Study to Investigate the Long-Term Safety Profile and Efficacy of Cimzia over 4 Years of Continuous Treatment in Patients with axSpA

RAPID-axSpA investigated the long-term safety profile and efficacy of Cimzia over 4 years of continuous treatment in patients with axial spondyloarthritis (axSpA), including both radiographic and non-radiographic axSpA [Figure 1].^1,2,3

Figure 1.
RAPID-axSpA trial design.
axSpA, axial spondyloarthritis; CZP, certolizumab pegol; LD, loading dose; Q2W, every 2 weeks; Q4W, every 4 weeks; PBO, placebo.
Adapted from: Landewé et al., 2013.

The RAPID-axSpA study randomised 325 patients, with 111 patients receiving Cimzia 400mg Q4W, 107 patients receiving Cimzia 200mg Q2W (following loading dose of 400mg at weeks 0, 2 and 4) and 107 patients receiving placebo. The trial was double-blind through to week 24.^1,2,3

At week 16 placebo non-responders were re-randomised 1:1 to the Cimzia arms. At week 24 the remaining placebo cohort were re-randomised 1:1 to the Cimzia arms and the trial remained dose-blind. From week 48 to 204 the trial was open label.^1,2,3,

Cimzia in RAPID-axSpA: Key Efficacy Trial Data

Primary efficacy endpoints

The primary outcome of RAPID-axSpA was ASAS20 response at week 12.^1,2,3

Figure 2.
ASAS response rates in axSpA patients from week 0 to week 24. ASAS20 response rate in the three treatment groups from week 0 to week 24.* p <0.001; § p=0.004 CZP versus PBO (2-sided Wald asymptotic test). ‡Placebo patients escaping at week 16 (n=56) were considered non-responders at weeks 16-24. Data corresponds to the NRI (non-responder imputation). PBO, placebo; CZP, Q2W, Q4W.
Adapted from: Landewé et al., 2013.

At week 12, a statistically significant higher proportion of patients in the Cimzia 200mg Q2W group (57.7%) and Cimzia 400mg Q4W group (63.6%) achieved an ASAS20 response compared with placebo (38.3%) (p=0.004 and p<0.001, respectively). This difference in ASAS20 response continued through week 24 in both Cimzia treatment groups and was achieved as early as week 1 (p<0.001).^1,2,3

ASA20 response at week 20, defined as an improvement of ≥ 20% and ≥ 1 unit on a 0-10 NRS, numerical-rating scale, in ≥ 3 of the following: Patient's Global Assessment of Disease Activity, Pain assessment, Function, Inflammation and no deterioration in the remaining area.

Figure 3.
At week 204 (NRI), of Cimzia randomised patients, ASAS20 and ASAS40 responses were achieved by 54.1 and 44.0% (NRI) and 83.7 and 68.1% (OC), respectively showing sustained efficacy from week 24.^1,2,3

Of the 325 patients randomised, 163 were included in the imaging set. Of these patients, 158 (97%) remained in the study to week 24, 146 (90%) to week 48 and 132 (81%) to week 96.⁴

Figure 4.
MRI remission in the imaging set of patients (n=163) from the RAPID-axSpA trial. Remission rates to week 96 in patients with (A) SI joint inflammation, (B) spinal inflammation and (C) both SI joint and spinal inflammation. Observed case data shown at week 12 for patients randomised to CZP at baseline and for all patients regardless of baseline randomisation thereafter. axSpA, CZP, nr-axSpA, non-radiographic axial spondyloarthritis; r-axSpA, radiographic axial spondyloarthritis; SI.
Adapted from: Braun et al., 2017.

• At week 12, the observed mean change from baseline (SD, standard deviation) in the SPARCC SI joint score was significantly greater for CZP-treated patients than patients given placebo: −4.8 (8.6) for patients treated with CZP (dose combined) compared with −1.6 (7.8) for placebo (p<0.001).⁴
• Improvements were seen in the spine for CZP-treated patients, with observed mean change from baseline scores (SD) in the Berlin score at week 12 of −2.9 (4.2) in the CZP-treated group (dose combined) compared with 0.2 (4.8) in the placebo group p<0.001.⁴
• Improvements to week 12 with both MRI-outcome measures were maintained through the dose-blind (to week 48) and the open-label (to week 96) trial periods.⁴

• SI joint remission was achieved by 30 of 57 (52.6%) CZP-randomised patients versus 0 of 26 placebo-randomised patients.^v
• Spinal remission was achieved by 31 of 50 (62.0%) CZP-randomised patients and 3 of 23 (13.0%) placebo-randomised patients.⁴
• Of patients with both SI joint and spinal inflammation at baseline, 11/29 (37.9%) CZP patients and 0/11 (0.0%) placebo patients achieved MRI remission of both sites.⁴

MRI remission rates at week 12 were sustained to week 96 for all patients in the imaging set treated with CZP (i.e., including patients re-randomised from placebo to CZP).⁴

At week 204, total resolution of enthesitis was seen in [Figure 5]:

• 66% of AS (n=58) and 61% of nr-axSpA (n=46) patients with MASES>0 at baseline.
• 71% of AS (n=17) and 78% of nr-axSpA (n=18) patients with heel enthesitis at baseline.²

Figure 5.
Efficacy in enthesitis in both subpopulations.
For patients with baseline enthesitis MASES >0: axSpA: n = 148 (67.9% of CZP-randomised patients); AS: n = 78 (64.4% of CZP-randomised patients); nr-axSpA n = 70 (72.2% of CZP-randomised patients).
Adapted from: Van der Heijde et al., 2017.

A rapid response to CZP was observed in the alleviation of pain, with clinically relevant improvements observed from day 2 for both dosing regimens compared to placebo [Figure 6].⁵

Figure 6.
Change from baseline in daily pain. Values (no.) for PBO, CZP, 200 mg Q2W, and 400 mg Q4W, respectively, are total axial spondyloarthritis: 106, 111, and 107; AS: 57, 65, and 56; and non-radiographic AS: 49, 46, and 51.
Adapted from: Sieper et al., 2015.

Of 218 axSpA patients randomised to CZP at Wk0 (121 AS; 97 nr-axSpA0, 203 (93%) completed Wk24 and 142 (65%) Wk204.⁶

Cimzia in RAPID-axSpA: Key Safety Profile Data at Week 24

Treatment Emergent Adverse Events (TEAEs) were similar between all CZP and placebo groups, mostly mild (56.2% CZP vs 48.6% placebo) to moderate (36.1% CZP vs 33.6% placebo) in severity, and generally considered by the investigator as unrelated to study medication. Few serious TEAEs were reported overall (5% CZP vs 4.7% placebo); no deaths were reported.^1,2,3

*placebo escape at week 16.

†Preferred terms.

‡Serious infections reported: haemophilus infection and laryngitis.

§High-level term.

¶Serious general disorders and administration site conditions was two cases of non-cardiac chest pain; serious investigation TEAE was one case of gamma-glutamyltransferase increased.

CZP

Adapted from: Landewe et al., 2014

Safety profile and patient-reported outcomes: 4 year outcomes from RAPID-axSpA

There were no new safety signals identified with the increased exposure, which was shown to have an acceptable long-term safety profile to CPZ, compared to placebo.²