2%
    15
    46.9%
    24
    64.9%
    19
    54.3%
    10
    45.5%
    13
    54.2%
    2
    100%
    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%
    2
    100%
    11
    61.1%
    99
    48.8%
    Race (NIH/OMB) (Count of 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%
    Asian
    0
    0%
    1
    3.1%
    0
    0%
    1
    2.9%
    2
    9.1%
    4
    16.7%
    2
    100%
    1
    50%
    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%
    Black or African American
    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%
    1
    50%
    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%
    Unknown or Not Reported
    4
    12.9%
    4
    12.5%
    3
    8.1%
    3
    8.6%
    0
    0%
    2
    8.3%
    0
    0%
    0
    0%
    2
    11.1%
    18
    8.9%

    Outcome Measures

    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)
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 31 32 37 35 22 24
    Number [Percentage of participants]
    61.29
    197.7%
    6.25
    19.5%
    35.14
    95%
    5.71
    16.3%
    45.45
    206.6%
    8.33
    34.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Epoch 2: crFMF: 150 mg, Epoch 2: crCMF: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Fisher's exact test
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Epoch 2: HIDS/MKD: 150 mg, Epoch 2: HIDS/MKD: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0020
    Comments
    Method Fisher's exact test
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Epoch 2: TRAPS: 150 mg, Epoch 2: TRAPS: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0050
    Comments
    Method Fisher's exact test
    Comments
    2. Secondary Outcome
    Title Percentage of Participants Who Achieve Physician's Global Assessment (PGA) < 2
    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

    Outcome Measure Data

    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
    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.
    Measure Participants 31 32 37 35 22 24
    Number [Percentage of participants]
    64.52
    208.1%
    9.38
    29.3%
    45.95
    124.2%
    5.71
    16.3%
    45.45
    206.6%
    4.17
    17.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Epoch 2: crFMF: 150 mg, Epoch 2: crCMF: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 16.96
    Confidence Interval (2-Sided) 95%
    4.15 to 69.21
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Epoch 2: HIDS/MKD: 150 mg, Epoch 2: HIDS/MKD: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0006
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 13.63
    Confidence Interval (2-Sided) 95%
    2.83 to 65.59
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Epoch 2: TRAPS: 150 mg, Epoch 2: TRAPS: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0028
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 23.79
    Confidence Interval (2-Sided) 95%
    2.52 to 224.86
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Percentage of Participants With the Serologic Remission
    Description Serologic remission was defined as C-reactive protein <= 10 mg/L.
    Time Frame 16 weeks

    Outcome Measure Data

    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
    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.
    Measure Participants 31 32 37 35 22 24
    Number [Percentage of participants]
    67.74
    218.5%
    6.25
    19.5%
    40.54
    109.6%
    5.71
    16.3%
    36.36
    165.3%
    8.33
    34.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Epoch 2: crFMF: 150 mg, Epoch 2: crCMF: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 29.78
    Confidence Interval (2-Sided) 95%
    5.86 to 151.31
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Epoch 2: HIDS/MKD: 150 mg, Epoch 2: HIDS/MKD: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0010
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 12.71
    Confidence Interval (2-Sided) 95%
    2.53 to 63.89
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Epoch 2: TRAPS: 150 mg, Epoch 2: TRAPS: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0149
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 6.64
    Confidence Interval (2-Sided) 95%
    1.20 to 36.57
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Percentage of Participants With Normalized Serum Amyloid A (SAA) Level
    Description Normalized SAA was defined as SAA <= 10 mg/L.
    Time Frame 16 weeks

    Outcome Measure Data

    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
    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.
    Measure Participants 31 32 37 35 22 24
    Number [Percentage of participants]
    25.81
    83.3%
    0.00
    0%
    13.51
    36.5%
    2.86
    8.2%
    27.27
    124%
    0.00
    0%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Epoch 2: crFMF: 150 mg, Epoch 2: crCMF: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0286
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 17.46
    Confidence Interval (2-Sided) 95%
    0.92 to 332.92
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Epoch 2: HIDS/MKD: 150 mg, Epoch 2: HIDS/MKD: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0778
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 5.26
    Confidence Interval (2-Sided) 95%
    0.53 to 51.97
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Epoch 2: TRAPS: 150 mg, Epoch 2: TRAPS: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0235
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 16.69
    Confidence Interval (2-Sided) 95%
    1.04 to 268.50
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    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)
    Description A responder was defined as a participant who had no flare between week 16 and week 40.
    Time Frame 40 weeks

    Outcome Measure Data

    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
    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.
    Measure Participants 9 10 6 7 4 5
    Number [Percentage of participants]
    77.8
    251%
    30.0
    93.8%
    50.0
    135.1%
    14.3
    40.9%
    75.0
    340.9%
    40.0
    166.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Epoch 2: crFMF: 150 mg, Epoch 2: crCMF: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0513
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 8.17
    Confidence Interval (2-Sided) 95%
    0.75 to 113.44
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Epoch 2: HIDS/MKD: 150 mg, Epoch 2: HIDS/MKD: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2168
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 6.00
    Confidence Interval (2-Sided) 95%
    0.27 to 366.24
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Epoch 2: TRAPS: 150 mg, Epoch 2: TRAPS: Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3571
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 4.50
    Confidence Interval (2-Sided) 95%
    0.15 to 313.49
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    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
    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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/4 (75%) 1/18 (5.6%) 1/46 (2.2%) 0/46 (0%) 8/46 (17.4%) 6/72 (8.3%) 1/72 (1.4%) 16/72 (22.2%) 5/63 (7.9%) 0/63 (0%) 16/63 (25.4%) 0/61 (0%) 0/61 (0%) 9/61 (14.8%) 3/71 (4.2%) 1/71 (1.4%) 18/71 (25.4%) 3/61 (4.9%) 0/61 (0%) 17/61 (27.9%)
    Blood and lymphatic system disorders
    Anaemia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Lymphadenopathy 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Neutropenia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 1/72 (1.4%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Pancytopenia 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Cardiac disorders
    Cardiac failure congestive 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Pericarditis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Congenital, familial and genetic disorders
    Familial mediterranean fever 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 3/63 (4.8%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 2/61 (3.3%) 0/61 (0%) 2/61 (3.3%)
    Hyper IgD syndrome 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 1/72 (1.4%) 0/72 (0%) 3/72 (4.2%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 1/71 (1.4%) 0/71 (0%) 4/71 (5.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Tumour necrosis factor receptor-associated periodic syndrome 0/4 (0%) 0/18 (0%) 1/46 (2.2%) 0/46 (0%) 3/46 (6.5%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Endocrine disorders
    Thyroiditis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Gastrointestinal disorders
    Abdominal pain 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 1/72 (1.4%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Ascites 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Constipation 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Diarrhoea 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Dysphagia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Ileal ulcer 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Inguinal hernia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 1/63 (1.6%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 1/61 (1.6%) 0/61 (0%) 0/61 (0%)
    Umbilical hernia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 1/63 (1.6%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 1/61 (1.6%) 0/61 (0%) 2/61 (3.3%)
    Vomiting 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    General disorders
    Hyperpyrexia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 1/72 (1.4%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 1/71 (1.4%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Polyserositis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Pyrexia 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 3/46 (6.5%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 1/63 (1.6%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 1/61 (1.6%) 0/61 (0%) 1/61 (1.6%)
    Hepatobiliary disorders
    Bile duct stone 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Granulomatous liver disease 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Hepatic cirrhosis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Hepatic failure 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Immune system disorders
    Drug hypersensitivity 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Infections and infestations
    Acute sinusitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Anal abscess 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Appendicitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Atypical pneumonia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 1/63 (1.6%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Bronchitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Cellulitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Conjunctivitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Diarrhoea infectious 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 1/72 (1.4%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 1/71 (1.4%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Gastroenteritis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Gastroenteritis rotavirus 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Herpes virus infection 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Infectious colitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Influenza 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Laryngitis 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Orchitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Pelvic abscess 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Peritonitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Pharyngitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Pharyngotonsillitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Pneumonia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 1/72 (1.4%) 0/72 (0%) 4/72 (5.6%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 1/71 (1.4%) 0/71 (0%) 4/71 (5.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Pyelonephritis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Septic shock 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Tonsillitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 1/72 (1.4%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 1/71 (1.4%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Urinary tract infection 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Vulval abscess 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Injury, poisoning and procedural complications
    Scar 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Metabolism and nutrition disorders
    Dehydration 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 1/72 (1.4%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 1/71 (1.4%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Hypercalcaemia 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Hypokalaemia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Obesity 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Bursitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Nervous system disorders
    Seizure 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 1/72 (1.4%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Psychiatric disorders
    Depression 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Intentional self-injury 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Schizophrenia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Suicidal ideation 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Suicide attempt 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Renal and urinary disorders
    Acute kidney injury 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 1/63 (1.6%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Laryngeal stenosis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Oropharyngeal pain 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Pleurisy 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Vocal cord polyp 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Skin and subcutaneous tissue disorders
    Drug eruption 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Granulomatous rosacea 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Pyoderma gangrenosum 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Other (Not Including 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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/4 (100%) 18/18 (100%) 14/46 (30.4%) 1/46 (2.2%) 43/46 (93.5%) 25/72 (34.7%) 1/72 (1.4%) 68/72 (94.4%) 29/63 (46%) 2/63 (3.2%) 54/63 (85.7%) 4/61 (6.6%) 1/61 (1.6%) 61/61 (100%) 7/71 (9.9%) 1/71 (1.4%) 70/71 (98.6%) 10/61 (16.4%) 2/61 (3.3%) 56/61 (91.8%)
    Blood and lymphatic system disorders
    Anaemia 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 1/72 (1.4%) 0/72 (0%) 4/72 (5.6%) 1/63 (1.6%) 0/63 (0%) 3/63 (4.8%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 4/71 (5.6%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%)
    Lymphadenopathy 0/4 (0%) 0/18 (0%) 1/46 (2.2%) 0/46 (0%) 4/46 (8.7%) 1/72 (1.4%) 0/72 (0%) 18/72 (25%) 0/63 (0%) 0/63 (0%) 5/63 (7.9%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%) 0/71 (0%) 0/71 (0%) 18/71 (25.4%) 0/61 (0%) 0/61 (0%) 5/61 (8.2%)
    Neutropenia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 3/46 (6.5%) 1/72 (1.4%) 0/72 (0%) 4/72 (5.6%) 0/63 (0%) 0/63 (0%) 3/63 (4.8%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%) 0/71 (0%) 0/71 (0%) 4/71 (5.6%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%)
    Cardiac disorders
    Atrial fibrillation 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Tachycardia 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Congenital, familial and genetic disorders
    Familial mediterranean fever 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 15/63 (23.8%) 2/63 (3.2%) 19/63 (30.2%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 5/61 (8.2%) 2/61 (3.3%) 20/61 (32.8%)
    Hyper IgD syndrome 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 5/72 (6.9%) 1/72 (1.4%) 19/72 (26.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 1/71 (1.4%) 1/71 (1.4%) 20/71 (28.2%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Tumour necrosis factor receptor-associated periodic syndrome 0/4 (0%) 0/18 (0%) 2/46 (4.3%) 0/46 (0%) 6/46 (13%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 6/61 (9.8%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Ear and labyrinth disorders
    Ear pain 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 2/46 (4.3%) 0/72 (0%) 0/72 (0%) 10/72 (13.9%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 10/71 (14.1%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Endocrine disorders
    Hyperthyroidism 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Eye disorders
    Eye allergy 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Eye pain 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 2/46 (4.3%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 3/71 (4.2%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Scleritis 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Gastrointestinal disorders
    Abdominal discomfort 0/4 (0%) 3/18 (16.7%) 1/46 (2.2%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Abdominal pain 0/4 (0%) 4/18 (22.2%) 2/46 (4.3%) 0/46 (0%) 14/46 (30.4%) 3/72 (4.2%) 0/72 (0%) 25/72 (34.7%) 4/63 (6.3%) 0/63 (0%) 16/63 (25.4%) 1/61 (1.6%) 0/61 (0%) 18/61 (29.5%) 1/71 (1.4%) 0/71 (0%) 25/71 (35.2%) 1/61 (1.6%) 0/61 (0%) 16/61 (26.2%)
    Abdominal pain upper 0/4 (0%) 1/18 (5.6%) 1/46 (2.2%) 1/46 (2.2%) 5/46 (10.9%) 1/72 (1.4%) 0/72 (0%) 14/72 (19.4%) 0/63 (0%) 0/63 (0%) 6/63 (9.5%) 0/61 (0%) 1/61 (1.6%) 6/61 (9.8%) 0/71 (0%) 0/71 (0%) 14/71 (19.7%) 0/61 (0%) 0/61 (0%) 6/61 (9.8%)
    Aphthous ulcer 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 16/72 (22.2%) 0/63 (0%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 17/71 (23.9%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Constipation 1/4 (25%) 1/18 (5.6%) 1/46 (2.2%) 0/46 (0%) 2/46 (4.3%) 0/72 (0%) 0/72 (0%) 5/72 (6.9%) 0/63 (0%) 0/63 (0%) 4/63 (6.3%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%) 0/71 (0%) 0/71 (0%) 5/71 (7%) 0/61 (0%) 0/61 (0%) 5/61 (8.2%)
    Dental caries 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Diarrhoea 2/4 (50%) 4/18 (22.2%) 1/46 (2.2%) 1/46 (2.2%) 8/46 (17.4%) 2/72 (2.8%) 0/72 (0%) 22/72 (30.6%) 1/63 (1.6%) 0/63 (0%) 12/63 (19%) 0/61 (0%) 1/61 (1.6%) 12/61 (19.7%) 0/71 (0%) 0/71 (0%) 23/71 (32.4%) 0/61 (0%) 0/61 (0%) 13/61 (21.3%)
    Dyspepsia 0/4 (0%) 2/18 (11.1%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 0/63 (0%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Gastric dilatation 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Gastritis 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 3/46 (6.5%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Haemorrhoids 1/4 (25%) 0/18 (0%) 1/46 (2.2%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 1/61 (1.6%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Mouth ulceration 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 1/72 (1.4%) 0/72 (0%) 4/72 (5.6%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 4/71 (5.6%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Nausea 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 4/46 (8.7%) 0/72 (0%) 0/72 (0%) 8/72 (11.1%) 0/63 (0%) 0/63 (0%) 5/63 (7.9%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%) 0/71 (0%) 0/71 (0%) 8/71 (11.3%) 0/61 (0%) 0/61 (0%) 6/61 (9.8%)
    Proctitis 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Stomatitis 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Teething 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Toothache 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 2/46 (4.3%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 1/63 (1.6%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 1/61 (1.6%) 0/61 (0%) 2/61 (3.3%)
    Vomiting 1/4 (25%) 1/18 (5.6%) 1/46 (2.2%) 0/46 (0%) 6/46 (13%) 2/72 (2.8%) 0/72 (0%) 12/72 (16.7%) 1/63 (1.6%) 0/63 (0%) 5/63 (7.9%) 0/61 (0%) 0/61 (0%) 7/61 (11.5%) 1/71 (1.4%) 0/71 (0%) 12/71 (16.9%) 0/61 (0%) 0/61 (0%) 6/61 (9.8%)
    General disorders
    Asthenia 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 3/46 (6.5%) 0/72 (0%) 0/72 (0%) 6/72 (8.3%) 0/63 (0%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%) 0/71 (0%) 0/71 (0%) 6/71 (8.5%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Fatigue 0/4 (0%) 0/18 (0%) 1/46 (2.2%) 0/46 (0%) 3/46 (6.5%) 0/72 (0%) 0/72 (0%) 6/72 (8.3%) 1/63 (1.6%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%) 0/71 (0%) 0/71 (0%) 6/71 (8.5%) 1/61 (1.6%) 0/61 (0%) 1/61 (1.6%)
    Influenza like illness 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 2/46 (4.3%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 3/63 (4.8%) 0/63 (0%) 6/63 (9.5%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 6/61 (9.8%)
    Injection site reaction 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 7/46 (15.2%) 1/72 (1.4%) 0/72 (0%) 9/72 (12.5%) 0/63 (0%) 0/63 (0%) 11/63 (17.5%) 0/61 (0%) 0/61 (0%) 8/61 (13.1%) 0/71 (0%) 0/71 (0%) 9/71 (12.7%) 0/61 (0%) 0/61 (0%) 11/61 (18%)
    Malaise 1/4 (25%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 4/72 (5.6%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 4/71 (5.6%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Non-cardiac chest pain 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 4/46 (8.7%) 0/72 (0%) 0/72 (0%) 3/72 (4.2%) 0/63 (0%) 0/63 (0%) 7/63 (11.1%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%) 0/71 (0%) 0/71 (0%) 3/71 (4.2%) 0/61 (0%) 0/61 (0%) 7/61 (11.5%)
    Pyrexia 1/4 (25%) 5/18 (27.8%) 1/46 (2.2%) 1/46 (2.2%) 14/46 (30.4%) 11/72 (15.3%) 0/72 (0%) 39/72 (54.2%) 3/63 (4.8%) 0/63 (0%) 13/63 (20.6%) 0/61 (0%) 1/61 (1.6%) 19/61 (31.1%) 4/71 (5.6%) 0/71 (0%) 40/71 (56.3%) 2/61 (3.3%) 0/61 (0%) 13/61 (21.3%)
    Infections and infestations
    Bronchitis 2/4 (50%) 1/18 (5.6%) 1/46 (2.2%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 10/72 (13.9%) 0/63 (0%) 1/63 (1.6%) 0/63 (0%) 1/61 (1.6%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 11/71 (15.5%) 0/61 (0%) 1/61 (1.6%) 1/61 (1.6%)
    Conjunctivitis 2/4 (50%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 4/46 (8.7%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 1/63 (1.6%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 5/61 (8.2%) 0/71 (0%) 0/71 (0%) 3/71 (4.2%) 1/61 (1.6%) 0/61 (0%) 2/61 (3.3%)
    Cystitis 0/4 (0%) 1/18 (5.6%) 1/46 (2.2%) 1/46 (2.2%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 1/61 (1.6%) 1/61 (1.6%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Ear infection 1/4 (25%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 7/72 (9.7%) 0/63 (0%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 8/71 (11.3%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Gastroenteritis 2/4 (50%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 5/46 (10.9%) 0/72 (0%) 1/72 (1.4%) 10/72 (13.9%) 1/63 (1.6%) 0/63 (0%) 8/63 (12.7%) 0/61 (0%) 0/61 (0%) 6/61 (9.8%) 0/71 (0%) 1/71 (1.4%) 11/71 (15.5%) 1/61 (1.6%) 0/61 (0%) 9/61 (14.8%)
    Influenza 1/4 (25%) 2/18 (11.1%) 1/46 (2.2%) 0/46 (0%) 5/46 (10.9%) 0/72 (0%) 0/72 (0%) 14/72 (19.4%) 1/63 (1.6%) 0/63 (0%) 10/63 (15.9%) 1/61 (1.6%) 0/61 (0%) 7/61 (11.5%) 0/71 (0%) 0/71 (0%) 14/71 (19.7%) 0/61 (0%) 0/61 (0%) 11/61 (18%)
    Lower respiratory tract infection 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 0/63 (0%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Nasopharyngitis 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 1/72 (1.4%) 0/72 (0%) 4/72 (5.6%) 0/63 (0%) 0/63 (0%) 3/63 (4.8%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 5/71 (7%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%)
    Oral herpes 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 4/46 (8.7%) 0/72 (0%) 0/72 (0%) 3/72 (4.2%) 2/63 (3.2%) 0/63 (0%) 3/63 (4.8%) 0/61 (0%) 0/61 (0%) 5/61 (8.2%) 0/71 (0%) 0/71 (0%) 3/71 (4.2%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%)
    Otitis media 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 4/46 (8.7%) 0/72 (0%) 0/72 (0%) 9/72 (12.5%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%) 0/71 (0%) 0/71 (0%) 9/71 (12.7%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Otitis media acute 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 1/72 (1.4%) 5/72 (6.9%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 1/71 (1.4%) 5/71 (7%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Paronychia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 4/72 (5.6%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 4/71 (5.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Pharyngitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 7/72 (9.7%) 0/63 (0%) 0/63 (0%) 8/63 (12.7%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 7/71 (9.9%) 0/61 (0%) 0/61 (0%) 8/61 (13.1%)
    Pharyngotonsillitis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 5/72 (6.9%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 5/71 (7%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Pilonidal cyst 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Pneumonia 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 4/72 (5.6%) 0/63 (0%) 0/63 (0%) 3/63 (4.8%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 4/71 (5.6%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%)
    Respiratory tract infection 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 2/46 (4.3%) 1/72 (1.4%) 0/72 (0%) 8/72 (11.1%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%) 0/71 (0%) 0/71 (0%) 8/71 (11.3%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Rhinitis 1/4 (25%) 2/18 (11.1%) 0/46 (0%) 0/46 (0%) 8/46 (17.4%) 0/72 (0%) 0/72 (0%) 14/72 (19.4%) 1/63 (1.6%) 0/63 (0%) 3/63 (4.8%) 0/61 (0%) 0/61 (0%) 10/61 (16.4%) 0/71 (0%) 0/71 (0%) 15/71 (21.1%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%)
    Sialoadenitis 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Sinusitis 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 2/46 (4.3%) 0/72 (0%) 0/72 (0%) 3/72 (4.2%) 0/63 (0%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%) 0/71 (0%) 0/71 (0%) 3/71 (4.2%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Tonsillitis 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 3/46 (6.5%) 1/72 (1.4%) 0/72 (0%) 3/72 (4.2%) 1/63 (1.6%) 0/63 (0%) 8/63 (12.7%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%) 1/71 (1.4%) 0/71 (0%) 3/71 (4.2%) 1/61 (1.6%) 0/61 (0%) 8/61 (13.1%)
    Tonsillitis bacterial 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Tracheitis 0/4 (0%) 2/18 (11.1%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Upper respiratory tract infection 0/4 (0%) 3/18 (16.7%) 2/46 (4.3%) 0/46 (0%) 10/46 (21.7%) 3/72 (4.2%) 0/72 (0%) 22/72 (30.6%) 1/63 (1.6%) 0/63 (0%) 12/63 (19%) 1/61 (1.6%) 0/61 (0%) 13/61 (21.3%) 1/71 (1.4%) 0/71 (0%) 22/71 (31%) 1/61 (1.6%) 0/61 (0%) 12/61 (19.7%)
    Urinary tract infection 0/4 (0%) 0/18 (0%) 1/46 (2.2%) 0/46 (0%) 4/46 (8.7%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 0/63 (0%) 0/63 (0%) 9/63 (14.3%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 9/61 (14.8%)
    Viral infection 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 2/46 (4.3%) 0/72 (0%) 0/72 (0%) 7/72 (9.7%) 0/63 (0%) 0/63 (0%) 6/63 (9.5%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%) 0/71 (0%) 0/71 (0%) 7/71 (9.9%) 0/61 (0%) 0/61 (0%) 6/61 (9.8%)
    Viral tonsillitis 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Viral upper respiratory tract infection 1/4 (25%) 5/18 (27.8%) 1/46 (2.2%) 0/46 (0%) 11/46 (23.9%) 0/72 (0%) 0/72 (0%) 20/72 (27.8%) 0/63 (0%) 0/63 (0%) 7/63 (11.1%) 1/61 (1.6%) 0/61 (0%) 16/61 (26.2%) 0/71 (0%) 0/71 (0%) 20/71 (28.2%) 0/61 (0%) 0/61 (0%) 8/61 (13.1%)
    Vulvovaginal candidiasis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 6/72 (8.3%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 6/71 (8.5%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Injury, poisoning and procedural complications
    Contusion 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Ligament sprain 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 4/72 (5.6%) 0/63 (0%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 4/71 (5.6%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Skin abrasion 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Thermal burn 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 1/63 (1.6%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Wound 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Investigations
    Alanine aminotransferase increased 1/4 (25%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 3/71 (4.2%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Aspartate aminotransferase increased 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Blood creatine phosphokinase increased 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 3/72 (4.2%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 3/71 (4.2%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    C-reactive protein increased 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 2/72 (2.8%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 3/71 (4.2%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Eosinophil count increased 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Glomerular filtration rate decreased 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Neutrophil count decreased 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Neutrophil count increased 1/4 (25%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 1/63 (1.6%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Serum amyloid A protein increased 1/4 (25%) 3/18 (16.7%) 2/46 (4.3%) 0/46 (0%) 4/46 (8.7%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 7/61 (11.5%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    White blood cell count increased 1/4 (25%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 1/63 (1.6%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 2/71 (2.8%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Metabolism and nutrition disorders
    Dehydration 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Hypocalcaemia 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Hypophosphataemia 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/4 (25%) 5/18 (27.8%) 2/46 (4.3%) 0/46 (0%) 6/46 (13%) 1/72 (1.4%) 0/72 (0%) 18/72 (25%) 2/63 (3.2%) 0/63 (0%) 11/63 (17.5%) 1/61 (1.6%) 0/61 (0%) 11/61 (18%) 1/71 (1.4%) 0/71 (0%) 18/71 (25.4%) 0/61 (0%) 0/61 (0%) 12/61 (19.7%)
    Arthritis 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Back pain 1/4 (25%) 2/18 (11.1%) 0/46 (0%) 0/46 (0%) 6/46 (13%) 0/72 (0%) 0/72 (0%) 10/72 (13.9%) 0/63 (0%) 0/63 (0%) 13/63 (20.6%) 0/61 (0%) 0/61 (0%) 8/61 (13.1%) 0/71 (0%) 0/71 (0%) 10/71 (14.1%) 0/61 (0%) 0/61 (0%) 14/61 (23%)
    Intervertebral disc disorder 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Joint swelling 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 4/63 (6.3%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%)
    Musculoskeletal chest pain 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Musculoskeletal pain 0/4 (0%) 2/18 (11.1%) 2/46 (4.3%) 0/46 (0%) 3/46 (6.5%) 0/72 (0%) 1/72 (1.4%) 6/72 (8.3%) 1/63 (1.6%) 0/63 (0%) 4/63 (6.3%) 0/61 (0%) 0/61 (0%) 5/61 (8.2%) 0/71 (0%) 1/71 (1.4%) 6/71 (8.5%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%)
    Myalgia 0/4 (0%) 3/18 (16.7%) 0/46 (0%) 0/46 (0%) 4/46 (8.7%) 0/72 (0%) 0/72 (0%) 7/72 (9.7%) 1/63 (1.6%) 0/63 (0%) 7/63 (11.1%) 0/61 (0%) 0/61 (0%) 7/61 (11.5%) 0/71 (0%) 0/71 (0%) 7/71 (9.9%) 0/61 (0%) 0/61 (0%) 7/61 (11.5%)
    Neck pain 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 3/46 (6.5%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Pain in extremity 1/4 (25%) 3/18 (16.7%) 1/46 (2.2%) 0/46 (0%) 5/46 (10.9%) 0/72 (0%) 0/72 (0%) 7/72 (9.7%) 2/63 (3.2%) 0/63 (0%) 8/63 (12.7%) 0/61 (0%) 0/61 (0%) 8/61 (13.1%) 0/71 (0%) 0/71 (0%) 7/71 (9.9%) 1/61 (1.6%) 0/61 (0%) 9/61 (14.8%)
    Spinal pain 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Tendon pain 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Tenosynovitis stenosans 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pyogenic granuloma 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Nervous system disorders
    Dizziness 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 2/46 (4.3%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 4/63 (6.3%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%)
    Headache 1/4 (25%) 2/18 (11.1%) 3/46 (6.5%) 0/46 (0%) 12/46 (26.1%) 4/72 (5.6%) 0/72 (0%) 30/72 (41.7%) 2/63 (3.2%) 0/63 (0%) 16/63 (25.4%) 1/61 (1.6%) 0/61 (0%) 14/61 (23%) 1/71 (1.4%) 0/71 (0%) 31/71 (43.7%) 0/61 (0%) 0/61 (0%) 16/61 (26.2%)
    Somnolence 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Reproductive system and breast disorders
    Breast mass 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Polycystic ovaries 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Vaginal haemorrhage 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 0/4 (0%) 3/18 (16.7%) 0/46 (0%) 0/46 (0%) 9/46 (19.6%) 3/72 (4.2%) 0/72 (0%) 21/72 (29.2%) 2/63 (3.2%) 0/63 (0%) 6/63 (9.5%) 0/61 (0%) 0/61 (0%) 12/61 (19.7%) 0/71 (0%) 0/71 (0%) 21/71 (29.6%) 2/61 (3.3%) 0/61 (0%) 6/61 (9.8%)
    Epistaxis 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 3/46 (6.5%) 0/72 (0%) 0/72 (0%) 6/72 (8.3%) 0/63 (0%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%) 0/71 (0%) 0/71 (0%) 6/71 (8.5%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Oropharyngeal pain 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 6/46 (13%) 2/72 (2.8%) 0/72 (0%) 22/72 (30.6%) 2/63 (3.2%) 0/63 (0%) 8/63 (12.7%) 0/61 (0%) 0/61 (0%) 7/61 (11.5%) 1/71 (1.4%) 0/71 (0%) 22/71 (31%) 1/61 (1.6%) 0/61 (0%) 8/61 (13.1%)
    Pleuritic pain 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Pneumonitis 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Rhinitis allergic 0/4 (0%) 1/18 (5.6%) 1/46 (2.2%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 1/61 (1.6%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Rhinorrhoea 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 2/46 (4.3%) 1/72 (1.4%) 0/72 (0%) 7/72 (9.7%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 7/71 (9.9%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Skin and subcutaneous tissue disorders
    Dermatitis allergic 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Drug eruption 2/4 (50%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Eczema 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 2/46 (4.3%) 0/72 (0%) 0/72 (0%) 6/72 (8.3%) 0/63 (0%) 0/63 (0%) 2/63 (3.2%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 7/71 (9.9%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Erythema 0/4 (0%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 1/46 (2.2%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 5/63 (7.9%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 5/61 (8.2%)
    Keloid scar 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Pain of skin 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Pyoderma gangrenosum 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Rash 0/4 (0%) 0/18 (0%) 1/46 (2.2%) 0/46 (0%) 8/46 (17.4%) 1/72 (1.4%) 0/72 (0%) 5/72 (6.9%) 1/63 (1.6%) 0/63 (0%) 3/63 (4.8%) 0/61 (0%) 0/61 (0%) 8/61 (13.1%) 0/71 (0%) 0/71 (0%) 5/71 (7%) 0/61 (0%) 0/61 (0%) 3/61 (4.9%)
    Rash pruritic 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Skin ulcer 1/4 (25%) 0/18 (0%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%)
    Urticaria 1/4 (25%) 0/18 (0%) 1/46 (2.2%) 0/46 (0%) 4/46 (8.7%) 0/72 (0%) 0/72 (0%) 3/72 (4.2%) 0/63 (0%) 0/63 (0%) 1/63 (1.6%) 0/61 (0%) 0/61 (0%) 4/61 (6.6%) 0/71 (0%) 0/71 (0%) 3/71 (4.2%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%)
    Vascular disorders
    Hypertension 0/4 (0%) 2/18 (11.1%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 1/72 (1.4%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 2/61 (3.3%) 0/71 (0%) 0/71 (0%) 1/71 (1.4%) 0/61 (0%) 0/61 (0%) 0/61 (0%)
    Hypotension 0/4 (0%) 1/18 (5.6%) 0/46 (0%) 0/46 (0%) 0/46 (0%) 0/72 (0%) 0/72 (0%) 0/72 (0%) 0/63 (0%) 0/63 (0%) 0/63 (0%) 0/61 (0%) 0/61 (0%) 1/61 (1.6%) 0/71 (0%) 0/71 (0%) 0/71 (0%) 0/61 (0%) 0/61 (0%) 0/61 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.

    Results Point of Contact

    Name/Title Study Director
    Organization Novartic Pharmaceuticals
    Phone 862-778-8300
    Email novartis.email@novartis.com
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT02059291
    Other Study ID Numbers:
    • CACZ885N2301
    First Posted:
    Feb 11, 2014
    Last Update Posted:
    May 17, 2018
    Last Verified:
    Apr 1, 2018