# Abstract

 

## Introduction The objective of this study was to assess the impact of certolizumab pegol (CZP) treatment on health-related quality of life (HRQoL), fatigue and other patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA). 

## Methods Patients with active RA (N = 982) were randomized 2:2:1 to subcutaneous CZP (400 mg at weeks 0, 2 and 4; followed by CZP 200 mg or 400 mg) plus methotrexate (MTX) every other week, or placebo (PBO) plus MTX. PRO assessments included HRQoL, fatigue, physical function, arthritis pain and disease activity. Adjusted mean changes from baseline in all PROs were obtained using analysis of covariance (ANCOVA) applying last observation carried forward (LOCF) imputation. The proportion of patients achieving clinically meaningful improvements in each PRO was obtained using logistic regression and by applying non-responder imputation to missing values after rescue medication or withdrawal. The correlations between PRO responses and clinical responses were also assessed by tetrachoric correlation using non-responder imputation. 

## Results Patients treated with CZP plus MTX reported significant (*P* < 0.001), clinically meaningful improvements in HRQoL at the first assessment (week 12); reductions in fatigue, disease activity and pain and improvements in physical function were reported at week 1. In particular, CZP-treated patients reported improvements in mental health. Mean changes from baseline in the SF-36 Mental Component Summary (MCS) at week 52 for CZP 200 mg and 400 mg plus MTX, and PBO plus MTX were 6.4, 6.4 and 2.1, respectively (*P* < 0.001). In addition, mental health and vitality scores in CZP-treated patients approached age- and gender-adjusted US population norms. Improvements in all PROs were sustained. Similar benefits were reported with both CZP doses. Changes in SF-36 MCS scores had the lowest correlation with disease activity scores (DAS28) and American College of Rheumatology 20% improvement (ACR20) response rates, while improvements in pain showed the highest correlation. 

## Conclusions Treatment with CZP plus MTX resulted in rapid and sustained improvements in all PROs, indicating that the benefits of CZP extend beyond clinical efficacy endpoints into areas that are more relevant and meaningful for patients on a daily basis. 

## Trial Registration ClinicalTrials.gov NCT00152386. # Results 

## Patients A total of 982 patients were randomized in RAPID 1: 393 to CZP 200 mg plus MTX, 390 to CZP 400 mg plus MTX, and 199 to PBO plus MTX. Of these, 255 (64.9%), 274 (70.3%) and 43 (21.6%) completed 52 weeks of treatment, respectively \[[28](#)\]. At baseline, 82% of patients were female, with mean age 52 years, 77% rheumatoid factor positive, mean disease duration 6.2 years, and having failed a mean of 1.4 disease-modifying antirheumatic drugs (DMARDs; excluding MTX). The burden of RA at baseline was significant, as evidenced by patient-reported global assessment of disease activity, pain, physical function, and fatigue scores (Table [1](#)). In particular, SF-36 domain scores at baseline were markedly lower than age- and gender-matched US population norms, and SF-36 MCS and PCS scores reflected a significant psychological burden as well as physical impairments. ::::table-wrap

::: caption
Baseline disease activity and PRO scores (ITT population)
:::

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Characteristic, mean (SD) CZP 200 mg + MTX CZP 400 mg + MTX PBO + MTX
(n = 393) (n = 390) (n = 199)

______________________________________________________________________

DAS28, range 0-10 6.9 (0.8) 6.9 (0.8) 7.0 (0.9)

PtGA VAS, range 0-100 mm 63.1 (20.3) 64.1 (18.3) 64.2 (19.6)

Pain VAS, range 0-100 mm 62.1 (20.0) 63.8 (17.2) 63.6 (19.9)

HAQ-DI, range 0-3 1.7 (0.6) 1.7 (0.6) 1.7 (0.6)

Fatigue NRS, range 0-10 6.4 (2.0) 6.5 (1.9) 6.7 (2.0)

SF-36

PCS, range 0-100\* 30.9 (6.5) 30.8 (6.8) 30.5 (5.8)

MCS, range 0-100\* 40.0 (11.2) 39.3 (11.1) 38.6 (11.4)

Domains, range 0-100

Physical Functioning 33.4 (21.4) 32.9 (21.2) 32.0 (20.1)

Role Physical 13.3 (23.7) 12.9 (25.4) 11.2 (20.8)

Bodily Pain 30.6 (15.3) 28.9 (15.9) 28.5 (14.7)

General Health 35.3 (16.5) 35.9 (17.5) 34.9 (15.6)

Vitality 35.8 (18.0) 36.1 (18.6) 32.9 (17.4)

Social Functioning 50.9 (23.8) 48.1 (24.0) 46.6 (25.2)

Role Emotional 32.4 (39.1) 28.9 (38.1) 30.9 (38.7)



## Mental Health 53.8 (20.1) 53.5 (20.7) 52.2 (21.2)

- mean US population normative value equals 50

CZP = certolizumab pegol; DAS28 = disease activity score; HAQ-DI =
health assessment questionnaire-disability index; ITT = intent to treat;
MCS = mental component summary; MTX = methotrexate; NRS = numeric rating
scale; PBO = placebo; PCS = physical component summary; PRO =
patient-reported outcomes; PtGA = patient's global assessment of
disease activity; SD = standard deviation; SF-36 = short-form 36-item
health survey; VAS = visual analog scale.:::: 

## Health-related quality of life and fatigue RA patients receiving CZP plus MTX reported statistically significant improvements in HRQoL compared with PBO plus MTX by the first post-baseline assessment (week 12; *P* < 0.001); improvements in all eight SF-36 domains (Table [2](#)), PCS (Figure [1a](#)), and MCS (Figure [1b](#)) were sustained to week 52. In particular, mean changes from baseline at week 12 for the CZP 200 mg plus MTX, CZP 400 mg plus MTX, and PBO plus MTX groups were 5.6, 5.5 and 2.0 for the SF-36 MCS, respectively (Table [2](#); *P* < 0.001). Significantly more patients treated with CZP plus MTX than PBO plus MTX also reported improvements in SF-36 MCS equal to or greater than the MCID from weeks 12 to 52 (Table [2](#); *P* < 0.05). <figure> <p><img src="" /></p> <figcaption>Adjusted mean change from baseline in SF-36 PCS <strong>(a)</strong> and MCS <strong>(b)</strong> scores over 52 weeks (ITT population, LOCF). *<em>P</em> < 0.001 for CZP vs PBO by ANCOVA (LOCF imputation). ANCOVA = analysis of covariance; CZP = certolizumab pegol; ITT = intent to treat; LOCF = last observation carried forward; MCID = minimal clinically important difference; MCS = mental component summary; MTX = methotrexate; PBO = placebo; PCS = physical component summary; SF-36 = short-form 36-item health survey.</figcaption> </figure> ::::table-wrap
::: caption
Improvements in health-related quality of life at weeks 12, 24 and 52
(ITT population, LOCF)*
:::

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```
                     Week 12       Week 24       Week 52                                                                             
```

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```
                     CZP 200 mg   CZP 400 mg   PBO          CZP 200 mg   CZP 400 mg   PBO          CZP 200 mg   CZP 400 mg   PBO
                     + MTX        + MTX        + MTX        + MTX        + MTX        + MTX        + MTX        + MTX        + MTX
                     (n = 393)     (n = 390)     (n = 199)     (n = 393)     (n = 390)     (n = 199)     (n = 393)     (n = 390)     (n = 199)
```

PCS

Mean score (SD) 36.1 (8.9) 36.8 (8.4) 30.7 (7.1) 37.8 (9.5) 38.4 (8.8) 31.4 (7.3) 38.1 (9.5) 38.9 (8.9) 31.5 (7.4)

Mean change from BL 5.8 (0.5)† 6.4 (0.6)† 0.7 (0.6) 7.7 (0.4)† 8.3 (0.4)† 1.8 (0.6) 7.8 (0.4)† 8.6 (0.4)† 1.7 (0.6)

% MCID 38.2† 36.5† 21.4 46.6† 51.7† 10.9 42.2† 46.1† 11.5

MCS

Mean score (SD) 45.5 (11.5) 45.7 (11.6) 41.4 (10.8) 45.6 (11.5) 45.6 (11.6) 41.3 (10.7) 45.8 (11.4) 45.4 (11.5) 41.1 (10.8)

Mean change from BL 5.6 (0.7)† 5.5 (0.7)† 2.0 (0.8) 6.3 (0.6)† 6.5 (0.6)† 2.3 (0.8) 6.4 (0.6)† 6.4 (0.6)† 2.1 (0.8)

% MCID 36.0‡ 33.3 28.1 41.1† 41.9† 13.0 39.2† 38.1† 9.9

Physical Functioning

Mean score (SD) 45.1 (25.8) 46.1 (24.6) 31.2 (21.0) 47.6 (26.5) 48.8 (24.7) 33.3 (22.2) 49.3 (26.9) 50.3 (24.9) 33.1 (22.3)

Mean change from BL 11.4 (1.4)† 12.2 (1.4)† -1.0 (1.7) 15.6 (1.2)† 16.5 (1.2)† 1.9 (1.6) 16.7 (1.2)† 17.9 (1.2)† 1.7 (1.6)

% MCID 32.1† 33.6† 18.4 42.0† 46.6† 10.7 38.0† 44.3† 9.7

Role Physical

Mean score (SD) 34.1 (38.3) 33.9 (38.5) 15.0 (28.0) 37.2 (40.4) 38.6 (40.2) 18.0 (30.2) 37.7 (40.3) 39.2 (41.8) 17.3 (30.2)

Mean change from BL 24.8 (2.4)† 24.2 (2.5)† 6.4 (2.9) 27.8 (2.0)† 29.1 (2.0)† 9.4 (2.8) 26.9 (2.1)† 29.1 (2.0)† 8.1 (2.9)

% MCID 24.9† 24.5‡ 13.9 33.0† 36.8† 10.3 32.2† 31.1† 8.2

Bodily Pain

Mean score (SD) 47.8 (20.1) 49.6 (20.4) 33.1 (18.5) 51.4 (22.3) 53.4 (20.8) 33.2 (19.4) 52.0 (22.8) 53.9 (22.2) 34.0 (20.1)

Mean change from BL 18.0 (1.3)† 20.2 (1.4)† 4.5 (1.6) 23.3 (1.1)† 25.8 (1.1)† 6.3 (1.5) 23.5 (1.1)† 26.2 (1.1)† 6.8 (1.6)

% MCID 45.9‡ 43.3‡ 33.3 52.5† 58.2† 15.9 48.8† 50.7† 14.9

General Health

Mean score (SD) 44.0 (18.9) 48.4 (19.6) 36.9 (18.0) 47.4 (19.6) 48.5 (19.7) 37.2 (17.1) 47.5 (20.3) 47.6 (19.2) 36.9 (16.6)

Mean change from BL 8.9 (1.1)† 11.1 (1.1)† 2.4 (1.3) 13.2 (0.9)† 14.0 (0.9)† 3.7 (1.2) 13.0 (0.9)† 13.0 (0.9)† 3.1 (1.3)

% MCID 31.1 32.7‡ 24.2 44.3† 45.7† 11.3 40.3† 40.6† 10.3

Vitality

Mean score (SD) 48.2 (21.4) 50.0 (21.3) 37.0 (19.1) 50.9 (21.6) 51.4 (21.3) 38.3 (19.9) 50.7 (21.7) 51.1 (20.9) 38.4 (20.0)

Mean change from BL 12.9 (1.3)† 14.4 (1.4)† 2.8 (1.6) 15.5 (1.1)† 16.2 (1.1)† 4.7 (1.5) 15.1 (1.0)† 15.6 (1.0)† 4.5 (1.5)

% MCID 35.5‡ 35.3‡ 27.0 45.1† 45.7† 12.2 40.8† 42.8† 11.2

Social Functioning

Mean score (SD) 64.8 (25.2) 64.0 (24.4) 50.6 (25.1) 66.6 (25.7) 65.7 (24.4) 50.8 (25.7) 67.2 (25.9) 66.2 (25.3) 50.6 (25.4)

Mean change from BL 15.6 (1.6)† 14.7 (1.6)† 2.6 (1.9) 18.3 (1.3)† 18.1 (1.3)† 3.4 (1.8) 18.5 (1.3)† 18.6 (1.3)† 3.2 (1.8)

% MCID 39.5‡ 36.8 30.1 45.3† 48.3† 11.7 43.5† 44.4† 11.2

Role Emotional

Mean score (SD) 50.4 (43.0) 50.8 (43.9) 37.4 (41.2) 50.2 (42.9) 54.1 (43.4) 36.3 (40.9) 52.8 (43.0) 53.9 (43.5) 35.7 (40.6)

Mean change from BL 19.2 (2.8)‡ 19.3 (2.9)‡ 6.6 (3.3) 22.2 (2.2)† 26.4 (2.2)† 7.8 (3.1) 23.9 (2.3)† 26.1 (2.2)† 7.1 (3.1)

% MCID 25.5‡ 22.4 17.4 31.7† 33.2† 10.8 29.0† 29.7† 9.2

Mental Health

Mean score (SD) 64.1 (19.4) 64.5 (20.2) 56.1 (19.7) 64.3 (20.1) 63.8 (20.2) 56.3 (21.1) 64.3 (20.4) 63.3 (19.9) 55.8 (21.1)

Mean change from BL 9.3 (1.2)† 8.9 (1.2)† 2.1 (1.4) 11.0 (1.0)† 10.5 (1.0)† 3.7 (1.3) 10.7 (1.0)† 9.9 (1.0)† 3.0 (1.4)



## % MCID 33.3‡ 27.4 27.0 40.8† 37.1† 14.3 37.3† 33.9† 11.2

\*SF-36 PCS, MCS and domain scores, adjusted mean change from baseline,
and percentage of patients reporting improvements meeting or exceeding
MCID. Changes from baseline were analyzed using ANCOVA with region and
treatment as factors, and baseline as covariate (using LOCF imputation
of missing data).

†*P* < 0.001; ‡*P* < 0.05.

BL = baseline; CZP = certolizumab pegol; ITT = intent to treat; LOCF =
last observation carried forward; MCID = minimal clinically important
difference; MCS = mental component summary; MTX = methotrexate; PBO =
placebo; PCS = physical component summary; SD = standard deviation;
SF-36 = short-form 36-item health survey.:::: Figure [2](#) shows the SF-36 domain scores for the CZP 200 mg and PBO groups compared with normative values from an age/gender-matched US population. Baseline domain scores reflect the largest decrements in the Role Emotional mental domain, and the physical domains of Role Physical and Physical Function (Figure [2](#)). Improvements exceeding MCID were evident in all domains at week 12 and were sustained through week 52, with the Mental Health and Vitality domains approaching US population normative values. <figure> <p><img src="" /></p> <figcaption>Spydergram of SF-36 domains at baseline and weeks 12 and 52 (ITT population, LOCF). Physical domains: Physical Function (PF), Role Physical (RP), Bodily Pain (BP), General Health (GH). Mental domains: Vitality (VT), Social Function (SF), Role Emotional (RE), Mental Health (MH). Domain scores are plotted from 0 (worst) at the center to 100 (best) at the outside; demarcations along axes of the domains present changes of 10 points, representing 1 - 2 times MCID. As the RAPID 1 protocol included RA subjects recruited outside North America, available US normative data offer a 'benchmark', but less realistic goal for therapy. Changes from baseline for all SF-36 domains were statistically significant for CZP versus PBO at Weeks 12 and 52; <em>P</em> < 0.05. CZP = certolizumab pegol; ITT = intent to treat; LOCF = last observation carried forward; MCID = minimal clinically important difference; PBO = placebo; RA = rheumatoid arthritis; RAPID 1 = RA PreventIon of Structural Damage 1; SF-36 = short-form 36-item health survey.</figcaption> </figure> Statistically significant and clinically meaningful reductions in fatigue were reported by more patients treated with CZP plus MTX than PBO plus MTX throughout the study (*P* < 0.001; Figure [3a](#)). At week 1, mean changes from baseline in FAS were -1.3 and -1.2 for CZP 200 mg and 400 mg plus MTX, respectively, compared with -0.5 for the PBO plus MTX group (*P* < 0.001), and by the end of the study (week 52), mean changes from baseline were -2.6, -2.5 and -0.8, respectively (*P* < 0.001). Statistically more CZP plus MTX patients also reported reductions in fatigue equal to or greater than the MCID compared with PBO plus MTX (*P* < 0.001; Figure [4a](#)). At week 52, 48.9% and 48.6% of CZP 200 mg- and 400 mg-treated patients reported fatigue reductions equal to or greater than the MCID compared with only 12.6% of PBO-treated patients (*P* < 0.001). <figure> <p><img src="" /></p> <figcaption>Improvements in fatigue <strong>(a)</strong>, physical function <strong>(b)</strong>, pain <strong>(c)</strong> and disease activity <strong>(d)</strong> over 52 weeks (ITT population, LOCF). \*<em>P</em> < 0.001 for CZP vs PBO by ANCOVA (LOCF imputation). ANCOVA = analysis of covariance; CZP = certolizumab pegol; FAS = fatigue assessment scale; HAQ-DI = health assessment questionnaire - disability index; ITT = intent to treat; LOCF = last observation carried forward; MCID = minimal clinically important difference; MTX = methotrexate; PBO = placebo; PtGA = patient's global assessment of disease activity; VAS = visual analog scale.</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>Patients (%) achieving minimum clinically important differences in fatigue <strong>(a)</strong>, physical function <strong>(b)</strong>, pain <strong>(c)</strong>, and disease activity <strong>(d)</strong> over 52 weeks (ITT population, LOCF). *<em>P</em> < 0.001 for CZP vs PBO by repeated measures logistic regression. CZP = certolizumab pegol; FAS = fatigue assessment scale; HAQ-DI = health assessment questionnaire - disability index; ITT = intent to treat; LOCF = last observation carried forward; MCID = minimal clinically important difference; MTX = methotrexate; PBO = placebo; PtGA = patient's global assessment of disease activity; VAS = visual analog scale.</figcaption> </figure> 

## Patient-reported physical function, pain and global assessment of disease activity Rapid, statistically significant improvements in physical function, as assessed by HAQ-DI, were reported by patients treated with CZP plus MTX compared with PBO plus MTX (Figure [3b](#); *P* < 0.001). By the end of the study at week 52, mean scores were 1.1 for both CZP plus MTX treatment groups, respectively, compared with baseline scores of 1.7. Significantly more CZP plus MTX-treated patients than PBO plus MTX-treated patients reported HAQ-DI improvements equal to or greater than the MCID throughout the trial (*P* < 0.001). CZP-treated patients also reported statistically significant improvements in physical function that met or exceeded MCID as reported above for SF-36 PCS (Figure [1a](#)) and Physical Functioning domain scores (Table [2](#)). CZP-treated patients reported significant improvements from baseline in pain VAS (Figure [3c](#)) and patient's global assessment of disease activity (Figure [3d](#); *P* < 0.001), evident at week 1 and sustained through week 52. Significantly more CZP plus MTX-treated patients than PBO plus MTX-treated patients also reported clinically meaningful reductions in pain (Figure [4c](#)) and improvements in global assessment of disease activity (Figure [4d](#)) throughout the trial (*P* < 0.001). Results were similar regardless of CZP dose (200 mg or 400 mg). Sensitivity analyses showed that improvements in all PROs were consistent with the LOCF results. 

## Comparison of patient-reported outcomes with DAS28 and ACR20 response rates To explore the relation between the patient-reported outcomes and the physician-reported assessments of disease, PRO responses (as defined by improvements in physical function, pain, fatigue and SF-36 scores equal to or greater than the MCIDs) were compared with DAS28 responses (defined as a decrease from baseline of ≥ 1.2) and ACR20 response rates at week 52. In general, PRO responses were in agreement with clinical responses as determined by either improvements in RA signs and symptoms (ACR20 response rates) or decrease in disease activity (DAS28 scores; Table [3](#)). As expected, classification of response according to physical function and pain was highly correlated with ACR20 response rates, with 88.8% and 93.6% of patients treated with CZP 200 mg plus MTX being classified the same by physical function/ACR20 and pain/ACR20, respectively. Correlations between fatigue and ACR20 responses were also high (90.0%) as were those between patient's global assessment of disease activity (98.0%), while changes in HRQoL (SF-36 PCS and MCS scores) had the lowest correlation with ACR20 responses (84.3% and 77.4%, respectively). ::::table-wrap
::: caption
PRO response by clinical response* at week 52 (CZP 200 mg plus MTX
group, ITT population)
:::

```
                                                 ACR20 response by (%)                                                                                                                                  
```

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```
                                                 SF-36 PCS                 SF-36 MCS         HAQ-DI            Pain              FAS               PtGA                                                 
                 **Clinical response**           No                        Yes               No                Yes               No                Yes               No     Yes    No     Yes    No     Yes
```

**PRO response** No 45.5 14.7 43.4 19.5 44.4 8.7 44.4 3.8 44.1 7.1 86.9 2.0
Yes 1.0 38.8 3.1 33.9 2.6 44.4 1.0 38.2 2.8 45.9 0 11.1
Tetrachoric correlation (ASE) 0.9450 (0.0178) 0.8389 (0.0356) 0.9504 (0.0152) 0.9804 (0.0076) 0.9574 (0.0135) 0.9996 (0.0053)

```
                                                 **DAS response by (%)**                                                                                                                                
                                                                                                                                                                                                        
                                                 **SF-36 PCS**             **SF-36 MCS**     **HAQ-DI**        **Pain**          **FAS**           **PtGA**                                             
                                                                                                                                                                                                        
                 **Clinical response**           No                        Yes               No                Yes               No                Yes               No     Yes    No     Yes    No     Yes
```

**PRO response** No 44.2 16.5 43.2 20.4 43.6 10.0 43.6 5.1 43.9 7.7 44.1 4.9
Yes 1.0 38.2 2.1 34.4 2.1 44.4 2.1 49.2 1.8 46.7 1.5 49.5
Tetrachoric correlation (ASE) 0.9344 (0.0204) 0.8674 (0.0322) 0.9496 (0.0156) 0.9776 (0.0085) 0.9672 (0.0114) 0.9833 (0.0069)

\*Clinical response = DAS or ACR20 response.

ACR20 = American College of Rheumatology 20% improvement; ASE =
asymptomatic standard error; CZP = certolizumab pegol; DAS = disease
activity score; FAS = fatigue assessment scale; HAQ-DI = health
assessment questionnaire-disability index; ITT = intent to treat; MCS =
mental component summary; MTX = methotrexate; PtGA = patient's global
assessment; PCS = physical component summary; PRO = patient-reported
outcomes; SF-36 = short-form 36-item health survey:::: Results were similar for correlations between PRO responses and DAS28 responses, with SF-36 PCS and MCS scores showing the lowest correlations with DAS28 responses (82.4% and 77.6%, respectively) and physical function, fatigue, pain and global assessment of disease activity showing the highest correlations (88.0%, 90.6%, 92.8% and 93.6%, respectively).


Extracted trial result:
Outcome: Short-Form 36-Items improvement (continuous)
Intervention: Certolizumab 400 mg
Comparator: Control
Intervention group size: 390
Intervention mean: 38.9
Intervention standard deviation: 8.9
Comparator group size: 199
Comparator mean: 31.5
Comparator standard deviation: 7.4
Notes: Used values for PCS after 52 weeks (final timepoint).