Study of Apremilast to Treat Subjects With Active Ankylosing Spondylitis

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Ankylosing Spondyloarthritis

Intervention / Treatment
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* Drug: Apremilast tablet 20 mg
* Drug: Apremilast tablet 30 mg BID
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apremilast 20 mg<br>Apremilast 20 mg was taken orally twice a day (BID) | Drug: Apremilast tablet 20 mg<br>* Apremilast 20 mg was taken orally twice a day (BID)<br>* Other names: Otezla; CC-10004;|
| Experimental: Apremilast 30 mg<br>Apremilast 30 mg was taken orally twice a day | Drug: Apremilast tablet 30 mg BID<br>* Apremilast 30 mg was taken orally twice a day<br>* Other names: Otezla; CC-10004;|
| Placebo Comparator: Placebo<br>Identically matched placebo tablets were taken orally twice a day | Drug: Placebo<br>* Identically matched placebo tablets were taken orally twice a day during the placebo controlled phase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved an Assessment of SpondyloArthritis International Society 20 (ASAS 20) Response at 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: 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 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 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 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) | Baseline and Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at 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. | Baseline and Week 24 | 
| Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at 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. | Baseline and Week 24 | 
| Percentage of Participants Who Achieved an Assessment of SpondyloArthritis International Society 20 (ASAS) Response at 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: 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 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 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 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) | Baseline and Week 24 | 
| Change From Baseline in the Ankylosing Spondylitis Quality of Life (ASQoL) Summary Score at 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. | Baseline and Week 24 | 
| 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 | 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 | Baseline and Week 24 | 
| Change From Baseline in Bath Ankylosing Spondylitis Metrology Index-Linear (BASMI-Linear) at 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. | Baseline and Week 24 | 
| Change From Baseline in the Radiographic Score Using the Modified Stoke Ankylosing Spondylitis Spine Score (m-SASSS) at Week 104 and Week 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. | Baseline to Week 104 and 260 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Phase | 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. | 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. | 
| Number of Participants With Treatment Emergent Adverse Events During the Apremilast Exposure Period | 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. | Week 0 to week 260; overall mean duration of exposure to apremilast 20 mg and 30 mg BID was 160.96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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spondylitis, spondyloarthritis, Spondyloarthropathy, Oral preparation