Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42567   clinical trials with a EudraCT protocol, of which   7008   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group, Study Followed by a Dose-Blind Period and Open-Label Follow-Up to Evaluate the Efficacy and Safety of Certolizumab Pegol in Subjects with Moderate to Severe Chronic Plaque Psoriasis

    Summary
    EudraCT number
    2014-003513-28
    Trial protocol
    DE   CZ   HU  
    Global end of trial date
    24 Oct 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Nov 2019
    First version publication date
    08 Nov 2019
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    PS0005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02326298
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Biopharma SPRL
    Sponsor organisation address
    Allée de la Recherche 60, Brussels, Belgium, B-1070
    Public contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of certolizumab pegol (CZP) administered subcutaneously (sc) at the doses of CZP 400 mg every 2 weeks (Q2W) and CZP 200 mg Q2W after a loading dose of CZP 400 mg at Weeks 0, 2, and 4 in the treatment of moderate to severe chronic plaque psoriasis (PSO).
    Protection of trial subjects
    During the conduct of the study all participants were closely monitored.
    Background therapy
    Background therapy/concomitant medication as permitted in the protocol.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    16 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 78
    Country: Number of subjects enrolled
    Canada: 42
    Country: Number of subjects enrolled
    Czech Republic: 24
    Country: Number of subjects enrolled
    Germany: 77
    Country: Number of subjects enrolled
    Hungary: 13
    Worldwide total number of subjects
    234
    EEA total number of subjects
    114
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    221
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The study started to enroll participants in December 2014 and concluded in October 2018 from multiple sites in Europe and North America. 234 participants were included in the Randomized Set (RS) shown in the Participant Flow.

    Pre-assignment
    Screening details
    The study included a 5 Week Screening Period, a Double-blind Initial Treatment Period up to Week 16, a Dose-blind Maintenance Treatment Period up to Week 48, an Open-label Treatment Period up to Week 144 and a Post Study Safety Follow-up Period up to Week 152. Participant Flow refers to the Randomized Set, Open Label Set and Maintenance Set.

    Period 1
    Period 1 title
    Initial Period (Week 0 to Week 16)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Assessor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo Q2W
    Arm description
    Placebo sc injection Q2W. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16, who did not achieve a PASI75 response at Week 16 received CZP 400 mg at Weeks 16, 18 and 20 (loading doses) followed by CZP 200 mg Q2W starting at Week 22. •PASI75 responders at Week 16 continued to receive Placebo. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the Open-label Extension (OLE) Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections every 2 Weeks (Q2W), administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Arm title
    CZP 200 mg Q2W
    Arm description
    CZP 400 mg at Weeks 0, 2, 4, followed by CZP 200 mg Q2W from Week 6 to Week 14. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16 continued to receive CZP 200 mg Q2W. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the OLE Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W. Depending on PASI50 or PASI75 responses at Week 60 or a later time point, participants may have switched to CZP 400 mg Q2W or withdrew from the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks (Q2W) or 400 mg Q2W, were administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Arm title
    CZP 400 mg Q2W
    Arm description
    CZP 400 mg Q2W through Week 14. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16 continued to receive CZP 400 mg Q2W. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the OLE Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W. Participants who achieved a PASI75 response during the OLE Period may have switched to CZP 200 mg Q2W.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks (Q2W) or 400 mg Q2W, were administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Number of subjects in period 1
    Placebo Q2W CZP 200 mg Q2W CZP 400 mg Q2W
    Started
    51
    95
    88
    Completed Week 16
    46
    92
    87
    Finished Wk16 started Maintenance Period
    46
    92
    85
    Completed
    46
    92
    85
    Not completed
    5
    3
    3
         Lack of efficacy
    1
    -
    -
         Adverse event after completing wk16
    -
    -
    2
         Adverse event, non-fatal
    -
    -
    1
         Consent withdrawn by subject
    3
    2
    -
         Lost to follow-up
    1
    1
    -
    Period 2
    Period 2 title
    Maintenance Period (Week 16 to Week 48)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Carer, Investigator, Assessor
    Blinding implementation details
    Participants who entered the escape arms of the study received open-label CZP 400 mg every two weeks.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo/Placebo Q2W
    Arm description
    This arm consisted of participants initially randomized in the Placebo arm, who achieved a PASI75 response at Week 16 and continued to receive Placebo in the Maintenance Period (Week 16 to Week 48).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections every 2 Weeks (Q2W), administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Arm title
    Placebo/CZP 200 mg Q2W
    Arm description
    This arm consisted of participants initially randomized in the Placebo arm, who achieved a PASI50 response at Week 16 but not a PASI75 response and received CZP 400 mg at Weeks 16, 18, and 20 (loading doses) followed by CZP 200 mg Q2W (starting at Week 22).
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks (Q2W) or 400 mg Q2W, were administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections every 2 Weeks (Q2W), administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Arm title
    CZP 200 mg Q2W/CZP 200 mg Q2W
    Arm description
    This arm consisted of participants initially randomized in the CZP 200 mg Q2W arm, who achieved a PASI50 response at Week 16 and continued to receive CZP 200 mg Q2W.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks (Q2W) or 400 mg Q2W, were administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Arm title
    CZP 400 mg Q2W/CZP 400 mg Q2W
    Arm description
    This arm consisted of participants initially randomized in the CZP 400 mg Q2W arm, who achieved a PASI50 response at Week 16 and continued to receive CZP 400 mg Q2W.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks (Q2W) or 400 mg Q2W, were administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Arm title
    Placebo/Escape CZP 400 mg Q2W
    Arm description
    This arm consisted of participants initially randomized in the Placebo arm, who did not achieve a PASI50 response at Week 16 escaped from the blinded treatment and received unblinded CZP 400 mg Q2W, for 16 weeks. Participants who did not achieve PASI50 after 16 weeks of unblinded treatment were withdrawn from the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections every 2 Weeks (Q2W), administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks (Q2W) or 400 mg Q2W, were administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Arm title
    CZP 200 mg Q2W/Escape CZP 400 mg Q2W
    Arm description
    This arm consisted of participants initially randomized in the CZP 200 mg Q2W arm, who did not achieve a PASI50 response at Week 16 escaped from the blinded treatment and received CZP unblinded 400 mg Q2W, for 16 weeks. Participants who did not achieve PASI50 after 16 weeks of unblinded treatment were withdrawn from the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks (Q2W) or 400 mg Q2W, were administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Arm title
    CZP 400 mg Q2W/Escape CZP 400 mg Q2W
    Arm description
    This arm consisted of participants initially randomized in the CZP 400 mg Q2W arm, who did not achieve a PASI50 response at Week 16 escaped from the blinded treatment and received unblinded CZP 400 mg Q2W, for 16 weeks. Participants who did not achieve PASI50 after 16 weeks of unblinded treatment were withdrawn from the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks (Q2W) or 400 mg Q2W, were administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Number of subjects in period 2
    Placebo/Placebo Q2W Placebo/CZP 200 mg Q2W CZP 200 mg Q2W/CZP 200 mg Q2W CZP 400 mg Q2W/CZP 400 mg Q2W Placebo/Escape CZP 400 mg Q2W CZP 200 mg Q2W/Escape CZP 400 mg Q2W CZP 400 mg Q2W/Escape CZP 400 mg Q2W
    Started
    3
    5
    74
    77
    38
    18
    8
    Completed Week 48
    3
    5
    71
    70
    33
    13
    7
    Finished Wk48 entered Open-label Period
    3
    5
    69
    70
    33
    13
    7
    Completed
    3
    5
    69
    70
    33
    13
    7
    Not completed
    0
    0
    5
    7
    5
    5
    1
         Pregnancy
    -
    -
    -
    1
    -
    -
    -
         Patient did not achieve PASI50 response
    -
    -
    1
    2
    -
    4
    -
         Adverse event, non-fatal
    -
    -
    -
    -
    1
    -
    -
         Patient cannot attend visits
    -
    -
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    -
    -
    1
    3
    1
    1
    1
         No valid reason stated by patient
    -
    -
    -
    -
    1
    -
    -
         Did not achieve PASI50 after week 48
    -
    -
    2
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    1
    2
    -
    -
    Period 3
    Period 3 title
    Open-label Period (Week 48 to Week 144)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo/CZP 200 mg Q2W OLE
    Arm description
    This arm consisted of participants who received dose-blind Placebo during the Maintenance Period, who achieved a PASI50 response at Week 48 and entered the OLE Period receiving CZP 200 mg Q2W.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections every 2 Weeks (Q2W), administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks (Q2W) or 400 mg Q2W, were administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Arm title
    CZP 200 mg Q2W/CZP 200 mg Q2W OLE
    Arm description
    This arm consisted of participants who received blinded CZP 200mg Q2W in the Maintenance Period, who achieved a PASI50 response at Week 48 and entered OLE on the CZP 200mg Q2W dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks (Q2W) or 400 mg Q2W, were administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Arm title
    CZP 400 mg Q2W/CZP 200 mg Q2W OLE
    Arm description
    This arm consisted of participants who received blinded CZP 400mg Q2W in the Maintenance Period, who achieved a PASI50 response at Week 48, and entered OLE on the CZP 200mg Q2W dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks (Q2W) or 400 mg Q2W, were administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Arm title
    Escape CZP 400 mg Q2W/CZP 400 mg Q2W OLE
    Arm description
    This arm consisted of participants who received open-label CZP 400mg Q2W in the Maintenance Period and entered OLE on the CZP 400mg Q2W dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Certolizumab pegol
    Investigational medicinal product code
    CZP
    Other name
    Cimzia
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections: 200 mg every 2 Weeks (Q2W) or 400 mg Q2W, were administered at separate injection sites: lateral abdominal wall and upper outer thigh.

    Number of subjects in period 3
    Placebo/CZP 200 mg Q2W OLE CZP 200 mg Q2W/CZP 200 mg Q2W OLE CZP 400 mg Q2W/CZP 200 mg Q2W OLE Escape CZP 400 mg Q2W/CZP 400 mg Q2W OLE
    Started
    3
    74
    70
    53
    Completed
    3
    54
    51
    44
    Not completed
    0
    20
    19
    9
         Protocol deviation
    -
    -
    -
    1
         Protocol violation
    -
    -
    -
    1
         Lack of efficacy
    -
    1
    1
    -
         Adverse event, serious fatal
    -
    1
    -
    -
         Did not achieve PASI50
    -
    2
    7
    3
         Adverse event, non-fatal
    -
    3
    3
    -
         Consent withdrawn by subject
    -
    7
    2
    1
         Lost to follow-up
    -
    6
    6
    3

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Placebo Q2W
    Reporting group description
    Placebo sc injection Q2W. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16, who did not achieve a PASI75 response at Week 16 received CZP 400 mg at Weeks 16, 18 and 20 (loading doses) followed by CZP 200 mg Q2W starting at Week 22. •PASI75 responders at Week 16 continued to receive Placebo. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the Open-label Extension (OLE) Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W.

    Reporting group title
    CZP 200 mg Q2W
    Reporting group description
    CZP 400 mg at Weeks 0, 2, 4, followed by CZP 200 mg Q2W from Week 6 to Week 14. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16 continued to receive CZP 200 mg Q2W. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the OLE Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W. Depending on PASI50 or PASI75 responses at Week 60 or a later time point, participants may have switched to CZP 400 mg Q2W or withdrew from the study.

    Reporting group title
    CZP 400 mg Q2W
    Reporting group description
    CZP 400 mg Q2W through Week 14. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16 continued to receive CZP 400 mg Q2W. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the OLE Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W. Participants who achieved a PASI75 response during the OLE Period may have switched to CZP 200 mg Q2W.

    Reporting group values
    Placebo Q2W CZP 200 mg Q2W CZP 400 mg Q2W Total
    Number of subjects
    51 95 88 234
    Age categorical
    Units: Subjects
        <=18 years
    0 0 0 0
        Between 18 and 65 years
    45 90 86 221
        >=65 years
    6 5 2 13
    Age continuous
    Units: Years
        arithmetic mean (standard deviation)
    47.9 ± 12.8 44.5 ± 13.1 43.6 ± 12.1 -
    Gender categorical
    Units: Subjects
        Female
    16 28 28 72
        Male
    35 67 60 162
    Subject analysis sets

    Subject analysis set title
    Placebo Q2W (RS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo sc injection Q2W. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16, who did not achieve a PASI75 response at Week 16 received CZP 400 mg at Weeks 16, 18 and 20 (loading doses) followed by CZP 200 mg Q2W starting at Week 22. •PASI75 responders at Week 16 continued to receive Placebo. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the OLE Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W. Participants formed the Randomized Set (RS).

    Subject analysis set title
    CZP 200 mg Q2W (RS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    CZP 400 mg at Weeks 0, 2, 4, followed by CZP 200 mg Q2W from Week 6 to Week 14. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16 continued to receive CZP 200 mg Q2W. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the OLE Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W. Depending on PASI50 or PASI75 responses at Week 60 or a later time point, participants may have switched to CZP 400 mg Q2W or withdrew from the study. Participants formed the RS.

    Subject analysis set title
    CZP 400 mg Q2W (RS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    CZP 400 mg Q2W through Week 14. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16 continued to receive CZP 400 mg Q2W. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the OLE Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W. Participants who achieved a PASI75 response during the OLE Period may have switched to CZP 200 mg Q2W. Participants formed the RS.

    Subject analysis set title
    CZP 200 mg Q2W (TCS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This arm consisted of all participants who received CZP 200 mg at any time during the study.

    Subject analysis set title
    CZP 400 mg Q2W (TCS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This arm consisted of all participants who received CZP 400 mg at any time during the study.

    Subject analysis sets values
    Placebo Q2W (RS) CZP 200 mg Q2W (RS) CZP 400 mg Q2W (RS) CZP 200 mg Q2W (TCS) CZP 400 mg Q2W (TCS)
    Number of subjects
    51
    95
    88
    188
    167
    Age categorical
    Units: Subjects
        <=18 years
    0
    0
    0
    0
    0
        Between 18 and 65 years
    45
    90
    86
    177
    160
        >=65 years
    6
    5
    2
    11
    7
    Age continuous
    Units: Years
        arithmetic mean (standard deviation)
    47.9 ± 12.8
    44.5 ± 13.1
    43.6 ± 12.1
    44.9 ± 12.9
    44.8 ± 12.1
    Gender categorical
    Units: Subjects
        Female
    16
    28
    28
    55
    52
        Male
    35
    67
    60
    133
    115

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Placebo Q2W
    Reporting group description
    Placebo sc injection Q2W. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16, who did not achieve a PASI75 response at Week 16 received CZP 400 mg at Weeks 16, 18 and 20 (loading doses) followed by CZP 200 mg Q2W starting at Week 22. •PASI75 responders at Week 16 continued to receive Placebo. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the Open-label Extension (OLE) Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W.

    Reporting group title
    CZP 200 mg Q2W
    Reporting group description
    CZP 400 mg at Weeks 0, 2, 4, followed by CZP 200 mg Q2W from Week 6 to Week 14. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16 continued to receive CZP 200 mg Q2W. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the OLE Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W. Depending on PASI50 or PASI75 responses at Week 60 or a later time point, participants may have switched to CZP 400 mg Q2W or withdrew from the study.

    Reporting group title
    CZP 400 mg Q2W
    Reporting group description
    CZP 400 mg Q2W through Week 14. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16 continued to receive CZP 400 mg Q2W. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the OLE Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W. Participants who achieved a PASI75 response during the OLE Period may have switched to CZP 200 mg Q2W.
    Reporting group title
    Placebo/Placebo Q2W
    Reporting group description
    This arm consisted of participants initially randomized in the Placebo arm, who achieved a PASI75 response at Week 16 and continued to receive Placebo in the Maintenance Period (Week 16 to Week 48).

    Reporting group title
    Placebo/CZP 200 mg Q2W
    Reporting group description
    This arm consisted of participants initially randomized in the Placebo arm, who achieved a PASI50 response at Week 16 but not a PASI75 response and received CZP 400 mg at Weeks 16, 18, and 20 (loading doses) followed by CZP 200 mg Q2W (starting at Week 22).

    Reporting group title
    CZP 200 mg Q2W/CZP 200 mg Q2W
    Reporting group description
    This arm consisted of participants initially randomized in the CZP 200 mg Q2W arm, who achieved a PASI50 response at Week 16 and continued to receive CZP 200 mg Q2W.

    Reporting group title
    CZP 400 mg Q2W/CZP 400 mg Q2W
    Reporting group description
    This arm consisted of participants initially randomized in the CZP 400 mg Q2W arm, who achieved a PASI50 response at Week 16 and continued to receive CZP 400 mg Q2W.

    Reporting group title
    Placebo/Escape CZP 400 mg Q2W
    Reporting group description
    This arm consisted of participants initially randomized in the Placebo arm, who did not achieve a PASI50 response at Week 16 escaped from the blinded treatment and received unblinded CZP 400 mg Q2W, for 16 weeks. Participants who did not achieve PASI50 after 16 weeks of unblinded treatment were withdrawn from the study.

    Reporting group title
    CZP 200 mg Q2W/Escape CZP 400 mg Q2W
    Reporting group description
    This arm consisted of participants initially randomized in the CZP 200 mg Q2W arm, who did not achieve a PASI50 response at Week 16 escaped from the blinded treatment and received CZP unblinded 400 mg Q2W, for 16 weeks. Participants who did not achieve PASI50 after 16 weeks of unblinded treatment were withdrawn from the study.

    Reporting group title
    CZP 400 mg Q2W/Escape CZP 400 mg Q2W
    Reporting group description
    This arm consisted of participants initially randomized in the CZP 400 mg Q2W arm, who did not achieve a PASI50 response at Week 16 escaped from the blinded treatment and received unblinded CZP 400 mg Q2W, for 16 weeks. Participants who did not achieve PASI50 after 16 weeks of unblinded treatment were withdrawn from the study.
    Reporting group title
    Placebo/CZP 200 mg Q2W OLE
    Reporting group description
    This arm consisted of participants who received dose-blind Placebo during the Maintenance Period, who achieved a PASI50 response at Week 48 and entered the OLE Period receiving CZP 200 mg Q2W.

    Reporting group title
    CZP 200 mg Q2W/CZP 200 mg Q2W OLE
    Reporting group description
    This arm consisted of participants who received blinded CZP 200mg Q2W in the Maintenance Period, who achieved a PASI50 response at Week 48 and entered OLE on the CZP 200mg Q2W dose.

    Reporting group title
    CZP 400 mg Q2W/CZP 200 mg Q2W OLE
    Reporting group description
    This arm consisted of participants who received blinded CZP 400mg Q2W in the Maintenance Period, who achieved a PASI50 response at Week 48, and entered OLE on the CZP 200mg Q2W dose.

    Reporting group title
    Escape CZP 400 mg Q2W/CZP 400 mg Q2W OLE
    Reporting group description
    This arm consisted of participants who received open-label CZP 400mg Q2W in the Maintenance Period and entered OLE on the CZP 400mg Q2W dose.

    Subject analysis set title
    Placebo Q2W (RS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo sc injection Q2W. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16, who did not achieve a PASI75 response at Week 16 received CZP 400 mg at Weeks 16, 18 and 20 (loading doses) followed by CZP 200 mg Q2W starting at Week 22. •PASI75 responders at Week 16 continued to receive Placebo. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the OLE Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W. Participants formed the Randomized Set (RS).

    Subject analysis set title
    CZP 200 mg Q2W (RS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    CZP 400 mg at Weeks 0, 2, 4, followed by CZP 200 mg Q2W from Week 6 to Week 14. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16 continued to receive CZP 200 mg Q2W. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the OLE Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W. Depending on PASI50 or PASI75 responses at Week 60 or a later time point, participants may have switched to CZP 400 mg Q2W or withdrew from the study. Participants formed the RS.

    Subject analysis set title
    CZP 400 mg Q2W (RS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    CZP 400 mg Q2W through Week 14. Treatment received from Week 16 - 48 was based on initial treatment and response to treatment: •PASI50 responders at Week 16 continued to receive CZP 400 mg Q2W. •PASI50 non-responders at Week 16 were removed from blinded study medication and escaped to unblinded CZP 400 mg Q2W. Participants who received unblinded CZP 400 mg Q2W for 16 weeks and did not achieve a PASI50 response were withdrawn from the study. •PASI50 non-responders at Week 32 or a later time point were withdrawn from the study. Participants who completed the Maintenance Period (with PASI50 response at Week 48) entered the OLE Period on CZP 200 mg Q2W. Week 48 completers in the escape arm continued to receive CZP 400 mg Q2W or may have switched to CZP 200 mg Q2W. Participants who achieved a PASI75 response during the OLE Period may have switched to CZP 200 mg Q2W. Participants formed the RS.

    Subject analysis set title
    CZP 200 mg Q2W (TCS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This arm consisted of all participants who received CZP 200 mg at any time during the study.

    Subject analysis set title
    CZP 400 mg Q2W (TCS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This arm consisted of all participants who received CZP 400 mg at any time during the study.

    Primary: Proportion of subjects who achieve a Psoriasis Activity and Severity Index (PASI75) response at Week 16

    Close Top of page
    End point title
    Proportion of subjects who achieve a Psoriasis Activity and Severity Index (PASI75) response at Week 16
    End point description
    The PASI75 response assessments are based on at least 75% improvement in the PASI score from Baseline. This is a scoring system that averages the redness, thickness, and scaliness of the psoriatic lesions (on a 0-4 scale), and weights the resulting score by the area of skin involved. Body divided into 4 areas: head, arms, trunk to groin, and legs to top of buttocks. Assignment of an average score for the redness, thickness, and scaling for each of the 4 body areas with a score of 0 (clear) to 4 (very marked). Determining the percentage of skin covered with PSO for each of the body areas and converting to a 0 to 6 scale. Final PASI= average redness, thickness, and scaliness of the psoriatic skin lesions, multiplied by the involved psoriasis area score of the respective section, and weighted by the percentage of the person’s affected skin for the respective section. The minimum possible PASI score is 0= no disease, the maximum score is 72= maximal disease.
    End point type
    Primary
    End point timeframe
    At Week 16
    End point values
    Placebo Q2W (RS) CZP 200 mg Q2W (RS) CZP 400 mg Q2W (RS)
    Number of subjects analysed
    51
    95
    88
    Units: percentage of participants
        number (not applicable)
    6.5
    66.5
    75.8
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 200 mg Q2W (RS)
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    28.962
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    6.968
         upper limit
    120.371
    Notes
    [1] - The p-value for the primary analysis was evaluated at a 2-sided significance level of 0.025 for each CZP dose versus (vs) PBO.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 400 mg Q2W (RS)
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    45.66
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    10.657
         upper limit
    195.634
    Notes
    [2] - The p-value for the primary analysis was evaluated at a 2-sided significance level of 0.025 for each CZP dose vs PBO.
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 200 mg Q2W (RS)
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Regression, Logistic
    Parameter type
    Estimated difference in responder rate
    Point estimate
    60
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    47.92
         upper limit
    72.17
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 400 mg Q2W (RS)
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Regression, Logistic
    Parameter type
    Estimated difference in responder rate
    Point estimate
    69.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    57.65
         upper limit
    80.99

    Primary: Proportion of subjects who achieve a Physician’s Global Assessment (PGA) Clear or Almost Clear (with at least 2-category improvement) response at Week 16

    Close Top of page
    End point title
    Proportion of subjects who achieve a Physician’s Global Assessment (PGA) Clear or Almost Clear (with at least 2-category improvement) response at Week 16
    End point description
    The Investigator assessed the overall severity of Psoriasis (PSO) using the following 5-point scale: 0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe.
    End point type
    Primary
    End point timeframe
    At Week 16
    End point values
    Placebo Q2W (RS) CZP 200 mg Q2W (RS) CZP 400 mg Q2W (RS)
    Number of subjects analysed
    51
    95
    88
    Units: percentage of participants
        number (not applicable)
    4.2
    47.0
    57.9
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 200 mg Q2W (RS)
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    20.116
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    3.699
         upper limit
    109.399
    Notes
    [3] - The p-value for the primary analysis was evaluated at a 2-sided significance level of 0.025 for each CZP dose vs PBO.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 400 mg Q2W (RS)
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    31.143
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    5.687
         upper limit
    170.548
    Notes
    [4] - The p-value for the primary analysis was evaluated at a 2-sided significance level of 0.025 for each CZP dose vs PBO.
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 200 mg Q2W (RS)
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Regression, Logistic
    Parameter type
    Estimated difference in responder rate
    Point estimate
    42.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    30.7
         upper limit
    54.86
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 400 mg Q2W (RS)
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Regression, Logistic
    Parameter type
    Estimated difference in responder rate
    Point estimate
    53.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    41.33
         upper limit
    65.94

    Secondary: Proportion of subjects who achieve a Psoriasis Activity and Severity Index (PASI90) response at Week 16

    Close Top of page
    End point title
    Proportion of subjects who achieve a Psoriasis Activity and Severity Index (PASI90) response at Week 16
    End point description
    The PASI90 response assessments are based on at least 90% improvement in the PASI score from Baseline. This is a scoring system that averages the redness, thickness, and scaliness of the psoriatic lesions (on a 0-4 scale), and weights the resulting score by the area of skin involved. Body divided into 4 areas: head, arms, trunk to groin, and legs to top of buttocks. Assignment of an average score for the redness, thickness, and scaling for each of the 4 body areas with a score of 0 (clear) to 4 (very marked). Determining the percentage of skin covered with PSO for each of the body areas and converting to a 0 to 6 scale. Final PASI= average redness, thickness, and scaliness of the psoriatic skin lesions, multiplied by the involved psoriasis area score of the respective section, and weighted by the percentage of the person’s affected skin for the respective section. The minimum possible PASI score is 0= no disease, the maximum score is 72= maximal disease.
    End point type
    Secondary
    End point timeframe
    At Week 16
    End point values
    Placebo Q2W (RS) CZP 200 mg Q2W (RS) CZP 400 mg Q2W (RS)
    Number of subjects analysed
    51
    95
    88
    Units: percentage of participants
        number (not applicable)
    0.4
    35.8
    43.6
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 200 mg Q2W (RS)
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    36.668
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    5.717
         upper limit
    235.193
    Notes
    [5] - The p-value for this analysis as used in the fixed sequence testing procedure was evaluated at a 2-sided significance level of 0.025 for each CZP dose vs PBO.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 400 mg Q2W (RS)
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    50.606
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    7.88
         upper limit
    324.988
    Notes
    [6] - The p-value for this analysis as used in the fixed sequence testing procedure was evaluated at a 2-sided significance level of 0.025 for each CZP dose vs PBO.
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 200 mg Q2W (RS)
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Regression, Logistic
    Parameter type
    Estimated difference in responder rate
    Point estimate
    35.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.85
         upper limit
    49.87
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 400 mg Q2W (RS)
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Regression, Logistic
    Parameter type
    Estimated difference in responder rate
    Point estimate
    43.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.56
         upper limit
    58.71

    Secondary: Change from Baseline in Dermatology Life Quality Index (DLQI) at Week 16

    Close Top of page
    End point title
    Change from Baseline in Dermatology Life Quality Index (DLQI) at Week 16
    End point description
    The DLQI is a subject-reported questionnaire designed for use in adult participants with PSO. The DLQI is a skin disease-specific questionnaire aimed at the evaluation of how symptoms and treatment affect patients’ health related quality of life (HRQoL). This instrument asks participants about symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. It has been shown to be valid and reproducible in PSO patients. The DLQI score ranges from 0 to 30 with higher scores indicating lower HRQoL. A higher than of equal to (>=) 4-point change in the DLQI score (DLQI response) has been reported to be meaningful for the patient (within-patient minimal important difference Basra et al, 2015) a DLQI absolute score of lower than or equal to (=<) 1 indicates DLQI remission (i.e., no or small impact of the disease on HRQoL).
    End point type
    Secondary
    End point timeframe
    At Week 16
    End point values
    Placebo Q2W (RS) CZP 200 mg Q2W (RS) CZP 400 mg Q2W (RS)
    Number of subjects analysed
    51
    95
    88
    Units: Scores on a scale
        least squares mean (standard error)
    -3.3 ± 0.80
    -9.3 ± 0.58
    -10.2 ± 0.60
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 200 mg Q2W (RS)
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [7]
    Method
    ANCOVA
    Parameter type
    Adjusted Mean Treatment Differences
    Point estimate
    -6
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -8.18
         upper limit
    -3.81
    Notes
    [7] - P-value obtained for each treatment group comparison tested at a significance level of 0.025 in the fixed sequence testing procedure.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    The statistical analysis of the co-primary efficacy variables and key secondary efficacy variables accounted for multiplicity by using a fixed sequence testing procedure.
    Comparison groups
    Placebo Q2W (RS) v CZP 400 mg Q2W (RS)
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    ANCOVA
    Parameter type
    Ajusted Mean Treatment Differences
    Point estimate
    -6.84
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -9.05
         upper limit
    -4.62
    Notes
    [8] - P-value obtained for each treatment group comparison tested at a significance level of 0.025 in the fixed sequence testing procedure.

    Secondary: Proportion of subjects who achieve a Physician’s Global Assessment (PGA) Clear or Almost Clear (with at least 2-category improvement) response at Week 48

    Close Top of page
    End point title
    Proportion of subjects who achieve a Physician’s Global Assessment (PGA) Clear or Almost Clear (with at least 2-category improvement) response at Week 48
    End point description
    The Investigator assessed the overall severity of Psoriasis (PSO) using the following 5-point scale: 0= clear, 1= almost clear, 2= mild, 3= moderate, 4= severe.
    End point type
    Secondary
    End point timeframe
    At Week 48
    End point values
    CZP 200 mg Q2W (RS) CZP 400 mg Q2W (RS)
    Number of subjects analysed
    95
    88
    Units: percentage of participants
        number (confidence interval 95%)
    52.7 (41.99 to 63.32)
    69.5 (59.24 to 79.77)
    No statistical analyses for this end point

    Secondary: Proportion of subjects who achieve a Psoriasis Activity and Severity Index (PASI75) response at Week 48

    Close Top of page
    End point title
    Proportion of subjects who achieve a Psoriasis Activity and Severity Index (PASI75) response at Week 48
    End point description
    The PASI75 response assessments are based on at least 75% improvement in the PASI score from Baseline. This is a scoring system that averages the redness, thickness, and scaliness of the psoriatic lesions (on a 0-4 scale), and weights the resulting score by the area of skin involved. Body divided into 4 areas: head, arms, trunk to groin, and legs to top of buttocks. Assignment of an average score for the redness, thickness, and scaling for each of the 4 body areas with a score of 0 (clear) to 4 (very marked). Determining the percentage of skin covered with PSO for each of the body areas and converting to a 0 to 6 scale. Final PASI= average redness, thickness, and scaliness of the psoriatic skin lesions, multiplied by the involved psoriasis area score of the respective section, and weighted by the percentage of the person’s affected skin for the respective section. The minimum possible PASI score is 0= no disease, the maximum score is 72= maximal disease.
    End point type
    Secondary
    End point timeframe
    At Week 48
    End point values
    CZP 200 mg Q2W (RS) CZP 400 mg Q2W (RS)
    Number of subjects analysed
    95
    88
    Units: percentage of participants
        number (confidence interval 95%)
    67.2 (57.09 to 77.39)
    87.1 (79.81 to 94.45)
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from Baseline (Week 0) until the Post Study Safety Follow-up Visit (Week 152).
    Adverse event reporting additional description
    Participants randomized to PBO switched to CZP 200mg Q2W or CZP 400mg Q2W at Week 16. Participants randomized to CZP were exposed for up to 144 weeks, leading to a significantly lower exposure in the PBO than CZP arm. Considering the imbalance of such comparison, AEs reported while participants were on PBO are not included in this summary.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    CZP 400 mg Q2W (TCS)
    Reporting group description
    This arm consisted of all participants who received CZP 400 mg at any time during the study.

    Reporting group title
    CZP 200 mg Q2W (TCS)
    Reporting group description
    This arm consisted of all participants who received CZP 200 mg at any time during the study.

    Serious adverse events
    CZP 400 mg Q2W (TCS) CZP 200 mg Q2W (TCS)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 167 (11.38%)
    14 / 188 (7.45%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Gastric bypass
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactoid reaction
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Strangulated hernia
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site reaction
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 167 (1.20%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic haematoma
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blepharochalasis
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cirrhosis alcoholic
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    1 / 167 (0.60%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyoderma gangrenosum
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle atrophy
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Borrelia infection
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected bite
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    CZP 400 mg Q2W (TCS) CZP 200 mg Q2W (TCS)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    85 / 167 (50.90%)
    95 / 188 (50.53%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 167 (8.38%)
    9 / 188 (4.79%)
         occurrences all number
    41
    18
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    5 / 167 (2.99%)
    9 / 188 (4.79%)
         occurrences all number
    5
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 167 (2.40%)
    14 / 188 (7.45%)
         occurrences all number
    5
    16
    Back pain
         subjects affected / exposed
    11 / 167 (6.59%)
    12 / 188 (6.38%)
         occurrences all number
    12
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    51 / 167 (30.54%)
    54 / 188 (28.72%)
         occurrences all number
    95
    86
    Upper respiratory tract infection
         subjects affected / exposed
    26 / 167 (15.57%)
    21 / 188 (11.17%)
         occurrences all number
    42
    28

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Nov 2015
    The Global Protocol Amendment 1 included the following changes: -CIMPASI-1 (name of the PS0005 protocol) was added. -Updated study contact information and serious adverse event (SAE) reporting contact information. -Added the secondary efficacy variable: at least 90% reduction from Baseline in PASI (PASI90). -Removed the other efficacy variables: absolute PASI score and absolute body surface area (BSA) affected by PSO. -Corrected: the Subject Questionnaire for Tuberculosis (TB) was removed as a safety variable. -Clarified the responsibilities of the unblinded and blinded study personnel. -Provided additional details regarding breaking the treatment blind in an emergency situation. -Revised Exclusion Criteria number (#) 21 to add secukinumab and require a 24-week washout period. -Allowed flexibility of self-administration of certolizumab pegol (CZP) during the Open-label Treatment Period. -Corrected: subject treatment assignment was stratified by site.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/29660421
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA