Study of Apremilast to Treat Subjects With Active Ankylosing Spondylitis (POSTURE)

• ClinicalTrials.gov Identifier: NCT01583374
• Recruitment Status: Completed
• First Posted: April 24, 2012
• Results First Posted: March 17, 2015
• Last Update Posted: May 12, 2020
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Tracking Information

• First Submitted Date: April 20, 2012
• First Posted Date: April 24, 2012
• Results First Submitted Date: February 24, 2015
• Results First Posted Date: March 17, 2015
• Last Update Posted Date: May 12, 2020
• Actual Study Start Date: May 2, 2012
• Actual Primary Completion Date: February 24, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 25, 2019)

Percentage of Participants Who Achieved an Assessment of SpondyloArthritis International Society 20 (ASAS 20) Response at Week 16 [ Time Frame: Baseline and Week 16 ]

ASAS 20 was defined as achieving an improvement from baseline of ≥ 20% and ≥ 1 unit in at least 3 of 4 ASAS domains on a scale of 0 to 10 units and no worsening from baseline of ≥ 20% and ≥ 1 unit in the remaining ASAS domain on a scale of 0 to 10 units. The 4 ASAS domains are:

1. Patient Global Assessment of Disease (0 - 10 unit Numerical Rating Scale [NRS]); participant marks a box with an X on a 0 - 10 unit NRS; the left-hand box of 0 = not active and the right-hand box = very active
2. Total Back Pain (0 to 10 unit NRS); participant marks a box with an X on a 0 - 10 unit NRS; the left-hand box of 0 = "no pain" and the right-hand box = "most severe pain"
3. Function (Bath AS Functional Index [BASFI] NRS 0 - 10 unit); participant provides a self-administered survey of 10 questions assessing for degree of mobility and functional ability
4. Inflammation domain is determined by the mean of 2 Bath AS Disease Activity Index NRS Questions #5 and #6 for morning stiffness) (0 - 10 unit)

Original Primary Outcome Measures (submitted: April 23, 2012)

Assessment in Ankylosing Spondylitis (ASAS 20) [ Time Frame: Up to 16 weeks ]

ASAS 20 at Wk 16

Current Secondary Outcome Measures (submitted: October 25, 2019)

• Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 24 [ Time Frame: Baseline and Week 24 ]
  The BASFI is a composite score based on a self-administered survey of 10 questions using a 0 to 10 unit numerical rating scale (NRS) that assesses the degree of mobility and functional ability. The survey consists of 8 questions regarding function in AS and the last 2 reflect the ability to manage everyday life. The patient marks a box with an X on a 0 to 10 unit NRS for 10 questions; the left-hand box of 0 = easy; the right-hand box = impossible. The resulting 0 to 100 score is divided by 10 to give a final 0 to 10 BASFI score. The overall score is the mean of the 10 items and ranges from 0 to 10. A higher score correlates to reduced functional ability.
• Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 24 [ Time Frame: Baseline and Week 24 ]
  The BASDAI is a composite score based on a participant self-administered survey of six questions measured using a 0 to 10 unit numerical rating scale (NRS) that assessed the participants' five major symptoms of AS: 1) fatigue; 2) spinal pain; 3) peripheral joint pain/swelling; 4) areas of localized tenderness; 5a) morning stiffness severity upon wakening; 5b) morning stiffness duration upon wakening. The participant was asked to mark the box with an X on a 0 to 10 unit NRS for each of the 6 questions. To give each of the five symptoms equal weighting, the mean of the two scores relating to morning stiffness was taken. The resulting 0 to 50 score was divided by 5 to give a final 0 to 10 BASDAI score. A BASDAI score of 4 or greater was considered to be indicative of active AS disease.
• Percentage of Participants Who Achieved an Assessment of SpondyloArthritis International Society 20 (ASAS) Response at Week 24 [ Time Frame: Baseline and Week 24 ]
  ASAS 20 was defined as achieving an improvement from baseline of ≥ 20% and ≥ 1 unit in at least 3 of 4 ASAS domains on a scale of 0 to 10 units and no worsening from baseline of ≥ 20% and ≥ 1 unit in the remaining ASAS domain on a scale of 0 to 10 units. The 4 ASAS domains are:

  1. Patient Global Assessment of Disease (0 - 10 unit Numerical Rating Scale [NRS]); participant marks a box with an X on a 0 - 10 unit NRS; the left-hand box of 0 = not active and the right-hand box = very active
  2. Total Back Pain (0 to 10 unit NRS); participant marks a box with an X on a 0 - 10 unit NRS; the left-hand box of 0 = "no pain" and the right-hand box = "most severe pain"
  3. Function (Bath AS Functional Index [BASFI] NRS 0 - 10 unit); participant provides a self-administered survey of 10 questions assessing for degree of mobility and functional ability
  4. Inflammation domain is determined by the mean of 2 Bath AS Disease Activity Index NRS Questions #5 and #6 for morning stiffness) (0 - 10 unit)
• Change From Baseline in the Ankylosing Spondylitis Quality of Life (ASQoL) Summary Score at Week 24 [ Time Frame: Baseline and Week 24 ]
  The ASQoL is a validated disease specific patient reported outcomes instrument to assess the impact of ankylosing spondylitis on the quality of life of individuals with emphasis on the ability of the person to fulfill his or her needs. It consisted of 18 items requesting a yes (score=1) or no (score=0) response to questions related to the impact of pain on sleep, mood, motivation, ability to cope, activities of daily living, independence, relationships, and social life. The summary score ranges 0-18 with higher scores indicating worse quality of life.
• Change From Baseline in the Physical Component Summary Score (PCS) of Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) at Week 24 [ Time Frame: Baseline and Week 24 ]
  The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) was a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Norm-based scores (based on US general population with mean of 50 and standard deviation of 10) were used in analyses. Higher scores indicate a higher level of functioning. The PCS encompasses physical functioning, role-physical, and bodily pain, as well as general health and vitality. A positive change from baseline score indicates an improvement
• Change From Baseline in Bath Ankylosing Spondylitis Metrology Index-Linear (BASMI-Linear) at Week 24 [ Time Frame: Baseline and Week 24 ]
  The BASMI-Linear was designed to assess axial status (ie, cervical, dorsal and lumbar spine, hips, and pelvic soft tissue) and to define clinically significant changes in spinal movement. Five dimensions of movement (lateral lumbar flexion, tragus to wall, forward lumbar flexion, maximal intermalleolar distance, and cervical rotation) were measured and normalized on 0 to 10 unit NRS. The average of these scores was the total BASMI score, ranging from 0-10 with higher values indicating more severe limitation in spinal mobility.
• Change From Baseline in the Radiographic Score Using the Modified Stoke Ankylosing Spondylitis Spine Score (m-SASSS) at Week 104 and Week 260 [ Time Frame: Baseline to Week 104 and 260 ]
  The Modified Stoke Ankylosing Spondylitis Spine Score is a scoring method used to determine the amount or degree of ankylosing spondylitis disease that is in the spine based on x-ray radiographs of the spine. The m-SASSS scores 0-3. 0 = No abnormality, 1 = Erosion, Sclerosis or Squaring, 2 = Syndesmophyte, 3 = Total bony Bridging at each Site. An increase in the m-SASSS indicated a worsening of AS disease.
• Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Phase [ Time Frame: From Week 0 to Week 24; the median duration of exposure was 23.57 weeks for the placebo arm, 23.71 weeks for the apremilast 20 mg arm and 24.00 weeks for the apremilast 30 mg arm. ]
  A TEAE was an adverse event (AE) with a start date on or after the date of the first dose of IP and no later than 28 days after the last dose of IP for participants who discontinued early. A serious AE = results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect; or constitutes an important medical event. The severity of AEs was assessed based on the following scale: Mild = asymptomatic or mild symptoms, clinical or diagnostic observations only; Moderate = symptoms cause moderate discomfort; Severe = symptoms causing severe pain discomfort.
• Number of Participants With Treatment Emergent Adverse Events During the Apremilast Exposure Period [ Time Frame: Week 0 to week 260; overall mean duration of exposure to apremilast 20 mg and 30 mg BID was 160.96 weeks ]
  A TEAE was an adverse event (AE) with a start date on or after the date of the first dose of IP and no later than 28 days after the last dose of IP for participants who discontinued early. A serious AE = results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect; or constitutes an important medical event. The severity of AEs was assessed based on the following scale: Mild = asymptomatic or mild symptoms, clinical or diagnostic observations only; Moderate = symptoms cause moderate discomfort; Severe = symptoms causing severe pain discomfort.

Original Secondary Outcome Measures (submitted: April 23, 2012)

• Change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) [ Time Frame: Up to 24 weeks ]
  Change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI)
• Change from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [ Time Frame: Up to 24 weeks ]
  Change from baseline in Bath Ankylosing Spondylitis Disease Activity Index(BASDAI)
• Assessment in Ankylosing Spondylitis (ASAS 20) [ Time Frame: Up to 24 weeks ]
  Assessment in Ankylosing Spondylitis (ASAS 20)
• Change from baseline in the Physical Component Summary score (PCS) of Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) [ Time Frame: Up to 24 weeks ]
  Change from baseline in the Physical Component Summary score (PCS) of Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36)
• Change from baseline in Bath Ankylosing Spondylitis Metrology Index-linear (BASMI-lin) [ Time Frame: Up to 24 weeks ]
  Change from baseline in Bath Ankylosing Spondylitis Metrology Index-linear (BASMI-lin)

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

Descriptive Information

• Brief Title: Study of Apremilast to Treat Subjects With Active Ankylosing Spondylitis
• Official Title: A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF APREMILAST (CC-10004) IN THE TREATMENT OF ACTIVE ANKYLOSING SPONDYLITIS
• Brief Summary: Apremilast is a new, orally available, small molecule drug that specifically inhibits phosphodiesterase 4 (PDE4), an enzyme that modulates inflammatory cytokines. This clinical study tests whether apremilast can improve the signs and symptoms of ankylosing spondylitis.
• Detailed Description: Patients were randomized in a 1:1:1 ratio to placebo, apremilast 20 mg BID and apremilast 30 mg BID. The duration of the study was approximately 5 years. The double blind period (when patients nor the physician knew whether placebo or apremilast was taken) was 24 weeks. At Week 16, participants who did not have either a ≥ 20% improvement or a ≥ 1 unit improvement from baseline in at least two of the four SpondyloArthritis international Society (ASAS) domains were entered in "early escape" from their current treatment in a double-blinded manner. However, such participants were permitted to continue in the study. At Week 24, participants may have entered a long-term extension phase for up to an additional 4.5 years (236 weeks). At "second escape" (at Week 24), apremilast 20 mg BID treated participants transitioned to receive double-blinded apremilast 30 mg BID and remained on double-blinded apremilast 30 mg BID because they continued to improve with a longer duration of treatment. After Week 24 and during the early portion of the long-term extension through Week 52, all participants continued on either double-blinded apremilast 20 mg BID or 30 mg BID treatment. After all participants had completed Week 52 or had terminated early from the study and the 52-week data base was locked, apremilast 20 mg BID or 30 mg BID treatment was provided.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Ankylosing Spondyloarthritis

Intervention

• Drug: Apremilast tablet 20 mg
  Apremilast 20 mg was taken orally twice a day (BID)
  Other Name: Otezla; CC-10004
• Drug: Apremilast tablet 30 mg BID
  Apremilast 30 mg was taken orally twice a day
  Other Name: Otezla; CC-10004
• Drug: Placebo
  Identically matched placebo tablets were taken orally twice a day during the placebo controlled phase.

Study Arms

• Experimental: Apremilast 20 mg
  Apremilast 20 mg was taken orally twice a day (BID)
  Intervention: Drug: Apremilast tablet 20 mg
• Experimental: Apremilast 30 mg
  Apremilast 30 mg was taken orally twice a day
  Intervention: Drug: Apremilast tablet 30 mg BID
• Placebo Comparator: Placebo
  Identically matched placebo tablets were taken orally twice a day
  Intervention: Drug: Placebo

Publications *

• Gladman DD, Kavanaugh A, Gómez-Reino JJ, Wollenhaupt J, Cutolo M, Schett G, Lespessailles E, Guerette B, Delev N, Teng L, Edwards CJ, Birbara CA, Mease PJ. Therapeutic benefit of apremilast on enthesitis and dactylitis in patients with psoriatic arthritis: a pooled analysis of the PALACE 1-3 studies. RMD Open. 2018 Jun 27;4(1):e000669. doi: 10.1136/rmdopen-2018-000669. eCollection 2018.
• Kavanaugh A, Gladman DD, Edwards CJ, Schett G, Guerette B, Delev N, Teng L, Paris M, Mease PJ. Long-term experience with apremilast in patients with psoriatic arthritis: 5-year results from a PALACE 1-3 pooled analysis. Arthritis Res Ther. 2019 May 10;21(1):118. doi: 10.1186/s13075-019-1901-3.
• Taylor PC, van der Heijde D, Landewé R, McCue S, Cheng S, Boonen A. A Phase III Randomized Study of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, for Active Ankylosing Spondylitis. J Rheumatol. 2021 Aug;48(8):1259-1267. doi: 10.3899/jrheum.201088. Epub 2021 Feb 15.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 24, 2016): 490
• Original Estimated Enrollment (submitted: April 23, 2012): 456
• Actual Study Completion Date: October 25, 2018
• Actual Primary Completion Date: February 24, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Must have a documented diagnosis of ankylosing spondylitis as defined by low back pain and stiffness, which improves with exercise, but is not relieved by rest for more than 3 months prior to screening. At the completion of screening procedures, a documented diagnosis of definite active AS, as defined by the modified New York criteria (1984) whereby both criteria, at least 1 radiographic criterion and at least 1 clinical criterion, must be met
• Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is ≥ 4
• Total back pain is ≥ 4
• On stable dose of AS medication (or lack of medication) prior to randomization and through week 24

Exclusion Criteria:

- Prior treatment with a Tumor Necrosis Factor (TNF) blocker and any biologic treatment for AS

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: Australia, Austria, Bulgaria, Canada, Czechia, Estonia, France, Germany, Hungary, Netherlands, Poland, Romania, Russian Federation, Slovakia, Spain, Sweden, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01583374
• Other Study ID Numbers: CC-10004-AS-001; 2011-001555-37 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
• URL: http://www.amgen.com/datasharing

• Responsible Party: Amgen
• Study Sponsor: Amgen
• Collaborators: Not Provided

Investigators

• Study Director: MD; Amgen

• PRS Account: Amgen
• Verification Date: October 2019