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Dose escalation of certolizumab pegol from 200 mg to 400 mg every other week provides no additional efficacy in rheumatoid arthritisAn analysis of individual patient-level data.

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ARTHRITIS & RHEUMATISM
Vol. 63, No. 8, August 2011, pp 2203–2208
DOI 10.1002/art.30387
© 2011, American College of Rheumatology
BRIEF REPORT
Dose Escalation of Certolizumab Pegol From 200 Mg to 400 Mg Every Other
Week Provides No Additional Efficacy in Rheumatoid Arthritis: An Analysis of
Individual Patient-Level Data
Jeffrey R. Curtis,1 L. Chen,1 K. Luijtens,2 I. Navarro-Millan,1 N. Goel,3 L. Gervitz,3 and M. Weinblatt4
Objective. To determine whether certolizumab
pegol (CZP) dosage escalation from 200 mg to 400 mg
every other week benefits some patients with rheumatoid arthritis (RA).
Methods. In the extension of the Rheumatoid
Arthritis Prevention of Structural Damage 1 (RAPID 1)
study into an open-label study, all patients received CZP
400 mg every other week in combination with methotrexate (MTX). Before the open-label phase of the study,
patients had received CZP 200 mg or 400 mg every other
week, or placebo every other week, as add-on therapy to
MTX. The open-label study included those who had
completed the RAPID 1 study (to week 52) and also
those who had been withdrawn from the study (at week
16, due to inadequate response). At 12 weeks and 48
weeks after enrollment in the open-label study, changes
in the Disease Activity Score in 28 joints (DAS28) were
compared in dose-escalation patients (200 mg increased
to 400 mg every other week) versus stable-dosage pa-
tients (400 mg every other week), using cumulative
probability plots of individual patient-level data.
Results. In the group of patients who had completed the RAPID 1 study and had moderate or severe
disease activity at entry into the open-label study, and in
those who had been withdrawn early from the RAPID 1
study, the median DAS28 improvements 12 weeks after
enrollment into the open-label study were similar in the
dose-escalation and stable-dose groups. Individual
patient-level data revealed no greater likelihood of
response in the group of patients who received an
increased dosage of CZP versus those in whom a stable
dosage was maintained, whether they had completed the
RAPID 1 study or had been withdrawn early.
Conclusion. Although patient heterogeneity in
clinical settings is acknowledged, the present results
indicate that increasing the dose of CZP from 200 mg to
400 mg offers little additional benefit in RA, even for
selected patients.
Tumor necrosis factor (TNF) inhibitors provide
substantial benefit for a majority of patients with rheumatoid arthritis (RA), although some patients experience only a partial response to these agents. It is
uncertain whether dosage escalation or increased dose
frequency will improve clinical response in partial responders. Previous studies with some TNF inhibitors
suggest limited benefit with dose escalation in RA
patient populations (1–7). However, in a clinical setting,
there is uncertainty regarding optimal treatment of
individual patients. Depending on the TNF inhibitor,
many rheumatologists elect to increase the dose or its
frequency, as seen in up to one-third of RA patients (8).
In the Rheumatoid Arthritis Prevention of Structural Damage (RAPID) 1 and 2 trials, the PEGylated
anti-TNF agent certolizumab pegol (CZP) was evaluated as add-on therapy to methotrexate (MTX) and was
administered at a dosage of 200 mg or 400 mg every
other week to patients with an inadequate response to
ClinicalTrials.gov identifiers: NCT00152386 and
NCT00175877.
Support for both the RAPID 1 study and its open-label
extension and for the current analysis was provided by UCB.
1
Jeffrey R. Curtis, MD, MS, MPH, L. Chen, PhD, I. NavarroMillan, MD: University of Alabama at Birmingham; 2K. Luijtens,
PhD: UCB, Brussels, Belgium; 3N. Goel, MD (current address:
Array BioPharma, Morrisville, North Carolina), L. Gervitz, PhD:
UCB, Smyrna, Georgia; 4M. Weinblatt, MD: Brigham and Women’s
Hospital, Boston, Massachusetts.
Dr. Curtis has received consulting fees, speaking fees, and/or
honoraria from Pfizer (less than $10,000) and from Roche/Genentech,
UCB, Centocor, CORRONA, and Amgen (more than $10,000 each).
Dr. Goel has stock and stock options in UCB. Dr. Gervitz has stock
options in UCB. Dr. Weinblatt has received consulting fees, speaking
fees, and/or honoraria from UCB, Amgen, Pfizer, Centocor, Roche,
and Bristol-Myers Squibb (less than $10,000 each).
Address correspondence to Jeffrey R. Curtis, MD, MS, MPH,
Division of Clinical Immunology and Rheumatology, University of
Alabama at Birmingham, FOT 805D, 510 20th Street South, Birmingham, Alabama 35294. E-mail: jcurtis@uab.edu.
Submitted for publication May 4, 2010; accepted in revised
form March 31, 2011.
2203
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CURTIS ET AL
MTX, after an initial loading regimen of 400 mg given at
weeks 0, 2, and 4 (9,10). Overall, clinical outcomes were
similar in patients receiving 200 mg or 400 mg CZP
every other week (9,10). However, it was not possible to
determine if patients who did not have an adequate
response to CZP 200 mg administered every other week
would benefit from an escalation of the dosage.
In an ongoing open-label phase following the
RAPID 1 study, the long-term efficacy and safety of
combined CZP and MTX in RA are being assessed. In
the open-label study, the CZP dosage either was escalated from 200 mg to 400 mg every other week or
remained stable at 400 mg every other week. In this
study, we evaluated individual patient-level data to
determine how much benefit was obtained when the
dosage of 200 mg every other week was escalated to 400
mg, compared to those who received a stable dose of 400
mg.
PATIENTS AND METHODS
Patients. Patients who entered the open-label phase of
the RAPID 1 study were included in this analysis. Two
populations were eligible for enrollment and escalation of the
CZP dosage: those who had completed the RAPID 1 study (at
52 weeks) and those who had been withdrawn early because of
an inadequate response to CZP (measured at weeks 12 and 14,
with an inadequate response defined as failure to fulfill the
American College of Rheumatology 20% improvement criteria [ACR20], making the patient eligible to enroll in the
open-label study at week 16). This analysis was restricted to
patients from the population that completed the RAPID 1
study and whose disease activity was moderate or severe (i.e.,
not low) at the time of entry into the open-label study at week
52 (because if disease activity was low, there would be little
room for improvement, i.e., a “floor” effect). Low disease
activity was defined as a Disease Activity Score in 28 joints
(DAS28) of ⱕ3.2 (11).
All patients in the open-label study received 400 mg of
CZP every other week in combination with MTX. Individual
patient-level data were evaluated using a novel approach of
cumulative distribution of changes in the DAS28 (calculated
using the erythrocyte sedimentation rate [ESR]) between the
time of enrollment in the open-label study and several of the
later time points. Within each population, changes in the
DAS28 from the time of open-label study enrollment were
compared between patients who received 200 mg of CZP every
other week as add-on therapy to MTX in the RAPID 1 study
and then received an increased dosage of 400 mg every other
week in combination with MTX in the open-label study
(dose-escalation patients), and those who received CZP at a
stable dosage of 400 mg every other week as add-on therapy to
MTX throughout both the RAPID 1 study and the open-label
study (stable-dose patients).
Institutional review boards or ethics committees approved the study protocol at each center. All patients provided
written informed consent, and the study was conducted in
accordance with the Declaration of Helsinki.
End points and analyses. Descriptive characteristics
and DAS28 changes at the time of entry into the open-label
study (week 52 for those who had completed the RAPID 1
study, week 16 for those who had been withdrawn early) were
calculated for 4 groups of patients: those who had completed
the RAPID 1 study and then were given an escalated dosage
of CZP, those who had completed the RAPID 1 study and
were maintained on a stable dosage of CZP, those who were
withdrawn early from the RAPID 1 study and were given an
escalated dosage of CZP, and those who were withdrawn early
from the RAPID 1 study and were maintained on a stable
dosage of CZP. The last DAS28 observation was carried
forward when a patient withdrew or used rescue medication.
The number of patients who had withdrawn or used rescue
medication ranged from 5.7% to 25.4%, depending on the time
point.
In the population that completed the RAPID 1 study,
mean changes in the DAS28 between patients who received an
escalated dosage of CZP and those whose dosage was maintained were evaluated at 12 weeks, 24 weeks, 36 weeks, and 48
weeks after enrollment in the open-label study. In addition to
changes in the DAS28, we also evaluated changes in the tender
joint count (TJC), the swollen joint count (SJC), and the ESR.
Individual patient-level data were examined using cumulative probability plots of the change in the DAS28 at 12
weeks and 48 weeks after enrollment in the open-label study.
Values close to the horizontal line (y ⫽ 0) indicated patients
who had the same DAS28 at a later time point after enrollment
in the open-label study as they did at the time of enrollment
(i.e., before dose escalation for dose-escalation patients);
negative values represented an improvement in the DAS28,
and positive values represented worsening disease activity.
Separate curves compared dose-escalation patients with stabledose patients. A 1.2-point change (2 times the measurement
error) in the DAS28 from baseline was considered meaningful
(12).
RESULTS
At week 52, 243 patients who completed the
study began receiving an escalated dosage of CZP, from
200 mg every other week in the RAPID 1 study to
400 mg every other week in the open-label study, and
265 patients who completed the study maintained a
stable dosage, receiving CZP 400 mg every other week in
both the RAPID 1 study and the open-label study. The
median DAS28 at the time of enrollment in the openlabel study was similar for these dose-escalation and
stable-dose patients (3.5 versus 3.4, respectively).
Among the dose-escalation and stable-dose patients in
the completer group, 118 (48.6%) and 122 (46.0%),
respectively, had moderate or severe disease activity
(DAS28 ⬎3.2) at the time of enrollment in the openlabel study (week 52 of the RAPID 1 study). The disease
characteristics of the dose-escalation and stable-dose
NO EFFICACY OF DOSE ESCALATION OF CERTOLIZUMAB PEGOL
Figure 1. Change in the Disease Activity Score in 28 joints (DAS28)
over time since enrollment in the open-label study (OLE) in the
patients who completed the certolizumab pegol (CZP) trial and had
moderate to severe disease activity, and who had either received an
escalated dosage of CZP from 200 mg to 400 mg every other week or
maintained a stable dosage of CZP 400 mg every other week. Data are
presented as box plots, where the boxes represent the 25th to 75th
percentiles, the lines within the boxes represent the median, and the
lines outside the boxes represent the minimum and maximum change.
patients who completed the RAPID 1 study were similar
at the time of enrollment in the open-label study
(mean ⫾ SD disease duration 7.5 ⫾ 4.3 years and 7.4 ⫾
4.1 years, respectively, Health Assessment Questionnaire disability index [13] 1.1 ⫾ 0.6 and 1.1 ⫾ 0.6,
respectively, and DAS28 4.4 ⫾ 0.9 and 4.4 ⫾ 0.9,
respectively).
The mean change in the DAS28 from study
baseline to enrollment in the open-label study was
similar in dose-escalation patients and stable-dose patients (both –2.7). Similarly, there were no significant
differences in the mean TJC (–24.8 versus –24.6) or SJC
(–18.6 versus –18.7) between the dose-escalation and
stable-dose subgroups. The median ESR values were
also similar in the dose-escalation and stable-dose patients who completed the RAPID 1 study (30.0 mm/hour
[interquartile range 20.0–50.0] and 30.5 mm/hour [interquartile range 19.0–45.0], respectively).
On average, no additional clinical benefit was
observed at weeks 12, 24, 36, and 48 after dose escalation (Figure 1). Individual patient-level data for the
subgroup of patients who completed the RAPID 1 study
and had moderate or severe disease activity at the time
of enrollment in the open-label phase showed that the
number of patients experiencing improvement in the
DAS28 after 12 weeks was nearly identical in the
dose-escalation and stable-dose populations (Figure 2).
2205
Similarly, 12 weeks after enrollment in the open-label
study, the median change in the DAS28 in this subgroup
of patients who had completed the RAPID 1 study was
–0.34 in the dose-escalation group and –0.28 in the
stable-dose group. At this time point among patients
who had moderate or severe disease activity at the time
of enrollment in the open-label study, 16.1% of the
dose-escalation patients (19 of 118) and 19.7% of the
stable-dose patients (24 of 122) exhibited improvement
in the DAS28 (⬎1.2 units).
Among those who had been withdrawn from the
RAPID 1 study at week 16 and entered the open-label
phase, 91 patients received an escalated dosage, and 71
patients maintained a stable dosage. The mean changes
in the DAS28 (–1.1 and –1.0), TJC (⫺6.0 and ⫺6.4), and
SJC (–5.7 and –4.3) were similar in the dose-escalation
and stable-dose patients, respectively. The median ESR
was similar between the dose-escalation and stable-dose
subgroups (30.0 mm/hour [interquartile range 14.0–
45.0] and 27.5 mm/hour [interquartile range 15.5–40.5],
respectively). Patients in both groups had similar mean
levels of improvement in the DAS28 at weeks 12, 24, 36,
and 48 after enrollment in the open-label study (data not
shown). The decrease in the median DAS28 at 12 weeks
after enrollment was –0.72 in the dose-escalation group
and –0.55 in the stable-dose group. The proportion of
patients exhibiting improvement in the DAS28 and the
magnitude of improvement were similar in the doseescalation and stable-dose groups (Figure 3). A total of
21% of the dose-escalation patients (18 of 86) showed
improvement of ⬎1.2 units in the DAS28 from the score
at enrollment 12 weeks previously, compared with 30%
Figure 2. Change in the Disease Activity Score in 28 joints (DAS28)
at 12 weeks after enrollment in the open-label study (OLE) in the
subgroups of patients who had received an escalated dosage or had
maintained a stable dosage of certolizumab pegol (CZP) and had
moderate or severe disease activity (DAS28 ⬎3.2) at the time of
enrollment. The median change in the DAS28 for the CZP 200 mg and
400 mg groups combined (dashed line) and change in the DAS28
(⫾1.2 units from baseline) (dotted lines) are indicated.
2206
CURTIS ET AL
Figure 3. Change in the Disease Activity Score in 28 joints (DAS28)
at 12 weeks after enrollment in the open-label study (OLE) in patients
who had been withdrawn early from the certolizumab pegol (CZP)
trial and who had received an escalated dosage or maintained a stable
dosage. The median change in the DAS28 for the CZP 200 mg and
400 mg groups combined (dashed line) and change in the DAS28
(⫾1.2 units from baseline) (dotted lines) are indicated.
of the stable-dose patients (19 of 64). Results on individual probability plots were similar between the doseescalation and stable-dose patients, as determined by the
TJC, SJC, and ESR (data not shown).
DISCUSSION
In this analysis of individual patient-level data
from the RAPID 1 study and its extension into an
open-label phase, there was no clinically meaningful
improvement in disease activity with CZP dosage escalation from 200 mg to 400 mg every other week. This was
evident in patients who completed 52 weeks in the
RAPID 1 study and had moderate or severe disease
activity as well as in those who were withdrawn early at
week 16 due to inadequate response (measured by the
ACR20 at weeks 12 and 14).
For both cohorts, the proportion of patients
experiencing a clinically meaningful improvement in the
DAS28 (⬎1.2 units) was almost identical between the
dose-escalation and stable-dose groups. Among the patients who completed the RAPID 1 study and had
moderate or severe disease activity at the time of
enrollment in the open-label study, ⬃18% exhibited an
improvement in the DAS28 of ⬎1.2 units at week 12
after enrollment in the open-label study, with no differences between the dose-escalation and stable-dose
groups (16% and 20%, respectively). Among the patients who had been withdrawn from the RAPID 1 study
early, ⬃25% had an improvement in the DAS28 of ⬎1.2
units at week 12 in the open-label phase, with no
differences between the dose-escalation and stable-dose
groups (21% and 30%, respectively). While the heterogeneity of patients in a real-world setting is acknowledged, the present results indicate that CZP dosage
escalation from 200 mg to 400 mg every other week is of
negligible benefit, even for selected patients, compared
with those who received a stable dosage of 400 mg every
other week.
Although patients who had been withdrawn early
from the RAPID 1 study experienced some improvement 12 weeks after enrollment in the open-label study
(median DAS28 change –0.69 for the combined groups),
the likelihood of improvement in the dose-escalation
group was similar to that in the stable-dose group,
suggesting that the longer duration of CZP therapy, and
not dose escalation, accounted for this change. However,
it is also possible that some improvement may be related
to the unblinding that occurred (i.e., once patients
entered the open-label phase, they became aware that
they were receiving active therapy, which may have
influenced patient-reported measures and physiciancollected data). Regression to the mean and patientlevel variability in measurement of the DAS28 may be
other potential explanations for the observed clinical
improvement.
Few reported studies have examined the effect of
dose escalation with TNF inhibitors using individual
patient-level data. Our results are similar to those of
most other studies showing minimal benefit of higher
doses of TNF inhibitors in patients with RA (1–7). For
example, a study of infliximab showed that there were no
significant differences in efficacy between the 3-mg/kg
and 10-mg/kg doses (2). However, a post hoc pharmacokinetic model showed that reducing the interval between doses from 8 weeks to 6 weeks increased infliximab serum trough levels (14), suggesting that increasing
dose frequency, but not dose, might lead to clinical
benefit in certain individuals. Similarly, patients participating in a large safety trial who were receiving infliximab 3 mg/kg or 10 mg/kg every 8 weeks had similar
response rates, irrespective of dose (7). A post hoc
analysis of dose escalation in the same study population
(4) did suggest a clear benefit of infliximab dose escalation for some patients; however, even among these
NO EFFICACY OF DOSE ESCALATION OF CERTOLIZUMAB PEGOL
patients, the improvement may not have been clinically
meaningful in all cases.
A limitation of most of these studies is the
comparison of clinical response to 2 different doses, but
not specifically to dose escalation. Additionally, in contrast to our analyses, these earlier reports often presented the effects of dose escalation as group means
rather than at an individual level, thereby obscuring any
potential benefit for selected patients. Further support
for the limited benefit of dose escalation of TNF inhibitor therapy for most patients (whose mean ⫾ SD
DAS28 prior to a dose decrease was 3.2) was demonstrated in a study in which only 1 of 18 RA patients
receiving infliximab experienced a disease flare after the
dose was lowered from 5 mg/kg to 3 mg/kg (15).
In clinical practice, patients are often prescribed
TNF inhibitors at higher doses or at an increased
frequency compared with what was initially prescribed
(8,16), despite negligible or unclear benefits of dose
modification. For example, an analysis of RA patients in
the US showed that dose frequency was increased in
⬃40% of patients receiving infliximab (16). Dose escalation of TNF inhibitors is also relatively common
internationally (17). It is unclear as to why some physicians might choose to escalate the dose of TNF inhibitors despite limited evidence to support this practice. It
may be rooted in physicians’ belief that an initial response to TNF inhibitor therapy and the subsequent lack
of efficacy in some patients might be due to the formation of anti-drug antibodies. The incidence of anti-drug
antibodies appears to be higher in patients treated with
infliximab (18,19). Dose escalation in some patients,
perhaps those in whom anti-drug antibodies have developed, may increase drug levels and overcome associated
loss of efficacy (20). The data in our study were not
analyzed in relation to the presence of anti-CZP antibodies, although the impact of this factor on our results
is likely to be minimal.
In conclusion, this analysis of individual patientlevel data suggests that CZP dose escalation is not
beneficial in RA patients with an early inadequate
response or in those in whom low disease activity has not
been achieved after 1 year of treatment. These results
should help guide decisions regarding the optimal use of
CZP in clinical practice. In patients who exhibit an
inadequate response to CZP, a change in therapy is
preferable to dose escalation.
ACKNOWLEDGMENTS
We thank Owen Davies from UCB for critical review
of the manuscript. We acknowledge the editorial services of
2207
Jaya Kolipaka and Andrew Richardson from PAREXEL,
funded by UCB.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Curtis had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Curtis, Navarro-Millan, Weinblatt,
Chen.
Acquisition of data. Curtis, Navarro-Millan, Goel, Weinblatt.
Analysis and interpretation of data. Curtis, Chen, Luijtens, NavarroMillan, Goel, Gervitz, Weinblatt.
ROLE OF THE STUDY SPONSOR
UCB sponsored the RAPID 1 clinical trial and the open-label
phase of the study, from which these analyses were performed. Data
were analyzed by Dr. Kristel Luijtens (UCB). UCB had no influence
on the decision to publish the data.
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