Patients and methods

Patients and study treatment

The patient population and study design have been reported previously.9 Briefly, eligible patients were randomised equally to receive CP-690,550 5 mg, 15 mg or 30 mg twice daily, or placebo. Patients continued their stable background arthritis treatment.

Study assessments

Efficacy measurements were assessed at baseline and weeks 1, 2, 4, 6 (end of treatment) and 8 (first follow-up visit). To determine the patient’s assessment of arthritis pain and patient’s global assessment of disease activity, 100 mm visual analogue scales were used. Physical functioning was measured using the Health Assessment Questionnaire-Disability Index (HAQ-DI) and health status was measured using the self-administered Short Form-36 (SF-36; version 2, standard 4-week recall). The SF-36 was completed by patients at baseline, week 6 and during the post-dosing follow-up period at week 12.

Changes from baseline were compared with published thresholds for minimum clinically important differences, identifying improvements perceptible to patients from baseline to week 6. In this study, for the HAQ-DI, the minimum clinically important difference that reflected a meaningful improvement in physical function was a decrease of ⩾0.3. A change of 5 points in domain scores and 2.5 points in the physical and mental components summary scores was considered to reflect minimum clinically important changes in the SF-36.10

Statistical analyses

Full details of the statistical analyses used are described in the article by Kremer et al.9 Briefly, dichotomous variables were analysed at each visit using a normal approximation to the binomial distribution for the difference in response rates, with no pooled standard deviation and no continuity correction. Continuous variables were analysed using a longitudinal, linear mixed model and missing values were assumed to be missing at random. Statistical significance was declared when the p value was ⩽0.05, with no adjustment for multiple comparisons. Effect sizes for the mean comparison of continuous variables were estimated using Cohen’s d.

Results

Patient disposition has been described previously,9 and details of the study population at baseline are given in the online supplementary table W1.

Patient’s assessment of arthritis pain

Figure 1a shows the mean change from baseline in pain scores for all treatment groups. Decreases from baseline were statistically significant compared with placebo at all time points (p<0.01) and in all treatment groups. At week 6, the differences from baseline in mean (SE) visual analogue scale scores for the patient’s assessment of arthritis pain were −31.42 (3.16) (p⩽0.001; D = −0.84; 95% CI −27.93 to −10.39; longitudinal linear model), −37.67 (2.98) (p<0.001; D = −1.12; 95% CI −33.99 to −16.84), −42.89 (3.14) (p<0.001; D = −1.36; 95% CI −39.42 to −21.84) and −12.26 (3.22) in the 5 mg, 15 mg, 30 mg and placebo treatment groups, respectively. Responses analysed by percentage improvement are shown in online supplementary fig W1.

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Figure 1

(a) Mean (SE) change from baseline in the patient’s assessment of arthritis pain; (b) mean (SE) change from baseline in the patient’s assessment of disease activity.

Patient’s assessment of disease activity

Patients treated with CP-690,550 showed statistically significant (p<0.01; longitudinal linear model) decreases from baseline in disease activity at all time points compared with placebo (fig 1b). Decreases from baseline were highly significant (p<0.001) at all time points in the CP-690,550 15 mg and 30 mg twice-daily treatment groups.

Health Assessment Questionnaire-Disability Index

Dose-dependent improved physical functioning was demonstrated by decreases in HAQ-DI scores (table 1). Decreases from baseline were statistically significant (p<0.05; longitudinal linear model) compared with placebo at all time points and CP-690,550 doses, with p values <0.001 occurring in the CP-690,550 30 mg twice-daily treatment group at all time points and in the CP-690,550 5 mg and 15 mg twice-daily treatment groups at weeks 4 and 6. The percentages of patients achieving clinically meaningful improvements in HAQ-DI score (⩾0.3 units) at week 6 was statistically significant for CP-690,550 5 mg (p = 0.03; 95% CI 2.2 to 40.3), 15 mg (p<0.001; 95% CI 20.7 to 56.1) and 30 mg (p<0.001; 95% CI 22.3 to 58.3) twice-daily treatment groups compared with placebo (table 1; normal approximation test).

SF-36

Statistically significant differences between the CP-690,550 30 mg twice-daily treatment and placebo groups were seen across all domains of the SF-36 (fig 2a). At week 6, statistically significant changes from baseline in the physical component summary score were recorded for CP-690,550 5 mg (8.3; p<0.001; D = 0.72; 95% CI 2.6 to 8.5), 15 mg (8.8; p<0.001; D = 0.80; 95% CI 3.1 to 9.1) and 30 mg (9.9; p<0.001; D = 0.94; 95% CI 4.1 to 10.1) twice-daily treatment groups compared with placebo (2.7) (longitudinal linear model). Clinically meaningful improvement in the physical component summary score was achieved by 80% (p<0.001; 95% CI 16.9% to 52.9%), 73% (p = 0.005; 95% CI 8.4% to 46.1%), 79% (p<0.001; 95% CI 15.0% to 51.8%) and 45% of patients, respectively, in the CP-690,550 5 mg, 15 mg, 30 mg twice-daily and placebo treatment groups (normal approximation test; fig 2b). Mean changes from baseline to week 6 in mental component summary scores were 5.30 (p = 0.18; D = 0.26; 95% CI −1.26 to 6.57), 5.85 (p = 0.11; D = 0.32; 95% CI −0.74 to 7.15), 9.81 (p<0.001; D = 0.71; 95% CI 3.16 to 11.16) and 2.64 for the 5 mg, 15 mg, 30 mg twice-daily and placebo treatment groups, respectively (longitudinal linear model). Clinically meaningful improvement in the mental component summary score was achieved by 57% (p = 0.63; 95% CI −14.8% to 24.5%), 62% (p = 0.33; 95% CI −10.0% to 29.1%), 67% (p = 0.13; 95% CI −4.5% to 34.5%) and 52% of patients, respectively, in the CP-690,550 5 mg, 15 mg, 30 mg twice-daily and placebo treatment groups (normal approximation test).

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Figure 2

(a) Mean (SE) change from baseline at week 6 in SF-36 domain and component scores; (b) percentage of patients with clinically meaningful improvement in SF-36 domain (>5) and component (>2.5) scores at week 6.

Discussion

Treatment with CP-690,550 resulted in consistent clinically meaningful and highly statistically significant patient-reported improvements in disease-related symptoms, physical functioning and health status. Improvements were rapid, with patients reporting improvements in pain, disease activity and functional status by week 1 of treatment with CP-690,550. Mean changes from baseline exceeded indicators of minimal clinically relevant benefit and a large majority of patients achieved clinically meaningful improvements in their condition by week 6. The rapid and broadly consistent patient-reported benefits of treatment with CP-690,550 were in line with the primary efficacy data from this trial.9

The results reported here provide important new information, in addition to the primary efficacy and safety data from this study. It has been argued that PRO measures should be considered of equal importance to traditional measures of clinical efficacy, since they bring the patient’s voice into the trial. Recent data suggest that the SF-36 bodily pain, SF-36 physical functioning, SF-36 physical component summary, HAQ-DI, patient’s assessment of arthritis pain and the patient’s global assessment of disease activity may be more sensitive to detecting differences between treatment and placebo groups within clinical trials than tender joint counts.4 PRO measures are also indicative of future disability and healthcare costs.11 For instance, functional status has been shown to be the most consistent and strongest determinant of the costs of RA. Declining functional status results in significant increases in costs to both the patient and the healthcare system.12 Long-term follow-up of a patient’s physical functioning status is also a powerful predictor of mortality in RA.13

While direct comparisons with results from trials of other agents cannot be made, the PRO measures data reported here compare favourably with those achieved with other approved agents used as monotherapy in the treatment of RA. A 12-week, placebo-controlled, phase 2 monotherapy study examined the efficacy and safety of adalimumab (Humira) 20 mg, 40 mg or 80 mg in patients unresponsive to previous traditional DMARD treatment (baseline 28-joint count Disease Activity Score (DAS28) of 7.0, compared with 5.7–6.2 in this CP-690,550 study).14 After 12 weeks, patients in the 40 mg adalimumab treatment group (the dose chosen for the extension phase of the study beyond week 12) reported a mean (SD) point decrease in pain score of 35.3 (29.4) (baseline 73.4 (19.4)), a 37.6 (27.9) point decrease in self-reported disease activity (baseline 75.7 (19.5)) and a 0.47 (0.43) point decrease in HAQ-DI (baseline 1.73 (0.68)).14 Despite the shorter duration of this CP-690,550 trial, the results reported here compare favourably, with a mean (SE) decrease in pain score of 37.7 (3.0) (baseline 67.5 (2.9)), 37.8 (3.0) in self-reported disease activity (baseline 69.3 (2.9)) and 0.72 (0.06) in HAQ-DI (baseline 1.66 (0.08)) for patients in the CP-690,550 15 mg treatment group. However, it should be noted that longer-term studies have shown that adalimumab in combination with methotrexate is more efficacious than monotherapy.15 (For a full report of all ACR component scores in the CP-690,550 study, please see Kremer et al.9)

Treatment with CP-690,550 resulted in rapid and sustained clinically meaningful and statistically significant improvements in patients’ disease-related symptoms, health and functional status. Trials of longer duration will further characterise the potential for CP-690,550 to relieve the burden of RA on patients, their family or caregivers and the healthcare system.