A Study to Determine the Effect of Methotrexate (MTX) Dose on Clinical Outcome and Ultrasonographic Signs in Subjects With Moderately to Severely Active Rheumatoid Arthritis (RA) Treated With Adalimumab (MUSICA)

The DAS28(CRP) score includes 28 tender joint counts, 28 swollen joint counts, C-reactive protein, and participant's global assessment of disease activity. Scores on the DAS28(CRP) range from 0 to 10. A DAS28(CRP) score ≥ 5.1 indicates high disease activity, and a DAS28(CRP) score \< 2.6 indicates clinical remission. Least squares means and 95% CI were from 2-way ANCOVA model with effects for baseline DAS28(CRP) value, treatment group, and prior methotrexate dose group.

Time frame: Week 24

Population: All participants who were randomized and received at least one dose of study medication (intent to treat). Missing responses were imputed using last observation carried forward (LOCF).

The HAQ-DI is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily 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 were summed and averaged to provide an overall score ranging from 0 (no disability) to 3 (very severe, high dependency disability). The minimal clinically important difference (MCID) defined for the HAQ-DI is a change from baseline of ≤ -0.22. Normal physical function is defined by HAQ-DI score of \< 0.5. Negative change from baseline in the overall score indicates improvement.

Time frame: Baseline, 24 weeks

Population: All participants who were randomized and received at least one dose of study medication (intent to treat). Missing responses were imputed by carrying forward the value at early termination visit (LOCF).

Response, as defined by ACR50 criteria at week 24. A participant is a responder if the following 3 criteria for improvement from baseline are met: ≥ 50% improvement in tender joint count; ≥ 50% improvement in swollen joint count; and ≥ 50% improvement in at least 3 of the 5 following parameters: physician global assessment of disease activity, participant global assessment of disease activity, participant assessment of pain, disability index of the health assessment questionnaire, and acute phase reactant value (C-reactive protein).

Time frame: Baseline, 24 weeks

Population: All participants who were randomized and received at least one dose of study medication (intent to treat). Missing responses were imputed by carrying forward the value at early termination visit (LOCF).

Response, as defined by ACR70 criteria at week 24. A participant is a responder if the following 3 criteria for improvement from baseline are met: ≥ 70% improvement in tender joint count; ≥ 70% improvement in swollen joint count; and ≥ 70% improvement in at least 3 of the 5 following parameters: physician global assessment of disease activity, participant global assessment of disease activity, participant assessment of pain, disability index of the health assessment questionnaire, and acute phase reactant value (C-reactive protein).

Time frame: Baseline, 24 weeks

Population: All participants who were randomized and received at least one dose of study medication (intent to treat). Missing responses were imputed by carrying forward the value at early termination visit (LOCF).

PD U/S assessed the severity of synovial inflammation in both hands (bilateral wrists, metacarpophalangeal joints 2, 3, 5, and metatarsophalangeal joint 5). Bilateral images based on dorsal midline imaging of the wrist, dorsal and volar imaging of metacarpophalangeal joints, and dorsal imaging alone of metatarsophalangeal joints are scored using a 4-grade scale: grade 0 or normal = normal joint (no Doppler signal); grade 1 or mild = mild synovitis (≤ 3 isolated signals); grade 2 or moderate = moderate synovitis (\> 3 isolated signals or a confluent signal in \< 50% of synovial area); grade 3 or marked = marked synovitis (signals in ≥ 50% of the synovial area). Each image is rated 0 to 3, for a total possible score ranging from 0 to 48 (16\*0, 16\*3) for 2 hands. Higher grade/score=more severe disease. Change = week 24 score - baseline score.

Time frame: Baseline, 24 weeks

Population: All participants who were randomized and received at least one dose of study medication (intent to treat). Missing responses were imputed by carrying forward the value at early termination visit (LOCF).

The least squares mean percentage change in MOS Sleep Problem Index 9 from baseline to week 24. The MOS Sleep Problem Index 9 consists of 9 questions to assess sleep, including how long it takes the participant to fall asleep (1=0 to 15 minutes, to 5=more than 60 minutes); and aspects of related to quality of sleep, including how often the participant felt that the sleep was not quiet, felt rested upon waking, awakened short of breath or with a headache, felt drowsy during the day, had trouble falling sleep, how often were awaken, had trouble staying awake during the day, and got needed amount of sleep (1=all the time; 5=none of the time). Least squares means and 95% CI were from 2-way ANCOVA model with effects for baseline MOS Sleep Problem Index value, treatment group, and prior methotrexate dose group.

Time frame: Baseline, 24 weeks

Population: All participants who were randomized and received at least one dose of study medication (intent to treat). Missing responses were imputed by carrying forward the value at early termination visit (LOCF).

Serum trough concentrations of adalimumab assessed at week 24 (24 weeks after the 1st dose).

Time frame: Week 24

Population: All participants with available pharmacokinetics at week 24: For Adalimumab + Low Dose Methotrexate, n = 134; for Adalimumab + High Dose Methotrexate, n = 140.