Certolizumab Pegol in Subjects With Active Axial Spondyloarthritis

• ClinicalTrials.gov Identifier: NCT01087762
• Recruitment Status: Completed
• First Posted: March 16, 2010
• Results First Posted: December 25, 2013
• Last Update Posted: August 1, 2018
• Sponsor: UCB BIOSCIENCES GmbH
• Information provided by (Responsible Party): UCB Pharma ( UCB BIOSCIENCES GmbH )

Tracking Information

• First Submitted Date: March 15, 2010
• First Posted Date: March 16, 2010
• Results First Submitted Date: November 6, 2013
• Results First Posted Date: December 25, 2013
• Last Update Posted Date: August 1, 2018
• Study Start Date: March 2010
• Actual Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 9, 2012)

Assessment in Axial Spondyloarthritis International Society 20 % (ASAS20) Response Criteria at Week 12 [ Time Frame: Week 12 ]

The ASAS20 is defined as an improvement of at least 20 % and absolute improvement of at least 1 unit on a 0 to 10 Numeric Rating Scale (NRS) in at least 3 of the 4 following domains:

• Patient's Global Assessment of Disease Activity
• Pain assessment (total spinal pain)
• Function (represented by Bath Ankylosing Spondylitis Functional Index (BASFI))
• Inflammation (the mean of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) questions 5 and 6 concerning morning stiffness intensity and duration)

and absence of deterioration in the potential remaining domain (deterioration is defined as a relative worsening of at least 20 % and an absolute worsening of at least 1 unit).

• Original Primary Outcome Measures (submitted: March 15, 2010): Assessment in Ankylosing Spondylitis Response Criteria (ASAS20) response [ Time Frame: Week 12 ]

Current Secondary Outcome Measures (submitted: November 6, 2013)

• Assessment in Axial Spondyloarthritis International Society 20 % (ASAS20) Response Criteria at Week 24 [ Time Frame: Week 24 ]
  The ASAS20 is defined as an improvement of at least 20 % and absolute improvement of at least 1 unit on a 0 to 10 Numeric Rating Scale (NRS) in at least 3 of the 4 following domains:

  • Patient's Global Assessment of Disease Activity
  • Pain assessment (total spinal pain)
  • Function (represented by Bath Ankylosing Spondylitis Functional Index (BASFI))
  • Inflammation (the mean of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) questions 5 and 6 concerning morning stiffness intensity and duration)

  and absence of deterioration in the potential remaining domain (deterioration is defined as a relative worsening of at least 20 % and an absolute worsening of at least 1 unit).
• Change From Baseline in the Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 12 [ Time Frame: From Baseline to Week 12 ]
  The BASFI assesses physical function in comprising 10 items relating to activities during the past week. Each item ranges from 0 ("Easy") to 10 ("Impossible"). The BASFI is the mean of the 10 scores such that the total score ranges from 0 to 10, with lower scores indicating better physical function. A negative value in BASFI change from Baseline indicates an improvement from Baseline. The higher the negative value the better the improvement.
• Change From Baseline in the Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 24 [ Time Frame: From Baseline to Week 24 ]
  The BASFI assesses physical function in comprising 10 items relating to activities during the past week. Each item ranges from 0 ("Easy") to 10 ("Impossible"). The BASFI is the mean of the 10 scores such that the total score ranges from 0 to 10, with lower scores indicating better physical function. A negative value in BASFI change from Baseline indicates an improvement from Baseline. The higher the negative value the better the improvement.
• Change From Baseline in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 12 [ Time Frame: From Baseline to Week 12 ]
  The BASDAI is a validated self-reported instrument which consists of six 10 unit horizontal Numerical Rating Scales (NRSs) to measure severity of fatigue, spinal and peripheral joint pain and swelling, enthesitis, and morning stiffness (both severity and duration, respectively) over the last week. The final BASDAI score ranges from 0 to 10, with lower scores indicating lower disease activity. A negative value in BASDAI change from Baseline indicates an improvement from Baseline. The higher the negative value the better the improvement.
• Change From Baseline in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 24 [ Time Frame: From Baseline to Week 24 ]
  The BASDAI is a validated self-reported instrument which consists of six 10 unit horizontal Numerical Rating Scales (NRSs) to measure severity of fatigue, spinal and peripheral joint pain and swelling, enthesitis, and morning stiffness (both severity and duration, respectively) over the last week. The final BASDAI score ranges from 0 to 10, with lower scores indicating lower disease activity. A negative value in BASDAI change from Baseline indicates an improvement from Baseline. The higher the negative value the better the improvement.
• Change From Baseline in the Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 12 [ Time Frame: From Baseline to Week 12 ]
  The BASMI characterizes the spinal mobility of subjects with axial Spondyloarthritis (SpA) and Ankylosing Spondylitis (AS). It is a disease-specific measure consisting of 5 clinical measures to reflect subject axial status: cervical rotation; tragus to wall distance; lateral lumbar flexion; lumbar flexion (modified Schober test); intermalleolar distance. According to the linear definition of the BASMI a score of 0 to 10 is calculated for each item based on the measurement. The mean of the sum of the 5 scores provides the BASMI score. The higher the BASMI score the more severe the patient's limitation of movement due to their axial SpA. A negative value in BASMI change from Baseline indicates an improvement from Baseline. The higher the negative value the better the improvement.
• Change From Baseline in the Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 24 [ Time Frame: From Baseline to Week 24 ]
  The BASMI characterizes the spinal mobility of subjects with axial SpA and AS. It is a disease-specific measure consisting of 5 clinical measures to reflect subject axial status: cervical rotation; tragus to wall distance; lateral lumbar flexion; lumbar flexion (modified Schober test); intermalleolar distance. According to the linear definition of the BASMI a score of 0 to 10 is calculated for each item based on the measurement. The mean of the sum of the 5 scores provides the BASMI score. The higher the BASMI score the more severe the patient's limitation of movement due to their axial SpA. A negative value in BASMI change from Baseline indicates an improvement from Baseline. The higher the negative value the better the improvement.
• Change From Baseline in the Spine Ankylosing Spondylitis Spine Magnetic Resonance Imaging (MRI) Scoring System for Disease Activity (ASspiMRI-a) in the Berlin Modification at Week 12 [ Time Frame: From Baseline to Week 12 ]
  The Berlin modification of the ASspiMRI-a is a scoring system with a concentration on Short-Tau-Inversion Recovery (STIR) sequences without other fat saturation techniques. It quantifies changes in 23 Vertebral Units (VU) of the spine. A VU is defined as the region between 2 virtual lines through the middle of each vertebra. Active inflammation is scored by grading the degree of bone marrow edema from 0 to 3 in 1 dimension on 1 or more consecutive slices that represent the highest level of inflammation in a particular VU. Total spine ASspiMRI-a score in the Berlin modification can range from 0 to 69 with higher scores indicating higher disease activity. A negative value in total spine ASspiMRI-a score change from Baseline indicates an improvement from Baseline. The higher the negative value the higher the reduction of inflammation.
• Change From Baseline in Sacroiliac Spondyloarthritis Research Consortium of Canada (SPARCC) Score at Week 12 [ Time Frame: From Baseline to Week 12 ]
  The SPARCC scoring method for lesions found on the Magnetic Resonance Imaging (MRI) is based on an abnormal increased signal on the Short-Tau-Inversion Recovery (STIR) sequence, representing bone marrow edema. Total Sacroiliac (SI) joint SPARCC score can range from 0 to 72 with higher scores indicating higher joint inflammation. A negative value in SPARCC change from Baseline indicates an improvement from Baseline. The higher the negative value the higher the reduction of inflammation.

Original Secondary Outcome Measures (submitted: March 15, 2010)

• Assessment in Ankylosing Spondylitis Response Criteria (ASAS20) response [ Time Frame: Week 24 ]
• Change from Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) [ Time Frame: Week 12, Week 24 ]
• Change from Baseline in Spondyloarthritis Research Consortium of Canada (SPARCC) spine score [ Time Frame: Week 12 ]
• Change from Baseline in sacroiliac (SPARCC) score [ Time Frame: Week 12 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Certolizumab Pegol in Subjects With Active Axial Spondyloarthritis
• Official Title: Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Efficacy and Safety of Certolizumab Pegol in Subjects With Active Axial Spondyloarthritis
• Brief Summary: The study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of two dose regimens of Certolizumab Pegol (CZP) in subjects with active axial Spondyloarthritis (axial SpA).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Spondyloarthropathies

Intervention

• Biological: CZP 200 mg Q2W
  200 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 2 weeks (Q2W).
  Other Names:

  • Cimzia
  • CZP
  • Certolizumab Pegol
• Biological: CZP 400 mg Q4W
  400 mg subcutaneous (sc) injection of Certolizumab Pegol (CZP) every 4 weeks (Q4W).
  Other Names:

  • Cimzia
  • CZP
  • Certolizumab Pegol
• Other: Placebo
  Matching Placebo to CZP injection.

Study Arms

• Experimental: CZP 200 mg Q2W

  Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards.

  At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

  Interventions:

  • Biological: CZP 200 mg Q2W
  • Other: Placebo
• Experimental: CZP 400 mg Q4W

  Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards.

  Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.

  Interventions:

  • Biological: CZP 400 mg Q4W
  • Other: Placebo
• Placebo Comparator: Placebo

  Matching Placebo to CZP injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group on Week 16.

  After 24 weeks, all subjects were randomized to active treatment with CZP 200 mg Q2W or CZP 400 mg Q4W.

  Intervention: Other: Placebo
• Placebo to CZP 200 mg escape on Week 16
  Matching Placebo to CZP injections from Week 0 to Week 16. Subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group on Week 16 and were treated with three loading doses of CZP 400 mg sc on Weeks 16, 18 and 20, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 22 onwards. Additionally, Placebo injections were administered as appropriate in order to maintain the study blind.
  Interventions:

  • Biological: CZP 200 mg Q2W
  • Other: Placebo
• Placebo to CZP 400 mg escape on Week 16
  Matching Placebo to CZP injections from Week 0 to Week 16. Subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group on Week 16 and were treated with three loading doses of CZP 400 mg sc on Weeks 16, 18 and 20, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 24 onwards. Additionally, Placebo injections were administered as appropriate in order to maintain the study blind.
  Interventions:

  • Biological: CZP 400 mg Q4W
  • Other: Placebo
• Placebo to CZP 200 mg on Week 24
  Matching Placebo to CZP injections from Week 0 to Week 24. Three loading doses of CZP 400 mg sc were given on Weeks 24, 26 and 28, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 30 onwards. Additionally, Placebo injections were administered as appropriate in order to maintain the study blind.
  Interventions:

  • Biological: CZP 200 mg Q2W
  • Other: Placebo
• Placebo to CZP 400 mg on Week 24
  Matching Placebo to CZP injections from Week 0 to Week 24. Three loading doses of CZP 400 mg sc were given on Weeks 24, 26 and 28, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 32 onwards. Additionally, Placebo injections were administered as appropriate in order to maintain the study blind.
  Interventions:

  • Biological: CZP 400 mg Q4W
  • Other: Placebo

Publications *

• Landewé R, Braun J, Deodhar A, Dougados M, Maksymowych WP, Mease PJ, Reveille JD, Rudwaleit M, van der Heijde D, Stach C, Hoepken B, Fichtner A, Coteur G, de Longueville M, Sieper J. Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study. Ann Rheum Dis. 2014 Jan;73(1):39-47. doi: 10.1136/annrheumdis-2013-204231. Epub 2013 Sep 6.
• Landewé R, Nurminen T, Davies O, Baeten D. A single determination of C-reactive protein does not suffice to declare a patient with a diagnosis of axial spondyloarthritis 'CRP-negative'. Arthritis Res Ther. 2018 Sep 14;20(1):209. doi: 10.1186/s13075-018-1707-8.
• van der Heijde D, Dougados M, Landewé R, Sieper J, Maksymowych WP, Rudwaleit M, Van den Bosch F, Braun J, Mease PJ, Kivitz AJ, Walsh J, Davies O, Bauer L, Hoepken B, Peterson L, Deodhar A. Sustained efficacy, safety and patient-reported outcomes of certolizumab pegol in axial spondyloarthritis: 4-year outcomes from RAPID-axSpA. Rheumatology (Oxford). 2017 Sep 1;56(9):1498-1509. doi: 10.1093/rheumatology/kex174.
• van der Heijde D, Deodhar A, Fleischmann R, Mease PJ, Rudwaleit M, Nurminen T, Davies O. Early Disease Activity or Clinical Response as Predictors of Long-Term Outcomes With Certolizumab Pegol in Axial Spondyloarthritis or Psoriatic Arthritis. Arthritis Care Res (Hoboken). 2017 Jul;69(7):1030-1039. doi: 10.1002/acr.23092. Epub 2017 Jun 2.
• Rudwaleit M, Rosenbaum JT, Landewé R, Marzo-Ortega H, Sieper J, van der Heijde D, Davies O, Bartz H, Hoepken B, Nurminen T, Deodhar A. Observed Incidence of Uveitis Following Certolizumab Pegol Treatment in Patients With Axial Spondyloarthritis. Arthritis Care Res (Hoboken). 2016 Jun;68(6):838-44. doi: 10.1002/acr.22848.
• Sieper J, Kivitz A, van Tubergen A, Deodhar A, Coteur G, Woltering F, Landewé R. Impact of Certolizumab Pegol on Patient-Reported Outcomes in Patients With Axial Spondyloarthritis. Arthritis Care Res (Hoboken). 2015 Oct;67(10):1475-80. doi: 10.1002/acr.22594.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 21, 2012): 325
• Original Estimated Enrollment (submitted: March 15, 2010): 315
• Actual Study Completion Date: August 2015
• Actual Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Documented diagnosis of adult-onset axial Spondyloarthritis (SpA) of at least 3 months' duration as defined by the specified Assessment of Spondyloarthritis International Society (ASAS) criteria

• Active disease as defined by:

  • Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4
  • Back pain ≥ 4 on a 0 to 10 Neurobehavioral Rating Scale (NRS) (from BASDAI item 2)
  • C-Reactive Protein (CRP) > ULN (Upper Limit of Normal) and/or current evidence (ie, within the last 3 months from Screening) for Sacroiliitis on Magnetic Resonance Imaging (MRI) as defined by Assessment of Spondyloarthritis International Society (ASAS) criteria
• Intolerance to or inadequate response to at least 1 Nonsteroidal Anti-Inflammatory Drug (NSAID)

Exclusion Criteria:

• Presence of total Spinal Ankylosis ("bamboo spine")
• Diagnosis of any other Inflammatory Arthritis
• Prior treatment with any experimental biological agents for treatment of Axial Spondyloarthritis (SpA)
• Exposure to more than 1 TNF-antagonist or to more than 2 previous biological agents for Axial Spondyloarthritis (SpA)
• History of or current chronic or recurrent infections
• High risk of infection
• Recent live vaccination
• Concurrent malignancy or a history of malignancy
• Class III or IV congestive heart failure - New York Heart Association (NYHA)
• Demyelinating disease of the central nervous system
• Female subjects who are breastfeeding, pregnant or plan to become pregnant during the study or within 3 months following the last dose of the investigational product
• Subjects with any other condition which, in the investigator's judgment, would make the subject unsuitable for inclusion in the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Belgium, Brazil, Canada, Czechia, France, Germany, Hungary, Italy, Mexico, Netherlands, Poland, Spain, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01087762
• Other Study ID Numbers: AS001; 2009-011719-19 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: UCB Pharma ( UCB BIOSCIENCES GmbH )
• Study Sponsor: UCB BIOSCIENCES GmbH
• Collaborators: Not Provided

Investigators

• Study Director: UCB Clinical Trial Call Center; +1 877 822 9493 UCB

• PRS Account: UCB Pharma
• Verification Date: November 2016