Trial Outcomes & Findings for Study of Apremilast to Evaluate the Safety and Effectiveness for Patients With Rheumatoid Arthritis (NCT NCT01285310)

NCT ID: NCT01285310

Last Updated: 2020-05-08

Results Overview

Percentage of participants with an American College of Rheumatology 20% Improvement (ACR 20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: * ≥ 20% improvement in 68 tender joint count; * ≥ 20% improvement in 66 swollen joint count; and * ≥ 20% improvement in at least 3 of the 5 following parameters: Subject's assessment of pain (measured on a 100 mm visual analog scale \[VAS\]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (\[HAQ-DI\]); C-Reactive Protein.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 237 participants
• Primary outcome timeframe: Baseline and Week 16
• Results posted on: 2020-05-08

Participant Flow

A total of 302 subjects were screened for inclusion in this study, and 237 participants randomized in parallel in a 1:1:1 ratio to treatment groups. The first participant was enrolled on 27 December 2010; the last participant completed week 24 visit on 23 February 2012.

Participant milestones

Measure	Placebo Participants initially randomized to placebo tablets twice daily in the 24-week placebo-controlled phase. Participants who did not have at least 20% improvement in swollen and tender joint counts at Week 16 were transitioned onto 20 mg Apremilast twice daily (early escape), and were designated as Placebo/Apremilast 20mg EE.	Apremilast 20 mg Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 20 mg apremilast tablets twice daily (BID) for up to Week 52 in the active treatment. At week 52, participants were given the option to remain on active treatment for 1 additional year (extension phase) as assigned during the active treatment phase.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 30 mg apremilast tablets twice daily (BID) for up to Week 52 in the active treatment. At week 52, participants were given the option to remain on active treatment for 1 additional year (extension phase) as assigned during the active treatment phase.	Placebo/Apremilast 20mg EE Participants initially randomized to receive placebo twice daily and were transitioned due to early escape (EE) at Week 16 to receive 20 mg apremilast for up to week 24. At week 24, participants were continued on Apremilast 20 mg BID for up to Week 52. At week 52, they were given the option to remain on active treatment for 1 additional year (extension phase) as assigned during the active treatment phase.	Placebo / Apremilast 20 mg XO Participants initially randomized to receive placebo twice daily who were transitioned at Week 24 (XO) to receive 20 mg apremilast for up to Week 52. At week 52, they were given the option to remain on active treatment for 1 additional year (extension phase) as assigned during the active treatment phase.
Placebo Controlled Phase: Weeks 0-24 STARTED	79	82	76	0	0
Placebo Controlled Phase: Weeks 0-24 COMPLETED	70	67	61	0	0
Placebo Controlled Phase: Weeks 0-24 NOT COMPLETED	9	15	15	0	0
Active Treatment Phase: Weeks 25-52 STARTED	0	63	60	27	42
Active Treatment Phase: Weeks 25-52 COMPLETED	0	31	34	17	23
Active Treatment Phase: Weeks 25-52 NOT COMPLETED	0	32	26	10	19

Reasons for withdrawal

Measure	Placebo Participants initially randomized to placebo tablets twice daily in the 24-week placebo-controlled phase. Participants who did not have at least 20% improvement in swollen and tender joint counts at Week 16 were transitioned onto 20 mg Apremilast twice daily (early escape), and were designated as Placebo/Apremilast 20mg EE.	Apremilast 20 mg Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 20 mg apremilast tablets twice daily (BID) for up to Week 52 in the active treatment. At week 52, participants were given the option to remain on active treatment for 1 additional year (extension phase) as assigned during the active treatment phase.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 30 mg apremilast tablets twice daily (BID) for up to Week 52 in the active treatment. At week 52, participants were given the option to remain on active treatment for 1 additional year (extension phase) as assigned during the active treatment phase.	Placebo/Apremilast 20mg EE Participants initially randomized to receive placebo twice daily and were transitioned due to early escape (EE) at Week 16 to receive 20 mg apremilast for up to week 24. At week 24, participants were continued on Apremilast 20 mg BID for up to Week 52. At week 52, they were given the option to remain on active treatment for 1 additional year (extension phase) as assigned during the active treatment phase.	Placebo / Apremilast 20 mg XO Participants initially randomized to receive placebo twice daily who were transitioned at Week 24 (XO) to receive 20 mg apremilast for up to Week 52. At week 52, they were given the option to remain on active treatment for 1 additional year (extension phase) as assigned during the active treatment phase.
Placebo Controlled Phase: Weeks 0-24 Adverse Event	3	4	6	0	0
Placebo Controlled Phase: Weeks 0-24 Lack of Efficacy	1	7	3	0	0
Placebo Controlled Phase: Weeks 0-24 Non-compliance	1	0	2	0	0
Placebo Controlled Phase: Weeks 0-24 Withdrawal by Subject	3	3	2	0	0
Placebo Controlled Phase: Weeks 0-24 Lost to Follow-up	0	1	1	0	0
Placebo Controlled Phase: Weeks 0-24 Other	1	0	1	0	0
Active Treatment Phase: Weeks 25-52 Adverse Event	0	2	3	0	2
Active Treatment Phase: Weeks 25-52 Lack of Efficacy	0	4	3	1	0
Active Treatment Phase: Weeks 25-52 Withdrawal by Subject	0	3	0	2	2
Active Treatment Phase: Weeks 25-52 Study Termination by sponsor	0	21	19	6	15
Active Treatment Phase: Weeks 25-52 Other	0	1	0	0	0
Active Treatment Phase: Weeks 25-52 Non-compliance	0	1	1	1	0

Baseline Characteristics

Study of Apremilast to Evaluate the Safety and Effectiveness for Patients With Rheumatoid Arthritis

Baseline characteristics by cohort

Measure	Placebo n=79 Participants Placebo: Oral Placebo tablets administered twice daily (BID) for 24 weeks during the placebo-controlled phase followed by 20mg Apremilast tablets administered BID for up to 1.5 years in active treatment / active treatment extension phase. Participants who are nonresponders were transitioned early to 20 mg Apremilast BID at Week 16.	Apremilast 20 mg n=82 Participants Apremilast 20 mg: 20 mg oral Apremilast tablets administered twice daily (BID) for 24 weeks during the placebo-controlled phase and continued 20mg Apremilast tablets administered BID for up to 1.5 years in the active treatment / active treatment extension phase.	Apremilast 30 mg n=76 Participants Apremilast 30 mg: 30 mg oral Apremilast tablets administered twice daily (BID) for 24 weeks during the placebo-controlled phase and continued 30mg Apremilast tablets administered BID for up to 1.5 years in the active treatment / active treatment extension phase.	Total n=237 Participants Total of all reporting groups
Age, Continuous	56.5 years STANDARD_DEVIATION 12.45 • n=5 Participants	58.6 years STANDARD_DEVIATION 11.84 • n=7 Participants	52.6 years STANDARD_DEVIATION 11.87 • n=5 Participants	56.0 years STANDARD_DEVIATION 12.26 • n=4 Participants
Sex: Female, Male Female	62 Participants n=5 Participants	65 Participants n=7 Participants	55 Participants n=5 Participants	182 Participants n=4 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	17 Participants n=7 Participants	21 Participants n=5 Participants	55 Participants n=4 Participants
Duration of Rheumatoid Arthritis Diagnosis	11.98 years STANDARD_DEVIATION 12.104 • n=5 Participants	8.46 years STANDARD_DEVIATION 6.856 • n=7 Participants	7.76 years STANDARD_DEVIATION 7.833 • n=5 Participants	9.41 years STANDARD_DEVIATION 9.351 • n=4 Participants

PRIMARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set consisting of all participants randomized as specified in the protocol; participants who were randomized in error and did not receive any dose of study drug were excluded. Participants who withdrew early or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.

Percentage of participants with an American College of Rheumatology 20% Improvement (ACR 20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 20% improvement in 68 tender joint count;
• ≥ 20% improvement in 66 swollen joint count; and
• ≥ 20% improvement in at least 3 of the 5 following parameters: Subject's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index ([HAQ-DI]); C-Reactive Protein.

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants With an American College of Rheumatology 20% Improvement (ACR 20) Response at Week 16	35.4 percentage of participants	28 percentage of participants Interval -27.7 to 7.0	34.2 percentage of participants Interval -16.2 to 13.8	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; Last observation carried forward (LOCF) imputation was used.

The Health Assessment Questionnaire - Disability Index (HAQ-DI) was a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=80 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 16	-0.106 units on a scale Standard Deviation 0.4173	-0.114 units on a scale Standard Deviation 0.5036	-0.209 units on a scale Standard Deviation 0.4469	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; Participants who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders.

Percentage of participants with an American College of Rheumatology 20% Improvement (ACR 20) response. A participant was a responder if the following 3 criteria for improvement from baseline were met:

• ≥ 20% improvement in 68 tender joint count;
• ≥ 20% improvement in 66 swollen joint count; and
• ≥ 20% improvement in at least 3 of the 5 following parameters: Subject's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index ([HAQ-DI]); C-Reactive Protein

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants With an American College of Rheumatology 20% Improvement (ACR 20) Response at Week 24	24.1 percentage of participants	19.5 percentage of participants	27.6 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=80 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 24	-0.069 units on a scale Standard Deviation 0.4328	-0.080 units on a scale Standard Deviation 0.4653	-0.227 units on a scale Standard Deviation 0.4910	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; LOCF imputation was used.

The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) is 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). The concepts measured by the SF-36 are not specific to any age, disease, or treatment group, allowing comparison of relative burden of different diseases and the relative benefit of different treatments. Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from baseline score indicates an improvement.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=78 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=75 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in the Medical Outcome Study Short Form 36-item (SF-36) Physical Functioning Domain at Week 16	1.48 units on a scale Standard Deviation 6.937	1.64 units on a scale Standard Deviation 7.036	3.33 units on a scale Standard Deviation 6.970	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included. LOCF imputation was used.

The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the:

• 28 tender joint count (TJC),
• 28 swollen joint count (SJC),
• Subject's Global Assessment of Disease Activity measured on a 100 mm visual analog scale (VAS), where 0 mm = lowest disease activity and 100 mm = highest;
• Physician's Global Assessment of Disease Activity -measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest.

The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI:

Remission: ≤ 2.8; Low Disease Activity: > 2.8 and ≤ 10; Moderate Disease Activity: > 10 and ≤ 22; High Disease Activity: > 22

Outcome measures

Measure	Placebo n=77 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=79 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in the Clinical Disease Activity Index (CDAI) at Week 16	-11.52 units on a scale Standard Deviation 14.850	-9.49 units on a scale Standard Deviation 12.998	-11.38 units on a scale Standard Deviation 13.230	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included. LOCF imputation was used.

The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the:

• 28 tender joint count (TJC),
• 28 swollen joint count (SJC),
• Subject's Global Assessment of Disease Activity measured on a 100 mm visual analog scale (VAS), where 0 mm = lowest disease activity and 100 mm = highest;
• Physician's Global Assessment of Disease Activity -measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest.

The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI:

Remission: ≤ 2.8; Low Disease Activity: > 2.8 and ≤ 10; Moderate Disease Activity: > 10 and ≤ 22; High Disease Activity: > 22

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants Who Achieve Low Disease Activity or Remission Based on the Clinical Disease Activity Index (CDAI) ≤ 10 at Week 16	17.7 percentage of participants	12.2 percentage of participants	10.5 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included. LOCF imputation was used.

The DAS28 measures the severity of disease at a specific time and is derived from the following variables:

• 28 tender joint count (TJC28)
• 28 swollen joint count (SJC28), which do not include the distal interphalangeal (DIP) joints, the hip joint, or the joints below the knee;
• C-reactive protein (CRP)
• Subject's global assessment of disease activity (SGA )

DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity.

A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=80 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in Disease Activity Score 28 (DAS28) (Using C-Reactive Protein) (CRP) at Week 16	-0.90 units on a scale Standard Error 1.272	-0.73 units on a scale Standard Error 1.079	-0.90 units on a scale Standard Error 1.168	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; LOCF imputation was used.

Joint tenderness is the presence of pain in a joint when pressure is applied by the examiner to elicit tenderness. The 68 tender joint count evaluates the following joints: upper-temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist, meta-carpophalangeal, proximal interphalangeal and distal interphalangeal; lower: hip, knee, ankle, midtarsal, metatarsophalangeal and proximal interphalangeal.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=81 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Tender Joint Count at Week 16	-33.08 percent change Standard Error 5.154	-26.92 percent change Standard Error 5.058	-33.68 percent change Standard Error 5.221	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; LOCF imputation was used.

Joint swelling is soft tissue swelling that is detectable along the joint margins and is assessed by inspection and direct palpation of the joint, by the examiner. The ACR 66 swollen joint count evaluates the following joints: upper-temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist, metacarpophalangeal, proximal interphalangeal and distal interphalangeal; lower: knee, ankle, midtarsal, metatarsophalangeal and proximal interphalangeal.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=81 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Swollen Joint Count at Week 16	-36.96 percent change Standard Error 5.432	-34.38 percent change Standard Error 5.328	-40.22 percent change Standard Error 5.502	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; LOCF imputation was used.

The Subject Assessment of Pain was measured asking the participant to place a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents "no pain," and the right-hand boundary (score = 100 mm) represents "pain as severe as can be imagined." The distance from the mark to the left-hand boundary was recorded in millimeters.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=80 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Subject Assessment of Pain at Week 16	30.50 percent change Standard Error 16.584	-5.03 percent change Standard Error 16.369	-7.87 percent change Standard Error 16.800	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; LOCF imputation was used.

The Subject Global Assessment of Disease Activity was measured asking the participant to place a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents " lowest disease activity," and the right-hand boundary (score = 100 mm) represents " highest disease activity." The distance from the mark to the left-hand boundary was recorded in millimeters.

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Subject Global Assessment of Disease Activity at Week 16	10.84 percent change Standard Error 10.004	-3.50 percent change Standard Error 9.872	11.19 percent change Standard Error 10.131	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; Last observation carried forward (LOCF) imputation was used.

The Physician Global Assessment of Disease Activity was measured asking the physician to assess the subject's current arthritis disease activity by placing a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents " lowest disease activity," and the right-hand boundary (score = 100 mm) represents " highest disease activity." The distance from the mark to the left-hand boundary was recorded in millimeters.

Outcome measures

Measure	Placebo n=77 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=80 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Physician Global Assessment of Disease Activity at Week 16	-28.82 percent change Standard Error 4.478	-28.22 percent change Standard Error 4.440	-32.66 percent change Standard Error 4.540	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; LOCF imputation was used.

The Health Assessment Questionnaire - Disability Index (HAQ-DI) was a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=80 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 16	-9.43 percent change Standard Error 5.307	-3.50 percent change Standard Error 5.234	-10.20 percent change Standard Error 5.416	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; LOCF imputation was used.

C-Reactive Protein (CRP) is a substance produced by the liver that increases in the presence of inflammation in the body. An elevated CRP level is identified with blood tests and is considered a non-specific "marker" for disease.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=81 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the High Sensitivity C-Reactive Protein (CRP) at Week 16	41.99 percent change Standard Error 30.559	46.69 percent change Standard Error 30.027	100.04 percent change Standard Error 31.127	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; LOCF imputation was used.

The erythrocyte sedimentation rate (ESR) is a blood test that can reveal inflammatory activity. The subject's blood is placed in a tall, thin tube, red erythrocytes gradually settle to the bottom. Inflammation can cause the cells to clump together. Because these clumps of cells are denser than individual cells, they settle to the bottom more quickly.

The ESR test measures the distance red blood cells fall in a test tube in one hour. The farther the red blood cells have descended, the greater the inflammatory response.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=81 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 16	6.81 percent change Standard Error 10.633	13.98 percent change Standard Error 10.522	-9.39 percent change Standard Error 10.681	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included. LOCF imputation was used.

The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue.

A positive change from baseline score indicates an improvement.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=78 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=75 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 16	2.7 units on a scale Standard Error 0.96	1.5 units on a scale Standard Error 0.96	2.6 units on a scale Standard Error 0.98	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; Last observation carried forward (LOCF) imputation was used.

The Health Assessment Questionnaire - Disability Index (HAQ-DI) was a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability.

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants Who Achieve an Improvement of ≥ 0.22 Units From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 16	39.2 percentage of participants	35.4 percentage of participants	52.6 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; LOCF imputation was used.

The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue.

A positive change from baseline score indicates an improvement.

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants Who Achieve an Improvement of at Least 4 Units From Baseline in the Functional Assessment of Chronic Illness Therapy -Fatigue (FACIT-Fatigue) at Week 16	39.2 percentage of participants	35.4 percentage of participants	42.1 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; Participants who discontinued early, or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.

EULAR response criteria classify each participant as a good, moderate or non-responder to treatment based on the degree of improvement from baseline and the level of disease activity at the endpoint. EULAR response is derived using the individual subject's DAS28 as the measure of severity of disease.

Good or moderate response is defined as follows: Good response: DAS28 at the time point ≤ 3.2 and improvement from baseline > 1.2 Moderate response: DAS28 at the time point > 3.2 and improvement from baseline > 1.2, or DAS28 at the time point ≤ 5.1 and improvement from baseline > 0.6 and ≤ 1.2

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants Who Achieve the European League Against Rheumatism (EULAR) Response Criteria Using CRP at Week 16	46.8 percentage of participants	41.5 percentage of participants	44.7 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full analysis set; Participants who discontinued early, or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.

Percentage of participants with an American College of Rheumatology 50% Improvement (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 50% improvement in 68 tender joint count;
• ≥ 50% improvement in 66 swollen joint count; and
• ≥ 50% improvement in at least 3 of the 5 following parameters:

Subject's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [(HAQ-DI)]); C-Reactive Protein.

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants With an American College of Rheumatology 50% Improvement (ACR 50) Response at Week 16	11.4 percentage of participants	4.9 percentage of participants	9.2 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Full Analysis Set = The FAS consisted of all participants who were randomized as specified per protocol during the placebo controlled period. The last observed joint assessment (at baseline or post-baseline) was used for joints unassessed at Week 16.

Percentage of participants with an American College of Rheumatology 70% Improvement (ACR70) response. A participant was a responder if the following 3 criteria for improvement from baseline were met:

• ≥ 70% improvement in 68 tender joint count;
• ≥ 70% improvement in 66 swollen joint count; and
• ≥ 70% improvement in at least 3 of the 5 following parameters: Subject's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index ([HAQ-DI]); C-Reactive Protein

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants With an American College of Rheumatology 70% Improvement (ACR 70) Response at Week 16	2.5 percent of participants	1.2 percent of participants	0.0 percent of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full Analysis Set = The FAS consisted of all participants who were randomized as specified per protocol during the placebo controlled period. The last observed joint assessment (at baseline or post-baseline) was used for joints unassessed at Week 24.

Percentage of participants with an American College of Rheumatology 50% Improvement (ACR 50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 50% improvement in 68 tender joint count;
• ≥ 50% improvement in 66 swollen joint count; and
• ≥ 50% improvement in at least 3 of the 5 following parameters:

Subject's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [(HAQ-DI)]); C-Reactive Protein.

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants With an American College of Rheumatology 50% Improvement (ACR 50) Response at Week 24	6.3 percentage of participants	4.9 percentage of participants	15.8 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full Analysis Set = The FAS consisted of all participants who were randomized as specified per protocol during the placebo controlled period. The last observed joint assessment (at baseline or post-baseline) was used for joints unassessed at Week 24.

Percentage of participants with an American College of Rheumatology 70% Improvement (ACR 70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 70% improvement in 68 tender joint count;
• ≥ 70% improvement in 66 swollen joint count; and
• ≥ 70% improvement in at least 3 of the 5 following parameters:

Subject's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [(HAQ-DI)]); C-Reactive Protein.

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants With an American College of Rheumatology 70% Improvement (ACR 70) Response at Week 24	3.8 percentage of participants	2.4 percentage of participants	5.3 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) is 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 were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from Baseline score indicates an improvement.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=78 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=75 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in the Medical Outcome Study Short Form 36-item (SF-36) Physical Functioning Domain at Week 24	1.78 units on a scale Standard Error 0.849	1.66 units on a scale Standard Error 0.850	3.76 units on a scale Standard Error 0.865	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; Participants who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders. LOCF imputation was used.

The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the:

• 28 tender joint count (TJC),
• 28 swollen joint count (SJC),
• Subject's Global Assessment of Disease Activity measured on a 100 mm visual analog scale (VAS), where 0 mm = lowest disease activity and 100 mm = highest;
• Physician's Global Assessment of Disease Activity -measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest.

The CDAI score ranges from 0-76 where lower scores indicate less disease activity.The following thresholds of disease activity have been defined for the CDAI:

Remission: ≤ 2.8; Low Disease Activity: > 2.8 and ≤ 10; Moderate Disease Activity: > 10 and ≤ 22; High Disease Activity: > 22

Outcome measures

Measure	Placebo n=77 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=79 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in the Clinical Disease Activity Index (CDAI) at Week 24	-10.40 units on a scale Standard Error 1.597	-9.46 units on a scale Standard Error 1.571	-11.63 units on a scale Standard Error 1.602	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the:

• 28 tender joint count (TJC),
• 28 swollen joint count (SJC),
• Subject's Global Assessment of Disease Activity measured on a 100 mm visual analog scale (VAS), where 0 mm = lowest disease activity and 100 mm = highest;
• Physician's Global Assessment of Disease Activity -measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest.

The CDAI score ranges from 0-76 where lower scores indicate less disease activity.The following thresholds of disease activity have been defined for the CDAI:

Remission: ≤ 2.8; Low Disease Activity: > 2.8 and ≤ 10; Moderate Disease Activity: > 10 and ≤ 22; High Disease Activity: > 22

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants Who Achieve Low Disease Activity or Remission Based on the Clinical Disease Activity Index (CDAI) ≤ 10 at Week 24	16.5 percentage of participants	12.2 percentage of participants	21.1 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; Participants who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders. LOCF imputation was used.

The DAS28 measures the severity of disease at a specific time and is derived from the following variables:

• 28 tender joint count
• 28 swollen joint count, which do not include the DIP joints, the hip joint, or the joints below the knee;
• C-reactive protein (CRP)
• Subject's Global Assessment of Disease Activity.

DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity.

A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=80 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in Disease Activity Score 28 (DAS28) Using CRP at Week 24	-0.82 units on a scale Standard Error 0.139	-0.78 units on a scale Standard Error 0.137	-0.91 units on a scale Standard Error 0.141	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

Joint tenderness is the presence of pain in a joint when pressure is applied by the examiner to elicit tenderness. The 68 tender joint count evaluates the following joints: upper-temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist, meta-carpophalangeal, proximal interphalangeal and distal interphalangeal; lower: hip, knee, ankle, midtarsal, metatarsophalangeal and proximal interphalangeal.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=81 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Tender Joint Count at Week 24	-30.81 percent change Standard Error 5.909	-26.21 percent change Standard Error 5.800	-27.80 percent change Standard Error 5.987	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

Joint swelling is soft tissue swelling that is detectable along the joint margins and is assessed by inspection and direct palpation of the joint, by the examiner. The ACR 66 swollen joint count evaluates the following joints: upper-temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist, metacarpophalangeal, proximal interphalangeal and distal interphalangeal; lower: knee, ankle, midtarsal, metatarsophalangeal and proximal interphalangeal.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=81 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Swollen Joint Count at Week 24	-34.41 percent change Standard Error 5.876	-32.56 percent change Standard Error 5.764	-41.43 percent change Standard Error 5.952	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

The Subject Assessment of Pain was measured asking the participant to place a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents "no pain," and the right-hand boundary (score = 100 mm) represents "pain as severe as can be imagined." The distance from the mark to the left-hand boundary was recorded in millimeters.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=80 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Subject Assessment of Pain at Week 24	28.16 percent change Standard Error 16.111	-6.66 percent change Standard Error 15.902	-9.66 percent change Standard Error 16.320	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

The Subject Global Assessment of Disease Activity was measured asking the participant to place a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents " lowest disease activity," and the right-hand boundary (score = 100 mm) represents " highest disease activity." The distance from the mark to the left-hand boundary was recorded in millimeters.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=80 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Subject Global Assessment of Disease Activity at Week 24	15.04 percent change Standard Error 8.566	0.70 percent change Standard Error 8.453	2.54 percent change Standard Error 8.675	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

The Physician Global Assessment of Disease Activity was measured asking the physician to assess the subject's current arthritis disease activity by placing a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents " lowest disease activity," and the right-hand boundary (score = 100 mm) represents " highest disease activity." The distance from the mark to the left-hand boundary was recorded in millimeters.

Outcome measures

Measure	Placebo n=77 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=80 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Physician Global Assessment of Disease Activity at Week 24	-29.98 percent change Standard Error 4.740	-24.13 percent change Standard Error 4.700	-31.78 percent change Standard Error 4.805	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

The Health Assessment Questionnaire - Disability Index (HAQ-DI) was a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=80 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24	-6.59 percent change Standard Error 5.171	-5.01 percent change Standard Error 5.100	-12.30 percent change Standard Error 5.277	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

C-Reactive Protein (CRP) is a substance produced by the liver that increases in the presence of inflammation in the body. An elevated CRP level is identified with blood tests and is considered a non-specific "marker" for disease.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=81 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the High Sensitivity C-Reactive Protein (CRP) at Week 24	39.14 percent change Standard Error 30.504	47.43 percent change Standard Error 29.972	106.22 percent change Standard Error 31.071	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

The erythrocyte sedimentation rate (ESR) is a blood test that can reveal inflammatory activity. The subject's blood is placed in a tall, thin tube, red erythrocytes gradually settle to the bottom. Inflammation can cause the cells to clump together. Because these clumps of cells are denser than individual cells, they settle to the bottom more quickly.

The ESR test measures the distance red blood cells fall in a test tube in one hour. The farther the red blood cells have descended, the greater the inflammatory response.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=81 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 24	-0.06 percent change Standard Error 9.531	11.99 percent change Standard Error 9.431	-6.60 percent change Standard Error 9.573	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue.

A positive change from baseline score indicates an improvement.

Outcome measures

Measure	Placebo n=78 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=78 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=75 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 24	1.7 units on a scale Standard Error 1.01	0.5 units on a scale Standard Error 1.01	3.4 units on a scale Standard Error 1.03	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; Participants who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders.

The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability.

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants Who Achieve an Improvement of ≥ 0.22 Units From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 24	20.3 percentage of participants	25.6 percentage of participants	32.9 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue.

A positive change from baseline score indicates an improvement.

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants Who Achieve an Improvement of at Least 4 Units From Baseline in the Functional Assessment of Chronic Illness Therapy -Fatigue (FACIT-Fatigue) at Week 24	26.6 percentage of participants	14.6 percentage of participants	26.3 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: Full analysis set; Participants who discontinued early, or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.

EULAR response criteria classify each participant as a good, moderate or non-responder to treatment based on the degree of improvement from baseline and the level of disease activity at the endpoint. EULAR response is derived using the individual subject's DAS28 as the measure of severity of disease.

Good or moderate response is defined as follows: Good response: DAS28 at the time point ≤ 3.2 and improvement from baseline > 1.2 Moderate response: DAS28 at the time point > 3.2 and improvement from baseline > 1.2, or DAS28 at the time point ≤ 5.1 and improvement from baseline > 0.6 and ≤ 1.2

Outcome measures

Measure	Placebo n=79 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=82 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants Who Achieve the European League Against Rheumatism (EULAR) Response Criteria Using CRP at Week 24	40.5 percentage of participants	29.3 percentage of participants	35.5 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included. Reporting Groups

Percentage of participants with an American College of Rheumatology 20% Improvement (ACR 20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 20% improvement in 68 tender joint count;
• ≥ 20% improvement in 66 swollen joint count; and
• ≥ 20% improvement in at least 3 of the 5 following parameters: Subject's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index ([HAQ-DI]); C-Reactive Protein.

Outcome measures

Measure	Placebo n=23 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants With an American College of Rheumatology 20% Improvement (ACR 20) Response at Week 52	47.8 percentage of participants Interval 26.8 to 69.4	51.3 percentage of participants Interval 34.8 to 67.6	30.9 percentage of participants Interval 19.1 to 44.8	38.2 percentage of participants Interval 25.4 to 52.3

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The Health Assessment Questionnaire - Disability Index (HAQ-DI) was a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability.

Outcome measures

Measure	Placebo n=24 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 52	-0.219 units on a scale Standard Deviation 0.4287	-0.192 units on a scale Standard Deviation 0.4728	-0.155 units on a scale Standard Deviation 0.5501	-0.277 units on a scale Standard Deviation 0.4281

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) is 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 were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from Baseline score indicates an improvement.

Outcome measures

Measure	Placebo n=24 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in the Medical Outcome Study Short Form 36-item (SF-36) Physical Functioning Domain at Week 52	2.11 units on a scale Standard Deviation 6.959	3.50 units on a scale Standard Deviation 10.146	2.56 units on a scale Standard Deviation 9.978	5.23 units on a scale Standard Deviation 10.227

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the:

• 28 tender joint count (TJC),
• 28 swollen joint count (SJC),
• Subject's Global Assessment of Disease Activity measured on a 100 mm visual analog scale (VAS), where 0 mm = lowest disease activity and 100 mm = highest;
• Physician's Global Assessment of Disease Activity -measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest.

The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI:

Remission: ≤ 2.8; Low Disease Activity: > 2.8 and ≤ 10; Moderate Disease Activity: > 10 and ≤ 22; High Disease Activity: > 22

Outcome measures

Measure	Placebo n=23 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in the Clinical Disease Activity Index (CDAI) at Week 52	-16.22 units on a scale Standard Deviation 8.722	-20.70 units on a scale Standard Deviation 14.253	-14.77 units on a scale Standard Deviation 14.220	-17.68 units on a scale Standard Deviation 13.331

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the:

• 28 tender joint count (TJC),
• 28 swollen joint count (SJC),
• Subject's Global Assessment of Disease Activity measured on a 100 mm visual analog scale (VAS),, where 0 mm = lowest disease activity and 100 mm = highest;
• Physician's Global Assessment of Disease Activity -measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest.

The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI:

Remission: ≤ 2.8; Low Disease Activity: > 2.8 and ≤ 10; Moderate Disease Activity: > 10 and ≤ 22; High Disease Activity: > 22

Outcome measures

Measure	Placebo n=24 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=56 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants Who Achieve Low Disease Activity or Remission Based on the Clinical Disease Activity Index (CDAI) ≤ 10 at Week 52	16.7 percentage of participants Interval 4.7 to 37.4	41.0 percentage of participants Interval 25.6 to 57.9	25.0 percentage of participants Interval 14.4 to 38.4	27.3 percentage of participants Interval 16.1 to 41.0

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The DAS28 measures the severity of disease at a specific time and is derived from the following variables:

• 28 tender joint count (TJC28)
• 28 swollen joint count (SJC28), which do not include the distal interphalangeal (DIP) joints, the hip joint, or the joints below the knee;
• C-reactive protein (CRP)
• Subject's global assessment of disease activity (SGA).

DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity.

A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.

Outcome measures

Measure	Placebo n=23 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=54 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in the Disease Activity Score 28 (DAS 28) Using CRP at Week 52	-1.18 units on a scale Standard Deviation 0.717	-1.68 units on a scale Standard Deviation 1.243	-1.10 units on a scale Standard Deviation 1.290	-1.38 units on a scale Standard Deviation 1.264

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

Joint tenderness is the presence of pain in a joint when pressure is applied by the examiner to elicit tenderness. The 68 tender joint count evaluates the following joints: upper-temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist, meta-carpophalangeal, proximal interphalangeal and distal interphalangeal; lower: hip, knee, ankle, midtarsal, metatarsophalangeal and proximal interphalangeal.

Outcome measures

Measure	Placebo n=24 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=40 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=56 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Tender Joint Count at Week 52	-55.47 percent change Standard Deviation 24.072	-62.70 percent change Standard Deviation 38.785	-43.88 percent change Standard Deviation 38.728	-54.03 percent change Standard Deviation 43.200

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included..

Joint swelling is soft tissue swelling that is detectable along the joint margins and is assessed by inspection and direct palpation of the joint, by the examiner. The ACR 66 swollen joint count evaluates the following joints: upper-temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist, metacarpophalangeal, proximal interphalangeal and distal interphalangeal; lower: knee, ankle, midtarsal, metatarsophalangeal and proximal interphalangeal.

Outcome measures

Measure	Placebo n=24 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=40 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=56 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Swollen Joint Count at Week 52	-59.40 percent change Standard Deviation 28.088	-67.73 percent change Standard Deviation 42.431	-57.31 percent change Standard Deviation 45.480	-66.74 percent change Standard Deviation 30.277

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The Subject Assessment of Pain was measured asking the participant to place a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents "no pain," and the right-hand boundary (score = 100 mm) represents "pain as severe as can be imagined." The distance from the mark to the left-hand boundary was recorded in millimeters.

Outcome measures

Measure	Placebo n=24 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Subject Assessment of Pain at Week 52	44.63 percent change Standard Deviation 184.396 • Interval -33.23 to 122.5	15.78 percent change Standard Deviation 176.601 • Interval -41.47 to 73.03	-11.69 percent change Standard Deviation 42.608 • Interval -23.2 to -0.17	-3.73 percent change Standard Deviation 98.150 • Interval -30.26 to 22.8

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The Subject Global Assessment of Disease Activity was measured asking the participant to place a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents " lowest disease activity," and the right-hand boundary (score = 100 mm) represents " highest disease activity." The distance from the mark to the left-hand boundary was recorded in millimeters.

Outcome measures

Measure	Placebo n=24 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Subject Global Assessment of Disease Activity at Week 52	14.20 percent change Standard Deviation 76.243	33.31 percent change Standard Deviation 186.069	-5.20 percent change Standard Deviation 73.593	8.22 percent change Standard Deviation 83.321

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The Physician Global Assessment of Disease Activity was measured asking the physician to assess the subject's current arthritis disease activity by placing a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents " lowest disease activity," and the right-hand boundary (score = 100 mm) represents " highest disease activity." The distance from the mark to the left-hand boundary was recorded in millimeters.

Outcome measures

Measure	Placebo n=23 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=40 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=56 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Physician Global Assessment of Disease Activity at Week 52	-41.30 percent change Standard Deviation 35.683	-49.10 percent change Standard Deviation 45.037	-41.19 percent change Standard Deviation 47.417	-44.85 percent change Standard Deviation 41.822

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast Participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The Health Assessment Questionnaire - Disability Index (HAQ-DI) was a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability.

Outcome measures

Measure	Placebo n=24 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=54 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Week 52	-13.32 percent change Standard Deviation 35.634	-10.53 percent change Standard Deviation 49.600	-8.20 percent change Standard Deviation 44.369	-22.46 percent change Standard Deviation 31.856

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast Participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

C-Reactive Protein (CRP) is a substance produced by the liver that increases in the presence of inflammation in the body. An elevated CRP level is identified with blood tests and is considered a non-specific "marker" for disease.

Outcome measures

Measure	Placebo n=23 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=40 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in the High Sensitivity C-Reactive Protein (CRP) at Week 52	13.34 percent change Standard Deviation 90.641	82.14 percent change Standard Deviation 226.455	104.25 percent change Standard Deviation 210.138	79.33 percent change Standard Deviation 205.501

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast Participants as Randomized/ Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The erythrocyte sedimentation rate (ESR) is a blood test that can reveal inflammatory activity. The subject's blood is placed in a tall, thin tube, red erythrocytes gradually settle to the bottom. Inflammation can cause the cells to clump together. Because these clumps of cells are denser than individual cells, they settle to the bottom more quickly.

The ESR test measures the distance red blood cells fall in a test tube in one hour. The farther the red blood cells have descended, the greater the inflammatory response.

Outcome measures

Measure	Placebo n=23 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=40 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=54 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 52	-6.28 percent change Standard Deviation 40.585	17.15 percent change Standard Deviation 244.497	4.83 percent change Standard Deviation 51.294	-15.99 percent change Standard Deviation 53.892

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast Participants as Randomized/ Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue.

A positive change from baseline score indicates an improvement.

Outcome measures

Measure	Placebo n=24 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Change From Baseline in the FACIT-Fatigue Scale Score at Week 52	3.50 units on a scale Standard Deviation 11.085 • Interval 22.1 to 63.4	3.18 units on a scale Standard Deviation 9.236 • Interval 44.6 to 76.6	2.87 units on a scale Standard Deviation 9.650 • Interval 32.0 to 59.4	3.47 units on a scale Standard Deviation 11.115 • Interval 27.0 to 54.1

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast Participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The Health Assessment Questionnaire - Disability Index (HAQ-DI) was a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability.

Outcome measures

Measure	Placebo n=24 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants Who Achieve an Improvement of ≥ 0.22 Units From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 52	58.3 percentage of participants Interval 36.6 to 77.9	43.6 percentage of participants Interval 27.8 to 60.4	40.0 percentage of participants Interval 27.0 to 54.1	58.2 percentage of participants Interval 44.1 to 71.3

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: Apremilast participants as randomized during the apremilast exposure period.

Percentage of participants with an American College of Rheumatology 50% Improvement (ACR 50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 50% improvement in 68 tender joint count;
• ≥ 50% improvement in 66 swollen joint count; and
• ≥ 50% improvement in at least 3 of the 5 following parameters:

Subject's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [(HAQ-DI)]); C-Reactive Protein.

Outcome measures

Measure	Placebo n=29 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=42 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=82 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=76 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants With an American College of Rheumatology 50% Improvement (ACR 50) Response at Week 52	3.4 percentage of participants Interval 0.1 to 17.8	11.9 percentage of participants Interval 4.0 to 25.6	4.9 percentage of participants Interval 1.3 to 12.0	5.3 percentage of participants Interval 1.5 to 12.9

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: Apremilast participants as randomized/transitioned (AAR Population); population consists of all participants who were randomized or transitioned to apremilast at any time during the study. Only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.

Percentage of participants with an American College of Rheumatology 70% Improvement (ACR 70) response. A participant was a responder if the following 3 criteria for improvement from baseline were met:

• ≥ 70% improvement in 68 tender joint count;
• ≥ 70% improvement in 66 swollen joint count; and
• ≥ 70% improvement in at least 3 of the 5 following parameters: Subject's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index ([HAQ-DI]); C-Reactive Protein

Outcome measures

Measure	Placebo n=24 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=40 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=56 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants With an American College of Rheumatology 70% Improvement (ACR 70) Response at Week 52	0.0 percentage of participants Interval 0.0 to 14.2	5.0 percentage of participants Interval 0.6 to 16.9	7.1 percentage of participants Interval 2.0 to 17.3	5.5 percentage of participants Interval 1.1 to 15.1

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast participants as Randomized/Transitioned (AAR) Population; participants with a Baseline value and a Week 52 value are included.

The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from baseline score indicates an improvement.

Outcome measures

Measure	Placebo n=24 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants Who Achieve an Improvement of at Least 4 Units From Baseline in the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) at Week 52	41.7 percentage of participants Interval 22.1 to 63.4	61.5 percentage of participants Interval 44.6 to 76.6	45.5 percentage of participants Interval 32.0 to 59.4	40.0 percentage of participants Interval 27.0 to 54.1

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: The Apremilast Participants as Randomized/ Transitioned (AAR) Population; only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.

The EULAR response criteria classify each subject as a good, moderate or non-responder to treatment based on the degree of improvement from baseline and the level of disease activity at the endpoint. EULAR response is derived using the individual subject's DAS28 as the measure of severity of disease.

Good or moderate response is defined as follows: Good response: DAS28 at the time point ≤ 3.2 and improvement from baseline > 1.2 Moderate response: DAS28 at the time point > 3.2 and improvement from baseline > 1.2, or DAS28 at the time point ≤ 5.1 and improvement from baseline > 0.6 and ≤ 1.2

Outcome measures

Measure	Placebo n=23 Participants Participants initially randomized to receive placebo tablets twice daily.	Apremilast 20 mg n=39 Participants Participants initially randomized to receive 20 mg apremilast tablets twice daily.	Apremilast 30 mg n=54 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.	Apremilast 30 mg n=55 Participants Participants initially randomized to receive 30 mg apremilast tablets twice daily.
Percentage of Participants Who Achieve the European League Against Rheumatism (EULAR) Response Criteria Using CRP at Week 52	69.6 percentage of participants Interval 47.0 to 86.8	82.1 percentage of participants Interval 66.5 to 92.5	63.0 percentage of participants Interval 48.7 to 75.7	65.5 percentage of participants Interval 51.4 to 77.8

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

Percentage of participants with an American College of Rheumatology 20% Improvement (ACR 20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 20% improvement in 68 tender joint count;
• ≥ 20% improvement in 66 swollen joint count; and
• ≥ 20% improvement in at least 3 of the 5 following parameters: Subject's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index ([HAQ-DI]); C-Reactive Protein.

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability.

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

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). The concepts measured by the SF-36 are not specific to any age, disease, or treatment group, allowing comparison of relative burden of different diseases and the relative benefit of different treatments. Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from baseline score indicates an improvement.

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the:

• 28 tender joint count (TJC),
• 28 swollen joint count (SJC),
• Subject's Global Assessment of Disease Activity measured on a 10 mm visual analog scale (VAS), where 0 mm = lowest disease activity and 10 mm = highest;
• Physician's Global Assessment of Disease Activity -measured on a 10 mm VAS, where 0 mm = lowest disease activity and 10 mm = highest.

The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI:

Remission: ≤ 2.8 Low Disease Activity: > 2.8 and ≤ 10 Moderate Disease Activity: > 10 and ≤ 22 High Disease Activity: > 22

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the:

• 28 tender joint count (TJC),
• 28 swollen joint count (SJC),
• Subject's Global Assessment of Disease Activity measured on a 10 mm visual analog scale (VAS), where 0 mm = lowest disease activity and 10 mm = highest;
• Physician's Global Assessment of Disease Activity -measured on a 10 mm VAS, where 0 mm = lowest disease activity and 10 mm = highest.

The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI:

Remission: ≤ 2.8 Low Disease Activity: > 2.8 and ≤ 10 Moderate Disease Activity: > 10 and ≤ 22 High Disease Activity: > 22

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

The DAS 28 measures the severity of disease at a specific time and is derived from the following variables:

• 28 tender joint count (TJC28)
• 28 swollen joint count (SJC28), which do not include the distal interphalangeal (DIP) joints, the hip joint, or the joints below the knee;
• C-reactive protein (CRP)
• Subject's global assessment of disease activity (SGA ). A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.

DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity.

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

The Individual ACR Components were defined as follows:

1. Tender Joint Count (out of 68 joints)

2. Swollen Joint Count (out of 66 joints)

3. Subject Assessment of Pain (0 to 100 mm VAS)

4. Subject Global Assessment of Disease Activity (0 to 100 mm VAS)

5. Physician Global Assessment of Disease Activity (0 to 100 mm VAS)

6. HAQ-DI Score

7. Acute Phase Reactant High Sensitivity C-Reactive Protein (hsCRP, mg/dL) Erythrocyte Sedimentation Rate (ESR)

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue.

A positive change from baseline score indicates an improvement.

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

The Health Assessment Questionnaire - Disability Index (HAQ-DI) was a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability.

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

Percentage of participants with an American College of Rheumatology 50% Improvement (ACR 50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 50% improvement in 68 tender joint count;
• ≥ 50% improvement in 66 swollen joint count; and
• ≥ 50% improvement in at least 3 of the 5 following parameters: Subject's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [(HAQ-DI)]); C-Reactive Protein.

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

Percentage of participants with an American College of Rheumatology 70% Improvement (ACR 70) response. A participant was a responder if the following 3 criteria for improvement from baseline were met:

• ≥ 70% improvement in 68 tender joint count;
• ≥ 70% improvement in 66 swollen joint count; and
• ≥ 70% improvement in at least 3 of the 5 following parameters: Subject's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Subject's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Subject's self-assessment of physical function (Health Assessment Questionnaire - Disability Index ([HAQ-DI]); C-Reactive Protein

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

The FACIT-Fatigue scale was a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue.

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Year 2

Population: Analysis not performed.

EULAR response criteria classify each participant as a good, moderate or non-responder to treatment based on the degree of improvement from baseline and the level of disease activity at the endpoint. EULAR response is derived using the individual subject's DAS28 as the measure of severity of disease.

Good or moderate response is defined as follows: Good response: DAS28 at the time point ≤ 3.2 and improvement from baseline > 1.2 Moderate response: DAS28 at the time point > 3.2 and improvement from baseline > 1.2, or DAS28 at the time point ≤ 5.1 and improvement from baseline > 0.6 and ≤ 1.2

The study was terminated before the 2-year time point was reached due to lack of clinical efficacy.

Outcome measures

Outcome data not reported

Adverse Events

Week 24: Placebo

Serious events: 1 serious events

Other events: 15 other events

Deaths: 0 deaths

Week 24: Apremilast 20 mg

Serious events: 6 serious events

Other events: 26 other events

Deaths: 0 deaths

Week 24: Apremilast 30 mg

Serious events: 4 serious events

Other events: 23 other events

Deaths: 0 deaths

Study Termination: Apremilast 20 mg

Serious events: 16 serious events

Other events: 49 other events

Deaths: 0 deaths

Study Termination: Apremilast 30 mg

Serious events: 7 serious events

Other events: 29 other events

Deaths: 0 deaths

Serious adverse events

Measure	Week 24: Placebo n=79 participants at risk Participants randomized to placebo tablets twice daily during the placebo-controlled phase. Includes data through Week 16 for participants who escaped early, and through Week 24 for all other participants.	Week 24: Apremilast 20 mg n=82 participants at risk Participants randomized to receive 20 mg apremilast tablets twice daily during the 24-week placebo-controlled phase.	Week 24: Apremilast 30 mg n=76 participants at risk Participants randomized to receive 30 mg apremilast tablets twice daily during the 24-week placebo-controlled phase.	Study Termination: Apremilast 20 mg n=153 participants at risk Participants who received 20 mg apremilast, regardless of when the apremilast exposure started (at Week 0, 16, or 24), up until Study Termination.	Study Termination: Apremilast 30 mg n=76 participants at risk Participants who received 30 mg apremilast, regardless of when the apremilast exposure started (at Week 0, 16, or 24), up until Study Termination.
Infections and infestations Cellulitis	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Infections and infestations Staphylococcal abscess	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Infections and infestations Appendicitis	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.2% 1/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.2% 1/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Metabolism and nutrition disorders Diabetes mellitus	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.2% 1/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Psychiatric disorders Bipolar disorder	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Psychiatric disorders Suicidal ideation	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Nervous system disorders Transient ischaemic attack	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.2% 1/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 2/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Cardiac disorders Atrial fibrillation	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.2% 1/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Respiratory, thoracic and mediastinal disorders Costochondritis	1.3% 1/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Injury, poisoning and procedural complications Concussion	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.2% 1/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Infections and infestations Empyema	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Infections and infestations Herpes Zoster	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Infections and infestations Meningitis viral	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.2% 1/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Infections and infestations Viral upper respiratory tract infection	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Mesothelioma malignant advanced	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Blood and lymphatic system disorders Leukocytosis	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Nervous system disorders Loss of consciousness	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Cardiac disorders Supraventricular tachycardia	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Vascular disorders Rheumatoid vasculitis	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Vascular disorders Varicose vein	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Gastrointestinal disorders Peritonitis	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Hepatobiliary disorders Cholelithiasis	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 2/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Renal and urinary disorders Renal failure acute	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
General disorders Foreign body reaction	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Injury, poisoning and procedural complications Pubis Fracture	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Injury, poisoning and procedural complications Wrist Fracture	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Cardiac disorders Cardiac congestive failure	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.65% 1/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.

Other adverse events

Measure	Week 24: Placebo n=79 participants at risk Participants randomized to placebo tablets twice daily during the placebo-controlled phase. Includes data through Week 16 for participants who escaped early, and through Week 24 for all other participants.	Week 24: Apremilast 20 mg n=82 participants at risk Participants randomized to receive 20 mg apremilast tablets twice daily during the 24-week placebo-controlled phase.	Week 24: Apremilast 30 mg n=76 participants at risk Participants randomized to receive 30 mg apremilast tablets twice daily during the 24-week placebo-controlled phase.	Study Termination: Apremilast 20 mg n=153 participants at risk Participants who received 20 mg apremilast, regardless of when the apremilast exposure started (at Week 0, 16, or 24), up until Study Termination.	Study Termination: Apremilast 30 mg n=76 participants at risk Participants who received 30 mg apremilast, regardless of when the apremilast exposure started (at Week 0, 16, or 24), up until Study Termination.
Infections and infestations Nasopharyngitis	5.1% 4/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	7.3% 6/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	3.9% 3/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	7.2% 11/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	7.9% 6/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Infections and infestations Upper respiratory tract infecetion	2.5% 2/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	3.7% 3/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	6.6% 5/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	5.9% 9/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	9.2% 7/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	2.4% 2/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	5.3% 4/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	2.6% 4/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	5.3% 4/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Nervous system disorders Headache	1.3% 1/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	11.0% 9/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	9.2% 7/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	7.8% 12/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	10.5% 8/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Vascular disorders Hypertension	0.00% 0/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	2.4% 2/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	0.00% 0/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	5.9% 9/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.3% 1/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Gastrointestinal disorders Nausea	7.6% 6/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	8.5% 7/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	13.2% 10/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	8.5% 13/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	13.2% 10/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Gastrointestinal disorders Diarrhoea	2.5% 2/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	8.5% 7/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	7.9% 6/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	9.2% 14/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	7.9% 6/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Gastrointestinal disorders Abdominal pain upper	3.8% 3/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	3.7% 3/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	6.6% 5/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	2.0% 3/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	6.6% 5/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.
Gastrointestinal disorders Vomiting	1.3% 1/79 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	1.2% 1/82 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	3.9% 3/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	2.0% 3/153 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.	6.6% 5/76 • All AEs were recorded by the Investigator from the time the participant signed the informed consent to 28 days after the last dose of investigational product.

Additional Information

Anne McClain

Celgene Corporation

Phone: 888-260-1599

Email: clinicaltrialdisclosure@celgene.com

Results disclosure agreements

• Principal investigator is a sponsor employee Results from a center cannot be submitted for publication before results of multicenter study are published unless it is more than 1 year since study completion. Then, Investigator can publish if manuscript is submitted to Celgene 60 days prior to submission. If Celgene decides publication would hinder drug development, Investigator must delay submission for up to 90 days. Investigator must delete confidential information before submission or defer publication to permit patent applications.
• Publication restrictions are in place

Restriction type: OTHER