Symptoms and General Pathology

All Conditions

Infections

Musculoskeletal Diseases

Rare Diseases

Necrosis

Spondylitis

Spondylarthritis

Spondylitis, Ankylosing

Communicable Diseases

Bone Diseases

Bone Diseases, Infectious

Spinal Diseases

Arthritis

Joint Diseases

Axial Spondyloarthritis

Spondylarthropathies

Ankylosis

Spondylarthropathy

All Drugs and Chemicals

Anti-Inflammatory Agents

Antirheumatic Agents

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Adalimumab

Tumor Necrosis Factor Inhibitors

Adalimumab 40 mg every other week, subcutaneous

adalimumab (D2E7)

placebo

Laura Redden, MD, PhD

The objective of this study was to evaluate the safety and efficacy of adalimumab 40 mg given every other week (eow) in subjects with active ankylosing spondylitis (AS) who have had an inadequate response to, or who are intolerant to, treatment with at least 1 nonsteroidal anti-inflammatory drug (NSAID) and who may have also failed treatment with at least 1 disease-modifying antirheumatic drug (DMARD).

Human Anti-tumor Necrosis Factor (TNF) Monoclonal Antibody Adalimumab in Subjects With Active Ankylosing Spondylitis

A Phase 3 Multicenter Study of the Safety and Efficacy of the Human Anti-TNF Monoclonal Antibody Adalimumab in Subjects With Active Ankylosing Spondylitis

ASAS 20 responders - improvement of \>=20% and absolute improvement of \>=10 units from Baseline in a visual analog scale (VAS) for \>=3 of 4 domains; Patient's Global Assessment of disease activity VAS (0 \[none\]-100 \[severe\]), Total Back Pain VAS (0 \[no pain\]-100 \[severe\]), BASFI VAS (0 \[easy\]-100\[impossible\]); and Inflammation VAS (0 \[none\]-10 \[very severe\]) and absence of deterioration in the potential remaining domain, defined as a worsening of \>=20% and a net worsening of \>=10 units. Applied to each scale and not to an overall global scale.

Radiographic progression was based on change in mSASSS scoring (comparison of the means) from double-blind Baseline visit to Week 104. The mSASSS is the sum of the lumbar and cervical spine score ( 0 \[no change\] to 72 \[progression\]), derived from scoring the anterior site of the lumbar spine (T12 to S1) and the cervical spine (C2 to T1) as either 0 (normal), 1 (erosion, sclerosis, or squaring), 2 (syndesmophyte), 3 (bridging syndesmophyte), or N (vertebral body not evaluable). Data from NCT00195819 was compared with data from AS patients in OASIS.

ASAS 20 responders - improvement of \>=20% and absolute improvement of \>=10 units from Baseline in a visual analog scale (VAS) for \>=3 of 4 domains; Patient's Global Assessment of disease activity VAS; (0\[none\]-100 \[severe\]), Total Back Pain VAS; (0 \[no pain\]-100 \[severe\]), BASFI VAS (0 \[easy \]-100\[impossible\]); and Inflammation VAS (0 \[none\] to 10 \[very severe\]) and absence of deterioration in the potential remaining domain, defined as a worsening of \>=20% and a net worsening of \>=10 units. Applied to each scale and not to an overall global scale.

ASAS 50 responders - improvement of \>=50% and absolute improvement of \>=20 units from Baseline in a visual analog scale (VAS) for \>=3 of 4 domains: Patient's Global Assessment of disease activity VAS (0 \[none\] to 100 \[severe\]); Total Back Pain VAS (0 \[no pain\] to 100 \[severe\]); BASFI VAS (0 \[easy\] to 100\[impossible\]); and Inflammation VAS (1 \[none\] to 10 \[very severe\]); and absence of deterioration in the potential remaining domain, defined as a worsening of \>=20% and a net worsening of \>=10 units. Applied to each scale and not to an overall global scale.

ASAS 70 responders - improvement of \>=70% and absolute improvement of \>=30 units from Baseline in a visual analog scale (VAS) for \>=3 of 4 domains: Patient's Global Assessment of disease activity VAS (0 \[none\] to 100 \[severe\]), Total Back Pain VAS; (0 \[no pain\] - 100 \[severe\]), BASFI VAS (0 \[easy\] to 100\[impossible\]); and Inflammation VAS (1 \[none\] to 10 \[very severe\]); and absence of deterioration in the potential remaining domain, defined as defined as a worsening of \>= 20% and a net worsening of \>= 10 units. Applied to each scale and not to an overall global scale.

Evaluation of the effect of adalimumab 40 mg every other week (eow) on patient's global assessment of disease activity. The patient was to assess his/her disease activity in the past week using a visual analog scale (VAS) on a scale of 0 to 100 mm with no activity being indicated by 0 and severe activity by 100.

The patient assesses his/her disease activity for the past week using a Patient Global Assessment of Disease on visual analog scale (VAS) with 0 being none and 100 being severe.

BASFI consist of a set of 10 questions designed to determine the degree of functional limitation in subjects with AS. The BASFI score was derived based on the average of questions 1 through 10. The first 8 questions considered activities related to functional anatomy and the final 2 questions assessed the subject's ability to cope with everyday life over the last week. A 100-mm visual analog scale (VAS) was used to answer the questions and the mean of the ten scales gave the BASFI score a value between 0 (easy) and 100 (impossible).

BASFI consisted of 10 Visual Analog Scale (VAS) questions with a response ranging from 0 (easy) to 100 (impossible). The BASFI score was derived based on the average of questions 1 through 10. A responder is a subject who demonstrates an absolute improvement of at least 10 units and a percentage improvement of at least 20% from Baseline.

Evaluation of the effect of 40 mg every other week (eow) adalimumab on Total Back Pain VAS. The subject was to assess his/her disease activity in the past week using a total spine VAS on a scale 0 (no pain) to 100 (severe pain).

Participants assessed disease activity in the past week using a total spine VAS on a scale 0 (no pain) to 100 (severe pain). A responder is a participant who demonstrates an absolute improvement of at least 10 units and a percentage improvement of at least 20% from Baseline.

The inflammation score is the mean of the two morning stiffness-related BASDAI visual analog scale (VAS) scores (items 5 and 6 of the BASDAI): overall level of morning stiffness (0 \[none\] to 10 \[very severe\]) and duration of morning stiffness (0 \[0 hours\] to 10 \[2 or more hours\]). A decrease in inflammation represents improvement.

The inflammation score is the mean of the two morning stiffness-related BASDAI visual analog scale (VAS) scores (items 5 and 6 of the BASDAI): overall level of morning stiffness (0 \[none\] to 10 \[very severe\]) and duration of morning stiffness (0 \[0 hours\] to 10 \[2 or more hours\]). A decrease in inflammation represents improvement.

A responder is a participant who demonstrates an absolute improvement of at least 10 units and a percentage improvement of at least 20% from Baseline in inflammation (mean of the BASDAI questions 5 and 6 on scale of 0 \[none\] to 10 \[very severe\].

The BASDAI is a questionnaire with 6 questions that subject completes by marking answers on a 10-cm Visual Analog Scale (VAS) during the last week with responses that range from 0 (none) to 10 (very severe) and measures severity of fatigue, spinal and peripheral joint pain, localized tenderness and morning stiffness. The final BASDAI score ranges from 0 (none) to 10 (very severe). Improvement in BASDAI by 20% was assessed. BASDAI Scoring:

Measure each item of the BASDAI in centimeters (out of a total of 10) BASDAI Score = 0.2 (Item 1 + Item 2 + Item 3 + Item 4 + Item 5/2 + Item 6/2).

The BASDAI is a questionnaire with 6 questions that subject completes by marking answers on a 10-cm Visual Analog Scale (VAS) during the last week with responses that range from 0 (none) to 10 (very severe) and measures severity of fatigue, spinal and peripheral joint pain, localized tenderness and morning stiffness. The final BASDAI score ranges from 0 to 10. Improvement in BASDAI by 50% was assessed. BASDAI Scoring:

Measure each item of the BASDAI in centimeters (out of a total of 10) BASDAI Score = 0.2 (Item 1 + Item 2 + Item 3 + Item 4 + Item 5/2 + Item 6/2).

The BASDAI is a questionnaire with 6 questions that subject completes by marking answers on a 10-cm Visual Analog Scale (VAS) during the last week with responses that range from 0 (none) to 10 (very severe) and measures severity of fatigue, spinal and peripheral joint pain, localized tenderness and morning stiffness. The final BASDAI score ranges from 0 to 10. Improvement in BASDAI by 70% was assessed. BASDAI Scoring:

Measure each item of the BASDAI in centimeters (out of a total of 10) BASDAI Score = 0.2 (Item 1 + Item 2 + Item 3 + Item 4 + Item 5/2 + Item 6/2).

The BASDAI is a questionnaire with 6 questions that subject completes by marking answers on a 10-cm Visual Analog Scale (VAS) during the last week with responses that range from 0 (none) to 10 (very severe) and measures severity of fatigue, spinal and peripheral joint pain, localized tenderness and morning stiffness. The final BASDAI score ranges from 0 (none) to 10 (severe). A decrease in BASDAI represents improvement. BASDAI Scoring: 1) Measure each item of the BASDAI in centimeters (out of a total of 10) 2) BASDAI Score = 0.2 (Item 1 + Item 2 + Item 3 + Item 4 + Item 5/2 + Item 6/2).

Evaluation of the mean changes in CRP in subjects with adalimumab exposure from Baseline through 5 years. The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation via the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation. A decrease in CRP indicates improvement.

ASAS 40 responders - improvement of \>=40% and absolute improvement of \>=20 units from Baseline in a visual analog scale (VAS) for \>=3 of 4 domains; Patient's Global Assessment of disease activity VAS (0 \[none\] to 100 \[severe\]); Total Back Pain VAS (0 \[no pain\] to 100 \[severe\]); BASFI VAS (0 \[easy\] to 100\[impossible\]); and Inflammation VAS (1 \[none\] to 10 \[very severe\]); and absence of any deterioration in the potential remaining domain. Applied to each scale and not to an overall global scale.

The change in ASAS 5/6 was evaluated for the effect of adalimumab on structural damage.

ASAS 5/6 criteria is the 20% improvement in 5 out of 6 domains (physical function \[BASFI\], Total Back Pain, Patient's Global Assessment of Disease Activity, Inflammation \[mean of Questions 5 and 6 of the BASDAI\], spinal mobility \[BASMI\], and acute phase reactants \[CRP\]).

ASAS partial remission was calculated as follows: A value below 20 on a 0 - 100 point scale in each of the four domains of the ASAS (Patient's Global Assessment of Disease Activity, Pain, Function, and Inflammation). Partial remission is also regarded as a low disease activity state.

BASMI measures the range of motion based on five clinical measurements: 1) cervical rotation, 2) tragus to wall distance, 3) lumbar side flexion, 4) lumbar flexion (modified Schober's) and 5) intermalleolar distance. BASMI 0 = indicates mild disease involvement, 1 = moderate disease, and 2 = severe disease involvement. The results for cervical rotation and lumbar side flexion are the means of the left and right measurements. Scoring range 0-10. The higher the BASMI score, the more severe was the subject's limitation of movement due to their AS.

The patient is in a sitting position on the examination table with the hands on the hips. A pen mark is made at the xiphisternum and a tape measure placed around the circumference of the patient's chest at this level. The patient is asked to take a deep breath and to exhale as completely as possible while looking directly ahead. The measurement (in cm) is noted. The patient is asked to inhale as deeply as possible and the measurement (in cm) is noted. The difference in the 2 measurement points (in cm) constitutes the value for CE.

An increase in chest expansion represents improvement

MASES is measured by scoring of entheses of 0 (no tenderness) to 3 (severe tenderness) at 13 sites on the body. The score was derived as the sum of the 13 scores divided by 3 and the total range is 0 to 13 (minimum to maximum number and severity of enthesitis).

BAS-G was measured by two VAS scores (0 to 100 mm) to reflect the effect of Ankylosing Spondylitis on subject's well-being over the past week and over the last 6 months, respectively. The average of these two scores was reported.

Change from Baseline in the swollen joint index. An assessment of 44 joints for SJC done by physical examination. Joint swelling was classified as present ("1"), absent ("0") or injected/replaced ("9"). The joints assessed were: Sternoclavicular, Acromioclavicular, Shoulder, Elbow, Wrist, Metacarpophalangeal (1-5), Thumb interphalangeal, Proximal interphalangeal (2-5, Knee, Ankle, and Metatarsophalangeal (1-5).

Assessment of 46 joints for TJC was done by physical examination. Joint tenderness was classified as present ("1"), absent ("0") or injected/replaced ("9"). The joints assessed were: Sternoclavicular, Acromioclavicular, Shoulder, Elbow, Wrist, Metacarpophalangeal (1-5), Thumb interphalangeal, Proximal interphalangeal (2-5, Hip, Knee, Ankle, and Metatarsophalangeal (1-5).

The physician will globally assess the subject's current disease state using a 100-mm VAS scale with 0 being very good and 100 being very bad.

The subject was to assess his/her nocturnal pain intensity for the past week using a Nocturnal Pain Visual Analog Scale (Nocturnal Pain VAS). The range was 0 to 100 mm with no pain being indicated by 0 and worse possible pain by 100.

SF-36 is a standardized survey evaluating 8 aspects of functional health and well being; physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for a section is an average of the individual question scores, which are scaled 0 (no functioning) to 100 (highest level of functioning). The SF-36 Health Survey Index was completed by participants. Components of the SF-36 included the PCS and MCS, respectively. An increase in SF-36 PCS or MCS indicated improvement.

SF-36 is a standardized survey evaluating 8 aspects of functional health and well being; physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for a section is an average of the individual question scores, which are scaled 0(no functioning) to 100 (highest level of functioning).

Responders were subjects whose change in PCS score fulfilled the Minimal Clinically Important Difference (MCID). The MCID for PCS was determined by a \>= 3.0 point increase during exposure to adalimumab.

SF-36 is a standardized survey evaluating 8 aspects of functional health and well being; physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for a section is an average of the individual question scores, which are scaled 0(no functioning) to 100 (highest level of functioning).

Responders were subjects whose change in MCS fulfilled the Minimal Clinically Important Difference (MCID). The MCID for MCS was determined by a \>= 3.0 point increase during exposure to adalimumab.

The HUI-3 is a generic approach to the measurement of health status and assessment of health-related quality of life (HRQL). The HUI-3 classification is comprised of a total score and 8 attributes - Vision, Hearing, Speech, Ambulation, Dexterity, Emotion, Cognition and Pain. The attributes are measures on a scale from the worst score of 0 to best score of 1. The total score scale ranges from dead (= 0) and perfect health (= 1). The total score can have a negative score that is interpreted as worse than dead and the lower limit is -0.36. An increase in the HUI-3 score represents improvement.

ASQoL determined participants' quality of life and is comprised of 18 questions (yes or no) to be completed by the participant. Each statement on the ASQoL is given a score of "1" or "0." All item scores were summed to give a total score or index. Total scores ranged from 0 (good quality of life) to 18 (poor quality of life) related to ability to cope, relationships, mood, sleep, motivation, activities of everyday living, independence, and social life. Decrease in ASQoL score represents improvement.

ASQoL determined participants' quality of life and is comprised of 18 questions (yes or no) to be completed by the participant. Total scores ranged from 0 (good quality of life) to 18 (poor quality of life) related to ability to cope, relationships, mood, sleep, motivation, activities of everyday living, independence, and social life. Decrease in ASQoL score represents improvement. Responders are participants with a minimal clinically important difference (MCID) \<= -1.8 points. MCID was determined by a \>= 1.8 score decrease during exposure to adalimumab.

Completed by subject at each visit. The Patient Acceptable Symptoms State (PASS) was a participant-reported outcome where participants were expected to respond (yes/no) to the following question:

Considering all the different ways your disease is affecting you, if you would stay in this state for the next months, do you consider that your current state is satisfactory?

Abbott

By duration of exposure to any adalimumab 40 mg eow, subcutaneous

Any Adalimumab

Subjects on active treatment received SC injection of 40 mg adalimumab every other week.

Subjects on placebo treatment received SC injection of matched placebo every other week.

Placebo

Total

Age, Categorical

Age Continuous

Sex: Female, Male

United States

Europe

Region of Enrollment

Interim results are shown for subjects after 12 weeks for efficacy parameters and 24 weeks for safety parameters. Subjects who discontinued the study before Week 12 and subjects with missing values were classified as nonresponders for efficacy.

Global Medical Services

ASAS 20 response rates of the adalimumab group were compared with the placebo group using Pearson's Chi-square test. The counts and percentages were calculated for total sample and by therapy group. Statistical tests were 2-sided. For the statistical analysis, subjects with missing data before Week 12 were considered as nonresponders. The comparisons were performed at an alpha level = 0.05.

Responder

Nonresponder

Missing

Number of Responders With a Reduction of Signs and Symptoms of Ankylosing Spondylitis (AS) as Measured With ASAS International Working Group Response Criteria (ASAS 20).

Adalimumab in M03-607 (N = 237)

OASIS (N = 169)

By duration of exposure to adalimumab 40 mg every other week, subcutaneous

The OASIS cohort is a historical control group of Dutch, French, and Belgian patients with AS who have been followed up since 1996. These patients participated in a follow-up study on the natural course of AS with conventional (non-biologic) treatment.

Mean Change in the Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) Compared Against a Historical Control Group (Outcomes in Ankylosing Spondylitis International Study [OASIS]) Using the ANCOVA Model Adjusting for Baseline mSASSS Score

Week 12 Responders (n = 310)

Week 24 Responders (n = 298)

Week 52 Responders (n = 282)

Week 76 Responders (n = 269)

Week 104 Responders (n = 261)

Week 128 Responders (n = 242)

Week 156 Responders (n = 234)

Week 180 Responders (n = 226)

Week 208 Responders (n = 217)

Week 220 Responders (n = 210)

Week 232 Responders (n = 204)

Week 244 Responders (n = 187)

Week 260 Responders (n = 125)

By Duration of Exposure to Adalimumab 40 mg every other week, subcutaneous

Any Adalimumab Set - includes all participants who received at least 1 dose of adalimumab during the study, in either the double-blind or the open-label phase. 204 participants were randomized to 40 mg adalimumab every other week (eow) and 107 to placebo. The Any Adalimumab Set is analyzed by duration of exposure (weeks) to adalimumab.

Number of Subjects With a Reduction of Signs and Symptoms as Measured in Assessments of Ankylosing Spondylitis (ASAS) 20 - Through Week 260 of Adalimumab Exposure

Number of Subjects With a Reduction of Signs and Symptoms as Measured in Assessments of Ankylosing Spondylitis (ASAS) 50 - Through Week 260 of Adalimumab Exposure

Number of Subjects With a Reduction of Signs and Symptoms as Measured in Assessments of Ankylosing Spondylitis (ASAS) 70 - Through Week 260 of Adalimumab Exposure

Week 12 (n = 309)

Week 24 (n = 297)

Week 52 (n = 281)

Week 76 (n = 268)

Week 104 (n = 260)

Week 128 (n = 241)

Week 156 (n = 233)

Week 180 (n = 225)

Week 208 (n = 216)

Week 220 (n = 209)

Week 232 (n = 203)

Week 244 (n = 186)

Week 260 (n = 124)

Mean Change in Patient's Global Assessment of Disease Activity in Subjects With Adalimumab Exposure Through Week 260

Week 12 Responders (n = 309)

Week 24 Responders (n = 297)

Week 52 Responders (n = 281)

Week 76 Responders (n = 268)

Week 104 Responders (n = 260)

Week 128 Responders (n = 241)

Week 156 Responders (n = 233)

Week 180 Responders (n = 225)

Week 208 Responders (n = 216)

Week 220 Responders (n = 209)

Week 232 Responders (n = 203)

Week 244 Responders (n = 186)

Week 260 Responders (n = 124)

Number of Subjects With a Reduction of Signs and Symptoms as Measured in Patient's Global Assessment of Disease Activity (an Individual Component of ASAS 20) Through Week 260 of Adalimumab Exposure

Week 12 (n = 310)

Week 24 (n = 298)

Week 52 (n = 282)

Week 76 (n = 269)

Week 104 (n = 261)

Week 128 (n = 242)

Week 156 (n = 234)

Week 180 (n = 226)

Week 208 (n = 217)

Week 220 (n = 210)

Week 232 (n = 205)

Week 244 (n = 187)

Week 260 (n = 125)

Mean Change in the Bath Ankylosing Spondylitis Functional Index (BASFI) in Subjects With Adalimumab Exposure Through Week 260

Week 232 Responders (n = 205)

Number of Subjects With a Reduction of Signs and Symptoms as Measured in BASFI (an Individual Component of ASAS 20) Through Week 260 of Adalimumab Exposure

Week 232 (n = 204)

Mean Change in Total Back Pain Visual Analog Scale (VAS) in Subjects With Adalimumab Exposure Through Week 260

Number of Subjects With a Reduction of Signs and Symptoms as Measured in Total Back Pain (an Individual Component of ASAS 20) Through Week 260 of Adalimumab Exposure

Mean Change in Inflammation (Mean of BASDAI Questions 5 and 6) in Subjects With Adalimumab Exposure Through Week 260

Number of Subjects With a Reduction of Signs and Symptoms as Measured in Inflammation (Individual Component of ASAS 20) (Mean of BASDAI Questions 5 and 6) Through Week 260 of Adalimumab Exposure

Number of Subjects With a Reduction of Signs and Symptoms as Measured in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 20 Through Week 260 of Adalimumab Exposure

Number of Subjects With a Reduction of Signs and Symptoms as Measured in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 Through Week 260 of Adalimumab Exposure

Number of Subjects With a Reduction of Signs and Symptoms as Measured in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 70 Through Week 260 of Adalimumab Exposure

Mean Change in BASDAI in Subjects With Adalimumab Exposure Through Week 260

Week 12 (n = 308)

Week 24 (n = 294)

Week 52 (n = 279)

Week 76 (n = 264)

Week 104 (n = 258)

Week 128 (n = 238)

Week 156 (n = 230)

Week 180 (n = 224)

Week 208 (n = 215)

Week 220 (n = 207)

Week 260 (n = 123)

Mean Change in C-Reactive Protein (CRP) (mg/dL) in Subjects With Adalimumab Exposure Through Week 260

Number of Subjects With a Disease Controlling Clinical Response From Adalimumab as Measured in Assessments of Ankylosing Spondylitis (ASAS) 40 - Through Week 260 of Adalimumab Exposure

Week 156 Responders (n = 232)

Week 220 Responders (n = 208)

Number of Subjects With a Disease Controlling Clinical Response From Adalimumab as Measured in Assessments of Ankylosing Spondylitis Ankylosing Spondylitis (ASAS) 5/6 in Subjects With Adalimumab Exposure Through Week 260

Number of Subjects With a Disease Controlling Clinical Response From Adalimumab as Measured by ASAS Partial Remission Response in Subjects With Adalimumab Exposure Through Week 260

Spots Global Cancer Trial Database for Human Anti-tumor Necrosis Factor (TNF) Monoclonal Antibody Adalimumab in Subjects With Active Ankylosing Spondylitis

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